BSE INQUIRY DFA 17 Medicines and medical devices

DFA 17

� Medicines and medical devices

Draft Factual Accounts
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6 October 1999

This is one of a series of documents intended to provide an account as at the date of publication of the factual evidence received by the Inquiry. The documents do not make any judgements about the implications of the facts or point to any conclusions. They are simply working drafts seeking in a neutral way to set out relevant evidence. They do not contain any expressions of opinions by the Secretariat or the Committee of the Inquiry. The series will only cover certain areas of the evidence.

The DFAs may contain inaccuracies and omissions. The purpose of publishing them is to invite corrections, additions and comments. The Inquiry has received suggestions for such corrections and additions in relation to DFAs already published. This is helpful in furthering the work of the Inquiry; all suggestions are considered and used to update the Secretariat�s working papers which will form the basis of the Committee�s Report in due course. The DFAs should not be treated as setting out a complete and accurate appreciation of the relevant facts.

You are invited to let the Secretariat know of any errors, inaccuracies or material omissions in this DFA. It would be helpful if you could distinguish suggested amendments to the DFA from more general comments which would not involve such amendment. Please write to:

������������������

The Secretary

The BSE Inquiry

6th Floor

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Hercules Road

London SE1 7DU

Email to : inquiry@bse.org.uk

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Responses should reach the Secretariat by 6 November 1999 for them to be assistance to the Inquiry.

Medicines and medical devices

Introduction............................................................................................................................ 4

A summary of the legislative requirements for medicinal products and medical devices����� 4

Legislation on medicinal products.................................................................................... 6

European regulation................................................................................................................. 7

UK Regulation before January 1995...................................................................................... 9

The licensing authority............................................................................................................ 9

The Medicines Commission and other bodies under the 1968 Act.................................. 10

Product licences.................................................................................................................... 14

Products requiring a product licence - �medicinal products�............................................. 15

Granting, renewing, suspending, revoking and varying licences........................................ 19

Confidentiality....................................................................................................................... 21

Provision of information....................................................................................................... 21

UK Regulation since January 1995...................................................................................... 22

Legislation relating to medical devices......................................................................... 23

Legislation relating to homoeopathic products........................................................... 26

The Joint Committee on Vaccination and Immunisation (JCVI).............................. 27

Structure of agencies with responsibility for medicines and medical devices...... 28

Medicines Division/ Medicines Control Agency............................................................... 28

Function.................................................................................................................................. 28

Structure of the Medicines Division/MCA � administrative and professional staff, their roles and responsibilities............................................................................................... 28

Relationship between the Medicines Division/MCA and the Advisory Committees...... 35

Communication with Ministers............................................................................................ 37

Relationship between the Medicines Division/MCA and the Chief Medical Officer..... 40

Supplies Technology Division/Medical Devices Directorate/Medical Devices Agency 41

Function.................................................................................................................................. 41

Structure of the Supplies Technology Division/Medical Devices Directorate/Medical Devices Agency - their roles and responsibilities.............................................................................. 41

Veterinary Medicines Directorate....................................................................................... 43

Structure of the Veterinary Medicines Division � administrative and professional staff, their roles and responsibilities............................................................................................... 43

Chronology of events.......................................................................................................... 47

Early Consideration............................................................................................................... 48

1988........................................................................................................................................ 56

March 1988............................................................................................................................ 59

First reactions........................................................................................................................ 59

Southwood Committee: first meeting.................................................................................. 69

Medicines Division Review.................................................................................................. 78

Southwood Committee: second meeting........................................................................... 104

Southwood Committee: third meeting............................................................................... 111

1989...................................................................................................................................... 114

Joint CSM/VPC Guidelines considered............................................................................ 115

Southwood Committee: fourth meeting............................................................................ 126

Prelude to publication of the Southwood Report............................................................. 127

Cabinet consideration.......................................................................................................... 145

The Southwood Report........................................................................................................ 146

The Joint Guidelines............................................................................................................ 149

Issue of guidelines to holders of licences for human medicinal products..................... 151

Issue of guidelines to holders of licences for veterinary medicines.............................. 153

Issue of guidelines regarding medical devices.................................................................. 154

The Tyrrell Committee........................................................................................................ 157

Response to questionnaire.................................................................................................. 160

Risk to humans..................................................................................................................... 173

The BSE Working Group (on human medicinal products): first meeting...................... 180

1990...................................................................................................................................... 198

BSE Working Group: second meeting............................................................................... 200

Other routes of transmission (SEAC: first meeting)....................................................... 204

Agriculture Select Committee........................................................................................... 206

BSE Working Group: third meeting................................................................................... 209

Spongiform Encephalopathy in a pig.................................................................................. 212

BSE Working Group: fourth meeting................................................................................ 214

1991...................................................................................................................................... 218

1992...................................................................................................................................... 220

BSE Working Group: fifth meeting................................................................................... 221

1993...................................................................................................................................... 224

1994...................................................................................................................................... 224

1995...................................................................................................................................... 225

1996...................................................................................................................................... 225

Introduction

1.               This draft factual account details certain aspects of the story relating to BSE and medicines, in particular:

(i.)        Initial notification of BSE to Department of Health and Medicines Division

(ii.)      Action taken by those responsible for the safety of human medicines, veterinary medicines, and medical devices, in response to the emergence of BSE, leading to the issue of joint CSM/VPC guidelines.

(iii.)    Medicines aspects of the report of the Southwood Working Party.

(iv.)    Medicines aspects of the first interim report of the Tyrrell Committee.

(v.)      Action taken by MD/MCA, VMD and MDD to ensure compliance with the guidelines by manufacturers, including in relation to existing stocks.

(vi.)    The actions and recommendations of the CSM�s BSE Working Party.

(vii.)  Medicines and the introduction of the specified bovine offal ban.

It also includes sections summarising the relevant legislation, departmental structures, and bodies and individuals involved.

Many meetings dealing with BSE involved discussion of a variety of issues.� In this draft factual account, the aspects of meetings that have been highlighted focus on medicines and medical devices, even if other issues were discussed.

A summary of the legislative requirements for medicinal products and medical devices

2.               Before 1 January 1995, the essential framework for regulating medicinal products in the UK was set by the Medicines Act 1968[1] (�the 1968 Act�). Central to the 1968 Act is a licensing system. In summary, that system inter alia prohibits the sale or supply of a medicinal product, except in accordance with a licence (referred to as a �product licence�), prohibits the manufacture of a medicinal product, except in accordance with a licence (referred to as a �manufacturer�s licence�), and prohibits the distribution by way of wholesale dealing of medicinal products, except in accordance with a licence (referred to as a �wholesale dealer�s licence�).

3.               The licensing requirements of the 1968 Act relate to medicinal products, that is substances or articles for use wholly or mainly by being administered to human beings or animals for medicinal purposes.[2] Medicinal purposes are:

�a) treating or preventing disease;

b) diagnosing disease or ascertaining the existence, degree or extent of a physiological condition;

c) contraception;

d) including[3] anaesthesia;

e) otherwise preventing or interfering with the normal operation of a physiological function�.� [4]

4.               Examples of medicinal products that come in solid dose form are: tablets; capsules; lozenges; and pastilles. Other medicinal products include: creams; lotions; ointments; patches; liniments; drops; pessaries; suppositories; and vaccines.[5] The definition of a medicinal product also includes herbal remedies.[6]

5.               In addition, the 1968 Act and regulations made under it place (or placed in the period covering the Inquiry�s terms of reference) licensing requirements on certain other substances. These include: surgical ligatures; sutures; contact lenses; intra-uterine contraceptive devices; and a wide range of substances, such as heparin, that are used as ingredients in the manufacture of medicinal products.

6.               Various products fall on the borderlines between foods and medicinal products, between medical devices and medicinal products or between cosmetics and medicinal products, for example vitamin supplements. There are regulations governing whether such products are to be treated as medicinal products (principally, if they are sold with indications) or not. The Medicines Control Agency (MCA) offers advice on their status in cases of doubt.The Medical Devices Agency (MDA) offers similar advice about the status of medical devices.

7.               Certain products and substances are excluded from the licensing requirements of the 1968 Act, the main ones being herbal remedies and medical devices.

8.               The MCA has stated to the Inquiry that the distinction between medicinal products and medical devices lies in the way in which the product achieves its principal intended action.

�The action of a medicinal product is typically achieved by pharmacological, immunological or metabolic means. In the case of a medical device, the principal intended action is typically fulfilled by physical means. A medical device may contain a material which would normally be regarded as a medicinal substance�if that substance has action ancillary to the principal action of the device�.[7]

9.               Before 1993 there were no product specific regulations for medical devices. Those devices that were not treated as medicines were covered by general product safety legislation. However, the Procurement Directorate (PD) and the Medical Devices Directorate (MDD) operated the Manufacturers Registration Scheme (MRS), which was voluntary. Each manufacturer was able to decide whether to join the scheme.� There were no statutory controls of the MRS.� Purchasers (mainly the NHS) were advised to buy devices only from manufacturers registered on the scheme.[8]

10.            Separate regulation of medical devices began with the Active Implantable Medical Devices Directive 90/385/EEC as implemented in the UK by the Active Implantable Medical Devices Regulations 1992[9] (SI 1992, 3146 as amended).[10] Separate regulation of most other medical devices (with the exception of in vitro diagnostic medical devices e.g. pregnancy and HIV test kits and blood grouping reagents) began with the Medical Devices Directive 93/42/EEC, as implemented in the UK by the Medical Devices Regulations 1994.

[11]

11.            Herbal remedies are regarded as medicinal products but are exempt from the licensing requirements of the 1968 Act under certain conditions. A herbal remedy is defined in section 132 as:

�a medicinal product consisting of a substance produced by subjecting a plant or plants to drying, crushing or any other process, or of a mixture whose sole ingredients are two or more substances so produced, or of a mixture whose sole ingredients are one or more substances so produced and water or some other inert substance.�

[12]

Legislation on medicinal products

12.            Medicines in the United Kingdom, both human and veterinary, are regulated for their safety, efficacy and quality in accordance with the Medicines Act 1968 and relevant European Community Directives and Regulations.� Since 1965 there has been an increasing body of European legislation which has applied to the UK since accession to the EC in 1973.� The interaction between the European and the UK legislation is summarised below.

European regulation

13.            European regulation of medicinal products was introduced with the adoption of Council Directive 65/65[13].� The system was based on the grant of a marketing authorisation by the competent authority of the Member State in question (i.e. a decentralised system).� It provided that no product within the scope of the Directive could be placed on the market in a Member State unless an authorisation had been issued by the competent authority of that Member State.[14]�

14.            The Directive seeks to harmonise the requirements to be fulfilled by those seeking authorisation and the provisions relating to the granting of authorisations.� It provides grounds upon which authorisation to market a medicinal product is to be refused.[15]� It also specifies grounds upon which a marketing authorisation may be suspended or revoked, including where the product proves to be harmful in the normal conditions of use.[16]� A Member State is not permitted to refuse, suspend or revoke an authorisation to market a medicinal product except on the grounds set out in the Directive.[17]

15.            Originally only �proprietary medicinal products� were subject to the European regulatory system[18].� �Medicinal product� and �proprietary medicinal product� are defined by Article 1 of Directive 65/65/EEC:

�1. Proprietary medicinal product:

Any ready-prepared medicinal product placed on the market under a special name and in a special pack.

2. Medicinal product:

Any substance or combination of substances presented for treating or preventing disease in human beings or animals.

Any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings or in animals.�[19]

16.            No specific action was taken at the time the UK joined the EC to implement Directive 65/65/EEC.� In practice, therefore, the competent authority of the UK for the purposes of the Directive was the Licensing Authority, and such products were dealt with under the Medicines Act 1968.

17.            Articles 2 and 3 of Directive 65/65/EEC were amended by Directive 89/341/EEC[20] to bring within the scope of the European system industrially produced medicinal products previously excluded. Exceptions were provided for medicinal products prepared on the basis of a magistral or officinal formula; medicinal products intended for research and development trials; and intermediate products intended for further processing by an authorised manufacturer.� Member States may also, in accordance with legislation in force, exclude specials (i.e. medicinal products specially prepared or imported to order for a particular patient).[21]�

18.            In the UK the Medicines Act 1968 (Amendment) Regulations 1992 gave effect to these changes with effect from 3 April 1992, by way of amendment to the Medicines Act 1968.[22]�

19.            Comprehensive provision was made implementing the Community legislation in UK law by the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994, with effect from 1 January 1995.� As of that date section 7 of the 1968 Act ceased to apply to those medicinal products for human use to which Chapters II to V of Council Directive 65/65/EEC apply; instead, they are regulated by the Medicines for Human Use (Marketing Authorisations Etc) Regulations 1994.[23]

20.            The Regulations provide for applications for marketing authorisations to be made, and considered by the licensing authority, in accordance with the relevant Community provisions[24].

21.            In 1975 Council Directives 75/318[25] and 75/319[26] were adopted to continue the process of approximation of Member States� legal, regulatory and administrative provisions relating to medicinal products.� Directive 75/319[27] set up the Committee for Proprietary Medicinal Products (CPMP), in order to facilitate the adoption of common decisions by Member States on the authorisation of medicinal products for human use on the basis of the scientific criteria of quality, safety and efficacy.

22.            The introduction to the Annex to Directive 75/318 states that, in assembling a dossier for application, applicants for a market authorisation of a new product shall �take into account� Community guidelines relating to the quality, safety and efficacy of medicinal products for human use published by the Commission.[28]�

23.            In addition to the decentralised system, Council Regulation 2309/93[29] introduced a central Community procedure for authorisation and supervision of medicinal products. This provides a single marketing authorisation to market a product in all Member States of the European Union and is administered by the European Medicines Evaluation Agency.� The procedure is compulsory for technologically advanced medicinal products listed in part A of the Annex to the Regulation, and is optional for the novel medicinal products listed in part B of the Annex, for instance products developed by innovative biotechnological processes, products containing new active substances not authorised in any Member State, and new products derived from human blood.�

UK Regulation before January 1995

24.            Prior to 1 January 1995, the Medicines Act 1968[30] (�the 1968 Act�) was therefore the primary legislation providing the structure for the regulation of medicinal products in the UK.� Much of the detailed legislation in this area is provided by delegated legislation under the 1968 Act.

The licensing authority

25.            The �licensing authority� is responsible for the grant, renewal, variation, suspension and revocation of licences.� Section 6(1) of the 1968 Act defines �the licensing authority� as the �body of Ministers� listed in section 1(1) of the Act.� These are �the Health Ministers� and �the Agriculture Ministers,� i.e. the Secretary of State for Health, the Minister of Agriculture, Fisheries and Food and the corresponding Ministers in Northern Ireland, Scotland and Wales.�

26.            Under section 6(2) of the 1968 Act, any one of the above Ministers may perform the functions of the licensing authority.� By virtue of section 6(3), where one of the Ministers does act alone he acts as the licensing authority and not on behalf of the other Ministers.� In practice, the functions of the licensing authority in relation to medicines for human use in the UK have throughout the period 1985-96 been performed by the Secretary of State for Health.[31] Similarly, the functions of the licensing authority in relation to medicines for animals have been performed by the Minister of Agriculture, Fisheries and Food.

27.            Licences granted pursuant to sections 7 and 8 may contain such provisions as the licensing authority considers appropriate (section 20(1)(a));[32] certain standard provisions are found in the Medicines (Standard Provisions for Licences and Certificates) Regulations 1971[33].

The Medicines Commission and other bodies under the 1968 Act

28.            The 1968 Act provided for the establishment of the Medicines Commission, and laid down requirements as to its composition and role. By virtue of section 3 of the Act, the Medicines Commission are required to advise the Health and Agriculture Ministers on matters relating to the execution of the Act, the exercise of powers conferred by it, and otherwise relating to medicinal products.� They are to do this where either the Commission consider it expedient, or they are required by the Minister(s) in question to do so. Section 2 of the Act provides that the Medicines Commissioners should number no fewer than eight, and should include at least one person having �wide and recent� experience in, and have shown capacity in, the following activities:

(i.)        the practice of medicine (other than veterinary medicine);

(ii.)      the practice of veterinary medicine;

(iii.)    the practice of pharmacy;

(iv.)    chemistry other than pharmaceutical chemistry;

(v.)      the pharmaceutical industry.

29.            The Medicines Commission is obliged to send to the Ministers an annual report with respect to the performance of its functions.[34]

30.            Section 4 of the 1968 Act empowers Ministers to establish committees (often referred to as �section 4 committees�) for any purpose connected with the execution of the 1968 Act or the exercise of any power conferred by it, including:

(i.)        giving advice with respect to safety, quality or efficacy;

(ii.)      promoting the collection and investigation of information relating to adverse reactions for the purpose of enabling such advice to be given.

31.            Ministers appoint members of the section 4 committees,[35] and are obliged when establishing them to have regard to recommendations made by the Medicines Commission as to their number, function and membership.[36] Each of these committees is required to send an annual report with respect to the performance of its functions to the Commission and the Ministers.[37]

32.            A section 4 committee may, with the approval of the Ministers, appoint one or more sub-committees.[38]

33.            There are a number of section 4 committees, which provide specialist advice on particular areas.

Committee on Safety of Medicines (CSM)

34.            The CSM was established for the purposes of �giving advice with respect to safety, quality and efficacy, in relation to human use, of any substance or article (not being an instrument, apparatus or appliance) to which any provision of the [Medicines] Act [1968] is applicable� and �promoting the collection and investigation of information relating to adverse reactions, for the purpose of enabling such advice to be given.�[39]

35.            Professor Asscher said that during his time as Chairman, the CSM met once a month for meetings which lasted for one or two days.[40]� He also stated that the Chairman bears ultimate responsibility for the advice given.[41]� In addition, he said that the CSM is an expert advisory committee and officials generally remain silent at its meetings[42] but:�

�I should make it clear that the Chairman of the CSM played no part in and had no responsibility for setting the agenda for CSM meetings.� The first knowledge that members of CSM had about the issues that were due to be considered at meetings came from reading their blue bags for that meeting.� However, it was my practice to receive the blue bags for each of the CSM�s subcommittees and, as a result, I would at a slightly earlier stage have had some idea what issues would be coming up at the next CSM meeting.� However, I would not be in a position, at that stage, to influence the agenda for the CSM meeting; nor would I need to because every item considered by a CSM subcommittee is also considered at the following meeting of the CSM.� I did, however, on first assuming the chairmanship of the CSM, bring my influence to bear on subcommittee chairmen to minimise the number of hearings (presentations by industry) at CSM meetings by the introduction of pre-hearing procedures.� This resulted in a considerable saving of committee time.�[43]

36.            Mr Hagger has said in his statement to the Inquiry:

��during the period 1984-1990, I had responsibility for administrative issues relating to the CSM.� Although the Secretary to the Committee was the grade 7 in MB1C, I was not responsible for the work of the bulk of the secretariat of the Committee who were professional staff, comprising physicians, pharmacists and scientists.�[44]

37.            The Biologicals Sub-Committee (BSC) and BSE Working Group (BSEWG) were established by, and reported to, the CSM. The role of the BSE Working Group was different from that of the Biologicals Sub-committee with which it was associated. The Working Group did not have to deal with applications for products, but rather its role was to advise the section 4 committees on the possible hazards to man of human medicinal products, with special reference to BSE.[45]

38.            Professor Collee (with regard to the CSM Biologicals Sub Committee) talked about the role of officials in his Statement to the Inquiry.� He said:

�After the meeting there was a Chairman�s debriefing session with officials.� This would last about half an hour and was used to prepare a draft of the minutes with officials.� I often amended the draft minutes.� The purpose of the debriefing meetings was to ensure that officials fully understood the committee�s advice and had accurately minuted that advice.� The actual implementation of advice was carried out by officials.�[46]

The agenda for meetings was set by officials from within the Medicines Division (and later the Medicines Control Agency) who, in doing so, would bear in mind the current timetable of the CSM.

39.            Mr Hagger�s statement notes:

�In general, senior administrators would only get involved following a CSM meeting if it was clear that an issue dealt with there required a Ministerial decision, appeared to have wider implications and/or was likely to become public and attract press interest.� In these circumstances both the Head of the Division and the Professional Head would usually have leading roles.�[47]

Committee on Dental and Surgical Materials (CDSM)

40.            The CDSM was established to exercise the same functions as the CSM, in respect of:

�(i) substances or articles which are for dental or surgical use, being �

(a) instruments, apparatuses or appliances to which any provision of the Act is applicable, or

(b) medicinal products or other substances or articles (not being instruments, apparatuses or appliances) to which any provision of the Act is applicable and in respect of which neither the Committee on Safety of Medicines nor the Veterinary Products Committee is the appropriate committee within the meaning of section 4(6) of the Act,

whether or not used in conjunction with any other such substance, article, instrument, apparatus or appliance;

(ii) the substances and fluids described in paragraph 2 of Schedule 1 to the Medicines (Specified Articles and Substances) Order 1976 (substances and fluids for use with contact lenses or blanks).�[48]

41.            The CDSM was abolished in 1994.[49]

Veterinary Products Committee (VPC)

42.            The VPC was established in 1970 with the following terms of reference:

�a)�� To give advice with respect to safety, quality and efficacy in relation to the veterinary use of any substance or article (not being an instrument, apparatus or appliance) to which any provision of the Medicines Act 1968 is applicable.

b)��� To promote the collection of information relating to suspected adverse reactions for the purpose of enabling such advice to be given.�[50]

43.            The VPC is very similar to the CSM.� As its name implies, it is concerned with veterinary products that were serviced by MAFF.[51] Like the CSM, the VPC also had a Biologicals Sub-Committee (BSC) which was established by it and reported to it.[52]

Committee on the Review of Medicines (CRM)

44.            The CRM was established[53] to advise on the safety, quality and efficacy of substances and articles that were on the market before the 1968 Act came into force and which had been granted licences of right[54].� Provision was made by s 25 of the 1968 Act for the grant of licences of right in respect of such medicinal products. Some 39,035 Product Licences of Right were granted for those products already on the market at that time.[55] The Order establishing the CRM provides:

�Without prejudice to the Committee on Safety of Medicines, in connection with the review by the licensing authority of the safety, equality and efficacy of substances or articles in respect of which product licences granted under Part II of the Act are in force, there shall be established a committee to be called the Committee on the Review of Medicines for the purpose of considering and giving advice with respect to the safety, quality and efficacy, in relation to human use, of any substance or article to which any provision of the Act is applicable.�

45.            The work of the CRM was completed in 1991 and it was abolished.[56]

The British Pharmacopoeia Commission (BPC)

46.            The BPC is responsible for preparing new editions of the British Pharmacopoeia and the British Pharmacopoeia (Veterinary) and for keeping those up-dated. It is also responsible for maintaining liaison with the European Pharmacopoeia Commission and for the publication of British approved names under Section 100 of the Medicines Act.[57]

Product licences

47.            Until 1 January 1995, product licences were governed principally by section 7 of the 1968 Act, which prohibits the sale, supply or export of (or procurement of the sale, supply or export of) a medicinal product except in accordance with a product licence granted for the purposes of section 7.� Similarly, procuring the manufacture or assembly of such a product for sale or supply is prohibited save in accordance with a product licence. From 1 January 1995, section 7 of the 1968 Act ceased to apply to those medicinal products for human use to which Chapters II to V of Council Directive 65/65/EEC apply; instead, they are regulated by the Medicines for Human Use (Marketing Authorisations Etc) Regulations 1994.[58]

48.            There are a number of exemptions to the prohibition set out in section 7, including exemptions relating to:

(i.)        anything done in accordance with a clinical trial certificate or animal test certificate (i.e. where medicines are used in clinical trials)[59];

(ii.)      medicines made, or imported, to order, for a particular patient (sometimes referred to as �specials�);[60]

(iii.)    homoeopathic medicinal products which have been granted a certificate of registration (since 13 February 1994).[61]

49.            Section 8 of the 1968 Act governs manufacturers� and wholesale dealers� licences.

Products requiring a product licence - �medicinal products�

50.            A �medicinal product� is defined by the 1968 Act as �any substance or article (not being an instrument, apparatus or appliance) which is manufactured, sold, supplied, imported or exported for use wholly or mainly � by being administered to one or more human beings or animals for a medicinal purpose.� The definition also includes any substance or article (not being an instrument, apparatus or appliance) used as an ingredient in such a substance or article, where such use as an ingredient is in a pharmacy or hospital, by a practitioner or in the course of a business including the retail sale (or supply in circumstances corresponding to retail sale) of herbal remedies.[62]�

51.            Therefore, only products to be administered for a �medicinal purpose� are medicinal products within the meaning of the 1968 Act.� �Medicinal purposes� are defined[63] as follows:

�(a) treating or preventing disease;

(b) diagnosing disease or ascertaining the existence, degree or extent of a physiological condition;

(c) contraception;

(d) including[64] anaesthesia;

(e) otherwise preventing or interfering with the normal operation of a physiological function � .�

52.            Section 130(9) of the 1968 Act provides that �administer�:

�means administer to a human being or an animal, whether orally, by injection or by introduction into the body in any other way, or by external application, whether by direct contact with the body or not; and any reference in this Act to administering � a substance or article is a reference to administering � it either in its existing state or after it has been dissolved or dispersed in or diluted or mixed with, some other substance used as a vehicle.�

53.            The position of certain substances and appliances is clarified by other provisions in the 1968 Act.

Dental fillings, bandages and surgical dressings

54.            Section 130(5) of the 1968 Act expressly provides that medicinal products shall not be taken to include the substances used in dental surgery for filling dental cavities; and bandages and other surgical dressings.[65]� However, �medicated dressings� have been, since 1 January 1995, expressly included within the meaning of medicinal products if �their medication has a curative function which is not limited to sterilising the equipment� and the dressing does not fall within the scope of certain European regulations relating to medical devices.[66]

Other specified articles

55.            By virtue of sections 104 and 105 of the 1968 Act[67] the Ministers have power to make an order applying certain provisions of the Act to categories of substances which would otherwise not be categorised as medicinal products. Although many of the orders have now been amended, orders made under sections 104 or 105, have enabled sections 7 and 8 of the 1968 Act to be applied inter alia to the following substances:

(i.)        Surgical ligatures and sutures prepared from any animal tissue for use in surgical operations upon the human body; surgical ligatures and sutures and absorbent or protective material for use in surgical operations upon the human body capable of being absorbed by body tissues.[68]

(ii.)      Contact lenses, contact lens solutions and intra-uterine contraceptive devices.[69]

(iii.)    A wide variety of substances used as ingredients in the manufacture of medicinal products, including, for example, heparin and preparations of the pituitary when used as an ingredient in a medicinal product for parenteral injections, insulin, sera and vaccines;[70] and any substance wholly or partly derived from animals not specified elsewhere in the schedule to the relevant Order when used as an ingredient in a medicinal product for administration to animals.[71]

From 1 January 1995, a number of orders made under sections 104 and 105 of the Act were modified by the Medical Devices (Consequential Amendments � Medicines) Regulations 1994 so that the Act ceased to apply to a number of products that were treated as medical devices under Community law.� These included certain surgical ligatures, surgical sutures, absorbent and protective materials, intra-uterine contraceptive devices, substances associated with contact lenses, and contact lenses.[72]

Herbal Remedies

56.            Certain categories of herbal remedies are exempted from the restrictions imposed by sections 7 and 8 of the 1968 Act by section 12, which provides:[73]

�12� (1) The restrictions imposed by sections 7 and 8 of this Act do not apply to the sale, supply, manufacture or assembly of any herbal remedy in the course of a business where �

(a)�� the remedy is manufactured or assembled on premises of which the person carrying on the business is the occupier and which he is able to close so as to exclude the public, and

(b)�� the person carrying on the business sells or supplies the remedy for administration to a particular person after being requested by or on behalf of that person and in that person�s presence to use his own judgment as to the treatment required.

(2) Those restrictions also do not apply to the sale, supply, manufacture or assembly of any herbal remedy where the process to which the plant or plants are subjected in producing the remedy consists only of drying, crushing or comminuting, and the remedy is, or is to be, sold or supplied �

(a)�� under a designation which only specifies the plant or plants and the process and does not apply any other name to the remedy, and

(b)�� without any written recommendation (whether by means of a labelled container or package or a leaflet or in any other way) as to the use of the remedy.�

Borderline products - cosmetics and foods

57.            The Medicines (Exemption from Licenses) (Foods and Cosmetics) Order 1971 exempts (subject to certain qualifications explained below) from the restrictions imposed by sections 7 and 8 of the 1968 Act, medicinal products wholly or mainly for use by being administered to human beings, which are to be for sale either for oral administration as a food or for external use as a cosmetic.[74]� The Order contains the following definitions:[75]

�(2)� In this order, unless the context otherwise requires -

�

�cosmetic� means any substance or preparation intended to be applied to the various surfaces of the human body including epidermis, pilary system and hair, nails, lips and external genital organs, or the teeth and buccal mucosa wholly or mainly for the purpose of perfuming them, cleansing them, protecting them, caring for them or keeping them in condition, modifying their appearance (whether for aesthetic purposes or otherwise) or combating body odours or normal body perspiration;

�food� includes beverages, confectionery and articles and substances as ingredients in the preparation of food and includes any manufactured substance to which there has been added any vitamin and which is advertised (within the meaning of Section 92 of the Act) as available and for sale to the general pubic as a dietary supplement;

�medicinal product� includes articles or substances specified in orders made under section 104 or section 105 of the Act which are for the time being in force �

�mineral salts� means salts of any one or more of the following, iron, iodine, calcium, phosphorus, fluorine, copper, potassium, manganese, magnesium or zinc;

�vitamin preparation� means any medicinal product the active ingredients of which consist only of vitamins or vitamins and mineral salts;

�vitamins� means any one or more of the following, vitamins A, B1, B2, B6, C, D and E, biotin, nicotinamide, nicotinic acid, pantothenic acid and its salts, biflavonoids, inositol, choline, para-aminobenzoic acid, cyanocobalamin or folic acid; � .�

58.            By virtue of the Order, the exemption to the requirements of sections 7 and 8 does not apply to a medicinal product sold with written particulars specifying its curative or remedial function in relation to a disease specified;[76] to a medicinal product for oral administration as a food, being a vitamin (or other) preparation falling within one of the descriptions in the schedule to the Order;[77] to a medicinal product being a cosmetic containing antibiotic, hexachlorophane, any hormone in a proportion in excess of 0.004% or resorcinol in a proportion in excess of 1%;[78] or to any other medicinal product sold with written particulars specifying the dosage relevant to its medicinal purpose.[79]� Further, the exemption does not apply to medicinal products in respect of which there are, or are to be, directed to practitioners advertisements or representations of the nature and in the manner described in section 96 of the 1968 Act.[80]

59.            The Medicines Control Agency offers advice on the status of products in cases of doubt.� In looking at borderline products the MCA will consider ��the ingredients and function of the product as well as how it is presented to the public through labelling, packaging, advertising and promotion.�[81]

Granting, renewing, suspending, revoking and varying licences

60.            Applications for the grant of product licences were, until 1993, governed by the Medicines (Applications for Product Licences and Clinical Trial and Animal Test Certificates) Regulations 1971[82]. Paragraph 12 of schedule 1 to those regulations requires the applicant for a licence to give the licensing authority particulars of all active constituents, all colouring matter, flavouring agents and perfumes and all other constituents.� Paragraph 16 requires a description of the method of manufacture or assembly of the medicinal product, substance or article; and paragraph 17 requires a description of the method of manufacture of each active constituent.�

61.            These regulations were replaced by the Medicines (Applications for Grant of Product Licences - Products for Human Use) Regulations 1993[83] in respect of medicinal products for human use.

62.            The 1968 Act provides that in dealing with an application for the grant of a product licence the licensing authority shall in particular take into consideration several factors including �the safety of medicinal products of each description to which the application relates�.[84]� The licensing authority may[85]:

(i.)        grant a licence containing such provisions as it considers appropriate;

(ii.)      if, having regard to the provisions of the Act and any Community obligation, it considers it necessary or expedient to do so, refuse to grant a licence.

63.            Before refusing to grant a licence on any grounds relating to �the safety, quality or efficacy of medicinal products� the licensing authority is obliged to consult the �appropriate committee� or (if there is no such committee) the Commission.[86]�� The �appropriate committee� means any committee established under section 4 for giving advice with respect to safety, quality or efficacy, or for promoting the collection and investigation of information relating to adverse reactions for the purpose of enabling such advice to be given.[87]�

64.            A licence expires at the end of a period of 5 years from the date upon which it was granted or last renewed, or at the end of any shorter period specified in the licence.[88]�� The licence holder may apply for the licence to be extended for a further period of 5 years from the date upon which it would otherwise expire.[89]� The licensing authority may:

(i.)        renew the licence, with or without modifications;

(ii.)      grant a new licence containing such provisions as the licensing authority consider appropriate;

(iii.)    if, having regard to the provisions of the Act, it considers it necessary or expedient to do so, refuse to renew the licence or grant a new licence.

65.            Before refusing to renew a licence on any grounds relating to �the safety, quality or efficacy of medicinal products� the licensing authority is again obliged to consult the �appropriate committee� or (if there is no such committee) the Medicines Commission.[90]

66.            By virtue of section 28 of the 1968 Act the licensing authority may suspend, revoke or vary the provisions of a product licence on the grounds set out in section 28(3), which include:[91]

��(g) that medicinal products of any description to which the licence relates can no longer be regarded as products which can safely be administered for the purposes indicated in the licence, or can no longer be regarded as efficacious for those purposes;

(h) That the specification and standards to which medicinal products of any such description are manufactured can no longer be regarded as satisfactory��

67.            Except for suspension in the case of urgency under Section 2 of the Act, where the licensing authority propose to suspend, revoke or vary a product licence on any of the grounds specified in section 28(3)(g) or (h), they may not do so except after consultation with the appropriate committee or, if there is none, with the Medicines Commission.[92]

68.            Where the appropriate Committee or the Medicines Commission are consulted in relation to the proposed refusal, suspension, variation or revocation of a licence, and they have reason to think (in the case of refusal) that they may be unable to advise the licensing authority to grant the licence, or to grant it unless it contains provisions otherwise than in accordance with the application, or (in the case of suspension, variation or revocation) that they may have to advise the licensing authority that the product licence ought to be suspended, revoked or varied, they must afford to the applicant/licence holder a right to make written or oral representations prior to their giving such advice to the licensing authority.[93]

69.            Any reference in the 1968 Act to safety or the interests of safety is to be construed in accordance with section 132(2), which provides that considerations of safety, in relation to any substance or article, shall be taken to include inter alia consideration of the extent (if any) to which the substance or article if used without proper safeguards, is capable of causing danger to the health of the community.�

Confidentiality

70.            Section 118 of the Medicines Act 1968 provides that a person shall be guilty of an offence if he discloses to any other person-

(i.)        any information with respect to any manufacturing process or trade secret obtained by him in premises which he had entered under the right of entry provided by section 111 of the Act;

(ii.)      any information obtained by or furnished to him in pursuance of the Act;

unless the disclosure was made �in the performance of his duty�.

Provision of information

71.            Section 44 of the Medicines Act provides that where an application has been made to the licensing authority for a licence the licensing authority:

�Before determining the application, may request the applicant to furnish to the licensing authority such information relating to the application as the licensing authority may consider requisite: and, where any such request has been made, the licensing authority shall not be required to determine the application until either-

a) the information requested has been furnished to them, or

b) it has been shown to their reasonable satisfaction that the applicant is unable to furnish the information�

72.            Subsection 3 states that the licensing authority may request information of the holder of a clinical trial certificate or animal test certificate where it is considered:

�That circumstances exist by reason of which it is necessary to consider whether the licence or certificate should be varied, suspended or revoked; and the information required by such a notice shall be such as appears to the licensing authority, or is represented to them by the Commission or by the committee, to be requisite for considering that question.�

73.            Subsection 4 states that this does not have effect in the case of a licence of right or of a certificate issued in pursuance of section 37(4) of the Medicines Act 1968:

�Whether the licence or certificate has been renewed or not; and, in the case of such a licence or certificate, a notice under this section may be served at any time and may require any information which, in the opinion of the licensing authority, would be relevant if-

sections 25 and 37(4) of this Act had not been enacted, and the licensing authority were then dealing with an application, by the person who is the holder of the licence or certificate, for the grant or issue of a licence or certificate containing the same provisions as those contained in the licence or certificate in question.�

UK Regulation since January 1995

74.            As noted above, from 1 January 1995 section 7 of the 1968 Act ceased to apply to those medicinal products for human use to which Chapters II to V of Council Directive 65/65/EEC apply; instead, they are regulated by the Medicines for Human Use (Marketing Authorisations Etc) Regulations 1994.[94] Section 7 of the 1968 Act is now limited to a residual category of products which require UK product licences but do not require marketing authorisations for the purposes of Community law.� Section 8 remains applicable.� Other provisions of the 1968 Act, including the continued operation of the Medicines Commission and its section 4 committees, remain in force.

Legislation relating to medical devices

75.            Instruments, apparatuses and appliances are excluded from the licensing requirements of the 1968 Act, as they do not fall within the definition of a medicinal product. One category of such items is medical devices.

76.            There were no product-specific regulations for medical devices before 1 January 1993.� Those that were not treated as medicines were covered by general product safety legislation.� The Procurement Directorate (PD) and later the Medical Devices Directorate (MDD) operated the Manufacturers Registration Scheme (MRS), membership of which was voluntary.� There were no statutory controls of the MRS.� Purchasers (mainly the NHS) were advised to buy devices only from manufacturers registered on the scheme. (With the introduction of European legislation the scheme was gradually wound down and finally ceased in June 1998.)[95]

77.            Before 1993, if there was a need to remove an unsafe medical device from the UK market, the Consumer Protection Act 1987 could have been used (and later the General Product Safety Regulations 1994). In addition, a member of the MRS failing to meet the requirements of the scheme could be removed from the register. A reporting system also operated to encourage manufacturers and users to report details of any adverse incidents involving medical devices.[96]

78.            Separate regulation of medical devices began with regulation of �active� implantable devices.� From 1 January 1993 the Active Implantable Medical Devices Directive 90/385/EEC, as implemented in the UK by the Active Implantable Medical Devices Regulations 1992[97] came into force. There was a transition period that lasted until 31 December 1994.� These regulations apply to active (i.e. relying on a source of power other than that generated by the human body or gravity) implants, partial or whole, left in the body, including pacemakers.[98]

79.            Regulation 2 included the definition of an �active implantable medical device�:

��instrument, apparatus, appliance, material or other article, whether used alone or in combination, together with any accessories or software necessary for its proper functioning, which -

(a) is intended by the manufacturer to be used for human beings �

(i)��� in the diagnosis, prevention, monitoring, treatment or alleviation of disease or injury;

(ii)�� in the investigation, replacement or modification of the anatomy or of a physiological process, or

(iii)� in the control of conception;

(b) does not achieve its principal intended action by pharmacological, chemical, immunological or metabolic means, even if it is assisted in its function by such means;

(c) relies for its functioning on a source of electrical energy or a source of power other than that generated directly by the human body or by gravity; and

(d) is intended to be totally or partially introduced into the human body�and which is intended to remain in the human body after completion of the surgical or medical procedure during which it is introduced;

even if it is intended to administer a medicinal product as defined in the Medicines Act 1968 or incorporates as an integral part a substance which, if used separately, would be a medicinal product as so defined; �[99]

80.            Regulation of certain other devices (excluding in vitro diagnostic medical devices) was introduced with the implementation in the UK of the Medical Devices Directive 93/42/EEC, by the Medical Devices Regulations 1994.[100] The transition period lasted until 14 June 1998.� For the purposes of those regulations, a medical device is defined as follows:[101]

�� an instrument, apparatus, appliance, material or other article, whether used alone or in combination, together with any software necessary for its proper application, which -

(a) � is intended by the manufacturer to be used for human beings for the purpose of -

(i)��� diagnosis, prevention, monitoring, treatment or alleviation of disease,

(ii)�� diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap,

(iii)� investigation, replacement or modification of the anatomy or of a physiological process, or

(iv)� control of conception; and

(b) � does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, even if it is assisted in its function by such means, even if it is intended to administer a medicinal product as defined in Council Directive 65/65/EEC or incorporates as an integral part a substance which, if used separately, would be a medicinal product as so defined and which is liable to act upon the body with action ancillary to that of the device; ��

81.            There are a number of express exceptions to which the Medical Devices Regulations 1994 do not apply.[102] These include in vitro devices, active implantable devices covered by Council Directive 90/385/EEC as amended (implemented into UK law by the Active Implantable Medical Devices Regulations 1992 (SI No 3146)), transplants or tissues or cells of animal origin, unless a device is manufactured utilising animal tissue which is rendered non-viable, and non-viable products derived from animal tissue.[103]

82.            Both sets of medical devices regulations are made pursuant to sections 11 and 27(2) of the
Consumer Protection Act 1987and section 2(2) of the European Communities Act 1972.� They require the devices in question to comply with the relevant essential requirements.

83.            Under the Directives, Member States of the EU have the right to withdraw from their territory any product that they consider endangers public health.[104]

84.            The responsible authority to enforce these directives in the UK is the Secretary of State for Health acting through the MDA, although local authorities have some enforcement responsibilities for medical devices that are also consumer goods.� The MDA�s duties include ensuring compliance and evaluating adverse incident reports provided by manufacturers and users under a statutory duty.[105] The Regulations provide for a vigilance system whereby information concerning serious incidents in the UK must be notified by the MDA to the EU and other Member States, so that any necessary action can be taken at European level.[106] The MDA said it has received no reports of adverse incidents associated with infection involving medical devices that incorporate material of animal origin. Finally the MDA assesses notifications for clinical investigations.[107]

85.            Independent accreditation bodies, known as Notified Bodies, are used to check manufacturers� claims of conformity for everything except the lowest risk devices.� These bodies are monitored by the MDA.[108]

86.            In January 1995 the Medical Devices Directive came into force[109] which covered, inter alia, devices containing or consisting of non-viable animal tissues, with a transitional period until 14 June 1998.

Legislation relating to homoeopathic products

87.            Homoeopathy is a school of medicine based on the theory that where large doses of drugs produce symptoms of a disease in healthy people, when administered in small amounts those drugs will cure the same symptoms.� The smaller the amount, the greater the paradoxical effect.� Homoeopathic drugs are therefore diluted to a concentration of approximately 10-30. At this dilution, there may not be a single molecule of active ingredient left in the preparation.[110]

88.            Prior to 1994 homoeopathic medicinal products that satisfied the definition of medicinal product in the 1968 Act were subject to its licensing requirements.[111] In fact in 1971 there would have been many product licences of right for homoeopathic products.[112]� A new homoeopathic product with no indications might escape the controls of the 1968 Act.� One with indications, which was subject to the licensing regime, would be unlikely to satisfy the ground of efficacy necessary to obtain a licence.[113]

89.            A special, simplified registration procedure was introduced by the Medicines (Homoeopathic Medicinal Products for Human Use) Regulations 1994,[114]which implement in part Council Directive 92/73/EEC.[115]� They make provision for the grant by the licensing authority of a certificate of registration for homoeopathic medicinal products, which authorises the placing on the market of the product in question[116].� The exception to the requirements of section 7 of the 1968 Act was introduced to correspond with the coming into force of these regulations on 14 February 1994.� The Directive and Regulations are concerned with quality and safety, rather than clinically proven efficacy, recognising that there are many users of these products regardless of their clinically proven efficacy, and that there is therefore a need for regulation.

90.            Homoeopathic medicinal product is defined for the purposes of the Regulations as �a medicinal product (which may contain a number of principles) prepared from products, substances or compositions called homoeopathic stocks in accordance with a homoeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by any pharmacopoeia used officially in a Member State.�[117]� The definition is taken from Council Directive 92/73/EEC article 1. �Article 2[118] provides exceptions for homoeopathic medicinal products prepared in accordance with a magistral or officinal formula and for those satisfying the exclusions set out in Articles 1(4) and 1(5) of Directive 65/65/EEC.�

91.            The Advisory Board on the Registration of Homoeopathic Products[119] was established in February 1995 for the purpose of giving advice with respect to the safety and quality of homoeopathic medicinal products.[120]

The Joint Committee on Vaccination and Immunisation (JCVI)

92.            The JCVI is a Non-Departmental Public Body. It is a statutory expert Standing Advisory Committee established in England and Wales under the NHS Act 1977 (section 6(3)) and NHS (Standing Advisory Committees) Order 1981 (Schedule, part II) as the Standing Advisory Committee on Vaccination and Immunisation. It is also a Sub-Committee of the National Professional Advisory Council covering Scotland. The JCVI is a statutory body in England and Wales but not in Scotland or Northern Ireland.[121]

93.            The JCVI�s terms of reference, prior to April 1995[122] were:

�To advise the Secretaries of State for Health, Scotland, Wales and Northern Ireland on matters relating to the prevention of communicable disease through immunisation.�

94.            After April 1995[123] new terms of reference were agreed by Ministers. These were:

�To advise the Secretaries of State for Health, Scotland, Wales and Northern Ireland on matters relating to communicable diseases, preventable and potentially preventable, through immunisation.�

95.            The terms of reference were changed following a general review of the JCVI, its workings and membership. There was recognition of the fact that the JCVI may on occasion be called upon to give advice on other related aspects of communicable disease as well as immunisation, and needed to have the flexibility to advise as new vaccines became available.[124]

96.            The JCVI is not responsible for issues of vaccine safety. It makes recommendations to Ministers on the use of vaccines that have already been licensed for use in the UK. It is the CSM that has overall responsibility for advising Ministers on the safety of medicines.[125]

Structure of agencies with responsibility for medicines and medical devices

Medicines Division/ Medicines Control Agency�

Function

97.            The function of the Medicines Division (MD), and later the Medicines Control Agency (MCA), was, inter alia, to ensure that all medicinal products met acceptable standards of quality, safety and efficacy. It was the executive arm of Government responsible for regulating the pharmaceutical sector and implementing policy in this area.[126]

Structure of the Medicines Division/MCA � administrative and professional staff, their roles and responsibilities

98.            Until the creation of the Medicines Control Agency on 11 July 1991, the Medicines Division was organised in three parallel structures. One consisted of medical staff, another pharmaceutical staff and another administrative staff.[127] Responsibility for staff in these structures was essentially dividedbetween the professional staff and the administrative staff, with the professional staff reporting to the Senior Principal Medical Officer (SPMO) or the Chief Pharmaceutical Officer and the administrative staff reporting to the Under Secretary.[128]

99.            Over the period 1984-89 the Medicines Division employed some 300 people, 200 of whom were administrative staff and 100 of whom were professionals (20 doctors and 80 pharmacists).[129]

100.         In the medical structure the SPMO, Dr Gerald Jones over the period 1986-91, was responsible for all professional work concerning drug regulation, new drug applications, adverse reactions, review of existing products, advertising, legal status and the servicing of all the advisory committees.� In addition he states that he had responsibility for policy formulation and advice to ministers.[130] The SPMO had three Principal Medical Officers (PMOs) reporting to him. He in turn reported to the Deputy Chief Medical Officer (DCMO).[131]

101.         Dr Gerald Jones notes in his statement to the Inquiry that:

��my task was of an overall supervisory role rather than to intervene in the scientific judgments of the individual expert committees.� [132]

102.         The PMOs headed three medical branches. These were:

(i.)        MB3A: New drugs and biological products � Dr Jefferys from September 1986 to 1990;

(ii.)      MB3B: Review of medicines and the CDSM � Dr WJ Jenkins from 1987 to September 1988 and Dr Adams from September 1988 to May 1990; and

(iii.)    MB4: Adverse reactions and post marketing surveillance � Dr Mann from 1986 to 1988 and Dr Wood from 1989-90.[133]

103.         In his Statement to the Inquiry Dr David Jefferys gave an indication of how the Medicines Division operated up until 1991. He said that he worked closely with Mr David Hagger the Grade 5 Assistant Secretary of MB1 whose main responsibilities were policy co-ordination, the administrative secretariat of the Committee of Safety of Medicines (CSM), and information services. Mr Hagger reported to the Under Secretary in the Division, Mr Norman Hale until 1987 and then Mr C Wilson. Dr Jefferys also worked with pharmaceutical colleagues who operated through a separate reporting structure to the Deputy Chief Pharmaceutical Officer, Mr Sandy Stewart, and on to the Chief Pharmaceutical Officer, Dr Brian Wills.[134]

104.         Dr Jefferys has also commented on how BSE was dealt with in the structure of Medicines Division.� He said:

�The issues raised by BSE did not naturally fall within the remit of MB3A or any other single group within Medicines Division. Indeed BSE never became the responsibility of MB3A or any other single group. Instead BSE was always handled on a team basis across the Division as a whole. Those involved in handling BSE were drawn from all parts of the Division and no single individual had the lead on handling the issues raised by BSE. In fact the issues raised by BSE predominantly fell to be considered by pharmacists rather than to toxicologists or physicians because BSE was primarily a pharmaceutical issue although it required medical input.�[135]

105.         Dr Wills explains the relationship between Pharmacy Division and Medicines Division:

�As Chief Pharmacist, I headed the Pharmacy Division (PH), which dealt with the practice of pharmacy; pharmacy in the NHS and international pharmacy.� Everybody within that division ultimately reported to me.� The Inquiry should understand that the Pharmacy Division was entirely separate from Medicines Division and the pharmacists within the Medicines Division did not report to me.� I was however professional head of all the 100 or so pharmacists who worked within different divisions of the Department of Health.�[136]

106.         In her Statement to the Inquiry Dr Frances Rotblat, a Senior Medical Officer (SMO), said she reported to Dr Jefferys from August 1986. She was one of a number of SMOs reporting to Dr Jefferys, the only one specialising in biologicals. She said that she worked closely with Dr John Purves, a Superintending Pharmacist in MB5A. Dr Rotblat was the medical assessor to the CSM Biologicals sub-committee.[137]

107.         In the pharmaceutical structure, the Chief Pharmaceutical Officer (Grade 4 level) was responsible for professional and pharmaceutical aspects of the Medicines Act, the Medicines Inspectorate and the British Pharmacopoeia Commission. Over the period 1986-91 this was Dr Wills. Prior to June 1990, the Chief Pharmaceutical Officer was not within the Medicines Division. After June 1990 he was in the Medicines Division, reporting to the Under Secretary of Medicines Division.[138]

108.         The Chief Pharmaceutical Officer had two Deputy Chief Pharmaceutical Officers (Grade 5 level) reporting to him. They were responsible for the professional and pharmaceutical aspects of the Medicines Act and the Medicines Inspectorate respectively. The Deputy Chief Pharmaceutical Officer with responsibility for the professional and pharmaceutical aspects of the Medicines Act had a Grade 6 working to him. This was Dr Purves who had the lead responsibility for biologicals and was the pharmaceutical assessor to the CSM

Biologicals sub-committee.[139]

109.         Dr Purves comments in his statement to the Inquiry:

�The role of the pharmacists is to evaluate the acceptability of the quality of the product, the manufacturing process and materials used in manufacture.�� When there are issues of concern the advice of experts is sought through the various Sub-committees, which reported to the CSM.�[140]

110.         During this period, the co-ordination of BSE issues was handled by the administrative staff with professional support from the various branches of the Medicines Division.[141]

111.         The recommendation to create the Medicines Control Agency (MCA) came from the Evans-Cunliffe Report. The Report was published on 26 January 1988 and the Government�s response to the recommendations was given in April 1988. Considerable resources and attention were directed during the second half of 1988 and the whole of 1989 to the introduction and establishment of the new MCA to replace the Medicines Division.[142]

112.         The Evans and Cunliffe Report was commissioned in 1987.[143]� The terms of reference for the report outlined by Ministers were:

�To examine the issues for DHSS arising from the increases in licence applications and other work under the Medicines Act and to recommend ways of dealing expeditiously with this work, while maintaining adequate standards for the safety, efficacy and quality of human medicines in the United Kingdom.�[144]

113.         Under the heading �Ways of Improving� the Report stated:

�There is chronic difficulty in recruiting the best professional staff, and computing support is antediluvian.� The complex organisational structure prevents effective management, and overall the Division is unduly constrained from without and lacks resilience within.�[145]

114.         The Report made the following observations about the technology at the disposal of the Medicines Division:

�The thousands of current and previous licence applications are moved around the office in cardboard folders, the so-called gold files.� It is astonishing that that there is no reliable way of finding files within the building.� Some months ago, DHSS introduced a file tracking system in which staff read-off bar codes into a central computer, but it is not yet comprehensive nor fully operational.� File-tracking is an essential tool not only for finding and linking files but also for monitoring the transit of work through the organisation.� We RECOMMEND that a high priority be given to completing and developing the file-tracking system.�[146]

115.         On staffing the following comments were made:

�The other principal area of difficulty relates to staff: because civil service salaries for pharmacists and doctors are uncompetitive and there is too little secretarial and other support, it is difficult to recruit experienced professional staff for this highly specialised work and � once trained and experienced � they leave for posts in industry.� Other rigidities compound the problem, for example the control of staff numbers by arbitrary headcount, and the dilatory procedures for filling vacancies.�[147]

116.         In his oral evidence to the Inquiry Dr G Jones commented on staffing in the Medicines Division:

�There was, unfortunately, a considerable turnover of staff.� We were recruiting almost permanently.� The board recruiting doctors from outside, I called it virtually a standing committee; it had to meet � which I served on � virtually every 3 months.� As soon as you were able to appoint a doctor you found that someone had moved on within the Department.� The Division stood at about 20 or 25 doctors at that time.�[148]

117.         Dr Jefferys also commented on staffing levels in Medicines Division:

�At that stage [1988], there were only 5 physicians in MB3A, one of whom was working full time on the Opren litigation. For most of this period we were actively recruiting for a sixth physician. In addition, there were 3 toxicologists in the group. However, for much of this period only one toxicologist was working full time because both the other toxicologists were on extended maternity leave.

By contrast, there are now 27 medical assessors, 8 toxicologists and 4 statisticians in the Licensing Division and 26 physicians in the Post-Licensing Division (including Pharmacovigilance activities). In total there are now approximately 550 staff within the Medicines Control Agency. In 1988 the figure was closer to 220.�[149]

118.         Dr Jefferys outlined the effect this had on resources in Medicines Division:

�In summary, I would estimate that over the last 10 years the volume of work carried out by the physicians within MB3A and its present day equivalent has increased by a little more than 100%. But in the same period, the number of physicians has increased six or sevenfold and the quality of the support services for those physicians has also greatly improved. In short, MB3A along with the rest of Medicines Division was, in 1988, in my view severely overstretched. This was a point expressly made in the Evans/Cunliffe Report. The position was not helped by the fact that, at that time, the Medicines Division was required to operate under both head count and pay restraints.

These resource difficulties inevitably had implications for the work of the Division. For example, in 1988, renewals of product licences were handled purely administratively without input from physicians because of the staff shortages. In addition, the processing of abridged licence applications was subject to a two year backlog. By summer 1989 the position had started to improve in that the number of physicians within MB3A had increased to 7 and the work on the Opren litigation had decreased, but the major improvement only occurred in the early 1990s with the full establishment of the MCA.�[150]

Later he said:

�It is worth noting that the issues of prioritisation and resources were contemporaneously being addressed by the Evans/Cunliffe review which, when it reported, highlighted the serious resource limitations and the difficulties posed by a lack of functional organisation. These were the major changes which were addressed in the creation of the Medicines Control Agency (MCA).�[151]

119.         Sir Christopher France, in oral evidence to the Inquiry, said that the MCA was:

��in many ways a continuation of the Medicines Division.� What was different was that instead of being as it were a core part of the Department of Health [DH], it became one of the so-called next steps agencies and therefore was given certain operational freedoms that it would not have had as part of the Department.� But it is -- its core function of controlling medicines remained the same as between the 31st March and 1st April.�[152]

120.         The establishment of the MCA reorganised the business of the Medicines Division along multi-disciplinary functional lines. On 11 July 1991 the MCA became an Executive Agency of the Department of Health.�� The freedoms of Agency status were intended to help it meet the challenges of new developments in medicine; of completion of the EC single market; and of a European system for regulating medicines.[153]

121.         Dr Keith Jones says in his statement to the Inquiry:

�The aim was to replace the Medicines Division with an Executive Agency of the Department of Health to be called the Medicines Control Agency.� Although the MCA would still be part of the Department of Health, it would have greater managerial autonomy than a Division and would be self-financing.�[154]

122.         In place of the old structure of the Medicines Division, the new MCA had several Business Groups. Management lines were reorganised and the professional and medical staff integrated.[155] The new Business Groups were in place by June 1990, although the reporting lines remained as under the Medicines Division until July 1991[156].

123.         �These Business groups were:

(i.)        Business A: New drugs and European Licensing;

(ii.)      Business B: Abridged licensing;

(iii.)    Business C: Pharmacovigilance business;

(iv.)    Business D: Inspection and enforcement;

(v.)      Business E: Executive support business; and

(vi.)    Business F: British Pharmacopoeia.[157]

124.         The Agency was headed by a Director or Chief Executive, Dr Keith Jones, and each Business group by a Business Manager (of Grade 4 level) who reported to the Chief Executive. The Chief Executive was fully responsible and accountable to the Secretary of State for Health for the efficient management, overall performance and future development of the Agency. Ministers and the DH were not involved in the day to day management of the MCA.[158]

125.         Dr Keith Jones clarifies his role in his statement to the Inquiry:

�On my appointment as Director of the MCA all staff within the Medicines Division nominally reported to me.� However, in practice the existing lines of command continued and I reported jointly to the Deputy Secretary responsible for medicines policy and to the Deputy Chief Medical Officer (DCMO) until MCA became a Next Steps Agency in 1991.[159]

�When the MCA became an executive agency on 11 July 1991, my title changed to that of Chief Executive, and I became responsible and accountable directly to the Secretary of State for the efficient management, overall performance and future development of the MCA.� My role is primarily that of a medically, scientifically informed manager: I am there to oversee the running of the MCA and since July 1991, to advise Ministers on matters of medicines control.�[160]

126.         Dr Jefferys said in his Statement to the Inquiry that under the new structure he was given wider responsibility as the Business Manager for Business A: New Drugs and European Licensing. He was responsible for the medical, scientific and pharmaceutical staff involved in the assessment of new drugs including biological products. In addition he was responsible for the secretariat to the CSM and for the Biological and Biotechnological Unit that was headed by Dr Purves. Dr Jefferys reported to Dr Keith Jones.
[161]

127.         Dr Rotblat said in her Statement that a separate Biological and Biotechnological Unit was set up shortly after the MCA became operational. In late 1990 Dr Purves was appointed unit manager and Dr Rotblat was the SMO. Initially she was the only SMO in the unit but later another post was created because of the high workload. After Dr Purves was appointed unit manager, Dr Rotblat�s involvement with BSE became more limited as Dr Purves took over the responsibility for the work on BSE. To begin with Dr Purves reported to a Group Manager, Dr Ritchie, but after about one year, Dr Ritchie left the MCA and was not replaced. After that Dr Purves reported directly to Dr Jefferys who in turn reported to the Chief Executive.[162]

128.         In the Autumn of 1994, there was a further reorganisation into the MCA[163] with the five following divisions:

(i.)        Licensing Division;

(ii.)      Post Licensing Division;

(iii.)    Inspection and Enforcement Division;

(iv.)    Executive Support Division;

(v.)      Finance Division.

129.         The Agency was still headed by the Chief Executive, Dr Keith Jones, and each Division by a Grade 4 Business Manager.[164]

Relationship between the Medicines Division/MCA and the Advisory Committees

130.         Mr Wilson says in his statement to the Inquiry that �[t]he Division provided, amongst other things, the Secretariat and professional support for the Committee on Safety of Medicines (CSM) and the Medicines Commission��[165]

131.         Dr Jefferys has also said:

��Medicines Division was inevitably dependent on its advisory committees whose members were highly distinguished scientists and clinicians. The committees met according to fixed timetables. For example, the CSM and SEAR met once per month and the Biologicals subcommittee met once every two months. It would have been very difficult to have altered the timetable of these committees� meetings save in a case of emergency.�[166]

132.         Dr Jefferys said in his Statement that there was a very close relationship between the Medicines Division/MCA and the medicines advisory committees (set up under the Medicines Act 1968). There was almost daily contact between the Chairman of the CSM and senior members of the Medicines Division/MCA. There was also frequent contact between the Medicines Division/MCA and other prominent members of the CSM between committee meetings. On a matter of such importance as BSE, the Chairmen of the committees and subcommittees would be kept very closely informed on all developments.[167]

133.         Dr Jefferys also stated that medicines required a considerable number of decisions to be made. Many of them could be taken by the Medicines Division/MCA, as the executive arm of the Licensing Authority, without referring them to expert advisory committees. However many others did need to be referred to the advisory committees and certain types of decision were required to go before the CSM under the requirements of the Medicines Act. The CSM was also consulted on matters of general policy.[168]

134.         Dr Jefferys gave the following example of the interaction between the Medicines Division/MCA and the CSM[169]. Before each CSM meeting there were a number of other meetings, the first of which was an agenda and pre-briefing meeting. This meeting was held on the Tuesday of the week of a CSM meeting and was only attended by officials from the Medicines Division/MCA. It was used to identify in advance any political issues that might need to be communicated to Ministers, the CMO or other officials in DH. The meeting was also used to decide what issues should be placed before the CSM at future meetings.

135.         On the Wednesday of the week of a CSM meeting, there was a lunch time meeting attended by the Chairman of the CSM (and possibly the Vice-Chairman), the Secretary to the CSM and its principal assessors (from the Medicines Division/MCA). Principal assessors might be from either the medical or pharmaceutical structure and were more senior than a medical or pharmaceutical assessor. This was followed in the afternoon by a full briefing meeting for the Chairman and Vice-Chairman at which other officials were present.

136.         The CSM itself met on Thursdays although the meetings sometimes continued into Friday.

137.         Dr Jefferys has commented on prioritisation of work within Medicines Division:

�The Division obviously had to, and did, prioritise its work. However, it is important to understand that there were considerable limitations on our ability to prioritise our work since most was demand led. First, EC and national legal timeframes applied to much of the work with the result that it would not have been possible for us to have ceased carrying out that work. For example, legal timeframes applied in EC multistate and Concertation procedures and cases where a hearing date had been set for a company to argue its case before one of Medicines Division�s advisory committees. There were also deadlines for getting applications before committees and we were sometimes threatened with legal action when we risked missing deadlines. In addition, at that time, MB3A was responsible for clinical trials which took up about 40 � 50% of one physician�s time and probably 50% of one toxicologist�s time. The Licensing Authority was required to determine a CTX within 35 days if it had any objections failing which it was assumed to have approved the application.�[170]

Communication with Ministers

138.         The administrators within Medicines Division/MCA were primarily responsible for reporting to Ministers on matters relating to medicines. Before 1991 Mr Hagger, who was responsible for the CSM�s secretariat, would send submissions to Ministers, including any on BSE and medicines. An administrator considering whether and what to report to Ministers would discuss the matter with the Head of the Administrative Division (Mr Hale and subsequently Mr Wilson) and/or the Head of the Medical Division (Dr G Jones). There was no formal framework for deciding what matters (in particular those flowing from the recommendations of the CSM) should be referred to Ministers.[171]� Dr Jefferys states that �[o]fficials had to apply their own judgement when deciding what matters to refer to Ministers.�[172]

139.         Mr Hagger has commented to the Inquiry:

�The bulk of my normal work comprised such things as considering courses of action to meet actual or anticipated licensing issues; preparing reports; briefings and occasional submissions for senior officers or ministers��[173]

140.         In oral evidence to the Inquiry Dr G Jones said that on the vast majority of routine business the Minister would not be involved:

�If it were something highly controversial, well in some cases Ministers had to be consulted of course, especially on orders, but if it were not quite as drastic as that but still highly controversial, then senior officers and Ministers would be consulted anyway as a matter of common sense and courtesy. But it would be rare.�[174]

141.         Dr Jefferys� approach to this issue was that if he was ever in doubt about whether a matter should be referred to Ministers, he would discuss it with senior colleagues in the Medicines Division/MCA including the SPMO or Chief Executive. Other officials in DH such as the DCMO or those in the Minister�s private office might also be consulted. At the end of that process, if he was still in doubt he would err on the side of recommending referring the matter to Ministers.[175]� Dr Jefferys also notes:

�A large number of issues are in fact referred to Ministers, partly because a considerable number of PQs are tabled on medicines based issues. In addition, Ministers sometimes ask the CSM to advise on a particular issue and then inform Parliament that they have asked the CSM to advise and that they are awaiting that advice.�[176]

142.         Professor Asscher has stated

�The CSM reported to the Licensing Authority. Ministers are, as a matter of law, the Licensing Authority. However, my understanding of the arrangement was that decisions were de jure taken by Ministers; but were de facto taken by the Medicines Division/Medicines Control Agency.

I should emphasise that the CSM did not report directly to Ministers. As far as I can recall, I never wrote directly to Ministers during the whole of my time as Chairman of the CSM�.[177]�

He also says that he �had no meetings with either Ministers or the Chief Medical Officer (CMO) over BSE.�[178]

143.         Ms Edwina Currie, Minister of Health between September 1986 and December 1988, told the BSE Inquiry that :[179]

�� I would not dream of overruling people who were on the various senior medical committees, the Committee on Safety of Medicines existed exactly to advise Ministers on what was and was not safe.

The system worked extremely fast. I could be informed within hours if a problem had arisen, for example, with a batch of vaccines. I would not be asked for my permission to withdraw it from the market; the Committee had the power, with the pharmaceutical industry, to act extremely quickly in the public interest. I would be told, if necessary I would give my retrospective approval; and then I would find myself facing press enquiries about it.�

It generated considerable confidence, amongst Ministers, in the approach that was being taken by the Committee on Safety of Medicines. I believe the technical responsibility lay with the Chief Medical Officer, who of course, he is not just an official like any other official he is a senior person who would feel himself, I am sure and I hope, obliged to take action first in the public interest and get hold of Ministers and tell them as soon as possible afterwards. In some cases the CMO would then answer for his actions in public, and in some cases Ministers would.�

144.         When questioned about whether she would have looked to the CMO for advice on medicines and pharmaceuticals, Mrs Virginia Bottomley, Secretary of State for Health from April 1992 to July 1995, replied that the CMO:

��had a role in relation to medicines and pharmaceuticals, but essentially the [MCA] was established in 1989�The [CSM] actually advised the [MCA] on the safety, quality and efficacy of medicines and they had a range of expertise across the necessary sciences, which obviously was broader than the Chief Medical Officer�s area of expertise, so had I been unhappy about the reports back from the Medicines Control Agency, certainly I might have raised it with the Chief Medical Officer or one of his staff��[180]

145.         When Mr Dorrell, Secretary of State for Health from July 1995 to May 1997, was questioned about who he would look to for advice on medicines, and particularly in relation to BSE, he replied

�There is a clear statutory framework laid out as I understand it.� That is that the Medicines Control Agency is responsible for marshalling and preparing the evidence which then goes to the Committee for Safety of Medicines and the Committee for Safety of Medicines�reaches conclusions based on the evidence submitted to it by the MCA and, on the basis of those conclusions, offers advice to Ministers as the Licensing Authority�

The Chief Medical Officer in that context is an independent source of advice, if you like, to the Secretary of State, or to Ministers to the Licensing Authority, on how they should react to advice that comes from the CSM.� But it is, I think -- it certainly did not happen in my time that the CMO expressed a different view from the CSM.� I think it is extremely unlikely that he would do that, much more likely that if he felt that action needed to be taken, he would act by changing the machinery rather than by commenting on the advice that came out of the machinery.�[181]

Relationship between the Medicines Division/MCA and the Chief Medical Officer

146.         The Chief Medical Officer (CMO) is a second Permanent Secretary in the Department of Health (DH). The CMO works closely with the Permanent Secretary in the DH and advises the government generally on matters affecting public health.� The CMO is the professional head of the DH�s medical staff, and represents the UK on health matters in the EU and internationally.[182]

147.         Sir Donald Acheson says in his statement to the Inquiry:

�The Chief Medical Officer is the principal adviser on medical and public health matters, not only to Ministers in the Department of Health but to the Ministers in other government departments and to the Government as a whole.� It follows that the field over which the CMO is required to provide advice extends far beyond his own personal professional experience.� It is therefore necessary for him to be supported by an extensive advisory machinery.�[183]

148.         At the beginning of the period in question the DH administrative staff reported to the Permanent Secretary and the medical and scientific staff reported to the CMO.� As the person managerially accountable for the medical staff, the CMO could therefore address his responsibility for the quality of medical advice within the DH.[184]

149.         Before the creation of the MCA the SPMO in the Medicines Division reported to the Deputy Chief Medical Officer (DCMO) and therefore the CMO[185].

150.         Sir Donald Acheson, the CMO from January 1985 to October 1991, said in oral evidence to the Inquiry that the

��Medicines Division�seemed to have a slightly different line of accountability.� All the doctors in the Department in my day were accountable to me, which was, I believe, essential.� It guaranteed my independence.� Now, the Senior Principal Medical Officer in the Medicines Division also had to deal with the Medicines Act�.

And he had a line of accountability of some sort to the Medicines Commission, which was appointed by the Medicines Act. Now in practical terms the way this affected me and my colleagues was that we were told that a number of the things that we wanted to discuss were confidential in the commercial sense under the Act, and that they could not discuss them with us. Now, I do not want to make too much of that because --� I think it is part of the background, but having said that they were as receptive as they could be to my various interventions�.[186]

151.         After the introduction of the MCA in July 1991 the reporting arrangements changed, and the Chief Executive reported directly to the Secretary of State for Health. There was no formal relationship between the Chief Executive and the CMO, although the CMO was routinely kept informed on MCA issues pertaining to public health.[187]

152.         The CSM was not responsible under the relevant legislation to the CMO, although the practice on all sensitive public health issues was, and is, for officials to minute the CMO at the same time as minuting Ministers.[188]

Supplies Technology Division/Medical Devices Directorate/Medical Devices Agency

Function

153.         The main function of the MDA (in its various forms) is to ensure that medical equipment and devices used in the UK meet appropriate standards of safety, quality and performance[189] and that these standards comply with the relevant Directives of the European Union[190].���

Structure of the Supplies Technology Division/Medical Devices Directorate/Medical Devices Agency - their roles and responsibilities

154.         Until the creation of the Medical Devices Agency (MDA), responsibility for ensuring the safety of medical devices rested with the Supplies Technology Division (STD) and then the Medical Devices Directorate (MDD).[191]

155.         The STD existed up until 1 August 1990 and was a part of the NHS Procurement Directorate. The NHS Procurement Directorate was managed by a Grade 3, and the STD by a Director, Mr Gordon Higson, at Grade 4 level. The function of the STD was to promote and investigate safety for a wide range of medical devices and equipment, and to provide scientific and technical services including quality audits of medical device manufacturers, some research and development, and technical evaluations of some products.[192]

156.         Within the STD there were three areas which had responsibility for aspects of bovine products used in medical devices. These were: implants; sterilisation; and the Manufacturer Registration Scheme (MRS). The job responsibilities in these areas were considerably wider than just considering the use of bovine products in medical devices. It appears that after November 1987 both the implants and sterilisation areas were headed by the Grade 5, Miss Marilyn Duncan. Prior to that they had been headed by Miss Duncan but at a Grade 6 level. Until July 1988, Miss Duncan reported to the Director of STD and thereafter to the Director of the NHS Procurement Directorate. She had two Grade 6 and two Grade 7 staff members reporting to her on both the issues of implants and sterilisation. Technical responsibilities for the MRS were devolved throughout the organisation.[193]

157.         In August 1990 the Procurement Directorate was re-organised: the procurement role was removed from the STD and transferred to the newly created NHS Supplies Authority. The STD was renamed the Medical Devices Directorate. The Procurement Directorate continued to be managed by a Grade 3, and the MDD was managed by a Director, Mr Alan Barton, at Grade 4 level. Mr Barton reported to Dr Jeremy Metters, the Deputy Chief Medical Officer.[194]� Two Grade 5 and four Grade 6 staff reported to Mr Barton, as well as two Senior Medical Officers.� The function of the MDD was to ensure that a wide range of medical devices and equipment met acceptable standards of safety, quality and effectiveness and that these standards complied with EC Directives.� It was also responsible for the evaluation of devices and equipment.[195]

158.         Under this new structure the same three areas were responsible for aspects of bovine products used in medical devices. The implants and sterilisation areas continued to be headed by Miss Duncan, a Grade 5, with two Grade 6 and two Grade 7 staff members working to her. Miss Duncan reported to the Director of the MDD. In June of 1992 a technical area was set up with responsibility for the MRS. This was headed by a Grade 6 and had one Grade 7 staff member.[196] The area headed by Miss Duncan was known as Safety and Quality until September 1992 and then as Device Technology and Safety.

159.         On 27 September 1994 the MDD was replaced by the MDA. It was managed by a Chief Executive, Mr Alan Kent, at Grade 4 level, who had been appointed in October 1993 in expectation of Agency status. He was responsible for the day to day running of the Agency and was supported by a senior management team and a total of 170 staff, many of whom had professional and technical qualifications.[197] The staff were organised in several businesses, four of a functional nature, one of a medical and nursing nature which supported the functional areas, and two administrative areas. These were detailed in the 1995 Civil Service Yearbook as:

(i.)        European business and standards;

(ii.)      Device technology and safety;

(iii.)    Device evaluation and publications;

(iv.)    Manufacturer Registration Scheme;

(v.)      Medical and Nursing;

(vi.)    Corporate management;[198] and

(vii.)  Corporate finance (added after the Civil Service Yearbook was compiled).

160.         The Chief Executive was directly accountable to the Secretary of State for Health and fully responsible for the efficient management, performance and future development of the Agency. The Secretary of State was answerable to Parliament for all matters concerning the Agency, but Ministers would only expect to intervene in the running of the agency in exceptional circumstances. If, exceptionally, Ministers needed to intervene, the effects of such intervention on the Agency�s targets would be made explicit.[199]

161.         The areas responsible for aspects of bovine products used in medical devices continued to be implants; sterilisation; and the MRS. The first two of these areas came under the �Device Technology and Safety� business unit and were headed by Dr Eamonn Hoxey, a Grade 5. He reported to the Chief Executive and had two Grade 6 and two Grade 7 staff concerned with implants and sterilisation.

Veterinary Medicines Directorate

Structure of the Veterinary Medicines Division � administrative and professional staff, their roles and responsibilities

162.         Before the creation of the Veterinary Medicines Directorate (VMD) in 1989 three bodies in MAFF undertook regulation of veterinary medicines. These were:

(i.)        Animal Health Division III/Animal Medicines Division (MAFF Animal Health Group) which was responsible for policy matters relating to veterinary medicines. The Division was managed by a Grade 5, Mr K Wilkes between 1986-87, and Mr F Scollen between 1988 and April 1989. The Grade 5 reported to the Head of Animal Health Group, Mr J Hepburn between 1986-87 and Mr Cruickshank between 1988 and April 1989.

(ii.)      Medicines Unit (Central Veterinary Laboratory (CVL)) which was responsible for the assessment of non-biological products and administrative staff who formed the Veterinary Products Committee (VPC) secretariat. It was managed by Mr Alastair Kidd and staffed by veterinary surgeons and scientists;

(iii.)    Biological Products and Standards Department (BP&S), also part of CVL, which was responsible for the assessment of applications for immunological veterinary medicines and inspections of their manufacturing premises. It was managed by Dr Denise Thornton and staffed by veterinary surgeons and scientists.[200]

163.         The formal channel of communication and co-ordination between the Animal Medicines Division and the two areas responsible for veterinary medicines in CVL was from the Grade 5 managing the Animal Medicines Division, to the Director of the CVL, Dr Watson.[201]

164.         Dr Rutter�s statement to the Inquiry outlines the relationship between the VMD and the Department of Health:

�From the time the VMD was set up, its staff had regular contact with officials from the Department of Health through attendance of Department of Health officials at the Scientific Secretariat and the VPC.� In addition, Dr. Lee served as the VMD representative on the BSE Working Group of the Biologicals Sub Committee of the CSM from September 1989, which enabled the updating and sharing of information between the VMD and its equivalent in the Department of Health, the Medicines Control Agency (MCA).� VMD staff attended meetings of the Medicines Commission and I met the Chief Executive of the MCA at various meetings.�[202]

165.         Dr Thomas Little, Deputy Director of the CVL from 1986-1990, said in his Statement to the Inquiry that he had specific responsibility for veterinary medicines and in particular for the Medicines Unit and the Biological Products and Standards Department.� He had fairly frequent contact with the Animal Medicines Division in the Animal Health Group, who were responsible for policy and administration side of veterinary medicines. He also briefed the Chairman of the Veterinary Products Committee (VPC) before meetings and attended meetings of the VPC.� When necessary,� he attended meetings of the Medicines Commission and various other committees which dealt with human medicines.[203]

166.         Professor Armour outlined the role of the VPC:

�The Committee advised on applications for test licences and product licences for individual veterinary products and general policy, including guidelines for registration of veterinary medicines.� During my chairmanship, it also had the task of reviewing all pharmaceutical products given a Licence of Right when the Medicines Act was introduced in 1968 and all other licences awarded prior to 1984; this was to conform with European regulations (see EC Directives 81/851 and 81/852.�[204]

167.         On 1 April 1989 the Animal Medicines Division merged with the Medicines Unit and part of the Biological Products and Standards Department to form the VMD. The VMD was responsible for licensing and control of animal medicines and medicated feedstuffs, and control of veterinary residues. It was a part of the Pesticides, Veterinary Medicines and Emergencies Group and was headed by a Director of Grade 4 level, Dr J Rutter. Two Deputy Directors of Grade 5 level, one responsible for professional matters (Mr Kidd) and one responsible for administrative matters (Mr Scollen), reported to him.[205]

168.         With the establishment of the VMD, the work was allocated between three multi-disciplinary professional and administrative teams, each headed by a professional (Grade 6 level) and administrative (Grade 7 level) team leader reporting to the appropriate Deputy Director. The three teams which reported to the Deputy Directors, were:

(i.)        Pharmaceuticals � responsible for assessing applications and administering product licences for pharmaceutical products. Also responsible for international and European aspects of market authorisations and legislation for these products. This team co-ordinated VMD interests on policy developments relating to these matters;

(ii.)      Biologicals and recombinant products � responsible for assessing applications and administering product licences for biological and recombinant products. Also responsible for administering the Suspected Adverse Reactions scheme for all veterinary products. This team also co-ordinated VMD interest in policy developments relating to biologicals and recombinant products. The administrative staff in this team provided the secretariat services to the Veterinary Products Committee; and

(iii.)    Feed additives- responsible for assessing applications and administering product licences for all veterinary medicinal products administered in feed or drinking water with the exception of oral vaccines. Also responsible for co-ordinating VMD interests in policy developments relating to these matters. The Finance team reported to the Head of Administration in this team.[206]

169.         The VMD became an Executive Agency on 2 April 1990. It was responsible for all aspects of licensing and control of animal medicines and medicated feedstuffs including the protection of the consumer from potentially hazardous residues in food.

170.         As an Executive Agency it was headed by a Director, or Chief Executive. The Director, Mr Rutter, was responsible for the day to day running of the VMD and as before had two Deputy Directors reporting to him (on professional and administrative matters). The work of the VMD continued to be allocated between three multi-disciplinary professional and administrative teams, each headed by a professional and administrative manager. The roles and responsibilities of these teams remained as they had been, but Finance became a separate branch and the IT branch was created. These areas both reported to the Deputy Director for Administration (now Mr C Lawson).[207]

171.         The Minister was not involved in the day to day running of the VMD, but had the right to issue directions to the Director (Chief Executive) on matters relating to priorities, resources and general policy.[208]

172.         The VMD was a service provider for MAFFs policy divisions, and as such had to provide services under the policy of �value for money�. The VMD and MAFF agreed on the services to be provided and any changes in requirements or priorities were made following the agreement of the Chief Executive.[209]

173.         This structure remained in place until the 1992 Review of the Organisation and Management of VMD, which was implemented in April 1993. As a result of the review, two Director positions (at Grade 5 level) were created. One was the Director of Licensing, and the other the Director of Policy and Finance. These were essentially the same as the Deputy Director positions before the reorganisation, except that they had different responsibilities.[210]

174.         The Director of Licensing, Dr K Woodward, was responsible for all technical matters relating to the assessment of product licences and other applications. He was also responsible for all administrative work relating to their issue, inspection of UK and overseas manufacturers of immunological products, inspection arrangements, the Suspected Adverse Reactions Surveillance Scheme, and the VPC Secretariat. The Teams reporting to the Director of Licensing were:

(i.)        Pharmaceuticals and Feed Additives � with a Grade 6 Licensing Manager, Mr J O�Brien;

(ii.)      Immunologicals and Suspected Adverse Reactions � with a Grade 6 Licensing Manager, Dr A Lee; and

(iii.)    Licensing Support � with a Senior Executive Officer Head of Branch, Ms H Oliver. This team was responsible for the VPC Secretariat.

175.         The Director of Policy and Finance, Mr C Lawson, was responsible for all licensing policy matters and the distribution of veterinary medicines. He also had responsibility for supporting the UK delegation to the European committee (CVMP), the review of veterinary medicines, and homoeopathics. General administrative, finance and IT matters were also dealt with in this section. The teams reporting to the Director of Policy and Finance were:

(i.)        Licensing Policy � with a Grade 7 Head of Branch, Mr A Harvey;

(ii.)      European and Information Policy � with a Grade 7 Head of Branch, Mr A Taylor;

(iii.)    Residues and Office Support - with a Grade 7 Head of Branch, Mr C Bean;

(iv.)    Finance - with a Grade 7 Head of Branch, Mr M Addison; and

(v.)      IT - with a Grade 7 Head of Branch, Mr N Paterson.[211]

176.         This structure remained in place until 1996 when a Business Unit was set up under a Grade 6, Mr J FitzGerald. This Unit took over responsibility for general administrative, finance, and IT matters, which left the Director of Policy responsible exclusively for policy matters relating to veterinary medicines.[212]

Chronology of events

177.         In June 1983 MAFF prepared a reference document on use of substances of animal origin in the manufacture of veterinary vaccines. In the section headed �a guide to current practice� it said:

�Restrictions are placed upon the use of substances of animal origin in order to minimise the risk associated with pathogens which may be present in these materials. Unless there is a risk from a heat resistant pathogen such as the scrapie agent, no restrictions are placed on substances sterilised by autoclaving provided that the complete mass is held at a minimum of 115OC for at least 15 minutes. Restrictions on the use of substances that can not be sterilised by autoclaving vary according to the target species, the species of origin, the country of origin and whether the substance undergoes at any stage treatment which will inactivate contaminating agents.�[213]

178.         In 1985 Dr A G Dickinson, the Director of the Neuropathogenesis Unit in Edinburgh, contributed to a paper in the Lancet which discussed concerns over the possibility of infection of human growth hormone with CJD. The paper said that the main concern was the risk of �cross-contamination between stages of the process. This will arise from a lack of appreciation of the extreme aseptic standards which are necessary.�[214]

Early Consideration

179.         In his Statement to the Inquiry Mr John Sloggem said that in July 1987 he was asked in his capacity as a Pharmaceutical Officer in Medicines Division, to process a CTC (Clinical Trial Certificate) application for a drug that was a bovine brain extract containing phospholipids. The reason that the company was applying for a CTC was that its application for a CTX (Clinical Trial Exemption) had been refused in January 1984. One of the reasons for rejecting the 1984 application was that the company had not been able to satisfy Medicines Division about its freedom from transmissibility of transmissible agents, including virus particles.[215] Mr Sloggem also notes that �[t]he company had at that time been advised that if it wished to proceed to a clinical trial, a CTC would be required, necessitating an application for a CTC which would be formally considered by CSM and its Sub-Committees.�[216]

180.         Mr Sloggem also said[217]:

�In the file I found a copy of a letter of 4th April 1984 from the Medicines Division, responding to a letter from the company which had asked for clarification of the type of viruses concerned. This letter of 4th April 1984 confirmed that, in relation to the issue of virus infection, evidence would be needed in view of the bovine brain source to satisfy the Committee [CSM] that slow virus contamination was not a problem.

As I have said, I had previously been aware of CJD and sheep scrapie.� I had not, until I read this letter, been aware of any slow virus issue relating to bovines. In light of the terms of the letter of 4th April 1984 I read the rest of the CTX file where I found a manuscript reference to the question of a slow virus associated with bovines possibly having been raised by Dr John Griffin who was then the Professional Head of Medicines Division�.

�In� light of this reference I decided that I should inquire into the situation further. In July 1987 I telephoned Dr Taylor with whom�I had previously worked professionally and discussed HGH and CJD issues, and he told me that a bovine encephalopathy had recently been recognised, I sent him some information about the production methodology in outline so that he could comment on the possibility of �bovine slow virus� transmission.�

181.         On 24 August 1987 Dr David Taylor of the Neuropathogenesis Unit (NPU) wrote to Mr Sloggem in reply to earlier correspondence, about the �scrapie-like disease which is occurring in bovines�. He stated:

�Regarding the scrapie-like disease which is occurring in bovines, the results of transmission studies are not available yet but the histopathology is identical with sheep scrapie, and scrapie-associated fibrils (SAF) have been detected (SAF have only been seen in preparations from transmissible scrapie-like diseases although other neurological diseases have been investigated). The disease seems to be occurring in Friesians, particularly those which have been improved by imported Holsteins.� I believe that there was talk of its occurrence in the United States at the recent International Congress of Virology held in Edmonton but no details were known.

As far as the product procedure is concerned, exposure to the solvents would be likely to lead to approximately a two log loss of infectivity. Other unquantifiable losses are likely to occur not through inactivation but by mechanical removal, for example by precipitation, filter absorption etc. Infectivity could survive through to the end-product because the scrapie-associated protein has a co-valently linked glycolipid at its carboxyl terminus (see enclosed reference).� This could result in the co-fractionation of at least some infectivity.�[218]

182.         On 31 August 1987 Dr Taylor wrote a further letter to Mr Sloggem in which he summarised the position about oral transmissibility of scrapie, Kuru and CJD.� Mr Sloggem had asked for his opinion because the product in question was for oral administration.[219]

Note:� The Committee for Safety of Medicines Biologicals Sub-Committee meeting on 9 September 1987 (below) is dealt with further in RFA 5 � The Early Days (and update).

183.         The Committee for the Safety of Medicines (CSM) Biologicals Sub-Committee met on 9 September 1987.[220]� Professor Gerald Collee, Chairman of the Biologicals Sub-Committee, chaired the meeting, which was also attended by several senior members of the Department of Health and Social Security�s (DHSS) Medicines Division, including Dr David Jefferys, as Medical Assessor, Dr J Purves, as Pharmaceutical Assessor, Dr Paul N Adams and Dr Frances Rotblat.

184.         Dr Little, Head of MAFF�s Medicines Unit, also attended this meeting. He recalled in his Statement to the BSE Inquiry that at that meeting he discussed BSE in the context of medicinal products, both human and veterinary.[221] Dr Little said:

�One of the products discussed during the meeting was composed of human dura mater.� This was under review at the meeting because of a case of CJD associated with its use.� The official from the Department of Health presenting the case was Dr Adams.

Although the minutes of the meeting make no reference to it, I made a mention at the meeting of the occurrence of BSE in cattle.� I believe (although I cannot now be sure) that I mentioned BSE during the course of the formal meeting.� I can remember that a discussion of scrapie resulted from my mention of BSE.� Professor Collee impressed me with his knowledge of scrapie.� It may be that my mention of BSE and Professor Collee�s comments on scrapie arose during discussion on Dr Adams� paper on the dura mater products.

Although I am uncertain about the precise context in which I raised BSE, I am certain that Professor Collee and Dr Adams were present when I mentioned BSE.�

185.         Dr Little expanded on this statement in oral evidence to the Inquiry:

��I believe that what I have said was that there had, following some mention of scrapie, which I think I can explain, that there was a similar condition in cattle that we were investigating; and I did not go beyond that. I made a very simple statement, that there was a similar condition in cattle, BSE, which we, CVL, were involved in investigating.�[222]

186.         The minutes of the meeting on 9 September 1987 make no reference to BSE.[223]

187.         Drs Adams, Purves and Rotblat do not recall BSE being raised at the meeting.[224]� Professor Collee, in his Statement to the Inquiry, states that human dura mater was discussed at the meeting, as was the transmission of microbial agents, including what were known at the time as the �slow viruses.�� He also says:

�I am asked by the Inquiry whether I have any recollection of Dr Little mentioning BSE to me at this meeting, whether formally or otherwise, I have no such recollection and I am as confident as I can be that no such mention was made to me�.[225]

188.         Dr Jefferys said in his statement:

�I understand that there has been a suggestion that the issue of an emerging problem with BSE might have been drawn to the attention of DHSS at a meeting of the Biologicals subcommittee held in Market Towers in September 1987. I have no recollection of this. There is no mention of it in the minutes of the meeting, nor in subsequent minutes of the CSM to whom the subcommittee reported� If mention was made of an emerging problem in the margins of the meeting, one would still have expected this to have been followed up with a formal letter. In addition, if it was raised at the meeting I would have expected its omission to have been corrected in the minutes or at subsequent meetings of the Biologicals subcommittee or the CSM. However, it is not mentioned in the minutes of subsequent meetings of either of those committees.�[226]

189.                    Dr Little also recalls that he had an informal discussion on the subject of BSE at the end of the meeting.[227]

190.                    Dr Little has given further evidence on this informal discussion at his oral hearing. He was asked about who was present for the discussion about the specific product, and the implications of BSE to it. He replied:

�The real answer is I cannot remember.� At the end of the meeting I spoke to Gerry Collee, and when I spoke to him about it -- and I spoke to Paul Adams.� We were all congregated at the end of the table. Whether they overheard the conversation with whoever it was about the product or not I could not be certain at this point in time.�We were all together at the end of the table, at the end of the meeting, having a discussion.� They may not have heard.� It is quite possible they did not.� They may have left.�[228]

191.         In relation to the BSC meeting on 9 September 1987, Dr Little also says:

�I recall that after the meeting was formally concluded, but before everyone had dispersed, someone approached me from the Department of Health ("DoH"), whom I now deduce must have been Mr Sloggem.� He informed me that a product consisting of an extract of bovine brain was currently under review and that he was aware of the BSE problem, and had concerns about it in relation to this product.� He also told me that someone from DoH would be writing to MAFF about these concerns.�[229]

192.         Mr Sloggem has said that he was interested in the discussion of possible transmission of CJD by dura mater products because of his previous work in connection with human growth hormone and transmission of CJD.[230]� He comments:

�I do not recall Dr Little contributing to that discussion or mentioning BSE during any such discussion. I had not met Dr Little prior to 9.9.87 and until my attention was drawn to the minutes of the BSC meeting of 9.9.87, did not recall that he had attended that meeting.

Before receiving the Inquiry�s letter of 9.7.99 with the enclosed copy transcript of Dr Little�s oral evidence given on 7.7.99 and his second supplementary statement I had no recollection of any discussions at the 9.9.87 BSC meeting.� Having now read the minutes and these documents I only recall matters as indicated above.� Certainly if there had been a discussion of the kind Dr Little suggests took place I believe that what he has said about it would have jogged my memory.

My comments above about my lack of recollection of what Dr Little describes need to be placed in context.� I note, in particular, that he said in his evidence that he recalled a specific discussion about a bovine brain product and the risk from BSE in relation to it.� I note also that while in oral evidence he said that somebody said �they� would be writing to MAFF, in his supplementary statement he said first that I said to him that �someone from DH� would be writing to MAFF about BSE concerns in relation to the product I was assessing (paragraph 19) and secondly that I said I personally would contact MAFF in relation to my concerns (paragraph 22).� I believe that I would have said none of these things.

If I had discussed with anyone the bovine brain extract product which I was then assessing with input on BSE from Dr David Taylor at NPU, it would have been with my line manager, Mrs Glenda Sylvester, who also attended the BSC meeting on 9.9.87 and with whom, as the product file demonstrates, I had discussed the product on 24.7.87.� I had no authority to say that I or anyone else within DH would write to MAFF about a general scientific issue.� In connection with my assessment of the bovine brain extract product I was already, by 9.9.87, communicating with Dr Taylor on the issue of �bovine slow virus��

�

On 9.9.87 there was no reason for me to talk to Dr Little, whom as I say I had never met, about the product I was assessing.� I had obtained the information about the bovine slow virus which I needed directly from Dr Taylor.

�

It seems to me that communication within NPU could have led to the fact of my concerns about bovine slow virus, in relation to the product I was assessing, becoming known to Dr Little and others in MAFF.� Certainly the BSC itself was not, by 9.9.87, aware of the bovine brain extract product I was assessing and which was presented to it for the first time in January 1988.

�

I had, by 9.9.87, formed the impression from my contact with Dr Taylor that the bovine slow virus issue was a matter which was not widely known and should not be publicised.� I do not believe that I would, therefore, have felt it open to me to approach someone I had not met before,� ie Dr Little, to tell him about what I knew.� Neither, as I have explained above, would it have been open to me to suggest that either I or someone else within DH would write to MAFF about the subject in general.� I had already involved NPU and obtained the information I needed from Dr Taylor to put the issue to BSC in my paper on the bovine brain extract.�Furthermore I agree with Dr Little that an issue of this significance would have been expected to have been dealt with at a more senior inter-departmental level.�[231]

193.         On 10 September 1987 Dr Bill Watson, Head of Central Veterinary Laboratories (CVL), wrote to Mr Rees the Chief Veterinary Officer (CVO)� [232]saying, in relation to BSE, that the CVO would wish to consider the addition of the following information in a submission to the Minister of which he had previously submitted a draft:

�DHSS are aware of the problem. Concern is being expressed about the possible human health risks due to products for human use which contain an emulsion of bovine brain.�

The minute went on to say:

�This matter was discussed by Dr Little with DHSS colleagues attending the Committee of Safety of Medicines Sub-Committee Biological Products on Wednesday, 9 September, and I understand that they will be writing to us.�

194.         Dr Little comments in his supplementary statement:

�I have seen a minute from Dr Watson to Mr Rees dated 10th September, 1987. I believe the minute accurately reflects what I told Dr Watson. It was my understanding that someone from the Department of Health would be writing or otherwise getting in touch with MAFF to discuss their concerns.�[233]

195.         On 14 September 1987 a meeting took place at the NPU between Dr Watson, Dr Dickinson, Dr Kimberlin and Dr Hope.� A file note prepared by Dr Watson on 16 September 1987 records:

�Obtained details of the brain treatment with lecithin prior to use orally in treating patients with neurological disease.

The following day briefly discussed matter with Peter Biggs.�[234]

196.         On 1 October 1987 Dr G Wood signed a commercial in confidence paper about �the possibilities of contamination of hormone preparations, produced by genetic engineering, by unconventional slow viruses (spongiform encephalopathy agents)�.[235] The paper said, on page 2:

�Having considered spongiform encephalopathy agent contamination purely in the context of genetic engineering and its products, there remains the broader likelihood of contamination by such agents in any product incorporating substances of animal origin in their production or formulation, including genetically engineered products (for instance, possible serum components in bacterial culture media).

To avoid the possibility of contamination by unconventional slow viruses, the following suggestions may be of value.

1.��� Do not use material direct from animals (particularly from neural tissues).

2.��� If using genetic engineering, take only the information from the animal, not the informational molecule, and construct the gene sequence from the amino acid sequence of the purified natural product.

3.��� Do not use substances of animal origin in growth media for novel host organisms when producing substances by genetic engineering unless they can possibly be avoided.

4.��� Do not use animals, particularly mammals, as the novel host organism.

�

There are, apparently, still some barriers to free exchange of information and queries with the companies involved or with their suppliers.� Eventually, when fuller information can be obtained, it may be possible to be more assured of the safety or otherwise of these products w.r.t. contamination by pathogens.�

197.         In December 1987 Mr Peter Luff, from the Biological Products and Standards (BPS) Department in the Central Veterinary Laboratory (CVL), prepared a document entitled �bovine spongiform encephalopathy � implications for biological products�. The paper was based on the assumption that BSE was caused by an unconventional scrapie-like agent which had spread within the UK cattle population and that the most likely source was meat and bonemeal containing sheep by-products incorporated into cattle and in particular calf feed. Mr Luff set out what he saw as the three main approaches to containing the potential BSE threat, of which he considered only the third to be viable. The approaches were as follows:

�1.�� Everything derived from cattle represents a potential BSE threat. The use of such substances is not permitted unless they have undergone a process to inactivate this agent. The only acceptable treatment is two cycles of autoclaving at 126 C (20 psi) for 30 minutes with cooling to [less than] 35 C in between.

This will effectively stop the use of bovine serum and cell cultures in vaccine production, and the use of therapeutic bovine anti-serum. Serum albumin will also be adversely affected.

2.��� Tracing techniques could be used to designate acceptable sources for bovine products.

At the present state of the epidemic this approach is unusable as the picture is changing almost daily. Even if sufficient data were available, the logistics of collecting serum, for instance, would be unworkable in practice.

3.��� Risks should be assigned to particular products or groups of products, and action taken against these as necessary in light of the knowledge about the scrapie agent in natural and experimental hosts. There is a risk involved with this approach as there may be subtle differences between the distributions of BSE and scrapie agents, and knowledge of scrapie is anyway incomplete. However, the risks associated with reliance on imported substances are probably greater. As a general rule, the harvesting of any substance from suspected or confirmed cases should not be allowed. Also, it should be remembered that there is no possibility of testing production components or final product for the presence of BSE agent.�[236]

198.         The paper prepared by Mr Luff then considered particular bovine products and their associated risks. He made the following points[237]:

�a)�� SERUM AND SERUM PRODUCTS: There is no evidence that serum from scrapie infected animals contains any infectious agent, although many attempts have been made. It seems reasonable to assume that the use of these substances is not associated with a risk of BSE agent contamination.

It may not be unreasonable, though, for manufacturers to use for anti-serum production only animals with the lowest risk of exposure to the BSE agent. At the present time this means those derived from suckler herds not feeding concentrates, and with no history of contact with BSE.

b)��� OTHER TISSUES: Tissue distribution of scrapie infectivity is uneven. Maximum titres occur in neural and �lymphoid� tissues. Lower amounts occur in placenta, salivary and adrenal glands, pancreas, liver (from work in sheep and goats), lung, kidney, intestine and uterus (from additional work on mice). The use of these tissues should be firmly discouraged. If such use is necessary, then the product should be treated as 1 above.

Traces of scrapie agent have also been isolated from muscle late in the incubaation (sic) period of the disease. This constitutes a smaller risk, given the low titre and short duration of its presence. A single cycle of 126 C for 30 mins is probably adequate treatment for such products, which tend to be the somewhat diverse �peptones� used in bacteriological media and sometimes as freeze-drying stabilizers.

There are two special cases to consider � hormones and similar extracts, and cell cultures.

HORMONES etc: Although the extraction processes involve the use of various organic solvents, which tend to have a deliterious (sic) effect on scrapie infectivity, extracts must be considered to be potentially contaminated � indeed Creutzfeld-Jackob disease has been transmitted by the use of human growth hormone extracted from cadaver pituitaries. It is therefor (sic) not possible to regard bovine gland extracts as deserving special consideration; they must be autoclaved as above. Such products are not likely to be effective after such treatment. The use of pituitary extracts for super-ovulation is not apparently controlled under the Medicines Act. This is an anomaly which requires urgent reconsideration.

CELL CULTURES: Primary cell cultures could transmit an unconventional agent mechanically. Their use should not be permitted. Given the probability of vertical transmission, it is not possible to set up �SPF� herds to get around this problem. Cell lines are a different matter. No unconventional agent has been grown in cell culture. It seems reasonable to assume that the agent of BSE will not replicate in cell cultures either. There is also no evidence that whatever constitutes a �genome� in these agents can integrate into host cell genome, so the danger in the use of cell lines is again one of mechanical transmission. With the number of passages required to produce a validated cell line there seems to be no real need to impose any general BSE-related requirements. This is, of course, a theoretical argument. Given that the risk, regardless of its absolute size, will be related to the degree of contamination of the original tissue, the use of cells derived from tissues that could carry a high burden of infectivity (neural and �lymphoid�) should not be allowed.

c)��� SECRETIONS and EXCRETIONS: Scrapie agents have not been isolated from any natural secretions or excretions. This includes saliva, milk, urine and faeces. It seems reasonable to regard these materials as not constituting a BSE-related risk. However, it is assumed that one way that scrapie is spread is through the ingestion of infected placentae, with the agent passing through the gut and being excreted in faeces. It may be possible to question the use of bovine faeces, or at least products derived from them. This has implications for lung worm vaccines. Calves, though, are not major consumers of placentae, and they are maintained in quarantine for a period before use, so there doesn�t seem to be an appreciable risk.

The situation with bile may not be so straightforward. I don�t know that bile has ever been looked at for scrapie infectivity. One could argue that the absence of agent in faeces suggests that it isn�t present in bile, but that there must be a considerable dilution effect. It is probably better to err on the safe side and a require a single 126 C, 30 min cycle for this substance.

d)��� OVA and SPERM: The situation here is uncertain, but of no direct concern for biological products in Medicines Act terms. However, the areas of AI and embryo transfer require some investigation.�

1988

199.         Dr Rotblat said in her Statement to the Inquiry that she first became aware of a scrapie-like disease in cattle around January 1988. She said that:

�At around this time the Biologicals subcommittee was considering a Clinical Trial Certificate (CTC) application for an oral medical product containing an extract of bovine brain. I did not handle this application which was dealt with by Dr Hilton amongst others. The CTC was refused and the company later withdrew the application. However, for the purposes of considering the application my pharmaceutical colleague, Mr Sloggem, had previously enquired of the Edinburgh Neuropathogenesis Unit whether there was a bovine equivalent of scrapie and had been told that there was. Mr Sloggem mentioned this to me informally at around this time in the course of discussions about the CTC application. The impression which I received was that the scrapie-like disease was a long standing albeit rare disease in cattle; I did not get the impression that it was a new disease. Dr Taylor�s short letter was subsequently included in the papers that went before the Biologicals subcommittee. It should be noted that Dr Taylor�s letter did not specifically refer to BSE and contained very little scientific information about the nature of the scrapie-like disease.� [238]

200.         On 6 January 1988 the CSM Biologicals Sub-Committee met.[239] The minutes of the meeting show that an application by G[240] was considered. This was the product that contained animal brain that Mr Sloggem had corresponded with Dr Taylor about in July and August 1987. The minutes do not record any discussion of BSE.� At its meeting on 25 February 1988, the CSM considered the Biologicals Sub-Committee�s conclusions and agreed with the BSC in advising against the issue of a CTC for the product.[241]

201.         Professor Collee said in his Statement to the Inquiry that he remembers the Committee on Safety of Medicines (CSM) Biologicals Sub-Committee considering a product containing emulsion of animal brain on 6 January 1988. He states

�From the record of product applications made to the Biologicals Sub-Committee I note that on 6th January 1988 an application for a clinical trial certificate was submitted in respect of certain capsules. The paper which accompanied that application, prepared by John Sloggem, contained a reference to recent reports of a slow virus type syndrome in cattle and referred to the issue of slow virus transmission which this type of syndrome in cattle might raise. I believe that this reference was the first that I had seen to the condition that subsequently came to be known as BSE.

The product itself was unusual in that it contained bovine brain phospholipids as an active constituent. This would have given rise to concerns about its use on grounds that were distinct from any question of slow viruses. Any preparation that used animal brain as an active constituent would require meticulous scrutiny so as to ensure that appropriate safeguards against potentially contaminating conventional infectious agents were in place. Brain components are protective against sterilising agents and it would be difficult to sterilise an emulsion of bovine brain without destroying at least some of its supposed biological properties.

In relation to this product, the Sub-Committee were asked to advise whether viral inactivation studies should be carried out with specified organisms and whether slow virus transmission was considered a problem.

The Sub-Committee�s advice was to the effect that it was concerned about possible infection with transmissible agents and that validation of the extraction process to show the removal of slow virus derived from the starting material should be undertaken and the results reported when available. The Sub-Committee considered that studies using suitable hardy viruses and spiking experiments should be undertaken and reported. The product was refused a clinical trial certificate because of these concerns and for several other reasons as well.� [242]

202.         In relation to the product considered at the 6 January meeting, Dr Jefferys says:

�The product under consideration was already both widely available and used in many parts of Europe at the time. It was never even allowed for Clinical Trials in the United Kingdom, but subsequently ran into adverse reaction problems and was withdrawn in other parts of Europe.� All this was well recorded in the public literature.� I make this point because I think it can be seen that Mr. Sloggem had very diligently made an assessment and raised a matter of concern which was thoroughly debated and endorsed by the Biologicals Sub Committee and by the CSM.�[243]

203.         On 6 January 1988 there was also a meeting of the Veterinary Products Committee (VPC) Biologicals Sub-Committee. The minutes indicate that the following was discussed:

�8.2 Bovine Spongiform Encephalopathy

1)��� A draft paper from BP&S entitled Bovine Spongiform Encephalopathy � implications for biological products was tabled.

2)��� After a brief discussion it was agreed that an amended paper should be distributed to all members for discussion at the next Biologicals meeting.�[244]

204.         On 3 February 1988 the VPC Biologicals Sub-Committee considered a paper on the implications of BSE for Biological products (prepared by Peter Luff, from BPS CVL, and referred to at paragraphs 197 and 198 above, but subsequently amended) [245]. The minutes of the meeting show:

�7.4 The paper outlined three options:

1. All vaccines containing bovine products should be heat treated for 2 cycles of 126�C for 30 minutes. This was considered a severe untenable option as it would affect virtually all product licence holders;

2. Vaccine manufacturers would only use bovine products from herds, certified as free of clinical disease.

This option was considered a satisfactory option by some members of the committee.

3. All bovine tissues should be assigned to different risk groups and each group would be treated separately.� The suggested groups were based on work that had been generated using the scrapie agent. There was concern about the use of brain, neural and lymphoid tissue and pituitary. (It was noted with concern that hormone extracts could be manufactured by a veterinary surgeon for administration to animals under his care without any Medicines Act control). Use of these products should be discouraged. Conversely serum products were considered to be of little concern.

This option was considered the most appropriate by some members of the committee.

7.5 After considerable discussion it was agreed that no action be taken at present but that the situation should be reviewed again in six months time unless any new developments within that time required urgent action.�

March 1988

205.         On 2 March 1988 the Biologicals Sub Committee of the CSM met.[246]

206.         On 3 March 1988 Mr Derek Andrews, the Permanent Secretary of MAFF wrote to Sir Donald Acheson, the Chief Medical Officer (CMO), telling him about BSE.[247] Sir Donald in his Statement to the Inquiry said this was the first time that he was told about BSE.[248]

First reactions

207.         On 17 March 1988 Dr Watson and Mr Alastair Cruickshank, Under Secretary of MAFF, attended a meeting with the CMO and senior medical officials at the DHSS to discuss BSE.[249] The minute of the meeting records:

�6.�� Biological products were produced of bovine origin and this applied to a significant proportion of insulin despite genetically manufactured sources.� In addition, cell cultures for many vaccines used a bovine serum medium.� Dr Harris undertook to speak to the Director of NIBSC about biological products.

�

13.�� Mr Cruickshank thought it necessary to assess the risk in humans in order to justify the cost of any control measures taken by MAFF.� Although it would be possible to monitor diabetics, it could take 20 years or more before we would be able to assess whether any risk existed from bovine insulin.� In the meantime, with some 40 or so new cases in cattle a month, the disease would become newsworthy and it was important that both government departments arrange appropriate action before this happened.

14.�� In conclusion it was agreed that urgent advice was necessary on biological products and the disposal of sick animals.� The options would be outlined to Ministers (of both government departments) and they would be asked to agree the setting up of an expert advisory group.�

208.         A note on the meeting written by Mr Cruickshank states:

��After some discussion of the data provided by CVL, it became clear that all those present found it very difficult to give any clear advice on the subject. The meeting appeared to be tending towards the view that there is probably no risk in drinking milk or eating flesh from animals affected with BSE, but that the position was much less clear in relation to brains, spleens and other organs. This raised questions about the safety of human vaccines prepared using bovine material.�

The CMO concluded the meeting saying that �he suspected there was no risk, but that it could take 30 � 40 years to prove this.�[250]

209.         It was agreed that urgent advice was necessary on biological products and the disposal of sick animals.[251] It was thought that Ministers should be advised to set up an expert committee who �should meet two or three times and examine all the information available�, and provide advice to Agriculture and Health Ministers. The minute stated that the Committee �might be asked as a priority to advise on the use of bovine material in manufacturing vaccines...�[252]� The CMO later recommended that the working party should be chaired by Sir Richard Southwood, Professor of Zoology at Oxford University.[253]�

210.         On 21 March 1988 the CMO briefed Health Ministers on BSE. In his oral evidence to the BSE Inquiry Sir Donald recalled that it was Lord Newton, Minister of Health, who received this briefing.[254]� Later in his oral evidence he explained,� ��I was concerned about biologicals from the beginning and that is indicated in my minute to the Minister after my meeting on 17 March, it was specifically mentioned.�[255]�� In this minute the CMO said:

�Their [officials from MAFF, PHLS & DHSS] unanimous view, with which I concur, is that, although a risk to human health through the consumption of milk or meat from infected cattle or through the use of bovine tissue-based biologicals in the pharmaceutical industry is likely to be low, in view of the lethal nature of the virus and the uncertainties, further expert advice is needed as soon as possible.�

The CMO sought agreement from Ministers for the setting up of an expert group advising on the implications of BSE for human health and any preventative action that could be taken as a result of its findings.[256]� The Minister agreed.

211.         On 24 March 1988 the CSM held a meeting.[257]

212.         On 4 April 1988 Mr Hagger sent Dr Jefferys a copy of the CMO�s submission to Ministers.[258]

213.         On 11 April 1988 Mr Wilson, Grade 3 Administrative Head of Medicines Division, minuted Dr Jefferys on the subject of BSE.[259]

214.         On 13 April 1988, Dr Jefferys replied to Mr Wilson.� He concluded that he �would be happy to look into the matter further if you wish but my view at present is that we should await the deliberations of the proposed expert group�[260] before taking any further action on the matter of bovine tissue based biologicals in the pharmaceutical industry. In coming to this view he wrote:

�I would have thought that the risk of infection and the transmission of BSE from the use of bovine tissue based biologicals in the pharmaceutical industry is likely to be less than that from infected food products. I base my views on the facts that much smaller quantities of biological materials are used in pharmaceuticals than would be ingested, and secondly that since the virus particles are resistant to heat, then they will not be inactivated by cooking, etc. For recent products we have taken a very stringent view on the quality control to avoid the risk of transmitting infection. We have demanded �spiking� studies with hardy viruses (these are rather similar to the scrapie virus).

There are still a significant number of older products which are subject to the review procedure.� I understand that these are likely to be reviewed in the next year.� It might be worth asking Dr Wood to comment on the approach that will be taken to the review of these products.� [261]

215.         Dr Jefferys notes in his statement to the Inquiry that in Medicines Division �the agreed approach was to await the findings and report from the Southwood Working Party before finalising our advice on BSE and medicines.�[262]

216.         In paragraph 5 of the 13 April minute Dr Jefferys said� �A further final thought is that recently we have required certificates that the animals from which biological products are derived are healthy.�� In his Statement to the Inquiry Dr Jefferys said that[263]: �I believe that it is likely that the certificates mentioned in paragraph 5 of my minute would have been certificates from veterinary practitioners verifying that the animals from which biological materials were derived were healthy�. He was unable to recall what would have constituted a healthy animal. A handwritten minute from Mr Wilson to Dr Jones on the face of this minute, says� �You will wish to see and perhaps show to Dr Wood.� Subject to that I would go along with 6 below� (which said that the Medicines Division should await the deliberations of the proposed expert group.)[264]

217.         On this paragraph Dr Jefferys also notes:

�Paragraph 5 of my minute was intended to inform Mr. Wilson, at that time the senior administrator of the Medicines Division, of a requirement which was being made by pharmacist colleagues in Medicines Division in conjunction with outside experts. �As stated in paragraph 60 of my witness statement, (WS No 419) this minute was �an immediate and initial response� to a request from Mr. Wilson and should be read as such.� In addition, I should emphasise that within Medicines Division this issue would have been handled by pharmacists and the Pharmaceutical Secretariat to the Biologicals subcommittee rather than physicians because it concerned the quality of the materials used in the manufacture of medicines.� [265]

218.         In his Statement to the Inquiry Dr Jefferys stated that at this time,� �work was commissioned from across the Division to determine the extent of usage of bovine material both as an active ingredient and as an excipient or as an intermediate in the manufacturing process.�[266]

219.         Dr Jefferys has commented further:

�Although I have no recollection now of discussions and meetings that took place during this period, I am as sure as I can be that BSE would have been discussed at a senior management level within the Division. It seems to me highly probable that it featured at the monthly Divisional management group meetings co-chaired by the SPMO (Dr Gerald Jones) and the Grade 3 administrative head of the Division (Clive Wilson) part of the purpose of which was to consider emerging issues. Certainly I think the divisional view was that BSE raised highly technical issues on which specialist expert advice would be required and that we should await such advice.�[267]

220.         On 28 April 1988 the CSM met.[268]

221.         On 4 May 1988 the Biologicals Sub-committee of the CSM met.[269]

222.         On 16 May 1988 the National Institute for Biological Standards and Control (NIBSC) held a preliminary meeting on the subject of BSE and biological medicinal products for human use.[270] Mr Wilesmith, the epidemiologist from CVL who was investigating the origins of BSE, and Dr Richard Kimberlin, an expert in TSEs from the Neuropathogenesis Unit (NPU), attended.

223.         Dr Little explained the role of the NIBSC in his supplementary statement to the Inquiry:

�The NIBSC operates under the Biological Standards Act 1975 and the National Biological Standards Board (Functions) Order 1976. It reports to the Department of Health and is the body responsible for research and statutory testing of biological products for human use. Its aim is to safeguard and enhance public health through the standardisation and control of biological substances used in medicine.�[271]

224.         A note of the 16 May 1988 meeting records that those present concluded:

�Bovine spongiform encephalopathy presents features suggesting that it is caused by a scrapie like agent although this is not yet unequivocally proven. The incidence varies geographically with a lower incidence in the North. In the absence of data on transmission the properties of the agent are expected to be similar to those of the causative agents of scrapie and Creutzfeldt-Jakob disease, which are, in practical terms, undetectable by existing technology and cannot be selectively destroyed, although they may be removed. If BSE is held to be a problem, the only option is to ensure that bovine materials for manufacture of biological medicinal products are derived from cattle in areas free of the disease.

It is possible that transmission to humans many not be readily effected under existing conditions. This statement is based on experience with scrapie which is unlikely to cause a disease in humans under natural conditions, and in particular has been shown to be epidemiologically unlinked to Creutzfeldt-Jakob disease. There is no evidence for transmission of scrapie to occupational groups such as shepherds and veterinarians which have high exposure to sheep and scrapie infected sheep.� This is true for research workers and abbattoir [sic] workers or butchers, where there may be exposure to brain tissues. The tissue distribution of infectious agents may also act against ease of transmission. In particular serum is a poor source of infectivity in animals infected by scrapie. Vertical transmission of acquired Creutzfeldt-Jakob disease, kuru or BSE has not been demonstrated. Transmission of scrapie from infected ewes to their lambs occurs with relatively high frequency, however, implying possible transplacental spread or transmission via milk. It is thus possible that BSE poses no real threat to human health provided the main exposures are either as a contaminant of food stuffs which will be minimised by inspection of animals, or from products which are not contaminated with nervous tissue. The information on which to base a decision is however extremely sparse.�[272]

225.         Those at the meeting recommended further action to be taken in this area. It was agreed that studies should �be set up involving NIBSC and Wellcome Biotechnology and other parties to attempt to demonstrate the presence of scrapie-like agents in calf serum by inoculation into mice and hamsters and other species.� It was acknowledged that such experiments would be very lengthy. It was also agreed that �Consideration should be given to a survey of licensed products in respect to the use of bovine or ovine material in their manufacture, and the origin of the bovine or ovine materials.�[273]

226.         On 19 May 1988, the issue of bovine products in pharmaceuticals was raised at a meeting between Sir Derek Andrews, Permanent Secretary at MAFF, the CMO and Sir Richard Southwood, proposed chair of the working party on BSE. The CMO thought Sir Richard�s committee should consider, � The risks inherent in using bovine material in the preparation of biologicals.��� He went on to comment that� ��urgent advice on the question of the manufacture of biologicals from cattle material.� would be needed.[274]

227.         The minutes also record that Sir Richard indicated to the CMO that he hoped to be able to come forward with an interim report by early October. The CMO said that he would want advice as soon as possible on whether there were any steps that needed to be taken to safeguard human health.

228.         On 20 May 1988, Dr Pickles minuted Mrs J Alderman[275].� The minute said:

�2.�� The tissues most likely to be affected are brains.� Are there any licensed products for human or veterinary use made from bovine or sheep or goat brains?� What about rabies vaccines, or some of the unreviewed homoeopathies?

3.        There is the wider question of whether other tissues could carry the agent.� After brain, the next most likely tissues are lymph nodes or placenta.� Again, what licensed products for human or veterinary use are there made from bovine or sheep lymph nodes/placenta?

4.        I do not know how sophisticated your record system is these days, but would it be feasible to list those products that involve bovine tissue during manufacture, eg bovine serum albumin in vaccine production?�

229.         On 20 May, Dr Pickles minuted Dr Jefferys[276] in the following terms:

�Bovine Spongiform Encephalopathy

1.��� I believe you know that there is a joint MAFF-DHSS group looking at this problem. I have now been roped into the secretariat.

2.��� We would like to be sure that possible transmission through medicinal products can be ruled out for both humans and animals. Some positive evidence that it appears not to have been so transmitted would be nice. Since we know so little about BSE, we may have to look at scrapie, which is endemic in UK sheep. Is this a problem you should put before biologicals sub-committee?

3.��� Questions for them might be:-

������������� -��� are there any products prepared from bovine or sheep brain which need to be looked at? If rabies vaccine has been made using sheep/goat brain, are there adequate human follow-up data to be sure no viral infections might have been transmitted?

������������� -��� Can we assume that the �dose� of any infectious agent administered in non-parenteral medicinal products would have been so small in comparison with doses from food that such products need not be considered further

������������� -��� Are there any bovine (or sheep) materials used in production processes of parenterals that might be capable of introducing an infectious agent (eg bovine serum albumin in vaccine production, or bovine insulin)?

4.��� We have no evidence that BSE can be a risk to humans. If, however, we could identify a group of people who might have received parenteral �BSE agent� through medicinal products then they would be a group that might warrant special study.

5.��� I note in your minute of 13 April you take some reassurance from recent requirements that animals used in production of biological products should look healthy and be certified as so. With a long-incubation infection (currently thought to be 2 to 6 years) lack of physical signs cannot be taken to signify freedom of disease. So we cannot be sure.

6.��� May be [sic] you would like to discuss this with me. If you do put the problem to Biologicals Sub-Committee, please involve me if you can.�

230.         On 23 May 1988, Mrs Alderman replied to Dr Pickles� letter of 20 May stating that she had been able to retrieve two computer printouts of products from the database because the constituents had the word �bovine� in their names.� She continued, �This was, unfortunately, the only way to do it.�[277]

231.         On 24 May 1988 Dr Jefferys replied to Dr Pickles.[278] He said that the CSM Biologicals Sub-Committee had not formally discussed the matter but had done so informally whilst assessing an individual application: �For some months now the Sub-Committee have been regularly requiring appropriate �spiking� studies to be undertaken with hardy viruses and these would include bovine products.� Therefore he felt �reasonably confident about taking appropriate action for the new products.� He thought that �the major concern here is with the parenteral products.�

232.         His minute continued:

�4. With regard to previously licensed products, then we have no evidence of hazard, but clearly we cannot provide reassurance given the timescale for possible incubation and infection.

5. As you will be aware from your previous work with the Review, many of the older products are PLRs (since many of the biological PLRs still have not been reviewed). I am therefore copying this minute to Dr Wood since she will need to take account of this during the review of these products.

6. Oral Products

As I previously stated, I would have thought the risk from oral medicinal products must be very small in comparison to the risk from food. I base this on the assumption that the infectious agent is probably not heat-sensitive and therefore will not be removed by normal cooking.

7. Parenteral Products

I accept that there may be a different consideration of parenteral products. I presume that the major agents would be bovine insulin, and bovine serum albumen in vaccine production. If you were looking for a group of people to study, then I would have thought those who have received bovine insulin might be the most appropriate group. I suppose it might be possible to undertake a retrospective study comparing those who have received bovine insulin versus those who have received porcine or ideally human insulin. I presume the endpoint would have to be the development of an encephalopathic syndrome. The danger in constructing such a study would be the scientific risks of confounding, etc. and the political risk of worrying large numbers of diabetic patients.

8. These thoughts are very preliminary ones.� It also occurs to me that this is more of a long term issue and that it may well involve William Jenkins since this is rather more an ADR problem than a New Drugs Group issue.� I am therefore copying your minute to him.� It may be appropriate for Sue Wood, William and I to have a discussion with you at a mutually convenient time.�

233.         In his Statement to the Inquiry Dr Jefferys commented on his minute of 24 May 1988:

�In my minute, I set out some preliminary thoughts on the issues raised. I focused primarily on previously licensed products and said that with respect to them, we had no evidence of hazard, but I recognised that we could not provide reassurance given the timescale for possible incubation and infection. I thought that the risk from oral medicinal products would be very small in comparison to the risk from food. The major concern was with parenteral products, the major agents being bovine insulin and the use of foetal calf serum and bovine serum albumen in vaccine production (although neither foetal calf serum nor bovine serum albumen were used as active ingredients in vaccines). This reply reflected the consideration which had been given to this matter during the months of April and May.�[279]

234.         On 25 and 26 May 1988 the CSM met.[280]

235.         On 2 June 1988, Dr Pickles responded to Mrs Alderman requesting a further database search and asking about bovine insulin, which was not on the list of products, although licensed.� She also asked about the species used in the manufacture of any licensed rabies vaccines.[281]

236.         Mrs Alderman replied on 3 June 1988, listing products containing� bovine insulin and noting there were two rabies vaccines listed but the species used in manufacture was not shown.[282]

237.         On 6 June 1988 Mr Lawrence wrote to Sir Richard Southwood and enclosed some brief answers to the questions that had been tabled at the meeting on 19 May.[283] In relation to Q6, which asked �What is meat and other material from scrapie infected sheep used for - does it include pet food and material for biological products?� Part of the answer stated:

�There has been one instance of inadvertant [sic] transmission of the scrapie agent to sheep through louping ill vaccine (Gordon, Bronlee and Wilson 1939). One of the three batches of vaccine made in 1935 at the Moredun Institute contained the scrapie agent resulting in 7% of the recipients of the 18, 000 doses in the batch developing scrapie. This vaccine was made from formalin-inactivated sheep brain, and brought to the attention of research workers that formalin, at a concentration of 0.35% for at least 3 months, which inactivated conventional viruses, did not totally inactivate the scrapie agent.

It would appear that companies producing biological products take sensible precautions to exclude the use of tissues and fluids from scrapie infected animals.�

Answers to other questions also included references to biological products.

238.         On 7 June 1988 the VPC Biologicals Sub-Committee met. The minute of the meeting records that on the issue of BSE members noted �the disease would become a notifiable disease from 1 July 1988� and agreed that the BP&S document, first discussed at the January 1988 VPC Biologicals Sub-Committee meeting, should be re-examined and a set of guidelines drawn up for the industry. A meeting between Medicines Unit, BP&S and CVL experts on the disease would be arranged as soon as possible to discuss guidelines.[284]

239.         On 8 June 1988 a meeting was held between the Medicines Unit in MAFF, Biological Products and Standards Department(BP&S), and CVL to discuss the implications of BSE for biological products containing bovine extracted material.[285] Dr Little chaired the meeting, and also present were Mr Bradley, Mr Dawson, Mrs Evans, Mr Gray, Mr Kidd, Mr Luff, Dr Thornton, and Mr Wilesmith. The meeting discussed bovine biological products and the following bovine tissues used in biological products: serum; peptone/meat digest; pituitary extract; beef brain and brain infusion broths; tissue cultures derived from bovine tissues; ox bile and faeces. The recommendations of the meeting were as follows:

�Recommendation

The greatest concern was the use of pituitary gland products. It was agreed that the Medicines Unit should prepare a paper to advise Animal Medicines Division, Tolworth on the course of action to be taken.

It was agreed that BP&S should draw up a full list of all the tissues involved in biological products. Medicines Unit would produce a list for pharmaceutical products. A chart of risk assessment should be made for each of the tissues in relation to the products, together with appropriate treatments for each tissue.

It was agreed that some form of guidance should be given to companies at the next NOAH meeting of 11 July.�

240.         On 10 June 1988 Dr Little, Deputy Director of CVL sent a minute to Mr Kyle, a Veterinary Surgeon at MAFF, about the use of bovine tissue in veterinary medicines.[286]� He said �We are urgently reviewing all users of bovine tissues, sera, etc. in veterinary medicines to determine what risks exist in relation to BSE, what action we need to take under the Medicines Act and what advice we can offer to manufacturers.� He also noted �[s]ome veterinary surgeons are quite legally using this exemption from the Medicines Act contained in Section 9(2) to prepare gonadotrophins from pituitary glands from various species, including cattle.�

241.         Mr Wilkes replied to Dr Little�s minute of 10 June 1988, which he was copied, on 13 June 1988.[287] He pointed out that there was a small loophole that could allow the use of uncontrolled bovine pituitary extract.� He concluded:

�We might be able to block that loophole by a ban on sale or supply on grounds of safety�but I would think that you would want statutory provisions to bite on either collection of material or on administration of the product.� For that purpose animal health legislation might provide a better bet.�

242.         Mr Kyle replied to Dr Little on 14 June 1988.[288]� He noted that animal health legislation was unlikely to assist and suggested that advice be taken from the Legal Branch. If they could not provide a solution, voluntary compliance should be sought from veterinary surgeons.

Southwood Committee: first meeting

Note:� Further information on this topic is available in RFA 1 � The Southwood Working Party (and update).

243.         On 20 June 1988, the Southwood Working Party met for the first time. The members of the Southwood Committee were Professor Sir Richard Southwood, Professor Epstein, Dr Martin and Sir John Walton. Mr Wilesmith attended as an expert advisor. The joint secretariat was Dr Pickles from DHSS and Mr Lawrence from MAFF. Bovine material in pharmaceuticals was discussed.[289]� It was noted that cattle material had been used thus far instead of sheep because of scrapie. The laboratory use of foetal calf serum was also mentioned as a potential health risk. It was agreed that Dr Pickles would make enquiries into the use of bovine materials in pharmaceuticals.

244.         On 20 June 1988, Dr Pickles minuted Dr Lewis, at the time Private Secretary to the Chief Medical Officer, telling her that Dr Martin, who was also a member of the Medicines Commission, would be raising the matter informally with Medicines Division. She advised that since the next meeting was a long way off she had promised to make further enquiries into the use of bovine materials in pharmaceuticals. She also noted that she had written again to Medicines Division suggesting formal discussion of the problem at CSM or a sub-committee.� She said that because much of the relevant information was protected by the Medicines Act, there were limits to what she could do herself.[290] She said in paragraph 4:

�The next move was for Sir Richard to write to Andrews (copied to CMO) with the preliminary views.

������������� i)�� known affected cattle should not be allowed to enter the human food chain, nor to be processed for pet food.[ A compensation scheme would be needed to optimise compliance]

������������� ii)� additional transmission experiments are clearly needed, for example using meat and bone meal from scrapie sheep and using scrapie milk.

������������� iii) an expert working party, preferably under the auspices of the MRC, should be set up to look at a research programme to answer the questions we have identified.

������������� iv) additional action might be needed to prevent farmers destroying all offspring of affected cows and spoiling natural experiments on vertical transmission.�

Dr Pickles also noted:

�An approach was to be made to the MRC asking for information about their reports on CJD and about the research programme they fund in Edinburgh. (I am also writing to Dr Metters to let him know what is going on, in case this comes up in MRC-DHSS discussions).�

The final paragraph of Dr Pickles� minute[291] said:

�The next meeting was planned for 10 November and Sir Richard was talking of a first report early next year. This is a more leisurely timetable than I had in mind, but maybe we do not need to wait formal meetings of the group to see some action. It will be many months before we can expect any substantial new data. The letter proposed in paragraph 4 above asks that attention is directed to the most urgent matters.�

245.         On 21 June 1988� Dr Pickles wrote to Dr Gerald Jones, Medical Head of Medicines Division[292], copied to Dr Harris (DCMO), Mr Wilson, Dr Jefferys and Mr Lister, with silent copies to Dr Martin and Mr Lawrence. The minute said:

�BSE, Spongiform Encephalopathies and Medicinal Products

1.���������� You will have heard of this new disease of British cattle which is thought to be due to scrapie agent, introduced via sheep offal in cattle feeding stuffs. I am part of the secretariat of a working party, chaired by Sir Richard Southwood, which is looking into the implications of this disease. This group had its first meeting yesterday.

2.���������� We are clearly concerned that �BSE-agent� may be transmitted in medicines. Whilst the epidemiology does not suggest that the current cases in cattle are causally linked with the use of veterinary products, we are concerned about veterinary as well as human medicines in case we facilitate yet more species jumps. Much of the relevant information about ingredients and production processes is not accessible to us so we will look to the section 4 committees (and the Biological sub committee) to review this problem. All of them, including the VPC and CDSM, might have an interest. Dr Martin is a member of Sir Richard�s working party, and might raise the problem informally at a Commission pre-meeting.

3.���������� I have been in correspondence with Dr Jeffreys and others about this. I understand the pharmaceutical industry are also concerned: they had been using bovine not sheep products in various processes because scrapie is endemic in British sheep. Now they need to worry about possible dangers to their workers handling bovine materials as well as possible infection in their final products.

4.���������� Questions we might want to have answered are:

������������� -��� the highest risk would be from parenterals prepared from brain (eg rabies vaccine). Any species in which transmissible spongiform encephalopathies have been described would be suspect (�natural� infections in sheep, goats, cattle, deer, mink, but can be transmitted to hamster, mouse, guinea-pig etc). Are sterilisation processes adequate for the most resistant strain of scrapie agent or for CJD agent? Should companies be asked to include investigation for inclusion of scrapie agent (eg mouse innoculation [sic]) in at least some batches?

������������� -��� If BSE behaves like scrapie, then we might expect other nervous tissue, spleen, lymph nodes and placenta to be contaminated. Infection has been described in other tissues too, eg gut wall, and we can not [sic] be sure blood is free. Do we know what bovine materials are used in which products, both as the active ingredient and in production? Bovine active ingredients in human products include insulin, vasopressin, bone, immune globulins, fibrin, dermal collagen, albumin. Bovine serum albumin and fetal calf serum must be used in preparation of very many products. For each of these products would any �BSE agent� be destroyed or eliminated in processing? If not, and the product is administered parenterally or topically into an open wound, might there be a risk? [For oral products, there would only be a trivially increased load on top of that taken in food in omnivores/carnivores including man. But for some herbivores, this might allow the agent to be introduced into yet another species].

������������� -��� Would it be appropriate to arrange for monitoring of cases who have received any of these suspect products in the past? Could studies be undertaken in recipients of bovine insulin without causing alarm. Would recipients of collagen or fibrin implants be another group for study? Perhaps some animal recipients of suspect products should also be studied.

������������� -��� Should we restrict our concern to products manufactured in the UK, since BSE has not been described elsewhere?

������������� -��� Should we step up the physical examination of animals involved in medicine production, ensuring a neurological assessment is included and only healthy animals are used

������������� -��� Pending results of further investigations, should we insist all ruminants used for the production of human or veterinary products are not fed any time since birth supplementary animal protein as in meat and bone meal? Should the same rules apply to any other animals involved in production of human or veterinary medicines? This seems to me to be an easy option for the industry (assuming bovine serum albumin can be bought in from countries overseas where such supplementation is not used) and would be a responsible step. It would provide reassurance if, as I suspect, it is not possible to come up with answers to the other questions.

5.���������� Is this a topic you will want to raise with the FDA at the forthcoming Tripartite?

6.���������� As you know, BSE is of particular concern to CMO. He has asked me to keep him fully posted as to progress. Following yesterday�s meeting of the working party, I have let him know I am writing to you to suggest this potential problem is discussed by your expert committees. Please let me know if there is any further information I could provide for you. I would value the chance to be present as an observer when the issue gets discussed in committee.�

246.         Dr G Jones said in his Statement to the Inquiry that:

�While I have no direct memory, no doubt upon receiving this letter I would have picked up the phone to Dr Jeffreys (who had been copied in the letter) and I [sic]ascertained that the review process was by then well in hand. I knew that Dr Jeffreys had already been involved because Dr Pickles in her third paragraph explicitly refers to this.�[293]

247.         Commenting on this minute in his Statement to the Inquiry Dr Jefferys said:

�Dr Pickles clearly felt that BSE should be considered by the Biologicals subcommittee at the first available opportunity.� The Biologicals subcommittee met once every two months.� By 21st June, the papers for the next meeting (which would have been held in the first week in July) would already have been prepared and sent out to subcommittee members and thus, in practice, the first available opportunity would have been the September meeting.� I believe that it was in fact decided to work towards preparing a paper for the November meeting of the Biologicals subcommittee.� At its September meeting, the subcommittee was informed of the emergence of BSE and the fact that a paper was being prepared on the subject for consideration at the November meeting.�[294]

248.         Dr Jefferys has said that the practicalities of preparing a paper:

��required the allocation of a Senior Medical Officer and Pharmacist to carry out the necessary work of summarising what was then known about the disease and identifying the potential issues to which the disease gave rise. I am sure that decisions as to who should do the work must have been arrived at after discussion between the various branches of Medicines Division. I would have needed to allocate a medical officer and, I think from recollection Mr Stewart would have needed to allocate a pharmacist. Questions of availability over the summer period together with the current workload of individual medical officers and pharmacists would undoubtedly have played a part in our discussion.�[295]

249.         Dr Rotblat commented on the initial view of BSE and medicines in her Statement to the Inquiry:

�During the summer of 1988, I was involved in discussions in Medicines Division about how to deal with the potential problem posed by BSE for the safety of medicines.� A difficulty was that very little information was available to us at that time.� However, we knew that the Government had established the Southwood Working Party and we consequently felt that only limited action could be taken until we had seen and considered the report of the Working Party.� Nevertheless, some preliminary consideration could be given to the issues raised by BSE for the safety of medicines and a considerable amount of such work was done within Medicines Division before the views of the Southwood Working Party became available to Medicines Division.�[296]

250.         On 30 June 1988 the CSM met.[297]

251.         On 3 July 1988, Dr Martin responded to Dr Pickles� minute of 21 June 1988 (which Dr Pickles had copied to him). He said:

�I mentioned the problem, of BSE and scrapie agents in relation to the use of vaccines and pharmaceutical products, at the pre-meeting of the Medicines Commissioners. It seems that the appropriate information on the use of animal products could be obtained. At some stage I believe someone will have to look closely at this aspect.

Without condemnation of the carcase of BSE cases, the risk of tissues etc from such animals being used by the pharmaceutical industry will not be reduced, and the number of cases seems to be increasing. It seems unlikely that the Minister of Agriculture will ever consider paying compensation for affected animals. It will thus not be in the farmer�s interest to report such cases if he can avoid doing so. No farmer will admit to having or seeing scrapie in his flock and I image (sic) BSE may be the same way.

However it is likely that any possible horizontal and lateral transfer will not multiply the number of cases as much as by ingestion of contaminated feed. The new Order should certainly help in that respect, both with BSE and scrapie.�[298]

Dr Pickles copied this minute to Mr Lawrence for information.

252.         On 5 July 1988 the VPC Biologicals Sub-Committee held a meeting and discussed draft guidelines prepared by Mr Wood of CVL and the minutes of the meeting held on 8 June 1988.[299] The following points were made in relation to Mr Wood�s paper:

�5.3 �.

1)��� The greatest concern was over the use of pituitary gland extracts by veterinary surgeons. However, this use was correct within the terms of the Medicines Act (Section 9.2). It had been agreed that individual letters, indicating the hazard of using these products, would be sent to the vets concerned.

2)��� At least 16 pituitary based products had Product Licences of Right. It was agreed that for these products and those containing extracts of adrenal, pancreas and thyroid glands, letters should be sent to the licence holders asking for further information on the sources of gland, methods of manufacture, etc.

3)��� Other hormone based products would be considered under the hormone review for which guidance notes were being prepared.

4)��� Neural or lymphoid tissue including brain infusion broths, from the UK, were unacceptable unless heated at 136 oC for 18 minutes, which would probably render the tissues unusable. Pigs or horse brains tissue or non-UK tissues might be acceptable.

5)��� Foetal calf serum and new born calf serum collected without prior brain penetrative stunning were considered to be acceptable for use.

6)��� Several treatments were proposed for other tissues including peptone meat broths. The more acceptable method for the tissues, was considered to be heat treatment at 126 oC for 2 cycles of 30 minutes each with cooling in between. A higher temperature of 136 oC for 18 minutes was considered preferable, but it would probably lead to the treated tissues being unable to support optimal growth.

7)��� Horse meat was often used for peptone meat broths and this could be used as an alternative to bovine meat.

8)��� Bile could not be heat treated at 126 oC without denaturation. Although bile was not essential the companies considered that it improved growth. It was suggested that a controlled source could be used for bile.

9)��� All manufacturers who currently use brain material should be asked to consider alternative materials or methods.

5.4 �������� It was agreed that an amended version of the BSE document�should be tabled at the forthcoming NOAH meeting. The amended paper would also be presented to DHSS and NIBSC.

It was considered that the DHSS should be kept informed of any developments with BSE.�

253.         On 6 July 1988, following the meeting of 5 July, Mr Wood prepared a revised paper[300] about �BSE and Biological Products�. It covered a number of proposals for control of UK origin bovine derived substances to be used for veterinary purposes.

��Proposals for such controls follow, along with some discussion of reasons.

1.��� No product obtained from an animal suspected or confirmed to be BSE affected is acceptable for use. This point applies to, and where necessary overrides all of the following.

2.��� Only serum collected without prior brain-penetrative stunning is acceptable for use�.

3.��� Neural and lymphoid tissue is unacceptable unless it is first held at 136 oC for 18 mins. This applies, for instance, to Brain/Heart infusion broth. Alternatives would be to use bovine material of non-UK origin or to substitute, eg equine brain for bovine.

4.��� For other tissues, alternatives for consideration at this meeting are:

a) 136 oC for 18 mins

or

b) 126 oC for 2 cycles of thirty minutes with cooling between

or

c) 126 oC for 1 cycle of thirty minutes�.

5.��� Milk and milk products are acceptable for use�.

6.��� Primary cell cultures are not acceptable�.

7.��� Cell lines are acceptable provided they are not derived from neural or lymphoid tissue or cells�.

8.��� Faeces are acceptable for use provided they are obtained from a controlled source herd with no signs of infection that is not fed on offal derived concentrates�.

9.��� Bile is acceptable if obtained from a controlled source as in 8�.

10.�� Hormones derived from bovine tissues should not be used�.�

254.         On 6 July 1988 the Biologicals Sub Committee of the CSM met.[301]

255.         On 11 July 1988 there was meeting between the VPC Biologicals Sub-Committee and NOAH. A note of the meeting recorded that Mr Wood introduced his paper setting out the conditions under which material of bovine origin may be used in biological products. It was recognised by parties at the meeting that some of the requirements might cause difficulties to individual companies in their existing production processes. It was agreed that companies would consider the implications and send comments to BP&S as soon as possible. Mr Cook also agreed to obtain information from NOAH members on pharmaceutical products which contained bovine material from UK sources. In addition NOAH would formulate their response to the June bovine guidelines paper and forward it to MAFF in September after which a meeting would be arranged to discuss outstanding points.[302]

256.         On 11 July 1988, Dr Pickles wrote to Dr Minor, Head of Virology at the National Institute for Biological Standards and Control (NIBSC), in the following terms:

�As we discussed today on the phone, I have lead responsibility for BSE here in DHSS. For your information, here is a copy of the note I have prepared for our press office. Also, in confidence, a note about the implications of BSE for biological products I sent to Dr Jones[dated 21 June 1988]. You had better not let Medicines Division know you have seen this, but there will be no excuse for not having a proper discussion at the next Biologicals Committee. Perhaps you could let me know if it does not appear to be on the agenda when you receive the papers.�[303]

257.         On 11 July 1988, Dr Minor wrote to Dr Jefferys of the Medicines Division and enclosed a copy of the Report of a meeting on BSE held at NIBSC on 16 May 1988 (apparently incorrectly referred to as 4 May 1988 in a handwritten note on the face of the letter). Dr Minor said �the Report was mentioned briefly at the last biological sub-committee [of NOAH] and it was suggested that I send it to you for circulation�.[304] Dr Wood sent a copy of the same report to Drs Harris, Pickles and Rotblat and it was sent on to Mr Lawrence.

258.         On 14 July 1988 Professor Collee replied to a query from Mrs Baker, at the Pharmaceutical Secretariat of the Medicines Division, concerning a collagen product that was to be considered by the CDSM.[305]� He said that his knowledge of the BSE agent was scanty and that he was influenced by the recent paper by Holt and Phillips.� Following a summary of publications on inactivation studies and iatrogenic infection, Professor Collee suggested that Dr Kimberlin could be approached for an update and advised that Mrs Baker should seek assurances from the manufacturers concerning the efficacy of their sterilisation techniques and their batch control of the radiation procedure.� He expressed the hope that:

��in future, products of this nature will be submitted to CSM (Biologicals).� It is not really satisfactory to try to deal with them on an ad hoc basis�but I hope that my comments are helpful. Of course, I shall defer to my specialist virological colleagues on CSM(B) who may find my bacteriological views on virus-like agents a little quaint.�[306]

His letter was copied to Professor Banatvala, Dr Schild and Dr Tyrrell.

259.         On 16 July 1988 a letter from Mr A Kidd and Mr A Gray of the Veterinary Products Committee Medicines Unit CVL was published in the Veterinary Record. The letter read:

�The recent paper by Sreenan (VR.June25, page 624) prompts us to write regarding the use of pituitary derived follicle stimulating hormones of ovine or bovine origin�.

Apart from the legal position, we also wish to draw attention to the possible transmission of BSE or Bovine Spongiform Encephalopathy and to the potential hazard of using tissues of brain origin from cattle.

We are particularly concerned where bovine or ovine pituitary tissue is involved in the preparation of follicle stimulating hormones. The potential risk disseminating the scrapie agent by this means is well established and there is some evidence to suggest that a similar risk of spreading the agent of BSE may be associated with the use of bovine brain tissue.

If brain tissues are necessary at all in the production of any veterinary medicine, species other then sheep and cattle should be employed wherever possible�[307]

260.         On 21 July 1988 the CMO wrote to Mr Derek Andrews about a proposed advisory group on BSE related research.[308]� After suggesting group members he commented� �With people of this quality, if and when the unfortunate time comes where a human health hazard becomes painfully evident, we will be able to justify what we have done in that we will have obtained advice at the very highest possible level.��

261.         On 28 July 1988 the CSM held a meeting.[309]

262.         On 11 August 1988 the CMO sent a copy of his letter of 21 July 1988 to Sir Richard Southwood.[310]

263.         On 30 August 1988 Sir Richard replied agreeing with the CMO about the proposed advisory group[311]. He added that

�...the only outstanding practical matter that we need to address at the present time is the use of Serum in pharmacological work�Clearly, this is not a matter in which it would be easy for a British Government Department to issue regulations insisting of [sic] the use of foreign material, but I wondered if something could be done �through the usual channels� to check the policy of pharmaceutical companies concerned. I imagine your medicine section will know which companies use Bovine serum or other products in their preparations.�

Medicines Division Review

264.         In September 1988, Dr Purves and Dr Rotblat prepared a paper for the CSM in which they recommended certain action.� Dr Rotblat commented on this in her Statement to the Inquiry:

�I believe that Dr Jefferys had asked us to prepare this paper.� However, I am unable to recall when he first asked us to prepare it.� I have some recollection that a decision was taken to prepare the paper so that it could be put before the November meeting of the Biologicals subcommittee and Dr Jefferys probably told Dr Purves and I to work towards completing it in time for that meeting.� I believe that when Dr Jefferys asked us to prepare it, he probably told us to prepare it as soon as we could given our existing workloads.� I do not believe that Dr Jefferys either told us to drop all our other work and concentrate exclusively on BSE or told us that the paper was a low priority.� I imagine that the paper was probably put together over 3-4 weeks.� It would appear that the paper was completed by 20th September (see minute dated 20th September from me to Dr Jefferys).�[312]

The paper was sent to Dr Jefferys on 20 September 1988 for internal distribution.[313]

265.         Dr Jefferys has commented on the procedure involved in preparing such a paper:

�The practice and policy of Medicines Division was to put detailed, thorough and carefully prepared papers to the advisory committees; this was inevitably time-consuming. The Biologicals subcommittee would have expected the paper prepared for it on BSE to conform to this practice and the paper prepared by Dr Rotblat and Dr Purves did - it was a substantial piece of work containing a considerable amount of information on which the Committee could come to a considered judgement. The contents of such papers had to be capable of withstanding detailed scrutiny which could conceivably include legal action.

In addition to the time actually spent preparing the paper there was and remains about a 3 � 4 week �lead period� in that a paper has to be completed more than three weeks before a subcommittee meets so that it can be checked, photocopied, distributed to the members so that they have adequate time to read it and prepare for the meeting. It was the practice to issue papers two weeks before a meeting to committee members. This would have meant that if a paper was to be put to the September meeting of the subcommittees, it would have had to be available no later than the middle of August.�[314]

266.         Dr Purves has said that:

�Before the matter was raised at the Biological Subcommittee meeting on 7 September 1988 and before Dr Rotblat forwarded our draft Paper on BSE to Dr Jefferys on 20 September 1988, there would have been a considerable amount of internal discussion about BSE.� We were generalists, we did not have specialist knowledge about slow viruses so we naturally would have sought the advice of others � including experts from outside the organisations.

�it was not within our normal course of business to prepare a paper on a general topic such as a new disease.�[315]

267.         Dr Rotblat also said that although BSE was a new disease, there was, within Medicines Division, an existing framework to analyse the disease. The framework was based on previous methods of analysing analogous products. The two principles underlying this method were ensuring the safety of the raw ingredients and, by the use of sterilisation or inactivation procedures in the process of manufacture, minimising any remaining risk. These principles lay behind the paper that she and Dr Purves presented.[316]

268.         The paper, submitted under a cover note, had two main parts.[317] The first part, entitled �Bovine Spongiform Encephalopathy�, was described as providing a background to the problem of BSE.� The second part, entitled �Bovine Spongiform Encephalopathy �Action by Medicines Division� contained recommendations for action on which the cover note asked the Committee for advice.� The paper also included a number of appendices. (See below.)

269.         Dr Purves has stated:

�The purpose of the paper was to:

(1)�� summarise the current information on BSE;

(2)�� identify the issues that BSE raised for biological products - to consider the possible risk of transmission of the disease to humans through biological products containing or consisting� of bovine materials; and

(3)     present draft recommendations for the Committee's consideration.

It was designed to be a discussion paper for the Committee.� As was our practice, we presented specific, but draft, recommendations to the Committee to assist in giving focus to the deliberations.�� Additional recommendations would be included as a result of discussion at committee.

We were very aware that the Southwood Working Group had been set up,� given its expert advice in this area and that before implementing industry wide measures, we would need further guidance from our group of experts.� However, in the interim we did not hesitate in examining the issue and formulating proposals for action.� These could be reviewed in the light of the subsequent recommendations that came from the Southwood Working Party including that Party's assessment of the possible risks associated with biological products.�[318]

270.         The background part of the paper, �Bovine Spongiform Encephalopathy�, after describing the disease and some of its characteristics, went on to state:

�Before considering the implications of a BSE agent with respect to medicines, there is merit in reviewing briefly what is known about the agent. From the terms of reference of the working group, it is evident that little is known about the disease or the causal agent. The limited information available (APPENDIX 4- [see below]) would appear to indicate that BSE could be caused by a scrapie-like agent about which there are still many unknowns. As a result of this paucity of hard information on the agent and the disease, it is difficult to see what positive action can be taken by the Division, at least in the short term. In spite of this initial response, concentrating primarily on the relatively narrow aspects of agent and disease, it would be prudent to widen the considerations at least in a preliminary way to cover related aspects, namely,

2.1�� The animal species from which tissue may be sourced for use in the manufacture of medicinal products.

2.2�� The significance, if any, of the various types of tissue that may be used.

2.3�� The ability of the manufacturing and purification procedures to destroy or remove viral or virus-like agents.

2.4�� The products involved, the type of tissue they contain and the relative risk to the patient on administration of a contaminated product, parenterally, topically and orally.

Taking these issues seriatim, the first relates to the animal species from which the required tissue is sourced. The current problem relates to the bovine spongiform encephalopathy disease: however, should our concern be restricted to bovine material or should it be extended to other species in which a transmissible spongiform encephalopathy has been described eg goats, sheep? Regardless of the species involved, the next question might be to consider the merits of stepping up the physical and neurological examination of animals, to [sic] tissue of which is going to be used in the manufacture of medicines? The response to this might not be clear since, while there is merit in increasing the depth of examination of the animals health, the findings are severely limited because of the incubation period of the BSE agent. In an attempt to take action in the short term, it has been suggested that all ruminants, from which tissue will be used, should not be fed, at any time from birth, supplementary animal protein. This action has been proffered� following speculation that cattle may have contracted the disease through being fed contaminated feed supplement derived from sheep in which scrapie is endemic. The problem here is there are no facts to back up this speculation.

Were this speculation true then it might be helpful to take such action, although it would not overcome the problem of possible transmission by some other means.

The second issue relates to the significance of the various types of tissue that may be used in the manufacture of a medicinal product eg CNS, other nervous tissue, spleen, serum etc. The question here is if the source animal were to be infected with the BSE agent, would there be any relationship between the type of tissue used and the contamination of the product? With the lack of hard information available on the BSE agent, it is unlikely that a clear answer will be available to this question. Another question posed centred on the fact that since this disease appears to be confined to the UK �should we restrict our concerns to products manufactured (presumably from animals sourced) in the UK�? In response to this, it has already been stated that �with all the difficulties of diagnosis, negative evidence of its presence in cattle of other countries should be treated with due caution�. Thus, it would seem inadvisable to restrict our concerns to bovine materials sourced from UK cattle.

The third topic relates to the ability of the manufacturing process to destroy or remove viral or virus-like agents. For some time now, this information has been sought from companies with respect to viruses, the characteristics of which are known. One cannot be quite so pragmatic where the BSE agent is concerned because of the general paucity of information about its properties. As a consequence of this, it is impossible, at this juncture at least, to say that the agent, were it to contaminate a product, would be destroyed or removed by sterilisation or any other manufacturing or purification process. Indeed, if the agent is like scrapie, then it, too, might be extremely resistant to inactivation by heat, irradiation or by various chemicals.

The fourth and final topic relates to the medicinal product and covers three issues. It is clear there is a need to know which products contain bovine tissues, along with details of the type of tissue used in manufacture, so that a database is available for discussion later. In addition, consideration may need to be given to the risks associated with parenteral, topical and oral administration, should the product be contaminated by the BSE agent. Having given some consideration to the issue of the BSE agent and how it might impinge on the manufacture of medicinal products, these topics should be discussed so that some proposals may be presented for both short and medium term action. Some questions we may wish to ask are:

1.��� which products include bovine material and, therefore may contain the BSE agent;

2.��� what follow-up action is required especially in the absence of definitive information on the properties of the BSE agent;

3.��� what could be asked of companies in answer to concerns about BSE in addition to our current policy, where, in the last year or so, we have been asking for details of the quality of starting materials and the ability of the manufacturing and purification procedures to remove or inactivate hardy viruses;�

271.         The second part of the paper, entitled �Bovine Spongiform Encephalopathy � Action by Medicines Division�� states:

�1.Product Licence Situation

The computer list shows 53 product licences extant for preparations of bovine origin and of these 42 are for insulin.

It is not clear how complete this list is, particularly on the review side where there may be grounds for concern, especially with regard to products for cellular therapy.

There is no computer list showing the use of products such as bovine albumin and foetal calf serum in the process of manufacture. The latter is fairly widely used in tissue culture work.

For the purpose of recommended actions products will be divided into those for oral and parenteral use and those derived from brain, tissue, and blood.

2. Products derived from brain

There are no licensed products derived from bovine brain.

3. Products from tissue

3.1 Parenteral use

There are three products in this category:

������ i.��������� Insulin

������ ii.�������� Bovine collagen implants

������ iii.�������� Bovine fibrin implants.

The latter two are used in surgery and are the province of the CDSM.

3.2 Oral use

There are two products in this category:

i.���� Bovine fibrin powder used as a haemostatic

ii.���� A sugar coated tablets which are alleged to contain ox bile. (I note the comment from MAFF suggesting that bile is safe from transmission of BSE).

4. Products derived from Bovine Blood

4.1 For parenteral use

There are two H products for parenteral use which contain bovine immunoglobulines, these are:

B, ampoules and [redacted]

single plant preparation injection. (PLRs)

4.2 Oral

B pilules and single plant preparation pills, H.

C Vitamin B12 absorption test kit which contains bovine albumin.

5. New products

CSM through the Biologicals Sub-Committee have been asking companies who put in applications for bovine products to show the ability of their manufacturing procedures to inactivate scrapie and similar agents. No new licences for these products have been granted for some time.

6. Summary

6.1 Oral products

No action should be taken with regard to these products in view of the widespread consumption of beef by the population at large.

6.2 Parenteral products

The major problem here appears to be with insulin. The use of bovine insulin is rapidly declining and maybe restricted to those patients who have antibodies to the human preparation, or who cannot tolerate it. In this case bovine insulin is life saving, and the risk to benefit would currently be in favour of retaining its use. In addition to this for parenteral products in general:

i.���� All cattle used for the preparation of these products should come from certified healthy herds, and not to have been given food supplements containing material of animal origin.

ii.���� No brain or lymphoid tissue should be used in parenteral products.

iii.��� Manufacturers of parenteral products should show that their manufacturing procedure is capable of inactivating scrapie-like agents.

iv.��� While the agent of BSE is not known it is not possible to advise specific inactivation processes.

7. Recommendations for action

i.���� No licensing action should be taken against oral products.

ii.���� All bovine products should come from cattle from healthy herds, which have not been given food supplements containing material of animal origin. No brain or lymphoid tissue should be used in parenteral products.

iii.��� Manufacturers of parenteral products should show that their manufacturing processes are capable of inactivating scrapie-like agents.

iv.��� All licences for new products from bovine material should comply with the above.�

v.��� The Review/CDSM Sections should carry out a search for preparations containing bovine material.

vi.��� There should be an article in MAIL requesting manufacturers to identify bovine preparations used in the manufacturing process. Bovine albumin and foetal calf serum should come from healthy herds.

vii.�� The ADR database should be searched for ADRs to bovine products.

viii.� The Committee is asked to consider whether to take any action against bovine insulin or whether the risk/benefit ratio is appropriate.�[319]

272.         Appendix 1 to the paper is headed �BSE and Biological Products for Human Use� and is a report of the meeting held at NIBSC on 16 May 1988 (see paragraphs 191-193).

273.         Appendix 2 was a magazine article from the New Scientist dated 11 August 1988 entitled �Mad Cows and Ministers Lose their Heads� with a sub-heading �Will a New �Mystery� Disease Inexorably Spread through British Cattle and Put Consumers at Risk or is the Panic Unnecessary?��

274.         Appendix 3 is headed �BSE and Biological Products� and is the paper by G W Wood of CVL prepared on 6 July 1988 (see paragraphs 213-214 above).

275.         Appendix 4 is headed �Options for the control of scrapie and its counterpart in cattle� by A G Dickinson and D N Taylor of Neuropathogenesis Unit, Edinburgh.� It explains some characteristics of the disease and implications for its control in animals.

276.         Dr Purves comments on aspects of the paper in his statement to the Inquiry:

�The first part of the background paper set out general issues which needed to be discussed at the Committee, namely:

1.��� The animal species from which tissue may be sourced for use in the manufacture of medicinal products ;

[We wanted the Committee to consider whether we should be restricting our concern to only the geographic source of the bovine material i.e. avoiding material from the UK or including other species in which a transmissible spongiform encephalopathy had been found i.e. goats, sheep].

2.��� The significance if any of the various types of tissue that may be used in the manufacture of medicinal products.

[The essential question here was, if the source animal were to be infected with the BSE agent, would there be a relationship between the type of tissue used and the contamination of the product?]

3.��� The ability of the manufacturing and purification procedures to destroy or remove viral or virus-like agents;

[This was an inquiry we would always make of an application for a product, which may have contained a virus.� At the stage of writing the paper, it was impossible to say whether the BSE agent could be destroyed or removed by sterilisation or any other manufacturing or purification process.]

4.��� The evaluation of the products involved the assessment of the geographic source of the tissue, the type of tissue they contained and the relative risk to the patient of administration of a potentially contaminated product parenterally, topically and orally.�

[We identified here that there was a need to know which products contained bovine tissues along with details of the source and type of tissues used in manufacture and that a database should be set up.]�[320]

277.         In relation to the computer database Dr Purves has commented that:

�It was clear that it did not identify all medicinal products that included bovine materials as excipients or ingredients used in the manufacture of the product.� The information it had given however was still useful as a basis for initial discussion.� It helped to identify what were some of the practical issues and that there was the need for further information from the industry.�[321]

278.         Dr Jefferys has also said that by September 1988:

��I am sure everybody in the Division concerned with BSE had begun to realise the potential inadequacy of the divisional database for pursuing an enquiry of this nature. These problems were clearly identified in the Evans/Cunliffe Report which led to the development and installation of a completely new database in 1993�.[322]

279.         Dr Rotblat and Dr Purves have commented on the recommendations contained in the paper in their statements to the Inquiry.� Dr Rotblat says:[323]

�i.��� No licensing action should be taken against oral products.

[The reasoning behind this was that it would have been inconsistent to take action against such products when no action was proposed against food containing bovine material.]

ii.���� All bovine products should come from cattle from healthy herds, which have not been given food supplements containing material of animal origin. No brain or lymphoid tissue should be used in parenteral products.

iii.��� Manufacturers of parenteral products should show that their manufacturing processes are capable of inactivating scrapie-like agents.

[These two recommendations were principally the work of Dr Purves assisted by Mr Sloggem. This was because they predominantly raised pharmaceutical rather than medical issues. The principles behind these two recommendations were those commonly adopted to preclude the transmission of agents by biological products. These principles were, first, to ensure the quality and safety of the ingredients and, secondly, to minimise, through sterilisation during the manufacturing process, any remaining risk. I presume that Dr Purves and Mr Sloggem framed the concept of �healthy herds� and specifically mentioned brain and lymphoid tissue following discussions between them and MAFF. I believe that the ban on the use of brain and lymphoid tissue in parenteral products was always intended to apply to their use in the manufacture of medicinal products in addition to their use as ingredients. It is clear from our paper that we were, at this time, aware of the widespread use of materials such as bovine serum in the manufacture of medicines.]

iv.��� All licences for new products from bovine material should comply with the above.

[I believe that recommendations ii and iii were always intended to apply to existing products. The purpose of this recommendation was to ensure that they were also applied to new products.]

v.��� The Review and CDSM (Committee on Dental and Surgical Materials) Sections should carry out a search for preparations containing bovine material.

vi.��� There should be an article in MAIL (the Medicines Act Information Leaflet) requesting manufacturers to identify bovine preparations used in the manufacturing process. Bovine albumin and foetal calf serum should come from healthy herds.

vii.�� The ADR (Adverse Drug Reactions) database should be searched for ADRs to bovine products.

[I consider that an analysis of recommendations (v) � (vii) makes it clear that the recommendations were intended to apply to existing products as well as to new products. The Review Section of Medicines Division served the CRM which did not consider anything other than existing medicinal products. The purpose of the proposed article in MAIL was to obtain information about the use of bovine preparations in the manufacture of existing products. The ADR database provided information about adverse reactions to existing products. The reason for searching it was to consider whether any adverse reactions had been recorded in respect of existing medicinal products connected with bovine material.]

viii.� The committee is asked to consider whether to take any action against bovine insulin or whether the risk/benefit ratio is appropriate.

[Bovine insulins were the only product derived from bovine tissue that fell within the remit of the CSM. Bovine collagen implants and bovine fibrin implants fell within the remit of CDSM.]�

280.         Dr Purves has stated to the Inquiry:

�The draft recommendations would have been formulated by Dr Rotblat, and myself, as well as other members of the Biologicals Team.� I cannot specifically recall who was responsible for each, although I note Dr Rotblat states that recommendations (ii) and (iii) were mainly the work of myself and Mr Sloggem.� Because of the team approach to this BSE issue, I believe that each of the recommendations would have been discussed widely within the Biologicals Unit before they went to the Subcommittee.� I believe I also would have discussed them with Dr Minor of the NIBSC and most probably had them agreed by other senior officials within Medicines Division.�[324]

281.         Dr Purves also comments: [325]

�I agree with Dr Rotblat�s comments on recommendations (i), (iv)-(viii) and have added my own comments to (ii), (iii) and (iv).

�

ii.���� All bovine products should come from cattle from healthy herds, which have not been given food supplements containing material of animal origin.� No brain or lymphoid tissue should be used in parenteral products.�

[The aim here was to focus on the source of the starting material.� If it was safe then infected material would not enter the manufacturing process.� Looking at the source of the starting materials was something we did in assessing all applications for Product Licences.� It was clear to me that before we could "refine" this recommendation, we would need input from specialists (probably from MAFF) about how to define "healthy herds".� That question was not within our remit.]�

iii.��� Manufacturers of parenteral products should show that their manufacturing processes are capable of inactivating scrapie-like agents.

[Again, this was a factor we would look at in assessing all applications for Product Licences.� It reflected the very cautious approach we took with applications for new drugs.� If the pharmaceutical companies could not prove that they could inactivate infective agents, their product licence applications would not be approved].

�

vi.��� There should be an article in MAIL (the Medicines Act Information Leaflet) requesting manufacturers to identify bovine preparations used in the manufacturing process.� Bovine albumin and foetal calf serum should come from healthy herds.

[We were aware that we had to go to the pharmaceutical industry directly to get comprehensive information about which bovine materials were used in the manufacture of their medicines.� We knew the computer list was incomplete.]�

282.         On 6 September 1988 the VPC Biologicals Sub-Committee held a meeting and noted that� ��some replies had been received from companies using pituitary glands in their products. Copies of the BSE document had also been sent to DHSS and NIBSC.�[326]

283.         On 6 September 1988 Sir Richard Southwood�s letter of 30 August was copied to Dr Harris (DCMO with responsibility for Medicines Division).[327]� The CMO asked him to provide the advice requested by Sir Richard. Dr Harris passed this to Dr Jones on 8 September 1988.[328]

284.         On 7 September 1988 the CSM Biologicals Sub-Committee held a meeting.� The minutes record the following on BSE at point 7.3:

�Dr Purves informed the Sub-Committee that a paper was being prepared for internal discussions.� A paper would then be submitted to the Sub-Committee at a later date.�[329]

285.         On 16 September 1988 Dr Jones replied to Dr Harris in relation to Sir Richard Southwood�s letter of 30 August saying that:

��The use of bovine serum in the manufacture of medicinal products is one of a number of questions being considered at the moment. Dr Pickles has already requested advice on a number of issues. If you agree I think we should give a considered reply to the Advisory Group on BSE with respect to all the issues.�[330]

286.         A hand-written note at the top of this letter stated �I agree but you should write to Sir Richard stating that you will let him have the information as soon as it is to hand.� This appears to have been signed by Dr Harris.

287.         On 22 September 1988 Dr Jones wrote to Sir Richard. He said:

�I am replying to your letter of 30 August addressed to our Chief Medical Officer. We are currently examining the potential problems of BSE with respect to medicinal products. This will involve consideration of a number of different issues including the difficult one of use of bovine serum or BSA in pharmaceutical manufacture. Also we will be discussing with our expert advisory committees. I will ensure that your advisory group has all the information relating to medicinal products as soon as it becomes available.�[331]

At the bottom of the page is written �silent copy Dr Jeffreys � please note our undertaking above (via Dr Pickles I presume)�.

288.         On 22 and 23 September 1988 the CSM held a meeting.[332]

289.         On 26 September 1988, Dr Pickles sent a minute[333] to Dr Jones in the following terms:

�I was pleased to see from your minute of 16 September to Dr Harris that you will be giving a considered reply to the advisory group on BSE. I have been asking for comment from Medicines Division for some months now and have made several suggestions as to pertinent questions that could be put before your expert committees. As yet, I understand that the topic has only been raised informally at Biologicals. You explained to me that it has lower priority than other work before you at the moment.

The next meeting of Southwood�s group is on the 10 November. Will I have something positive to report at that meeting from Medicines Division?�

290.         In relation to this minute, Dr Rotblat says in her statement to the Inquiry:

�I should emphasise that I never regarded BSE as a low priority issue; nor, to the best of my knowledge, did any of my colleagues.�[334]

291.         Dr Gerald Jones spoke of his perception at the time of the priority of BSE and medicines in his oral evidence to the BSE Inquiry.[335]

�MR THOMAS: Can I ask you on what basis -- who decided on the priority given to BSE?

DR JONES: Myself; but I am not here to speak on behalf of others who can speak for themselves, but that was a view of my own senior staff and the Chairman of the CSM.� At one point I did ask them what their views were about the concern.� We all knew that there was this appalling mess in cattle with horrendous consequences for the cattle and agriculture. On the food side we knew in June there was, whatever the words are, remote, theoretical risk to human health on the food side.

Our perception was the risk to human health from the medicinal products was, if anything, even lower; but that, nevertheless you had to check all the products inside and outside and take whatever was reasonable action.� But it was not regarded with the pressing concern of, for example, manufacturing defects with medicines, that could lead to the deaths of patients overnight; serious adverse reactions, which were collected by the Division at the rate of 15 to 20,000 a year.� These are adverse reactions in patients taking medicines; or publications, case control studies, showing that breast cancer is linked to the oral contraceptive.� When I say "linked", this has been recorded allegedly causally related to oral contraceptives.� These were the most pressing issues you would be facing in Medicines Division, then or now, in my opinion.�[336]

Dr Jones also said:

�DR JONES: 

�I do not want to overplay this when I say no one believed that this was a pressing priority.� But I would like to stress that it was an exchange going on in July and the relevant staff in Medicines Division prepared papers in August and September and October and November.� It went through the Committee structure.

What I am not prepared to say is we should have recalled the Committee on Safety of Medicines in August, and the staff should drop everything to have looked at this in August.� That in my view would have been completely indefensible.� On the other hand, we did not put it away and forget about it for six months. People dealt with it over the summer period; and in October/November it went for its first crack at the committees.�[337]

292.         On the perception of BSE risk in medicinal products compared to food, Dr Jones said the following[338]:

�SIR NICHOLAS PHILLIPS: I am interested in your perception of the BSE risk being even less than the perceived risk in relation to food because the Southwood Committee considered that the most serious risk would relate to medicinal products injected into people, as opposed to ingestion of food?

DR JONES: By injected, it depends which ones you are referring to.� There are a small number -- well, a small number, I am not sure of the exact number.� There would be a small number of products which contained bovine material.� The obvious example would be bovine insulin.��� There would be a larger number of parenterals which had been in contact with bovine material during manufacture.� There would have been a veritable army of oral products which would have had contact with bovine material.� I suppose the oral products would be dismissed.� With respect to the parenterals, I have seen some of the literature here and everybody seems to be concerned about vaccines.� That would have been my estimate then or now.

Vaccines are normally -- you only get two or three doses and maybe one booster.� There are other parenteral preparations which you would be taking more frequently. Obviously insulin will be taken daily or several times a day.� The view that we had was that if you take the parenterals, the biological products, foetal bovine serum or some foetal bovine material of other type would have been used at some point during the manufacture, perhaps at 5 per cent.� But the product then goes through extensive fractionation and separation stages. If any were to end up, it would have to be one of the most potent infective agents known to man.� We were doing things as a precaution in case we were wrong.�

But I do not think anybody seriously expected that you would get, in a final product of a vaccine produced in culture with cells with 5 per cent foetal bovine serum, that you would end up with infectious agent at the end that could pose a risk.� If it were a risk it would either be zero or so close to zero that it could never be detected.� That was the view.� As I say, I am giving it as my view now, but if I may, at that time Dr Pickles was concerned quite rightly because she wanted to get her work done.

I think it must have been in September or October I asked my three branch heads and the Chairman on the Committee on Safety of Medicines the same question, to ensure that it was not just me.� I said:� If you had, on a scale of zero to ten to estimate where you think is the greatest concern at the moment, ten being the most serious, where would you place breast cancer and the Pill, and where would you place BSE and medicinal products?� They all independently gave the same answer. Breast cancer was at eight or nine on this scale and bovine products and medicinal products was at about one.� I agreed with them.� My understanding of what was going on.

But nevertheless, having said that, steps were taken to clean up the British market.

SIR NICHOLAS PHILLIPS: If you asked the same question now or maybe were asking the same question now, would the answer be the same?

DR JONES: My view, I cannot answer for them now.� My view, yes.� I did not think then that medicinal products posed a risk with BSE and, sticking only to medicinal products; and that is my view today.� I do not think medicinal products up to, say, late 1988, early 1989 when nothing could be done, I did not think that they posed a risk then or now.�

293.         Professor Collee also comments on the risks from parenteral products and vaccines in his statement to the Inquiry:

�We certainly regarded the greatest risk, if there was one, as being attached to parenteral and implantation products.� The point should be made, however, that all parenteral products are not the same and by the same token not all parenteral products involve the same degree of risk. That point is very important when one turns to consider the question of vaccines. By the January 1990 meeting of the BSE Working Party, the available knowledge at that time led us to the view that the risk from those products was not only remote, but very remote�.[339]

294.         Dr Jones also gave his views on the relative safety of oral and topical medicines. He had been asked about the distinction between pharmaceutical products containing bovine material and those that come into contact with bovine material as part of the manufacturing process.� He highlighted the problem of identifying those products that had used bovine material in manufacture only.� In response to a question about whether the MD database would indicate if a product contained animal offals, he said:

�DR JONES: As an active ingredient, clearly, for all the excipients.� Well, on the oral side that could not be so.� I mean, things like magnesium stearate, I think they are in hundreds of medicines.� Magnesium stearate is the thing that is used to make powder slippery before tableting.� At some point it has been prepared from stearate acid, and that means it has come from fat, and some of the fats would have been from the cow.� I do not think anyone would suggest that could possibly be a risk to human health; but you would not know the source stearate acid and the fat that went in to make magnesium stearate.� It depends on what products you are talking about and how much detailed information you would require. There is not a general answer, it requires looking at individual files and maybe contacting the manufacturer for additional information not on your files.�[340]

Later in oral evidence Dr Jones also said:

�PROFESSOR FERGUSON-SMITH: Topical medicines are absorbed --

DR JONES: Absolutely.� This would not apply to the ordinary topical medicines, creams, ointments et cetera.� That clearly someone -- group of people had formed the view that the risk in that regard was like all orally excluded completely here, that topicals would be broadly excluded.

PROFESSOR FERGUSON-SMITH: Who would take that view?

DR JONES: It was a view formed in Medicines Division by advice from the Section 4 Committee, the dominant one.� Probably other sub-committees and the people on this combined group between BPC and CSM.�� This would be a collective exercise.� You recall earlier there was an exchange of correspondence between Southwood and Asscher, without being personal, not seeing quite eye to eye.� I think it was made quite clear then that large groups of products would be put aside and oral and topical clearly amongst those.

�

SIR NICHOLAS PHILLIPS: You mention Southwood and Asscher not being eye to eye as far as your own perceptions.� Do you think Southwood was making too much of a fuss in this area?

DR JONES: I think that is a harsh way to put it.� Southwood was looking at one specific issue, that is all he was asked to do for the Department.� Asscher and others on the medicine side, not just Asscher but the CSM, they were looking at hundreds of problems all the time and much more serious and pressing than this.� It is understandable that two people in different contexts would not have exactly the same point of view.� I must say I think in the end by the time this went out, at the same time as the Southwood Report, there was no difference of opinion between the two sides.�[341]

�

He also added:

�DR JONES: It is quite difficult to know the dose of a preparation given topically.� Of course it is not like the oral parenteral routes.� Again what we are talking about here in most cases would be creams, ointments et cetera which would have clearly fatty and oily materials in them, and at some point they may or may not have been derived from the source, from the cow.� I do not think anyone really would have been regarding that as a serious public health risk.� I really do not believe that.� This is an extra precautionary step over and above parenteral.� I really do not think that the Department would have been discussing something for the treatment of haemorrhoids or mouth ulcers.� The list goes on and on.� The line would be drawn somewhere to behave in a responsible yet reasonable way towards the industry.�[342]

295.         On 29 September 1988 Dr Jones minuted the CMO with a copy to Dr Jefferys, Dr Adams and Dr Pickles.[343] He said:

�Further to our telephone conversation and my letter to Sir Richard Southwood I am providing the information on timing you requested. The internal review by divisional medical and pharmaceutical staff is complete and a draft paper with various recommendations has been prepared. This will be discussed by the Committee on Safety of Medicines and the Committees [sic] on Dental and Surgical Materials (CDSM) in November. The various sub-committees (Safety, Efficacy, Biologicals and Pharmaceutical) will have considered the subject before the meetings of the main Committees. A considered view on the whole issue will therefore be available in late November. It is unlikely that the Committee on Review of Medicines (CRM) will be able to contribute significantly because it meets early in November before the sub-committee meetings. (The Biologicals sub-committee, CRM and CDSM meet at 2 monthly intervals).�[344]

296.         On 6 October 1988 the CMO wrote to Sir Richard Southwood about the progress on the review of biological products. The letter said:

�Further to your letter of 30 August, I am informed that a considered view on the whole issue of biologicals and bovine spongiform encephalopathy should be available in late November. You will appreciate that a number of our advisory committees including the Committee on Safety of Medicines and the Commttees (sic) on Dental and Surgical Materials, together with their sub-committees will have had to consider this important issue before we can reach the type of conclusion which is authoritative and which will be of most use to your Committee.�[345]

297.         On 12 October 1988 Dr Pickles wrote to Dr Jefferys, with copies to Dr Purves and Dr Rotblat, thanking him for a copy of the paper prepared by Dr Rotblat and Dr Purves for the Biologicals Sub-Committee who were to meet on 2 November 1988. She said:�

�1.�� Thanks for sending me a copy of the paper for Biol. Please let me know when to expect it on the agenda and so when I should turn up.

2.��� I had hoped to have seen the paper in draft and regret not having had an opportunity to help those writing the paper. I think they might have found my comments useful and have saved discussion time at the meeting.

3.��� I have spoken to Dr Rotblat on the phone. If there is a chance to amend the paper before it goes to SEAR (I guess copies have already been made for Biol) then points you could look at are:

������ Page 1: total number of confirmed cases of BSE now over 1100

������ Page 4: there are plenty of facts to back up the hypothesis that food supplements prepared from sheep are linked with the emergency [sic]of BSE in cattle. Epidemiology is here being dismissed as �speculation�.

������ Page 5: there are good reasons for believing the problem could well be restricted to UK cows.

Product licence position

Under parenteral use, perhaps you need to look at [redacted � PL Licence No] which are bovine [redacted � PL Licence No] (but this may only be synthetic [redacted � PL Licence No] of bovine type). Also P is of bovine origin � but perhaps you are including this under collagen or fibrin implants.

Recommendations

I find some of the recommendations (eg iii) confusing as written since it is not clear whether they are to apply to all products, to all parenterals, to all parenterals of biological origin, or to all parenterals with bovine� ingredients, or to those parenterals of bovine origin from herds fed animal protein, or only to parenterals with bovine ingredients from British herds fed animal protein that might have been contaminated. (!)

4.��� In attempting to clarify what I think the authors intended I found I came up with some queries (as indicated below).

Redrafted recommendations

a. No action proposed against any non-parenteral products

b. New (? and renewed /reviewed) licences for parenteral products of bovine (?other animal) origin or using bovine ingredients:

������������� i��� actives/ingredients to be taken only from healthy herds not fed animal protein (?Britain only)

������������� ii�� manufacturing processes to be shown capable of inactivating scrapie agent (?even if b i. applies)

������������� iii�� brain and lymphoid tissue not to be used in any part of manufacture (?unless otherwise justified)

c. Current licences for parenteral �biological� products

������������� i��� licence holders to be asked to identify all bovine ingredients used (?and then asked to notify LA where they do not comply with bi-iii above)

������������� ii�� (compulsory?) variation to be considered for any parenteral products with bovine actives (eg bovine insulin) (?and bovine ingredients) which do not comply with b (?i-iii or only i and iii) above

d. Licence holders are to be advised of these recommendations by means of a MAIL article.

e. CDSM/CRM/ADR sections to be alerted to concern over (?parenteral only) products of bovine origin.

5.��� But there are also other recommendations on the MAFF list that could be looked at and easily incorporated into any recommendations of your own eg not using serum from cows killed by brain-penetrative stunning. Perhaps it would be wise to find out what has been happening in VPC before you put the problem to CSM and its sub committees (different recommendations about acceptability of non-British bovine sources could be embarrassing and would give legitimate grounds for appeal to the MC).

6.��� Dr Jones has promised to write to Sir Richard Southwood with the advice of the expert committees. I trust you feel there is sufficient information in this paper to enable Biol to give its decision at the November meeting. On the bovine insulins, for example, the range of options might need spelling out including, as it seems to me, doing nothing or merely adding a data sheet warning, to restricting the indications to those who cannot tolerate human insulin, or varying the source material to non-British or non-protein supplemented sources. In fact, the only option hinted at seems to be revocation which is clearly overkill. But perhaps these options come at a later stage.

7.��� I feel really bad about having to badger you about a �problem� that may not even exist but it is I that has to face Sir Richard and CMO and explain the lack of progress.

I hope you take these comments in the constructive spirit in which they are given.�[346]

298.         Dr Rotblat said in her statement to the Inquiry:

�Dr Pickles said that she regretted not having had the opportunity to help in the writing of the paper. My only comment on that suggestion is that it would have been extremely unusual to involve an official from the Department of Health in the drafting of a Medicines Division paper.�[347]

299.         Dr Purves notes:

�One comment Dr Pickles made about our draft recommendations was that we should have looked at, and incorporated into our recommendations, those made by MAFF on veterinary products with bovine materials.� We had most certainly considered the MAFF [sic] on recommendations and indeed had appended them as Appendix 3 to our own report.�[348]

300.         On 14 October 1988 Dr Jefferys replied.[349] He said:

�1.�� I refer to your minute of the 12 October.

2.��� A copy of the BSE paper was sent to you as soon as it was available. You will appreciate with the present demands on our professional resources and the tight timescale that the paper could not have been sent to you earlier.

3.��� The paper has already been copied for circulation to the Biologicals Sub-Committee and to SEAR (which meets on the 4th November, two days after Biologicals). I note that you will be at the Biologicals Sub-Committee and therefore you will be able to give us an updated figure as to the number of confirmed cases of BSE. There will be plenty of virological advice at the Biologicals Sub-Committee.

4.��� The purpose of the paper is to provide a framework and basic recommendations. The second stage of the procedure will be to look at individual products if the Committees feel there is a problem and that action is necessary. This work will principally fall to CRM and CDSM.

5.��� The recommendations are a matter for the Committees. They will have the MAFF list before them. I think it is important that the recommendations are correct, rather than we seek conformity for the sake of conformity.

6.��� With regard to bovine insulin, we first need to decide whether there is a problem. If there is, then with Professor Harry Keen on Biologicals and Professor George Alberti on SEAR we have considerable diabutalogical expertise to frame any recommendations which might be necessary.�[350]

301.         On 20 October 1988 the CSM held a meeting.[351]

302.         On 1 November 1988 the CRM met and the minutes note that a paper on BSE �would be put to the Biologicals Sub-Committee for their expert consideration and that there would be an opportunity for the CRM to consider further.�[352]

303.         On 2 November 1988 the CSM Biologicals Sub-Committee met to discuss the paper prepared by Dr Rotblat and Dr Purves (see paragraphs 264 - 281 above). Mr Ayling, Dr Adams and Dr Pickles also attended this meeting. The Sub-Committee recommended the following:

�7.1 Bovine Spongiform Encephalopathy

Following a full discussion the Sub-Committee made the following recommendations -

a.��� No immediate licensing action should be taken against oral products, in which bovine material has been used.

b.��� All bovine materials should come from cattle from appropriately certified healthy herds, which have not been given food supplements containing material of animal origin. No brain or lymphoid tissue should be used in parenteral products.

c.��� Manufacturers of parenteral products should show that their manufacturing processes are capable of eliminating scrapie-like agents.

d.��� All licences for new products from bovine materials should comply with the above.

e.��� There should be an article in MAIL requesting manufacturers to identify products in which bovine materials had been used. Bovine albumin and foetal calf serum should come from appropriately certified healthy herds.

f.         The above should be drawn to the attention of the review/CDSM sections along with the need to search for preparations containing bovine material.

g.        The above should be drawn to the attention of the ADR Section and SEAR along with the need to search the ADR database for reactions to bovine products.

7.2   The Sub-Committee also recommended that Licensing Authority�s attention should be drawn to the need to give ongoing consideration as to whether action was required on bovine insulin and heparin products.�[353]

304.         In his Statement to the Inquiry Professor Collee commented on this meeting in the following terms:

�I recall reading the Purves/Rotblat paper with admiration . I thought that it was balanced and well researched. I recall that my preliminary feeling was that it seemed unlikely that the BSE agent would be transmissible to man, but that the possible consequences of transmission were potentially alarming.[354]

Everyone who attended the Biologicals Sub-Committee meeting on 2nd November was exercised by the issue of BSE. At the meeting, there was a very full discussion of the Purves/Rotblat paper, which was used as a baseline; we then had a wider, general discussion of the issues raised and I would have summarised these. We then went on carefully to discuss each of the recommendations which had been made. It appears that Dr Purves attended the meeting although Dr Rotblat did not. Dr Purves may well have introduced the paper; he certainly answered questions on it. Dr Pickles would almost certainly have contributed to the discussion.[355]

We faced considerable uncertainty at this time. I knew from my knowledge of other models of infectivity that parenteral delivery of similar agents was likely to be more effective than other potential routes of transmission, such as an oral challenge. I was also aware the infection could �home onto� particular organs or tissues; that brain was likely to be such an organ and that there might also be risks from the use of nervous tissue. The Purves/Rotblat paper had additionally drawn attention to possible risks from lymphoid tissue; I believe that I was unaware of the possibility of lymphoid tissue posing a particular risk before reading this paper. I was, however, alive to the concept of sub-clinical infection.[356]

On the other hand we were conscious that scrapie; which had existed in sheep for more than 200 years, had not been shown to have any implications for human health. It was not merely that people who had eaten lamb or mutton had not developed CJD. The evidence also suggested that those who had eaten high-risk tissues (eg sheep brain) had not developed CJD. In addition, those who worked in high-risk occupations had not developed CJD from contact with infected sheep, including those who had worked in situations where there might have been a risk of contamination of cuts or wounds.[357]

In order that the meeting is seen in the appropriate context, it should be remembered that at this time we had no idea that the disease would become as widespread as it did. The Purves/Rotblat paper spoke of approximately 500 cases of this new disease; even if the figure was closer to a thousand cases, we were still talking about relatively small numbers of cattle in any herd.�[358]

305.         In his Statement to the Inquiry Professor Collee commented on each of the CSM Biologicals Sub-Committee recommendations:

�Recommendation (a): �

Our approach was based on the premise that the disease appeared to parallel scrapie, which had not been shown to be transmissible to man by the oral route. In the absence of further evidence we felt that it would be alarmist to take the view that BSE could be transmitted by the oral route, particularly in the case of orally administered medicinal products where the dose involved would be much smaller than in food. We added the word �immediate� to the recommendation to take account of the fact that the position might need to be changed if further relevant evidence came to light.

Recommendation (b): �

As to the first sentence of this recommendation, the words �appropriately certified� were added after discussion at the meeting. We knew that we would need further advice from MAFF on how to define this concept.

In due course, we learned that certification would not be workable and the phrase did not appear in the guidelines which ultimately went to manufacturers.

So far as the second sentence of this recommendation was concerned, I believe that we intended this recommendation to apply not only to the use of brain and lymphoid tissue in parenteral products, but also to the use of brain and lymphoid tissue in the manufacture of parenteral products.

I cannot specifically recall whether or not the question of topical products was discussed at this particular meeting, but I believe that topical products would have been thought of as very unlikely to pose a hazard to man and therefore did not warrant our immediate concern.

Recommendation (c): �

I cannot recall precisely why it was that we used the word elimination instead of inactivation. It may be that by use of the word elimination we had in mind the need for the wider manufacturing process (including sourcing) to eliminate the agent.

Recommendation (d): �

It was always our intention that the recommendations should apply to both existing and new products, rather than merely new products alone. The proposed article in the Medicines Act Information Leaflet (MAIL), for example, was to ask manufacturers to identify products in which bovine material had been used. Another recommendation was that the attention of the Review section (which only dealt with existing medicines) should be drawn to the recommendations. Thus, whilst I understand the fact that Sir Richard Southwood was concerned about the possibility of our only looking at new products, that was not our intention. The difficulty with existing products, however, was that they had to be identified first. That proved to be a very time-consuming task.

Recommendation (e): �

As I have stated, the intention was that the article in MAIL would be aimed at (and seen by) manufacturers of both new and existing products. I believe that the purpose of the article at this stage would have been to discover the extent of the use of bovine material, rather than to issue guidelines to industry.

I believe that the express reference to bovine albumin and foetal calf serum was made because we wanted to ensure that the use of these products, which we knew to be considerable, was not overlooked.

Recommendation (f): �

As I have explained, our intention was that the guidelines would apply to all products and it therefore made sense for the guidelines to be drawn to the attention of those committees.

Recommendation (g): �

This was included to ensure that the ADR section looked for any evidence of a link between existing medicinal products connected with bovine material and adverse reactions in humans.

The Sub-Committee also recommended that the Licensing Authority�s attention should be drawn to the need to give ongoing consideration as to whether action was required on bovine insulin and heparin products.

The Purves/Rotblat paper was able to identify these products as containing bovine material from the computer database. In particular, insulin had been identified in the paper as potentially the greatest problem (insulin is used virtually directly in the product; this is different from the indirect use of material in vaccines). In the event, it was discovered that no bovine insulins were manufactured from UK sourced material, save for one sample consignment in 1988 (see page 8 of Paper 1 submitted to the BSE Working Party in September 1989)�[359]

306.         On topical products Professor Collee also said the following:

�As to topical products, one of the obvious reasons for our not being concerned about those products was the barrier provided by the skin.� I regard topical products, when applied to intact skin, as involving even less risk than products taken orally, though applications to broken skin would potentially involve a greater risk.� I believe we would also have discussed the possibility of infection being spread by the application of topical products to open wounds.� However, the lack of epidemiological evidence of CJD-like illness amongst those occupationally exposed to spongiform encephalopathies (e.g. butchers and farm hands) encouraged us to regard this issue as a very low risk.� In addition, the topical products involved appeared to contain low risk bovine material.�[360]

307.         Dr Jefferys has commented:

�Once the Purves/Rotblat paper had been submitted to the expert advisory committees, consideration of the issues raised by BSE for the safety of medicines became a matter for the expert advisory committees who were supported and assisted in their task by officials from Medicines Division. It should be remembered that a number of such committees were involved. SEAR, the CRM and the CDSM were all involved in considering the recommendations of the Biologicals subcommittee and the CSM.�[361]

308.         On 2 November 1988 Dr Pickles minuted Mr Lawrence, with a copy to Dr Jefferys, in the following terms:

�1.�� The Biological Sub committee of CSM today discussed BSE. The unconfirmed minutes of the meeting should be available in a day or two but the main conclusions as I recollect them are as in the attachment.

2.��� The problem has already been discussed in outline by the Committee of (sic) Dental and Surgical Materials (CDSM) who will now be taking action in the light of today�s decision. The safety, efficacy and adverse reactions (SEAR) sub committee of CSM will be discussing BSE on Friday and the main CSM later this month. Not until that stage would it be appropriate for any formal comment to go from the Licensing Authority back to Sir Richard�s Group. But I can give an interim progress report next week.

3.��� I hope we can persuade Sir Richard that the issue is now being looked at in depth by the appropriate experts who also have the executive power to do something about it. This means Sir Richard needs only a passing reference in his own report.

4.��� An area where I am still unclear is what, if anything, is happening with veterinary products. I have seen a draft paper from G W Wood (dated 6 July �88) but do not know if this was before or after consideration by the VPC. Please could you find out for me what progress there is there?�[362]

309.         The attachment to Dr Pickles� letter was headed �Outline of Comments and Recommendations from Biological Sub-committees of CSM to November 1988�. It said:

�1.�� This potential problem needs to be taken seriously. The best working hypothesis is that BSE agent will have the same properties as scrapie agent. Medicinal products of concern could become contaminated in any of 3 ways:

a).�� bovine ingredients

b).�� bovine materials used in part of the manufacturing process eg BSA

c).�� bovine brain/heart infusion broth and similar products being used as culture medium. Whilst these media are autoclaved, the temperatures used may not be high enough.

The absence of disease in animals/herds must not be taken as absence of infection.

2.��� There is incomplete information on the licensed products potentially affected, as many products with licences of right (PLR�s) do not have even active ingredients correctly identified on the computer records. Non-active ingredients/materials of bovine origin may also be missed out. Some collagen implants of bovine origin as used by cosmetic clinics are not even licensed.

3.��� Questions could now be asked about many other products eg heparin, although it is believed all of this is now imported from overseas.

4.��� There is no need for action on any oral products.

5.��� Ideally, all bovine material in parenterals should come from healthy �approved� herds which have not been fed animal protein; processes should be such as to inactivate or eliminate scrapie or similar agents; alternatives to brain-penetrative stunning should be used for killing; brain and lymphoid tissue should not be used. But it is accepted evidence of elimination of scrapie-like agents may be unachievable in practice and some biological products may be physically damaged by processes adequate to destroy scrapie agent.

6.��� Whilst bovine insulins have only a very small place now in therapy, and safer alternatives are available for all but a handful of patients who do not take to human insulins, it would be premature to warn clinicians of the BSE-risk and this would run the risk of adverse publicity. Urgent review of bovine insulins, most if not all of which may be manufactured overseas� where BSE is not of concern, is what is needed next.

7.��� Were pigs to be susceptible to BSE/scrapie, then this would have very serious impact on supply of insulins.

8.��� The subcommittees recommendations could form the �framework� on which specific proposals for specific products could then be formulated by the secretariat and then brought back to the committee. Further information would be sought from MAFF and other experts on how disease-free herds, procedures and countries might be identified.

9.��� Biologicals also comment on the urgent need for further research in this area and were informed that the Southwood working party had reached the same conclusions.�[363]

310.         On 4 November 1988 the CSM SEAR (Sub-Committee on Safety, Efficacy and Adverse Reactions) met to discuss BSE and endorsed the findings of the Biologicals Sub-Committee meeting two days earlier.[364]� The minutes also record that SEAR� ��commented that appropriate research should be encouraged in this area, because of the many unresolved issues which makes risk assessment difficult.�

311.         On 8 November 1988 a meeting was held between NOAH and MAFF.[365] The minutes record that the following points were raised at the meeting on the BSE situation:

�4. BSE situation � progress discussion

i)���� �There is also possibility that BSE exists in the USA following tests carried out in Wisconsin.

As a result of these tests bovine material from the US can no longer be recommended for inclusion in biological products.�

312.         Problems with supply of bovine material were identified together with the possibility of a change in production methods. The minute of the meeting records that:

��It was felt that the publication of the guidelines was required to protect the UK image and demonstrate to the Commission that we had a clear action policy. We remain the only MS to have admitted to recognising the disease so far�.[366]

Southwood Committee: second meeting

313.         On 10 November 1988 the Southwood Committee met for the second time. The minutes recorded the following:

�Veterinary and biological products

2.(i)������� The outcome of preliminary discussions in the Veterinary Products Committee and Biologicals Sub-Committee of the Committee on Safety of Medicines (CSM) were reported. It was considered that a number of practical steps could be taken through advice to manufacturers on a voluntary basis. It was emphasised that advice should be given in relation to existing as well as new products. Sir Richard Southwood agreed to write to the Chairman of CSM on this issue. It was also agreed that the Report should contain a section on veterinary and medicinal products advising that the VPC and Biological Sub-Committee should have regard to the emergence of BSE in making recommendations and that they should take account of the products currently in use as well as new ones. Although possibly outside the Working Party�s terms of reference it was suggested that the use of sheep serum should be examined in human medicinal products.�[367]

The word �possibly� was a hand written addition.

314.         On 14 November 1988 Sir Richard wrote to Professor Asscher, Chairman of the CSM,� in the following terms:

�I understand that the Committee on Safety on Medicines is shortly to consider whether bovine spongiform encephalopathy presents a hazard in those medicinal products for human use that have been manufactured from bovine sources. At a recent meeting of the expert working party which has been set up by MAFF and DH to consider the implications of this desase (sic), we were informed of the provisional conclusions of the Biologicals Subcommittee.

We were pleased to hear of the detailed consideration that was given to this issue. As you may know, we have already identified the pressing need for more research in this area. We understand that in due course you may be considering whether licensing action of some sort is appropriate in relation to any specific products. We trust that any steps that are thought necessary to safeguard new medicinal products will be applied also to existing products. There are various measures that manufacturers could take to reduce or eliminate the risk of contamination by BSE agent in pharmaceuticals and which could be introduced by agreement with relative ease and with no detriment to the product. Those steps include using material only from healthy herds not fed ruminant-derived protein; avoiding use of brain or lymphoid tissue directly or in culture media; and reducing nervous tissue contamination of serum by ensuring animals are not destroyed by brain-penetrative stunning. You may like to consider whether informal advice on these lines to the pharmaceutical industry might be helpful. Other steps, such as ensuring the manufacturing processes are such as to eliminate any scrapie or similar agent, seem likely to prove more problematic.

We look forward to hearing your considered view when you have completed your deliberations.�[368]

315.         Professor Asscher has stated that �[t]his letter and Sir Richard�s other letters to me would have been circulated within the Medicines Division at the time.�[369]� He also said:

�I am glad that, in his letter, Sir Richard recognised that informal action was likely to be preferable to a formal licensing approach. As explained in paragraphs 64 - 66 of this statement, there would, at this time, have been no grounds for taking formal licensing action. Informal action is almost always preferable to formal licensing action. However, persuading the industry to accept informal recommendations was not necessarily going to be as easy a task as suggested in Sir Richard�s letter dated 14 November 1988�.[370]

316.         Dr Pickles minuted Dr Jefferys on 15 November 1988 saying that Sir Richard Southwood �might be writing to CSM/MD to encourage the implementation of any action thought necessary to existing products as well as to any new ones.�[371]� She goes on to say that:

��the current intention is for the working party report to contain a paragraph or two about medicinal products but to leave the recommendation to something like �the attention of the LA, the CSM and the VPC are drawn to the potential of transfer of BSE between animals or species in medicinal products, and are asked to take any appropriate action�. OK?�

Dr Pickles� note also addressed concern about scrapie in products from sheep.

317.         On 16 November 1988 the CDSM considered the paper discussed by the CSM Biologicals Sub-Committee at its meeting on 2 November 1988. The minutes record that the Committee noted the paper had been put to the Biologicals Sub-Committee and would now be seen by the CSM. The CDSM were to be kept informed of any developments. The Committee�s view was that at this stage synthetic materials should be used in surgery wherever possible and materials of bovine origin should be used only where essential.[372]

318.         On 17 November 1988 a full meeting of the CSM was held, chaired by Professor Asscher[373]. The minutes record in relation to BSE:

�7.1 The Committee discussed the paper and endorsed the recommendations of the SEAR and Biologicals Sub-Committees.

7.2�� The committee also noted the letter from Sir Richard Southwood (Tabled Paper 4).� The Committee agreed that the Chairman should reply to Sir Richard Southwood detailing the view of the Committee and referring to preliminary consideration of this matter by CRM and CDSM.�

319.         In his Statement to the Inquiry Professor Collee said[374]:

�On 17th November 1988, I attended a meeting of the CSM. I believe that I first saw the letter dated 14th November 1988 from Sir Richard Southwood to Professor Asscher at the meeting, when it was tabled. I am sure that there was a very full discussion of BSE at this meeting and that I played a large part in that discussion.

I am unable to recall our detailed discussions on Sir Richard�s letter. My recollection is that we saw it as a constructive letter rather than a critical letter. Sir Richard�s points were taken on board and guided the further detailed discussions which took place after the CSM meeting, leading up to the joint guidelines sent out in March 1989. The Inquiry will wish to know that it would have been most unusual for recommendations to be altered by the CSM without detailed working level discussion beforehand.�

320.         Professor Asscher also commented on this meeting in his Statement to the Inquiry:

�My first involvement with BSE occurred in the course of preparing for the CSM meeting which took place on 17 November 1988.� The CSM was, however, aware of the issues involving CJD and human growth hormone at this time and of the occurrence of CJD following dura mater implants.� They had come to our attention in the course of considering product licences for dura mater.� These experiences made us particularly wary of parenteral, as compared to oral, medicinal products.� At the time, the fact that scrapie had not transmitted to man also gave us reassurance that BSE was unlikely to be acquired by the oral route.�[375]�

321.         Professor Asscher also said in his Statement that copies of the Biological Sub-Committee�s recommendations were sent to the Chairman of the CRM (Professor David Lawson), the Chairman of the CDSM (Professor Colin Berry) and to MAFF. Professor Lawson had been present at the CSM meeting.[376]

322.         On 18 November 1988, Dr Jefferys circulated Dr Pickles� minute of 15 November to Drs Jones, Rotblat, Purves, Adams and Wood, saying:

�I would have thought that we could take comfort in the fact that scrapie has been present in sheep for many years and we have no evidence of any human threat posed by infected sheep in relation to medicinal products.� However, it might be appropriate if we checked the computer database to see how many medicinal products may derive from ovine material.�[377]

323.         On 24 November 1988 Professor Asscher replied to Sir Richard�s letter of 14 November. A draft reply had been prepared by Dr Jefferys and circulated for comments to Dr G Jones, Mr Wilson, Dr Adams, Dr Wood, Dr Purves, Mr Hagger, Miss Simpkins, Dr Rotblat and Mr Whitbread.[378] The letter stated[379]:

�The CSM has now considered the issue of bovine spongiform encephalopathy at its recent November meeting. The Committee endorsed the views of the Biologicals and SEAR (Safety, Efficacy and Adverse Reactions) Sub Committees. I understand that you had already been sent the views of those Sub Committees. I can now attach the recommendations from the full CSM.

Preliminary discussions have also taken place within the Committee on the Review of Medicines and Committee on Dental and Surgical Materials to consider what action needs to be taken in relation to specific existing products.

I hope you will agree that we now have in progress the appropriate action to safeguard both new medicinal products and existing products.�

324.         Professor Asscher said in his Statement to the Inquiry:

�I wish to make it clear that the CSM always intended its recommendations to apply to existing as well as new products and the draft guidelines reflected this. The draft sixth recommendation would not have stated that the earlier recommendations should be drawn to the attention of the review (i.e. CRM) section of Medicines Division had the recommendations only been intended to apply to new products.�[380]

�As to the second recommendation, Sir Richard Southwood appeared to be concerned that the proposed ban on the use of bovine brain and lymphoid tissue would not apply to the use of such tissues in the manufacture of parenteral products. However, the CSM was aware at this time of the use of bovine material in the manufacture of medicinal products (see paper prepared by Dr Rotblat and Dr Purves).The draft second recommendation was always intended to apply to the use of brain and lymphoid tissue in the manufacturing process as well as its use as an active ingredient.

It should also be made clear that we were relying on MAFF and the Southwood Working Party to assist us to define the concept of a �healthy herd� and to advise which bovine tissues were likely to pose the greatest risk.�[381]

325.         On 24 November 1988 there was a meeting between Mr MacGregor, Minister for Agriculture, Mr Meldrum, Mr Cruickshank, Mr Thompson, Sir Donald Acheson, Sir Richard Southwood and Dr Pickles.� This meeting was held to discuss the implementation of recommendations thus far and the progress of the Southwood Report. In relation to medicines it was recorded in a note prepared by the PS/Minister that:

�8.�� Sir Richard thought it was also important with a view to containing the disease to ensure that veterinary products (eg. serum) were properly controlled. Mr Meldrum confirmed that a control system had been introduced on a voluntary basis. He undertook to let Sir Richard have full details of what had been done.�[382]

326.         On 7 December 1988 Sir Richard replied to Professor Asscher�s letter of 24 November 1988. He stated:

��I am glad that the CSM has now considered the problems posed by bovine spongiform encephalopathy. I will put your letter before my colleagues at our next meeting, and I know they will want to join me in thanking you for your response.

Perhaps I might make two initial comments on the recommendations of the CSM. In the first place, I would strongly endorse and underline the importance of items 5-7 and also the �remark� below. As I wrote to you in my earlier letter, my colleagues and I are most anxious to ensure that existing products were identified and that manufacturers ensured that they conformed to the safety recommendations. The second point is that I believe in practice �the certification of healthy herds� is going to be more difficult, because as you know, this disease may be present for many years in an asymptomatic condition, thus certification would have to depend on evidence that food supplements containing material of animal origin have not been fed to the herds for as long as six or seven years or the lifetime of the animals concerned. I am not sure what arrangement the Ministry of Agriculture has in mind for certifying herds as healthy from this point of view, but as you will appreciate, the absence of a case of BSE would not be a sufficient condition.�[383]

327.         Professor Asscher commented on this correspondence in his statement to the Inquiry:

��the CSM had always intended to apply its recommendations to existing products and I had previously informed Sir Richard Southwood of the fact that the CRM, which only deals with existing products, would be considering the issue. When considering Sir Richard�s comments on the problems of certifying herds as healthy, it should be remembered that it was Sir Richard who had previously suggested �using material only from healthy herds not fed ruminant-derived protein� and described this as a measure �which could be introduced by agreement with relative ease� (see letter dated 14 November 1988 from Sir Richard Southwood to me) The experts� understanding of the BSE epidemic was constantly evolving at this time. In the circumstances, the CSM and the officials in Medicines Division had to rely upon MAFF and the Southwood Working Party for the latest information and interpretation of the facts relating to the extent of the development of the BSE epidemic and the infectivity of different bovine tissues We also had to rely on MAFF for guidance as to how best to define the concept of a BSE-free herd.�[384]

328.         Dr Jefferys has commented that:

��a number of the recommendations needed to be considered with MAFF so as to ensure that they were practicable and scientifically justifiable. These usually involved areas of veterinary science in which MAFF could be expected to have a particular expertise. The concept of an �appropriately certified healthy herd� (recommendation (b)) and questions as to what manufacturing processes were capable of eliminating scrapie-like agents are obvious examples of such areas. MAFF themselves were at this time in the process of revising the draft guidelines which they had prepared in July 1988 and it was desirable that a consistent approach be adopted. It should be remembered that the same pharmaceutical companies produced both human and veterinary medicines.�[385]

329.         In relation to Medicines Division contact with MAFF, Dr Adams has said:

�Towards the end of 1988 I had various informal conversations with MAFF colleagues about BSE as I was keen to know more about the disease and any possible implications it might have for human health. I also recall that I went to the CVL to see Mr Bradley in December 1988 for the same reason and spoke to colleagues within the Medicines Division.�[386]

330.         On 8 December 1988 Dr Pickles wrote to Sir Richard. She said:

�I am not entirely happy with the reply from the chairman of the CSM. I do not see anything in their recommendations that gives me any confidence that they will be taking any necessary action on existing products, or indeed taking note of any of the points you raised in your letter (based, as I explained, on points raised in the biologicals sub Committee but which did not appear in their minutes). In case you would like to reply again I enclose at 4 a possible draft, but may be this is something you would like to discuss in more detail next week. For your information, I enclose at 5 the note I made following the biological subcommittee.�[387]

331.         On 15 December 1988 the CSM held a meeting. The Committee noted the letter from Sir Richard Southwood.[388]

332.         On 16 December 1988 Dr Jefferys minuted Dr Harris in the following terms:

�1.�� Dr Jones has asked me to detail the present position on BSE with regard to medicinal products.

2.��� A detailed paper considering the issues posed by BSE for medicinal products was considered by the three Sub Committees of the CSM during early November and by the CSM on the 17th November. Dr Hilary Pickles attended the meeting of the Biologicals Sub Committee and the draft recommendations of that Committee and of the Sub Committee on Safety, Efficacy and Adverse Reactions (SEAR) were sent to the Southwood committee which met on the 10th November. After the CSM meeting, Professor Asscher wrote to Sir Richard Southwood giving him and his committee the full recommendations of the CSM. These are attached as Annex A to this minute. The minute of the CSM meeting is set out in Annex B.

3.��� Sir Richard Southwood replied to Professor Asscher on the 7th December. This letter is attached as Annex C. The CSM considered the letter as a tabled paper at its meeting yesterday and felt that a reply was not necessary.

4.��� The professional secretariat are now pursuing the recommendations made by the CSM. The CRM and CDSM will be involved as necessary.

5.��� The CPMP (the Committee on Proprietary Medicinal Products) was informed of the UK action at its recent December meeting.�[389]

Southwood Committee: third meeting

333.         On 16 December 1988 the Southwood Working Party met for the third time. The minutes record the following:

�Matters arising

3.���������� The correspondence with Professor Asscher was discussed. It was felt that the response was somewhat complacent, particularly in relation to the problem of existing medicinal products. In the circumstances a further letter would be sent to Professor Asscher to suggest that practical advice could be given to the pharmaceutical industry. In addition the Chairman would write to Dr Little of the Veterinary Products Committee to establish what measures they were adopting in the light of this new disease problem.�[390]

334.         On 20 December 1988 Sir Richard Southwood wrote to Dr Little about the potential risk from using biological products manufactured from bovine sources in the light of the emergence of BSE in cattle.[391]� He said �[w]e are pleased to hear of the detailed consideration which is being given to this issue.� As you may know we have already identified the pressing need for more research in this area.�� He went on to request information on what consideration the VPC had given to licence applications to new products. He said,� ��we trust that any steps that are thought necessary to safeguard new products will also be applied to existing products.�� Sir Richard suggested some steps that could be taken by manufacturers to reduce any possible risk of contamination by the BSE agent:

��Presumably one solution would be to purchase material from abroad. Other possibilities might be to avoid the use of brain or lymphoid tissue directly or in culture media and reducing nervous tissue contamination of serum by ensuring that animals are not destroyed by brain penetrative stunning.��

He concluded by indicating that he would appreciate Dr Little�s �views on whether some form of guidance to the industry might be useful.�

335.         On 21 December 1988 Dr Pickles provided relevant papers on BSE and medicinal products to Dr Harris.[392]

336.         On 23 December 1988 Sir Richard wrote to Professor Asscher.[393]� He said the following:

�I wrote to you on 7 December with my initial comments to your letter of 24 November, which enclosed the recommendations of the CSM in relation to bovine spongiform encephalopathy.

I have now had the opportunity to obtain views from my colleagues on the working party and they have asked me to convey our continued concern. My letter of 14 November was written in the light of the draft recommendations we knew were to be put before the CSM and hoped the committee might have seen fit to amend their recommendations accordingly.

We interpret your recommendations as drafted to mean that conditions that may be impossible in practice will be demanded of new products of bovine origin, and yet other than for the insulins we see no firm commitment to look at existing products.

In my letter of 7 December I touched on one of the conditions that may prove very difficult in practice, the �certification of healthy herds� if this is to embrace those never fed ruminant protein. In the letter of 14 November I hinted at the problems there could be in another aspect, that of ensuring manufacturing processes are capable of eliminating scrapie agent. It is also not clear if the exclusion of brain and lymphoid tissue concerns only active ingredients or intermediates and culture media also, and whether this is an absolute condition. Some flexibility may be needed in interpretation of these guidelines.

We understand that the CDSM and CRM will be informed of your recommendations and we trust they will take appropriate action. We note the recommendation to the Licensing Authority to consider bovine insulin and heparin, and would like reassurance that appropriate action would be taken against any other relevant parenteral products: this point is not clear from the CSM minutes.

As my letter of 14 November mentioned, there are various steps that could be taken relatively easily to reduce or abolish the �risk� and we believe some manufacturers have already taken these measures. But there could be other manufacturers who are in ignorance of the potential problem and who might benefit from informal advice. Perhaps you intended that the MAIL article would cover these aspects as well as being a search for information on ingredients not available in the Licensing Authority records. Dr Hilary Pickles who is on the secretariat of my group would be happy to assist in drafting any article of this sort. We see that a reduction in �risk� could result more rapidly from informal action, much of which we believe could be taken without formal licence variation, rather than relying on a formal licensing approach.

This new disease in cattle has caused us to question the possible risk to humans from zoonoses of all sort (sic), including perhaps some yet to be discovered. This is a general issue that the CSM may like to consider in relation to medicinal products of animal origin.

We are now finalising the report from my working party and will make reference to our concern about medicinal products and that we have drawn the attention of the Licensing Authority to that concern.�[394]

337.         On 23 December 1988 a draft guidance document on BSE and biological products was prepared by the BP&S Department of the CVL. It was prepared to give guidance in order to reduce the risks of inadvertently contaminating biological products with the BSE agent.[395]

338.         Sir Kenneth Calman told the BSE Inquiry that:[396]

�This was clearly a very important area at several different stages in the process. Right at the beginning in terms of the 1988/1989 issue, there was a very rapid review of all medicines, including vaccines which might or might not have contained products of a bovine nature. Because of that review all medicines were carefully considered and where there was a bovine product then this was changed rapidly to come from a bovine source outwith the United Kingdom.�

339.         In his Statement to the Inquiry Professor Asscher stated that Sir Richard�s comments on existing products:

��appear to be based on a continuing misunderstanding of CSM�s actions. As previously stated, the CSM had always intended that its recommendations should be applied to both existing and new products. It was for this reason that the CSM ensured that BSE was also considered by the CRM.�[397]

Professor Asscher also said:

�As Chairman of the CSM, my policy was always to attempt to use negotiation and recommendations rather than legal action. Formal regulation was only to be used in cases of extreme urgency or where the pharmaceutical industry had indicated an unwillingness to accept the CSM�s recommendations.

Informal action is invariably both quicker and cheaper than regulatory action. The pharmaceutical industry is highly professional and is normally content to accept the recommendations of the CSM. It is not in the interests of pharmaceutical companies to promote products which are being questioned on safety grounds.

I believe that in the case of BSE, the issuing of non-binding recommendations achieved a result that could not have been obtained through taking regulatory action. Licences cannot generally be revoked merely on the basis of a remote and theoretical risk. Such a revocation would very probably be overturned if legally challenged and we would never advise Ministers to take formal regulatory action in such circumstances. The risk posed by BSE was regarded as remote and theoretical and as such formal regulatory action could not have been scientifically justified. However, it was possible to achieve the same result through the issuing of recommendations because the industry wished to receive advice and was willing to accept it. As far as I am aware, no companies declined to follow the recommendations of the CSM on BSE and medicinal products.�[398]

340.         On this issue Dr Rotblat has said:

�I understand that the Inquiry may be interested in the reasons why non-binding guidelines were issued rather than formal regulatory action being taken. The issuing of non-binding informal recommendations is an integral part of the licensing process and the work of the MCA. Informal recommendations are used in the knowledge that regulatory action can be considered if it becomes necessary to do so. Pharmaceutical companies are very frequently told that if they comply with certain recommendations they will be granted a product licence. It is very unusual for a company to decline to follow the recommendations in such cases.

The use of informal recommendations in the handling of BSE was entirely in keeping with the CSM�s general practice - the issuing of recommendations/guidelines was the method adopted on every matter of a similar nature. One advantage of this approach was that, in general, the use of recommendations was quicker than the process of revocations and appeals.

The climate at the time was such that industry was very willing to comply with informal guidelines and to the best of my knowledge, no manufacturer refused to comply with the CSM/VPC guidelines on the use of bovine material. In the circumstances, there was never any need to take formal regulatory action with regard to BSE. Further, there was no need to impose formal deadlines on companies because, in my view, all companies changed sourcing as soon as they were able to do so.�[399]

1989

341.         In January 1989 the Medicines Unit, MAFF, prepared a revised version of the guidelines for the VPC. The covering note said: �the document is presented to members essentially for information but it will be helpful to have comments on it, and suggestions from the Committee will whenever possible be incorporated�. The note also stated �it is important to progress the guideline as quickly as possible so that it can be distributed to appropriate organisations, and manufacturers using material of bovine origin in their products�. The guideline recommendations, which dealt with the �selection and treatment of material obtained from cattle in the UK and destined for use in the preparation of biological products�, provided:

�I)��� COLLECTION

1.��� No product from a BSE affected animal is acceptable for use.

2.��� Material should be obtained only from BSE-free herds.

3.��� Brain-penetrative stunning is unacceptable where tissues are collected post mortem.

4.��� Instruments used to collect samples and holding vessels should either be virgin�or be sterilised. After use reusable instruments should be sterilised after cleaning. Disposable materials should be incinerated.

II)��� TISSUES UNSUITABLE FOR COLLECTION

1.��� Primary cell structures.

2.��� Endocrine glands including placenta.

3.��� Spleen and lymphoid tissue.

4.��� Neural tissue

III)� TISSUES AND OTHER MATERIALS SUITABLE FOR USE

It is recommended that wherever possible source animals are calves.

1.��� Serum. All cellular components must be removed.

2.���� Fetal calf serum provided great care is taken to avoid contamination by placenta and fetal fluids. All cellular components must be removed.

3.���� Milk, or products derived from milk collected aseptically from individual cows under 3 years old.

4.��� Faeces collected from the rectum.

5.��� Bile collected aseptically.

6.��� Cell lines not derived from� neural or lymphoid tissues or cells.

7.��� Sterilised tissues excluding those listed in II.�[400]

Joint CSM/VPC Guidelines considered

342.         On 3 January 1989 Drs Adams, Jefferys and Purves, of the Medicines Division DH, met Dr Little, Mr Kidd and Mr Bradley of MAFF.[401]� A note, taken by Dr Adams, recorded the following:

�Subject: BSE and Medicines Licensing

1.��� MAFF stated that BSE had come before the veterinary Biologicals Sub-Committee in November 1987. With increased notifications of the disease, the implications for veterinary medicinal products were discussed with NOAH in July 1988 when draft guidelines were presented. A redraft of these guidelines, following discussions with MAFF and MD will be presented to VPC in January 1989.

2.        MAFF filled in background on trade implications, the Southwood Committee, inclusion of BSE on the Zoonosis Order and undertook to provide relevant documents for information.

3.        MD described the progress of Committee considerations and unresolved questions such as

a). Is there a problem to man � what about scrapie in sheep which has not been associated with any human disease?

b). What is a �healthy herd�?

c). How may manufacturers be expected to show that scrapie is inactivated by specific processes?

d). How many products should be implicated?

MD stated concerns re bovine insulins, heparin; also re vaccines, monoclonal products and others that have used foetal calf serum/bovine albumin/bovine broth in manufacture.

4.��� MAFF considered that no herd could be guaranteed healthy, all have had some contact with animal (sheep) protein in feed-stuffs: the problem is not necessarily exclusive to UK, there is a risk of spread to to (sic) Europe especially as feed-stuffs are exported and export of calves, embryo and semen from UK is increasing. The US have had Transmissible Mink Encephalopathy from downer cow feed. Ireland have had 2 x confirmed BSE cases.

5.��� MAFF considered that the safest source of bovine material was from Australia/New Zealand where animal/tissue imports are strictly controlled and where scrapie is absent.

6.��� Collection of foetal calf serum (FSC) (sic) may be critical. In the diseased sheep, the placenta is heavily contaminated with scrapie; present collection of FCS is not be [sic]an aseptic procedure and great skill is needed to avoid the placenta.

7.��� No farm or abattoir can approach surgical cleanliness and many may be contaminated already with BSE.

8.��� Although high pressure/high temperature sterilisation is possible, MAFF understood that the industry was not equipped with high pressure vessels for processing.

9.��� MD/MAFF agreed that it was essential to keep �in step� especially as MAFF concerns about animal vaccines would cause DH great difficulties of supply if current stock had to be lost.

10.�� MD/MAFF agreed to maintain official links regarding all developments. MAFF would put revised guidelines to VPC in January after which MD/MAFF would meet again with expert advisors (NIBSC & Biols) to produce joint guidelines for industry. These will be published in MAIL with a request for information on products.

11.�� A resume of the present position would be made to Dr Harris DCMO by MD. Dr Murrell (Zoonosis) would be kept informed.

Post meeting note: The MD/MAFF working group involving NIBSC & Biols (CSM) will meet at 2.30pm Wednesday, February 1.�[402]

343.         In his Statement to the Inquiry, Dr Adams said[403] of the 3 January meeting:

�At the end of the meeting, MAFF and MD agreed to maintain official links regarding all developments. The immediate plan was that MAFF would put revised guidelines to VPC in January after which time MD/MAFF were to meet again with expert advisors to produce joint guidelines for the pharmaceutical industry, so that there would be a consistent message to industry. We agreed that it was essential to keep �in step.��

344.         On 4 January 1989 Mr Bradley minuted Dr Watson about the certification of BSE-free herds for sourcing material for biological products. He outlined a number of possible options for further discussion.[404]

345.         On 4 January 1989 the Biologicals Sub Committee of the CSM met.[405]

346.         On 5 January 1989 Dr Watson minuted Mr Meldrum, attaching a copy of Sir Richard Southwood�s letter of 20 December 1988 to Dr Little. Dr Watson stated that it had been agreed at the meeting on 3 January that �if possible both the veterinary and medical interests would be covered in a single note for the guidance of pharmaceutical companies.�[406]

347.         On 9 January 1989 Dr Adams and Dr Jefferys jointly minuted Dr Harris to update him on the current situation.[407]� They said:

�1.�� CSM considered a paper produced by the Secretariat at its November meeting, following detailed discussion by the Sub-Committees when experts from NIBSC were present. CSM endorsed a set of 7 recommendations.

The recommendations were forwarded to Sir Richard Southwood. He had been sent a preliminary (and in the event identical) set of recommendations following the meeting of the Biologicals Sub Committee at the beginning of November.

However, CSM recognised that it needed more advice from officials in MAFF about the veterinary aspects of their proposals. The Committee also felt that their recommendations were in the form of initial proposals and that these might need to be amended in the light of increased knowledge about the disease.

CRM and CDSM have been kept informed.

2.��� Since the CSM meeting, the Secretariats have been looking at the recommendations and seeking to implement them. During this time the following issues have become apparent.

i)���� MAFF have produced draft guidelines regarding the use of bovine material in veterinary medicines which will be put to the VPC at its meeting on the 19thJanuary.

ii) �� It was originally assumed that BSE was exclusively a UK problem. Officials from MAFF now suggest that this may no longer be the case and this has implications for the sourcing of bovine materials.

iii)��� CSM considered the problem in the light of a list of 43 products from our computer in which �bovine� was included in the description of active ingredients.

����������� You will be aware that the computer record cannot provide a complete list of all products in which bovine material has been used as excipient, or as an intermediate in manufacture. Such products would include vaccines and monoclonal antibodies.

����������� This poses a much greater problem since bovine albumin, foetal calf serum and bovine nutrient broths are extensively used in the production of most biological and biotechnological products and are used for all vaccines and in the production of most monoclonal antibodies.

3.��� Extensive discussions have taken place with officials from MAFF and there have been meetings between the Secretariats. There is agreement that we must keep �in step� particularly as MAFF is concerned about the safely (sic) of vaccines for animals. These are prepared in the same way as for humans and involve the use of foetal calf serum.

It is known that for sheep infected with scrapie there is a high concentration of the scrapie-like agent in the placenta. This means that very strict control must be given to the collection of foetal calf serum if the scrapie model is of relevance to BSE.

4.��� New recommendations for the collection of bovine material are to be discussed by the VPC this month. These recommendations will then be considered by the CSM, CRM, CDSM and their Sub Committees alongside the original recommendations made by the CSM, and their views will be sought on the period of implementation.

An amalgamation of the two sets of recommendations will mean a slight change in emphasis since the MAFF proposals concentrate upon the collection of the bovine material, whereas the initial CSM proposals were concerned more with the production of the medicinal product.

This would allow clarification of the definition of healthy cattle, and would give clear advice about the collection of foetal calf serum and bovine albumin. At the same time, the CSM will be asked to reconsider its third recommendation since this may be very restrictive (this was commented upon by Sir Richard Southwood in his letter of the 14th November to Professor Asscher).

5.��� It is proposed that DH Medicines Division and Medicines Unit of MAFF should agree a common set of guidelines about procedures for collecting and using bovine material. These will be published jointly in MAIL (the Medicines Act Information Leaflet).

In view of the uncertain information as to which products contain bovine material, companies will also be requested to supply details to MD.

MD and MAFF officials have arranged a working group (involving NIBSC and Biologicals Sub-committee) to ensure that the proposals will be practicable and capable of implementation over as short a time period as possible, and also should not damage the supply of important products such as vaccines and monoclonal antibodies for human use.

6.��� A particular problem which needs to be considered is that of products (vaccines in particular) which have been produced and are awaiting distribution. It has to be recognised that for some vaccines there may be supplies of up to 5 years.

It is clearly important to ensure each recommendation can be sustained without raising public alarm that could impair vaccination programmes.

7.��� The CSM recommendations are set out as Appendix A. The correspondence between Sir Richard Southwood and Professor Asscher are attached as Annex B and a draft of the proposed MAFF recommendations are attached as Annex C.

9.��� So far, neither Medicines Division nor MAFF have been given a sight of the interim report from Sir Richard Southwood and it would be most helpful if this could be made available.�[408]

348.         Dr Jones, Mr Wilson, Mr Stewart, Dr Pickles, Dr Wood, Dr Rotblat, Dr Purves, Dr Little, Mr Kidd and Mr Bradley were copied in on this minute.

349.         Dr Jefferys has commented that:

�All of these issues needed to be debated and required considerable technical expertise. They were not questions which admitted of simple straightforward answers; indeed this was leading edge science. It was felt that the guidelines which were eventually to be approved had to be capable of withstanding scientific scrutiny and possible legal challenge. The guidelines would have to be seen to be proportionate. If the eventual guidelines were clearly justifiable and practical the chances of universal compliance would be greatly increased.�[409]

350.         On 13 January 1989 Mr Scollen, of the MAFF Medicines Unit, sent a minute to Mr Cruickshank.[410]� It said:

�Dr Little, Mr Kidd, Mr Taylor and I have discussed the progress of the review being undertaken by DH and MAFF experts of the implications of BSE for the safe production of vaccines and other biological health products. You may also like to be brought up to date.

2. Given the nature of BSE and the lack of symptoms during its long incubation period, there is a problem in ensuring that foetal calf serum and other bovine material used in the preparation of biological products is free of contamination. While there may be safeguards which can be introduced for the future, there is a potential problem over existing stocks of vaccine, most of which will have been produced using some kind of bovine material. (The risk, or at least the perception of risk, could, of course, go much wider as Mr Meldrum points out in his minute of 10 January to PS/Minister.)

3. Medicines Unit and DH�s Medicines Division have prepared draft guidelines, respectively, on the selection and treatment of bovine material and production processes using it. The plan now is to combine the two so that the two Departments are seen by the industry to be speaking with one voice, particularly on a matter where they are so interdependent. There is also further work to be done in order to judge the need for more extensive action. For example, there are questions about the availability of BSE � free material even if overseas sources are included, the means of controlling production of the serum etc supplied to licensed vaccine manufacturers and the relationship, if any, between BSE and Creutzfeldt-Jacob Disease. Attention may be drawn to this last point by the inclusion of BSE in the Zoonosis Order and the restriction on the disposal of milk from suspect animals.

4. While there is potentially a need for radical � and expensive action, it is, of course, quite possible that in the course of a few years we will be able to demonstrate the effectiveness of the action already taken to eliminate BSE. Extravagant action now to deal with a contingent risk could then seem to be wholly disproportionate. Moreover, new collection methods would not deal with the problem of existing stocks of vaccine, noted above.

5. These are some of the issues to be pursued at a further meeting with DH on 1 February, which will be attended by Professor David Tyrrell among others. They will also be in the background to the reply which Dr Little will be preparing to the letter he has received from Professor Southwood. (I understand from Mr Lawrence, however, that Professor Southwood�s report may well be quite general in its recommendations for action in this area.) In my own view the issues involved centre on an assessment of the risks associated with maintaining or disrupting the supply of vaccines for human health purposes. The issue is therefore one to be addressed first and foremost in the human health context, with MAFF advising on the availability of animal material considered free of contamination. Judgements about what is needed and feasible on the animal medicines front can be more readily taken afterwards. In addition to the meeting on 1 February, I shall be taking up these points with Mr Wilson and his colleagues when they visit Tolworth on 23 January.�[411]

351.         This letter was copied to Mr Meldrum, Mr Little, Mr Kidd, Mr Suich, Mr Lawrence and Mr Taylor.[412]

352.         On 17 January 1989 Dr Pickles sent a letter to Sir Richard Southwood.� She commented that Medicines Division �appear to be taking the potential problem with medicinal products seriously at last� and that Sir Richard�s �latest letter to Professor Asscher should help.�[413]

353.         On 19 January 1989 the VPC met and considered their draft guidelines on veterinary medicinal products.[414]

354.         On 26 January 1989 Professor Asscher responded to Sir Richard Southwood�s letter of 23 December 1988 (see paragraph 336 above). He said:

�Thank you for your letter of the 23rd of December, which unfortunately did not reach Medicines Division until the 12th January.

The Secretariat of the CSM and also of the CRM and CDSM have been considering the initial recommendations which my Committee made and have been seeking to implement these.

We originally considered the problem of BSE in the light of the 43 products which our computer database showed to include bovine material as an active ingredient. We will now need to consider the possible hazard from the use of bovine material as an intermediate in the manufacture of products. This will include the use of bovine material in nutrient broths, foetal calf serum and the use of bovine serum albumin. You will be aware that these materials are used very extensively in the production of most vaccines, monoclonal antibodies and other biotechnologically derived products.

MAFF are also concerned about such products and they have now produced new draft guidelines regarding the use of bovine material in veterinary medicines: these are currently under consideration by the Veterinary Products Committee.

Following several meetings between Medicines Division officials and their counterparts at MAFF, it is hoped that a joint guideline for the manufacturers of both human and veterinary medicines can now be agreed and published. Therefore a further paper is being produced for consideration by the CSM and its Sub Committees. We will be reconsidering whether our recommendation that ��the manufacturing processes are capable of eliminating the scrapie agent� is too stringent. It will also be proposed that the CSM uses the definition of a BSE-free herd which has been proposed by MAFF (you will remember that my Committee deliberately chose the words �appropriately certified healthy herds� to allow us the freedom to obtain more expert advice from our veterinary colleagues).

We have to consider the impact on the supply of these important products whilst at the same time seeking to maintain public confidence in the vaccination programme. Many vaccines are stored for up to 5 years before being released and this will therefore have to be considered.

For all these products it will be important to ensure that our recommendations are practicable and can be scientifically justified.

Finally, I want to reassure you that CSM intends to take appropriate action in regard of products within its remit and that CRM and CDSM are being kept fully informed of our recommendations. I hope you will agree that the Secretariats and the Committees are giving considerable attention to this important issue.�[415]

355.         Professor Collee commented on this correspondence in his statement to the Inquiry:

�In general terms, my feeling is that Sir Richard, perhaps understandably, believed that we were not going to take certain action, which in fact we had intended to take all along. In every other respect, I regarded his comments as constructive and took them on board. By the time the guidelines were finalised, I believe that all of the points made by him had been addressed.�[416]

356.         Dr Jefferys saw or was copied in on the correspondence between Sir Richard Southwood and Professor Asscher on 14 November 1988, 24 November 1988, 7 December 1988, 23 December 1988 and 26 January 1989.[417]� Dr Adams saw the 14 November letter, a draft of the 24 November letter, and the 23 December and 26 January letters.� Dr Rotblat saw the letter from Professor Asscher to Sir Richard Southwood of 26 January 1989.[418]

357.         On 26 January 1989 the CSM held a meeting.[419]

358.         On 26 January 1989 Dr Little replied to Sir Richard Southwood�s letter of 20 December 1988.[420]� He said:

�The Veterinary Products Committee had a very full discussion on BSE at their last meeting on 19 January when they considered a set of draft guidelines which had been prepared by the Biologicals Committee in consultation with various experts at the Central Veterinary Laboratory and elsewhere.� The VPC have requested further information including a full list of products involved, including all the old medicines, to assess the likely effect of various control measures and their practicality.

The Biological Committee has discussed BSE on a number of occasions over the past year and we have met with the National Office of Animal Health (who represent the Veterinary pharmaceutical industry) in July, November and January and have warned them of the need to introduce control measures to avoid possible problems with material which could to (sic) be contaminated with BSE, and we have also met many of the individual product licence holders.

Given the difficulty of detecting the BSE agent our philosophy in drafting guidelines for consideration by the VPC has been to concentrate on the source and nature of the materials used in the manufacture of veterinary products.

The experience with Scrapie has led vaccine manufacturers to avoid sheep material.� One way forward with the current situation would be to substitute tissues from other species where either cattle or sheep material is used but this would cause widespread disruption of supplies.

Another way forward would be to use cattle material from a presumed BSE free source.� Manufacturers are already turning to overseas sources and particularly Ireland but the discovery recently of BSE in Ireland indicates the problem which may arise from this method of control.� Moreover, the presence of exotic diseases rules out tissues and sera from many other countries. It might be possible to certify some herds in the United Kingdom as free from BSE in the future but it will be a long time before the full range of products used in the manufacture of biologicals from foetal calf serum to milk casein, could be derived from such sources.

Another way forward is to look at the constituents of each product and assess the risk.� In some cases substitution may be possible � i.e. the use of synthetic media for Clostridial vaccines rather than cooked meat broths or pig bile instead of ox bile.� In other cases such as ox brain for pituitary hormones we have already stopped the use, as synthetic hormones are widely available.

Foetal calf serum poses a problem in that it will be difficult to find an adequate substitute.� Although the risk is likely to be very low, some manufactures (sic) are looking overseas for supplies.

We are also working very closely with colleagues in the Department of Health to ensure we issue consistent advice to manufacturers.

I will send you a copy of our guidelines when the VPC approves them.

This certainly is a very serious problem and we look forward to seeing your report and any other advice you may care to offer.�[421]

359.         This letter was copied to the CVO, Mr Cruickshank, Dr Watson, Mr Kidd, Mr Taylor, Dr Thornton, Mr Lawrence, Mr Wilesmith, and Dr Adams of Department of Health.[422]

360.         On 30 January 1989 Sir Richard wrote to acknowledge receipt of this letter and commented that veterinary medicines posed an �extremely difficult problem.�[423]

361.         On 1 February 1989 a small working party of MAFF and DH officials and experts met.This group was known as the �Human and Veterinary Medicines BSE Briefing Group (HVMBG)�. Those present were Drs Jefferys, Adams, Purves and Rotblat of DH Medicines Division, Dr Little, Mr Kidd and Mr Bradley from MAFF, Professor Collee, Dr Schild and Dr Minor of the Biologicals Sub-Committee of the CSM, and Dr Pickles representing the Southwood Committee Secretariat.[424]

362.         The meeting agreed the text of what were now to be joint VPC/CSM guidelines for product licence holders and manufacturers plus a timetable for clearance by various advisory committees to enable publication in MAIL (Medicines Act Information Leaflet) before Easter.[425]

363.         Dr Purves has commented:

�At that time we were very much aware that the Southwood Working Party was shortly to report on its findings.� We would have wanted to await the report from the Southwood Working Party before approaching the industry.�[426]

364.         Dr Jefferys has also said:

�I am sure that it was also felt that the questionnaire should be issued at the same time as the guidelines were sent to companies for a number of practical reasons. It was felt that neither guidelines nor a questionnaire were likely to be appropriate until the Southwood Working Party had provided an authoritative assessment of risk.�[427]

365.         On 2 February 1989 Mr Scollen minuted Mr Cruickshank about BSE and Biological Medicinal Products. The minute reported on the main conclusions of the 1 February 1989 meeting of the HVMBG, which Mr Scollen had attended. The minute noted[428]:

�3.�� The Working Group (as it is now termed) agreed:

i).��� on the text of joint MAFF/DH guidance for manufacturers;

ii).�� a timetable for their clearance by advisory committees and publication in MAIL before Easter;

iii).�� that further action especially on current stocks of the affected products, should be determined once the scale of the problem has been more precisely identified with the help of manufacturers;

iv).� that any such action would need to be based on a human health risk/benefit assessment.

The revised guidelines will be put to the VPC on 16 February, following a previous full discussion in the Committee on 19 January

�

5.��� The Working Group was also shown an extract from the current draft of the Report. There was general dismay at the drafting, which tends to highlight the (theoretical) risk via medicines and to relegate the qualification that the risk is remote. The paragraphs concerned also imply (mistakenly) that numerous, licensed human medicinal products are affected; that some but not all manufacturers have taken necessary action; that various safeguards could readily be introduced into the production and processing of bovine material; and that the Licencing Authority and its advisory committees need to have their attention drawn to the problems.

6.��� The Working Group felt that much of this was, at best, misleading. For example, many manufacturers have been alerted to the problem but there is no reason to believe that they are in a position to take effective, unilateral action. Moreover, the start of MAFF/DH work on the issue comfortably pre-dates the Southwood Committee.

7.��� Even if the Report is modified in the light of these reactions, its appearance seems likely to trigger a need for a major public relations job which takes full account of the medicines angle. Consistency between MAFF and DH will be essential and should be achievable. The guidelines themselves could subsequently generate similar pressures since they clearly do not address the issue of current stocks and they could prompt questions � for example � on the standards applicable in the collection of animal material at slaughterhouses for biological medicinal purposes.

8.��� While I have no doubts about the Working Group�s staged approach and the balance being struck between risks and benefits to human health, this will not be the easiest position to present to a potentially critical public prone to see the influence of commercial interests.�

366.         Mr Meldrum, Dr Little, Mr Suich, Mr Coe, Mr Kidd, Mr Bradley and Mr Taylor were copied this minute.

Southwood Committee: fourth meeting

367.         On 2 February 1989 Dr Pickles wrote a letter to Sir Richard Southwood. She stated the following:

��I attended yesterday a meeting of experts from both the VPC and Biols CSM together with DH/MAFF officials. I can give a full report tomorrow. They expressed concern at the proposed wording in the report (which I informed them about at the meeting in confidence). As Professor Asscher attempted to explain in his letter of 26 January the problem is very involved. They have now realised that virtually none of the current essential human or animal vaccines could comply with the CSM guidelines as agreed by their November meeting, and there may be several years of some vaccines in stock to make matters more difficult. Public confidence in the vaccination programme must not be put in jeopardy and yet supplies of some vaccines are very limited. After a late start, it now seems that both human and veterinary sides of the medicines business are working together and putting together a package of measures that seem sensible and workable (and indeed now incorporate all the points you raised with Professor Asscher in your earlier letters, and which I had raised with them separately). The attached note from a colleague of mine to our Deputy Chief Medical Officer gives some of the details. I can give more tomorrow. You might also find it useful to give a ring to Professor Gerry Collee, in Edinburgh �. He is Chairman of the Biologicals subcommittee (and also on a vaccination subgroup) and was present at yesterday�s meeting.

If you are content that all is now in hand, a briefer version of 5.3.3 might be adequate. I attach my suggestions. This treats CSM/VPC like HSE: ie the problem has been referred to the body with the statutory responsibility in that area and it is then for them to take appropriate action. I also have suggestions for minor alterations to the summary sections to make it clear that the Licensing Authority has already started addressing the problem.�[429]

368.         A handwritten note was written at the bottom of the page[430]:

�Since writing this we have discussed on the phone and it seems that the problem is resolved.�

369.         On 3 February 1989 the fourth meeting of the Southwood Committee took place and was recorded in an informal note by Dr Pickles on 6 February 1989.[431] Correspondence between Professor Asscher, Dr Little, Mr Andrews and Sir Richard Southwood was considered. Amongst the other items mentioned were the following:

�6.��������� Draft Report

The report was considered page by page and numerous minor alterations and corrections were made. The most significant changes were:

�

(iv)� The section on medicinal products was shortened substantially to give no details of changes that might reduce risk, since the statutory responsibility in this area lay with the Licensing Authority [Dr Pickles was able to report on the very satisfactory response now being taken by both the human and veterinary sides of the Licensing Authority, but also explained the potentially grave problems to supply of essential vaccines if fetal calf serum were to be considered at risk of being infected]�

Prelude to publication of the Southwood Report

370.         On 9 February 1989 the CMO minuted Dr Harris, the DCMO, in the following terms:

�My attention has been drawn to a sentence in Dr Pickles� draft of a submission to the Secretary of State on this matter. It reads: �At the present time we can�t give any complete guarantee of safety for human medicines that use bovine materials in manufacture such as most vaccines.� Having looked at the report I am not able to find any statement which supports this statement of concern. I have, however, therefore spoken to Dr Pickles on the telephone and she reports to me that for some considerable time she has had serious concern about the safety of bovine-based vaccines in the light of the fact it has been discovered that contamination with placental material (which is known to be heavily infected with the BSE particle) is a distinct possibility in the preparation of material for human vaccines derived from foetal serum. This matter as described to me by Dr Pickles gives me sufficient cause for concern to ask you to look into it urgently together with Medicines Divisions. I shall amend the submission to indicate that the question of the safety of vaccines derived from bovine material is a matter which has not been dealt with directly by Southwood�s group, but is one in which I am making urgent enquiries.�[432]

371.         Commenting on this letter during his oral evidence to the BSE Inquiry, the CMO said that this intervention was� �[q]uite contrary to my normal practice� and that he was �trying to stir up more activity in the Medicines Division�. He did not think that the issue had been resolved despite past reassurances.[433]

372.         The draft submission, referred to by the CMO in his minute of 9 February 1989, was written by Dr Pickles.[434] In relation to medicines it stated:

�Sir Richard Southwood is here presenting his report on bovine spongiform encephalopathy jointly to MAFF and DH ministers.� I can commend this report to you.

3.        In Sir Richard�s view the risk to human health is minimal.� Nevertheless he has alerted the Licensing Authority and the Health and Safety Executive to potential problems in their areas of responsibility.� At the present time, we cannot give any complete guarantee of safety for human medicines that use bovine materials in manufacture, such as most vaccines.� However, appropriate action is being taken by Medicines Division following advice from Committee on Safety of Medicines, the Committee on the Review of Medicines and the Committee on Dental and Surgical Materials and defensive briefing is being prepared for when the report becomes public.

�

��������������������������������� E D ACHESON�

373.         On 9 February 1989 the Southwood Report was presented to the Secretary of State for Health by the CMO.[435]� Sir Donald recommended the Report� �I regard it as a thorough study of the problem with sound and balanced conclusions. I recommend that it should be published as soon as possible.�[436]� On medicines he wrote,� �I am...putting work urgently in hand to satisfy myself that everything possible has been done to ensure (summary paragraph 10.5) that transfer of the BSE agent in human and veterinary medicinal products does not occur.�[437] The CMO said of the Southwood Report in his oral evidence to the BSE Inquiry:

�I thought it read extremely well. I thought it was a good report and I said so to Ministers. I also remember saying to Ministers that I had one thing I need further information on and that is biologicals.�[438]

374.         On 10 February 1989, Dr Adams sent the draft BSE guidelines to some staff in his division, MB3B.[439]

375.         On 13 February 1989, Dr Adams sought comments on the draft joint VPC/CSM guidelines from his staff and Miss Hepburn of MB5A.[440]

376.         On 13 February 1989 an internal meeting was held in Medicines Division. Present were Dr Adams, Mr Hagger, Dr Purves, Dr Rotblat, Mr Sloggem, Mr Bewley, Mr Love and Mrs Alderman.[441] The minutes note that the meeting was held because of the CMO�s concern regarding the Southwood Report which had by then been submitted to Ministers. The Report posed the questions �are medicines safe� and �are there any guarantees�. At the meeting it was agreed that children�s vaccines would be identified and that Medicines Division would find out from the companies concerned: whether the products contained bovine material; the source of the bovine material; what bulk stocks of vaccines were available; and how long it would take to switch to another product. In addition, a working group was to be established.

377.         Dr Rotblat said in her statement to the Inquiry:

�The action which I was asked to undertake was telephoning the pharmaceutical companies concerned and contacting Dr Tyrrell, whom it was hoped would become a member of the working group.�[442]

378.         In his Statement to the Inquiry Dr Adams said the following about the same meeting:

�On 13th February 1989, a meeting was held in response to recent concern which the CMO had expressed in the light of the Southwood Report (minute 9th February 1989 to Dr Harris). I believe that as Dr Jefferys was away on 13th and 14th February, I took the lead on this occasion in his absence. It was agreed at the meeting that:

i.)��� Children�s vaccines and the companies manufacturing those vaccines would be identified;

ii)��� Information concerning the bovine material within those vaccines, the source of that material, the bulk stock of vaccines post 1980 and additionally the length of time it would take to switch to another product would be sought;

iii)��� That a working group would be established to consider the Southwood Report and the paper to CSM. The proposed membership of the group was Professor Collee, Dr Tyrrell, Dr Kimberlin, Dr Minor, Dr Schilds, Dr Martin, Dr Pickles and various MAFF representatives.�[443]

379.         On 13 February 1989 Mr Lawrence distributed a minute to PS/Mr John MacGregor, Miss Phillips, Mr Gueterbock, Mr Smith, Professor Bell, Mr Cruickshank, Mr Meldrum, Mr Crawford, Mr Wentworth, Mrs Attridge, Drs Crossett, Watson and Little, Mr Myers, Mr Coe, Mr Suich, Mr McKinley, Mr Scollen, Mr Wilesmith, Mr Griffiths and Mr Alderton[444]. Attached was a brief for a meeting between the Minister and Sir Richard Southwood the following day, 14 February 1989. This note underlined the fact that the Working Party had concluded in paragraph 8.2 of their report that the risk of BSE transmission through the use of medicinal products was remote, but that various medical committees should be alerted.[445]

380.         The brief stated the following:

�11. The Minister should note, however, that the [draft] guidelines [to be issued to all manufacturers of medicinal products] represent a counsel of perfection:

i).��� Guidance 1, on the use of defined, BSE-free sources, will be severely restrictive.� A number of farms in the UK will meet these criteria but they have not been identified; farms overseas ostensibly meet the criteria but we cannot be sure that non-detection of BSE in all cases equates with freedom from the disease.� Moreover, many countries are unsuitable sources of medicinal material because of other, endemic diseases.� New Zealand, and possibly Australia, appear the safest sources, but their supply is unlikely to match demand.

ii).�� Most pharmaceutical companies buy from specialist producers of primary and intermediate material, whose activities lie outside the powers of the Medicines Act.� Product licence holders, who are responsible for the quality of their products, would therefore need to secure assurances from their suppliers that the guidance is being respected.� This might pose problems in a minority of cases and if serious doubts were to be raised about the quality of any product we could withdraw its licence.

iii).�� Guideline 4, on collection techniques, conflicts with normal practice is (sic) abattoirs, where most material is obtained.� This is unlikely to matter if reliable BSE-free sources are used, although a risk of cross-contamination might remain.

iv).� The sterilisation treatment recommended in Guideline 5 is generally inappropriate to biological medicines � which it would destroy � but would be suitable for some tools and equipment.�[446]

381.         On 14 February 1989 a meeting was held between the Minister for Agriculture, Fisheries and Food, and Sir Richard Southwood �to discuss the recommendations in the Working Party report, timing of publication, and handling.�[447] Also present were Mr Thompson, the Permanent Secretary, Mr Meldrum, Mr Cruickshank, Mr Lawrence, Dr Watson, Sir Donald Acheson (CMO), Dr Pickles and Mr Smith. Sir Donald said that there would be a special Working Party meeting on 22 February 1989, comprising people knowledgeable in biological and pharmaceutical areas to consider the implications for medicinal products. The CMO continued that it was hoped that this meeting would offer some reassurance on this area. He said it would be wise to delay publishing the Report until after this meeting. Sir Richard said �we were dealing with �probabilities� rather than certainties� in this area, and that made it difficult. In his opinion, care should be taken when sourcing medicinal material from any country with a significant sheep population and where sheep material might be fed to cattle. Mr Meldrum pointed out that this issue was extremely complex: some countries might be ostensibly BSE-free while having an underlying problem with the disease in a sub-clinical form in their animals. It was agreed to await the outcome of the 22 February meeting to be clear on this issue.

382.         On 14 February 1989 Dr Adams attended a meeting with Drs Rotblat and Purves, Mr Hagger, Mr Sloggem, Mr Bewley and Mrs Alderman.[448] �The purpose of the meeting was to discuss the action agreed on vaccines at the internal Medicines Division meeting the previous day.

383.         On 14 February 1989 Dr Adams minuted Dr Harris about the information received on human vaccines in response to telephone inquiries. It stated:

�Vaccines

We have contacted all the major vaccine product licence holders whose products are likely to be used in children.� Many manufacturers use bovine material.� As can be seen, this information is diverse and incomplete.� Each company stressed that they could not give an accurate assessment without detailed researches, given the complexity of sourcing/purchasing arrangements.

All the licences are detailed in appendix 1; the overview is as follows:

1.��� D have polio, measles, mumps, rubella, rotavirus vaccines.� All use bovine serum from a UK source and bovine commercial product from unknown source.� Some agent comes from the USA and New Zealand.

2.��� I gave most information (see Appendix 2).� All their vaccines apart from yellow fever, cholera and typhoid contain bovine material:

Oral polio; up to 1988, foetal calf serum was used from UK and New Zealand (pooled); since 1988 foetal calf serum only from New Zealand.� Large� stocks are held.

Rubella; bulk was made before 1979 from foetal calf serum from UK and New Zealand.� None has been made as there are some 15 years stock.

Diphtheria; UK bovine beef muscle and ox heart is used but since the end of 1988 this has been sourced from Eire.� There are 1,250 litres of stock.

Tetanus; this involves bovine material from UK mainlyScottish.� There are 21,000 litres of stock.

Pertussis; uses bovine material fromthe UK.� There are 63,000 litres of stock.

They consider that to switch to a non-UK source will take a minimum of 6-18 months and to switch to a non-bovine source will take a minimum of five years.

3.��� E have measles, mumps, MMR, rubella vaccines.� These are sourced from the USA and the company believes that US material only is used.

4.��� J have a measles vaccine using bovine serum from the UK.� There are 440,000 units of stock.

-����� They have also got MMR using bovine serum from the UK.

5.���� K have influenza, rubella, measles, MMR vaccines likely to be used in children.� Of those they think that only MMR contains bovine material which is probably a French origin.

6.��� L have diphtheria/tetanus and pertussis on clinical trial [redacted]; These use veal material, some of which has come from the UK and has been made by I (see above).

7.��� M have influenza vaccines which are made up in egg medium.

8.��� The Secretary of State has a number of licences.� We understand that the inactivated polio vaccine is no longer being used.� There is a stock of smallpox vaccine.� We have not been able to determine the source material.� (Made in sheep very unlikely to certain bovine ingredients).

9.��� N have acellular triple vaccine in which I material of UK bovine source has been used.

As far as I can see I are the sole supplier of pertussis vaccine which uses bovine casein digest.

You should also be aware that DH has made arrangements for meningococal vaccine to be available, on a named patient basis, from D and K.� Both companies use bovine media in production.�[449]

Dr Adams also set out details of forthcoming� expert group meetings (VPC, Human and Veterinary Medicines Working Group, and CSM).

384.         On 15 February 1989 Mr Wilson minuted Mr Hagger,[450] and said:

�I spoke to Dr Harris today about our intention to send copies of the Southwood report to the members of the Collee group and to CSM for their respective meetings next week. We will be stressing the sensitive confidential nature of the report and associated papers. He is content that this action is necessary if the group and CSM are able to give us their best advice. You may accordingly assume that we have his authority for this action.�

385.         On 15 February 1989 Mr Hagger minuted Mr Cunningham, Dr Salisbury, Mr Burton and Mr Dudley, with copies circulated within MD, to alert them to recent developments on BSE as they affected medicines and to invite representatives to the meeting on 22 February.[451]

386.         On 15 and 16 February 1989 the VPC met. They considered revised joint CSM/VPC guidelines. Also attached for members� information were copies of correspondence between Dr Little and Sir Richard Southwood.� The minutes record the following:

�18.2 Members made the following comments on the guidelines at VPC(89)38:-

1).�� Members asked for clarification of paragraph 4a.� It was explained that under the BSE Order, the head had to remain intact.� Clarification was provided on the methods of slaughter that could be allowed

2).�� It was considered that subject to CSM advice, pancreas should be included at paragraph 3.� (�Tissues excluded�), and this paragraph could apply to material of other species not just bovine origin.

3).�� It was considered that paragraph 4c should be expanded to exclude animals fed ruminant derived protein.

4).�� With reference to paragraph 2, it was considered that in practice it could not be guaranteed that animals had not been fed rations containing ruminant derived protein.

5).�� It was considered that bovine serum albumin should also be included in paragraph 4e.

6).�� Members also asked for clarification about the recommendation to use calves under 6 months of age.

18.3 Officials noted members� comments and subject to the above comments the Committee agreed VPC(89)38.�[452]

387.         On 17 February 1989 Mr Cruickshank minuted Mrs Stagg (PPS/Minister) with copies to Mr Guterbock, Mr Smith, Professor Bell, Mr Hadley, Mr Capstick, Mr Meldrum, Mr Wentworth, Mrs Attridge, Mr Myers, Mr Coe, Mr Suich, Mr Scollen and Mr Lawrence. The minute attached a draft paper for MISC 138, together with a draft announcement and Q&A brief.[453] Paragraph 8 of the draft paper said that the (Southwood) Report recommended that the attention of those involved in the licensing of medicines should be drawn to the emergence of BSE. Reference was made to the guidelines shortly to be issued to the pharmaceutical industry. Questions 5 � 10 of the Q&A brief attached to Mr Cruickshank�s minute addressed the issue of medicines.

388.         Also on 17 February 1989 Mr Bewley circulated a list of questions on BSE and medicinal products within DH with the aim of providing a question and answer briefing to DH and MAFF ministers.[454]

389.         On 19 February 1989 Professor Collee wrote to Dr Jefferys. He acknowledged the receipt of a copy of the Southwood Report on 10 February 1989[455].� He said� �I appreciate that the aim of Wednesday�s meeting of the Briefing Group is primarily to agree advice to CSM on 23.2.89�.� He also outlined a possible line of inquiry asking,� �Is there any evidence of an increased incidence of encephalopathic syndromes or CJD-like disease in patients who have been given bovine insulin from the early 1980�s?�� He went on to say,

�The object of such a model would be to seek justification for the reassuring public stance that many other considerations justify at this stage in our certain appreciation of the benefits of vaccines and other products , and our uncertain assessment of BSE as a real hazard to man.�

Professor Collee also stated:

�In relation to our consideration of particular product groups (item 3), there is some urgency to identify vaccines that have clear associations with bovine materials in their production. This especially applies to live vaccines that are processed gently.� It may not apply to heparin which is thermostable, but I suspect that bovine insulin also merits special consideration.�

390.         Prior to the meeting of the HVMBG on 22 February 1989, Mr Sloggem prepared a briefing note for Professor Collee. The note covered the issues concerning BSE as they related to medicinal products, taking account of what was in the Southwood report.[456]

391.         On 22 February 1989 the HVMBG met for the second time to consider medicines in the light of the Southwood Report and to give advice to the CSM which was due to meet next day.[457]� The minutes of the meeting record the following:

�Present:

Biologicals Sub Committee:��� Professor Collee (Chairman), Dr Minor, Dr Schild

Invited Experts: Professor Asscher, Professor Sir J Badenoch, Dr Kimberlin, Dr Martin, Professor Rawlins,

Department of Health Medicines Division: Dr Adams, Mrs Alderman (Secretary), Mr Bewley, Mr Hagger, Dr Jefferys, Mr Love, Dr Purves, Dr Rotblat, Mr Sloggem

Department of Health (Other): Dr Burton, Mr Colman, Mr L Wilson, Ms Nash, Dr Pickles, Dr Salisbury

MAFF:� Mr Bradley, Mr Kidd, Dr Little, Mr Scollen, Mr Wilesmith

Apologies for absence were received from Dr Tyrrell and Dr Sutton

1.���������� Information Exchange

1.1     It was thought that the Southwood Report would be published 24.2.89, when a press conference would be held, attended by CMO, CVetO, Sir Richard Southwood, and possibly representatives from MAFF.

1.2     The Southwood Committee considered that the most likely cause of BSE in cattle was feeding with protein derived from scrapie infected sheep. Although man has eaten scrapie infected sheep for many years, no incidence of BSE has been reported in humans. Because of the lengthy incubation period, no cases of BSE have been seen in humans arising from bovine sources and the Southwood Committee were of the opinion that cattle will prove to be �dead-end� hosts for the BSE causing agent, and it is unlikely that this (sic) will be any implications for human health.

1.3     Because of the above, clarification is needed on the acquisition of BSE by cattle via the oral route, which by analogy with scrapie is relatively inefficient. Although it is probably the primary route in cattle, there may be special factors involved, damage to the gut from roughage, causing an �injection� of BSE. It was felt that the oral route need not be of undue concern at this stage.

1.4     The slight theoretical risk of BSE being transferred to humans was considered to be more likely from products used parenterally by implantation than by the oral route. The implications of this for the vaccination programme (vaccines using bovine ingredients in manufacture) could be very serious and result in epidemics if public reaction turned against vaccination.

1.4�� The annual incidence of BSE in the UK at 31.12.88 was cited and represents 1 case per 1000 adult cattle (total population 4 million) but cases have not occurred uniformly throughout the UK.

1.5�� Despite the research and investigative studies already carried out on BSE, the cause of the relatively recent appearance of the disease in cattle has not been established and it may be the result of a mutant strain of scrapie being transmitted by the feedstuffs. There is a need for more research into BSE and a consultative research committee chaired by Dr Tyrrell has been set up to carry research initiatives forward.

2����������� CSM paper

2.1�� Joint proposed DH/MAFF draft guidelines

2.1.1        Draft guidelines covering all products licensed under the Medicines Act for human or veterinary use, for use parenterally in the eye or on open wounds and the source of bovine materials used in their manufacture had been drawn up.

2.1.2        Normally, in matters where there is as little knowledge as there is in the case of BSE, CSM would have been advised to take no action but to monitor the situation. Due to the publication of the� Southwood Report, this option is not open. It is not feasible to go to consultation with industry on the matter due to lack of time and the fact that this might be seen as our being led by industry. VPC had given broad approval to the draft guidelines.

2.1.3        The guidelines themselves were discussed. These are to be seen as a �gold standard�, and may be modified in the light of experience. It is intended that they should be parallel with those issued on the veterinary side, but not identical because they have more difficult problems to handle (BSE being a speculative hazard in man).

2.1.4        It was agreed that it would be better to try to eliminate BSE at source. The possibility of the identification of risk-free herds and their certification was discussed. Ideally, bovine materials obtained from calves should be taken from animals less than 6 months old, which have not been fed on ruminant-derived protein. The question of �BSE � free� countries was raised, but there are other pathogens which also need to be taken into consideration in selecting a source.

2.1.5        It was felt that to issue rules on oral products would challenge our concepts on foods, and cause problems with regard to gelatin capsules. The guidelines are a balance between flexibility and standards of ideal practice, and an attempt has been made to major on the question of source.

2.1.6        VPC had expressed anxiety about animal vaccines, and it was felt that in future we may need to ensure that bovine ingredients are not obtained as by-products of abattoirs. The possibility of herds being maintained specifically for this purpose was mentioned.

2.1.7        The question of excluded tissues was discussed. In the case of the intestine, this would eliminate heparin (although most of this is porcine sourced) and catgut. It was felt that the pancreas should not be excluded as this would eliminate bovine insulin.

2.1.8        The section headed �sterilisation� was clarified to refer to equipment used in production, and not to products themselves.

2.1.9        Anxiety was expressed over problems with availability of supply of vaccines if companies could not comply with the guidelines, as failures of supply could lead to epidemics. Drs Adams and Rotblat had, at the request of the CMO, contacted companies holding licences for vaccines, asking for information on the use of bovine ingredients. Most of the companies were aware of the problems of BSE and some have begun to take action. It was felt that most companies would welcome guidelines on this subject.

2.1.10     The question of unlicensed products involving bovine ingredients was raised. These are not subject to the Medicines Act and are controlled by Supplies Technology Division. Some preliminary screening of these products has taken place, and PD will follow the lead of CSM and issue similar guidelines.

2.2     Letter to licence holders

2.2.1����� The draft letter was discussed. MAFF and Department of Health are sending letters separately, those sent by MAFF being S.44 letters.

2.3     Questionnaires

2.3.1����� The background to the need for data was discussed, the problem at present being that we cannot identify products using bovine ingredients during the manufacture. The intention is to develop a full database of the use of bovine ingredients in human medicines, and companies will be asked to respond to the questionnaire by 1st May 1989. The questionnaire was seen to be adequate.

3.������������ Consideration of particular product groups

3.1��� Product groups likely to use bovine ingredients were listed and assessment of the theoretical risk involved in the use of vaccines and products in the other groups is required.

4.������������ Proposal for a Working Group on BSE

4.1��� It was agreed that a Working Group, associated with the Biologicals subcommittee should be set up, and a proposal of this was to be made to CSM. Suggestions for a core membership were made with other experts being brought in as needed.

5.������������ Form of statement and briefing for press

5.1��� The draft prepared by Medicines Division was discussed, and some amendments suggested.

6.������������ Other business

6.1��� Dr Burton asked to be kept informed as to CSM decisions, and also requested that a letter, guidelines and questionnaire be sent to him as holder of the Secretary of State licences.�[458]

Attached to the minute of this meeting was a template to be utilised in assessment of vaccines entitled �Medicinal Products Using Animal Matter�.[459]

392.         Dr Purves notes in relation to point 2.1.3 that:

�I think that was an important point.� Although a considerable amount of work and thought had gone into the guidelines, as we had such a limited knowledge of BSE, it would necessarily follow that as the pool of knowledge became greater the guidelines may have to be amended.�[460]

393.         Point 2.2 above refers to a draft letter.� A copy of a document headed �Draft Letter to Product Licence Holders.� Concern about BSE in Human Medicines� [thought by the Inquiry to be the draft referred to] reads as follows:

�Bovine Spongiform Encephalopathy (BSE) is a disease of cattle characterised by degenerative neurological changes culminating in the death of the animal.

Although there is no evidence to suggest that BSE may be transmitted to man, the Licensing Authority considers it prudent, having taken expert advice, including that of CSM and VPC, to advise that all manufacturers whose products contain bovine material should conform to a set of guidelines.� A copy of these is attached to this letter

BSE was made a notifiable disease in 1988 (under the Animal Health Act 1981).� It is therefore important that the Licensing Authority has completely up to date information on the use of animal tissues in the manufacture of medicinal products.

Accordingly I am writing to request information about all products which (sic) animal material has been used:��������� a).� as an active constituent�������������������������������������������������������� ������ b).� as an excipient�������������������������������������������������������������������������������� c).� during processing or manufacture

The information required is:

Company Name ������������������������������������������������������������������������������

������ PL/CTC/CTX Number and Product Name

������ Animal Ingredient (eg tissue, blood, etc)

Animal Species (eg bovine)

������ Purpose of inclusion (eg active, excipient, in-house use)

Country of origin of collected material

Does this product conform to the guidelines at present?

If not, over what timescale do you intend to apply the guidelines to this product?

What are your stocks of this product at present?

What is the anticipated utilisation of this product?

Information on each medicinal product must be submitted on a separate A4 form as attached.

This information should be addressed, for human medicines, to : The Information Room at Market Towers, by 1 May 1989.� Any professional enquiries should be made to Dr Rotblat (medical) Ext. �, and Dr Purves (pharmaceutical) Ext. �.�[461]�

The letter was to be signed by Mr Hagger

394.         As a result of the meeting, and the CSM�s endorsement of its conclusions, the BSE Working Group, chaired by Professor Collee, was set up. Its terms of reference were� �To advise the section IV Committees on the implications of BSE to human medicinal products.�[462]

395.         In a Statement to the Inquiry Dr Martin commented on the Statement of Sir Richard Southwood. About the second meeting of the HVMBG he said[463]:

�You may recall that I attended, on behalf of the Working Party, a meeting of the �Human & Veterinary Medicines Briefing Group Re. BSE� chaired by Professor Gerry Collee on 23.2.89. I was left with the impression that those on the human medicine side regarded BSE as an animal problem and that we, on your Working Party, were being excessively apprehensive. Your correspondence with Professor Asscher (Nov./Dec./Jan. 98/99) illustrates this. Because of our Report the health authorities found it necessary to take action.�

396.         Dr Kimberlin also commented on this meeting in his Statement to the Inquiry:

�On 22 February 1989, just before the publication of the �Southwood Report�, I attended a meeting to advise on the Proposed Joint CSM/VPC Guidelines for Industry�with regard to medicinal products. Several meetings followed over the next few years.�[464]

397.         On 22 February 1989 Miss Duncan minuted Dr Metters. Copies were sent to Drs Pickles, Sutton and Hoxey, Mr Luxton, Mr Allen and Mr Burton. This minute said, �As you will know from Dr Sutton we only became aware of the Southwood Report on Friday and it is clear that those compiling the report were unaware that there are a large range of unlicensed medical devices made from or containing material of bovine origin�, and that �from a public relations aspect the report does not draw attention to devices except for one reference to surgical implantation�. She went on to say that the majority of such products were manufactured in the USA, and continued:

�3.�� Irrespective of what public reaction, [sic] we may anticipate it is clear that the Department needs to take action to complement that which will be taken by Medicines Commission for licensed products.

4.        As soon as we were aware of the possible implications we prepared a provisional list of devices which from our Manufacturer Registration data and from individual specialist knowledge we know to contain animal origin material. A copy of that list will be made available as soon as possible.

5.        If you agree we would propose to follow whatever action CSM takes with a similar formal letter/questionnaire and consultative guidance (a) by facsimile to UK companies known to use bovine materials and (b) by post to all medical device companies making products which could conceivably include animal materials. The majority are in the USA.�[465]

398.         On 23 February 1989 Dr Richardson minuted Miss Duncan about Medical Devices of �Animal� origin. He noted that �Distinct types of areas appeared, eg �heparin� coated disposables, heart valves etc and have therefore been divided into categories as indicated.� The issue of sterilisation was also mentioned.[466]

399.         On 23 February 1989 Dr Metters replied to Miss Duncan�s minute of 22 February 1989, copies to all previous recipients. Dr Metters agreed that manufacturers of unlicensed medical devices with material of bovine origin should receive similar guidance and questionnaires to those the CSM were to give to manufacturers of licensed products. Dr Metters also noted the fact that sterilisation of products containing bovine material was one of the central uncertainties of BSE: nobody knew how infective it was, or of its potential to cross the species barrier. He advised that Dr Pickles should be kept closely informed on the subject of unlicensed medical devices.[467]

400.         On 23 February 1989 the CSM met[468] and fully endorsed the proposals of the HVMBG. This meeting was summarised in a minute from Mr Hagger to Dr McInnes, Private Secretary to the CMO.[469] This said the following:

�1.�� The Committee on Safety of Medicines (CSM) considered the Southwood Report and its implications for human medicines at its meeting on 23 February, and agreed with the Southwood Working Party that the risk to man of infection via medicinal products is remote.

2.      Before reaching this view the Chairman of the Committee on the Review of Medicines (CRM) and the Committee on Dental and Surgical Materials (CDSM) had been consulted. In addition, the CSM received a report of views expressed at a special meeting to discuss the subject held the previous day which was attended by representatives of CSM, other experts and officials from DH and MAFF (names at Annex A).

3.      An agreed statement by CSM, for use if required, is at Annex B. It was agreed that no special action was required on any existing products although the CRM is due to consider very soon a number of �old� products using bovine materials. More information was needed from manufacturers and it was planned that the licensing authority would write, within the next 2 weeks, to all licence holders for relevant details. A copy of the draft letter and questionnaire in respect of human medicines is at Annex C. (As there are considerably fewer veterinary products, MAFF will be following a slightly different means of contacting their licence holders.)

4.      The CSM and the Veterinary Products Committee have agreed on guidelines for good manufacturing practice which the licensing authority plan to send to licence holders at the same time as they write for information. The guidelines are intended to assist in strengthening the development of good manufacturing practice for the future, where animal materials are used (Annex D).

5.      The CSM also decided to establish a special working party to advise it on this subject. Terms of reference and the names of the proposed core membership is at Annex E. Three members are also members of the Tyrrell Research Committee referred to in Southwood including Dr Tyrrell.

6.      General agreement was expressed during the meeting on the urgent need for research in order to fill the current gap in information.

7.      Professor Asscher is on standby in case press and other interest was such as to require comment by a CSM spokesman (although the Press Office would continue to be the first line of approach).

8.      A short list of Qs and As are attached at Annex F. A fuller list will be ready tomorrow.�

401.         Paragraph 8 of the minutes of the CSM meeting deal with BSE as follows:

�8.1 The Committee noted tabled paper VI.

The Chairman gave a brief history of the background of this issue.

Professor Collee reported in detail on a meeting held the previous day, which included representatives of DH, MAFF and invited experts to consider the implications of the Southwood Report to human medicines.� Issues considered, included transmission by parenteral and oral routes, and tissues to be excluded from human medicines.� The minutes of the meeting are at annex D.

The Committee then considered the following in detail �

a.      the CSM position statement

b.     letter to licence holders and questionnaire

c.      guidelines to industry

d.     formation of Working Party, its terms of reference and membership.

The Committees [sic] decisions are at Annex E.

The need for research into BSE in relation to medicines manufacture was recognised by the Committee.

The Committee also advised that in-house applications should be assessed using the new guidelines as seen [sic] appropriate.

Members were informed that all press enquiries on BSE should be referred to the Chairman of CSM who would take advice from the Secretariat.�[470]

402.         The proposed membership of the CSM Working Party on BSE was Professor Asscher or Professor Rawlins, Professor Berry, Professor A Campbell, Professor Collee, Dr Kimberlin, Professor Lawson or Professor Kirby, Dr Schild or Dr Minor, Dr Taylor, Dr Tyrrell, a veterinary expert and Dr Will.[471]

403.         The Question and Answer briefing document which formed Annex F� said the following:

�1.�� Can BSE be transmitted to patients by medicines?

The Southwood Report suggests that there may be a remote theoretical risk of BSE being transmitted to patients by the use of injectable medicines derived from bovine material. The CSM agreed that the risk is remote.

2.��� Which medicines are affected?

Bovine material is used as an active ingredient in some medicines, for example, the older bovine insulins. Bovine material is also used in small quantities in the production and manufacture of many biological and biotechnologically derived medicines including vaccines and monoclonal antibodies.

3.��� Are the risks greater with some medicines than with others?

Theoretically, injectable (parenteral) products might seem to pose a greater risk than oral medicinal products, but the CSM agreed that the risk from either is remote.

4.��� How are medicines affected?

Bovine material is used both as an active ingredient (for example in products such as bovine insulin) and in very small quantities in the production and manufacture of a wider range of medicines.

5.��� Are some of the products available over the counter from pharmacies or shops?

A range of products available over the counter may contain bovine material as an active ingredient or an excipient, including oral products and injectable insulin which is obtainable only from a pharmacy. But the CSM agrees that any risk of transmission of the agent by medicines is remote.

6.��� Are existing stocks safe?

The CSM agreed with the Southwood Working Party that the risk of transmission of BSE via medicinal products to man is remote and there is therefore no reason to question the safety of existing products.

7.��� Are there alternatives to the use of bovine material in medicinal products (including vaccines)?

Certain products such as insulin are now produced by using genetic engineering techniques. While it might be possible to replace bovine materials by using other ingredients or manufacturing methods in some other products, the Licensing Authority would need to be satisfied about the safety of such products before they could be made generally available. It would take some time to undertake the work needed to introduce such a change.

8.��� Which patients are at risk?

Although bovine material has been used in a wide range of medicinal products, it is not possible to say that any particular patients are at risk since we have no evidence of transmission of BSE to man.

9.��� What risks exist to those who have already used these medicines?

There is no evidence to suggest that people who have used medicines containing bovine material are at any risk from contracting BSE.

10.�� How long will it be before risks are quantified?

It is very difficult to answer this question since we are talking only about a theoretical risk. It is one of the issues which will be considered by the new Consultative Committee on Research which has been established by the Government. The Committee on Safety of Medicines are also establishing a working party to advise them on BSE and human medicines.

11.�� What action is the Licensing Authority taking to ensure proper scrutinising of source materials and manufacturing processes?

The Licensing Authority has sought the advice of the Committee on the Safety of Medicines, the Veterinary Products Committee and other outside experts. Guidelines on good manufacturing practice have been produced and are being sent to all manufacturers.

12.�� Will the guidelines be published?

They will be sent to all manufacturers of licensed products shortly.

13.�� What is being done to reassure parents and doctors about vaccines?

The benefits of immunisation are well founded and not affected by the remote theoretical risk from the use of bovine material in vaccines. We see no reason to take any special steps to reassure parents and doctors at present. We are also taking the advice of the Joint Committee on Vaccination and Immunisation (the expert Committee which advises the Health Department on immunisation). If it proves necessary, the message about the benefits of immunisation can be addressed generally in the publicity material and the professional advice on immunisation provided for parents and doctors.

14.�� What advice is the Government giving about its vaccination programme?

The immunisation programme for children and adults is vital to individuals and the public health. There are very considerable benefits in the prevention of serious or fatal disease. By any reckoning these outweigh the remote and theoretical risk for BSE.

15.�� Is the vaccination programme put at risk because of BSE?

No. The measures being taken about the use of bovine material in medicines are merely precautionary against a remote and theoretical risk.

16.�� Are there any risks from BSE to anyone who has already been vaccinated?

The Southwood report describes the possibility as remote (para 8.2) but has alerted the Licensing Authority to the potential concern. This has led to plans to issue guidance to the pharmaceutical industry as a precautionary measure.�[472]

404.         The CSM Position Statement that was Annex B stated:

�The Committee on Safety of Medicines (CSM) has considered the safety of human medicines in the light of the report of the Working Party on Bovine Spongiform Encephalopathy (BSE) � the Southwood Report.� The CSM agrees with the Southwood Working Party that the risk to man of infection via medicinal products is remote.� As a precautionary measure, and for the sole aim of seeking to guard against what is no more than a theoretical risk to man, the CSM and the Veterinary Products Committee (VPC) have agreed joint guidelines on good manufacturing practice for the manufacturers of human and veterinary medicines who use bovine, or other animal, materials either as an ingredient or in the production process.� This guidance will be issued by the Licensing Authority to the manufacturers early in March.� Manufacturers will also be asked for further details about any animal materials used in their products and, where appropriate, to state how they propose to implement the guidelines in the future.� The need for further action will be considered by the Licensing Authority in the light of further information from the industry and expert advice.�[473]

405.         Professor Asscher discussed this position statement in his Statement to the Inquiry. He said:�

�It appears that the wording of this position statement differed from the wording of that approved by the Human & Veterinary Medicines Working Group the previous day, in that the second paragraph of the previous day�s statement was not used in the final version of the position statement. As far as I can recall, this change was made because the CSM�s general policy on BSE and medicinal products was adequately set out in the first paragraph. There was no reason specifically to draw attention to vaccines. There was no advantage to be gained from doing so and there were potential disadvantages in that the vaccination programme might have been put at risk.�[474]�

Cabinet consideration

406.         On 23 February 1989 the Southwood Report was discussed at a Cabinet meeting.[475] The minutes of this meeting show that John MacGregor, Minister of Agriculture and Food said ��in view of the intense current public interest in food safety and the risk of the working party�s findings being leaked, it was necessary to publish the report with as little delay as possible.�� With specific reference to vaccines the meeting minutes record that the proposed CSM/VPC Joint Guidelines that were about to be issued recommended� ��manufacturers of medicinal products to use non-bovine sources wherever possible�

407.       On 23 February 1989, DH and MAFF Ministers met with officials to discuss baby food and vaccines, two items of concern arising out of the Southwood Report. The Minister of Agriculture, Mr John MacGregor, and Kenneth Clarke, the Secretary of State for Health were told that the VPC and CSM had concluded the risk of transmission of BSE through vaccines was remote. Despite this reassurance the two committees, ��so as to be doubly sure in future�intended to take the opportunity to improve standards throughout the field of biologically derived medicinal products and had prepared additional guidelines for users of bovine material.�[476]

408.       On 24 February 1989 Mr Hagger minuted Mrs Goldhill, from the Secretary of State for Health�s Private Office, attaching a revised version of the Q & A brief he had sent earlier. This was copied to a number of DH officials.[477] Changes made since the earlier brief (see paragraph 403 above) were that Q7 now excluded the reference to vaccines and the new answer stated:

�In some cases alternatives have been introduced using genetic engineering techniques, for example certain insulins.�

409.         A new Q8 had been included which asked

�8.�� Why can�t we eliminate the use of bovine materials in all medicines?

It might be possible to find alternative ingredients and methods but development of this kind takes time and requires careful testing.�[478]

410.         The previous Q9 had been removed altogether:

�9.�� What risks exist to those who have already used these medicines?

There is no evidence to suggest that people who have used medicines containing bovine material are at any risk from contracting BSE.�[479]

The Southwood Report

411.         On 27 February 1989 PS/Mr MacGregor sent a final revised announcement for the Southwood Report to the PS/Prime Minister. It noted that the announcement would be made that afternoon by written answer.[480] It stated in relation to medicines that:

�� the Committee on the Safety of Medicines and the Veterinary Products Committee have considered the comments of the Working Party on the implications of BSE for the manufacture of pharmaceutical products from bovine material; and agree that any risk of transmission of BSE through medicinal products to man appear remote; as a precautionary measure however they have advised that additional guidance should be issued to medicine manufacturers on good manufacturing practice;�[481]

412.         On 27 February 1989 the Southwood Report was published.[482] Section 5.3.2 of the Report, under the heading �Possible Transmission to Man�, stated� �Information from several spongiform encephalopathies suggests that parenteral inoculation is much more efficient in transmitting disease than oral or topical exposure��� Section 5.3.3 continued:�

�The greatest risk in theory, would be from parenteral injection of material derived from bovine brain or lymphoid tissue.� Medicinal products for injection or surgical implantation which are prepared from bovine tissues might also be capable of transmitting infectious agents.� All medicinal products are licensed under the Medicines Act by the Licensing Authority following guidance, for example from the Committee on Safety on Medicine (CSM), the Committee on Dental and Surgical Materials (CDSM) and their sub-committees. The Licensing Authority have been alerted to potential concern about BSE in medicinal products and will ensure that scrutiny of source materials and manufacturing processes now takes account of BSE agent.�

413.         Section 5.3.4 dealt with occupational risk and section 5.3.5 then stated �In these, as in other circumstances, the risk of transmission of BSE to humans appears remote.�

414.         The recommendations with regard to medicinal products were contained in Section 8.2 where the Report stated:

�Although the risks appear remote the Working Party recommended that the attention of the Licensing Authority, the Committee on Safety of Medicines (CSM), the Committee on Dental and Surgical Materials and the Veterinary Products Committee (VPC) be drawn to the emergence of BSE so that they can take appropriate action. In this connection the Chairman of the Working Party has corresponded with the Chairman of the CSM and with the VPC.�

415.         Professor Collee discussed the Southwood Report and medicines in his statement to the Inquiry. He said:

�I understand the Inquiry has expressed some interest in the wording of the Southwood Report, so far as the degree of risk from parenteral medicinal products is concerned.� My own reading of the report, even today, is that the view being expressed was that the risk from parenteral products, even though expressed to be the greatest risk, was still being categorised as remote.�[483]

416.         In his Statement to the Inquiry Professor Asscher said that:

�Vaccines were the main group of existing products which came before the CSM for consideration. From my point of view, the risk-benefit analysis of existing stocks of vaccines was comparatively easy, principally for two reasons. The first was that the risk posed by BSE to human health was, during my time as Chairman of the CSM, always regarded as remote; that was certainly the view of the Southwood Working Party in its report. The second was that vaccines are very important to the protection of human health. The CSM�s judgement was that the risks associated with interruption of the UK vaccination programme were far greater than the potential risk of BSE being transmitted.�[484]

417.         On 1 March 1989 Professor Collee wrote to Dr Kimberlin[485] in the following terms:

�This is a short note to thank you very much for your valued help at London last week.� As you can imagine, I was heavily dependent on your expertise and authority in a very difficult field.� I do hope that you will allow me to say that your performance was impressive and was certainly appreciated by many other colleagues.�

418.         On 7 March 1989, the VPC Biologicals Sub-Committee met. The minutes record that �a joint set of guidelines had been agreed with the Department of Health. Separate questionnaires, prepared by MAFF and DH, had been sent out to all licence holders to be returned by May 1989.�[486]

419.         The CRM also met on 7 March 1989.[487] Dr Adams introduced a paper on BSE.[488]

420.         On 7 March 1989 David Mellor, the Minister of Health, announced the issue of the guidelines by way of reply to a Written Parliamentary Question. He said that the CSM agreed with the Southwood Working Party that any risk from injectable medicines including vaccines was both theoretical and remote, but as a purely precautionary measure, further guidance on good manufacturing practice in the area was about to be issued to manufacturers of all medicines including vaccines.[489]

The Joint Guidelines

421.         The Joint CSM/VPC Guidelines were as follows;[490]

�The following guidelines are addressed to PL/CTC/CTX holders and applicants.

1.��� Scope

It is recommended that all products licensed under the Medicines Act 1968 for human or veterinary use, that are administered parenterally or to the eye or to open wounds, should in general conform to this guidance if they contain material from a bovine source, or if bovine material has been used in their manufacture.

2.��� Tissues excluded

No brain or neural tissue, spleen, thymus and other lymphoid tissue, placental tissue or cell cultures of bovine origin should be used in manufacture.

Cattle source for all other tissues

Bovine material should come from animals, taken from a closed herd in the female line since 1980, in which no animal has been clinically suspected of having BSE, and which has not been fed rations containing ruminant derived protein during that period.

3.��� Collection techniques

All possible measures should be taken to avoid contamination of the bovine material with BSE agent, in particular:

no tissue is to be used in relevant medicinal products when collected post-mortem from a bovine animal after brain penetrative stunning.

all tissue collected from the bovine animal should be taken using sterile equipment. Needles, syringes, scalpel blades etc should be disposable items.

it is recommended that whenever possible, source animals should be calves up to 6 months old.

for serum: all cellular components must be removed.

for foetal calf serum: great care should be taken to avoid contamination by placenta and foetal fluids. All cellular components must be removed.

4.��� Sterilisation of equipment

When sterilisation procedures are used, they should be demonstrated to be capable of inactivating scrapie-like agents � at present thought to be autoclaving using a porous load cycle at 134�C-138�C for 18 minutes at 30 psi.

5.��� Product

Whenever possible, the product should be terminally sterilised by a validated method.

Although these guidelines relate to BSE and materials of bovine origin, they should also be considered as generally applicable to material from sheep, goats, deer, and other animals susceptible to scrapie like agents. These guidelines may need to be updated in the light of further scientific knowledge.�

422.         Professor Collee referred to the development of these guidelines in his statement to the Inquiry:

�The first attempt at drawing up guidelines was made by Dr Purves and Dr Rotblat, who made various recommendations in their paper prepared for the Biologicals Sub-Committee meeting which took place in November 1988.� I saw that paper shortly before the meeting.� Those recommendations were subject to a process of continual refinement by various groups until they were sent out to manufacturers in February 1989 as joint CSM/VPC guidelines.� In general, I would say that comments made by Sir Richard Southwood on the guidelines during that period were regarded as helpful and constructive.� The two or three months over which correspondence took place and the guidelines were drafted was a period of intense activity with a steep learning curve during which new information and ideas were regularly coming to light.

The guidelines were issued in February 1989 and intended to apply from then. However, we were aware that the complex way in which medicines are manufactured meant that manufacturers would often not be able to comply with the guidelines from the moment they received them. The questionnaire asked manufacturers to identify the time by which they believed they would be able to implement the guidelines.

It is also correct to say that the guidelines were viewed as best practice and we knew that as we progressed, we would have to be flexible��[491]

423.         Professor Collee also said that the guidelines� ��applied not only to new products, but also the future production of existing products which were already licensed.�[492]

424.         Professor Asscher also comments on the guidelines in his statement to the Inquiry:

�I believe that the guidelines addressed each of the points made by Sir Richard Southwood in his earlier correspondence with me. The first recommendation stated to which medicinal products the guidelines were intended to apply and clarified the CSM�s intention that they should apply both to the use of bovine material as an ingredient in medicines and to its use during the manufacture of medicines. It also made it clear that the guidelines were intended to apply to all medicinal products that fell within the remit of the CSM, including existing products. As previously stated, this had always been the CSM�s intention. Products which fell within the remit of the CDSM or the CRM were considered by those committees.�[493]

Issue of guidelines to holders of licences for human medicinal products

425.         On 9-10 March 1989 Mr Hagger, of Medicines Division, DH sent the CSM/VPC Guidelines, questionnaire and covering letter to all licensed manufacturers and product licence holders. The letter was distributed on the basis of the MAIL address list.[494]

426.         The letter read:

�Dear Licence holder*

Bovine Spongiform Encephalopathy: Guidance on good manufacturing practice and request for information

The Secretary of State for Health and the Minister for Agriculture have received the Report of the Working Party on Bovine Spongiform Encaphalopathy (sic), chaired by Sir Richard Southwood (�the Southwood Report�). One of the recommendations concern (sic) medicinal products licensed under the Medicines Act 1968 and 1971, and the licensing authority has been asked to take account of the BSE agent and to take appropriate action.

The Committee on Safety of Medicines (CSM) in consultation with the Chairman of CRM and CDSM has considered the Southwood Report and agrees that the risk to man of infected medicinal products is remote.

As purely precautionary measure, CSM and the Veterinary Products Committee have agreed joint guidelines for the manufacturers of human and veterinary medicines who use bovine, or other animal, materials as an ingredient or in the production process. A copy of the guidelines is overleaf. It is felt that the guidance represent a standard that this is deemed �best practice� for the future, and steps should be taken to implement it. However, it is realised that the guidance may not be fully applicable in all circumstances.

In order to update and complete our data on medicinal products, you are asked to fill in the attached form giving information about animal materials used in any of your medicinal products as specified in the guidelines (para 1). Information should be given on any �ingredient of animal origin as an active constituent, as an excipient, or used their manufacture (eg serum, enzymes, broth etc). In particular we are interested in the expected usage pattern of bulk and finished product where appropriate.�[495]

Recipients were asked to return the completed questionnaires by 1 May 1989.

427.         In his Statement to the Inquiry Professor Asscher commented on the covering letter saying:

�I understand the Inquiry is interested in why that letter described the recommendations as a �purely precautionary measure�.� The Southwood Report, which I read at the time, stated that the risk to human health from medicinal products was remote.� My understanding of the report was that the risk from all medicinal products was remote; I did not understand the report to say that the risk was only remote if action was taken in the form of the proposed guidelines being introduced.� The CSM was also of the view that the risk to human health from medicinal products was remote.� The fact that we thought the risk was remote per se explains why the guidelines were described as purely precautionary.�[496]

428.         Professor Collee has also commented on the phrase �purely precautionary measure�:

�I have to say that I saw the issuing of guidelines as being more than a precautionary measure; I did in fact regard action as a necessary measure. Nonetheless, I do not believe that the inclusion of that phrase would have made any difference in practice. The requirement to fill in the questionnaire was an obligation, not a request. The process was not completed until every single response had been received and analysed. Where necessary, when it was discovered that a product did not meet the guidelines, the matter was pursued until a satisfactory conclusion was reached. I believe that the pharmaceutical companies took the guidelines seriously.�[497]

429.         The CMO commented in his oral evidence, in reply to a question from counsel about whether Ministers felt they were �fire-proof�:

�I was concerned about biologicals from the beginning� and that is indicated in my minute to the Minister after my meeting on 17th March, it was specifically mentioned.� I also mentioned my concern about it later when I minuted him [Mr MacGregor] about the Southwood Report.� It is specifically noted in that.� So he knew that I was concerned, and it was really within the next few weeks that I personally got involved, in a way which is quite inappropriate in Civil Service terms�to tell them that they [the CSM and Biologicals Sub-Committee] must really focus down on biologicals and make sure; and that is I think one of the reasons why they wrote these 4,000 letters. I am not sure it is the only reason.�[498]

Issue of guidelines to holders of licences for veterinary medicines

430.         On 15 March 1989 Mr Scollen, of MAFF wrote to all licence and certificate holders for veterinary medicinal products in the following terms:

�Dear Licence Holder

SPONGIFORM ENCEPHALOPATHIES OF BOVINE, OVINE AND CAPRINE ORIGIN: GUIDANCE ON GOOD MANUFACTURING PRACTICE AND REQUEST FOR INFORMATION

The Minister of Agriculture, Fisheries and Food and the Secretary of State for Health have received the Report of the Working Party on Bovine Spongiform Encephalopathy (BSE), chaired by Sir Richard Southwood (�The Southwood Report�). One of these recommendations concerns medicinal products licensed under the Medicines Act 1968 and 1971, and the licensing authority has been asked to take account of the BSE agent and take appropriate action.

On the 10th March 1989, 2398 farms have had at least one confirmed case of BSE, the total number of cases being 3395. This represents an annual incidence in cows of 1 per 1,000 of the population at risk. These figures demonstrate the serious nature of the problem.

As a purely precautionary measure, the Veterinary Products Committee (the VPC) and the Committee on Safety of Medicines (CSM) have agreed joint guidelines for the manufacture of veterinary and human medicines which use material of bovine, ovine and caprine origin either as an ingredient or in the production process. A copy of the guidelines is attached. They represent a standard that is deemed to be �best practice� for the future, and steps should be taken to implement them. Where a company will find it impossible to meet the guidelines, or, where an alternative process is in use which is thought to give equivalent or better protection than the guidelines, details should be provided at (11) on the attached form.

Since BSE has been made a notifiable disease it is important that the licensing authority is aware to what extent material of bovine, ovine and caprine origin are used in the manufacture of licensed veterinary products (including products subject to Animal Test Certificates and Animal Test Exemptions and Emergency Vaccines).

In order to update and complete our data on veterinary medicinal products, you are asked to complete the attached form��[499]

431.         Recipients of this letter were asked to complete the enclosed questionnaire and return it to the Medicines Unit by 1 May 1989.

Issue of guidelines regarding medical devices

432.         On 13 March 1989 Mr Burton, a Grade 7 in charge of the Pharmaceutical Supplies and Technology section, sent a draft letter, intended for regional pharmaceutical officers and the Chairmen of Quality Control and Production Sub-Committees, to Mr Hagger and Mr Ayling for their comment.[500]The draft was mainly intended to ��pre-empt criticism from the NHS that non-licensed pharmaceuticals had slipped through the net.� The letter noted:

��the attached documents represent Medicines Division�s initial approach to the Pharmaceutical Industry and this package of documents is being copied to you for information. A similar exercise has been conducted to cover the medical device industry.�

It must be stressed that the Committee on the Safety of Medicines has agreed, in line with the Southwood Report, that the risk to man of infection via medicinal products is remote.

The Department does not consider it appropriate at the present time to extend this information gathering exercise to NHS manufactured �medicinal products� in general, but if any especially �at risk� products come to your attention I would be pleased to receive completed questionnaires which will then be considered at the same time as those from industry.�

Mr Burton asked for an early response so that letters could be sent soon to achieve their objective.

433.         On 16 March 1989 Mr Hagger minuted Mr Burton about �BSE and NHS manufactured medicinal products� in response to Mr Burton�s minute of 13 March 1989. The minute said:[501]

�2.�� We see no difficulties from an MD standpoint to the proposals in your minute and agree that it would seem appropriate for Miss Duncan to sign the letter.

3. �� I have a few small amendments to propose to your draft letter, as follows:-

a)��� Para 2, line 1, delete �initial� and inset [sic] �purely precautionary�.

�

c)��� Para 3, line 4, delete �especially at risk�. Rest of that line to read: �products come to your attention which appear not to conform to the joint CSM/Veterinary Products Committee Guidelines I would be�.

4.��� To amplify my comment at 3(c), I should say that it seems to me to be inappropriate to refer to products �especially �at risk�� when both Southwood and the CSM said that the risks to man were remote and theoretical. I have suggested � not conforming to the guidelines - as an alternative which should pick up the sort of cases we ought to know about while avoiding the need for a full scale questionnaire completing exercise in every case.�

434.         Some time after 16 March 1989 PD wrote in these terms to all the Regional Pharmaceutical Officers and the Chief Pharmacists of Scotland, Wales and Northern Ireland. �This letter was also sent to the Chairmen of the Pharmaceutical Production Sub-Committee and the Quality Control Sub-Committee.[502]

435.         On 17 March 1989 Miss Duncan issued guidelines to the manufacturers and suppliers of medical devices on the use of materials of animal origin.[503]The recipients of these were drawn from membership of the Manufacturers Registration Scheme (MRS) for sterile medical devices and surgical products. In all, 328 manufacturers were sent a copy of the guidelines and questionnaire.[504]

436.         �The letter said:

�Dear Manufacturer/Supplier

BOVINE SPONGIFORM ENCEPHALOPATHY:

GUIDANCE ON GOOD MANUFACTURING PRACTICE AND REQUEST FOR INFORMATION RELATING TO SURGICAL IMPLANTS AND BLOOD CONTACT MEDICAL DEVICES

The British Government have recently received the Report of a Working Party on Bovine Spongiform Encephalopathy, chaired by Sir Richard Southwood�One of the recommendations of this report concerns medicinal products licensed under the UK Medicines Act 1968 and 1971, and the licensing authority has been asked to take account of the BSE agent and to take appropriate action. In parallel with this action the NHS Procurement Directorate, Supplies Technology Division, are considering the implications of the BSE agent for those surgical implants and blood contact medical devices which fall outside the scope of the Medicines Acts.

Supplies Technology Division, in conjunction with the UK Committee of (sic) Safety of Medicines, has considered the Southwood Report and agrees that the risk to man of infection by BSE and other scrapie-like agents resulting from the use of such devices is remote. As a purely precautionary measure, we have developed the enclosed guidelines for manufacturers of medical devices who use bovine, or other animal materials, either as a component or in the production process. The guidance represents �best practice� for future manufacture and outlines the steps which should now be taken to implement it. It is realised that this guidance may not be fully applicable in all circumstances and it will be further developed in the light of experience.� [505]

437.         The letter went on to ask for the attached form, detailing information on the use of animal materials in medical devices, to be completed for each product and returned to PD by 1 May 1989.

438.         The guidelines were headed �Supplies Technology Division Guidelines for the Medical Device Industry on the use of Materials of Animal Origin�[506]. They included the following:

�1.�� Scope

It is recommended that all products in the following categories, which are supplied to hospitals in the United Kingdom, and which do not fall under the remit of the Medicines Act, should in general conform to this guidance if they contain material from a bovine source, or if bovine material has been used during their manufacture.

Categories:

a).�� Biological heart valves.

b)��� Other cardiovascular implants (eg vascular prostheses, cardiac patches etc)

c).�� Orthopaedic implants such as tendons, bone grafts etc.

d).�� Single use sterile devices that use such animal deviatives (sic) as heparin and gelatin in, for example, coatings.

e).�� Any other implantable products or products which come into contact with blood or the lymphatic system and which utilise materials of bovine origin.�� ��

439.         The guidelines also covered: the tissues to be excluded; cattle sources for all other tissues; collection techniques; sterilisation of equipment; and sterilisation of product. It was noted that the guidelines might need to be updated in the light of further scientific knowledge.

The Tyrrell Committee

440.         On 13 March 1989 the Tyrrell Committee met for the first time. The Committee was set up following a recommendation from the Southwood Working Party, to advise MAFF and DH on research into BSE and other transmissible spongiform encephalopathies. Dr Tyrrell headed the Committee and members included Dr Kimberlin (ex-Director of the Neuropathogenesis Unit, Edinburgh), Dr Watson (Director of the Central Veterinary Laboratory), Dr Will (Consultant Neurologist, Western General Hospital, Edinburgh). Dr Pickles from DH and Mr Maslin from MAFF acted as joint secretaries to the Committee.

441.         The Tyrrell Committee discussed the CSM/VPC Joint Guidelines, and the implications of using bovine material in plastic and other surgery were identified as matters to be considered.[507] �Dr Pickles was asked to produce a detailed paper and to circulate this before the next meeting.

442.         The CDSM met on 15 March 1989 and noted the guidelines, letter, questionnaire, position statement and membership of the Working Party.[508]

443.         On 15 March 1989 Mr Whitbread, Higher Executive Officer of the MCA responsible for the CSM and its Sub-Committees, minuted Dr Jefferys, Mr James, a solicitor, Dr Purves, Mr Hagger and Dr Adams in relation to the appointment of members to the BSE Working Party established by the CSM. He attached a draft letter of appointment together with a short background note.[509]�

444.         On 17 March 1989 Mr Hagger replied to Mr Whitbread�s minute of 15 March[510], stating that he would like the letters to make absolutely clear that:

�the Working Party is subordinate to the Section IV Committees and has been set up to advise them � i.e. so as to avoid any temptation for the Working Party to be seen as an entirely separate entity answerable to all and sundry (including the press).�

445.         On 21 March 1989 the NOAH Biologicals Sub-committee met members of MAFF. The minutes of the meeting record:

�9. BSE Guidelines

Dr Little gave a brief outline of the position to date. Sir Richard Southwood�s Report had thus far turned out to be a damp squib. However it was stressed that care must be taken to ensure that certain elements of the press do not get hold of the wrong impression about the safety of vaccines � both human and veterinary � and cause major problems.

The Guidelines had been issued by D of H on 10 March to all on the MAIL distribution list, which explained why veterinary product licence holders had received copies from D of H, and by MAFF veterinary product licence holders on 17 March. Dr Little pointed out that the guidelines took into account the fact that a high standard was being set, and also accepted that certain manufacturers may have other equivalent methods of attaining the required standard.�[511]

It was agreed that the guidelines �would be discussed by a small group after the next meeting.�

446.         On 30 March 1989 the CSM held a meeting.[512]

447.         On 31 March 1989 Mr Hagger sent a minute to Dr Pickles attaching copies of the papers on BSE considered by the CSM and its Biologicals Sub Committee.� These were itemised as follows:

�1.�� Paper appeared before the Biologicals and Safety, Efficacy and Adverse Reactions (SEAR) sub-committees in November 1988 (Pink sheets)

2.��� Recommendation from Biologicals and SEAR (plus pink sheets)

3.��� Extract from minutes of November CSM meeting.

4.��� Letter from Sir Richard Southwood to Professor Asscher set before December CSM meeting.

5.��� Paper set before February 1989 CSM (included 1,2,3 and 4 as annexes).

5.1�� Further correspondence between Professor Asscher and Sir Richard Southwood was also included.

6.��� Tabled paper set before February 1989 CSM, draft position statement and letter to product licence holders

7.��� Extract from minutes of the February CSM meeting.

7.1�� Minutes of the Human and Veterinary Medicines Briefing Group re. BSE.

7.2�� Position statement on BSE as agreed at February CSM meeting.� Letter, questionnaire and guidelines for industry.� Proposed membership of, and terms of reference for, working party on BSE.�[513]

448.         On 5 April 1989 Dr Pickles minuted Mr J Barnes (RMD) on BSE research to update him prior to his meeting with the MRC. Enclosed were minutes of the first meeting of the Tyrrell group and a paper, being a first attempt at listing all the relevant research areas:

�Those which might be thought of as falling in the DH/MRC field of interest are principally section 3; A3 to d, and B3, also C4 (although here the pharmaceutical industry or NIBSC might be expected to sponsor the work). However, much of the fundamental work planned by the NPU could be directly relevant to existing human disorders especially CJD. Their work and that of the CVL also could be important in determining whether humans have been or may be at risk from the bovine disorder, and also falls within our area of interest�� [514]

449.         On 11 April 1989 a paper prepared by Dr Pickles on BSE and Medicinal Products[515] was considered by the Tyrrell Committee.[516]� The paper outlined the conclusions of the Southwood Working Party as well as outlining some research questions of immediate interest to the MCA. The Annex to the document included a position statement of the CSM, a note on medicinal products that used bovine ingredients, and the CSM/VPC guidelines and letter to licence holders. The minutes of the meeting record:

�4.� BSE and medicinal products [CCRSE6]

Dr Tyrrell explained that this paper was mainly for the information of the Committee but did raise questions relevant to research needs. It correctly stated that the risks from BSE were small but that there was a need to be careful and conduct research.

Dr Kimberlin said that bovine insulins were an important product in this area. Pharmaceutical companies were asking where they could find BSE-free herds to draw on. Dr Tyrrell concluded that no herds could be said to be BSE free in the British Isles but that a few farms that had not used compound rations might provide a possible source. It was not however for the Committee to advise on this.

Dr Will made the point that the paper did not cover dental products and yet these might be of concern since Kuru transmission could have involved gum abrasions.�[517]

Dr Pickles passed this concern to Mr Howard, Senior Dental Officer Dental Division, in a minute dated 17 April 1989.[518]

450.         Dr Pickles� paper covered research questions of immediate interest to the MCA and the pharmaceutical industry.� These included:

�-���� can freedom from BSE-contamination be demonstrated in existing stocks of products at theoretical risk (many years supply of some vaccines, for example)

-����� for what processes/products are the risks sufficiently high to be worth subjecting to experimental test, eg with mouse inoculation

-����� how can BSE-free herds in the UK be demonstrated and material collected from these herds?

-����� what overseas sources of bovine material are acceptable?

-����� Are there any products for which the risk-benefit is now unacceptable (considered for the bovine insulins and heparin, but further action not thought appropriate at present)

-����� Should there be similar concern about other animal species used in pharmaceutical manufacture?�[519]

451.         On 13 April 1989 Dr Pickles minuted Mr Barnes, from RMD, about the meeting of the Tyrrell Committee on 11 April 1989. She listed specific points that related to DH interests:

�*��� the need to continue and expand basic work on spongiform encephalopathies �

*���� the national and international importance of the monitoring study of CJD�but note that we would look to the MRC to supervise and administer this study��

*���� neuropathological examination of CJD material �

*���� the restrictions that may be placed on undertaking the high priority research identified by the Tyrrell group caused by limitations in people with appropriate expertise

*���� the very high cost and lengthy nature of much of the research work identified as high priority, and that this will involve many thousands of animals�[520]

Response to questionnaire

452.         On 25 April 1989 PD met to consider the replies to the questionnaire from the manufacturers of medical devices. The minutes record that amongst those present were Miss Duncan, Dr Richardson, Mr Burton and Dr Hoxey. It was felt that to assess the accuracy of replies, letters should be sent to a random selection of the manufacturers asking for further information. Copies of all returned questionnaires were to be placed on the MRS files to allow their accuracy to be checked at the next MRS audit of the company. The validity of some of the replies so far received had been questioned at the meeting.[521]

453.         Over 80 manufacturers out of more than 330 had failed to respond. It was decided that the British manufacturers amongst these should be telephoned and foreign manufacturers sent reminder letters.[522]

454.         A paper entitled �Inactivation of scrapie-like agents�[523] was presented to the meeting by Mrs Dhell, a Higher Professional and Technology Officer for the PD, responsible for sterilisation and decontamination. It was suggested that this be forwarded to the trade association and to the Medicines Control Agency for comment.[524]

455.         In May 1989 a follow-up letter was sent to those medical device manufacturers who had stated that one or more of their products conformed to the PD guidelines. This letter was designed to understand how these manufacturers had arrived at their affirmative answers.[525]

456.         On 3 May 1989 the Biologicals Sub Committee of the CSM held a meeting.[526]

457.         On 12 May 1989 Miss Duncan, of PD, minuted Mr Hagger, of Medicines Division, and said:[527]

�1.�� I attach minutes of a meeting held to discuss the preliminary results of the questionnaire and future action.

2.��� Our main concerns at present are the poor response � just over half; the lack of response from some known UK manufacturers; doubts about the positive responses to GMP compliance and, what to do now.

3.��� With regard to the last point we will obviously rely heavily on decisions made in the MCA and are anxious to be involved with the meetings you intend from the beginning.�

458.         On 24 May 1989 Dr Pickles minuted Mr Hagger about the draft interim report of the Tyrrell committee. She attached a copy of the draft pharmaceutical section (C2), which included references to research on �bovine serum albumin and fetal calf serum and other common media that involve bovine materials�.[528] The draft report stated:

�2.� Pharmaceuticals

Part of the justification for using bovine rather than ovine material in pharmaceutical manufacture was because of uncertainty about the significance of scrapie in sheep.�Whilst there is no evidence of hazard in those biological medicinal products made using bovine ingredients or intermediates, the industry, drug regulators, the professions and the public naturally seek complete reassurance.

a.���� bovine serum albumin and fetal calf serum and other common media that involve bovine material: ic to mice.� Concern has been expressed about these materials not only by those involved in pharmaceutical manufacture but also by laboratory workers in immunology and microbiology, for example.� If procedures adequate to contain CJD agent had to be employed, much valuable experimental work would cease.� Artificial alternatives have been sought in recent years, mostly for economic reasons.� This trend will continue, although complete replacement of bovine material will not be possible and in pharmaceutical manufacture would have a lead-time of several years.� Titrations of the kind described in Cla are needed.� ***

b. similar attempts at transmission with various intermediates and perhaps also final products of pharmaceutical manufacture, chosen on theoretical grounds as plausibly contaminated with BSE including some when starting materials have been spiked or from known contaminated animals. An expert standing group of the CSM and VPC will be considering with the Medicines Control Agency, NIBSC and the Industry whether work in this area might be appropriate.�[529]

459.         The Right Honourable John MacGregor, MAFF Minister, in oral evidence told the BSE Inquiry that he had a meeting around 26 May 1989 with the CMO�s representative and others about the possible ban on specified bovine offal in human food:[530]

�Then we had a meeting on whenever it was, 26th May or some time, and the Chief Medical Officer's representative there spoke against it, Dr Metters, on the grounds that (a) it was going beyond Southwood advice and Southwood had not recommended it, and (b) there was a problem with vaccines, that they would not be able to withdraw them until September. I still took the line I did and made clear what we were going to do. I think this obviously went back to the Department of Health. The Chief Medical Officer said there is a problem for me on sensitivity of handling vaccines as there was for us, but he quite understood why we wanted to get ahead and not wait for a few more months. That was really what it was. It obviously was not -- it just -- it went away, it was not a problem�

460.         On 31 May 1989 Mr Cunningham minuted Dr Pickles and Dr Rubery about a meeting on 24 May 1989 with the CMO. The minute said:[531]

�Reference was made to the MCA and PD surveys of the use of bovine material in drugs, vaccines and unlicenced surgical implants. I subsequently spoke to Mr Hagger who told me that by no means all responses had been received by the deadline of 1st May and that it would take some time for the full response to be analysed. MCA was planning on a first meeting of their expert ad hoc group which would be advising the CSM and the JCVI in September. No decision had been made about whether the results of this survey should be made public and if so how.�

461.         On 5 June 1989 Mr Hagger replied to Dr Pickles� minute of 24 May 1989. He attached a copy of �the proposed membership and terms of reference of the CSM Working Party on BSE�.[532]� He commented that:

�3.�� We believe that we have understood the gist of item C2 b (bold print) although we did not find it clear.� We would expect the working group to comment willingly on relevant research protocols and perhaps to make its own suggestions for fruitful topics in this field.� However we were not expecting the working group to be asked to undertake the task described at b.� In fact this is the sort of issue on which the CSM�s working group was expecting to look to the Tyrrell group for information� - it is of course very helpful that Dr Tyrrell is in both groups.�

Mr Hagger also passed on the comments that �the primary reason for the use of bovine rather than ovine material is that there is more of it per animal� and ��complete reassurance� is never possible, given or even demanded by scientists.�

462.         In June 1989 the Interim Report of the Tyrrell Committee was completed (but not published). It listed research into possible transmission of BSE via pharmaceuticals as a high priority.[533] The report allocated stars to the various research options. Three stars indicated highest priority, two indicated medium priority for immediate work, and one star indicated low priority. Relevant sections of the report included sections A2 and C2:[534]

�A2. Human

Many extensive epidemiological studies around the world have contributed to the current consensus view that scrapie is not causally linked with CJD.� It is urgent that the same reassurance can be given about the lack of effect of BSE on human health. The best way of doing this is to monitor all UK cases of CJD over the next two decades. This UK cohort of CJD cases will be available for the testing of any future hypotheses.� The cost is low, the priority very high.� Prospective monitoring of putative �high risk� groups is more problematic: even a comprehensive nationwide survey of the relevant group might not provide any measurable gain over the usual surveillance for disease.

a. Surveillance of cases of CJD with particular reference to the overall incidence, the geographical distribution, the age and sex distribution, occupational history, association with medication; and any atypical clinical features.� There is a unique set of data of CJD gathered in England and Wales in the late 70�s and early 80�s.� Were BSE to prove a risk to humans, it must not be assumed that cases would present as typical CJD but perhaps, like with the iatrogenic cases associated with hGH, cases might have atypical features. A formal proposal for continuation and extension of the previous study has been received and we give it our full support.� We note the necessity for adequate facilities for the attendant neuropathology.� Alternative methods of monitoring disease, such as notifications to the CDSC [and CD (S) U] or from death certification, are considered inappropriate in a rare disease like CJD where the diagnosis can be difficult, even for the specialist.� Depending on the results of this surveillance, case control studies could then be mounted to test specific hypotheses, but in the view of the small numbers involved such methods would be technically difficult and might produce indeterminate results.� [Siv, Tiv][Southwood iv, Tyrrell iv]***

b. Prospective monitoring of groups with high exposure to bovine tissues, such as slaughtermen, veterinarians, and regular recipients of medicinal products of bovine origin.� Another classical technique in epidemiology is the prospective case-control study of those with presumed high exposure.� Such work in relation to �BSE risk� would need very careful design and might not prove realistic in practice.� The proposed surveillance of CJD (A2a) will, however, examine specifically for changes in occupational incidence. [Siv][Southwood iv]*�

463.         Section C2 recommended certain transmission experiments relating to pharmaceuticals[535]:

�C2. Pharmaceuticals

Whilst there is no evidence of hazard in those biological medicinal products made using bovine ingredients or intermediates, the industry, drug regulators, the professions and the public naturally seek reassurance.

a. Bovine serum albumin and fetal calf serum and other common media that involve bovine material: ic to mice. Concern has been expressed here not only by those involved in pharmaceutical manufacture but also by laboratory workers in regular contact with these materials, in immunology and microbiology for example.� Artificial alternatives have been sought in recent years, mostly for economic reasons.� This trend will continue, although complete replacement of bovine material will not be possible and in pharmaceutical manufacture would have a lead-time of several years. Titrations of the kind described in C1a are needed.***

b. Additional transmission studies specifically relevant to pharmaceutical manufacture.� We recommend that the Medicines Control Agency, with expert advice, considers the need for work in this area.�

464.         On 5 June 1989 Mr Hagger reported to Dr McInnes, Private Secretary to the Chief Medical Officer, on current progress of the human medicines questionnaire on the use of bovine by-products in human medicines. The 4,000 letters with questionnaires and guidelines sent out to all licence holders on 9-10 March 1989, had a deadline for return of the questionnaires of 1 May 1989. He reported that most licence holders had replied and that:

�The enquiry has produced a lot of material which will take time to study before papers can be prepared for a meeting on 6 September of the special working group set up by the CSM to advise it� At this stage, a preliminary scan of the data has not identified any information which would appear to warrant immediate special action.�The MCA is however taking account of the new guidelines in assessing applications for new licences and renewals.�[536].

465.         Dr Rotblat commented,� ��we received a large number of telephone calls from recipients over the next few weeks.�it became obvious from the calls that the industry felt that the easiest way of complying with the guidelines on safe sourcing was to source from outside the UK with New Zealand the preferred option.�[537]

466.         On 6 June 1989 a meeting took place between Z,[538] the producers of surgical catgut, and DH.� The minutes record the following:

�1.�� The meeting had been arranged following a request by the Company to discuss the application of the joint CSM/VPC Guidelines on BSE to 3 products.

2.��� The Company opened the meeting by stating that they saw no possibility of complying with the Guidelines, in particular for the major product , Surgical Catgut. DOH representatives suggested that a positive approach would be to consider the whole production process, starting with the source animal, with regard to potential points of intervention.

�

Clinical use of Catgut sutures

The company indicated that around 80% sutures used by UK surgeons were catgut, the rest synthetic.� Some specialists eg gynaecologists appeared to prefer catgut.

DOH asked about use in Neurosurgery, and the Company indicated that neurosurgeons tended to use synthetic absorbable sutures.

It was suggested that it would be useful to obtain a definitive picture of the spectrum of usage.

8.��� Forward Plan

8.1�� The Company was given an outline of likely DOH procedure, and that the first meeting of the Working Party on BSE would take place in September 1989.

8.2�� DOH informed the Company that the 2 renewal applications (Surgical Catgut and [redacted]) would be held pending the outcome of the Working Party on BSE.

8.3�� It was suggested that the Company should provide a dossier by mid-August containing further information on all the areas covered in the meeting, indicating

i.���� All current processes/procedures considered to limit the risk of BSE transmission by the product.

ii.���� Proposals for additional measures and when they can be implemented eg short-term � additional heat process medium to long-term � sourcing from Australasia.�[539]

467.         On 7 June 1989 Dr Metters sent a submission to Ministers and other DH Officials. The purpose of the submission was stated as being to �alert Ministers to additional precautionary measures that MAFF propose to take� to reduce the risk to humans from cattle offal, namely that MAFF proposed �to ban bovine offal from food for human consumption.� He stated that this had resulted from a combination of two factors: anecdotal evidence that some cases of infected cattle were not identified before slaughter, and the fact that the exclusion of offal from baby foods had drawn attention to the potential risk from bovine offal in other human foods.� He noted that the scientific evidence for widening the ban on offal had not changed since the publication of the Southwood Report.� He further noted that this action might draw attention to continued use of bovine material in licensed pharmaceutical preparations.[540]�

468.         In his Statement to the Inquiry Sir Donald Acheson said:[541]

�Although there was a conflict of view with my expert advisers, the new controls came entirely within MAFF's domain so I did not resist the ban and, with one 'caveat', supported it as an additional protection for human health without any apparent balancing disadvantage.

My �caveat� related to concern that an announcement of the SBO (sic) in advance of the anticipated reassurance concerning the safety of vaccines from the CSM might lead to a marked and unwarranted decline in the uptake of vaccines in children.� I had in mind a marked and extended previous reduction in the acceptance of whooping cough vaccine which had followed incorrect public allegations by a scientist that the administration of the vaccine carried a significant risk of encephalitis.� On the one hand I was aware that during the period 1980-1988, due to incomplete vaccination of our population of children, there had been 123 deaths from measles and 50 from whooping cough in England, together with a many times larger burden of illness and some long-term complications.� Against this I had to balance a remote risk of a fatal disease.� A warning was given to Ministers to this effect but in the event although the announcement was not delayed as I wished, it fortunately did not provoke an anti-vaccine scare.�

469.         On 8 June 1989 Dr Metters minuted Dr McInnes with copies to Dr Harris, Miss Pease, Drs Pickles and Rubery, Mr Hagger and others, about �MAFF�s meeting with Sir Richard Southwood� the previous day. The meeting had been attended by Mr Cruickshank, Mrs Attridge, Mr Meldrum, Mr Coe, Sir Richard Southwood, Dr Metters and Dr Pickles.[542]� The minute noted the discussion at the meeting, which centred on possible removal of bovine offal from the human food chain. The minute went on to say:[543]

�11. On timing Mr McGregor wants to make an announcement as soon as possible. MAFF officials expect this will be very early next week. MAFF�s first objective is to satisfy public pressure for a ban on offal. In their view it will not focus attention on bovine constituents of pharmaceuticals. But time will tell.�

470.         On 8 June 1989 Dr Pickles sent Mr Hagger an amended version of the draft of section C2 of the interim Tyrrell report which now stated:[544]

�b. additional transmission studies specifically relevant to pharmaceutical manufacture. The Medicines Control Agency, with expert advice, will be considering whether there is a need for work in this area.�[545]

471.         On 9 June 1989 Dr Metters minuted the CMO, Sir Donald Acheson, with copies to Dr Pickles, Dr Rubery and Mr Hagger, about the �Action proposed by MAFF Ministers on bovine offal�. The minute referred to a meeting on 6 June 1989 between Dr Metters and Mr MacGregor, in preparation for a meeting between Mr MacGregor and Sir Richard Southwood on 7 June 1989, attended by Dr Metters. The minute said:[546]

�5.�� Preliminary Briefing Meeting

Mr McGregor wished to decide the detailed line he would take in discussion with Sir Richard the following day. This briefing was attended by a large number of MAFF officials, including their Permanent Secretary. All MAFF officials had copies of various papers, which had not been copied to DH.�

472.         Paragraph 8 of the minute discussed �DH Points�:

�I told Mr McGregor of my conversation with Sir Richard Southwood earlier in the day, and I thought it unlikely Sir Richard would change his mind on the science. I mentioned Dr Tyrrell�s point about the inconsistency of banning bovine but not sheep offal. I also said that the CSM did not yet have the necessary data on which to consider pharmaceuticals with a bovine component and advise on any necessary action. A ban on bovine offal by MAFF could shift attention to the pharmaceutical problem.�

473.         Dr Metters also comments at paragraph 14 of the minute under �DH Interests�:

�The possibility that MAFF�s action may refocus attention on bovine constituents of pharmaceuticals cannot be ruled out.� While I put this point more than once, it cut little ice with MAFF officials.�

474.         On 9 June 1989 Mr Hagger also sent a minute to Mr Wilson[547], Grade 3 Administrative Head of Medicines Division, concerning the proposed offal ban. It was copied to, among others, Dr K Jones, Dr Adams, Dr Jefferys, Dr Rotblat, Dr Purves, Mr Love, Mr Sloggem, Mr Burton and Mr Scollen (MAFF). Mr Hagger attached a copy of Dr Metters� submission to the Secretary of State reporting on MAFF�s proposed offal ban. Mr Hagger noted:

�2.�� Another factor which might bring medicines back into the public debate of BSE is the likelihood that the Tyrrell report on BSE will be going to Ministers shortly and that it might then be published.

4.��� My minute to Dr McInnes summarised the MCA position over the enquiry. To go into a little more detail, an in-house MCA meeting has been arranged for Monday morning 12 June in my room, to be attended by professionals and administrators, to take consideration of the company replies a step further and to produce a �project plan� leading to the CSM�s working group meeting on 6 September. We expect PD/STD to be represented on Monday�.�

475.         In his Statement to the Inquiry Dr Jefferys said:

�On 9th June 1989, I was copied a minute from Mr Hagger to Mr Wilson about the proposed offal ban. It stated that the proposed ban was in response to increasing public pressure rather than any new scientific evidence. It went on to state that another factor which might bring medicines back into the public debate was the likelihood that the Tyrrell report on research would be going to Ministers shortly and that it might then be published. Extracts from the draft report were enclosed with the minute; paragraph C2b of the report referred specifically to the MCA. It stated �Additional transmission studies specifically relevant to pharmaceutical manufacture. We recommend that the Medicines Control Agency, with expert advice, considers the need for work in this area.� The Tyrrell Report on research was submitted on 13th June 1989.�[548]

476.         In relation to the draft report attached to Mr Hagger�s minute, Dr K Jones said in his Statement to the Inquiry:

�I did not disagree with the draft and therefore made no response.� Although the MCA is a regulatory body and as such does not carry out or fund research, I saw no reason why the CSM or its BSE Working Party should not make recommendations as to the type of studies which the experts considered would be helpful.� I would have expected the Tyrrell Report to be placed before the CSM and/or the BSE Working Party and for the CSM to respond as it thought appropriate.�[549]

477.         On 12 June 1989 an internal meeting in Medicines Division was held, to undertake a preliminary review of the replies from licence holders to the human medicines questionnaire.[550] Approximately 50-60 per cent of the product licence holders who had been contacted had replied. Products were divided into 7 notional categories in descending order of risk.� These were set out in a note of the meeting as:

�2.2.1���������� Products with bovine brain/lymphoid tissue as ingredients and administered by injection.

2.2.2����������� Products with bovine ingredients (other than brain/lymphoid tissue) and administered by injection.

2.2.3����������� Tissue implants, open wound dressing, surgical materials, dental and ophthalmic products with bovine ingredients.

2.2.4����������� Products with bovine ingredients and administered topically.

2.2.5����������� Products with bovine ingredients and administered orally.

2.2.6����������� Products with other animal/insect/bird ingredients and administered.

a.                by injection

b.               topically

c.                orally

2.2.7���������� Products/Ingredients of animal origin considered to be of no risk.�[551]

The first two categories were to be looked at by Dr Rotblat and Dr Purves, the third by Dr Adams and Dr Raine.[552]� No action was to be taken on the remaining products for the present.� It was also agreed that non-responders would be chased.[553]� The minutes note:

�Category 2.1���������� Products with bovine brain/lymphoid tissue as ingredients and administered by injection.

3 such products known at present, but could be more.� Action will need to be taken against these PLs in the light of MAFFs ban on bovine brain/lymphoid tissue in food.

Category 2.2 Products with bovine ingredients (other than brain/lymphoid tissue) and administered by injection.

This category includes those products containing foetal calf serum etc. and therefore covers injectable vaccines and other biologicals�

Category 2.3 Tissue implants, open wound dressing, surgical materials, dental and ophthalmic products with bovine ingredients

This MCA category matches those products of most concern to STD.

Sutures made from bovine material to be placed high on the agenda for the Working Party.

MCA have had discussions with Z who are producing a detailed submission on the subject.

Categories 2.4 to 2.6 Minimal emphasis and resource to be given to these categories at present�[554]

478.         The minutes also record the following:

�Dr Jefferys reported that Mr MacGregor (MAFF Minister) was due to ban all use of bovine brain and lymph tissue in human food (note: already banned in baby food.)� It was understood that this would be announced tomorrow (13 June) and that a CMO meeting would follow.�[555]

And later:

�MAFF had diverged from MCA at the time the Guidelines were sent out and all matters relating to veterinary medicines were being handled directly by MAFF.� Concern was expressed that MAFF could be developing independent policies in the face of pressure from their food sections.� MCA to liase more directly with MAFF in future.�[556]

479.         In her Statement to the Inquiry Dr Rotblat stated that non-responders were repeatedly written to by administrators until a satisfactory response was received.[557]

480.         The note of the meeting concludes with action items:

�a.� MB1B to �follow up� as a matter of urgency those licence holders who had not returned a questionnaire.

b.� MB1B to notify MAFF of the meeting and developments within MCA.

c.� Specific companies to be contacted by MB1B on matters arising from their completed questionnaires�.

d.� MB1B to continue updating the BSE database with replies in the classes at 2.2.1 � 2.2.7 above and summaries of the replies to be circulated to those attending the meeting for review.

e.� Papers to be prepared for presentation to the Working Group based on the information provided by licence holders in response to the questionnaire.� Responsibility for the papers was assigned as follows:

������������������ Dr Rotblat/Dr Purves � 2.2.1, 2.2.2, 2.2.4, 2.2.6, and 2.2.7.

������������������ Dr Adams/Dr Raine � 2.2.3

With a deadline for completion by end July 1989.�[558]

481.         In his Statement to the Inquiry, Dr Adams notes:

��By June 1989, we had received a number of responses from licence holders on the use of bovine materials in their products. A meeting was held within the Department of Health Medicines Division on 12th June 1989 in advance of the BSE Working Party meeting arranged for 6th September (minute dated 8th June from M.Love; agenda circulated 8th June). The responses had been broken down into categories (I do not recall by whom).� [559]

482.         On 13 June 1989, following the Medicines Division internal meetings of 12 June 1989, Mr Armstrong circulated lists dividing up the information which had been received in response to the BSE questionnaire into the various categories.[560]

483.         On 13 June 1989 Sir Donald Acheson minuted the Secretary of State about the Tyrrell Report on BSE research:

�2.�� �A large number of research areas are allocated high priority and this work will be laborious, time consuming and expensive. Almost all the recommended work is directly for MAFF (at the Central Veterinary Labs) or for the AFRC: the relatively small amount for DH/MRC (section A2a on page12) is being taken care of.�[561]

484.         On 13 June 1989 Dr Pickles circulated the Tyrrell Report to a number of people including Medicines Division.[562]

485.         On 27 June 1989 Mr Hagger minuted Dr Adams, Dr Jefferys, Dr Raine, Dr Rotblat, Dr Purves, Mr Sloggem, Mr Love and Mr Armstrong about keeping MAFF informed of MCA developments on BSE:

�Dr J M Rutter, the Director of the Veterinary Medicines Directorate, asked to be kept in touch with MCA developments on BSE.� He has seen my minute of 5 June to CM[O]�s office summarising progress to date and would like the Veterinary Medicines Directorate (VMD) to be involved in any meetings that we hold as well as being kept in touch with other significant developments.�[563]

486.         In her Statement to the Inquiry Dr Rotblat[564] said:

�I, and other colleagues, received a minute dated 29th June 1989 from Mr Armstrong[565] [separate to the one sent on 13 June 1989] enclosing lists dividing up the information received from pharmaceutical companies along the lines of the categories referred to at the meeting on 12th June. In addition, a list of ingredients which did not give cause for concern had been drawn up. The reason for drawing up such a list was to eliminate many of the responses to the BSE questionnaire from further consideration. The list primarily consisted of non-bovine products or very highly processed tallow derivatives principally used in oral medicinal products.�

487.         On 3 July 1989 Dr Pickles minuted Mr Maslin about cattle by-products and BSE. The minute said:[566]

�I was interested to see the list of by-products sent to the HSE. Those of particular concern included:

*small intestines: sutures ( I thought the source was ovine but you are checking this)

*spinal cord: pharmaceuticals

*thymus: pharmaceuticals

Are you able to give me more information on which UK manufacturers use these materials? Our proposed ban on bovine offal for human consumption would not affect these uses, I assume.�

488.         A handwritten note on Dr Pickles� minute from Mr Mark Hawkins, Higher Executive Officer at MAFF, to �John� said:[567]

�1. � A few companies make sutures out of intestinal linings, worth around �300 k p.a; probably some sheep used as well, but minimal.

2.��� Virtually all spinal cord goes for rendering, with just a very small amount going for pharmaceutical use.

3.��� About 30 % of thymus production goes for pharmaceutical use (approx �132 K pa).

Incidentally, some spleen also goes for pharmaceutical uses (approx �170 K pa). The main company involved with pharmaceuticals is Y[568] (MLC is trying to find a contact). Is Hilary serious about her final sentence? I would have thought that a) the staining would make these materials unusable (this is also MLC�s view) and b) if they are unfit for consumption, they are certainly unfit for medication. Has she forgotten iatrogenic CJD?�

Risk to humans

489.         On 4 July 1989 Dr Adams minuted Dr Raine about BSE. He said:

�Having seen Mr Armstrong�s print-out of the responses from the BSE questionnaire, the Z Catgut product seems to be the only UK source material and we would need a very strong justification to allow it to remain on the market�.Until now we had been of the view that many of the other catgut products were UK sourced as well. This is now shown not to be the case and I think Z and we have a problem!�[569]

490.         On 5 July 1989 Sir Richard sent Dr Tyrrell his reaction to his interim report (�The Tyrrell Report�). He stated:�

�Thank you very much for sending me the interim report of your Consultative Committee on Research.� I read it with considerable interest and admiration.� I think it�s excellent and I just hoe that the Ministry and others will, notwithstanding the ridiculous attitude towards public expenditure, find the necessary funds to undertake the high priority research.� I was horrified to discover a little while ago that the formal controlled study of possible vertical transmission had not been put in place.� The danger is, of course, that some of the early animals will be lost.�

You are absolutely right to point out gently how we were forced to argue from analogy with scrapie and one waits with some anxiety for the experimental confirmation of that assumption!

If you were making a few drafting changes the only point I would ask you to consider would be on page 4, paragraph 2.2 where you say �the Southwood group was correct in their belief that this disease would not have implications for human health say through food��.� A more complete picture of our belief would be given if you add �provided various safeguards, that they recommended, were instituted�.� Personally I would have thought the possibility of human infection was moderately high if some medicinal products were made from tissues of infected animals and injected into humans.�[570]�

491.         Kenneth Clarke, Secretary of State for Health, was shown this letter for the first time while giving oral evidence to the BSE Inquiry. He commented:�

��I am reacting in the way I suppose I would have reacted at the time when this is first put in front of me, when I got this out of a red box at some time: what on earth does Sir Richard mean by �moderately high�?� Then the next question is: What should we do about it?

�

If I had been shown this, I suppose I would have said how does this square with �risk is remote�?�[571]�

He was later asked what a Secretary of State would do confronted by a situation where there was a whole series of pharmaceutical products on the shelf derived from a bovine product which may be infected and have a moderately high risk of transmission if injected into humans. He replied� ��he would probably wind up ordering withdrawal of all the batches that might be affected�it could well mean that a significant number of patients may be infected by this.�[572]

492.         Professor Collee said:

�I have very recently been shown a copy of a letter dated 5th July 1989 from Sir Richard Southwood to Dr Tyrrell�

Sir Richard�s comments should be seen against the methodology involved in manufacturing medicinal products such as vaccines. The use of foetal calf serum in the manufacture of vaccines could not fairly be related to the example given by Sir Richard Southwood. Had I seen Sir Richard�s letter in 1989, I would have asked him to clarify his remark. As it stands, the remark poses a hypothetical situation. I would also have described to Sir Richard the discussions we had on various medicinal products and our views on the hazards that might be posed by those products.�[573]

493.         In his Statement to the Inquiry Professor Asscher stated the following with regard to this letter:

�I have been asked to comment on the letter dated 5 July 1989 from Sir Richard Southwood to Dr Tyrrell.� I should make it clear that I have not previously seen this letter.� I must confess that I am surprised by its contents.� The letter does not fit easily with the statement in the Southwood Report that the risk from medicinal products was remote.� Sir Richard�s comments are inconsistent with my understanding of his views; I believed that he considered the risk from all medicinal products to be remote.� I believe that if the CSM had seen this letter at the time we would have asked for clarification from Sir Richard.� We would have wanted to know his scientific basis for the comment that �Personally I would have thought the possibility of human infection was moderately high if some medicinal products were made from tissues of infected animals and injected into humans.�[574]������������������������������������������������������������� ��������������������������������������������������������������������������������������

494.         On 10 July 1989 Dr Raine replied to Dr Adams� minute of 4 July 1989, by way of a hand written note, which stated that the company involved [Z] had been informed of the �need to review the situation� and that she had arranged a meeting with them for 20 July.[575]

495.         On 14 July 1989 Dr John Purves minuted Dr Adams in the following terms.

�1.�� By copy of Dr June Raine�s minute about a meeting to be held with [Z] on Thursday 20 July, I note your observation that �we would need a very strong justification to allow it (catgut) to remain on the market�.

2.��� I was surprised to see that another meeting had been arranged with the Company without any prior multidisciplinary discussion.

3.��� You have identified some new information arising from the useful data provided by Murray Love�s group, in that it would appear only [Z] source raw material for this product from the UK.� The significance of this must be weighted against the fact that the presence of BSE in other countries cited has not been excluded.� In addition, when we are within six weeks of seeking the views of experts on how to deal with the whole problem of BSE in a range of pharmaceutical products, why have we picked out [Z] from all other companies?� You are no doubt aware of the minute of the meeting held at Market Towers with the Company on 6 June.� The Company�s keen awareness of the problem, scientific approach to solve it and responsible attitude � it was they who contacted the Agency for a meeting � all indicated to [sic] the pragmatic approach of letting them prepare a rounded paper on the topic, for submission to the expert Committee which is to meet at the beginning of September.� This they agreed to do.� They have been positive and helpful in their contacts with us.

4.��� Unless I am unaware of other information, it would seem premature to press this company on an issue about which the Agency is hoping to get expert advice in the near future.� Without good reasons, it seems iniquitous to isolate one Company for attention at this stage.

5.��� What is the objective of the meeting scheduled for next Thursday?

6.��� It would seem prudent � if the meeting with the Company is justified � to hold a briefing meeting to ensure a unified approach by Agency staff.�[576]

496.         In relation to paragraph 2 of this letter, Dr Purves has explained:

�I did not think it was a [sic] necessary to set up another meeting with Company Z.� The reason was that we were within about 6 weeks of seeking the views of experts at the first meeting of the BSE Working Group on how to deal with the whole problem of BSE in a range of pharmaceutical products.� I referred to the meeting held with the company on 6 June.�� It had been agreed with the company that they would present us with a dossier, by mid August, reporting on the manufacturing procedures used to limit the risk of BSE transmission by the product and their proposals on how they could comply with the guidelines.� We had advised them at that meeting that the Company�s position would be reviewed at the BSE Working Group meeting in September.� Although the information provided by Murray Love's group in the list was helpful, we were already aware of the catgut suture issue and had taken steps.� I did not think a second meeting was necessary since Company Z had already shown itself to be willing and able to take steps to comply with the guidelines.�[577]

497.         On 19 July 1989 Miss Green of the NOAH wrote to Mr Whitbread, a Higher Executive Officer of the MCA. The letter said:

498.         ��I am writing regarding the guidance on good manufacturing practice for human and veterinary medicines which use material of bovine, ovine and caprine origin, issued by MAFF to all licence and certificate holders for veterinary medicinal products.� Many NOAH members are concerned over the relevance and practicality of certain aspects of the guidelines and have been advised by MAFF that comments would be useful and are best addressed to the Department of Health as it was you that fronted the exercise.�[578]

499.         She also stated that �it is impossible to produce most types of bovine virus vaccines without the use of cell cultures of bovine origin�. She later stated that �according to the current approach adopted by the guidelines, virtually all cell cultures, of whatever origin could conceivably be prohibited by the guidelines from being used in vaccine manufacture�.� In relation to collection techniques, Miss Green noted that �it would be very difficult to obtain the quantities of sera (17, 000 litres per annum) required for all purposes from animals stunned using other techniques [other than brain penetration]�.

500.         On 26 July 1989 Dr Adams minuted Dr Jefferys regarding the letter of 19 July from NOAH. He stated that the points raised by NOAH had been foreseen.[579] Mr Gutowski of the MCA replied to Miss Green on 24 August 1989 saying that Miss Green�s comments would be taken into account during the study of animal materials used in medicinal products.[580] This correspondence was drawn to the attention of the first meeting of the BSE Working Party on 6 September 1989.[581]

501.         On 2 August 1989 Ms Margaret Williams, from X[582], wrote to Mr S Hutchins and said:[583]

�I have already spoken to our suppliers on the subject of BSE and the source of their raw material. The only information they have on the contamination and testing of the raw material is that the abattoirs used produce only food fit for human consumption. They did not think that any further control is at present possible on the raw intestine.�

502.         On 2 August 1989, Mr Gummer (MAFF) wrote to Mr Kenneth Clarke (Secretary of State for Health) regarding the programme of research covered by Dr Tyrrell�s report.[584] Mr Gummer explained the contents of the annexed lists of research:

�The programme of research covered by Dr Tyrrell�s report is set out in Annex 1. �The research programme is divided into 3 categories of urgency and at the Committee�s suggestion I have concentrated on the two most urgent categories.� In these two categories I have costed in Table 1 those parts of the programme that would fall to me to finance and I have indicated in Table 2 where responsibility for other parts of the programme would appear to fall.� In view of the wide public concern about this disease, I see no option for the Government other than to ensure that all the projects in these two higher categories are initiated.� Not to do so would lay us open to the criticism that, while we were aware of the potential danger of BSE, we had failed to research into the public and animal health aspects adequately.� I consider that in order to keep the initiative, I need to announce urgently that the Government has accepted the findings of the Tyrrell report as regards the projects to which it attaches higher priority, and that we are making money available so that work can begin on the most pressing recommendations that were considered by Tyrrell to be of primary importance.�[585]

503.         Next to the entry for C2a and C2b, in Table 2[586] annexed to Mr Gummer�s letter, is the comment:

�In these issues MAFF will have joint responsibility with DOH in support of the Medicines Act 1968.�

504.         On 4 August 1989 Dr Lee, of MAFF, wrote to Mr Armstrong of the Information Section DH, to give an update on the replies to the veterinary medicines questionnaire sent out on 15 March 1989.[587] �She reported that of the 245 companies targeted, 186 had provided replies. These covered 3,239 products of which 303 contained bovine, ovine, or caprine products. Dr Lee said that MAFF would be undertaking an initial analysis of these 303 returns in the near future.

505.         On 7 August 1989 Dr Metters sent a submission to the PS/Mr Kenneth Clarke advising the Minister�s agreement to the publication of the Tyrrell Report. He suggested that the announcement of the publication should include a reference to an early start being made on research falling to the Department of Health. He attached a draft letter to Mr Gummer which noted:

�The pharmacological studies in which our Departments have a joint interest will need to be considered again after we have the advice of an expert group convened under the Committee on Safety of Medicines. The advice from the group is not expected until September at the earliest.�[588]

506.         On 9 August 1989 Mr Roger Freeman, Parliamentary Under Secretary of State for Health, wrote to John Gummer, the Minister of Agriculture in the terms of Dr Metters� draft letter.[589]

507.         On 21 August 1989 Dr Adams minuted Mr Gutowski saying �information on the product � surgical cat gut � is concerning.�[590]

508.         On 21 August 1989 PD held a meeting to review the responses to the medical devices questionnaire.[591] �The minutes of the meeting state:

�Despite letters and telephone calls to the companies who have not replied the final response was still only about 66%.� The committee was concerned about the number of UK companies who have not yet responded.� Concern was also shown about BSE products being transported around Europe.

The Committee decided that a definitive list was needed of the companies in the UK and Europe, who have not responded.� These companies would be sent a 2ndreminder.�

Of the responses received, 46 manufacturers used animal material, of whom 26 used bovine material. Two of these manufacturers used UK sourced pericardium tissue.[592]

509.         The meeting also considered a paper entitled �Inactivation of Scrapie-Like Agents�,[593] which reviewed existing literature on inactivation studies and had been prepared to assist in discussion related to the validation of non-standard sterilization methods.

510.         On 24 August 1989 Mr Gutowski, of the MCA, replied to NOAH�s letter of 19 July 1989, saying that the concerns raised would be taken into account and that the Licensing Authority was continuing its study in the light of questionnaire responses.[594]

511.         On 30 August 1989 Mr Bradley minuted Dr Watson reporting on a meeting Mr Wilesmith, Mr Taylor, and he had with Z about suture material prepared from cattle. The minute stated that �[redacted] told us that [Z] had about 60% of the suture market in catgut; 90% being sourced from cattle and 10% sheep�. The minute also noted that �The quantity of gut required >100, 000 runner sets pa precluded any UK source such as a MAFF controlled BSE-free herd.�[595]

512.         On 30 August 1989 Dr Lee prepared a note on the BSE questionnaire returns from licence holders for veterinary medicines:

��An initial analysis has now been undertaken of the 303 �positive� returns received so far. Approximately 45 different ingredients of bovine or ovine origin have been mentioned.

As expected, the most common listed ingredient of animal origin is bovine serum (86 products)�.

A country (or countries) of origin has been stated for a high proportion of the tissues mentioned. However, where more detail has been available it is clear that, for many, the country stated is that where the material has been purchased and this is not always the country of origin of the animal tissue.

Different companies have interpreted the questions posed in different ways and some of the apparently complete returns are, in fact, incomplete.

Much further work and time would therefore be needed to gain as complete a picture as possible of all the substances of animal origin in all veterinary medicinal products.

Effort will need to be concentrated, in the meantime, on those products which, from the returns and knowledge of the products, can be identified as having possible risk of BSE contamination. Follow up letters with specific questions will be required for the licence holders of these products.�[596]

513.         On 5 September 1989 the CRM met and Dr Adams advised the Committee that the BSE working party would be discussing company responses to the questionnaire that accompanied the CSM/VPC guidelines on 6 September.[597]

The BSE Working Group (on human medicinal products): first meeting

514.         The HVMBG as part of its deliberations on 22 February had recommended the setting up of a BSE Working Group to advise the section 4 committees on the implications of BSE for human medicinal products. The CSM had accepted this recommendation. The BSE Working Group met for the first time six months later on 6 September 1989. Professor JG Collee was its chairman. Other members included Professors Asscher, Campbell, Lawson, Berry and Rawlins, Drs Kimberlin, Kirby, Taylor, Tyrrell, Watson, Will and Watt. DH and MCA officials were in attendance as well as Dr A Lee for MAFF. The minutes of the meeting recorded:[598]

�3. Since the publication of the Southwood Report, no further evidence had come to light to change the original view that the risk of BSE being transferred to humans is considered to be remote and theoretical. Hence the likelihood of the BSE agent affecting humans via medicinal products by the use of bovine material in the production process is also thought to be remote. Nevertheless the Working Group would need to consider this risk and balance it against the obvious and known advantages to health afforded by the current availability of medicines and vaccines incorporating bovine material. To date available evidence has suggested that cattle are likely to be a dead-end host for the BSE agent, but the Chairman [Professor Collee] sounded a note of caution and stressed the need for further investigative research into the disease, of which little is really known and quoted from the Southwood Report: -

�From present evidence, it is�most unlikely that BSE will have any implications for human health. Nevertheless, if the assessments of these (sic) likelihood are incorrect, the implications would be extremely serious.��

515.         It was reported that responses to the questionnaire were still being received; around 75% of licence holders had responded by this time. The Working Group emphasised the importance and desirability of achieving a total response. At that stage, the Working Group was told that BSE was confined to UK, the Channel Islands, Republic of Ireland, the Falkland Islands and Oman (the latter two probably in cattle imported from the UK).

516.         Dr Rotblat presented a paper, prepared by her and Dr Purves, to the group based on the results so far received from the March questionnaire.[599] The valid responses were divided into the following categories in order of concern[600]:

�Products with bovine brain/lymphoid tissue as ingredients and administered by injection.���������������������������������������������������������������������������������������� 111

Products with bovine ingredients (other than brain/lymphoid tissue) and administered by injection.��������������������������������������������������������������������������� 135

Tissue implants, open wound dressings, surgical materials, dental and ophthalmic products with bovine ingredients.��������������������������������������������������������������� 27

Products with bovine ingredients and administered topically.����� 5

Products with bovine ingredients and administered orally.��������� 9

Products with other animal/insect/bird ingredients.���������������� 131

Products with materials produced from animal material by chemical processes eg. stearic acid, gelatin and lanolin.������������������������������������������������������������ 156�

517.         The paper indicated that only two products were considered to give immediate concern[601],� ��although 176 products do not conform to the CSM/VPC guidelines.� These two were, first a range of� ��homoeopathic medicines [including 53 injectable ones] with material obtained from cattle and a number with material from the brain�, and secondly, a surgical catgut.

518.         Dr Purves has explained that the reason that only 2 types of product gave concern was that:

��of the non conforming products, only two groups of medicinal products were likely to contain bovine brain or lymphoid tissue sourced in the UK as ingredients as opposed to merely using them during the manufacturing process.� The other non-conforming products were not disregarded (they most certainly were not - as is clear from the rest of this statement) - but we were focusing on those that were of most concern first.� Because of the prolific use of bovine materials in medicines we had to target the products with theoretically the highest risk first.� We could not apply a knee jerk reaction to all non-complying products.�[602]

519.         The paper made the following recommendations[603]:

�1.�� That no licensing action is required at present in regard to products produced from bovine material other than brain, and sourced from outside the UK and Ireland.

2.        No licensing action at present regarding use of prepared bovine brain in nutrient media.

3.        The CRM should review the PLR for F[604] in view of the bovine brain used in manufacture.

4.        The Joint CSM, VPC guidelines should apply to all UK and Eire sourced bovine material. Companies which at present cannot comply should be encouraged to do so as soon as possible. The time-scale should be agreed with the licensing authority for each individual product.

5.        No licensing action is required at present in regard to products containing material from animals other than cattle.

6.        The Licensing Authority should continue to review scientific progress in the field of BSE, so as to be in a position to take licensing action in the future should this be necessary.�

520.         The paper also noted[605]:

�The above general and theoretical considerations must also take into account,

2.1     the findings of [the] Southwood Report in which it was stated that� �the risk to man of infection via medicinal products was remote�. It is important not to undermine this considered advice by demanding unnecessary assurances and information from manufacturers.

2.2     the paucity of hard scientific information on the nature of the BSE agent.

2.3     the type of bovine material used in the manufacture of products� (brain, lymphoid tissue sera etc.)

2.4     the type of product containing bovine material (injection, topical, oral etc).�

521.         The Working Group considered that on the evidence available products with bovine ingredients administered topically or orally, products with other animal/insect/bird ingredients, and products with highly processed animal material (e.g. lanolin, gelatin and stearic acid) [ie. the fourth to seventh of the MD categories, see paragraph 516 above] were not a cause for concern at the present time.

522.         The BSE Working Group made four general recommendations in relation to products falling within the first three categories:[606]

�1.�� That no licensing action is required at present in regard to products produced from bovine material or using prepared bovine brain in nutrient media and sourced from outside the United Kingdom, the Channel Isles and the Republic of Ireland provided that the country of origin is known to be free of BSE, has competent veterinary advisers and is known to practise good animal husbandry.

2.        The Joint CSM/VPC guidelines should apply to all bovine material sourced from UK, Channel Islands and the Republic of Ireland and any other area known to have BSE. Companies which at present cannot comply should be encouraged to do so as soon as possible. The timescale should be agreed with the Licensing Authority for each individual product as appropriate.

3.        No licensing action is required at present with respect to products containing material from animals other than cattle.

5.��� The Licensing Authority should continue to review scientific progress in the field of BSE, so as to be in a position to take licensing action in the future should this be necessary.�

523.         In his Statement to the Inquiry Professor Collee stated[607] that although the guidelines excluded the use of all bovine material of a certain type, regardless of its source, it was reported to the BSE Working Group that BSE was confined to the British Isles, except some cases that had occurred as a result of export. (The meetings of September 1989 and July 1990 provide more detail on this point). Accordingly the BSE Working Group were able to recommend that no action be taken on certain products using the excluded material, if it was appropriately sourced.�

524.         In her Statement to the Inquiry Dr Rotblat said[608] that she believed the reasoning behind identifying only two groups of products as giving cause for concern, was that only two groups were likely to contain bovine brain or lymphoid tissue as ingredients, as opposed merely to using them during the manufacturing process.�

525.         In relation to the first group, the homoeopathic products identified by the Rotblat and Purves paper as being of concern, the BSE Working Group noted that further follow-up action would be needed, with the possible involvement of the CRM.

526.         In relation to the second product (surgical catgut) identified by the Rotblat and Purves paper as giving cause for concern (which was the only such product in the third category) the BSE Working Group had before it a paper prepared by Dr Raine, based on information provided by the manufacturer Z. The paper said, inter alia:[609]

�1. Introduction

Surgical Catgut (PL� Z) represents the most immediate problem arising from the review of tissue implants, wound dressings, dental and surgical products containing material of bovine origin.� The reasons for concern are:

i.���� UK origin of the source material

ii.���� nature of the source material (serosal layer of bovine small intestine) and proximity to lymphoid tissue

iii.��� large scale production and use of product

�

2.��� Licensing Background

Surgical sutures which are capable of absorption by the body are licensed under the Surgical Materials Order 1971 (SI No 1267).� Z Surgical Catgut received a product licence of right in 1973, and a reviewed product licence was granted in April 1984.� An application for renewal was submitted in April 1989, and has not yet been determined pending the outcome of consideration by the Working Party on BSE.�

3.��� Surgical Catgut-BSE Questionnaire

Of the 9 product licences for surgical catgut, PL� , Z, is the only UK sourced product.

�

4.1 Scale of Production and use of Surgical Catgut

�One animal yields about 45 metres of intestine and the catgut manufacturing plant requires the input from 2,500 animals per day

4.2 Source Animal

4.2.1 Alternative Species

The utilisation of intestinal raw material from other species, for example porcine or caprine, on the scale required by Z is considered by the Company to be impracticable.

4.2.2 Country of Origin

The Company considers that the only safe material sources which could supply the quantities required are in Australia, and states that plans to change to Australian raw material are now well advanced.� This would entail procuring the equivalent of 10% of the annual cattle kill in Australia and 24% of the New Zealand kill, in a competitive raw material market.� The current projected date for commencing production from Australasian source material is 1991.

4.2.3 UK Cattle Source

The current raw material used cannot comply with the requirement that bovine material should come from animals taken from a closed herd in the female line since 1980, in which no animal has been clinically suspected of having BSE, and which has not been fed rations containing ruminant derived protein.

Z proposes to operate a limited selection procedure, confining raw material to �clean beef cattle� having an average age of 18 months to 2 years.� By January 1990, 18 month old cattle should not have been exposed to rations containing animal protein, since the Bovine Spongiform Encephalopathy Order 1988 prohibiting this came into force on 18 July 1988.

�

4.5 Catgut Manufacturing Process

A flow chart is provided at Appendix 3 of Company paper.� The catgut manufacturing process is basically a cleaning process involving a combination of physical and chemical operations.� The company contends that although no one step is known to be capable of inactivating BSE, there may be a cumulative effect against the BSE agent�

4.6 Clinical Usage

An alternative to the use of catgut, in the form of synthetic absorbable sutures, has been available since 1972, and conversion of the surgical profession to the use of synthetic materials would circumvent the BSE problem.

�

5. Z Proposals

The Company proposals are divided in to short-term and long-term objectives.

5.1�� Short Term������������������������������������������������������ Completed By

a.���� Source material � Feasibility studies

- operation of abattoir selection procedures����������������� End Aug 1989

- change over to Australasian raw material������������������ End Oct 1989

b.��� Manufacture � reintroduction of heat setting�������� End Dec 1989

c.���� Clinical � contraindicate in neurosurgery� ? 

and paediatric surgery

5.2�� Long Term

a.���� Commence production from Australasian ����������� ? 1991

sourced raw material

b.��� Conversion of surgical profession to use of �������� ? date

synthetic absorbable sutures rather than catgut

6.��� Medical Comment and Recommendation

�

6.3�� The opinion of the Working Party is sought on the reassurance offered by the short term safety measures proposed.

i.���� Use of �clean beef cattle� ie 18 months to 2 years.

ii.���� Procedures specified by Company in current manufacturing process, as in para 4.5 (enzyme, alkali, tanning, alcohol packing, terminal sterilisation 25KGys).

iii.��� Reintroduction of heat-setting step (149�C for 1 hour)

iv.��� Contraindications in neurosurgery and paediatric surgery.

6.4�� In the light of 6.3 above, the advice of the Working Party is sought on the renewal of the Z surgical catgut product licence.

������������������������������������������������������������������������������ J M RAINE�

527.         Dr Raine had also produced a paper entitled �Category 3: Tissue Implants, Open Wound Dressings, Surgical Materials, Dental and Ophthalmic Products with Bovine Ingredients � Review of Positive Responses to Questionnaire�.� This identified Z as failing to comply on one product.[610]

528.         The BSE Working Group recommended that[611]:

��when material used to manufacture catgut is UK or Channel Island or Eire sourced, the company should -

8.6.1� Use �clean beef cattle� ie 18 months to 2 years of age

8.6.2� It was also noted by the Working Group that the Company uses specified procedures including enzyme, alkali, tanning, alcohol packing, terminal sterilisation by irradiation (25 kgs), and a dry heat treatment step at 149�C.�

529.         The Working Group further considered that changeover to Australasian sourced raw material was the preferred option in the mid to long-term. It was noted that a minority of the BSE Working Group considered that �catgut should not be used in neurosurgery until or unless the materials are sourced from BSE free countries��[612]

530.         Professor Collee has also said to the Inquiry:

�The question of bovine-derived catgut sutures was also carefully discussed at the meeting. On receiving the draft minutes of this meeting, I amended them and added a Chairman�s note (paragraph 9) to reflect our discussion. In light of the Working Party�s advisory function, I was anxious that the comments on the use of catgut sutures in neurosurgery should be recorded. I was personally concerned by this issue. Since the relevant sutures were manufactured from bovine intestine, this bovine intestine might be contaminated with bovine lymphoid tissue. Although at this time it was not proven that lymphoid tissue harboured the BSE agent, lymphoid tissue was regarded, on the basis of the scrapie analogy, as being potentially infective.�[613]

531.         The BSE Working Group also heard a report from PD and agreed that ��there was no particular cause for concern here provided that the guidelines could be followed��

532.         On 7 September 1989 Dr Pickles minuted Mr Woolley about Dr Metters� minute of 7 August 1989.[614] She stated:

�3. I have discussed with Dr Dastgir [DH] and Dr Levy at the MRC and the most urgent project for us to progress is that identified in A2a of the report ie the �surveillance� of CJD cases. �The most sensible way to progress this is for DH to arrange to fund the basic study, and for any later additions � such as molecular biology on neuropathological specimens, or detailed investigation of certain occupational groups � could be covered by MRC-grant aided work grafted on. In the long term � and this is a study we envisage lasting for at least a decade � we might ask the MRC to take over even the basic study�. But for the sake of speed now, we need to start with DH funds�

4. I hope there is no need for me or you to worry about the other items that could be linked with DH interests. Project A2b has only one star � principally because the group doubted that such a study could be mounted to provide any more information than would arise from other routes. However, if preliminary findings from Dr Will�s work suggests it would be worthwhile, we could investigate this further in the coming years. In the meantime, I am approaching the OPCS, who are already looking at occupational groupings for all CJD deaths notified to them, in case they have any specific proposals. Item A2c is already taken care of by Professor Preece�s study [,] and the Medicines Control Agency, together with the pharmaceutical industry, will be taking care of C2a and b. I think it� unlikely they will be calling on RM�s funds, but that is up to them.

5. BSE is a new disease, and who knows what we may want to investigate in the future. For now it looks as if we will not be draining the RM�s coffers too much.�[615]

533.         On 7 September 1989, Dr Pickles minuted Mr Hagger.[616] She commented:

�1. As you will no doubt hear, we had a very useful meeting about BSE and medicinal products this afternoon.

2. One matter not discussed was research�� As I think we agreed earlier, we will look to the MCA to provide any necessary defensive briefing over the response to those items affecting them [see C2a and b on p18].

3. The general line is likely to be that we will try to get going all work starred +++ or ++, and if it is necessary and appropriate by direct funding.� As a result of today�s meeting, you may want to argue that the pharmaceutical problem is being circumvented by ensuring no potentially contaminated material will ever start into pharmaceutical processing � the line is up to you of course.� But if you are going to argue that these experiments are not now necessary, we must make sure Dr Tyrrell at least is willing to back you up.� From my preliminary chat with him this afternoon, I think you will find him very supportive of whatever line you want to take.

4. It is of course open to individual companies to demonstrate by transmission experiments that stockpiles of material they hold or B.S.A that went into them are not capable of transmitting agent to mice. They may find that they need this information to satisfy other regulatory agencies, even if the MCA is relatively relaxed in the short term.�[617]

534.         On 7 September 1989 Dr Pickles also minuted Mr Maslin, of MAFF, about the risk of BSE contamination of bovine gut. She said:

�1.�� We spoke�about yesterday�s meeting at the Medicines Control Agency which was also attended by Dr Watson.

2.��� I was concerned by some statements made by a commercial company with product licences for material made from UK-sourced bovine intestine. They claim that there is no way of physically separating the serosal layer from lymphatic tissue and they claim discussions with the CVL have backed up this view. In spite of the chemical treatments to which their product is exposed, the company proposes that the only long-term solution is to source their material in Australasia.

3.��� These statements seem inconsistent with what has been said in justification for the exclusion of sausage casings from the proposed offal ban. The statements made by the licence holder are of course confidential under the Medicines Act, but inevitably there is a risk that the advice they have received might become public�.�[618]

535.         On 13 September 1989 Dr Winship sent a letter to H,[619] the manufacturers of the homoeopathic products identified at the meeting of the BSE Working Group on 6 September as giving cause for concern. The letter said that the Licensing Authority required H to provide details about the country of origin of the cattle used for the bovine material in each of the listed products.[620]� In October Dr Winship prepared a paper for the CRM noting that the bovine materials used in these products were all sourced from West Germany.� In light of the information received, Dr Winship�s suggestion was that no further action was required in relation to the products concerned.[621]

536.         On 18 September 1989 a meeting was held between MAFF and DH Officials and a number of invited experts, to discuss BSE. Those present included Sir Richard Southwood and Drs Tyrrell and Kimberlin. Drs Metters and Pickles represented DH and the CVO and Mr Lawrence represented MAFF. According to the notes of the meeting they agreed that foetal calf serum was ��a low risk provided that care was taken when it was collected� and they noted that the issue of sutures was being looked at by the CSM.[622]

537.         On 19 September 1989 Dr Metters minuted Mr Hagger about the meeting. He said:[623]

�I attended a meeting at MAFF on 18 September called by the Chief Veterinary Officer Mr Meldrum to discuss various details of the proposed ban on bovine offal from food intended for human consumption�

The purpose was to discuss possible exceptions to the ban�[A] range of�matters were clearly in MAFF�s domain.

However, during the discussion two subjects were raised that are primarily for DH and MCA. These were:-

a: the potential risk of �catgut� derived from bovine intestinal origin. When bovine offal is to be excluded from human consumption on grounds of BSE risks, is it consistent to continue to allow the use of bovine derived catgut?

b: fetal calf serum. Here the problem identified was BSE risk through medicinal products containing fetal calf serum, or whose manufacture involves its use.

I indicated these subjects were primarily for DH MCA and that my understanding was MCA, having consulted the industry, would be holding a special meeting shortly to consider the various implications for BSE and licensed products that have a bovine constituents (sic) or in which bovine material is used during the manufacturing process.

MAFF officials are content to leave these issues to MCA. However, could you confirm that both are on the list of subjects to be discussed at the forthcoming meeting.�

538.         On 19 September 1989 Dr Raine minuted Dr Adams about surgical catgut.[624]� She noted that Z had proposed to change to the use of clean beef.� This proposal had been endorsed by the Working Party, but the company�s proposed action had met with opposition from abattoirs.

539.         On 20 September 1989 the CDSM met.� At this meeting the surgical catgut suture licence was renewed subject to conditions.[625]

540.         Mr Love sent a minute about catgut to Drs Jefferys, Rotblat, Adams, Raine and Purves, with a copy to Mr Hagger, on 21 September 1989.� He attached a copy of the minute from Dr Metters to Mr Hagger of 19 September.[626]

541.         On 21 September 1989 PD held a further meeting. A list had been drawn up of medical device manufacturers who had still not responded to the questionnaire and it was decided to send a second reminder to those manufacturers both in the UK and Europe.[627] Mr Burton reported on the first meeting of the BSE Working Group. The Working Group discussion on sutures was discussed in detail �as they offered a close parallel to PD products.�

542.         The meeting also heard a report on the follow-up letters sent to the ten randomly selected manufacturers who had indicated compliance with the guidelines in May 1989. Of the 8 replies received, 4 had changed their response, and the others stated that their animal materials were not susceptible to BSE.

543.         The meeting considered again[628] the paper on �Inactivation of Scrapie-like Agents� and agreed that it was suitable for distribution to manufacturers using bovine or porcine materials in their products. Finally, the meeting decided that the guidelines on tissue collection needed to be finalised and issued, the MCA was to be contacted on their plans for doing so.

544.         On 28 September 1989 the CSM met.[629] Professor Collee delivered an oral report on the BSE Working Group meeting of 6 September 1989.[630]� The CSM endorsed the findings of the Working Group.

545.         On 3 October 1989 Mr Lawrence�s submission to Ministers stated that it had been concluded that:

�(a)� the proposed exemption from staining and sterilisation for materials used in making pharmaceuticals (principally sutures produced from small and large intestines) should remain, on the basis that it would be for any controls to be applied under the Medicines Act, in the light of the views of the Committee on Safety of Dental and Surgical Materials.�[631]

546.         On 3 October 1989 Dr Pickles minuted Miss Duncan of the PD in relation to the proposed offal ban. She noted that she was aware that there were several unlicensed products made from cattle, and that she had �argued� not to ban collection of offal intended for pharmaceutical and related use, since more rigorous control would be applied later.� Dr Pickles also noted that the MAFF rules might only apply to products licensed under the Medicines Act and sought Miss Duncan�s comments as soon as possible.[632]

547.         On 4 October 1989 Dr Metters minuted Dr Pickles, copied to Dr K Jones, Director of the MCA.� The minute said:[633]

�6. At the MAFF meeting on 18 September Dr Kimberlin was content for calf spinal cord to remain in the carcass up to the age of 6 months as the evidence suggests that BSE entry to the CNS takes place later. Dr Kimberlin was much more concerned about the evidence that BSE appears much earlier in the reticulo-endotheial elements of bovine intestine.

7. Is there an inconsistency between the six month limit MAFF have in mind for the inclusion of bovine spinal cord in calf carcasses for human consumption and the 18 months � 2 years limit on bovine raw material from �clean beef cattle� used for the manufacture of surgical catgut?�

548.         On 5 October 1989 Dr Pickles provided Sir Donald Acheson with a brief for his meeting with Mr Gummer on 16 October. The brief stated that �Mr Gummer has already had several briefing sessions on BSE with MAFF officials, but may want to hear CMO confirm that the risk to humans is considered remote.� She noted that the MCA and the HSE were taking appropriate action on parenteral medicinal products of bovine origin and occupational inoculation. The brief also stated that the MCA were considering whether action on specific products was appropriate.[634]

549.         On 6 October 1989 Mr Burton replied on behalf of Miss Duncan to Dr Pickles� minute of 3 October 1989. The minute said:[635]

�3. We are pleased to note that, as a result of your intervention, the removal of specified bovine offal from the place of slaughter to a pharmaceutical manufacturer would remain permissible�

4. On the medical device front we are only currently aware of two British manufacturers using UK derived bovine material. Both make heart valves using pericardium and this tissue is not included in the definition of �specified bovine offal�. Consequently the proposed regulations should not affect these products. However if 8.1 of the proposals could be amended to read ��.pharmaceutical and other medical product manufacturers�� it would not then act as a barrier to any further developments. Products made from such offal would still come under the scope of the PD/STD Guidelines. We would be grateful if you would pass this view on to MAFF.

5. There may be some unlicensed medicinal products, used on a named patient basis, which would be assisted by proposal 8.1. This causes us some concern since rigorous licensing controls would be bypassed in these cases. I have been passing details of any such products to Mr Love as we become aware of them.

6. We also find it strange that research is not included alongside �instructional or diagnostic purposes� in 8.1 of the proposals.�

550.         On 9 October 1989 Dr Pickles minuted Dr Metters, in reply to his minute of 4 October. She said that �the advice to the MCA is now rather more practicable and realistic (and incidentally closer to what Sir Richard Southwood argued for a year back in correspondence with Professor Asscher), accepting more flexibility for material sourced overseas. But for injectables sourced in the UK their advice is unchanged.� Z were shifting their operation overseas but in the interim had volunteered to reduce the risk by using beef rather than milk cows, and use animals under 2 years.� She said that �The expert working party accepted this interim compromise, knowing neither being beef cattle nor being under 2 years was any real guarantee, but realising there was no alternative.� [636]

551.         On 10 October 1989 Mr Love minuted Dr Jefferys and said:[637]

�1. Following the meeting of the CSM at the end of September and its acceptance of the recommendations of the BSE Working Party, it would now seem appropriate for the LA to consider what action is required to take the exercise forward in line with the recommendations.

2. I have set out below some possible points which may or not be completely relevant and are certainly not exhaustive and I would be grateful for your opinion and those of the copy recipients of this minute [Drs Adams, Purves, Raine and Rotblat, Mr Hagger and Mrs Shersby] on the following

a. do the guidelines need updating as a result of the Working Party meeting?

b. what further action, if any, should be taken re notifying industry of the recommendations of the Working Party? (by means of a possible article in MAIL?)

c. should active encouragement now be given to those companies which do not meet the guidelines and source material from areas where BSE is known, to change within appropriate timescales to BSE free sources? This would be for all applicable products in the first three categories as set out in the Working Party minutes and not merely catgut.

d. a need to consider further products which may be stock-piled and not meet the guidelines.

e. a need to alert the CRM about the [homoeopathic] products and determine if any special action should be instigated.

3. Some or all of the above points may be unnecessary or are already being taken forward but I believe that the necessity for a coordinated LA role in the BSE exercise should now be considered along with �what needs to be done and by whom� being developed.�

552.          On 12 October 1989 Dr Metters replied to Dr Pickles� minute of 9 October 1989, with copies to Dr K Jones and Dr Jefferys. The minute said:[638]�

�Thank you for your minute of 9 October. I can see the practical reasons that led the Working Party to agree the interim arrangements proposed by Z while they are making arrangements to source their material from overseas.

2.��� As you say, the agreement with the Company is �confidential� so that there will be no direct comparisons between the �six month limit� that MAFF have in mind for offal with the �18 months to 2 years� for suture material from clean beef cattle.

3.��� The crucial question is, can we defend this difference between the age limits if the disparity becomes public knowledge? Can the difference be defended and justified on scientific grounds?�

553.         Dr Pickles replied to Dr Metters� minute by way of an undated hand-written annotation, copied to Dr K Jones and Dr Jefferys, stating, �We discussed. The ready defence is that these decisions were taken on expert advice.�[639]

554.         On 13 October 1989 Dr Jefferys minuted Mr Love in reply to his minute of 10 October. He said that he did not think that the CSM/VPC guidelines needed updating and there was no need to notify the industry further. He stated that he had discussed the matter with Dr Adams, Dr Purves and Mr Hagger and that they agreed that the Working Party needed to meet in January.� On companies not complying with the guidelines Dr Jefferys wrote that an in-house procedure would need to be considered for approaching those companies which did not comply with the guidelines and for establishing an acceptable timetable for them to do so.[640] Dr Jefferys said in his Statement to the Inquiry that Mr Hagger�s division was responsible for contacting manufacturers who did not respond to the questionnaire.� He also said that approaching those companies that did not comply with the guidelines and establishing an acceptable timetable for them to do so was the responsibility of the MCA and the Inspectorate rather than the CSM.[641]

555.         On 16 October 1989 Mr Love sent a handwritten minute to Mr Burton[642] and said:

�I have written to Dr. Jefferys suggesting a number of avenues that we in the MCA should possibly be considering following as next steps in the BSE exercise.

Aspects such as:

a) possible updating of guidelines and what steps do we need to take���� to ensure compliance

b) how do we propose to ensure that companies stop using material from areas where BSE is known

c) consideration of products which are stock-piled and do not meet the guidelines

d) further notification to industry � what form should it take

As soon as the MCA stance on these and other points is finalised I shall let you know.�

556.         On 31 October 1989, 129 human medicinal product licence holders had not responded to the BSE questionnaire despite a reminder being sent.[643]

557.         In November 1989 the paper �Inactivation of Scrapie-like Agents� was reviewed again by PD in relation to medical devices (see paragraphs 454, 509, 543 above for other considerations). The aim was to consider the knowledge and application of the inactivation methods suggested by various professional organisations.[644]� Following this review PD sent a letter to manufacturers in the industry requesting information they had about inactivation of agents akin to the causative agent for BSE.[645]�

558.         On 7 November 1989 the CRM considered the issue of the homoeopathic products.� It had before it the paper prepared by Dr Winship.� It considered that no further action was required.[646]

559.         �On 8 November 1989 a MAFF press release announced the implementation of the SBO ban, which was described as a �further� addition to the very tough measures which Sir Richard Southwood�s expert committee recommended earlier this year.� A copy of this document found on DH files has been annotated by hand �cc Adams, Purves, Baker and Sloggem.�[647]

560.         At some point between 8 and 18 November Dr Lee, of the Veterinary Medicines Directorate (VMD) MAFF, gave a speech on the subject of veterinary medicines.[648]� She stated� �BSE has few implications for production of veterinary medicines. Indeed, there would be no implications at all if the Veterinary Medicines Directorate and manufacturers did not take what is really a belt, braces and pieces of string approach to all aspects of safety and quality of veterinary medicines.�� She talked about re-assessing licence applications which became necessary after the emergence of BSE and came to the conclusion that� ��the implications of the emergence of BSE on the production of these products has been extremely limited and no evidence of problems have been identified.�

561.         On 9 November 1989 Mr Burton replied to Mr Love�s minute of 16 October 1989. He said:[649]

������ �2. Our next internal STD meeting on BSE is scheduled for 24 November 1989 and I would be particularly grateful for any update you can provide�Point a) [�Possible updating of guidelines and what steps MCA needs to take to ensure compliance�] is of special interest to us.�

562.         On 10 November 1989 Dr Metters minuted Mr Meldrum about the SBO ban. He also said that he was �glad to see that you had on reflection recommended that bovine intestines should be included from the offal ban�. He also said:[650]

�The questions of suture material of bovine origin is, as you know, being considered by the Committee on Safety of Medicines. The Committee will, interalia (sic), need to consider the implications, if any, of the offal ban.�

563.         On 13 November 1989 the Bovine Offal (Prohibition) Regulations 1989 came into effect.[651]

564.         On 15 November 1989 the Manager of Technical and Regulatory Affairs at Z wrote to Dr Raine. He said:[652]

�1.)� Z issued instructions effective from 14th September, 1989 that the company was ceasing to procure bovine serosal threads from all suppliers who could not comply with our requirement to supply clean beef material.

An initial fact finding visit to Australasia regarding the sourcing of our total raw material requirements for bovine serosal threads has just been completed. A 5 year contract has been signed with our supplier and it is expected that raw material supplies will come fully on stream in early 1990, although I can tell you that we have already begun to receive shipments. More specific time scales cannot be stated at this time but I can tell you that an equipment installation and personnel training programme is progressing well.�

The letter also noted that the company had around two months� stock of finished goods.

565.         On 15 November 1989 the Committee on Dental and Surgical Materials considered the matter of catgut sutures. They agreed with the recommendations of the BSE Working Group that the risk of taking action against the licences outweighed the theoretical risk from BSE and on that basis did not advise any action against the catgut licences under consideration.[653]� In a minute about sutures and BSE, Dr Adams noted that:

�CDSM are content to maintain their view, based on the BSE Working Party advice, that the risk of taking action against the licences far outweighs the theoretical risk from BSE.� Thus CDSM do not advise any action against the catgut licences.� [654]

566.         On 24 November 1989 PD held a meeting on BSE. It was reported that all the manufacturers sent the medical devices questionnaire had now replied and the information had been placed on a database. The minutes record that �[t]he committee felt that in future, companies that are inspected should be checked for usage of animal or human material in their product. New information could then be passed on to be placed on the database.�[655]� The survey revealed that 76 products from manufacturers worldwide were sourced from all kinds of animals. 34 of these products contained bovine materials of which 13 were sourced from the UK or Europe. Of these 13, bovine material constituted a major component in only three cases.[656]���

567.         On 27 November 1989 Mrs Shersby sent a minute to Dr Jefferys, Mr Hagger, Dr Adams, Dr Rotblat, Dr Raine, Dr Purves, Mr Love and Mr Sloggem about the forthcoming meeting of the MCA secretariat of the BSE Working Group.� She set out the proposed agenda for the BSE Working Group meeting, which included at item 3 whether the Working Group should re-examine and review the current guidelines and at item 6 the effect of the �Proposed Bovine Offal ban� on the human medicines situation. [657]

568.         The MCA Secretariat of the BSE Working Group met on 7 December 1989 to discuss the agenda for the BSE Working Group meeting, circulated by Mrs Shersby.[658]

569.         In December 1989 PD wrote to the Manufacturers Registration Scheme (MRS) Audit Team Leaders informing them that a database had been created on the manufacturers of sterile medical devices and surgical products using animal materials in their products. This was to be kept up to date and PD requested that information on animal materials be kept in the �Company Information� section of the audit reports.[659]

570.         On 8 December 1989 officials from PD met separately with the two medical device manufacturers whose products were of concern.[660] �The minute records that:

�The main purpose of the meeting was to discuss the companies [sic] current manufacturing procedures, future plans and their compliance with the BSE guidelines.� Their views were also sought as to the practical feasibility of the guidelines with respect to the manufacturing process, and any improvements that could be suggested.�

571.         On 13 December 1989 Mrs Shersby sent a minute to Dr Jefferys, copied to Dr Adams, Dr Rotblat, Dr Raine, Dr Winship, Dr Purves and Mr Love, attaching the draft agenda for the BSE Working Group meeting.� She asked Dr Raine to send her the papers (i.e. the press release and �draft regulations�) for Annex 1 as at item 9 (�MAFF - Proposed Bovine Offal Ban� � the affect on the human medicines situation).� She also asked Dr Raine to contribute paper 5 (comment from the secretariat on the proposed bovine offal ban - effect on human medicine situation).[661]

572.         On 19 December 1989 the agenda for the BSE Working Group meeting on 10 January 1990 was circulated by Mrs Shersby to Professor Collee and members of the BSE Working Group and Secretariat.� The agenda included at item 7,� �The Guidelines � Does the working group wish to re-examine and review the current guidelines?� Oral discussion� and at item 9,� �MAFF � Proposed Bovine Offal Ban � effect on human medicine situation.� MAFF press release and draft regulations attached at Annex 1.� Comment from the Secretariat � Paper 5�.[662]��

573.         Dr Pickles sent a minute to Mrs Shersby on 21 December 1989, attaching a copy of the Bovine Offal (Prohibition) Regulations 1989, and informing Mrs Shersby that these had come into effect in November.[663]

574.         On 28 December 1989 Dr Lee gave a further update on replies to the animal medicines questionnaire.[664]� Since August only four more replies had been received bringing the total to 190 companies. There were now 348 products identified as having substances of animal origin with 302 having materials of bovine, ovine or caprine origin as ingredients.

1990

575.         On 2 January 1990 the manufacturers of a number of allergen products provided updated information on their �current position�. An MCA summary document of this response notes that advice is sought from the BSE Working Party.� It also states:[665]

�2.2 BEEF RAW MATERIAL

The Company have not yet found a satisfactory source of supply, and are investigating European sources, or the use of a closed herd.

Decontamination procedures are also under consideration (phenol or autoclaving)

2.3 ANIMAL HAIR � COW, GOAT & SHEEP

The Company state that the animals from which the hair is collected are certified as being free from the symptoms of BSE at the time of slaughter.

It is not clear whether these animals are certified as fit for human consumption as fresh meat under the EEC directives and slaughtered in EEC approved abattoirs. This would mean that pre and post-mortem veterinary examination was required.

Autoclaving has been found unacceptable. Exposure to phenol or gamma-irradiation are being considered.

2.4 CULTURE MEDIA

2.4.1 MOULDS

The culture media for mould contain [a compound] which presumably is bovine in origin, but that is not specifically stated. A European source material is being investigated. Validation studies are required by the Company to show its acceptability. Data may be available by June 1990.

No information on the method of manufacture is given. The medium is said to be Tyndallised.

2.4.2 MITES

A liver digest sourced from Ireland is used. Alternative sourcing is being investigated.

The material is heated to 60� for 1 hour before use, and for 2 hours after the mites have been cultivated.� It is not clear if this is in the wet or dry state.

Autoclaving was found unacceptable.� Gamma-irradiation would be investigated, if the BSE working party think it is appropriate.

2.4.3 BACTERIA

Brain Heart Infusion Broth, from [a company] is used. The source of the calf brain is not known to [the Company], or it seems to [the supplier company] (page 3 of the letter). The final medium is said to be autoclaved at 121o for 15 minutes.

Alternative sources and autoclaving, using the recommended cycle are being investigated.�

576.         On 3 January 1990 Mrs Shersby minuted Professor Collee and the members and secretariat of the BSE Working Group on the meeting scheduled for 10 January 1990.� She referred to the agenda for that meeting.� Point 3 stated �Item 9 on the Agenda refers to the proposed Bovine Offal Ban.� This came into force on 13 November 1989 and SI No 2061 is attached to Annex 1.� Paper 5 has been deleted from the Agenda.�[666]

577.         On 9 January 1990 the interim report of the Tyrrell Committee was published.[667]

578.         Also on 9 January 1990 the CRM met.[668]

BSE Working Group: second meeting

579.       On 10 January 1990 the second meeting of the BSE Working Group was held.[669] Four papers were considered at the meeting. Paper 1 was from MAFF and discussed BSE in cattle in Britain. Paper 2 was a summary of responses to the questionnaire[670]. Paper 3 considered products other than catgut, using UK sourced beef and not meeting the guidelines[671]. Paper 4 concerned the manufacturer of surgical catgut sutures.[672]

580.         The minutes of the meeting note that it was reported that 94% of licence holders had responded to the questionnaire, their replies had been evaluated and appropriate action taken. The Working Group recommended that the MCA look at the licences of the non-responding licence holders.

581.         In relation to Paper 3, the minutes record that, with one exception (the range of allergen products referred to in paragraph 575 above) there were no products sourced from high-risk material (i.e. brain and lymphoid tissue) which did not meet the guidelines. The majority of products considered in Paper 3 used bovine serum albumin or foetal calf serum from UK sources. Most of these were vaccines. The paper identified four such products: (i) a measles vaccine; (ii) a tuberculin PPD product; (iii) an MMR vaccine; and (iv) a DTP vaccine.� The paper included information on the existing stocks of these vaccines, and asked for advice about the use of these stocks.[673]

582.         �The minutes note:

�6.3 [Two companies] have given assurances that they are converting to New Zealand sources for their products; however it is clear that there are stocks of vaccines made using BSA or FCS from UK herds.�[674]

583.         The Working Group considered the four vaccines identified as using UK sourced material.� They concluded that the benefits accruing from continuance of the vaccine programme� ��outweighed the very remote risk to the population from the use of bovine material in these products.�� The Working Group ��considered after some discussion that negotiations should take place to ensure that sources are changed as soon as possible and to replace existing stocks with new material whenever feasible.�[675]

584.         The Working Group considered the range of allergen products made by one company, which used bovine calf brain in culture media. The Working Group� ��decided that alternative sterilisation programmes suggested by the Company would not be effective and that effective programmes would destroy the nature of the materials being used.�� They agreed:

�6.4 �it was not reasonable to use calf brain from the UK if other sources, such as Australia and New Zealand are available, and a changeover to Australasian material within a reasonable timescale should be insisted upon by the Licensing Authority. The MCA will reply to the request for advice, taking into account the views expressed by the Working Group.�[676]

585.         The Working Group also considered the steps taken in relation to Z Surgical Catgut Sutures. This was dealt with in Paper 4, prepared by Mr Sloggem and Dr Raine[677]. The minutes of the meeting stated[678]:

�The Working Group approved the following changes in the Company�s working practices, some of which have already been introduced.

6.5.1 Changeover to material sourced from �clean beef cattle� of UK origin on 14 September 1989

6.5.2 Cessation of sourcing material from UK cattle on 20 November 1989.

6.5.3 Changeover to bovine material sourced from Australia from 5 February 1990.�[679]

586.         The Working Group recommended decontamination procedures be followed prior to the change to Australian sourcing.� It also asked for assurances that Z would replace stocks held in their own store as soon as they had assured stocks available.� Consideration was also given to a press briefing being available in the event of media approaches arising from the closure of the factory for the decontamination and cleansing operation.

587.         In his Statement to the BSE Inquiry, Professor Collee said of this meeting: �The minutes state that the Working Party regarded the risk from vaccines as very remote. The bovine materials involved were very low risk and, as a result, the risk from vaccines could generally be described as very remote rather than merely remote.�[680]

588.         Professor Collee also said[681] that he believes he had sought the advice of Dr David Taylor and others in advance of the meeting, on the likelihood of the BSE agent being present in foetal calf serum and bovine serum albumin, and that he had asked about the risk of maternal transmission in cattle and the risk of contamination of the material in the course of its collection.� Professor Collee also stated[682] that once new stocks of vaccines were manufactured, they expected existing stocks to be replaced. Dr Jefferys has commented that at the meeting:

��the working party discussed the hazard-to-benefit ratio for the vaccines and decided that the benefits accruing from continuance of the vaccine programme outweighed the very remote risk to the population from the use of bovine material in these products.�[683]

589.         A summary of the reports of the chairmen of Section 4 Committees was recorded in the meeting minutes. The Chairman of the CSM, Professor Asscher, stated that no further action was required on products in his domain.[684]� This view was echoed by the Chairman of the Committee for the Review of Medicines (CRM).� The Chairman of the CDSM also reported to the meeting.

590.         The minutes of the meeting also record, �It was considered that the guidelines had served their purpose well and that there was no need to amend them at this stage.�� Under the heading for paragraph 9, �MAFF - The Bovine Offal (Prohibition) Regulations 1989 SI No 2061� the minutes simply state, �A copy of these is attached as Annex 5.�

591.         In his Statement to the Inquiry Dr Adams said following about the meeting:

��the Chairman of the CRM explained that the committee had examined the products referred to it and that no further action was required: the licence of one of the products had lapsed and the other used bovine material from outside the UK.� The Chairman of the CDSM reported that the Committee had agreed with the recommendations of the Working Group and was content with the measures being taken on surgical catgut. The minutes record that he commented on the reservations which had been expressed by the members of the Working Group and said that he wished to make it clear that the selection of materials other than those established by clinical experience exposed patients to potential hazards greater than those posed by catgut.�[685]�

592.         On 12 January 1990 Dr Adams sent a minute to colleagues (including Dr Metters, Dr Jones, Dr Jefferys, Mr Hagger, Dr Raine, Dr Purves, Mr Sloggem)to say that the company which manufactured catgut sutures (Z) had brought forward the date of changing the source of its catgut from UK to Australasian bovine intestine. Production was intended to begin in February 1990 with the finished product being available from May 1990.[686]

593.         On 17 January 1990 the CDSM met and considered a paper on catgut sutures.[687]

594.         On 26 January 1990 PD met to discuss two medical device manufacturers using bovine material as a major ingredient.[688]� One manufacturer was now using material from calves under the age of six months and material from older animals was sourced from overseas. The other manufacturer was unable to comply with the guidelines and had added that it would not be able to do so in the near future. It was agreed to organise a further meeting with this company.

595.         The meeting also concluded that the paper �Chemical Methods for the Sterilisation of Animal Tissue Used in Medical Devices� should be amended to include tissue harvesting and presented to the next BSE Working Party meeting on 4 July 1990.

596.         On 20 February 1990 a meeting was held between PD and the one medical device manufacturer whose products did not meet the Medical Devices Guidelines[689] (see paragraph 594 above).� The company reiterated that it could not source its material from calves under six months and it was investigating the possibility of sourcing material from West Germany. The company was also investigating suitable sterilisation procedures which would not damage its product.

597.       On 22 February 1990 the CSM heard an oral report from Professor Collee and noted the minutes of the Working Group meeting.[690]

598.         On 14 March 1990 Dr Jefferys received a letter from the British Diabetic Association asking whether the CSM had discussed BSE with regard to the use of bovine insulins and if so whether a statement had resulted.� The letter said the issue was to be discussed at a meeting of their Professional Advisory Committee at the beginning of June.[691]

599.         On 26 March 1990 Dr Metters sent a minute to Mr Bewley, a Grade 7 with the MCA, responsible for the Committee on Safety of Medicines.� The minute was in relation to the European Commission decision to ban the export of certain bovine tissues and organs.� Dr Metters expressed concern about the possible effect of the decision on UK pharmaceuticals and asked about the number of products using bovine material sourced from the UK.[692]

600.         On 9 April 1990 Mr Barnes minuted Dr Pickles about DH research objectives:

�2. Our objectives are on two levels �

i)���� directly commissioned DH research

ii)��� area of DH interest without financial sponsorship.

3. Following the Southwood and Tyrrell Reports, the DH research effort so far has been concentrated on setting up a research surveillance system, to monitor the incidence of CJD. The two �Will� projects, one already contracted and the other � consisting of neuropathological support for the first � currently being refereed, were considered sufficient to satisfy our immediate policy objectives.

4. Another high priority area identified in the Tyrrell report which falls within DH�s responsibility concerns certain bovine materials used in pharmaceuticals. Dr K Jones [Dr Keith Jones (DH)], to whom this minute is copied, is asked to up-date us on the current position on whether this research is going ahead, and if so with what sponsorship�.

5. We agreed that DH should not, at least for the time being, be directly involved in, or seek to sponsor, any research into the direct transmission of CJD�.�[693]

Other routes of transmission (SEAC: first meeting)

601.         On 17 April 1990 Dr Jefferys sent a minute, on behalf of Dr K Jones to Dr Barnes on research. He said that the MCA was unaware of any research which had been commissioned or was being undertaken concerning bovine material used in pharmaceuticals. He added that the MCA would not be funding any research and it appeared that the industry had accepted the guidelines and had made arrangements to switch sourcing so as to comply with the guidelines.[694]

602.         On 26 April 1990 the CSM held a meeting.[695]� Mr Hagger says in his statement to the Inquiry that:

�� a letter from the British Diabetic Association concerning the safety of bovine insulin was considered and a response approved confirming there was no insulin sourced from cattle in the UK or Ireland and that the situation in other countries was being monitored.�[696]

603.         On 27 April 1990 Mr Bewley responded to Dr Metters minute of 26 March 1990. He set out the current situation with regard to the few licensed medicinal products which used bovine material sourced from the UK.[697]

604.         On 27 April 1990 Ms Campbell minuted Miss Duncan, Drs Richardson and Hoxey, Mrs Dhell, Mr Burton and Ms Turner, about a meeting with a medical device manufacturer that day. The minute said:[698]

�2. [the company] have made the decision that as from Monday April 30 manufacture of their [specifically named] heart valve will cease. Valves remaining on the shelves will be retrieved, but not on a recall basis.

�

4�No information regarding this decision will be sent by post in order to avoid stimulating widespread interest.

5. Please find attached a copy of the press report which [the company] plan to release. They have deliberately avoided mention of BSE in the hope of preventing the generation of wider media interest, with its associated implications. They also hope to keep [the parent company] out of press coverage.�

605.         On 30 April 1990 Dr Jefferys, on behalf of the CSM, replied to the British Diabetic Association.[699]� He �was able to inform the BDA that there were no bovine insulins sourced from cattle in the UK or Ireland.�[700]

606.         On 1 May 1990 Dr Metters sent Mr Bewley a minute about BSE and Commission Decision VI/7096/89.[701] He said:

�4.�� Paragraph 5 is the key to the safety of continued use of these vaccine stocks.� Here I note that the Working Group have considered the safety issue and agreed that continued use of existing stocks within the vaccine programme far outweigh the remote risk of BSE occurring through innoculation (sic).

5.��� While this risk may be remote, it would be desirable to pursue the policy of sourcing replacement vaccine stocks as soon as possible with New Zealand sourced products.

6.��� I am sure you will keep me informed with action taken to reduce whatever small risk there may be of BSE being transmitted through pharmaceutical products.�

607.         On 3 May 1990 Dr Pickles sent a minute to Mr Burton, a Grade 7 in charge of the Pharmaceutical Supplies and Technology section, requesting help in identifying UK suppliers of foetal calf serum and bovine serum albumin.[702]� She was concerned about the safety of laboratory reagents and wanted to make �discrete [sic] enquiries� based on the identities of these suppliers. She stressed that� �We must be careful in making these enquiries to be sure that we are not suggesting these materials in their original form are somehow dangerous (since of course we are not saying this for meat or other parts of the animal).� The enquiries confirmed that none of these suppliers were still using UK sources.[703]

608.         Some time after 16 May 1990, Dr Raine prepared a paper for the Committee on Dental, and Surgical Materials updating them on the status of Z Surgical Catgut Sutures. Under �Secretariat comment� she said:

�The Company has implemented as rapidly as possible the changeover from UK sourced raw material.� 100% finished product supplied is now derived from material sourced from Australia and New Zealand.

The advice of the Working Party is sought on the Secretariat view that no further action is [a handwritten annotation adds the word �currently�[704]] necessary on the part of the Licensing Authority.�[705]

609.         On 23 May 1990 PD met again.[706] Dr Richardson agreed to contact Professor Taylor at the Heart Valve registry to request a check of all death certificates of heart valve users who had died of any BSE/CJD related diseases and a full check from the start of the Registry in January 1986 of any reported deaths of any patients using the heart valves produced by these two companies. The meeting also noted that the company had ceased production of the bovine heart valve. An update was also given on the one remaining manufacturer�s attempt to comply with the guidelines relating to sourcing. Areas of research raised by the Tyrrell Report were discussed although it was decided to liaise with MAFF on projects of relevance if MAFF was prepared to co-operate.[707]

Agriculture Select Committee

610.         On 7 June 1990 Mr Love, of Medicines Division DH, sent Drs Jefferys, Adams, Rotblat, Purves, Raine and Mr Robertson a copy of DH�s draft memorandum on BSE for the Agriculture Select Committee.[708] Dr Rotblat minuted Mr Love the following day to say that she was �not happy with the section on medicinal products�. She said:

�1.�� �I feel that the sentence� �where risk is thought to be present, the MCA has powers to require products to be modified but this has not proved necessary so far in relation to worries about BSE� should be deleted. It appears to be totally contradictory to the following statement that companies appear to be changing sources for their bovine material.�[709]

611.         On 8 June 1990 Mr Love sent a minute to Dr Pickles about the draft memorandum for the Agriculture Select Committee on BSE.[710]� The draft memorandum made the point that the Medicines Control Agency (MCA) had recommended that all bovine material should be sourced from BSE free countries.

612.         On 11 June 1990 Mr Love minuted Drs Jefferys, Purves, Raine, Rotblat and Mr Hagger with a final submission on the medical section of the memorandum.[711]

613.         In the final memorandum produced by the DH for the Agriculture Select Committee the section on medicines stated:

�4. Medicinal Products and Medical Devices

The Medicines Control Agency (MCA) agreed in February 1989 and issued in March 1989 joint Committee on Safety of Medicines� (CSM)/Veterinary Products Committee (VPC) guidelines to the holders of all licensed medicinal products advising on the use of bovine material as an ingredient or in the production of parenteral medicinal products.

As a purely precautionary measure the MCA recommend that all bovine material should be sourced from BSE free countries with competent veterinary services. This has been accepted and implemented by manufacturers supplying the UK market.

The CSM through its high level BSE Working Party continues to monitor developments.��

Supplies Technology Division (STD) of the NHS Procurement Directorate have responsibility for medical devices and have issued similar guidance to manufacturers of surgical implants and blood contact devices. STD are liaising closely with the CSM Working Party on BSE.� [712]

614.         Mr Love also sent Question and Answer briefing material to the CMO on 20 June 1990, prior to the Agriculture Select Committee.� This material was copied to a number of people in MCA.[713]

615.         Sir Donald Acheson gave evidence to the Agriculture Select Committee on 20 June 1990. In answer to a question on BSE free herds in other countries, Sir Donald Acheson stated:

�That is really a veterinary question, but if behind it is the question of the safety of medicinal products perhaps I could say this: this is a crucial subject which was raised with me during 1988 about the time it was decided to set up the Southwood Committee, and of course I am sure the Committee knows that the safety and quality of medicines is a specialist subject in which ministers are the licensing authority and under the Medicines Act they are advised by the Committee on the Safety of Medicines and sister committees, which deal with other things like veterinary products and so on, but I have to satisfy myself on the public health aspects. Before we had the benefit of Sir Richard�s report the relevant committees and the Committee on Safety of Medicines were asked to consider the implications of BSE in medicines, and later a special expert group was set up which had cross-representation with the Tyrrell Committee to make sure the expertise was covered. In February 1989 the Committee on Safety of Medicines made a public statement at the same time as the publication of the Southwood Report, which agreed with Sir Richard Southwood, that the risk to man from medicinal products of bovine origin, which includes injectables, was remote on theoretical grounds. Now this reassured me that the stocks of medicine in this country, which of course might have been produced from material during the 1980s which to some degree had been contaminated with BSE, were nevertheless safe. That was a public statement made by the experts in that matter. The second issue, of course, is, well, if that is the case is there anything else that in prudence we should do now knowing there is this condition? The CSM decided that in future we should remove from medicinal products any bovine material that might have come from infected animals. Guidelines were issued in March 1989 to all manufacturers of medicinal and veterinary products in respect of any product wherever manufactured in the world which is licensed in this country� So we have belt and braces.� First of all, we have the pronouncement that we are talking about a theoretical risk; secondly, in order to be doubly sure, these recommendations have gone out with a code of practice which will seek to ensure that in future no bovine material that might have come from infected animals is used for medicinal products.� [714]

616.         On 15 June 1990 company I[715] sent a copy of their statement on BSE to Mr Love at MCA.[716] This statement had originally been sent to the BBC.� It said that none of their vaccines utilised tissues such as brain, spinal cord and spleen and that, in consultation with external experts, they had transferred their sourcing to outside the UK.� The statement finished by saying that I had been producing vaccines in compliance with UK Government Guidelines issued in 1989.

617.         On 29 June 1990 Mr Coleman, a Higher Executive Officer in STD responsible for the central purchase and supply of certain vaccines and sera, minuted Mr Burton, a Grade 7 in STD responsible for the Pharmaceutical Supplies and Technology section, about letters which had been received from vaccine manufacturers[717]. The minute commented on details in the letters about the current stocks of vaccines prepared using UK sourced bovine material. Dr Rotblat saw a copy of this minute. [718]

BSE Working Group: third meeting

618.         On 4 July 1990 the third meeting of the BSE Working Group took place. The Working Group considered again the range of allergen products:[719]

�Para 6.4: Discussions and correspondence are ongoing with [a company] on their range of allergen products�which use bovine sourced material not meeting the guidelines. These are diagnostic and therapeutic products containing a range of specific allergens. Calf-brain and an ox-liver digest were constituents of certain special culture media used in the production of some of the allergens. Animal hides and hairs were used to produce others. They are marketed for use in the management of allergies.

The Working Group considered that where bovine material was used it was essential that the licence holder should comply with the guidelines unless the material being used was derived from milk or casein. [The company] has been concerned about infringement of the Anthrax Regulations when importing hides or hairs.

�The licence holder will be contacted again; the discussions will be continued and the outcome reported to the next Working Group meeting. In the case of other animal components used in the manufacture of this range of allergens, such as sheep hair or cat hair a more relaxed approach was considered appropriate.�

619.         Paper 1 at the meeting was from MAFF and was an �[u]pdate on epidemiological aspects of BSE)[720]. The minutes record concern raised about the sources of bovine material from Australia and New Zealand being finite. The minutes said Australasian bovine material was being �taken up so that there is no spare supply capacity�.[721] The Working Group also considered the availability of bovine products from calves under the age of 6 months. Not subject to any ban, it was felt that these calves� ��could be incubating the disease, even though the prion or causative organism was not detectable�.

620.         The Working Group also had before it a paper prepared by Dr Rotblat which provided them with the latest factual information from two individual companies about their vaccine stocks.[722]

621.         The Working Group considered again the four vaccines previously identified. In relation to the MMR vaccine, this was not yet licensed, and it was recommended that a licence should only be granted if the bovine components complied with the guidelines.� The applicant was understood to have changed to a New Zealand source.� Other companies had licences and were producing sufficient quantities to meet demand. �The Working Group also recommended that existing trial batches prepared with UK bovine material should not be marketed.

622.         In relation to the tuberculin PPD, this was the only source of the product available, and there were stocks until September 1991.� The manufacturer used glycerol beef broth derived from bovine muscle.� It was changing to peptone broth as quickly as possible, and stocks would be replaced as appropriate.� The Working Group noted that replacement should be encouraged as quickly as practicable, but that since the use of glycerol beef broth was low on the list for potential infectivity and since there were no alternative sources, the hazard from having no available stocks outweighed the potential risks from use.

623.         In relation to the measles vaccine, the manufacturer was changing to a New Zealand source.� There were no stocks of single vaccine currently available and other stocks would be depleted by September 1990.�

624.         In relation to the DTP vaccine the Working Group recommended that a meeting should be held with the manufacturer to bring forward the time for compliance.

625.         Topical products were also discussed. It remained the position that they were not considered cause for concern.� In any event, the use of bovine material in topical products had been considered, and appeared to be confined to products by two manufacturers, the source of the material being Germany.�The Working Group considered that no further action was required by the MCA.

626.         The Working Group discussed reports of the diagnosis of three cases of Feline Spongiform Encephalopathy in cats. It was confirmed that there actually were two medicinal products using feline material. The minutes said:[723]

�The Working Group considered that because only three affected cats had been positively diagnosed to date and the aetiology of the spongiform encephalopathy was not fully understood, any action against products using feline material, even though UK sourced would be precipitate. These types of encephalopathy may have existed before current awareness of the condition.�

627.         The list of non-respondents to the questionnaire was reported to have been reduced to only four.[724]

628.         In her Statement to the Inquiry Dr Rotblat made the following comments on vaccines:

�Vaccines were the most important group of such products and the one with which I had most involvement.� Many vaccine manufacturers used foetal calf serum (FCS) in their production processes.� While the companies rapidly decided to source from New Zealand because that country had no history of scrapie, it was clear that this could not be done overnight because of the long time scale for manufacture of new batches of the vaccines.[725]

We held meetings with the companies and there were many discussions in the CSM and the BSE working group about this issue.� It was agreed that the benefits of the vaccination programme outweighed the theoretical risk of transmission and that the current vaccines could be used until new batches became available.� The theoretical risk of transmission of BSE had to be set against the disease which would occur if the vaccination programme was interrupted.� The vaccines in question had proven efficacy in protecting the public against serious diseases.� The fact that low risk bovine material had been used in the manufacturing process in no way outweighed the benefit derived from these vaccines.[726]

Such an approach would not have been possible had formal regulatory action such as revocation been taken, rather than non-binding recommendations being issued, because revocation of a product licence prevents the use of existing stocks of that product.[727]

I believe that pharmaceutical companies could not have produced new stocks of vaccines manufactured using non-UK sourced bovine material any quicker than they did.� The last to be replaced was a rarely used adult DTP vaccine which had a longer shelf life.� This was replaced in 1990/91 with a new batch made with New Zealand sourced bovine material.� I believe that this was the last vaccine to be replaced in this way.[728]

�

By the time of the final meeting of the BSE Working Group in July 1992 all vaccines available in the UK fully complied with the Joint CSM/VPC Guidelines and did not use UK sourced bovine material.[729]

Dr Rotblat also noted that the DTP vaccine was rarely used and it was used on adults rather than infants. [730]

629.         Dr Jefferys also comments on vaccines in his statement to the Inquiry:

�In all the deliberations the proven benefits of the medicine had to be set against the theoretical risk. I observed that the CSM paid very particular attention to vaccines. Here there was a very real concern to avoid any damage to the vaccine programme and the inevitable consequences that this would have. Even in 1989, most vaccines used material sourced from outside the UK.�[731]

630.         Professor Collee has also commented:

�In any consideration of vaccines we had also to take into account the obvious risk if stocks of vaccines were withdrawn. I should add, however, that once new stocks were manufactured, we expected existing stocks to be replaced.�[732]

631.         In his Statement to the Inquiry, Sir William Asscher said:

�When considering the question of vaccines, it is important to be aware that manufacturing vaccines is an art � it is not easy to manufacture large supplies of effective vaccines. Manufacturers tended to keep large stocks of existing vaccines which, in some cases, were likely not to be exhausted for as much as 5 years.�[733]

632.         On 26 July 1990, at a meeting of the CSM, Professor Collee reported on the meeting of the BSE Working Group on 4 July 1990.[734] The minutes of the CSM meeting said �[t]he Committee noted�the minutes of Working Party�s meeting of 4 July 1990�and endorsed the recommendations of the Working Party.�[735]

Spongiform Encephalopathy in a pig

633.         On 11 September 1990 Mr Meldrum minuted Mr Lowson, copied to Mrs Attridge, Mr Bradley, Mr Lawrence and Dr Pickles, about transmission of BSE to a pig.� He also commented in the minute that he had been concerned for some time about the comments that raw materials for medicines should be sourced from countries where BSE in cattle was believed not to have occurred.� He stated that this was a very weak argument to deploy since detection of disease depended on the surveillance programme and notification procedures.� He would prefer to source such material in countries where neither BSE nor scrapie was present, and which had not imported significant quantities of British cattle or meat and bone meal.[736]

634.         On 12 September 1990 Dr Metters minuted Dr Jones about SE in pigs.[737] Dr Jones minuted Dr Jefferys on the point the same day.[738] �Dr Jones said that he wished to consider the question of BSE and porcine derived therapeutic agents within a small group in order to determine the line that the MCA should take. He said that the working party would also need to take a view, following which he would advise Dr Metters on any necessary action. Dr Pickles minuted Dr Jefferys on the subject on 13 September 1990.[739]

635.         In his Statement to the Inquiry Professor Asscher said[740] that he had not seen the minute from Mr Meldrum to Mr Lowson.� He stated, however, that Mr Meldrum�s comments fail to appreciate that the February 1989 guidelines were not the only advice being given to manufacturers, and that in practice manufacturers had decided that they would be best advised to source from New Zealand or Australia.� After the BSE Working Group was established, it encouraged such an approach.� He considered that the extent of liaison between manufacturers, the CSM and BSE Working Group, the manufacturers� knowledge of the current position and their willingness to accept the advice of the CSM and BSE Working Group made it unnecessary formally to amend the recommendation on safe sourcing.� Professor Collee also stated[741] that he had not seen that minute, nor did he believe that the views expressed had been brought to the attention of the BSE Working Group or the CSM.� Dr Jefferys stated[742] that he had not seen the minute at the time.� He also noted that Dr Watson from the CVL attended the meetings of the BSE Working Group.

636.         Mr Sloggem said in his statement to the Inquiry:

��an issue had arisen concerning the possibility of porcine encephalopathy.� This was because one pig had developed "BSE" after being injected with a large dose of infected material directly into the brain.� In the light of the unnatural route of this infection, the members of the working party [on 31.10.90] did not consider it had significance in the use of porcine materials, as a possible porcine BSE hazard.�[743]

637.         In a minute to Dr Metters on 21 September 1990, Mr Hagger suggested the following line to take:

�There are no medicinal products licensed for use on the UK market which make use of UK derived porcine tissues with which any hypothetical �high risk� might be associated.� The results of the recent experimental work at the CVL will be carefully examined by the CSM�s working group on spongiform encephalopathy at its next meeting [in October].�[744]

638.         Dr Pickles comments in her statement to the Inquiry:

�A preliminary meeting of SEAC then took place on 7.9.90 which I attended.� Mr Pepper attended this meeting as a new member.� Papers were submitted by myself on behalf of DH and by MAFF and notes from CVL describing the transmission experiment.� The Committee accepted CVL�s conclusion that the experiment provided incontrovertible evidence that BSE could be transmitted to a pig.� The meeting stressed the importance of improving surveillance to ascertain whether SEs were occurring naturally in pigs in the UK although� it was felt that it was not likely to have gone unrecognised.� It was decided that it would be prudent to exclude specified bovine offal from the diet of all animals, including pigs and that non-UK sources be used for pharmaceutical products involving injectable or implantable porcine material.

The Inquiry has asked what action was taken subsequently about human medicines using porcine material.� I alerted Dr Metters immediately following the meeting and he passed this on to Dr Jones of the MCA.� I also provided further information direct to the MCA.� Later I was present at a meeting of the CSM BSE Working Party at a meeting on 31.10.90 at which the issue was discussed, informed by a listing of pharmaceuticals using porcine materials sourced in the UK.�� The Minutes record that a decision was taken that no action with regard to human medicines or medical devices was warranted at that time.�[745]

639.         At the CPMP meeting held on 11 October 1990, it was decided that a CPMP BSE working party would be set up to monitor the implications of BSE for the circulation of human medicinal products within the EC.[746]

BSE Working Group: fourth meeting

640.         On 31 October 1990 the 4th meeting of the BSE Working Group was held.[747] In relation to the range of allergen products that did not meet the joint Guidelines the minutes record:

�3.1 Para. 3: Progress to date in discussions with [a company] on their range of allergen products, using animal sourced materials was reported and the advice of the Working Group sought in relation to further action with regard to this group of products, for which there appears to be a continuing clinical requirement.

�

Cow-hair - The preferred source would be Australia or New Zealand or a closed herd in the UK. It is understood that [the company] has a closed herd in the UK, used to obtain sera for the production of their vaccines, and the company should be encouraged to use this source, since they were concerned that decontamination procedures necessary for overseas sources and required by the anthrax regulations could denature the material and alter its antigenicity.

Beef-veal � from Holland. The licence holder should be advised to specify that beef-veal from Holland was from milk fed animals.

Mycological media � containing ox-liver sourced from Italy as a component are acceptable as the source is not UK, provided that the usual assurances are given concerning good animal husbandry and adequate veterinary service

Bacteriological Media -� A peptone based medium now replaces the brain heart medium used previously. Since this is highly refined and autoclaved at 132 �C for 80 minutes, the Working Group considered the use of this material acceptable.�[748]

641.         Further consideration was given to the possible infection of foetal calf serum and it was suggested that the guidelines might need extending to cover methods of collection, should further investigations reveal cleanliness deficiencies in this area.

642.         Under item 9 �Porcine Material in Human Medicines and Devices� the Working Group:

��considered the extent to which porcine material is used in medicines and devices intended for human use and whether action to avoid or limit the use of any such material, originating in the United Kingdom is warranted at the present time.

�

The unanimous view of the Working Group was that since transmission of spongiform encephalopathy has only been seen under experimental conditions and in a single animal, no action with regard to human medicines or medical devices is warranted at present.�[749]

643.         Under item 10 �Dural implants � Requests for Advice� the advice of the Working Party was sought in relation to grant of a licence for a product derived from bovine pericardium and renewal of product licences for implants derived from human dura mater�and porcine dermis.[750]

644.         Under item 11 �Response to Questionnaire from Industry� it was reported that the four outstanding replies had now been received. One company had confirmed that bovine material was not used, and the other three confirmed that non-UK sourced material was used.

645.         Under item 14 �Vaccine Stock� it was reported that in regard to the vaccine stocks of one company:

�The Working Group considered that the Secretariat should explore with the Company the possibility that the unadsorbed vaccines which had limited usage should be replaced with batches using bovine materials which complied with the guidelines, especially where the stock out date extended beyond 1991. There may be some commercial loss to the licence holder but it is unlikely to be very large.[751]

This was the one outstanding vaccine identified at the previous Working Group meeting (see paragraph 624 above).

646.         In her Statement to the Inquiry Dr Rotblat said that the Working Group was updated on the position of the one outstanding vaccine: the DTP vaccine.[752]

647.         In November 1990 the VMD put together a report which detailed �response to questionnaires and compliance with guidelines� in relation to BSE. It was noted:

��Most of the companies have now made satisfactory arrangements. The VMD has recently written again to the smaller number of companies where further information and reassurance on satisfactory progress is required. The replies received to some of these may need to be considered by the committee in the future. In the meantime, the following are being brought to the attention of the Committee.

�1.�� A number of products for external use contain lanolin from UK sheep. A number of oral products contain gelatin from UK cattle. Such products were defined as outside the scope of the guidelines and it is proposed that no action is taken with regard to these.

2.        Lungworm vaccines are produced by harvesting larvae from the faeces of UK production calves. These calves are less then 6 months of age. Since faecal material is classed as a very low risk tissue for scrapie infectivity then the vaccines are given orally, it is proposed that no action is taken.

3.        Three products are manufactured in bovine origin brain heart infusion broth�The bovine material used for one of these has never been of UK origin and the other manufacturer has indicated that he has now changed to a non-UK source�It is considered that the use of any bovine brain material is to be discouraged. The two fish vaccine manufacturers have been trying to find an alternative growth medium. It is proposed that pressure is maintained on these two manufacturers to finalise this work.

�

5. �� Some of the questions on the BSE questionnaire were interpreted differently by different companies. As a result it is thought that we are likely to have incomplete data of when all stocks of batches of products made before changes to comply with the guidelines will be used up�.�[753]

648.         On 22 November 1990 the CSM met.[754] The minutes record that �[t]he Committee endorsed the recommendations of the Working Party relevant to the CSM and noted the advice given to the CDSM concerning their products and the action taken by the CDSM.�

649.         At the CSM meeting Professor Collee reported on the meeting of the BSE Working Group on 31 October 1990. In relation to vaccines he said:

�We are still worried about this matter, and it is right that we should continue to send signals to CSM�that present evidence allows us to give no absolute assurance but some relative assurance. Meanwhile, it seems unreasonable to allow vaccines that have some association with UK-sourced bovine products to be used when they could be replaced with batches that have been processed in compliance with the guidelines. Accordingly�our line of advice to CSM is hardening I would like you to count me amongst the hawks on this.�

650.         On 18 December 1990 MDD BSE Working Group met and discussed the 4th meeting of the BSE Working Group.[755] For bovine materials it was reported that the BSE Working Group considered that providing the Guidelines were adhered to and the material was sourced from outside the UK, then the bovine material would be acceptable. Sterilisation procedures were insisted upon. This point was taken up in the MDD Working Group discussion in relation to bovine heart valves. The meeting noted that bovine heart valves had 15 per cent of the total implant market. Concerns were expressed about sterilisation procedures that might alter the valve�s performance. It was suggested further research on sterilants was required. It was also reported the BSE Working Group had commented on the MDD paper �Guidance on Chemical Methods for the Sterilisation of Animal Tissues used in Medical Devices�. These comments would be incorporated before the paper was sent out to registered manufacturers of sterile medical devices.

1991

651.         On 8 January 1991 Dr Hoxey of the MDD wrote to Dr David Taylor of the Neuropathogenesis Unit (NPU). He asked to be kept informed of the NPU�s proposed research into the inactivation of the BSE agent, as the MDD had an interest in methods of sterilisation and disinfection.[756]

652.         On 6 May 1991 the proposed meeting of the BSE Working Party, scheduled for 2 July 1990, was cancelled. After discussions involving Professor Collee, Dr Keith Jones, Professor Asscher and Dr Jefferys it was decided that no new issues had arisen and thus there were no items to put on the agenda.[757]

653.         On 9 May 1991 Dr Jefferys wrote to Ms Murphy of the PHLS regarding a copy of a PHLS booklet on infections and communicable diseases in England and Wales � 1990.� He stated that:

�The view of the [MCA] is that it would be inappropriate to make any reference to medicinal products in relation to BSE.� The statements contained in the present report do not reflect the action which has been taken by the MCA and the BSE Working Party set up under the Committee on the Safety of Medicines.�[758]

654.         On 14 May 1991 Dr Pickles wrote to Dr David Taylor saying:

�One of the reasons the Medicines Control Agency took no action against natural bovine insulins was the belief that the pancreas would not be affected in BSE. If there is new evidence to challenge that view, I think they would like to know. What more information can you give us, or could you indicate who else we should approach?�[759]

655.         On 21 May 1991 Dr Jefferys replied to this letter from Dr Pickles, which he had been copied by Mrs Shersby. He said:

�As you state in our letter of the 14th May there were several reasons why the CSM Working Party decided that no action should be taken against bovine insulins. Foremost amongst these were that BSE remains a remote theoretical risk, bovine insulins are sourced from outside the UK (principally Argentina), the good manufacturing guidelines have been put in place and that the use of bovine insulin was small and restricted to diabetics who were intolerant of both the human insulins and porcine insulin.

Nevertheless, the BSE Working Party was set up to continue to review developments and if there is any new data we can always return to this question.�[760]

656.         On 23 July 1991 the BSE Working Group meeting scheduled for 29 October 1991 was cancelled. Again, the reason given was that no new issues had arisen and therefore there were no items to put on the agenda.[761]

657.         On 31 July 1991 the MDD BSE Working Group met and reviewed the information collected by Dr Hoxey and Mrs Dhell, a Higher Professional and Technology Officer responsible for sterilisation and decontamination, during a visit to the NPU.[762] Mrs Dhell had looked for information about the treatment of bovine heart valve materials with sodium hydroxide, but had found none. Reference had been found to the use of sodium metaperiodate, but it had been shown that this was not a good agent to be used for heart valve material; particular chemicals were shown not to be good inactivating agents. Also at this meeting, progress on the document �Guidance on Chemical Methods for the Sterilisation of Animal Tissues used in Medical Devices� was discussed.

658.         On 15 August 1991 Mr Bradley minuted Dr Little, Dr Shreeve and Mr Dawson about a meeting he had had that day with Dr Hoxey and Mrs Dhell. He said:[763]

�The same guidelines issued to pharmaceutical/biological manufacturers have been issued to MD manufacturers. No sourcing now occurs from UK cattle and the point was taken re sourcing from Europe, in regard to BSE cases, France and Switzerland and export of cattle to Portugal and MBM to Europe as well as the exposure of pigs and poultry. They were well versed in the BSE control regulations. Prompt action at the start of the epidemic reduced risk factors so low that they did not pursue transmission studies. Things are different now.

We exchanged information on source materials used in MD. I knew some things they did not and they refined my information. They had not thought all aspects through but generally had a sound approach.

RESEARCH

MDD had a research budget but now re-distributed. They are considering the need for R&D on infectivity of sourced tissues from cattle, pigs and perhaps poultry and are clear they would have to find this alone or in collaboration with industry. There is no rush and they may approach us say next year to conduct such experiments. This area did not seem to be fundable from AHVG except if there were food or animal health connotations.�

659.         On 8 November 1991 the MDD BSE Working Group met,[764] and reviewed a meeting between Dr Hoxey and Mr Bradley, of the Central Veterinary Laboratory. The MDD meeting concluded that more information was needed on the availability of data on CJD patients and/or implanted biological medical devices. The decision on whether to fund the testing of tissue was to be made following receipt of this information.

660.       On 12-14 November 1991 The World Health Organisation met in Geneva to discuss Transmissible Spongiform Encephalopathies and came to the conclusion that the careful selection of source material was the best way of securing safety from the theoretical/remote risk posed by bovine materials in medicinal products and medical devices. This meeting confirmed that the measures being taken in the UK were sufficient at that time to minimise the risk to all species including humans.[765]

661.         On 28 November 1991 SEAC�s attention was drawn at its 11th meeting to deactivation experiments conducted by Dr Taylor of NPU.[766]�� The Committee felt that the results, in themselves, were not sufficient to merit a change in existing DH guidance on decontamination of the CJD agent.

1992

662.         In 1992, the Spongiform Encephalopathy Advisory Committee interim report on research stated:[767]

��The [CSM/VPC] guidelines recommended that all products licensed under the Medicines Act 1968 for human or veterinary use that are administered parenterally or to the eye or to open wounds should in general conform to the guidance if they contained material from a bovine source or if bovine material was used during their manufacture. In the event the pharmaceutical industry decided to source bovine ingredients or bovine materials used during manufacture from BSE-free animals in BSE-free herds in BSE-free countries�In the light of this development the relevance of studies on the safety of pharmaceuticals manufactured from tissues from British cattle is now questionable.�

663.         On 8 April 1992 the Institute of Animal Health�s Neuropathogenesis Unit (NPU) and MAFF�s Central Veterinary Laboratory (CVL) held a further meeting in a series discussing BSE R&D.[768] One of the matters arising from the previous meeting was the inactivation experiments conducted by Dr Taylor of the NPU. The minutes record that the results of these experiments had been drawn to the attention of SEAC which had recommended that proposals for further work be drawn up. These had been passed over to MAFF and DH for consideration. DH felt that an immediate change to their advice on inactivation procedures would be an over-reaction.

664.         In May 1992 the European guidelines issued by the Committee on Proprietary Medicinal Products (CPMP) and titled �Minimising the Risk of Transmitting Agents causing Spongiform Encephalopathy via Medicinal Products� came into force.[769] The draft guidelines �were derived from and almost identical to the UK guidelines.�[770]

BSE Working Group: fifth meeting

665.         On 8 July 1992 the 5th meeting of the BSE Working Group took place[771]. Under item 3 �Minutes of the Previous Meeting� it was noted that in relation to the vaccine stocks of one company (the DTP vaccine): �This matter had now been resolved by the company producing a new batch with New Zealand FCS [foetal calf serum] of assured quality.�

666.         Under item 4.2 �Scientific Update� it was reported that:

�The statement that autoclaving at 134�C does not give complete destruction of the BSE agent indicated a potential problem. It was explained that the statement came from work on BSE or scrapie exposed in a porous load autoclave at 134�C for 18 minutes which was found not to be effective�More studies were required to determine whether or not 136�C would be effective in destroying the BSE agent within the standard time. A grant application to study the effectiveness of exposure to 136�C had been made but the studies had not yet started�.[772]

667.         Professor Asscher said[773] that he believed that manufacturers changed their sourcing as soon as possible regardless of the financial cost to them.� Dr Rotblat stated[774] that she believed pharmaceutical companies could not have produced new stocks of vaccines any quicker than they did, and that the last to be replaced was the rarely used adult DTP vaccine, which was replaced in 1990/1991 with a new batch made with New Zealand sourced bovine material.

668.         On 21 July 1992 Dr Minor, Head of Virology at NIBSC, wrote to Professor Collee:[775]�

�At a recent meeting in Heidelberg a gentleman from a gelatin manufacturing concern presented an account of the process which was very worrying. As you know, the assumption has been that gelatin is produced under such vigorous conditions that it gives no cause for concern, but the process he described was, to me, shockingly mild. Moreover he claimed that any old cow bone went into the production vat, including spine and skull�A number of other BSE working party members were present at the meeting, including John Purves, Richard Kimberlin and David Taylor, so it is possible that the matter was raised [at the BSE Working Group meeting of 8 July 1992]�

669.         On 30 July 1992 Dr Taylor of NPU in a letter to Professor Collee, commented on this subject. He said,[776]

�Like Philip [Minor], I was not impressed by the reassuring noises made � at the Heidelberg meeting. However, I am not really familiar with gelatin manufacturing processes in the UK�I would certainly be concerned if it is produced by a similar procedure to the German process described at the meeting.�

670.         On 31 July 1992 Dr Kimberlin wrote to Professor Collee about Dr Minor�s observations.[777] In summarising he said:

�a).� The general assumption that gelatin is of very low risk with regard to BSE contamination is still tenable.

b).�� Any uncertainty would be if the source material included significant amounts of brain and spinal cord from countries which either had reported BSE or were at risk of getting BSE cases, and which do not have a specified offals ban.

c).�� In these circumstances it might be reasonable to require either that these potential risk tissues were excluded from the source material, or that validation studies were carried out which were capable of demonstrating a clearance factor appropriate to the potential contamination.�

671.         On 5 August 1992 Dr Tyrrell wrote to Professor Collee saying that he had seen Dr Minor�s letter of 21 July and he thought it was �necessary to get more details��[778]

672.         On 18 August 1992 Professor Collee produced a written opinion on gelatin and BSE.[779]� He said:

�It is possible that gelatin is of low risk with regard to BSE contamination, but there are justifiable anxieties when the source material includes brain and spinal cord of cattle (or sheep) from countries with known cases of BSE or at risk of having BSE cases.

Validation studies to demonstrate the safety of processing and extraction procedures in this context would be commendable, but there are very significant practical difficulties and such an exercise would take some years.

It is reasonable to press for assurances with regard to quality and sourcing, analogous to those sought with respect to catgut sutures, in relation to gelatin manufactured for use in the pharmaceutical industry�Full compliance with the BSE guidelines should be required for the starting material.

ACKNOWLEDGEMENT

The writer acknowledges with thanks the help of his colleagues.� He is especially indebted to Dr Philip Minor who raised the matter, and to Dr Richard Kimberlin who contributed most of the facts on which this opinion is based.�

673.         On 28 August 1992 Dr Minor wrote to Professor Collee.[780] He said there

��may be a slight difficulty raised by the sentence in your summary requiring full compliance with the BSE guidelines. In the European version of the document�gelatin is specifically singled out as a product which given assurances of adequate collection and processing is unlikely to present any risk of contamination. The implication to me is that the source animal probably does not matter��

674.         On 11 September 1992 the CVO wrote a minute to Mr Lowson about BSE and gelatin.[781]� He said,� �I am a little concerned at the comment that the raw materials should be sourced from a BSE-free country. I have no difficulty with the definition applying to Australia and New Zealand, but not to other countries where they do not have an active surveillance system.�� He went on� �I am worried at the possibility that we may be clobbering the UK even though we have got excellent controls in place, but still be ignoring the unknown and unquantifiable risks from overseas.�

675.         On 18 September 1992 Mr Maslin minuted Mr K C Taylor, Mr R Bradley, Mr A J C Taylor and Mr S Hutchins about BSE and gelatin. He said that he had suggested to Diane Whyte, from DH, that as DH were the sponsoring department of the CSM, they should take the lead on the paper for the Tyrrell Committee.[782]��

676.         The CSM met on 23 and 24 September 1992. The minutes of the meeting state:[783]

�11. BSE Working Group � Chairman�s summary statement to CSM of 8th July 1992 Meeting

The Committee noted the report and Dr Rotblat confirmed that there was no cause for concern regarding the use of foetal calf serum.�

677.         At this meeting the issue of BSE and gelatin was deferred to another meeting.[784]

678.         In her Statement to the Inquiry Dr Rotblat said[785] that she recalled around:

�� 1992, a new EC Directive came into force, the effect of which was to require vaccines, blood products or immunologicals to be reviewed. Such products had previously continued to enjoy a product licence of right without being subject to the Review procedure. By then the CRM was no longer in existence and the review work was carried out by the Biologicals subcommittee and the CSM. Within the MCA, this work was carried forward by Dr [Mary] Duncan and Mrs Dow. BSE issues would have been taken into account by the pharmacist in this review.�

1993

1994

679.         On 7 June 1994 the MDD Spongiform Encephalopathy Working Party for Sterile Medical Devices met[786] and noted the publication of the �Guidance on Chemical Methods of Sterilisation for Animal Tissues in Medical Devices�. The meeting also noted that the Research Division had been funding some work by David Taylor on spongiform encephalopathies and their survival after autoclaving at 134�C-138�C.

680.         On 29 June 1994 the CMO, Sir Kenneth Calman, and the CVO, Mr Meldrum announced in a joint statement� �We have concluded that it would be consistent with the Government�s policy of extreme caution on BSE, and would be appropriate in the light of the latest information, to extend the definition of specified bovine offal to include the intestines and thymus of calves under 6 months of age.� An ongoing study had for the first time detected BSE infectivity outside the brain and spinal cord of cattle, namely at the end of the small intestine. This development gave rise to the possibility that the BSE agent could be present in offal from calves under the age of 6 months.[787]

681.         Mr Sloggem prepared a �BSE Position Paper� for the July meeting of the Biologicals Sub-Committee Meeting in which he concluded:

�Ensuring that bovine materials are only sourced from cattle which have not been fed ruminant feed is the biggest safeguard against BSE contamination of medicinal products.� A WHO meeting [sic] May 1993 indicated that appropriate measures were in place to control BSE�

Current research on the inactivation of TSE infectivity may require the revision of the CPMP TSE Guideline section on methods thought to inactivate TSE.�[788]

682.         On 27 September 1994 the MDD became the Medical Devices Agency (MDA).

1995

1996

683.         In March and April 1996 the MCA undertook an audit of UK medicines manufacturers. The MCA said in its letter of 1 April 1996 that the purpose of the audit was to� ��reassure itself that proper procedures are being followed.� [789] They also asked in this letter for written confirmation that the 1992 CPMP Guidelines were being complied with. The audit itself was carried out from 10 to 18 April 1996 and focussed on all those manufacturers of medicines that might contain material of bovine origin. Inspectors visited 166 sites in all. [790]

684.         On 28 March 1996 the CSM met to review the safety of medicines derived from bovine materials.[791] Dr Jefferys notes in his statement to the Inquiry:

�The Committee confirmed that all parenteral products manufactured using materials of bovine origin conformed to the CPMP guidelines and that patients could continue to take their recommended medications with full confidence. The Committee also satisfied itself of the safety of gelatine used in capsules containing medicines. A position statement to this effect was issued by the CSM confirming that all bovine material used in the manufacture of parenteral medicinal products was sourced from herds from outside the UK which had not been fed material of ruminant origin.�[792]

685.         On 4 April 1996 Mrs Oliver head of Licensing Administration wrote to authorisation holders individually requesting urgent information about �all ingredients of bovine origin in veterinary medicines authorised or manufactured in the UK� following the EC�s decision to ban UK exports which might contain BSE transmissible material. The letter said:

�I should be grateful if you would confirm that each of the products listed on the attached sheet, where appropriate, conformed to the Committee for veterinary medicinal products guidelines which were finally approved in January 1993. I should also be grateful for confirmation of the source of all ingredients (eg gelatin, sera etc) contained in the products, which are or might be of bovine origin if you either do or intend to export the product�.[793]

686.         A report of the audit was issued in a summary document on 26 April 1996.[794] It stated:

�The results of the audit:

re-confirmed that no bovine material of UK origin is used in the manufacture of vaccines or other injectable medicines in the UK since 1989. The audit confirms that all injectable products are therefore free from any risk associated with UK bovine materials;

re-confirmed certification of compliance with the 1992 CPMP guidelines;

established that since mid-April 1996 no pharmaceutical product for human use manufactured in the UK uses gelatin derived from materials of UK bovine origin;

established that there are three UK manufacturers of gelatin who supply gelatin certified for pharmaceutical use, and that they do not supply gelatin derived from materials of UK bovine origin to manufacturers of pharmaceutical products for human use in the UK;

established that in respect of tallow derivatives, as a result of a commercial decision virtually all UK manufacturers have moved away from using tallow derivatives which have been refined from tallow of UK bovine origin. However it should be noted that the UK produced a detailed paper on tallow derivatives, which was considered by the special meeting of the CPMP on 15 April 1996. The EMEA opinion of that meeting emphasised that the processes used to produce tallow derivatives which are used in pharmaceutical products are more than sufficient to render them safe.�

687.         The Report also notes that: �The audit has confirmed full compliance [with the 1992 CPMP Guidelines].� [795]

[1] L12

[2] L12 pA139-140

[3] sic presumably �inducing�

[4] L12 pA140

[5] DH01 Tab12 para 3

[6] L12 pA139-140

[7] DH01 Tab12 para 17

[8] DH01 Tab 13 para 1

[9] L14 Tab J p 1-32

[10] DH01 Tab 11

[11] (SI 1994 No 3017), L14 pJ33

[12] L12 Tab 12 p A145.

[13] L16 Tab 1 p 65

[14] L16 Tab 1 p 65 - article 3.

[15] L16 Tab 1 p 65 - article 5.

[16] L16 Tab 1 p 65 - article 11.

[17] L16 Tab 1 p 65 - article 21.

[18] See original article 2.

[19] L16 Tab 1 p 65 - article 1.

[20] L 16 p 191

[21] L16 Tab 1 p 66a

[22]L13 Tab D p 12

[23] L15 Tab U p 1- see in particular regulations 1(2) and 9(2).

[24] L15 Tab U p 4 -6

[25] L16 Tab 1 p 67

[26] L16 Tab 1 p 95

[27] L16 Tab 1 p 97 - article 8

[28] L16 Tab 1 p 70

[29] L16 p 3

[30] L12

[31] DHO1 Tab 14 para 9

[32] L12� p A27

[33] L13 Tab I p 1

[34] Section 5(2)

[35] Section 4(5)

[36] Sections 3(2) and� 4(1).

[37] Section 5(3).

[38] L13 Tab F p 2

[39] L13 Tab F p 7

[40] S Asscher para 8

[41] S Asscher para 5

[42] S Asscher para 13

[43] S Asscher para 9

[44] S Hagger para 16

[45] S Collee para 30

[46] S Collee para 24

[47] S Hagger para 18

[48] L13 Tab F p 9 [The Medicines (Committee on Dental and Surgical Materials) Order 1975 SI 1975/1473 article 2, as amended in 1980]�

[49] L13 Tab F p24 [By the Medicines (Committee on Dental and Surgical Materials)(Revocation) Order 1994 SI 1994/3120, because in connection with the implementation of Council Directive 93/42/EEC (OJ L169, 12.7.93, p.1) concerning medical devices, most of the substances and articles referred to were no longer covered by the Act; in the case of those remaining, the statutory functions of the CDSM fall to another s 4 committee or to the Medicines Commission.]

[50] M67 Tab 1

[51] T71 p16

[52]DM01 Tab 14

[53] L13 Tab F p22

[54] DH01 Tab6 p 2

[55] S Lawson para 8

[56] L13 Tab F p22 [By the Medicines (Committee on the Review of Medicines)(Revocation) Order 1992 SI 1992/606.]

[57] L13 Tab F p 6 [The Medicines (British Pharmacopoeia Commission)� Order 1970 SI 1970/1256, explanatory note.]

[58] L15 Tab U p8 [SI 1994 3144, s 9(2)]

[59] L12� pA46 [Medicines Act 1968 s 35]

[60] L12 pA19 [Medicines Act 1968 s 9]

[61] L12� pA16 [Medicines Act 1968 s 7(2A)]

[62] L12 Tab A p 139-140 [Medicines Act 1968 s 130]

[63] Section 130 (2)

[64] Presumably �inducing�

[65] Section 130 (5)

[66] Section 130 (5A)

[67] L12� pA115

[68] L15 Tab R p 1 [The Medicines (Surgical Materials) Order 1971 SI 1971 1267]

[69] L15 Tab R p 7 [The Medicines (Specified Articles and Substances) Order 1976 SI 1976/968]

[70] L15 Tab R p 17 [The Medicines (Control of Substances for Manufacture) Order 1971 SI 1971/1200 article 3 and schedule 1; since 11.4.94, this has applied only to ingredients for animal medicinal products, whereas previously human medicines had been included.]

[71] L15 Tab R p 20 [The Medicines (Control of Substances for Manufacture) Order 1971 SI 1971/1200 article 3 and schedule 1.]

[72] L13 Tab D p 27 [The Medical Devices (Consequential Amendments � Medicines) Regulations 1994]

[73] L12 pA22 [Medicines Act 1968 s 12]

[74] L13 Tab G p 26 [The Medicines (Exemption from Licenses) (Foods and Cosmetics) Order 1971 SI 1971/1410 article 2(1).]

[75] The Medicines (Exemption from Licenses) (Foods and Cosmetics) Order 1971 SI 1971/1410 article 1(2)

[76] Ibid, article 2(2)(a).

[77] Ibid, article 2(2)(b) and Schedule.

[78] Ibid, article 2(2)(c).

[79] Ibid, article 2(2)(d).

[80] Ibid, article 2(3).

[81] DHO1 Tab 13 para 6

[82] L 13 Tab H p1

[83] L13 Tab H p40A

[84] Section 19(1)(a)

[85] Section 20(1)

[86] Section 20(3)

[87] L12� pA13, 143 [Medicines Act 1968 s 4(6) and 132(1)]

[88] Section 24(1)

[89] Section 24(2)

[90] Section 24(4)

[91] L12 pA38

[92] L12 pA39,A151 [Medicines Act 1968 s 29(1) and� Schedule 2]

[93] L12� pA28, A151 [Medicines Act 1968 s 21 and Schedule 2]

[94] L15 Tab U p 1 - SI 1994/3144 - see in particular regulations 1(2) and 9(2).

[95] DH01 Tab 13 para 1

[96] DH01 Tab 13para 8-9

[97] L14 Tab J p 1 [The Active Implantable Medical Devices Regulations 1992 SI 1992/3146, amended by the Active Implantable Medical Devices (Amendment and Transitional Provisions) Regulations 1995 SI 1995/1671]

[98] DH01 Tab 11

[99]L14 Tab J p3

[100] L14 Tab J� p33 [The Medical Devices Regulations 1994 SI 1994/ 3017]

[101] L14 Tab J p35 [The Medical Devices Regulations 1994 article 2(1)]

[102] L14 Tab J p37 [Regulation 3(2)(b)]

[103] L14 Tab J p38 [Regulation 3(2)(g)]

[104] DH01 Tab 11

[105] DH01 Tab 11 p1-2

[106] DH01 Tab 13 para 10

[107] DH01 Tab 13 para 11

[108] DH01 Tab 11 p2

[109]DH01 Tab11

[110] Penguin Medical Encyclopedia (4th Edition 1996; Editors Peter Wingate and Richard Wingate).

[111] L 13 Tab H p1 [The Medicines (Applications for Product Licences and Clinical Trial and Animal Test Certificates) Regulations 1971 SI 1917/973 refer to applications for licences for homoeopathic products.]

[112] T71 p46

[113] T71 p 45

[114] L15 Tab T p1

[115] L16 Tab 1 p159

[116] L15 Tab T p1 [The Medicines (Homoeopathic Medicinal Products for Human Use) Regulations 1994 SI 1994/105 regulation 3]

[117] L13 Tab F p27 [Medicines (Advisory Board on the Registration of Homoeopathic Products) Order 1995 article 1.]

[118] L16 p 158

[119] L13 Tab F p27 [Established pursuant to sections 4 and 129(4) of the Medicines Act 1968 by the Medicines (Advisory Board on the Registration of Homoeopathic Products) Order 1995 SI 1995/309.]

[120] The Board considers those products which satisfy either the conditions set out in Article 7 of Council Directive 92/74/EEC (OJ No. L297, 13.10.92, p.12) or the conditions set out in paragraph (2) of Article 2 of the Medicines (Advisory Board on the Registration of Homoeopathic Products) Order 1995, namely that the product is one to which Article 2(1) of Council Directive 92/73/EEC OJ No. L297 13.10.92, p.8 applies; that it is for oral administration; that no specific therapeutic indication appears on the labelling or any associated information; and that an application for a certificate of registration (i.e. a certificate for the purposes of the Medicines (Homoeopathic Medicinal Products for Human Use) Regulations 1994 SI 1994/105: see Article 1(2) of the Medicines (Advisory Board on the Registration of Homoeopathic Products) Order 1995 SI 1995/309) or for renewal of such a certificate has been made, or the licensing authority proposes to suspend or revoke the certificate of registration.

[121] DH01 Tab 22

[122] DH01 Tab 22

[123] DH01 Tab 22

[124] DH01 Tab 22

[125] DH01 Tab 22

[126] DH01 Tab 6 p 1, S G Jones para 6

[127] S Jefferys para 8

[128] S G Jones para 3

[129] S G Jones para 3

[130] S G Jones para 3, M16 Tab 7

[131] S Jefferys para 8

[132] S G Jones para 8

[133] S Jefferys para 8-9, M16 Tab 22

[134] S Jefferys para 10

[135] S Jefferys 3 (WS 419B) para 18

[136] S Wills para 4

[137] S Rotblat para 8-9

[138] DH01 Tab 21

[139] M16 and S Rotblat para 8-9

[140] S Purves para 30

[141] S Jefferys para 11

[142] S Jefferys para 38

[143] M39 Tab 12

[144] M39 Tab 12 p7

[145] M39 Tab 12 p24

[146] M39 Tab 12 p24

[147] M39 Tab 12 p2

[148] T71 p23-24

[149] S Jefferys 3 (419B) para 6-7

[150] S Jefferys 3 (419B) para 9-10

[151] S Jefferys 3 (419B) para 13

[152] T79 p117-118

[153] M39 Tab 21 pp2, 4

[154] S K Jones para 8

[155] S Rotblat para 10

[156] DH01 Tab 21, S Jefferys para 12

[157] M16A Tab 7

[158] M39 Tab 21 p7

[159] S K Jones para 11

[160] S K Jones para 13

[161] S Jefferys para 12

[162] S Rotblat para 12-13

[163] S Jefferys p13

[164] M16A Tab 27

[165] S Wilson para 3.2

[166] S Jefferys 3 (WS419B) para 12

[167] S Jefferys para 53

[168] S Jefferys para 23

[169] S Jefferys para 24-27

[170] S Jefferys 3 (WS 419B) para 11

[171] S Jefferys para 29

[172] S Jefferys para 28

[173] S Hagger para 9

[174] T71 p25-26

[175] S Jefferys para 30

[176] S Jefferys para 33

[177] S Asscher para 15 - 16

[178] S Asscher para 19

[179] T84 p45-47

[180] T93 p13-14

[181] T88 p89-90

[182] S Hine para8

[183] S Acheson para 12

[184] S Acheson para18

[185] DH01 Tab21

[186] T79 p45-46

[187] DH01 Tab 21

[188] S Jefferys para 34

[189]M39 Tab22

[190]DH01 Tab11

[191] DH01 Tab11

[192] M16 Tab 12

[193] DH01 Tab 19

[194] DH01 Tab 21, Dh01 Tab 19, M16A Tab 7

[195] M16A Tab 12

[196] DH01 Tab 19

[197] M39 Tab 22 p3

[198] M16A Tab22

[199] M39 Tab 22 p7

[200] DM01 Tab 14, M16A, and S Little para5

[201] DM01 Tab 15

[202] S Rutter para 21

[203] S Little para 4

[204] S Armour para 5 i

[205] M16 Tab 26, S Cruickshank para 1.4, E6845, E7890

[206]DM01 Tab 15

[207] DM01 Tab 14 Annex 2 p4, DM01 Tab15

[208] DM01 Tab 15 Annex 2 p5

[209] DM01 TB 14 Annex 2 p6

[210] DM01 Tab 15

[211] DM01 Tab 15

[212] DM01 Tab 15

[213] YB 83/6.00/1.1-1.4

[214] J/L/1985II/837

[215] S Sloggem para 25-27

[216] S Sloggem para 26

[217] S Sloggem para 28-30

[218] YB87/8.24/2.1

[219] S Sloggem para 31

[220] YB 87/9.09/1.1-1.12

[221] S Little para 13-15

[222] T99 p51

[223] YB 87/9.09/1.1-1.12

[224] S Adams para 26, S Purves para 43 and S Rotblat para 42

[225] S Collee para 55

[226] S Jefferys para 57

[227] T99 p 52-53

[228] T99 p 55

[229] S Little 3 (331B) para 19

[230] S Sloggem 2 (WS 454A) para 4

[231] S Sloggem 2 (WS 454A) para 4-7, 10-12

[232] YB 87/9.10/1.1

[233] S Little 2 (331A) para 14

[234] YB 87/9.14/1.2

[235] YB 87/10.1/1.1-1.2

[236] YB87/12.00/1.1-1.3

[237] YB87/12.00/1.1-1.3

[238] S Rotblat para 44 and YB 87/8.24/2.1

[239] YB 88/1.06/2.12.2

[240] This company will be referred to as G throughout the DFA.� For reasons of confidentiality, product and company names cannot be used. We have adopted an alphabetical key for products and companies that are mentioned. This allows the story to be traced while protecting confidentiality.�

[241] YB 88/2.25/1.1-1.6 & 2.1-2.5

[242] S Collee para 56-59

[243] S Jefferys 3 (WS419B) para 27

[244] YB88/01.06/1.4

[245]YB 88/2.03/1.1-1.2

[246] YB 88/3.02/6.1-6.8

[247] YB 88/3.3/4.1

[248] S Acheson para 42

[249] YB 88/3.17/8.1-8.3

[250] YB 88/3.17/5.1

[251] YB 88/3.17/8.3

[252] YB 88/3.17/5.1

[253] YB88/03.21/1.3

[254] T79 p72-73

[255] T79 p91-92

[256] YB 88/3.21/1.1

[257] YB 88/3.24/3.1-3.7

[258] S Jefferys para 58

[259] S Jefferys 3 (WS419B) para 29

[260] YB 88/4.13/5.1

[261] YB88/4.13/5.1

[262] S Jefferys para 36

[263] S Jefferys 2 para 3-4

[264]YB 88/4.13/5.1,

[265] S Jefferys 2 (WS 419A) para 2

[266] S Jefferys para 61

[267] S Jefferys 3 (WS 419B) para 33

[268] YB 88/4.28/5.1-5.6

[269] YB 88/5.04/6.1-6.9

[270] YB 88/5.16/2.12.12

[271] S Little 2 (331A) para 12

[272] YB 88/5.16/2.10-2.11

[273] YB 88/5.16/2.12

[274] YB 88/5.23/4.3

[275] YB 88/5.20/12.1

[276] YB 88/5.20/4.1-4.2

[277] YB 88/5.23/9.1

[278] YB 88/5.24/3.1-3.2

[279] S Jefferys para 64

[280] YB 88/5.26/6.1-6.5

[281] YB 88/6.2/15.1

[282] YB 88/6.3/12.1

[283] YB 88/6.6/3.1-3.19

[284]YB 88/6.07/10.6

[285] YB 88/6.08/11.1-11.2

[286] YB 88/6.10/1.1

[287] YB 88/6.13/8.1, S Wilkes para13

[288] YB 88/6.14/6.1

[289] YB 88/6.20/2.1-2.5

[290] YB 88/6.20/7.1-7.25

[291] YB 88/6.20/7.3

[292] YB 88/6.21/4.1

[293] S. Jones para 11

[294] S Jefferys para 66

[295] S Jefferys 3 (WS 419B) para 36

[296] S Rotblat para 47

[297] YB 88/6.30/7.1-7.6

[298] YB 88/7.3/1.1

[299] YB 88/7.05/6.1-6.4

[300] YB 88/7.06/8.1-8.2

[301] YB 88/7.06/10.1-10.11

[302] YB88/7.11/12.1-12.4

[303] YB 88/7.11/8.1

[304] YB88/7.11/13.1

[305] YB 88/7.14/11.1-11.2

[306] YB 88/7.14/11.1-11.2

[307] J/VR/123/87

[308] YB 88/7.21/1.1

[309] YB 88/7.28/9.1-9.6

[310] YB 88/8.11/2.1

[311] YB 88/8.30/3.1 and S Acheson para 56

[312] S Rotblat para 51

[313] YB 88/9.20/3.1

[314] S Jefferys 3 (WS 419B) para 38-39

[315] S Purves para 50-51

[316] S Rotblat para 29

[317] YB 88/9.00/3.2-3.37

[318] S Purves para 56-58

[319] YB 88/09.00/3.7-3.9

[320] S Purves para 59

[321] S Purves para 63

[322] S Jefferys 3 (WS 419B) para 43

[323] S Rotblat para 56

[324] S Purves para 66

[325] S Purves para 67

[326] YB 88/9.06/5.1-5.4

[327] YB 88/9.6/2.1, S G Jones para 2

[328] YB 88/9.16/2.1

[329] YB 88/9.07/2.1-2.22

[330] YB 88/9.16/2.1

[331] YB 88/9.22/1.1

[332] YB 88/9.22/6.1-6.7

[333] YB 88/9.26/4.1

[334] S Rotblat para 49

[335] T71 p 37

[336] T71 pp 37-38

[337] T71 pp 47-48

[338] T 71 p39-41

[339] S Collee para 44

[340] T71 p44

[341] T71 p94-95

[342] T71 p96

[343] YB 88/9.29/4.1

[344] YB 88/9.29/4.1

[345] YB 88/10.06/1.1

[346] YB88/10.12/2.1-2.3

[347] S Rotblat para 57

[348] S Purves para 69

[349] YB 88/10.14/6.1

[350] YB 88/10.14/6.1

[351] YB 88/10.20/3.1-3.4

[352] YB 88/11.1/12.6

[353] S Jeffreys para 72 and YB 88/11.02/4.1-4.10

[354] S Collee para 66

[355] S Collee para 67

[356] S Collee para 68

[357] S Collee para 69

[358] S Collee para 70

[359] S Collee para 72-83

[360] S Collee para 108

[361] S Jefferys 3 (WS 419B) para 48

[362] YB 88/11.2/3.1

[363] YB 88/11.2/3.2-3.3

[364] YB 88/11.04/7.1-7.19

[365] YB 88/11.08/5.1-5.6

[366] YB88/11.08/5.2

[367] YB 88/11.10/2.1-2.4

[368] YB 88/11.14/6.1

[369] S Asscher para 36

[370] S Asscher para 50

[371] YB 88/11.18/2.2

[372]YB 88/11.16/6.1-6.7

[373] YB 88/11.17/9.1-9.4

[374] S Collee para 84- 85

[375] S Asscher para 35

[376] S Asscher para 38

[377] YB 88/11.18/2.1

[378] YB 88/11.18/3.1, S Jefferys para 79

[379] YB 88/11.24/1.1-1.2

[380] S Asscher para 40

[381] S Asscher para 41-42

[382] YB88/11.25/2.3,� S Meldrum para 57

[383] YB 88/12.7/1.1

[384] S Asscher para 44

[385] S Jefferys 3 (WS419 B) para 49

[386] S Adams para 42

[387] YB 88/12.8/1.1

[388] YB 88/12.15/9.1-9.5

[389] YB 88/12.16/3.1

[390] YB 88/12.16/1.1

[391] YB 88/12.20/2.1

[392] YB 88/12.21/4.1

[393] YB 88/12.23/1.1-1.2

[394] YB 88/12.23/1.1-1.2

[395] YB 88/12.23/2.1

[396] T66 p77

[397] S Asscher para 48

[398] S Asscher para 64-66

[399] S Rotblat para 32-34

[400] YB89/1.00/2.1-2.3

[401] YB 89/1.03/2.1-2.2

[402] YB 89/01.03/2.1-2.2

[403] S Adams para 44

[404] YB 89/1.4/1.1-1.3

[405] YB 89/1.04/5.1-5.16

[406] YB 88/1.5/1.1 ( Note: although doc dated 5/1/88 it is apparent the minute was sent 5/1/89 see YB89/9.1/1.2)

[407] YB 89/01.09/2.1

[408] YB 89/01.09/2.1-2.3

[409] S Jefferys 3 (WS 419B) para 51

[410] YB 89/1.13/1.1-1.2

[411] YB 89/1.13/1.1-1.2

[412] YB 89/1.13/1.2

[413] YB 89/1.17/1.1-1.2

[414] YB 89/1.19/6.1, S Rotblat para 64

[415] YB 89/1.26/1.1-1.2

[416] S Collee para 88

[417] S Adams para 36,40,41,48,� S Jefferys para 77,83,84,85,92

[418] S Rotblat para 66

[419] YB 89/1.26/7.1-7.8

[420] YB 89/1.26/2.1

[421] YB 89/01.26/2.1-2.2

[422] YB 89/1.26/2.1-2.2

[423] YB 89/1.30/1.1

[424] YB 89/2.1/4.1

[425] S Little para 8

[426] S Purves para 87

[427] S Jefferys 3 (WS 419B) para 55

[428] YB 89/2.2/4.1-4.2

[429] YB 89/02.02/1.1-1.2

[430] YB 89/2.02/1.1

[431] YB 89/2.03/2.1-2.4

[432] YB 89/2.09/7.1, S Acheson para63

[433] T79 p99-101

[434] YB 89/2.00/8.1-8.2

[435]YB 89/2.9/5.1-5.4

[436] YB 89/2.9/5.1

[437] YB 89/2.9/5.3

[438] T79� p89

[439] YB 89/2.10/3.1, S Adams para 52

[440] YB 89/2.13/10.1

[441] YB 89/2.14/7.1-7.3

[442] S Rotblat para 68

[443] S Adams para 53

[444] YB 89/2.13/2.1-2.18

[445] YB 89/2.13/2.6

[446] YB 89/2.13/2.7-2.8

[447] YB 89/2.14/5.1

[448] YB 89/2.15/8.1-8.3

[449] YB 89/2.14/2.1-2.2

[450] YB 89/2.15/9.1

[451] YB 89/2.15/3.1-3.2

[452] YB89/2.15/6.1

[453] YB 89/2.17/1.1-1.16

[454] YB 89/2.17/10.1-10.5

[455] YB89/02.19/1.1

[456] S Sloggem para 52

[457] YB 89/2.22/11.1-11.5

[458] YB 89/2.22/11.1-11.4

[459] YB89/2.22/11.5

[460] S Purves para 93

[461] YB 89/02.00/5.1

[462] YB/89/2.22/11.6

[463] S Martin para 16

[464] S Kimberlin para 6.2

[465] YB 89/2.22/10.1

[466]YB 89/2.23/10.1-10.11

[467] YB89/2.23/5.1

[468] YB 89/2.23/13.1-13.5

[469]� YB 89/2.23/6.1-6.2, S Adams para 60, S Jones para 17

[470] YB 89/2.23/13.5

[471] YB 89/2.23/6.8

[472] YB 89/2.23/6.9-6.11

[473] YB 89/2.23/6.4

[474] S Asscher para 58

[475] YB 89/02.23/9.1-9.5, S Clarke para24

[476] YB 89/2.23/3.1-3.2

[477] YB 89/02.24/12.1-12.5, S Asscher para 67

[478] YB 89/02.24/12.4

[479] YB 89/2.23/6.9-6.11

[480] YB 89/2.27/1.1-1.8

[481] YB 89/2.27/1.4

[482] IBD 1 Tab 2

[483] S Collee para 43

[484] S Asscher para 32

[485] YB 89/3.01/4.1

[486] YB89/3.7/2.1-2.2

[487] YB 89/3.7/6.1-6.6

[488] S Adams para 63, YB 89/3.6/6.1

[489] YB 89/3.07/4.1, S Asscher 69, S Jefferys 107

[490] YB 89/3.00/1.2

[491] S Collee para 39-41

[492] S Collee para 37

[493] S Asscher para 61

[494] S Hagger para 34

[495] YB 89/3.00/1.1-1.3

[496] S Asscher� para 60

[497] S Collee para 100

[498] T79 p92

[499] YB 89/3.15/4.1-4.2

[500] YB 89/3.13/10.1-10.2

[501] YB 89/3.16/7.1

[502]YB 89/3.00/3.1-3.8

[503] YB 89/3.17/10.1-10.5

[504]DH01 Tab11 p4

[505] YB 89/3.17/10.1-10.5

[506] YB 89/3.00/3.4-3.6

[507] YB 89/03.22/1.4

[508] YB 89/5.17/5.1, S Adams para 66

[509] YB 89/3.15/6.1-6.5

[510] YB 89/3.17/8.1

[511] YB 89/3.21/13.1-13.4

[512] YB 89/3.30/4.1-4.10

[513] YB 89/3.31/3.2

[514] YB89/4.5/4.1

[515] YB 89/4.00/1.1-1.7

[516] YB 89/4.11/2.2

[517] YB 89/4.11/2.2

[518] YB 89/4.17/5.1

[519] YB 89/4.00/1.1-1.2

[520] YB 89/4.13/6.1

[521] YB 89/5.12/10.1-10.3

[522] YB 89/5.12/10.2

[523] YB 89/8.21/10.4-10.17

[524] YB 89/5.12/10.3

[525]DH01 Tab11 p5

[526] YB 89/5.3/6.1-6.3

[527] YB 89/5.12/5.1

[528] YB 89/5.24/6.1-6.2

[529] YB 89/5.24/6.2

[530] T90 p139

[531] YB89/5.31/4.1

[532] YB 89/6.5/4.1

[533] YB 89/4.27/1.18, IBD 1 Tab 4

[534] IBD1 Tab 4� p10-15

[535] IBD 1 Tab 4 p15

[536] YB 89/6.5/3.1

[537] S Rotblat para 75

[538] this company will be referred to as Z throughout this DFA

[539] YB 89/6.06/10.1-10.3

[540] YB 89/6.7/6.1-6.3

[541] S Acheson para 70

[542] YB 89/6.7/1.1

[543] YB 89/6.8/7.1-7.2

[544] YB89/6.8/10.1-10.5

[545] YB 89/6.8/10.5

[546] YB89/6.9/5.1-5.4

[547] YB 89/6.9/14.1

[548] S Jefferys para 113

[549] S K Jones para 26

[550] YB 89/6.12/14.1-14.4

[551] YB 89/6.12/15.1

[552] S Adams para 74

[553] YB 89/6.12/14.1

[554] YB 89/6.12/14.2

[555] YB 89/06.12/14.1

[556] YB 89/06.12/14.2

[557] S Rotblat para 78

[558] YB 89/6.12/15.1

[559] S Adams para 74

[560] YB 89/6.13/16.1

[561] YB 89/6.13/10.1

[562] YB 89/6.13/18.1

[563] YB 89/6.27/7.1

[564] S Rotblat para 82

[565] YB 89/6.29/4.1

[566] YB89/7.3/4.1

[567] YB 89/7.03/8.1

[568] this company will be referred to as Y throughout this DFA

[569] YB89/07.04/3.1

[570] YB 89/7.05/11.1 & 19.1

[571] T87 p131

[572] T87 p133

[573] S Collee para 50-51

[574] S Asscher para 72

[575] YB89/07.04/3.1

[576] YB89/07.14/10.1

[577] S Purves para 115

[578] YB 89/7.19/11.1-11.3

[579] YB89/07.26/12.1

[580] YB 89/8.24/9.1

[581] YB 89/9.6/10.6

[582] this company will be referred to X throughout this DFA

[583] YB 89/8.2/6.1

[584] YB 89/8.2/2.1-2.9

[585] YB 89/8.2/2.2

[586] YB 89/8.2/2.7

[587] YB 89/8.04/9.1

[588] YB89/8.7/4.1-4.4

[589] YB 89/8.09/4.1-4.3, S Jefferys para 118

[590] YB 89/8.21/11.1

[591] YB 89/8.21/10.1-10.3

[592] DH01 Tab11 p5

[593]YB 89/8.21/10.4-10.17

[594] YB 89/8.24/9.1

[595] YB 89/8.30/1.1

[596] YB 89/8.30/6.1

[597] YB 89/9.5/5.2, S Adams para 80

[598] YB 89/9.6/10.1-10.12

[599] YB 89/9.06/10.3

[600] YB 89/9.06/11.2-11.3

[601] YB 89/9.06/11.3

[602] S Purves para 126

[603] YB 89/9.06/11.12

[604] this product will be referred to as F throughout this DFA

[605] YB 89/9.06/11.5

[606] YB89/9.6/10.7

[607] S Collee para 41

[608] S Rotblat para 80

[609] YB 89/9.06/13.1-13.6

[610] YB 89/9.06/14.1-14.4

[611] YB 89/9.06/10.5

[612] YB 89/9.6/10.4

[613] S Collee para 109

[614] YB 89/9.7/3.1

[615] YB 89/9.7/3.1-3.2

[616] YB 89/9.7/5.1

[617] YB 89/9.7/5.1

[618]YB 89/9.7/2.1

[619] This company will be referred to as H throughout the DFA.

[620] YB 89/9.13/7.1-7.2

[621] YB 89/10.00/5.1-5.2

[622] YB 89/9.20/3.1-3.3

[623] YB 89/9.19/10.1

[624] YB 89/9.19/11.1

[625] YB 89/11.15/17.2

[626] YB 89/9.21/13.1-13.2

[627]YB 89/9.21/12.1-12.7

[628]DH01 Tab11 p6

[629] YB 89/9.28/10.1-10.8

[630] YB89/9.28/10.3, S Collee para 112

[631] YB89/10.3/3.1

[632] YB89/10.3/7.1

[633] YB 89/10.4/2.1

[634] YB 89/10.5/3.1-3.5

[635] YB 89/10.06/5.1

[636] YB 89/10.9/2.1

[637] YB 89/10.10/7.1

[638] YB 89/10.12/8.1

[639] YB 89/10.12/8.1

[640] YB 89/10.13/6.1, S Adams para 85

[641] S Jefferys para 123 and 126

[642] YB 89/10.16/4.1

[643] YB 89/10.31/9.1, S Rotblat para 86

[644]DH01 Tab11 p6

[645]DH01 Tab11 p7

[646] YB 89/11.7/10.3, S Adams para 88

[647] YB 89/11.8/1.1

[648] YB 89/11.00/11.1-11.6

[649] YB 89/11.09/22.1

[650] YB 89/11.10/3.1

[651] L2� Tab 3B

[652] YB 89/11.15/18.1-18.2

[653] YB 89/11.15/17.1-17.3, YB 89/11.15/16.1

[654] YB 89/11.15/16.1

[655] YB 89/11.27/4.1

[656]DH01 Tab11 p7

[657] YB 89/11.27/3.1

[658] S Adams para 91

[659] DH01 Tab 11 p 8

[660]YB 89/12.12/8.1-8.3

[661] YB 89/12.13/12.1-2

[662] YB 89/12.19/9.1-9.2

[663] YB 89/12.21/6.1

[664]YB 89/12.28/1.1

[665] YB 90/1.02/3.1-3.2

[666] YB 90/1.03/2.1-2.9

[667] YB 90/1.20/1.2

[668] YB 90/1.9/11.1-11.6

[669] YB 90/1.10/1.1-1.24

[670] YB 90/1.10/10.1-10.4

[671] YB 90/1.10/9.1

[672] YB 90/1.10/8.1

[673] YB 90/1.10/1.4-1.5, YB 90/1.10/9.1

[674] YB 90/1.10/1.4

[675] YB 90/1.10/1.5

[676] YB 90/1.10/1.5

[677] YB 90/1.10/8.1-8.3

[678] YB 90/1.10/7.5

[679] YB 90/1.10/1.5

[680] S Collee para 116

[681] S Collee para 116

[682] S Collee para 49

[683] S Jefferys para 132, YB 90/1.10/7.5

[684] YB 90/1.10/1.6

[685] S Adams para 96

[686] YB/90/01.12/10.1

[687] YB 90/1.17/12.1-12.5

[688]YB 90/1.26/16.1-16.4

[689] DH01 Tab 11 p9

[690] YB 90/2.22/12.1-12..2

[691] YB 90/3.14/10.1, S Jefferys para 136

[692] YB 90/3.26/6.1

[693] YB 90/4.09/4.1-4.2

[694] YB 90/4.17/6.1, S Jefferys para 140

[695] YB 90/4.26/9.1-9.5

[696] S Hagger para 44

[697] YB 90/4.27/5.1, S Jefferys para 138

[698] YB 90/4.27/6.1-6.2

[699] YB 90/4.30/5.1

[700] S Jefferys para 141

[701] YB 90/5.01/8.1

[702] YB 90/5.3/5.1, S Pickles para59.4

[703] YB 90/7.16/5.1

[704] There is no indication of who wrote this annotation or when.

[705] YB 90/5.00/11.1-11.2

[706]YB 90/5.23/13.1-13.4

[707]DH01 Tab11 p10

[708] YB 90/6.7/19.1, YB90/06.04/14.1-14.6

[709] YB90/06.08/20.1, S Rotblat para 94-95

[710]YB 90/6.08/16.1-16.2

[711] YB90/06.11/23.1, S Rotblat para 83 & 84

[712] IBD 1 Tab7 p159

[713] YB 89/6.20/19.1-19.4

[714] IBD 1 Tab 7 p126

[715] This company will be referred to as I throughout the DFA.

[716] YB 90/6.15/22.1-22.3

[717] YB 90/6.29/8.1-8.2

[718] S Rotblat para 97

[719] YB90/7.4/1.3

[720] YB90/7.4/1.3

[721] YB90/7.4/1.4

[722] S Rotblat para 98

[723] YB90/7.4/1.7

[724] S Jefferys para 145

[725] S Rotblat para 36

[726] S Rotblat para 37

[727] S Rotblat para 38

[728] S Rotblat para 39

[729] S Rotblat para 41

[730] S Rotblat para 87

[731] S Jefferys para 55

[732] S Collee para 49

[733] S Asscher para 77

[734] YB90/07.26/15.1

[735] YB 90/7.25/12.1-12.16

[736] YB 90/9.11/5.1

[737] YB 90/9.12/2.1

[738] YB 90/09.12/6.1

[739] YB 90/9.13/4.1

[740] S Asscher para 88

[741] S Collee para 131

[742] S Jefferys para 146

[743] S Sloggem para 80

[744] YB 90/9.21/9.1

[745] S Pickles para 62.1-62.2

[746] YB 90/10.12/5.1

[747] YB 90/10.31/3.1-3.18

[748] YB 90/10.31/3.2

[749] YB 90/10.31/3.4

[750] YB 90/10.31/3.4-3.5

[751] YB 90/10.31/3.7

[752] S Rotblat para 112

[753] YB90/11.00/5.1-5.2

[754] YB 90/11.22/14.1-14.9

[755] DH01 Tab 11 p11

[756]DH01 Tab11 p11

[757] S Jefferys para 152

[758] YB 91/5.9/6.1

[759] YB 91/5.14/3.1

[760] YB 91/5.21/8.1

[761] S Jefferys para 156

[762]YB 91/7.31/8.1-8.6

[763] YB 91/8.15/9.1-9.2

[764]YB 91/11.08/4.1-4.4

[765] YB 91/11.12/2.1-2.19, DH01 Tab11 p9

[766] YB 91/11.28/2.1-2.4

[767] IBD 2 Tab 13 p11 para 4.15

[768] YB 92/4.8/6.1-6.2

[769] DH01 Tab6 p 13

[770] S Jefferys para 155

[771] YB 92/7.8/15.1-15.7

[772] YB 92/7.8/1.2

[773] S Asscher para 31

[774] S Rotblat para 39

[775] YB92/07.21/2.1

[776] YB92/07.30/3.1

[777] YB92/07.31/1.1-1.3

[778] YB 92/8.5/3.1-3.2

[779] YB92/08.18/4.1-4.2

[780] YB92/08.28/1.1

[781]YB 92/9.11/1.1

[782]YB 92/9.18/4.1

[783] YB 92/9.23/4.6

[784] YB 92/9.23/3.1-3.2

[785] S Rotblat para 121

[786]DH01 Tab11 p14-15, M39 Tab19

[787] YB 94/6.29/5.4-5.7

[788] YB 94/6.07/5.7

[789] YB 96/4.01/2.1

[790] DH01 Tab12 para 29-30

[791] YB 96/3.28/9.1-9.2

[792] S Jefferys para 176

[793] YB 96/4.04/5.1

[794] DH01 Tab 12 Annex D

[795] M39 Tab18

BSE INQUIRY

“Unprecedented” row delays second phase of BSE inquiry

BMJ 1999; 318 doi: https://doi.org/10.1136/bmj.318.7183.558 (Published 27 February 1999) Cite this as: BMJ 1999;318:558 Article Related content Metrics Responses This article has a correction. 

Please see: 

Correction - March 06, 1999 Witnesses at the inquiry into bovine spongiform encephalopathy claim procedures are unfair. Will the Bristol inquiry adopt the same methods, and will witnesses again cry foul? Clare Dyer, legal correspondent, reports Sparks have been flying behind the scenes at the inquiry into bovine spongiform encephalo-pathy (BSE). The bland press release issued last week by the inquiry announcing that it will not be able to report, as planned, in June 1999 and adding that it needs more time, contains little hint of the backstage drama, beyond a statement by the chairman, Lord Phillips, that “preparing for phase two is proving a more exacting process than we had anticipated, and we are anxious that it should be done fully and fairly.”

The word “unprecedented” has been used to describe the row that has blown up between the inquiry and lawyers representing civil servants from the Ministry of Agriculture, Fisheries, and Food and the Department of Health. Strongly worded letters have been exchanged between the lawyers and the inquiry, and judicial review has been threatened.

Phase one of the inquiry, the fact finding exercise, has ended after evidence from more than 300 witnesses was presented over 95 days. Civil servants have objected to the “draft factual accounts” produced on the various issues, and have posted them on the internet with an invitation for corrections to be made. Witnesses claim that these accounts, far from being factual, are “value laden” and prosecutorial, …

http://www.bmj.com/content/318/7183/558

Subject: History of Inquiry report delays Date: Fri, 22 Sep 2000 08:04:19 -0800 From: tom Reply-To: Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de

######### Bovine Spongiform Encephalopathy #########

Inquiring into inquiries Richard Smith BMJ 2000 321(7263): p. 715-716 http://bmj.com/cgi/content/full/321/7263/715

"...This inquiry is not alone in being criticised. The inquiry into the circumstances that resulted in bovine spongiform encephalopathy being passed to humans was supposed to report in June 1999 but has now had to enter a second stage to deal with "potential criticism, clarification, and conflicts of evidence." [7] The inquiry heard from over 300 witnesses, and many objected to the "draft factual accounts" published on the internet. These accounts were accused of being far from factual, "value laden" and wrong."

[Actually, no one has criticized the BSE Inquiry as far as I know, other than the 7 million pounds of MAFF lawyers. Everyone testifying had the opportunity to submit lengthy accounts of their own and most did. These claims about unfairness were never buttressed with any supporting specifics, but here is a journal reporter repeating them as if handed down on clay tablets.

Indeed, how can a reprinted memo be wrong or far from factual? It is their own words. The documents that Terry has been supplying are the very ones that were suppressed from the internet -- and the object of all the whining from the lawyers.

tom] 

Dyer C. "Unprecedented" row delays second phase of BSE inquiry. BMJ 1999; 318: 558 http://www.bmj.com/cgi/content/full/318/7183/558?ijkey=OAKJJor7RmxXA

BMJ;318:558 ( 27 February 1999) "Unprecedented" row delays second phase of BSE inquiry

Witnesses at the inquiry into bovine spongiform encephalopathy claim procedures are unfair. Will the Bristol inquiry adopt the same methods, and will witnesses again cry foul? Clare Dyer, legal correspondent, reports

Sparks have been flying behind the scenes at the inquiry into bovine spongiform encephalo-pathy (BSE). The bland press release issued last week by the inquiry announcing that it will not be able to report, as planned, in June 1999 and adding that it needs more time, contains little hint of the backstage drama, beyond a statement by the chairman, Lord Phillips, that "preparing for phase two is proving a more exacting process than we had anticipated, and we are anxious that it should be done fully and fairly."

The word "unprecedented" has been used to describe the row that has blown up between the inquiry and lawyers representing civil servants from the Ministry of Agriculture, Fisheries, and Food and the Department of Health. Strongly worded letters have been exchanged between the lawyers and the inquiry, and judicial review has been threatened.

Phase one of the inquiry, the fact finding exercise, has ended after evidence from more than 300 witnesses was presented over 95 days. Civil servants have objected to the "draft factual accounts" produced on the various issues, and have posted them on the internet with an invitation for corrections to be made. Witnesses claim that these accounts, far from being factual, are "value laden" and prosecutorial, contain errors of fact, and selective, and even inaccurate, quotes from documents and, thanks to technology, they have now been broadcast to the world.

The row is delaying the start of phase two, which is set to deal with "potential criticisms, clarification, and conflicts of evidence." The inquiry had planned to put "Salmon letters" the letters that witnesses receive before they appear before the inquiry detailing the criticisms they are likely to face on the internet, together with the witness"s response, on the day the witness gave evidence.

This is now being reconsidered. Those whose conduct comes under scrutiny at official inquiries inevitably feel vulnerable, and questions about fairness come with the territory. Britons are used to the adversarial process of court cases and disciplinary hearings by regulatory bodies like the General Medical Council (GMC). Unlike inquiries, however, these have a body of formal precedent laying down strict procedural rules. Court cases and GMC hearings take place in public but few documents are publicly available, and there are tight controls over what evidence can be admitted.

The inquisitorial process of the inquiries often comes as a shock to witnesses, and it is not accompanied by the strict procedural rules that operate in the court system. Though all the inquiry chairmen emphasise that they are not presiding over a court of law, that no one is accused, and that they are merely trying to get at the truth, to the witness whose professional reputation is on the line it can feel like a court of law but without the safeguards.

The internet has also introduced a new element into the equation. Everything is instantly available to the tabloid reporter or to fellow professionals halfway around the globe. The BSE inquiry has posted transcripts of evidence and witness statements on the internet. It also has a library of all its documents which the public can consult. Even documents such as civil service memos, thought when written to be protected by public interest immunity even from scrutiny by a court, are freely available to the public. Extracts have been read out in public, ensuring that they get on the internet.

If the inquiry is being delayed because of the anger and sense of injustice felt by witnesses, can the Bristol inquiry into paediatric heart surgery at Bristol Royal Infirmary, learn anything from the experience of the BSE team?

The Bristol inquiry, which starts on 16 March and is chaired by Ian Kennedy, professor of health law, ethics, and policy at University College London, is going to adopt some of the same procedures as used in the BSE inquiry. There are plans, for example, to put transcripts of evidence and witness statements on the internet.

The Bristol inquiry"s terms of reference go far beyond those of the General Medical Council"s investigation of the case, which itself prompted allegations of unfairness from the doctors" lawyers. The GMC considered only whether two surgeons at Bristol Royal Infirmary and the chief executive of United Bristol Healthcare Trust were guilty of serious professional misconduct, and looked at only 53 paediatric heart operations of two types, in which 29 babies died.

The inquiry will want to identify factors in the running of the hospital and the department which allowed the tragedy to happen. Illuminating evidence may come from three Bristol consultants two cardiologists and an anaesthetist who refused on legal advice to give evidence to the GMC. They will not have that choice at this inquiry because it is a statutory one; it will be convened under section 84 of the National Health Service Act 1977, which gives it the power to compel witnesses to attend, to call for documents, and to imprison anyone who refuses to comply. The inquiry into the personality disorder unit at Ashworth Hospital, chaired by Peter Fallon QC, a retired circuit judge, which reported in January, was also a section 84 inquiry. The BSE inquiry, by contrast, is a non-statutory inquiry, with no powers of compulsion.

In both types of inquiry, most of the decisions about how to proceed are taken by the inquiry panel, and particularly the chairman. The Bristol inquiry, for example, has still not finalised its thinking on Salmon letters. It has not yet decided which witnesses should receive them and how they should be framed, both being issues fraught with difficulty.

A recent comment from a spokesman for the Bristol inquiry suggests that its members are aware of the delicate nature of its work and the tightrope that it is going to have to walk. The spokesman said: "Lord Justice Scott [chairman of the inquiry investigating the sale of arms to Iraq] criticised Salmon letters as excessively adversarial. Ours is an inquisitorial process. At the same time there has to be a commitment to fairness."

Whether the present furore over the BSE inquiry will provide lessons for the Bristol inquiry team remains to be seen.

"Ours is an inquisitorial process. At the same time there has to be a commitment to fairness"

############ http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############

Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

Location: Virus and Prion Research

Title: Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

Author item Moore, Sarah item Kunkle, Robert item Kondru, Naveen item Manne, Sireesha item Smith, Jodi item Kanthasamy, Anumantha item West Greenlee, M item Greenlee, Justin

Submitted to: Prion Publication Type: Abstract Only Publication Acceptance Date: 3/15/2017 Publication Date: N/A Citation: N/A Interpretive Summary:

Technical Abstract: Aims: Chronic wasting disease (CWD) is a naturally-occurring, fatal neurodegenerative disease of cervids. We previously demonstrated that disease-associated prion protein (PrPSc) can be detected in the brain and retina from pigs challenged intracranially or orally with the CWD agent. In that study, neurological signs consistent with prion disease were observed only in one pig: an intracranially challenged pig that was euthanized at 64 months post-challenge. The purpose of this study was to use an antigen-capture immunoassay (EIA) and real-time quaking-induced conversion (QuIC) to determine whether PrPSc is present in lymphoid tissues from pigs challenged with the CWD agent.

Methods: At two months of age, crossbred pigs were challenged by the intracranial route (n=20), oral route (n=19), or were left unchallenged (n=9). At approximately 6 months of age, the time at which commercial pigs reach market weight, half of the pigs in each group were culled (<6 challenge="" groups="" month="" pigs="" remaining="" the="">6 month challenge groups) were allowed to incubate for up to 73 months post challenge (mpc). The retropharyngeal lymph node (RPLN) was screened for the presence of PrPSc by EIA and immunohistochemistry (IHC). The RPLN, palatine tonsil, and mesenteric lymph node (MLN) from 6-7 pigs per challenge group were also tested using EIA and QuIC.

Results: PrPSc was not detected by EIA and IHC in any RPLNs. All tonsils and MLNs were negative by IHC, though the MLN from one pig in the oral <6 5="" 6="" at="" by="" detected="" eia.="" examined="" group="" in="" intracranial="" least="" lymphoid="" month="" months="" of="" one="" pigs="" positive="" prpsc="" quic="" the="" tissues="" was="">6 months group, 5/6 pigs in the oral <6 4="" and="" group="" months="" oral="">6 months group. Overall, the MLN was positive in 14/19 (74%) of samples examined, the RPLN in 8/18 (44%), and the tonsil in 10/25 (40%). Conclusions:

This study demonstrates that PrPSc accumulates in lymphoid tissues from pigs challenged intracranially or orally with the CWD agent, and can be detected as early as 4 months after challenge.

CWD-infected pigs rarely develop clinical disease and if they do, they do so after a long incubation period. This raises the possibility that CWD-infected pigs could shed prions into their environment long before they develop clinical disease.

Furthermore, lymphoid tissues from CWD-infected pigs could present a potential source of CWD infectivity in the animal and human food chains.

https://www.ars.usda.gov/research/publications/publication/?seqNo115=337105

CONFIDENTIAL

EXPERIMENTAL PORCINE SPONGIFORM ENCEPHALOPATHY

While this clearly is a cause for concern we should not jump to the conclusion that this means that pigs will necessarily be infected by bone and meat meal fed by the oral route as is the case with cattle. ...

http://web.archive.org/web/20031026000118/www.bseinquiry.gov.uk/files/yb/1990/08/23004001.pdf

we cannot rule out the possibility that unrecognised subclinical spongiform encephalopathy could be present in British pigs though there is no evidence for this: only with parenteral/implantable pharmaceuticals/devices is the theoretical risk to humans of sufficient concern to consider any action.

http://web.archive.org/web/20030822031154/www.bseinquiry.gov.uk/files/yb/1990/09/10007001.pdf

 Our records show that while some use is made of porcine materials in medicinal products, the only products which would appear to be in a hypothetically ''higher risk'' area are the adrenocorticotrophic hormone for which the source material comes from outside the United Kingdom, namely America China Sweden France and Germany. The products are manufactured by Ferring and Armour. A further product, ''Zenoderm Corium implant'' manufactured by Ethicon, makes use of porcine skin - which is not considered to be a ''high risk'' tissue, but one of its uses is described in the data sheet as ''in dural replacement''. This product is sourced from the United Kingdom.....

http://web.archive.org/web/20030822054419/www.bseinquiry.gov.uk/files/yb/1990/09/21009001.pdf

 snip...see much more here ;

WEDNESDAY, APRIL 05, 2017

Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease

http://chronic-wasting-disease.blogspot.com/2017/04/disease-associated-prion-protein.html

*** U.S.A. 50 STATE BSE MAD COW CONFERENCE CALL 

Jan. 9, 2001 

[host Richard Barns] and now a question from Terry S. Singeltary of CJD Watch.

[TSS] yes, thank you, U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[no answer, you could hear in the back ground, mumbling and 'we can't. have him ask the question again.]

[host Richard] could you repeat the question?

[TSS] U.S. cattle, what kind of guarantee can you give for serum or tissue donor herds?

[not sure whom ask this] what group are you with?

[TSS] CJD Watch, my Mom died from hvCJD and we are tracking CJD world-wide.

[not sure who is speaking] could you please disconnect Mr. Singeltary

[TSS] you are not going to answer my question?

[not sure whom speaking] NO 

SNIP...read full transcript and history here;

http://tseac.blogspot.com/2011/02/usa-50-state-bse-mad-cow-conference.html

TUESDAY, JULY 18, 2017 

USDA announces Alabama case of Bovine Spongiform Encephalopathy Alabama

http://bovineprp.blogspot.com/2017/07/usda-announces-alabama-case-of-bovine.html

THURSDAY, JULY 20, 2017 

USDA OIE Alabama Atypical L-type BASE Bovine Spongiform Encephalopathy BSE animal feeds for ruminants rule, 21 CFR 589.200

http://bovineprp.blogspot.com/2017/07/usda-oie-alabama-atypical-l-type-base.html

SUNDAY, JULY 30, 2017 

Do we need to explain the occurrence of atypical scrapie?

http://nor-98.blogspot.com/2017/07/do-we-need-to-explain-occurrence-of.html

TUESDAY, JULY 18, 2017 

MINK FARMING USA TRANSMISSIBLE MINK ENCEPHALOPATHY TSE PRION DISEASE SURVEILLANCE AND TESTING

http://transmissible-mink-encephalopathy.blogspot.com/2017/07/mink-farming-usa-transmissible-mink.html

http://transmissible-mink-encephalopathy.blogspot.com/

WEDNESDAY, APRIL 05, 2017 

Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease 

http://chronic-wasting-disease.blogspot.com/2017/04/disease-associated-prion-protein.html 

TUESDAY, APRIL 18, 2017 

*** EXTREME USA FDA PART 589 TSE PRION FEED LOOP HOLE STILL EXIST, AND PRICE OF POKER GOES UP *** 

http://usdameatexport.blogspot.com/2017/04/extreme-usa-fda-part-589-tse-prion-feed.html 

WEDNESDAY, JULY 26, 2017 

APHIS USDA Emerging Animal Disease Preparedness and Response Plan July 2017

http://animalhealthreportpriontse.blogspot.com/2017/07/aphis-usda-emerging-animal-disease.html

http://equinespongiformencephalopathy.blogspot.com/

http://caninespongiformencephalopathy.blogspot.com/

Article 

Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism

 View ORCID ProfileAbhisek Mukherjee, Diego Morales-Scheihing, Natalia Salvadores, Ines Moreno-Gonzalez, Cesar Gonzalez, View ORCID ProfileKathleen Taylor-Presse, View ORCID ProfileNicolas Mendez, Mohammad Shahnawaz, View ORCID ProfileA. Osama Gaber, View ORCID ProfileOmaima M. Sabek, View ORCID ProfileDaniel W. Fraga, View ORCID ProfileClaudio Soto DOI: 10.1084/jem.20161134 | Published August 1, 2017

ArticleFigures & DataInfoMetrics Preview PDF Abstract

Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP–specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on β cell number and mass. Finally, induction of IAPP deposition and diabetic abnormalities were also induced in vivo by administration of IAPP aggregates prepared in vitro using pure, synthetic IAPP. Our findings suggest that some of the pathologic and clinical alterations of T2D might be transmissible through a similar mechanism by which prions propagate in prion diseases.

Submitted: 19 July 2016 Revision received 24 March 2017 Accepted: 19 June 2017 http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/ This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

View Full Text © 2017 Mukherjee et al.

http://jem.rupress.org/content/early/2017/07/31/jem.20161134

TUESDAY, AUGUST 1, 2017 

Could diabetes spread like mad cow disease?

http://betaamyloidcjd.blogspot.com/2017/08/could-diabetes-spread-like-mad-cow.html

TUESDAY, AUGUST 1, 2017 

Could Insulin be contaminated with and potentially spread, Transmissible Spongiform Encephalopathy TSE Prion, what if?

http://bovineprp.blogspot.com/2017/08/could-insulin-be-contaminated-with-and.html

Terry S. Singeltary Sr.