Volume 14: Responsibilities for Human and Animal Health
7. Human and veterinary medicines and cosmetics
Medicinal products: responsibilities
Introduction
The UK Licensing Authority
Advice to the Licensing Authority
Other UK Committees
Executive functions in relation to medicinal products
European responsibilities for medicinal products

Introduction

7.4 The Medicines Act 1968 and European Directives together established a framework of responsibilities and controls for human and veterinary medicinal products. The relevant legislation changed between 1985 and 1996 as a result of the gradual introduction of EC measures, connected with the Single Market, which added to and modified the Medicines Act 1968. The basic framework, however, remained the same.

7.5 The Medicines Act 1968 set out a system under which a Licensing Authority, advised by a Commission and Committees, was responsible for the licensing of human and veterinary medicinal products according to standards set out in the Act and Regulations made under it. The Licensing Authority's key concern was with ensuring the safety, quality and efficacy of medicinal products. ¹

7.6 European regulation of medicinal products had a framework similar to that of the Medicines Act, with control and regulation being achieved through a licensing system. It had two aspects: a decentralised system whereby each Member State provided a licensing regime for medicinal products within its jurisdiction; and, from 1993, a centralised system allowing for EU-wide licences, which were administered by the European Medicines Evaluation Agency (EMEA). European Regulation of medicinal products is outlined in more detail later in this chapter.

7.7 Until 1995, the Medicines Act 1968 and regulations made under it were the primary instruments through which the UK performed its European obligations in relation to medicinal products.

The UK Licensing Authority

7.8 As noted above, under the Medicines Act 1968 responsibility for the grant, renewal, variation, suspension and revocation of licences was given to the Licensing Authority. This comprised 'the Health Ministers' and 'the Agriculture Ministers' - ie, the Secretary of State for Health, the Minister of Agriculture, Fisheries and Food and the corresponding Ministers in Northern Ireland, Scotland and Wales ² - although any one of them acting alone was permitted to perform its functions. ³

7.9 In practice, the functions of the Licensing Authority in relation to medicines for human use in the UK were, throughout the period 1985-96, performed by the Secretary of State for Health. ⁴ Similarly, the functions of the Licensing Authority in relation to medicines for animals were performed by the Minister of Agriculture, Fisheries and Food.

7.10 During the period covered by this Report, the human medicines licensing functions of the Secretary of State for Health were delegated to officials working in the Medicines Division of the Department of Health (DH) or, after April 1989, officials working for the Medicines Control Agency (MCA). This arrangement was, however, subject to the normal legal principles relating to the extent to which ministerial functions may be delegated. ⁵ Similar arrangements were in place in the Ministry of Agriculture, Fisheries and Food (MAFF). This meant that product licences were in practice granted by officials, not by the Minister.

7.11 The Licensing Authority received advice from a number of statutory bodies, most importantly the Medicines Commission and Committees known as section 4 committees (see below).

Advice to the Licensing Authority

Medicines Commission

7.12 Section 2 of the Medicines Act 1968 ⁶ provided for the establishment of the Medicines Commission to advise the Ministers making up the Licensing Authority on matters relating to the execution of the Act or the exercise of any power conferred by it or otherwise relating to medicinal products, where either

1. the Commission considered it expedient; or
2. it was requested by the Minister or Ministers to do so. ⁷

There were to be no fewer than eight members of the Commission, including at least one person having 'wide and recent' experience of each of the following:

1. the practice of medicine (other than veterinary medicine);
2. the practice of veterinary medicine;
3. the practice of pharmacy;
4. chemistry other than pharmaceutical chemistry; and
5. the pharmaceutical industry. ⁸

7.13 The Medicines Commission was also required to recommend to Ministers the number, functions and membership of committees to be set up under section 4 of the Medicines Act (known as 'section 4 committees'), ⁹ and

. . . it also had an important role in one of the stages of the appeal mechanism

in respect of licences for medicinal products. ¹⁰ It was also required to send Ministers an annual report on the performance of its functions. ¹¹

Section 4 committees

7.14 Section 4 committees were established by Ministers to consider particular classes of substances or articles covered by the Act, for the purpose of:

(a) giving advice with respect to the safety, quality or efficacy or with respect to all or any two of those matters; and

(b) promoting the collection and investigation [of] information relating to adverse reactions, for the purpose of enabling such advice to be given. ¹²

7.15 Members of section 4 committees were appointed by Ministers having regard to recommendations made by the Medicines Commission as to their number, function and membership. ¹³ Each Committee was required to send an annual report on the performance of its functions to the Commission and the Ministers. ¹⁴

7.16 During the relevant period, there were five section 4 committees:

1. Committee on Safety of Medicines (CSM);
2. Veterinary Products Committee (VPC);
3. Committee on Dental and Surgical Materials (CDSM);
4. Committee on the Review of Medicines (CRM); and
5. British Pharmacopoeia Commission (BPC).

7.17 A section 4 committee could, with the approval of the Ministers, appoint one or more specialist subcommittees to supply information on all aspects of medicines including chemistry, pharmacy, biologicals, safety and efficacy. The various subcommittees could report to any of the section 4 committees, depending on the nature of the problem they were considering, and there was in practice a great deal of cross-membership between the various committees and subcommittees. ¹⁵ Recommendations made by subcommittees had to be passed on to the relevant section 4 committee and endorsed before officials could act on them. Committee and subcommittee members were part-time independent experts who were paid a nominal fee. ¹⁶

7.18 Dr David Jefferys, a Principal Medical Officer in Medicines Division of DH and then in the Medicines Control Agency, told the Inquiry that:

The Section 4 committees, particularly the Committee on the Safety of Medicines, have a very heavy workload. As a result, the CSM recommended many years ago that a number of advisory subcommittees, such as the Biologicals subcommittee, should be set up.

The subcommittees tend to devote more time to scrutinising the details of issues raised for their consideration whilst the Section 4 committees adopt a more general overview. The subcommittees are generally scheduled to meet approximately two weeks before the meeting of whichever Section 4 committee will ultimately consider the relevant issues.

In practice, there is a considerable overlap between the membership of the Section 4 committees and the membership of their subcommittees. This means that it is not necessary for all disciplines to be represented on a Section 4 committee provided that the relevant expertise is available in the subcommittees. In addition the CSM can ask the Licensing Authority to appoint further experts as 'members for the day' to provide additional expertise. ¹⁷

7.19 The Committee on Safety of Medicines (CSM) was established by the Medicines (Committee on Safety of Medicines) Order 1970 to advise on the safety, quality and efficacy of medicinal products for human use. It had overall responsibility for advising Ministers on the safety, quality and efficacy of human medicines. ¹⁸ It was also required to promote the collection and investigation of information relating to adverse reactions, to enable such advice to be given. During the period covered by this Report, the CSM met once a month; such meetings lasted for one or two days. ¹⁹ The Inquiry was told that the Chairman bore ultimate responsibility for the advice given. ²⁰

7.20 In relation to BSE, the CSM had two key subcommittees: the Sub-Committee on Biologicals, often known as the Biologicals Sub-Committee or BSC, and the BSE Working Group. The BSC's role was to advise the CSM in relation to medicinal products of a biological nature - ie, non-synthetic drugs such as vaccines, blood products, etc. ²¹ The BSE Working Group, on the other hand, was an ad hoc committee specifically set up to deal with BSE. Its role was to advise the section 4 committees on the possible hazards to man of human medicinal products, with special reference to BSE. ²²

7.21 The Veterinary Products Committee (VPC) was established in 1970 to advise on safety, quality and efficacy in relation to the veterinary use of medicinal products. The VPC also promoted the collection of information relating to suspected adverse reactions to enable such advice to be given. ²³ It advised on applications for test licences and product licences for individual veterinary products, and general policy, including guidelines for registration of veterinary medicines.

7.22 The Committee on Dental and Surgical Materials (CDSM) was established by the Medicines (Committee on Dental and Surgical Materials) Order 1975 to advise on the safety, quality and efficacy, for human or animal use, of substances and articles for dental and surgical use, to which the Medicines Act applied and which fell outside of the expertise of the CSM or the VPC. It was also responsible for substances and fluids for use with contact lenses. It had a role, too, in promoting the collection and investigation of information on adverse reactions for the purpose of giving advice. The CDSM was disbanded in 1994. ²⁴

7.23 The Committee on the Review of Medicines (CRM) was established in 1975 under the Medicines Act 1968 to advise on the safety, quality and efficacy of substances and articles that were on the market before the Act came into force and which had been granted 'licences of right' under section 25 of the Act ²⁵ (see below). This amounted to some 30,000 products, the review of which began in 1975. Once its work was completed in 1991, the CRM was disbanded. ²⁶

7.24 The British Pharmacopoeia Commission (BPC) was responsible for preparing new editions of the British Pharmacopoeia and the British Pharmacopoeia (Veterinary) and for keeping these up to date. The British Pharmacopoeias provide authoritative standards for the quality of substances, preparations and articles used in medicine and pharmacy. The BPC was also responsible for maintaining liaison with the European Pharmacopoeia Commission and, under section 100 of the Medicines Act, for the preparation of a list of British-approved names suitable for use as the names of substances and articles. ²⁷ The BPC had no role in relation to BSE.

Chief Medical Officer and Chief Veterinary Officer

7.25 Other advice to Ministers in relation to human and veterinary medicines came from the Chief Medical Officer (CMO) and the Chief Veterinary Officer (CVO). Vol. 15: Government and Public Administration describes the role and responsibilities of each of these officers.

7.26 Briefly, the CMO, a Grade 1A official, was:

. . . 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. ²⁸

7.27 The CMO also had ultimate line-management responsibility for the medical and scientific staff in DH until April 1995.

7.28 Mr Stephen Dorrell, Secretary of State for Health from July 1995 to May 1997, told the Inquiry about the relationship between the advisory Committees and the Chief Medical Officer:

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. ²⁹

7.29 In this context, the Inquiry was also told that while CSM was not responsible under the relevant legislation to the CMO, ³⁰ the practice on all sensitive public health issues was to minute the CMO at the same time as minuting Ministers. ³¹

7.30 The CVO, a Grade 3+ official, was the chief adviser on veterinary policy for Great Britain as a whole. ³²

Other UK Committees

7.31 The Joint Committee on Vaccination and Immunisation (JCVI), a non-departmental public body, was established under the NHS Act 1977 as a Standing Advisory Committee. ³³ Its terms of reference 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. ³⁴

7.32 Professor Alexander Campbell, chairman of the JCVI between April 1989 and May 1996, outlined its role:

The JCVI is an independent committee of experts which gives advice on vaccines and vaccine strategy to the Department of Health. For example, the JCVI makes recommendations on routine childhood and adult immunisation and particular vaccine campaigns which might be required from time to time. Although the committee deals primarily with issues relating to the vaccination of children, it also gives advice on all other issues involving vaccines, such as the protection of travellers. The committee is responsible for a publication entitled 'Immunisation Against Infectious Disease' . . .

. . .

The committee is made up of a number of experts from different fields, in areas such as virology, microbiology, paediatrics, general practice, epidemiology, infectious disease, community health and neurology. In addition, Consultants from the PHLS and members of the National Institute for Biological Standards and Control (NIBSC) usually attend meetings. Experts in a particular field can also be invited to attend as appropriate. ³⁵

7.33 The National Institute for Biological Standards and Control (NIBSC) had the object of securing high standards of quality, safety, efficacy and consistency of biological substances used in medicine. ³⁶ It was a specialist, laboratory-based organisation whose work fell into three main categories:

1. carrying out controls (the testing of the purity and potency of biological medicines prior to their release, on behalf of DH and the MCA and for the EU under European medicines legislation);
2. producing standards (ie, the preparation and evaluation of International and British Standards and Reference Preparations); and
3. research and development (to inform and enable the control and standards activities).

7.34 The NIBSC also had European and World Health Organisation (WHO) functions, and operated as a WHO International Laboratory for Biological Standards. It was overseen by the National Biological Standards Board, established by the Biological Standards Act 1975, and exercised the day-to-day functions of the Board on its behalf. ³⁷

Executive functions in relation to medicinal products

Human medicines

7.35 The executive arm of government responsible for operating the licensing regime for human medicinal products was the Medicines Division of DH and its successor, the Medicines Control Agency (MCA), which became an Executive Agency on 11 July 1991. These bodies carried out the functions of the Licensing Authority in relation to human medicines; ie, the operation of the licensing regime and safeguarding the public health by ensuring that medicines on the UK market met appropriate standards of safety, quality and efficacy. Medicines Division and the MCA provided secretariats for the Medicines Commission and the section 4 committees other than the VPC. They also had responsibilities for monitoring and enforcement in relation to medicinal product licences. The structure and operation of Medicines Division and the MCA are described further in Chapter 2 of vol. 7: Medicines and Cosmetics.

7.36 The recommendation to transform Medicines Division into the MCA came from the Evans-Cunliffe Report in 1987, which was a comprehensive study of the control of human medicines in the UK. ³⁸ The main conclusions of this report ³⁹ were that there were problems within the Medicines Division at that time which needed to be addressed:

Our study suggests that the UK approach to the control of medicines is sound, and the legislative framework satisfactory. Thanks to the contribution of assessors and advisory committees, its intellectual and judgmental qualities stand high. Medicines Division of DHSS has coped quite well with rising workload over a number of years, but is now showing signs of overload with increasing delays and minor documentary errors. 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. ⁴⁰

7.37 Officials in Medicines Division played an important role in the operation of the section 4 committees and their subcommittees. The secretariat of the committee would set the agenda for meetings. The subjects for discussion would generally arise from consideration of licence applications within the Division/Agency. Officials would bear in mind the need for recommendations from subcommittees to come forward to the main committee meetings. Officials were also responsible for preparing the many professional papers for the committee members to read for the meetings. At the meetings themselves, officials would generally not take an active role. However, they were responsible for actioning the advice of the committee and communicating it to others as necessary. This might involve briefing Ministers. ⁴¹

7.38 The Inquiry was told by Professor Asscher, chairman of the CSM, that:

. . . [T]he 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. ⁴²

7.39 In respect of the CSM Biologicals Sub-Committee, the Inquiry was told by its chairman Professor Collee:

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. ⁴³

Veterinary medicines

7.40 Within MAFF, there were until 1989 three bodies involved in the regulation of veterinary medicines. The Animal Health Division III/Animal Medicines Division, part of the Animal Health Group, was responsible for policy matters relating to veterinary medicines. The Medicines Unit at the Central Veterinary Laboratory (CVL) was responsible for the assessment of non-biological products and provided the administrative staff who formed the secretariat of the VPC. The Biological Products and Standards Department (BP&S), also part of CVL, was responsible for the assessment of applications for immunological veterinary medicines and inspections of their manufacturing premises.

7.41 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 Veterinary Medicines Directorate (VMD), which became an Executive Agency on 2 April 1990. The VMD was responsible for all aspects of licensing and control of animal medicines and medicated feedstuffs, for monitoring and controlling veterinary residues in animal products, and for monitoring suspected adverse reactions. ⁴⁴ The structure and operation of the bodies in MAFF responsible for veterinary medicines and the VMD are outlined further in Chapter 2 of vol. 7: Medicines and Cosmetics.

7.42 The establishment of the VMD had been recommended in a report in early 1988 entitled Review of Animal Medicines Licensing, ⁴⁵ which was prepared shortly after the Evans-Cunliffe Report on the licensing arrangements for human medicines. Its conclusions are set out in more detail in vol. 7: Medicines and Cosmetics. In summary, it emphasised that there was

little criticism of the general concept and indeed of the general correctness of decisions but considerable criticism of the operation of the system. ⁴⁶

7.43 It recommended better use of information technology; simplification of procedures and removal of unnecessary work; better communications between applicants and the licensing operation; improvements in staff recruitment, remuneration and management; and improved organisational structures. ⁴⁷

7.44 The secretariat of the VPC was provided by the Medicines Unit at the Central Veterinary Laboratory and then by the VMD. It set the agenda, provided papers and produced minutes of meetings, just as Medicines Division/MCA did for the committees considering human medicines.

7.45 Professor Armour, chairman of the VPC, told the Inquiry:

Of the licence applications received by the Medicines Unit/VMD, the VPC was asked to advise on approximately 30%. These were all novel substances or those where there might be a perceived problem. Otherwise, applications were dealt with by the Medicines Unit, CVL and later the VMD and a list of processed applications was provided to the VPC for information. All applications containing novel substances were seen in detail, as were all recommended for refusal. General policy matters were all presented for review and advice. At quarterly intervals a paper on all reported adverse reactions to licensed veterinary medicines was presented to VPC. ⁴⁸

7.46 The assessment work of the +VMD was supported by two non-statutory committees of officials, the Scientific Secretariat (for pharmaceutical products) and the Biologicals Committee (for immunological products). ⁴⁹ The meetings of these committees were attended only by officials and not by members of the VPC. ⁵⁰ Mr Alastair Kidd, Director of Licensing at the VMD, explained their operation:

At monthly meetings the Biologicals Committee and Scientific Secretariat considered licence applications for veterinary biological and pharmaceutical products respectively and the assessment reports of BP&S and Medicines Unit staff. The Scientific Secretariat of the VPC drew its members from a variety of sources including the Medicines Division of the Department of Health, and toxicologists from the Department of Health and from the Chemical Division of Porton Down. As far as the Biologicals Committee was concerned, the Department of Health was not represented and any contact with the Department of Health was on an informal basis. However, as technical documents were invariably submitted to the VPC, Department of Health officials were fully informed through their presence at VPC meetings and were able to comment or pass papers on to appropriate colleagues. The Biologicals Committee/Scientific Secretariat subsequently made recommendations as to whether a product authorisation should be granted or not. The comments of the appropriate committee were incorporated into the reports prior to assessment of licence applications by the VPC. ⁵¹

European responsibilities for medicinal products

The European Medicines Evaluation Agency

7.47 The centralised European licensing system was administered by the European Medicines Evaluation Agency (EMEA), which was set up in 1993 at the same time as the system for which it was responsible. ⁵² The EMEA consisted of the Committee for Proprietary Medicinal Products (CPMP), the Committee for Veterinary Medicinal Products (CVMP), a secretariat, an executive director and a management board. ⁵³

The CPMP and the CVMP

7.48 The CPMP was initially established in 1975 by Council Directive 75/319/EEC to advise the European Commission on issues of safety, quality and efficacy in relation to human medicinal products. ⁵⁴ It did so in much the same way as the CSM advises the Licensing Authority in the UK. ⁵⁵

7.49 A corresponding body for veterinary medicines, the CVMP, was set up in 1981 by Council Directive 81/851/EEC. It performs the same functions in respect of veterinary medicines as the CPMP performs for human medicines. ⁵⁶ As noted above, both of these committees now come under the umbrella of the EMEA.

7.50 These scientific committees, comprising two appropriately qualified members nominated by each Member State, ⁵⁷ were the mechanisms through which Member States had input into the licensing process. ⁵⁸ The members of the committees were required to ensure that there was appropriate coordination between the tasks of the EMEA and the work of the licensing authorities of individual Member States and their consultative bodies.

7.51 The CPMP and CVMP were able to establish working parties and expert groups to assist them. ⁵⁹ Dr John Purves of the UK Medicines Control Agency was a member of the ad hoc Working Party on Biotechnology/Pharmacy reporting to the CPMP, and Dr Geoffrey Schild of the NIBSC was chairman of this same group from 1986 until 1991. ⁶⁰ Dr A Lee of the Veterinary Medicines Directorate was the UK member of the Immunologicals Working Party of the CVMP. ⁶¹

7.52 In relation to BSE, both the CPMP and the CVMP issued guidelines entitled 'Minimising the Risk of Transmitting Agents Causing Spongiform Encephalopathy via Medicinal Products' in 1992 and 1993 respectively. ⁶² These are considered further in Chapter 6 of vol. 7: Medicines and Cosmetics.