Volume 7: Medicines and Cosmetics
2. The operation of medicines licensing
The licensing regime for human and veterinary medicinal products
Which products required a product licence?
Who granted a licence?
Advice to the Licensing Authority
Licences for medicinal products
How did the UK licensing regime interact with European regulation?

Which products required a product licence?

2.7 We have noted that a 'medicinal product' could not be sold or supplied except in accordance with a product licence. ¹ Medicinal products were defined as substances or articles, not being instruments, apparatuses or appliances, for use wholly or mainly by being administered to human beings or animals for medicinal purposes. ² Medicinal purposes are: ³

a. treating or preventing disease;

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

c. contraception;

d. including ⁴ anaesthesia;

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

2.8 The Medicines Act and regulations made under it also placed licensing requirements on certain other substances that fell outside this definition. These included: 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. ⁵

2.9 Conversely, certain products and substances that did fall within the definition of medicinal products were excluded from the licensing requirements of the Act. For example, the sale of medicinal products intended for human use as foods or cosmetics was excluded, subject to certain qualifications. ⁶ Also excluded were: medicines made, or imported, for particular patients, sometimes referred to as 'specials'; ⁷ in certain circumstances, herbal remedies; and, from 1994, homeopathic medicinal products granted a certificate of registration. ⁸ Prior to 1994 homeopathic products that satisfied the definition of a medicinal product in the Medicines Act were subject to its licensing requirements. ⁹

2.10 Various products fell 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 were regulations governing whether such products were to be treated as medicinal products or not. A key factor was whether they were sold 'with indications', ie, specified their use in treating a particular condition.

2.11 As we have noted above, medical devices, being instruments, apparatus or appliances, did not fall within the definition of medicinal products and were not included in the licensing regime. (Medical devices are discussed at paragraph 2.116 below.)

Who granted a licence?

2.12 Responsibility for the granting, renewal, variation, suspension and revocation of licences was given by the Medicines Act to the 'Licensing Authority'. Under the Act '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, comprised the Licensing Authority, ¹⁰ although any one of them acting alone was permitted to perform its functions. ¹¹

2.13 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. ¹² Similarly, the functions of the Licensing Authority in relation to medicines for animals were performed by the Minister of Agriculture, Fisheries and Food.

2.14 During the BSE period, although formally the Secretary of State for Health acted as the Licensing Authority for human medicines, in practice his or her functions were delegated to officials working in the Medicines Division of DH (and, after April 1989, officials working for the Medicines Control Agency (MCA)), subject to the normal legal principles relating to the extent to which ministerial functions may be delegated. ¹³ Similar arrangements were in place in MAFF. ¹⁴

2.15 We discuss later in this chapter the way in which those officials operated the licensing regime. The arrangements meant that product licences were physically granted by officials, not by the Minister. The constitutional convention whereby Ministers are accountable to Parliament for their own actions and also for those of their officials is discussed in vol. 15: Government and Public Administration.

Advice to the Licensing Authority

2.16 The Licensing Authority received advice from a number of sources.

Medicines Commission

2.17 The Medicines Act 1968 required that Ministers establish a Medicines Commission, made up of professionals with 'wide and recent experience' in the practice of medicine and pharmacy. ¹⁵ The Commission was required to advise the Ministers making up the Licensing Authority on matters relating to the execution of the Act and on medicines generally where the Commission considered it expedient or when requested by Ministers. It also acted as an appeal body in respect of advice given to the Licensing Authority by the section 4 committees (see below).

Section 4 committees

2.18 Under section 4 of the Medicines Act, Ministers had power to establish committees (known as 'section 4 committees') for any purpose connected with the execution of the Act, after having regard to recommendations of the Medicines Commission and after consultation with appropriate organisations. ¹⁶ The Medicines Commission had a specific duty to advise Ministers with regard to the number of section 4 committees, and to recommend appropriate membership. ¹⁷

2.19 Section 4 committees were established 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;

b. promoting the collection and investigation [of] information relating to adverse reactions, for the purpose of enabling such advice to be given. ¹⁸

2.20 At the time that BSE first came to be considered there existed a well-established network of section 4 committees. These advised on a wide range of different areas of medicines licensing and some took further advice from specialist subcommittees. The following committees gave consideration to BSE:

2.21 The Veterinary Products Committee (VPC): The terms of reference of the committee reflected the purposes described above, requiring it to advise on the 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 Act was applicable; and to promote the collection of information related to suspected adverse reactions for the purpose of enabling such advice to be given. ¹⁹

2.22 No subcommittee was established by the VPC to deal with BSE issues.

2.23 The Committee on the Dental and Surgical Materials (CDSM): This committee advised on questions of the safety, quality and efficacy of dental and surgical materials.

2.24 The Committee on the Review of Medicines (CRM): This committee was established to review the safety, quality and efficacy of medicines that had been on the market before the Medicines Act introduced licensing requirements. ²⁰ At that time these products were granted licences of right (see below). ²¹

2.25 The Committee on Safety of Medicines (CSM): The CSM advised on questions of the safety, quality and efficacy of human medicines that fell outside the remit of the CDSM and the CRM. Of the subcommittees reporting to the CSM those relevant to BSE were the Biologicals Sub-Committee (BSC) and, after its establishment in 1989, the BSE Working Group (described in Chapter 6).

2.26 The Licensing Authority was required to consult the relevant section 4 committee (or if there was none, the Medicines Commission) in certain circumstances, for example, where it was minded to refuse an application for a product licence ²² or to suspend, vary or revoke a licence ²³ (see below). Otherwise officials had a discretion whether to seek advice from section 4 committees in relation to any particular product.

2.27 Dr David Jefferys, Principal Medical Officer, told us:

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. ²⁴

Chief Medical Officer and Chief Veterinary Officer

2.28 We describe in vol. 15: Government and Public Administration the role and responsibilities of the Chief Medical Officer (CMO) and the Chief Veterinary Officer (CVO). 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. ²⁵

2.29 The CMO also had ultimate line management responsibility for the medical and scientific staff in DH. The CVO, a Grade 3+ official, was the chief adviser for veterinary policy for Great Britain as a whole. The CMO played a significant part in the events we describe in the following chapters, the CVO a lesser role.

National Institute for Biological Standards and Control

2.30 Another body that had a role in the BSE story in relation to medicines was the National Institute for Biological Standards and Control (NIBSC). It was established under the Biological Standards Act 1975 in order to secure high standards of quality, safety, efficacy and consistency of biological substances ²⁶ used in medicines. In fulfilling this role it devised standards for the quality, purity and potency of biological substances, tested batches of biological products on behalf of DH, carried out research and advised a number of bodies, including Medicines Division of DH and its section 4 committees. NIBSC staff were members of the BSC/CSM and of the BSE Working Group. ²⁷ The Central Veterinary Laboratory (CVL), rather than the NIBSC, carried out tests on veterinary biologicals. ²⁸

Licences for medicinal products

2.31 Prior to the introduction of a licensing regime by the Medicines Act 1968, manufacturers of medicines had been able to market products without having to satisfy an independent body as to their safety, quality and efficacy. However, from 1 September 1971, when the relevant provisions of the Act came into force, all medicines had to be licensed before they could be sold or supplied in the UK. ²⁹

2.32 Manufacturers of medicinal products that had been on the market before 1 September 1971 were able to apply for a Product Licence of Right (PLR) to which they were entitled, subject to certain conditions. ³⁰

2.33 As we noted above, human medicinal products with a PLR were to be reviewed for their safety, quality and efficacy by the CRM. This involved some 39,000 products. The VPC carried out a parallel review in relation to veterinary medicines and in 1988, 2,600 veterinary medicines were still to be reviewed. This review process became mandatory when the UK joined the EC in 1973 and its completion was required by May 1990. ³¹ These reviews placed a large extra burden on medicines licensing in both MAFF and DH at the time that consideration of BSE was being undertaken. ³²

2.34 Professor Lawson, Chairman of the CRM, told us:

At the completion of the review in 1990, less than 5,300 reviewed licences had been granted. Licences had either been allowed to lapse by companies or were revoked as a result of the review process. ³³

Product licences, clinical trial certificates and animal test certificates

2.35 As noted earlier, section 7 of the Medicines Act prohibited the sale, supply, export or import of a medicinal product except in accordance with a product licence. ³⁴

2.36 Anything done in accordance with a clinical trial certificate (CTC) or animal test certificate (ATC) was exempted from the prohibition set out in section 7. ³⁵ Such certificates might be issued where the Licensing Authority had consented, subject to the provisions of the certificate, to a clinical trial of a particular medicinal product on humans (CTC) or animals (ATC). ³⁶

2.37 Most product licences were held by pharmaceutical manufacturers. However, certain medicinal product licences were held by the Secretary of State for Health and administered on his or her behalf by the Supplies Technology Division (STD) of the NHS Procurement Directorate (PD). These licences were held by the Secretary of State either for strategic reasons, or because there was no commercial interest in the product, eg, drugs for rare diseases, or because a particular statute required it. ³⁷ In February 1989, 33 product licences were held by the Secretary of State for Health. Sixteen of these were antidotes for snake bites and of the remainder eleven were vaccines or biological products. ³⁸

2.38 Mr Burton of STD told the Inquiry:

It was a matter of historical fact that Secretary of State product licences had been held by Supplies and Technology Division ('STD'). Some of these licences related to welfare foods, some had been taken over from the Ministry of Defence and some arose as a result of an expressed public need for pharmaceutical treatments for rare diseases. ³⁹

Granting new licences

2.39 Detailed regulations governed applications for the grant of product licences. Until 1993 these were contained in the Medicines (Applications for Product Licences and Clinical Trial and Animal Test Certificates) Regulations 1971. ⁴⁰ Applicants for a licence were required to give the Licensing Authority particulars of all active constituents, all colouring matter, flavouring agents and perfumes and all other constituents. ⁴¹ They also had to describe the method of manufacture or assembly of the medicinal product, substance or article, ⁴² and the method of manufacture of each active constituent. ⁴³

2.40 In dealing with an application for the grant of a product licence the Licensing Authority was obliged to take into consideration several factors, including 'the safety of medicinal products of each description to which the application relates'. ⁴⁴ Having done so, the Licensing Authority could: ⁴⁵

1. grant a licence containing such provisions as it considered appropriate; or
2. if, having regard to the provisions of the Act and any Community obligation, it considered it necessary or expedient to do so, refuse to grant a licence.

2.41 When a licence application was submitted the administrative divisions responsible for medicines within MAFF and DH, respectively, would first establish that the application was complete. When all necessary information had been received the application would be the subject of assessment by the medical and scientific experts within the Departments.

2.42 We noted above that if the Licensing Authority was minded to refuse a licence on the grounds of its safety, quality or efficacy it had first to consult the appropriate section 4 committee or (if there was no such committee) the Medicines Commission. ⁴⁶ In other cases, officials exercised their discretion as to whether to refer the application to the section 4 committee. If the application was 'simple and satisfactory' it might be granted a product licence at that stage. ⁴⁷ Such 'simple' applications might involve products that were substantially the same as existing products that had been granted licences. Dr Purves, Principal Pharmaceutical Officer in Medicines Division, told us that 'any new developments where there was not a precedent for action taken by the Licensing Authority, would have been taken to the expert committees for their advice'. ⁴⁸

2.43 Even in cases where the section 4 committee had given advice, it was the Licensing Authority itself that was responsible for determining the application in question.

Existing licences: renewal, suspension, revocation and variation

2.44 Product licences were not granted indefinitely; they expired either five years after they were granted or last renewed, or at the end of any shorter period if specified in the licence. ⁴⁹ The licence holder could then apply for the licence to be renewed for a further period of five years and in such cases the Licensing Authority could:

1. renew the licence, with or without modifications;
2. grant a new licence containing such provisions as the Licensing Authority considered appropriate; or
3. if, having regard to the provisions of the Act, it considered it necessary or expedient to do so, refuse to renew the licence or grant a new licence. ⁵⁰

2.45 Before refusing to renew a licence on any grounds relating to 'the safety, quality or efficacy of medicinal products' the Licensing Authority was again obliged to consult the appropriate section 4 committee or (if there was no such committee) the Medicines Commission. ⁵¹

2.46 The Licensing Authority also had power to suspend, revoke or vary the provisions of a product licence on certain specified grounds, which included:

(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; or

(h) that the specification and standards to which medicinal products of any such description are manufactured can no longer be regarded as satisfactory. ⁵²

The Act did not specify the kinds of variation that might be made.

2.47 Except for suspension in a case of urgency, where the Licensing Authority proposed to suspend, revoke or vary a product licence on either of those grounds, they had first to consult the appropriate section 4 committee or, if there was none, the Medicines Commission. ⁵³

2.48 Where it appeared to the Licensing Authority that in the interests of safety it was necessary to suspend a licence with immediate effect, then it might do so for a period of up to three months. ⁵⁴ In such cases, it had to report the suspension to the appropriate section 4 committee, and the usual procedures were then brought into play. ⁵⁵

2.49 Suspension or revocation of a product licence would prevent sale or supply of stocks of the product. ⁵⁶ Dr Rotblat, Senior Medical Officer in Medicines Division, commented on action taken on medicinal products utilising bovine material. She told us that maintaining the vaccination programme:

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. ⁵⁷

2.50 Similarly, if a product licence were varied, sale or supply of stocks that did not comply with the varied licence would be unlawful.

Informal action

2.51 As well as the powers of refusal, suspension, amendment or revocation of a product licence, non-regulatory forms of action were also available to the Licensing Authority. Dr Jefferys told us:

It is important for the Inquiry to understand the distinction between formal regulatory action, such as suspending or revoking a product licence, and informal action, such as the issuing of non-binding guidelines or recommendations. The regulation of medicinal products is effected through a complicated legal framework. This legal framework guides everything that the Licensing Authority and its advisory committees do. Indeed a lawyer attends each meeting of the CSM to advise the Chairman on legal issues. In order to suspend a product licence, which is very rare, a paper has to go to the CSM setting out a risk-benefit analysis of the product in question and the matter then has to go to Ministers. In order to revoke a licence, the Licensing Authority has to make out a case that the risk-benefit ratio for the product concerned is such that it is unsafe (this is a difficult task given that, when the product had been granted a licence it would, by definition, have been found to have proven efficacy). In both such cases the burden of proof is on the Licensing Authority to make out its case. This means that no formal action can be taken against medicinal products unless there is an evidential basis for doing so.

By contrast, informal action, such as the issuing of guidelines or recommendations, depends upon the co-operation of pharmaceutical companies. Such an approach has the added advantage that it invariably produces a quicker result because it involves neither appeals nor legal processes. In the case of BSE, the pharmaceutical companies were happy to co-operate. ⁵⁸

Options available to deal with BSE

2.52 When officials were called upon to respond to the emergence of BSE, they had therefore to consider how to deal with medicinal products with existing product licences, including those that had been granted licences of right, and medicinal products for which a licence was sought, then or in the future.

2.53 For those products that were already licensed, they had power to vary, suspend or revoke the licence, if the conditions set out in the Medicines Act were met. Dr Jefferys pointed out the need for such action to be based on proper evidence. Alternatively, it was open to them to take informal action such as that described by Dr Jefferys.

2.54 For new product licence applications, the implications of BSE could be taken into account in assessing the safety of the product and determining whether it should be granted a licence. Conditions might be imposed on a licence, or a licence might be refused, but again only with a proper evidential basis. Informal guidance was also available in respect of such products.

Adverse reactions

2.55 One of the ways in which the safety of medicinal products that had been licensed was monitored was through the reporting of adverse reactions to them. This was achieved through the 'Yellow Card Scheme', under which doctors, coroners, dentists and pharmacists reported suspected adverse reactions on a voluntary basis, and the pharmaceutical industry reported them under statutory obligations. These adverse reactions were recorded in an adverse drug reactions database, now known as the Adverse Drug Reactions On-Line Information Tracking (ADROIT) database.

2.56 ADROIT records against each product details of active ingredients and of excipients. Reports of suspected adverse reactions are also recorded against the product. Reports are reviewed on a weekly basis to assess the causal relationship between the products and reported reactions and to identify possible risk factors contributing to the occurrence of reactions, for example age or underlying disease. Today, if an ingredient might be implicated in a suspected adverse reaction, ADROIT or the Product Licence User System (PLUS) database, used to record licensing data, can be interrogated to identify other products using such material. When a material is used in the manufacturing process but is not present in the finished product it will not be recorded in either the ADROIT or PLUS databases.

2.57 The Veterinary Medicines Directorate (VMD) also operated a 'Yellow Card Scheme' and reports from vets and from industry of adverse reactions to veterinary medicines were recorded in the Suspected Adverse Reactions Scheme (SARS) database. The VMD Annual Report shows that in 1999 there were 1,600 such reports. Potentially serious reactions are reviewed monthly and quarterly reports of all suspected reactions are provided to the VPC. Searches of the system can provide details of other similar authorised products and their ingredients.

How did the UK licensing regime interact with European regulation?

2.58 EC regulation of both human and veterinary medicinal products was introduced with the adoption of Council Directive 65/65/EEC. ⁵⁹ Its framework was similar to that of the Medicines Act: it was based on the grant of a 'marketing authorisation' by the competent authority of the Member State in question (ie, a decentralised system). 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. ⁶⁰

2.59 When the UK joined the EC, the Medicines Act was already in force and no new legislation was introduced to implement Directive 65/65/EEC. The competent authority of the UK for the purposes of the Directive was the Licensing Authority; the 'marketing authorisation' was the product licence; and applications were dealt with under the mechanisms of the Medicines Act 1968, consistently with the relevant EC rules.

2.60 Additional measures were introduced in 1975 ⁶¹ including mechanisms for the recognition by all Member States of product licences granted by any individual state. The Committee for Proprietary Medicinal Products (CPMP), a scientific committee, was also established; this advises the Commission on issues of safety, quality and efficacy in much the same way as the CSM advises the Licensing Authority in the UK. ⁶² A corresponding body for veterinary medicines, the Committee for Veterinary Medicinal Products (CVMP), was set up in 1981. It performs the same functions in respect of veterinary medicines as does the CPMP for human medicines. ⁶³ The CPMP and CVMP are now part of the European Medicines Evaluation Agency (EMEA), which was established to coordinate the evaluation and supervision of medicinal products in the Member States. ⁶⁴

2.61 The EU Commission publishes 'Guidelines on the quality, safety and efficacy of medicinal products for human use'. Since 1975 applicants for a market authorisation of a new product, in assembling a dossier for application, have been required to 'take into account' such guidance. ⁶⁵