Volume 14: Responsibilities for Human and Animal Health
7.
Human and veterinary medicines and cosmetics
Medicinal products: the licensing regime
Products covered under the Act
Licensing medicinal products
Monitoring, inspection and enforcement
Non-statutory controls
Restrictions on disclosure of information
EC regulation and its implementation into UK law
Products covered under the Act
7.53 The Medicines Act 1968 imposed licensing requirements on dealing in and manufacture of 'medicinal products', 1 which were defined as substances or articles, not being instruments, apparatus or appliances, for use wholly or mainly by being administered to human beings or animals for medicinal purposes. 2 'Medicinal purposes' included treating or preventing disease, diagnosing disease or ascertaining the existence, degree or extent of a physiological condition, and otherwise preventing or interfering with the normal operation of a physiological function. 3
7.54 The Medicines Act and Regulations made under it also placed licensing requirements on certain other substances that fell outside the definition of a medicinal product. 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. 4
7.55 Medical devices, being instruments, apparatus or appliances, did not fall within the definition of medicinal products and are discussed separately later in this chapter.
7.56 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. 5 A key factor was whether they were sold 'with indications', ie, specifying their use in treating a particular condition. They were also assessed with regard to their ingredients and function, and presentation to the public through labelling, packaging, advertising and promotion.
7.57 Certain products and substances, which did fall within the definition of medicinal products, were nonetheless excluded from the licensing requirements of the Act. Generally, they were covered under other regulatory regimes. The sale of medicinal products intended for human use as foods or cosmetics was excluded, subject to certain very specific qualifications. 6 Also excluded were: medicines made, or imported, for particular patients, sometimes referred to as 'specials'; herbal remedies under certain specified circumstances; and, from 1994, homeopathic medicinal products granted a certificate of registration. 7
Licences
7.58 The Medicines Act 1968 prohibited:
of a medicinal product, except in accordance with:
The Inquiry was primarily concerned with product licences, since it was products that contained bovine material which were relevant to the BSE story.
7.59 Before the introduction of this licensing regime, 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. 8
7.60 The licensing application provisions did not affect those engaged in selling, supplying, manufacturing, or assembling medicinal products that were on the market as at 1 September 1971. Such people could apply instead for a 'licence of right'. They would then be entitled to the grant of a product licence, subject to certain conditions. 9 The closing date for applications for a licence of right was 1 July 1972. 10 The transitional provisions in the Medicines Act, with two exceptions, expired on 1 September 1972. 11
7.61 A review of the safety, quality and efficacy of medicinal products granted product licences of right (PLRs) became mandatory when the UK joined the EC in 1973, with the review to be completed by 1990. 12 The CRM was set up in 1975 to review human medicinal products and the VPC carried out a parallel review of veterinary medicinal products.
Making and processing of licence applications
7.62 Applications for product licences were governed by the Medicines (Applications for Product Licences and Clinical Trial and Animal Test Certificates) Regulations 1971. 13 In relation to human medicines, these were superseded by the Medicines (Applications for Grant of Product Licences - Products for Human Use) Regulations 1993. 14 In essence, with an application for a product licence the applicant was required to submit the following data in full:
Qualitative and quantitative particulars of the constituents of the product;
Description of the method of preparation;
Therapeutic indications/contra-indications and side effects;
Posology (dosage), pharmaceutical form, method and route of administration and expected shelf-life;
Description of the control methods employed by the manufacturer;
Results of the physico-chemical, biological or microbiological tests, pharmacological and toxicological tests and clinical trials; and
Pre-clinical and clinical data. 15
7.63 Results of clinical trials were an important part of any product licence application. Clinical trials on humans or animals were investigations involving the administration of a medicinal product to one or more patients to assess its safety and efficacy. 16 Where the clinical trials for a particular medicinal product had been carried out in the UK, the trials themselves required an authorisation from the licensing authority. A Clinical Trial Certificate (CTC) for trials on humans or an Animal Test Certificate (ATC) for trials on animals could be issued where the licensing authority had consented - subject to the provisions of the certificate - to a clinical trial of a particular medicinal product. 17 However, the Licensing Authority could exempt a medicinal product from having to undergo clinical trials, by issuing a Clinical Trial Exemption Certificate (CTX).
7.64 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 the required information had been received, the application would be assessed by the medical and scientific experts within the Departments or, in the case of products to be licensed under the EC system, by assessors from two Member States nominated by the EMEA.
7.65 In assessing applications for product licences, particular consideration was given to the product's safety, quality and efficacy. Manufacturer's licence applications were assessed taking particular account of
An initial inspection lasting about three days was carried out to assess whether the manufacturer had the appropriate staff, facilities, systems and organisation to manufacture medicinal products consistently to the required quality. 18
7.66 Wholesale dealers were licensed with particular regard to the premises, equipment and record-keeping to be used for storage and distribution. 19
Granting new licences
7.67 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'. 20 Having done so, the Licensing Authority could:
- grant a licence containing such provisions as it considered appropriate; or
- 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. 21
7.68 If the Licensing Authority was minded to refuse a licence on the grounds of the product's safety, quality or efficacy, it had first to consult the appropriate section 4 committee or (if there was no such committee) the Medicines Commission. 22
7.69 In other cases, officials exercised their discretion about 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. Such 'simple' applications might involve products that were substantially the same as existing products that had been granted licences. Dr Purves of the MCA told the Inquiry 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. 23
7.70 However, even in cases where the section 4 committee had given advice, it was the Licensing Authority itself, not the committee, that was responsible for determining the application in question.
7.71 The Inquiry heard that decisions regarding the granting of licences were generally not referred to Ministers. When giving oral evidence, Mrs Edwina Currie, Parliamentary Under-Secretary for Health between 1986 and 1988, was asked:
Q: . . . medicinal products are licensed under the Medicines Act and there is a licensing authority so that basically you leave it to them. Would that be a fair way of putting it?
A: That would be right; but also it reflected considerable confidence in the way that system worked. It worked very well. 24
7.72 Mrs Virginia Bottomley, Secretary of State for Health between 1992 and 1995 told the Inquiry:
The process of the licensing of medicines was the territory of a number of highly qualified and highly regarded experts in that team. They, I think quite jealously, preserved that territory. Matters would be raised with Ministers if they were likely to cause public concern, if there was an issue that - if there was a problem, essentially, if the authority of the Minister was necessary. But for the most part they sought, I think, to consume their own smoke and deliver their objectives. 25
Existing licences: renewal, suspension, revocation and variation
7.73 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. 26 The licence holder could then apply for the licence to be renewed for a further period of five years. In such cases, the Licensing Authority could:
- renew the licence, with or without modifications;
- grant a new licence containing such provisions as the Licensing Authority considered appropriate; or
- 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. 27
7.74 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. 28
7.75 Under section 28 of the 1968 Act, the Licensing Authority also had power to suspend, revoke or vary the provisions of a product licence on certain specified grounds. These included:
(b) that any of the provisions of the licence has to a material extent been contravened by the holder of the licence or by a person procured by him to manufacture or assemble medicinal products of a description to which the licence relates;
. . .
(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; and
(h) that the specification and standards to which medicinal products of any such description are manufactured can no longer be regarded as satisfactory. 29
The Act did not specify the kinds of variation that might be made.
7.76 Except for suspension in a case of urgency, if the Licensing Authority proposed to suspend, revoke or vary a product licence on the grounds set out in paragraphs (g) or (h) of section 28(3), they had first to consult the appropriate section 4 committee or, if there was none, the Medicines Commission. 30 Schedule 2 of the Act gave the licence holder a right to be heard and a right of appeal where the Licensing Authority proposed to revoke, suspend or vary a licence.
7.77 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. 31 In such cases, it had to report the suspension to the appropriate section 4 committee, and the usual consultation and notification procedures were then brought into play, as appropriate. 32
Monitoring, inspection and enforcement
Introduction
7.78 Responsibility for monitoring, inspection and enforcement of the Medicines Act fell to the executive bodies responsible for medicinal product; ie, the MCA in relation to human medicines and the VMD for veterinary medicines. 33 Some of the avenues through which these tasks were carried out are summarised below.
7.79 After a product had received a licence, these bodies monitored its use throughout its life through 'pharmacovigilance' - ie, the process of monitoring a medicinal product on the market. This included: monitoring of adverse drug reactions; inspection of manufacturing sites; quality analysis of samples of marketed products; and enforcement of standards. 34
7.80 Under the European system, pharmacovigilance, inspection and enforcement activities remained the responsibility of Member States.
Adverse reactions
7.81 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 the MCA or the VMD. This was achieved through the 'Yellow Card Scheme', under which doctors, coroners, dentists, pharmacists and vets reported suspected adverse reactions on a voluntary basis, and the pharmaceutical industry reported them under statutory obligations.
7.82 For human medicines, these adverse reactions were recorded in what is now known as the Adverse Drug Reactions On-Line Information Tracking (ADROIT) database. ADROIT recorded against each product details of active ingredients, excipients, and reports of suspected adverse reactions. Such reports were 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. It is now possible, if an ingredient can be implicated in a suspected adverse reaction, to interrogate ADROIT or the Product Licence User System (PLUS) 35 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 is not recorded in either ADROIT or PLUS.
7.83 For veterinary medicines, reports of adverse reactions were recorded in the Suspected Adverse Reactions Scheme (SARS) database. Potentially serious reactions were reviewed monthly, and quarterly reports of all suspected reactions were provided to the VPC. Searches of the system could provide details of other similar authorised products and their ingredients.
7.84 The MCA also operated a Medicines Testing Scheme under which products already on the market were subjected to analytical quality examination. It also operated a 24-hour per day Defective Medicines Report Centre so that action could be taken in respect of faulty batches of medicines reaching the market. 36
Inspections
7.85 Inspections were carried out to ensure that manufacturers had the appropriate staff, facilities, systems and organisation to manufacture medicinal products consistently to the required quality. An inspection was conducted initially to assess an applicant for a manufacturer's licence and thereafter every two years to ensure continued compliance with good manufacturing practice (GMP). An inspection lasted on average three days and examined a selection of the premises, processes, procedures and records chosen by the inspector to enable him or her to come to a view on the general compliance with GMP. 37
7.86 An inspection could also look at other licensing concerns such as compliance with individual product specifications or processes. However, the primary responsibility for ensuring that an individual product was made in accordance with its licence lay with the manufacturer. 38 A manufacturer was required to have at its disposal a qualified person who was personally responsible for ensuring that medicinal products produced by the manufacturer complied with the product licence and relevant laws. 39 Inspections included an assessment of the systems used by the manufacturer to meet these responsibilities and of the manner in which the qualified person discharged his or her specified duties. 40
Enforcement
7.87 Where issues relating to product standards, manufacturing standards and storage requirements arose, the primary tool for achieving compliance available to the Licensing Authority was the risk or possibility of the relevant licence being withdrawn. 41
7.88 Where a product did not comply with the terms of the licence issued, action could be taken by the Licensing Authority to remove it from the market. For example, the licence could be suspended or revoked. There was no express power of recall in the Act but, if a licence was suspended or revoked, it would be an offence to supply the product and therefore in practice existing stocks could not be used.
7.89 As well as the Licensing Authority's powers to take licensing action in relation to medicinal products, there were powers of enforcement under Part VIII of the 1968 Act in respect of breaches of various provisions of the Act relating to the sale of medicinal products to consumers. Enforcement was the duty of the Secretaries of State for Health and for Scotland, and of the Health Minister in Wales and the Minister of Health and Social Services for Northern Ireland. 42 However, some duties fell to the Pharmaceutical Society or local authorities 43 or both, concurrently with the appropriate Minister. 44 The enforcement powers available to Ministers or the Pharmaceutical Society or local authorities included rights of entry 45 and powers to inspect, take samples and seize goods and documents. 46
7.90 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 of the MCA told the Inquiry:
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. 47
7.91 In relation to BSE, joint CSM/VPC guidelines were issued to manufacturers of medicinal products in March 1989. The implementation and effectiveness of these guidelines are discussed in vol. 7: Medicines and Cosmetics.
Restrictions on disclosure of information
7.92 Under section 118 of the Medicines Act it is an offence to disclose any information about manufacturing processes or trade secrets obtained by or supplied in pursuance of the Act, or obtained in premises by virtue of the Act's entry powers, unless the disclosure is made in the performance of duties.
EC regulation and its implementation into UK law
Decentralised system
7.93 European regulation of medicinal products was introduced with the adoption of Council Directive 65/65/EEC. 48 The system was based on the grant of a marketing authorisation 49 by the competent authority of the Member State in question (ie, a decentralised system). It provided that no proprietary medicinal product within the scope of the Directive could be placed on the market in a Member State unless the competent authority of that Member State had issued an authorisation. 50 Subsequent Directives introduced licensing requirements for medicinal product manufacturers and wholesalers. 51
7.94 Directive 65/65/EEC applied to proprietary medicinal products, defined in Article 1(1) as 'Any ready prepared medicinal product placed on the market under a special name and in a special pack'. From 1 January 1992 the scope of the EC scheme was widened by Directive 89/341/EEC to apply to all industrially-produced medicinal products. 52
7.95 As noted above, the Medicines Act 1968 and Regulations made under it were the primary instruments through which the UK performed its European obligations under this decentralised system. 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 65/65/EEC 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. The Medicines Act covered many of the areas in which new EC regulation was introduced and amendments were often minor.
Centralised system
7.96 In addition to the decentralised system, Council Regulation 2309/93 53 introduced a central Community procedure for authorisation and supervision of human and veterinary medicinal products. This provided a single marketing authorisation to market a product in all Member States of the European Union and was administered by the European Medicines Evaluation Agency (EMEA). Currently, the procedure is compulsory for products listed in part A of the Annex to the Regulation, which include technologically-advanced medicinal products and veterinary medicinal products intended for use as performance enhancers, growth promoters or to increase yield. The procedure 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. 54
UK implementation of European legislation
7.97 Comprehensive provision was made to implement the EC legislation on medicinal products into UK law in 1994. Effective from 1 January 1995, the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994 and the Marketing Authorisations for Veterinary Medicinal Products Regulations 1994 provided for applications for marketing authorisations to be made and considered by the Licensing Authority, in accordance with the relevant Community provisions. 55 Consequently, the Medicines Act provisions relating to licences for individual products applied only to a residual category of products which required UK product licences but did not require licences for the purposes of Community law.
1 L12 tab A pp. A15-19 sections 7 and 8
2 L12 tab A p. A139 section 130(1)
3 L12 tab A p. A140 section 130(2)
4 L15 tab R: Orders made pursuant to sections 104 and 105 of the Medicines Act 1968
5 For example, the Medicines (Exemption from Licences) (Foods and Cosmetics) Order 1971 SI 1971/1410 (L13 tab G pp. G26-28)
6 L13 tab G p. 27 article 2(1)
7 L12 tab A sections 13, 12, 7(2A)
8 S498 Lawson para. 8
9 L12 tab A section 16 and sections 25-27. The conditions were that the licence granted did not extend to any medicinal products other than those already on the market or being imported
10 L13 tab E p. E39 the Medicines (Closing Date for Applications for Licences of Right) Order 1972
11 L13 tab E p. E41 the Medicines (Termination of Transitional Exemptions) (No. 1) Order 1972. Transitional provisions in relation to ingredients and to wholesale dealing in medicinal products only for human use ended on 1 September 1974 and 1 June 1975 respectively (L13 tab E p. E44 the Medicines (Termination of Transitional Exemptions) (No. 2) Order 1974; L13 tab E p. E46 the Medicines (Termination of Transitional Exemptions) (No. 3) Order 1975)
12 S498 Lawson para. 9
13 L13 tab H p. 1
14 L13 tab H p. 40A
15 DH01 tab 6 para. 15
16 DH01 tab 6 para. 14. Section 31 of the Medicines Act 1968 defined the term 'clinical trial' L12 tab A pp. A39-40
17 L12 tab A pp. A39-51sections 31-39; the particulars required in an application for a CTC or ATC are set out in schedules 2 and 3 of the Medicines (Applications for Product Licences and Clinical Trial and Animal Test Certificates) Regulations 1971 (L13 tab H pp. 26, 29)
18 DH01 tab 12 para. 20
19 L12 tab A pp. A15-A19, sections 7, 8, 19(6)
20 L12 tab A p. A26 section 19(1)(a)
21 L12 tab A pp. A27-A28 section 20(1)
22 L12 tab A p. A28 section 20(3)
23 S535 Purves p. 5 para. 13
24 T84 pp. 44-45
25 T93 pp. 22-23
26 L12 tab A p. A32 section 24(1)
27 L12 tab A p. A32 section 24(2)
28 L12 tab A p. A33 section 24(4)
29 L12 tab A pp. A37-A38 section 28(3)
30 L12 tab A p. A39, A151 section 29(1) and schedule 2
31 L12 tab A p. A154 schedule 2 paras 10, 11
32 L12 tab A p. A154 schedule 2 paras 12, 13
33 DH01 tab 6 para. 18; DM01 tab 14 p. 4
34 DH01 tab 6 para. 18
35 Used to record licensing data
36 MCA Annual Report 1992/93 p. 7
37 DH01 tab 12 para. 20
38 DH01 tab 12 para. 21
39 L16 tab 1 pp. 103-04 Council Directive 75/319/EEC articles 21-22
40 DH01 tab 12 para. 21
41 DH01 tab 14 para. 14
42 L12 tab A pp A117-A121 sections 108(1), 109(1), 110(1)
43 In England and Wales, London Borough Councils, metropolitan District Councils and non-metropolitan County Councils; in Scotland, District Councils, and in Northern Ireland, District Councils
44 L12 tab A pp. A117-A121 sections 108(2), 109(2), 110(2)
45 L12 tab A p. A122 section 111
46 L12 tab A pp. A123-A124 section 112
47 S419 Jefferys pp. 16-17 paras. 43-44
48 L16 tab 1 p. 65
49 Under the European system the term 'marketing authorisation' is used in place of the term 'licence' used by the Medicines Act 1968
50 L16 tab 1 p. 66a article 3
51 Manufacturers of such products had to be licensed under Chapter IV of Directive 75/319/EEC; and wholesalers under Directive 92/25/EEC
52 DH01 tab 14 para. 5
53 L16 tab 1 p. 3
54 L16 tab 1 p. 30
55 L15 tab U; M11D tab 15 p. 3
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