The Penrose Inquiry

CHAPTER 12

LICENSING

Regulatory Framework - The Medicines Act 1968

12.1 The Act came into force in 1971 and, amended from time to time, governed the licensing of drugs and medicinal products from then until 1995. In contrast to previous legislation such as the Venereal Diseases Act 1917, the Therapeutics Act 1925 and the Cancer Act 1939 which were primarily directed at marketing of drugs, the 1968 Act dealt with safety.

12.2 The Act was introduced following a review of legislation relating to medicines prompted by the thalidomide tragedy in the 1960s. It brought together most of the previous legislation on medicines and introduced a number of other legal provisions for control. Speaking in 1971, Dr J P Griffin, Medicines Division, DHSS, said:[1]

…both public and Government were unprepared for the therapeutic explosion of the last thirty years. This complacency was rudely shattered by the thalidomide tragedy. The conscience of the public was troubled and the Government galvanised into activity.

12.3 Something had to be done, and legislation would take time. The thalidomide disaster triggered a response by many organisations including the Royal College of General Practitioners, the Association of the British Pharmaceutical Industry, and the Government’s Standing Medical Advisory Committee. The Standing Medical Advisory Committee set up a joint sub-committee on the safety of drugs, chaired by Lord Cohen. The Cohen Report expressed concern about drug safety, but also about the control of the quality of drugs; control of over-the-counter sales of medicine; the use of approved names and the regulation of therapeutic claims. The Report recommended that all new drugs and preparations should be submitted to a Committee on the Safety of Drugs.

12.4 In 1963 the Minister of Health set up the Committee on Safety of Drugs (CSD) known as the Dunlop Committee after its chairman Sir Derrick Dunlop. The Committee had no legal powers but collaborated with the Association for the British Pharmaceutical Industry (ABPI) and the Pharmaceutical Association of Great Britain (PAGB) in looking at toxicity tests, clinical trials, efficacy and adverse reactions during general use. The CSD established an adverse drug reaction reporting scheme, popularly known as the ‘Yellow Card Scheme’.

12.5 Proposals for new legislation to control medicines followed in 1967, and the 1968 Act resulted. The Act brought together everything to do with the control of medicines, for both human and animal use, including their promotion and sales. As from 1 September 1971, all medicines already on the UK market had to go through peer review and subsequent approval or be withdrawn. From 1971 all new medicines were subject to pre-marketing assessment for safety, quality and efficacy by the licensing authority. A UK Licensing Authority was responsible for the grant, renewal, variation, suspension and revocation of licences and certificates for medicines, and for the licensing of the sale, supply, importation and manufacture of medicines for the UK market. The Medicines Commission, an expert advisory committee, was set up to advise Ministers. The CSD became the Committee on Safety of Medicines (CSM) and later the Commission on Human Medicines (CHM).

12.6 The UK Licensing Authority formally brought together the Secretaries of State for Health and Agriculture, and, from 1968 to 1999 in Scotland, the Secretary of State for Scotland.[2] In practice it was the Medicines Division of the Department of Health that carried out the functions of the Licensing Authority for human medicines. Licensing was a reserved matter after devolution, and in 1999 the licensing functions of the Secretary of State for Scotland were transferred to the UK Secretary of State for Health and to the UK Minister of Agriculture Fisheries and Food.[3] In April 1989 the Medicines Division became the Medicines Control Agency (MCA), a self-financing executive agency of the Department of Health.

12.7 The function of the Medicines Commission was to advise Ministers on any matter relating to the Act. The Commission was made up of professionals with ‘wide and recent experience’ in the practice of medicine and pharmacy.[4] In particular it advised on representations by pharmaceutical companies and appeals against licensing decisions and on the establishment and membership of further committees. The Committee on Safety of Medicines (CSM) and the Committee on Review of Medicines (CRM) were established by the Medicines Commission under these powers. The Licensing Authority was required to consult the relevant advisory committee in certain circumstances such as where it was minded to refuse, suspend, vary or revoke a licence.[5] Otherwise officials had discretion whether or not to seek advice from the Committees.

12.8 The CRM was established to review the safety, quality and efficacy of medicines on the market before the Act introduced licensing requirements. The CRM checked approximately 39,000 existing products between 1971 and May 1990 as required by EC rules.[6] The CSM advised on questions of safety, quality and efficacy of human medicines.

12.9 The Medicines and Healthcare Products Regulatory Agency (MHRA), an executive agency of the Department of Health, was formed on 1 April 2003 with the merger of the MCA and the Medical Devices Agency (MDA). MHRA hosts and supports a number of expert advisory bodies, including the Commission on Human Medicines which replaced the Committee on the Safety of Medicines in 2005, and the British Pharmacopoeia Commission. As part of the European system of approval, MHRA may act as rapporteur or co-rapporteur for any given pharmaceutical application, taking on the bulk of the verification work on behalf of all members.

European legislation

12.10 Once the UK was admitted as a member of the European Community on 1 January 1973, EC rules on licensing applied. These were contained in Council Directive 65/65/EEC[7] on the approximation of the law on medicinal products. The Directive required Member States to adopt measures to ensure that no proprietary medicinal product could be placed on the market unless authorisation had been issued by a competent authority. Many of the requirements set out in Council Directive 65/65/EEC were included in the Medicines Act. Until 1995 the Medicines Act was the principal legislation under which the UK complied with the EC rules on regulation of medicinal products. With effect from 1 January 1995 the EC legislation on human medicines was implemented by the Medicines for Human Use (Marketing Authorisations Etc.) Regulations 1994. Council Regulation (EEC) No 2309/93[8] established a central co-ordinating body called the European Agency for the Evaluation of Medicinal Products (EMEA) and introduced a centralised procedure of authorisation of medicines by the European Commission to market a product in all Member States. Directive 2001/83/EC consolidated the previous Directives. Following consolidation the European Commission conducted a review of medicines legislation. This resulted in Directive 2004/27/EC which amended 2001/83/EC and Regulation (EC) No 726/2004 which replaced Regulation (EEC) No 2309/93. Directive 2001/83/EC governs national authorisation procedures. Regulation (EC) No 726/2004 governs the centralised procedure. Directive 2001/83/EC governs matters such as labelling and package leaflets, wholesale distribution and advertising. Directive 2001/20/EC governs the conduct of clinical trials.

12.11 Article 1(2) and (3) of Council Directive 65/65/EEC defined ‘medicinal product’ as including any substance for treating or preventing disease in human beings including ‘any matter irrespective of origin, which may be: human, e.g. human blood and human blood products’. Council Directive 65/65/EEC was modified by Article 34 of Council Directive 75/319/EEC which provided that Directive 65/65/EEC should not apply to ‘proprietary medicinal products based on human blood or blood constituents.’ Article 1(1) of Council Directive 89/381/EEC provided that 65/65/EEC and 75/319/EEC should apply to ‘medicinal products derived from human blood or human plasma’.

12.12 The European 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.

Licensing requirements

12.13 The Medicines Act 1968 provided that the sale, supply or export of any medicinal products required a product licence.[9] The manufacture or import of medicinal products required a manufacturing licence.[10] Premises where medicinal products were produced had to possess a manufacturer’s licence and were subject to regular inspection by the Medicines Division of the DHSS (and subsequently the MCA and MHRA). Detailed regulations governed applications for the grant of product licences. The required form for a product licence application was set out in the Medicines (Applications for Product Licences and Clinical Trial and Animal Test Certificates) Regulations 1971 (SI 1971/973).[11] The required form for a manufacturer’s licence application was set out in the Medicines (Applications for Manufacturer’s and Wholesale Dealer’s Licences) Regulations 1971/974.

Applications for licences

12.14 In order to obtain a product licence a manufacturer had to submit an application to the Licensing Authority usually with supporting evidence as to the product’s safety. The Licensing Authority required to take several factors into consideration including ‘…the safety of the medicinal products’.[12] An application could be granted by the Licensing Authority for straightforward applications. These usually involved applications for products that were substantially the same as existing products that had been granted licences. Usually the decision would be delegated to the CSM or one of its sub-committees. The licensing of blood products was delegated to the Biologicals sub-committee.

Suspension, variation and refusal

12.15 Licences were granted for a period of five years and the licence holder could then apply for a renewal of the licence, with or without modifications. If the Licensing Authority decided not to renew the licence it was obliged to consult the appropriate Committee. If there were no such Committee the Licensing Authority would have to consult the Medicines Commission.

12.16 The Licensing Authority also had power to suspend, revoke or vary the provisions of a product licence if the medicinal products could no longer ‘be regarded as products which can safely be administered for the purposes indicated in the licence, or as efficacious for those purposes’.[13]

12.17 Generally the Licensing Authority had to consult the Committees before varying, suspending or revoking a licence. In an emergency the Licensing Authority could suspend a licence with immediate effect for three months. A licence holder could apply for a variation of an existing licence in certain circumstances.[14]

Informal regulatory action

12.18 Informal action can also be taken by the Licensing Authority. This involves issuing non-binding guidelines or recommendations. In order to revoke or suspend a licence the burden of proof is on the Licensing Authority to show that the medicinal product is unsafe or not efficacious. That process can be time consuming. Informal action which depends on the cooperation of pharmaceutical companies has the advantage of producing a quicker result.

Exceptions to the licensing regimes

Medical treatment

12.19 Licensing restrictions did not apply to a doctor who was preparing or importing a medicinal product to his order for administration to a particular patient.[15] This was known as obtaining medicinal products on a ‘named patient basis’.

Clinical trials

12.20 In order to conduct clinical trials on a new medicinal product a manufacturer required to apply for a Clinical Trial Certificate (CTC) before testing the product on patients.[16] A doctor was considered to be carrying out a clinical trial if he administered a medicinal product primarily to determine what effect it had.[17] The Licensing Authority would take advice from the CSM and grant the application if it concluded that it did not involve serious risk to the trial subject. A doctor was permitted to carry out trials without a CTC if he notified the Licensing Authority of his intention to do so.

12.21 In March 1981 a new scheme was introduced by the Medicines Exemption from Licences (Clinical Trials) Order 1981. The Clinical Trials Exemption (CTX) scheme enabled the Licensing Authority to exempt a supplier from the need to hold a CTC for three years if certain undertakings were given. The CTX was renewable after three years. The Licensing Authority could withdraw the exemption if concerns were raised about the safety of the product. The applicant had an obligation to advise the Licensing Authority of any adverse reactions or anything else affecting the safety of the product. In 2004 the CTX scheme was replaced by the Clinical Trials Directive and the Medicines for Human Use (Clinical Trials) Regulations 2004.[18]

Pharmovigilance

12.22 As well as granting licences the Licensing Authority is also responsible for monitoring the continuing safety of the products it has licensed. This is arranged by collecting reports from doctors and dentists about any adverse reactions which patients have to any medicinal products. This function of pharmovigilance is delegated to the CSM. It can recommend to the Licensing Authority that a product licence should be revoked if it becomes apparent that the product can no longer be considered safe or efficacious.[19]

Crown Immunity

12.23 Crown Immunity is a doctrine that states that the sovereign cannot commit a legal wrong and is therefore immune from criminal prosecution or civil action. Institutions of the state are entitled to Crown Immunity. Unless otherwise provided, the Crown and its agencies are exempt from regulation. The Medicines Act provided that no exemption in the Act should be construed as derogating from Crown Immunity.[20] This was interpreted as meaning that parts of the NHS such as health boards and the blood transfusion services did not have to comply with the licensing regulations, so long as the Act remained unqualified. The facilities at BPL (Elstree), PFL (Oxford) and PFC (Edinburgh) were part of the National Health Service and therefore were considered to have immunity from the Medicines Act 1968. On 1 April 1991 Crown Immunity was removed from the NHS by the National Health Service Community Care Act 1990.[21]

Blood products

12.24 The Medicines Act regulated the manufacture, distribution and supply of ‘medicinal products’. ‘Products based on human blood or blood constituents’ were specifically excluded from the definition of medicinal product.[22] However the Act did not specifically exclude blood products. Between 1971 and 2005 blood products were therefore classified as medicinal products and subject to regulation under the Act. From 2005 the licensing of blood products was regulated by the Blood Safety Statutory Instrument 2005/50.

Licences for blood products

12.25 The provisions for product licences for blood products were set out in Section 3A of and Schedule 1A to the Medicines (Standard Provisions for Licences and Certificates) Regulations 1971. These Regulations provided inter alia that the licence holder had to take all necessary measures to ensure that the manufacturing and purifying processes used in the preparation of the blood products were properly validated, attained batch-to-batch consistency and guaranteed, in so far as the state of technology permitted, the absence of specific viral contamination. It provided that appropriate records relating to control measures should be kept. It also provided that the licence holder should take all necessary steps to ensure that the manufacturers notified the Licensing Authority of methods used to reduce or eliminate pathogenic viruses liable to be transmitted.