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This chapter describes the background to why it became necessary to regulate the use and supply of drugs, and the ways in which these processes are managed. • Basis for regulation: safety, efficacy, quality, supply • Present medicines regulatory system • Present day requirements • Counterfeit drugs • Appendix: the thalidomide disaster change the safety information e.g. add new warnings, or contraindications. The quality aspects may also need to be revised as manufacturing practices change. MAH's have strong profit motives for making claims about their drugs. Only governments can provide the assurance about all those aspects in the life of...

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  1. 5 Official regulation of medicines SYNOPSIS change the safety information e.g. add new warn- ings, or contraindications. The quality aspects may This chapter describes the background to why also need to be revised as manufacturing practices it became necessary to regulate the use and change. MAH's have strong profit motives for supply of drugs, and the ways in which these making claims about their drugs. Only governments processes are managed. can provide the assurance about all those aspects • Basis for regulation: safety, efficacy, quality, in the life of a medicine, (in so far as it can be supply provided). • Present medicines regulatory system The principles of official (statutory) medicines regu- • Present day requirements lation are that • Counterfeit drugs • No medicines shall be marketed without prior • Appendix: the thalidomide disaster licensing by the government. • A licence shall be granted on the basis of scientific evaluation1 of: — safety, in relation to its use: evaluation at the point of marketing is provisional in the sense Basis for regulation that it is followed in the community by a pharmacovigilance programme — efficacy (now often including quality of life) Neither patients nor doctors are in a position to — quality, i.e. purity, stability (shelf-life) decide for themselves across the range of medicines that they use, which ones are pure and stable, and 1 effective and safe. Except in the case of traditional herbal medicines (which They need assurance that the medicines they are can be ineffective and/or hazardous), as well as other offered fulfil these requirements and are supported substances used in the 'legitimate practice' of complementary medicine, for which this requirement cannot by information that permits optimal use. The be met. Official regulators, finding themselves between 'the information about and the usage of medicines gets rock' of maintaining scientific principles and 'the hard place' out of date, and there is an obligation on licence of banning complementary medicines that are popular with holders continually to review their licence with the public (a political impossibility), have reacted in accordance with the highest traditions of their calling as civil particular regard to safety. Marketing Authorisation servants. They have produced a compromise mix of Holders (MAH), i.e. pharmaceutical companies, reinterpreted regulations with circumspect labelling that will can also change the efficacy claims to their licence, allow these products to continue to be sold without, it is e.g. new indications, extension of age groups, or hoped, misleading the public. 73
  2. 5 OFFICIAL REGULATION OF MEDICINES — supply: i.e. whether the drug is suitable to be ation of synthetic drugs in the early 20th century unrestrictedly available to the public or when the traditional and familiar pharmacopoeia4 whether it should be confined to sales expanded slowly and then, in mid-century, with through pharmacies or on doctors' enormous rapidity. prescriptions; and what printed information The first comprehensive regulatory law that should accompany its sale (labelling, required premarketing testing was passed in the USA leaflets). in 1938, following the death of about 107 people due • A licence shall specify the clinical indications to the use of diethylene glycol (a constituent of anti- that may be promoted and shall be for a limited freezes) as a solvent for a stable liquid formulation of period (5 years), which is renewable on sulphanilamide for treating common infections5. It application. was convenient for children to take; the toxicity • A regulatory authority may order a drug to be (CNS, renal, hepatic) of ethylene glycol was already taken off the market at any time for good cause known. The only premarketing 'tests' were for • A licence may be varied by an application from appearance, fragrance and flavour. The procedure the MAH to update efficacy, safety and quality was compatible with the then-existing law in the sections. USA. The head of the company said he was sorry for the deaths but he felt no responsibility. Plainly manufacturers and developers are entitled Other countries did not take on board the lesson to be told what substances are regulated and what are provided by the USA and it took the thalidomide not2 and what kinds and amounts of data are likely to disaster of 1961 (Chapter 5, Appendix) to make persuade a regulatory authority to grant a marketing governments all over the world initiate com- application (licence) and for what medical purpose. prehensive control over all aspects of drug intro- In summary, medicines regulation aims to provide duction, therapeutic claims and supply. Those an objective, rigorous and transparent assessment governments that already had some control system of efficacy, safety and quality in order to protect and strengthened it. promote public health but not to impede the In the UK two direct consequences were the pharmaceutical industry. It may be appreciated that development of a spontaneous adverse drug reaction an interesting tension exists between regulator and reporting scheme (the Yellow Card system) and regulated.3 legislation to provide regulatory control on the safety, quality and efficacy of medicines through the systems HISTORICAL BACKGROUND of standards, authorisation, pharmcovigilance (see p. 69) and inspection (Medicines Act 1968). A further The beginning of substantial government interven- landmark was the establishment of the Committee tion in the field of medicines paralleled the prolifer- on Safety of Medicines in 1971 to advise the Licensing 2 Authority in the UK. Despite these protective sys- It is obviously impossible to list substances that will be tems, other drug disasters occurred. In 1974 the (3- regulated if anybody should choose one day to synthesise them. Therefore regulation is based on the supply of blocking agent practolol was withdrawn because of a 'medicinal products', i.e. substances are regulated according rare but severe syndrome affecting the eyes and to their proposed use; and they must be defined in a way that other mucocutaneous regions in the body (not will resist legal challenge (hence the stilted regulatory language). The following terms have gained informal 4 acceptance for 'borderline substances' (which may or may Pharmacopoeia: a book (often official) listing drugs, their not be regulated): nutriceutical: a food or part of a food that uses, standards of purity, etc. 5 provides medicinal benefits cosmeceutical: a cosmetic that also Report of the Secretary of Agriculture submitted in has medicinal use. response to resolutions in the House of Representatives and 3 However much doctors may mock the bureaucratic Senate (USA). 1937 Journal of the American Medical 'regulatory mind', regulation provides an important service Association 111: 583, 919. Recommended reading. A similar and it is expedient that doctors should have some insight episode occurred as recently as 1990-1992: See Hanif M et al into its working and some of the very real problems faced by 1995 Fatal renal failure caused by diethylene glycol in public servants who are trying to do good without risking paracetamol elixir: the Banglandesh epidemic. British losing their jobs. Medical Journal 311: 88. Note: diethylene glycol is cheap. 74
  3. REQUIREMENTS 5 detected by animal tests), and in 1982 benoxaprofen, member state (known as a reference member a nonsteroidal anti-inflammatory drug, was found state), which assesses the application and seeks to cause serious adverse effects including onycholysis opinion from the other (concerned) member and photosensitivity in elderly patients. In 1995, the states. Granting the licence will ensure new European regulatory system was introduced simultaneous mutual recognition in these other (below). states, provided agreement is reached among them. There is an arbitration procedure to resolve disputes. CURRENT MEDICINES REGULATORY • A product to be marketed in a single country can SYSTEMS have its licence applied for through the national route. All countries where medicines are licenced for use have a regulatory system. From the point of view of a The European systems are conducted according to potential MAH (pharmaceutical company) seeking strict timelines and written procedures and there are worldwide marketing rights, the regulatory bodies its regulations in place to handle disagreements between programmes must satisfy include the Food and Drug member states and rights of appeal for applications Administration (FDA) of the USA, the European against refusals to licence. Medicines Evaluation Agency (EMEA) of the Once a medicine is licenced for sale by one of the European Union (EU), and the Japanese Pharma- above procedures, its future regulatory life remains ceutical Affairs Bureau. The national regulatory within that procedure. Licences have to be reviewed bodies of the individual EU members remain in place every 6 months for the first 2 years, then annually and work with the EMEA (see below). National until 5 years, then renewed subsequently at 5-year licences can still be granted through individual intervals. The renewal of a licence is primarily the member states, and they maintain particular respon- responsibility of the MAH but requires approval sibility for the public health issues in their own from the regulatory authority. This is the opportunity country. Some appreciation of the system in Europe for MAHs to review, especially, the safety aspects to is important. Up until 1995, applications for licences keep the licence in line with current clinical practice. had to be made to these separate national authorities. Any major changes to licences must be made by This was enormously wasteful in time and man- variation of the original licence (safety, efficacy or power, as drug developers had to adapt their research quality, see below) and supported by data, which for and clinical development programmes to meet a major indication, can be substantial. diverse national (often bureaucratic) requirements. In addition to the introduction of the European system, significant harmonisation of practices and procedures at a global level (especially Europe, Japan Requirements and the USA), have also been achieved through the International Conferences on Harmonisation (see AUTHORISATION FOR CLINICAL p. 53, footnote 4). TRIALS IN THE UK In the European Union, drugs may be licensed in three ways: The 1968 Medicines Act laid down the terms under which investigations of a new potential med- • The centralised procedure allows applications to icine could be undertaken in man. The Licensing be made directly to the EMEA, which are then Authority6 does not have rigid requirements allocated for assessment to one member state concerning all the data that must be provided (the rapporteur) assisted by a second member before authorisation can be given for a clinical trial state (co-rapporteur). This approach is mandatory for biotechnology products and optional for new medicinal products. 6 The Licensing Authority consists of the responsible • The mutual recognition (or decentralised) Minister(s) and the Medicines Control Agency (MCA) — the procedure allows applicants to nominate one executive arm in the Department of Health. 75
  4. 5 OFFICIAL REGULATION OF MEDICINES of a new drug. This is left to the judgement of the or metabolites entering the food chain or water applicant but in any event will include a detailed where use may be massive, e.g. hormones. ' clinical trial protocol and supporting experimental animal pharmacology and toxicology. Regulatory review The MCA is advised by independent senior experts, sitting on the Committee on Safety of Using one of the regulatory systems described Medicines (CSM) and its subcommittees, on the above, an authority normally conducts a review in suitability of the application. If the opinion is two stages: favourable, a Clinical Trial Certificate (CTC) is issued 1. Examination of preclinical data to determine (valid for 2 years, and renewable) and the trial may whether the drug is safe enough to be tested for start. Where clinical trial data on a drug already exist (predicted) human therapeutic efficacy. the process can be accelerated by submitting 2. Examination of the clinical studies to determine summarised preclinical and human volunteer data on whether the drug has been shown to be pharmacokinetics and tolerability (the Clinical Trials therapeutically effective with safety appropriate Exemption or CTX procedure). If the MCA does not to its use.7 object within 35 days, the study may start. One further important aspect of regulation (or rather If the decision is favourable, the drug is granted a nonregulation) in the UK is that authorisation to marketing authorisation (for 5 years: renewable), start trials with a potential new medicine in healthy which allows it to be marketed for specified therapeutic volunteers is not required, although local ethics uses. The authority must satisfy itself of the adequacy review committee approval is required. This has of the information to be provided to prescribers in a provided incentive for novel drug investigation in Summary of Product Characteristics (SPC) and also humans but a European Union Directive, when in a Patient Information Leaflet (PIL). force, will remove this freedom and require that all The PIL must also be approved by the licensing clinical trials, i.e. including Phase 1, receive prior authority, be deemed fairly to represent the SPC, and regulatory approval. be comprehensive and understandable to patients and carers. Where a drug has special advantage, but also has special risk, restrictions on its promotion and REGULATORY REVIEW OF A NEW use can be imposed, e.g. isotretinoin and clozapine. DRUG APPLICATION Central to the decision to grant a marketing authorisation is the assessment procedure under- A drug regulatory authority requires the following: taken by professional medical, scientific, statistical • Preclinical tests and pharmaceutical staff at one of the national — Tests carried out in animals to allow some agencies. In the UK these are employed as civil prediction of potential efficacy and safety in servants within the MCA and are advised by various man (see Chapter 4) independent expert committees (see above). — Chemical and pharmaceutical quality checks, When a novel drug is granted a marketing autho- e.g. purity, stability, formulation. risation it is recognised as a medicine by independent • Clinical (human) tests (Phases 1,2,3) critics and there is rejoicing amongst those who have • The full process of regulatory review of a truly spent many years developing it. But the testing is not novel drug (new chemical entity) may take over; the most stringent test of all is about to begin. It months. will be used in all sorts of people of all ages and sizes • Knowledge of the environmental impact of and having all sorts of other conditions. Its use Pharmaceuticals Regulatory authorities expect can no longer be so closely supervised as hitherto. manufacturers to address this concern in their Doctors will prescribe it and patients will use it application to market new chemical entities. correctly and incorrectly. It will have effects that Aspects include manufacture (chemical pollution), packaging (waste disposal), pollution in immediate 7 Common sense dictates that what, in regulatory terms is use, e.g. antimicrobials and, more remotely, drugs 'safe' for leukaemia would not be 'safe' for anxiety. 76
  5. REQUIREMENTS 5 have not been anticipated. It will be taken in over- exceptional circumstances, they may be a condition dose. It has to find its place in therapeutics, through of the marketing authorisation. Voluntary guide- extended comparisons with other drugs available for lines are in use for postmarketing studies agreed the same diseases. Drugs used to prevent a long- between industry and the regulatory authorities. term morbidity (e.g. stroke in hypertensive patients) All company-sponsored trials that are relevant to can be proven effective only in outcome trials that the safety of a marketed medicine are included; are usually considered too expensive even to start they clearly state that such studies should not be until marketing of the drug is guaranteed. The effect conducted for the purposes of promotion. Other of a drug at preventing rare occurrences requires studies investigating the safety of a medicine that many thousands of patients, more than are usually are not directly sponsored by the manufacturer may studied during development. Similarly rare adverse be identified from various organisations, e.g. The events cannot be detected prior to marketing, and it Drug Safety Research Unit (Southampton, UK) using would be unethical to expose large numbers of trial Prescription-Event Monitoring (PEM), the Medicines patients to a novel drug for purely safety reasons.8 Monitoring Unit (MEMO) (Tayside, UK), and the use of computerised record linkage schemes (in place in the USA for many years) such as the UK General Postlicensing responsibilities Practice Research Database at the MCA. All these The pharmaceutical company is predominantly systems have the important capacity to obtain interested in gaining as widespread usage as fast information on very large numbers of patients, as possible, based on the efficacy of the drug demon- 10 000-20 000, in observational cohort studies and case- strated in preregistration trials. The regulatory control studies which complement the spontaneous authorities are more concerned with the safety reporting system (see Chapter 4). profile of the drug, and protection of public health. In the UK, many new drugs are highlighted as The most important source of safety data once the being under special consideration by the regulatory drug is in clinical use is spontaneous reporting of authorities, by marking the drug with a symbol, the adverse events, which will generate 'signals' and inverted black triangle T, in formularies. The regu- raise suspicion of infrequent but potentially serious latory authority communicates emerging data on adverse events caused by the drug.9 Proving the safety of drugs to doctors through letters or papers causal link from sporadic signals can be extremely in journals, through specialist journals e.g. Current difficult, and is entirely dependent on the number Problems in Pharmacovigilance in the UK, and for and quality of these spontaneous reports. In the very significant issues by direct ('Dear Doctor') UK, these reports are captured through the Yellow letters, and fax messages. Card system (see p. 69), which may be completed Two other important regulatory activities that by doctors, nurses or pharmacists. Other countries affect marketed drugs are: have their own systems. The importance of • Variations to licences encouraging accurate spontaneous reporting of • Reclassifications. adverse events cannot be overemphasised. Postmarketing (Phase 4) studies are not generally Variations are substantial changes instigated regulated by legislation, although in the EU, in usually by pharmaceutical companies, but some- times by the regulatory authority, to the efficacy, 8 safety or quality aspects of the medicine. Most Patients entering trials do not receive a novel drug because it may be the best drug for their condition: indeed, half significant variations involve additions to indica- (usually) are randomly assigned placebo or an alternate tions or dosing regimens, or to the warnings and agent. After marketing, doctors should use a new drug only contraindication sections of the SPC. They need when they believe it an improvement (in efficacy, safety, to be supported by evidence and undergo formal convenience or cost) on the older alternatives. 9 assessment. Waller P C, Wood S M 1998 Regulatory Aspects of Adverse Drug Reactions. In: Davies D M, Ferner R E, de Glanville H Reclassification means change in the legal status (eds) Davies's Textbook of Adverse Drug Reactions 5th edn, of a medicine and is the process by which a Chapman & Hall Medical, ch 3, pp 20-28. prescription-only medicine can be converted to one 77
  6. 5 OFFICIAL REGULATION OF MEDICINES that is available directly to the public through new and established medicines for cost effective- pharmacies and shops. It follows a rigorous assess- ness now operate through a government funded ment process with a particular stress on safety body called NICE (National Institute for Clinical aspects of the medicine and involves advice from Excellence). The impact of its recommendations on the Committee on Safety of Medicines, and requires health care, on costs and the pharmaceutical com- a change in secondary legislation. The purpose of panies response to it are awaited. reclassification is to allow easier access of the general public to effective and safe medicines. Licensed medicines for unlicensed indications Discussion Doctors may generally prescribe any medicine for It may be wondered why postlicensing/marketing any legitimate medical purpose.10 surveillance and pharmacovigilance should be But if doctors use a drug for an indication that is necessary. Common sense would seem to dictate that not formally included in the Product Licence ('off- safety and efficacy of a drug should be fully defined label' use) they would be wise to think carefully and before it is granted marketing authorisation. Pre- to keep particularly good records for, if a patient is licensing trials with very close supervision are dissatisfied, prescribers may find themselves having commonly limited to hundreds of patients and this to justify the use in a court of law. (Written records is unavoidable, chiefly because this close supervision made at the time of a decision carry substantial is impracticable on a large scale for a very long time. weight, but records made later, when trouble is Postlicensing studies are increasingly regarded already brewing, lose much of their power to as essential to complete the definitive evaluation of convince, and records that have been altered later drugs under conditions of ordinary use on a large are quite fatal to any defence.) scale, these programmes being preferable to attempts Manufacturers are not always willing to go to the to enlarge and prolong formal therapeutic trials. trouble and expense of the rigorous clinical studies It would also seem sensible to require developers required to extend their licence unless a new use is to prove that a new drug is not only effective but is likely to generate significant profits. They are pro- actually needed in medicine before it is licensed. But hibited by law from promoting an unlicenced use. a novel drug finds its place only after several, sometimes many, years, and to delay licensing is Unlicensed medicines and accelerated simply impracticable on financial grounds. This licensing ought not to be so, but it is so. A 'need clause' in licensing is not generally practicable if drug devel- Regulatory systems make provision for supply of opers are to stay in that business. This is why an unlicenced medicine, e.g. one that has not yet comparative therapeutic studies of a new drug with completed its full programme of clinical trials, for existing drugs are not required for licensing in patients who, on the judgement of their doctors, have countries having a research-based pharmaceutical no alternative amongst licensed drugs. The doctor industry. A 'need clause' is, however, appropriate must apply to the manufacturer who may supply for economically deprived countries (see World the drug for that particular patient and at the Health Organization Essential Drugs Programme); doctor's own responsibility. Various terms are indeed such countries have no alternative. used, e.g. supply on a 'named-patient' basis (UK); The licensing authority in the UK is not concerned 'compassionate' drug use (USA). It is illegal to exploit with the pricing of drugs or their cost effectiveness. this sensible loophole in supply laws to conduct The cost of medicines does however concern all research. Precise record-keeping of such use is governments, as part of the rising costs of national essential. health services. A serious attempt to control costs on drug usage by the introduction of national 10 In many countries this excludes supply of drugs such as guidelines on disease management (including the heroin or cocaine for controlled/supervised maintenance of use of individual drugs) and the appraisal of drug addicts. In the UK such supply is permitted to doctors. 78
  7. REQUIREMENTS 5 But there can be desperate needs involving large looms larger. Attempts to blame regulators for failing numbers of patients, e.g. AIDS, and regulatory to do good due to regulatory procrastination, the authorities may respond by licensing a drug before 'drug lag'12 do not induce the same feelings of horror completion of the usual range of studies (making it in regulators and their advisory committees that are clear that patients must understand the risks they induced by the prospect of finding they have are taking). Unfortunately such well-intentioned approved a drug that has, or may have, caused practice discourages patients from entering formal serious injury and that the victims are about to trials and may, in the long run, actually delay the appear on television.13 The bitterness of people definition of lifesaving therapies. injured by drugs, whether or not there is fault could be much reduced by the institution of simple non- adversarial arrangements for compensation (see Decision taking p. 10). This is not to ridicule the regulators and their It must be remembered always that, though there are advisers. They are doing their best, and commonly risks in taking drugs, there are also risks in not taking drugs, and there are risks in not developing new drugs. make good and sensible decisions that receive no congratulations. The responsibility to protect public health on the Counterfeit drugs one hand yet to allow timely access to novel med- icines on the other, is one shared by drug regulators Fraudulent medicines make up as much as 6% of and developers. It is complicated by an ever pharmaceutical sales worldwide. They present a increasing awareness of the risks and benefits serious health (and economic) problem in coun- (real, or perceived) of medicines by the general tries with weak regulatory authorities and lacking public. money to police drug quality. In these countries Some new medicines are registered with the counterfeit medicines may comprise 20-50% of high expectation of effectiveness and with very available products. The trade may involve false little safety information; rare and unpredictable labelling of legally manufactured products, in adverse events may take years to appear with order to play one national market against another; sufficient conviction that causality is accepted. also low-quality manufacture of correct ingre- In taking decisions about drug regulation, it has dients; wrong ingredients, including added ingre- been pointed out that there is uncertainty in three dients (such as corticosteroids added to herbal areas.11 medicine for arthritis); no active ingredient; false packaging. • Facts The trail from raw material to appearance on a • Public reaction to the facts pharmacy shelf may involve as many as four coun- • Future consequences of decisions. tries, with the final stages (importer, wholesaler) Regulators are influenced not only to avoid risk quite innocent, so well has the process been but to avoid regret later (regret avoidance) and this obscured. consideration has a profound effect whether or not Developed countries have inspection and enforce- the decision taker is conscious of it; it promotes ment procedures to detect and take appropriate defensive regulation. action on illegal activities. It is self-evident that it is much harder to detect and quanritate a good that is not done, than it is to 12 detect and quantitate a harm that is done. Therefore, Nevertheless, regulatory authorities have responded by although it is part of the decision-taker's job to providing a facility for 'fast-tracking' drugs for which clinical need may be urgent, e.g. AIDS (see above). facilitate the doing of good, the avoidance of harm 13 The very last thing a drug regulator wishes to be able to say is, 'I awoke one morning and found myself famous': 11 Lord Ashby 1976 Proceedings of the Royal Society of Lord Byron (1788-1824) on the publication of his poem, Medicine 69: 721. Childe Harold's Pilgrimage. 79
  8. 5 OFFICIAL REGULATION OF MEDICINES GUIDETO FURTHER READING Marketed Medicines (SAMM Guidelines). British Journal of Clinical Pharmacology 38: 95 Baber N 1994 International conference on Reichert J M 2000 New biopharmaceuticals in the harmonization of technical requirements for USA: trends in development and marketing registration of pharmaceuticals. British Journal of approvals 1995-1999. Trends in Biotechnology 18: Clinical Pharmacology 37: 401^04 364-369 Brass E P 2001 Changing the status of drugs from Richard B W et al 1987 Drug regulation in the United prescription to over-the-counter availability. New States and the United Kingdom: the Depo-Provera England Journal of Medicine 345: 810-816 story. Annals of Internal Medicine 106: 886-891; Collier J 1999 Paediatric prescribing: using unlicenced (An analysis of how drug regulators in the USA drugs and medicines outside their licensed and the UK came to opposite conclusions on the indications. British Journal of Clinical same data.) Pharmacology 48: 5-8 ON THALIDOMIDE Conroy S et al 2000 Survey of unlicenced and off label Chamberlain G 1989 The obstetric problems of the drug use in paediatric wards in European [now adult] thalidomide children. British Medical countries. British Medical Journal 320: 79-82 Journal 298: 6 DiMasi J A, Seibring M A, Lasagna L1994 New drug Dally A1998 Thalidomide: was the tragedy development in the United States from 1963 to preventable? Lancet 351:1197-1199 1992. Clinical Pharmacology and Therapeutics 55: Editorial 1981 Thalidomide: 20 years on. Lancet 2: 510 609-622 Mellin G W et al 1962 The saga of thalidomide. New Gale E A M, Clark A 2000 A drug on the market? England Journal of Medicine 267:1184-1192, Lancet 355: 61-63 1238-1244 Medicines Control Agency 1994 Guidelines for company-sponsored Safety Assessment of 80
  9. APPENDIX 5 Appendix: A tale to remember — the thalidomide disaster Thalidomide has provided a terrible lesson to the It was withdrawn from the [West] German market in world in regard to drug development, testing, November and from the British market in December naming, prescribing and consumption. It deserves 1961. By that time reports had also come from other to be remembered. countries. A case-control study showed that of In 1960-61 in [West] Germany an outbreak of 46 cases of phocomelia 41 mothers had taken phocomelia occurred. Phocomelia means 'seal thalidomide and of 300 mothers with normal babies extremities'; it is a congenital deformity in which none had taken thalidomide between the fourth the long bones of the limbs are defective and and ninth week of pregnancy. substantially normal or rudimentary hands and feet Prospective observational cohort studies were arise on, or nearly on, the trunk, like the flippers of quickly made in antenatal clinics where women a seal; other abnormalities may occur. Phocomelia had yet to give birth; though few, they provided is ordinarily exceedingly rare. evidence incriminating thalidomide. The worst had Most [West] German clinics had no cases during happened, a trivial new drug was the cause of the the 10 years up to 1959. In 1959, in 10 clinics, 17 most grisly disaster in the short history of modern were seen in 1959, 126 in 1960, 477 in 1961. The scientific drug therapy. Many thalidomide babies European outbreak seemed confined to [West] died, but many live on with deformed limbs, eyes, Germany (though a similar but smaller occurrence ears, heart and alimentary and urinary tracts.15 was simultaneously noted in Australia), and this, The [West] German Health Ministry estimated that with the steady increase, made a virus infection, thalidomide caused about 10 000 birth deformities in such as rubella, seem an unlikely cause. Radioactive babies, 5000 of whom survived and 1600 of whom fall-out was considered and so were x-ray exposure would eventually need artificial limbs. In Britain there of the mother, hormones, foods, food preservatives were probably at least 600 live births of malformed and contraceptives. One doctor, investigating his children of whom about 400 survived. The world total patients retrospectively with a questionnaire, found of survivors was probably about 10 000. that 20% reported taking a proprietary medicine, Thalidomide had been marketed in [West] Contergan, in early pregnancy. He questioned the Germany in 1956, in Britain in 1958, and in other patients again and 50% then admitted taking it; countries as a sedative and hypnotic and was many said they had thought the drug too obviously recommended for use in pregnant women. It had innocent to be worth mentioning initially.14 not been tested on pregnant animals. When it was In November 1961, the suggestion that a drug, eventually tested it was at first difficult to induce unnamed, was the cause of the outbreak was publicly fetal deformity (until it was used on New Zealand made by the same doctor at a paediatric meeting, White Rabbits). following a report on 34 cases of phocomelia. That Thalidomide, skilfully promoted and credulously night a physician came up to him and said, 'Will you prescribed and taken by the public — it was also sold tell me confidentially, is the drug Contergan? I ask without prescription — achieved huge popularity; because we have such a child and my wife took it 'became [West] Germany's baby-sitter'. It was a Contergan'. Several letters followed, asking the same routine hypnotic in hospitals, was even recom- question, and it soon became widely known that the mended to help children adapt themselves to a sedative drug thalidomide (Contergan, Distaval, convalescent home atmosphere and was sold mixed Kevadon, Talimol, Softenon) was probably the cause. with other drugs for symptomatic relief of pain, 15 For pictures of thalidomide deformities, see British 14 Illustrating the problem of retrospective research, e.g. case- Medical Journal 1962; 2: 646-647 and Journal of the American control studies; enquiries of patients are unreliable. Medical Association 1962; 180:1106-1114. 81
  10. 5 OFFICIAL REGULATION OF MEDICINES cough and fever. In 1960-61 it had become evident were born in the USA following indiscriminate pre- that prolonged use of thalidomide could cause marketing clinical trials. hypothyroidism and peripheral neuritis. The latter Thalidomide has anti-inflammatory and immuno- effect was the principal reason why approval for suppressant actions and retains a limited specialist marketing in the USA, as Kevadon, had been use in, for example, lepromatous leprosy,16 and oral delayed by the US Food and Drug Administration. ulceration in AIDS (some cases). Approval had still not been given when the fetal The thalidomide disaster provided the impetus effects were discovered and so general distribution for the introduction of national drug regulatory was avoided. Nonetheless some 'thalidomide babies' authorities worldwide. 16 Further cases of congenital malformations were reported in 1994 due to lax control of thalidomide use (Lancet 343: 433 and 344:196). Thalidomide is available in the UK on a 'named-patient' basis only, with a detailed patient information leaflet and with signed patient consent. 82
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