• Basis for regulation: safety, efficacy, quality, supply • Present medicines regulatory system • Present day requirements • Counterfeit drugs • Appendix: the thalidomide disaster Basis
Trang 1Official regulation of medicines
SYNOPSIS
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
Basis for regulation
Neither patients nor doctors are in a position to
decide for themselves across the range of medicines
that they use, which ones are pure and stable, and
effective and safe.
They need assurance that the medicines they are
offered fulfil these requirements and are supported
by information that permits optimal use The
information about and the usage of medicines gets
out of date, and there is an obligation on licence
holders continually to review their licence with
particular regard to safety Marketing Authorisation
Holders (MAH), i.e pharmaceutical companies,
can also change the efficacy claims to their licence,
e.g new indications, extension of age groups, or
change the safety information e.g add new warn-ings, 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 a medicine, (in so far as it can be provided)
The principles of official (statutory) medicines regu-lation are that
• No medicines shall be marketed without prior 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 that it is followed in the community by a pharmacovigilance programme
— efficacy (now often including quality of life)
— quality, i.e purity, stability (shelf-life)
1 Except in the case of traditional herbal medicines (which can be ineffective and/or hazardous), as well as other substances used in the 'legitimate practice' of complementary medicine, for which this requirement cannot
be met Official regulators, finding themselves between 'the rock' of maintaining scientific principles and 'the hard place'
of banning complementary medicines that are popular with the public (a political impossibility), have reacted in accordance with the highest traditions of their calling as civil servants They have produced a compromise mix of reinterpreted regulations with circumspect labelling that will allow these products to continue to be sold without, it is hoped, misleading the public.
73
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— supply: i.e whether the drug is suitable to be
unrestrictedly available to the public or
whether it should be confined to sales
through pharmacies or on doctors'
prescriptions; and what printed information
should accompany its sale (labelling,
leaflets)
• A licence shall specify the clinical indications
that may be promoted and shall be for a limited
period (5 years), which is renewable on
application
• A regulatory authority may order a drug to be
taken off the market at any time for good cause
• A licence may be varied by an application from
the MAH to update efficacy, safety and quality
sections
Plainly manufacturers and developers are entitled
to be told what substances are regulated and what are
not2 and what kinds and amounts of data are likely to
persuade a regulatory authority to grant a marketing
application (licence) and for what medical purpose
In summary, medicines regulation aims to provide
an objective, rigorous and transparent assessment
of efficacy, safety and quality in order to protect and
promote public health but not to impede the
pharmaceutical industry It may be appreciated that
an interesting tension exists between regulator and
regulated.3
HISTORICAL BACKGROUND
The beginning of substantial government
interven-tion in the field of medicines paralleled the
prolifer-2 It is obviously impossible to list substances that will be
regulated if anybody should choose one day to synthesise
them Therefore regulation is based on the supply of
'medicinal products', i.e substances are regulated according
to their proposed use; and they must be defined in a way that
will resist legal challenge (hence the stilted regulatory
language) The following terms have gained informal
acceptance for 'borderline substances' (which may or may
not be regulated): nutriceutical: a food or part of a food that
provides medicinal benefits cosmeceutical: a cosmetic that also
has medicinal use.
3 However much doctors may mock the bureaucratic
'regulatory mind', regulation provides an important service
and it is expedient that doctors should have some insight
into its working and some of the very real problems faced by
public servants who are trying to do good without risking
losing their jobs.
ation of synthetic drugs in the early 20th century when the traditional and familiar pharmacopoeia4
expanded slowly and then, in mid-century, with enormous rapidity
The first comprehensive regulatory law that required premarketing testing was passed in the USA
in 1938, following the death of about 107 people due
to the use of diethylene glycol (a constituent of anti-freezes) as a solvent for a stable liquid formulation of sulphanilamide for treating common infections5 It was convenient for children to take; the toxicity (CNS, renal, hepatic) of ethylene glycol was already known The only premarketing 'tests' were for appearance, fragrance and flavour The procedure was compatible with the then-existing law in the USA The head of the company said he was sorry for the deaths but he felt no responsibility
Other countries did not take on board the lesson provided by the USA and it took the thalidomide disaster of 1961 (Chapter 5, Appendix) to make governments all over the world initiate com-prehensive control over all aspects of drug intro-duction, therapeutic claims and supply Those governments that already had some control system strengthened it
In the UK two direct consequences were the development of a spontaneous adverse drug reaction reporting scheme (the Yellow Card system) and legislation to provide regulatory control on the safety, quality and efficacy of medicines through the systems
of standards, authorisation, pharmcovigilance (see
p 69) and inspection (Medicines Act 1968) A further landmark was the establishment of the Committee
on Safety of Medicines in 1971 to advise the Licensing Authority in the UK Despite these protective sys-tems, other drug disasters occurred In 1974 the (3-blocking agent practolol was withdrawn because of a rare but severe syndrome affecting the eyes and other mucocutaneous regions in the body (not
4 Pharmacopoeia: a book (often official) listing drugs, their uses, standards of purity, etc.
5 Report of the Secretary of Agriculture submitted in response to resolutions in the House of Representatives and Senate (USA) 1937 Journal of the American Medical Association 111: 583, 919 Recommended reading A similar episode occurred as recently as 1990-1992: See Hanif M et al
1995 Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Banglandesh epidemic British Medical Journal 311: 88 Note: diethylene glycol is cheap.
Trang 3detected by animal tests), and in 1982 benoxaprofen,
a nonsteroidal anti-inflammatory drug, was found
to cause serious adverse effects including onycholysis
and photosensitivity in elderly patients In 1995, the
new European regulatory system was introduced
(below)
CURRENT MEDICINES REGULATORY
SYSTEMS
All countries where medicines are licenced for use
have a regulatory system From the point of view of a
potential MAH (pharmaceutical company) seeking
worldwide marketing rights, the regulatory bodies its
programmes must satisfy include the Food and Drug
Administration (FDA) of the USA, the European
Medicines Evaluation Agency (EMEA) of the
European Union (EU), and the Japanese
Pharma-ceutical Affairs Bureau The national regulatory
bodies of the individual EU members remain in place
and work with the EMEA (see below) National
licences can still be granted through individual
member states, and they maintain particular
respon-sibility for the public health issues in their own
country Some appreciation of the system in Europe
is important Up until 1995, applications for licences
had to be made to these separate national authorities
This was enormously wasteful in time and
man-power, as drug developers had to adapt their research
and clinical development programmes to meet
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
and the USA), have also been achieved through the
International Conferences on Harmonisation (see
p 53, footnote 4)
In the European Union, drugs may be licensed in
three ways:
• The centralised procedure allows applications to
be made directly to the EMEA, which are then
allocated for assessment to one member state
(the rapporteur) assisted by a second member
state (co-rapporteur) This approach is
mandatory for biotechnology products and
optional for new medicinal products
• The mutual recognition (or decentralised)
procedure allows applicants to nominate one
member state (known as a reference member state), which assesses the application and seeks opinion from the other (concerned) member states Granting the licence will ensure simultaneous mutual recognition in these other states, provided agreement is reached among them There is an arbitration procedure to resolve disputes
• A product to be marketed in a single country can have its licence applied for through the national route
The European systems are conducted according to strict timelines and written procedures and there are regulations in place to handle disagreements between member states and rights of appeal for applications against refusals to licence
Once a medicine is licenced for sale by one of the above procedures, its future regulatory life remains within that procedure Licences have to be reviewed every 6 months for the first 2 years, then annually until 5 years, then renewed subsequently at 5-year intervals The renewal of a licence is primarily the responsibility of the MAH but requires approval from the regulatory authority This is the opportunity for MAHs to review, especially, the safety aspects to keep the licence in line with current clinical practice Any major changes to licences must be made by variation of the original licence (safety, efficacy or quality, see below) and supported by data, which for
a major indication, can be substantial
Requirements
AUTHORISATION FOR CLINICAL TRIALS IN THE UK
The 1968 Medicines Act laid down the terms under which investigations of a new potential med-icine could be undertaken in man The Licensing Authority6 does not have rigid requirements concerning all the data that must be provided before authorisation can be given for a clinical trial
6 The Licensing Authority consists of the responsible Minister(s) and the Medicines Control Agency (MCA) — the executive arm in the Department of Health.
Trang 45 O F F I C I A L R E G U L A T I O N O F M E D I C I N E S
of a new drug This is left to the judgement of the
applicant but in any event will include a detailed
clinical trial protocol and supporting experimental
animal pharmacology and toxicology
The MCA is advised by independent senior
experts, sitting on the Committee on Safety of
Medicines (CSM) and its subcommittees, on the
suitability of the application If the opinion is
favourable, a Clinical Trial Certificate (CTC) is issued
(valid for 2 years, and renewable) and the trial may
start Where clinical trial data on a drug already exist
the process can be accelerated by submitting
summarised preclinical and human volunteer data on
pharmacokinetics and tolerability (the Clinical Trials
Exemption or CTX procedure) If the MCA does not
object within 35 days, the study may start One
further important aspect of regulation (or rather
nonregulation) in the UK is that authorisation to
start trials with a potential new medicine in healthy
volunteers is not required, although local ethics
review committee approval is required This has
provided incentive for novel drug investigation in
humans but a European Union Directive, when in
force, will remove this freedom and require that all
clinical trials, i.e including Phase 1, receive prior
regulatory approval
REGULATORY REVIEW OF A NEW
DRUG APPLICATION
A drug regulatory authority requires the following:
• Preclinical tests
— Tests carried out in animals to allow some
prediction of potential efficacy and safety in
man (see Chapter 4)
— Chemical and pharmaceutical quality checks,
e.g purity, stability, formulation
• Clinical (human) tests (Phases 1,2,3)
• The full process of regulatory review of a truly
novel drug (new chemical entity) may take
months
• Knowledge of the environmental impact of
Pharmaceuticals Regulatory authorities expect
manufacturers to address this concern in their
application to market new chemical entities
Aspects include manufacture (chemical pollution),
packaging (waste disposal), pollution in immediate
use, e.g antimicrobials and, more remotely, drugs
or metabolites entering the food chain or water where use may be massive, e.g hormones '
Regulatory review
Using one of the regulatory systems described above, an authority normally conducts a review in two stages:
1 Examination of preclinical data to determine whether the drug is safe enough to be tested for (predicted) human therapeutic efficacy
2 Examination of the clinical studies to determine whether the drug has been shown to be
therapeutically effective with safety appropriate
to its use.7
If the decision is favourable, the drug is granted a marketing authorisation (for 5 years: renewable),
which allows it to be marketed for specified therapeutic uses The authority must satisfy itself of the adequacy
of the information to be provided to prescribers in a Summary of Product Characteristics (SPC) and also
a Patient Information Leaflet (PIL)
The PIL must also be approved by the licensing authority, be deemed fairly to represent the SPC, and
be comprehensive and understandable to patients and carers Where a drug has special advantage, but also has special risk, restrictions on its promotion and use can be imposed, e.g isotretinoin and clozapine Central to the decision to grant a marketing authorisation is the assessment procedure under-taken by professional medical, scientific, statistical and pharmaceutical staff at one of the national agencies In the UK these are employed as civil servants within the MCA and are advised by various independent expert committees (see above)
When a novel drug is granted a marketing autho-risation it is recognised as a medicine by independent critics and there is rejoicing amongst those who have spent many years developing it But the testing is not over; the most stringent test of all is about to begin It will be used in all sorts of people of all ages and sizes and having all sorts of other conditions Its use can no longer be so closely supervised as hitherto Doctors will prescribe it and patients will use it correctly and incorrectly It will have effects that
7 Common sense dictates that what, in regulatory terms is 'safe' for leukaemia would not be 'safe' for anxiety.
Trang 5have not been anticipated It will be taken in
over-dose It has to find its place in therapeutics, through
extended comparisons with other drugs available for
the same diseases Drugs used to prevent a
long-term morbidity (e.g stroke in hypertensive patients)
can be proven effective only in outcome trials that
are usually considered too expensive even to start
until marketing of the drug is guaranteed The effect
of a drug at preventing rare occurrences requires
many thousands of patients, more than are usually
studied during development Similarly rare adverse
events cannot be detected prior to marketing, and it
would be unethical to expose large numbers of trial
patients to a novel drug for purely safety reasons.8
Postlicensing responsibilities
The pharmaceutical company is predominantly
interested in gaining as widespread usage as fast
as possible, based on the efficacy of the drug
demon-strated in preregistration trials The regulatory
authorities are more concerned with the safety
profile of the drug, and protection of public health
The most important source of safety data once the
drug is in clinical use is spontaneous reporting of
adverse events, which will generate 'signals' and
raise suspicion of infrequent but potentially serious
adverse events caused by the drug.9 Proving the
causal link from sporadic signals can be extremely
difficult, and is entirely dependent on the number
and quality of these spontaneous reports In the
UK, these reports are captured through the Yellow
Card system (see p 69), which may be completed
by doctors, nurses or pharmacists Other countries
have their own systems The importance of
encouraging accurate spontaneous reporting of
adverse events cannot be overemphasised
Postmarketing (Phase 4) studies are not generally
regulated by legislation, although in the EU, in
8 Patients entering trials do not receive a novel drug because
it may be the best drug for their condition: indeed, half
(usually) are randomly assigned placebo or an alternate
agent After marketing, doctors should use a new drug only
when they believe it an improvement (in efficacy, safety,
convenience or cost) on the older alternatives.
9 Waller P C, Wood S M 1998 Regulatory Aspects of Adverse
Drug Reactions In: Davies D M, Ferner R E, de Glanville H
(eds) Davies's Textbook of Adverse Drug Reactions 5th edn,
Chapman & Hall Medical, ch 3, pp 20-28.
exceptional circumstances, they may be a condition
of the marketing authorisation Voluntary guide-lines are in use for postmarketing studies agreed between industry and the regulatory authorities All company-sponsored trials that are relevant to the safety of a marketed medicine are included; they clearly state that such studies should not be conducted for the purposes of promotion Other studies investigating the safety of a medicine that are not directly sponsored by the manufacturer may
be identified from various organisations, e.g The Drug Safety Research Unit (Southampton, UK) using Prescription-Event Monitoring (PEM), the Medicines 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 Practice Research Database at the MCA All these systems have the important capacity to obtain information on very large numbers of patients,
10 000-20 000, in observational cohort studies and case-control studies which complement the spontaneous
reporting system (see Chapter 4)
In the UK, many new drugs are highlighted as being under special consideration by the regulatory authorities, by marking the drug with a symbol, the inverted black triangle T, in formularies The regu-latory authority communicates emerging data on safety of drugs to doctors through letters or papers
in journals, through specialist journals e.g Current Problems in Pharmacovigilance in the UK, and for
very significant issues by direct ('Dear Doctor') letters, and fax messages
Two other important regulatory activities that affect marketed drugs are:
• Variations to licences
• Reclassifications
Variations are substantial changes instigated
usually by pharmaceutical companies, but some-times by the regulatory authority, to the efficacy, safety or quality aspects of the medicine Most significant variations involve additions to indica-tions or dosing regimens, or to the warnings and contraindication sections of the SPC They need
to be supported by evidence and undergo formal assessment
Reclassification means change in the legal status
of a medicine and is the process by which a prescription-only medicine can be converted to one
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that is available directly to the public through
pharmacies and shops It follows a rigorous
assess-ment process with a particular stress on safety
aspects of the medicine and involves advice from
the Committee on Safety of Medicines, and requires
a change in secondary legislation The purpose of
reclassification is to allow easier access of the
general public to effective and safe medicines
Discussion
It may be wondered why postlicensing/marketing
surveillance and pharmacovigilance should be
necessary Common sense would seem to dictate that
safety and efficacy of a drug should be fully defined
before it is granted marketing authorisation
Pre-licensing trials with very close supervision are
commonly limited to hundreds of patients and this
is unavoidable, chiefly because this close supervision
is impracticable on a large scale for a very long time
Postlicensing studies are increasingly regarded
as essential to complete the definitive evaluation of
drugs under conditions of ordinary use on a large
scale, these programmes being preferable to attempts
to enlarge and prolong formal therapeutic trials
It would also seem sensible to require developers
to prove that a new drug is not only effective but is
actually needed in medicine before it is licensed But
a novel drug finds its place only after several,
sometimes many, years, and to delay licensing is
simply impracticable on financial grounds This
ought not to be so, but it is so A 'need clause' in
licensing is not generally practicable if drug
devel-opers are to stay in that business This is why
comparative therapeutic studies of a new drug with
existing drugs are not required for licensing in
countries having a research-based pharmaceutical
industry A 'need clause' is, however, appropriate
for economically deprived countries (see World
Health Organization Essential Drugs Programme);
indeed such countries have no alternative
The licensing authority in the UK is not concerned
with the pricing of drugs or their cost effectiveness
The cost of medicines does however concern all
governments, as part of the rising costs of national
health services A serious attempt to control costs
on drug usage by the introduction of national
guidelines on disease management (including the
use of individual drugs) and the appraisal of
new and established medicines for cost effective-ness now operate through a government funded body called NICE (National Institute for Clinical Excellence) The impact of its recommendations on health care, on costs and the pharmaceutical com-panies response to it are awaited
Licensed medicines for unlicensed indications
Doctors may generally prescribe any medicine for any legitimate medical purpose.10
But if doctors use a drug for an indication that is not formally included in the Product Licence ('off-label' use) they would be wise to think carefully and
to keep particularly good records for, if a patient is dissatisfied, prescribers may find themselves having
to justify the use in a court of law (Written records made at the time of a decision carry substantial weight, but records made later, when trouble is already brewing, lose much of their power to convince, and records that have been altered later are quite fatal to any defence.)
Manufacturers are not always willing to go to the trouble and expense of the rigorous clinical studies required to extend their licence unless a new use is likely to generate significant profits They are pro-hibited by law from promoting an unlicenced use
Unlicensed medicines and accelerated licensing
Regulatory systems make provision for supply of
an unlicenced medicine, e.g one that has not yet completed its full programme of clinical trials, for patients who, on the judgement of their doctors, have
no alternative amongst licensed drugs The doctor must apply to the manufacturer who may supply the drug for that particular patient and at the doctor's own responsibility Various terms are used, e.g supply on a 'named-patient' basis (UK); 'compassionate' drug use (USA) It is illegal to exploit this sensible loophole in supply laws to conduct research Precise record-keeping of such use is essential
10 In many countries this excludes supply of drugs such as heroin or cocaine for controlled/supervised maintenance of drug addicts In the UK such supply is permitted to doctors.
Trang 7But there can be desperate needs involving large
numbers of patients, e.g AIDS, and regulatory
authorities may respond by licensing a drug before
completion of the usual range of studies (making it
clear that patients must understand the risks they
are taking) Unfortunately such well-intentioned
practice discourages patients from entering formal
trials and may, in the long run, actually delay the
definition of lifesaving therapies
Decision taking
It must be remembered always that, though there are
risks in taking drugs, there are also risks in not taking
drugs, and there are risks in not developing new drugs.
The responsibility to protect public health on the
one hand yet to allow timely access to novel
med-icines on the other, is one shared by drug regulators
and developers It is complicated by an ever
increasing awareness of the risks and benefits
(real, or perceived) of medicines by the general
public
Some new medicines are registered with the
high expectation of effectiveness and with very
little safety information; rare and unpredictable
adverse events may take years to appear with
sufficient conviction that causality is accepted
In taking decisions about drug regulation, it has
been pointed out that there is uncertainty in three
areas.11
• Facts
• Public reaction to the facts
• Future consequences of decisions
Regulators are influenced not only to avoid risk
but to avoid regret later (regret avoidance) and this
consideration has a profound effect whether or not
the decision taker is conscious of it; it promotes
defensive regulation
It is self-evident that it is much harder to detect
and quanritate a good that is not done, than it is to
detect and quantitate a harm that is done Therefore,
although it is part of the decision-taker's job to
facilitate the doing of good, the avoidance of harm
11 Lord Ashby 1976 Proceedings of the Royal Society of
Medicine 69: 721.
looms larger Attempts to blame regulators for failing
to do good due to regulatory procrastination, the 'drug lag'12 do not induce the same feelings of horror
in regulators and their advisory committees that are induced by the prospect of finding they have approved a drug that has, or may have, caused serious injury and that the victims are about to appear on television.13 The bitterness of people injured by drugs, whether or not there is fault could
be much reduced by the institution of simple non-adversarial arrangements for compensation (see
p 10)
This is not to ridicule the regulators and their advisers They are doing their best, and commonly make good and sensible decisions that receive no congratulations
Counterfeit drugs
Fraudulent medicines make up as much as 6% of pharmaceutical sales worldwide They present a serious health (and economic) problem in coun-tries with weak regulatory authorities and lacking money to police drug quality In these countries counterfeit medicines may comprise 20-50% of available products The trade may involve false labelling of legally manufactured products, in order to play one national market against another; also low-quality manufacture of correct dients; wrong ingredients, including added ingre-dients (such as corticosteroids added to herbal medicine for arthritis); no active ingredient; false packaging
The trail from raw material to appearance on a pharmacy shelf may involve as many as four coun-tries, with the final stages (importer, wholesaler) quite innocent, so well has the process been obscured
Developed countries have inspection and enforce-ment procedures to detect and take appropriate action on illegal activities
12 Nevertheless, regulatory authorities have responded by providing a facility for 'fast-tracking' drugs for which clinical need may be urgent, e.g AIDS (see above).
13 The very last thing a drug regulator wishes to be able to say is, 'I awoke one morning and found myself famous': Lord Byron (1788-1824) on the publication of his poem, Childe Harold's Pilgrimage.
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GUIDETO FURTHER READING
Baber N 1994 International conference on
harmonization of technical requirements for
registration of pharmaceuticals British Journal of
Clinical Pharmacology 37: 401^04
Brass E P 2001 Changing the status of drugs from
prescription to over-the-counter availability New
England Journal of Medicine 345: 810-816
Collier J 1999 Paediatric prescribing: using unlicenced
drugs and medicines outside their licensed
indications British Journal of Clinical
Pharmacology 48: 5-8
Conroy S et al 2000 Survey of unlicenced and off label
drug use in paediatric wards in European
countries British Medical Journal 320: 79-82
DiMasi J A, Seibring M A, Lasagna L1994 New drug
development in the United States from 1963 to
1992 Clinical Pharmacology and Therapeutics 55:
609-622
Gale E A M, Clark A 2000 A drug on the market?
Lancet 355: 61-63
Medicines Control Agency 1994 Guidelines for
company-sponsored Safety Assessment of
Marketed Medicines (SAMM Guidelines) British Journal of Clinical Pharmacology 38: 95
Reichert J M 2000 New biopharmaceuticals in the USA: trends in development and marketing approvals 1995-1999 Trends in Biotechnology 18: 364-369
Richard B W et al 1987 Drug regulation in the United States and the United Kingdom: the Depo-Provera story Annals of Internal Medicine 106: 886-891; (An analysis of how drug regulators in the USA and the UK came to opposite conclusions on the same data.)
ON THALIDOMIDE
Chamberlain G 1989 The obstetric problems of the [now adult] thalidomide children British Medical Journal 298: 6
Dally A1998 Thalidomide: was the tragedy preventable? Lancet 351:1197-1199 Editorial 1981 Thalidomide: 20 years on Lancet 2: 510 Mellin G W et al 1962 The saga of thalidomide New England Journal of Medicine 267:1184-1192, 1238-1244
Trang 9Appendix: A tale to remember — the thalidomide
disaster
Thalidomide has provided a terrible lesson to the
world in regard to drug development, testing,
naming, prescribing and consumption It deserves
to be remembered
In 1960-61 in [West] Germany an outbreak of
phocomelia occurred Phocomelia means 'seal
extremities'; it is a congenital deformity in which
the long bones of the limbs are defective and
substantially normal or rudimentary hands and feet
arise on, or nearly on, the trunk, like the flippers of
a seal; other abnormalities may occur Phocomelia
is ordinarily exceedingly rare
Most [West] German clinics had no cases during
the 10 years up to 1959 In 1959, in 10 clinics, 17
were seen in 1959, 126 in 1960, 477 in 1961 The
European outbreak seemed confined to [West]
Germany (though a similar but smaller occurrence
was simultaneously noted in Australia), and this,
with the steady increase, made a virus infection,
such as rubella, seem an unlikely cause Radioactive
fall-out was considered and so were x-ray exposure
of the mother, hormones, foods, food preservatives
and contraceptives One doctor, investigating his
patients retrospectively with a questionnaire, found
that 20% reported taking a proprietary medicine,
Contergan, in early pregnancy He questioned the
patients again and 50% then admitted taking it;
many said they had thought the drug too obviously
innocent to be worth mentioning initially.14
In November 1961, the suggestion that a drug,
unnamed, was the cause of the outbreak was publicly
made by the same doctor at a paediatric meeting,
following a report on 34 cases of phocomelia That
night a physician came up to him and said, 'Will you
tell me confidentially, is the drug Contergan? I ask
because we have such a child and my wife took
Contergan' Several letters followed, asking the same
question, and it soon became widely known that the
sedative drug thalidomide (Contergan, Distaval,
Kevadon, Talimol, Softenon) was probably the cause
14 Illustrating the problem of retrospective research, e.g
case-control studies; enquiries of patients are unreliable.
It was withdrawn from the [West] German market in November and from the British market in December
1961 By that time reports had also come from other countries A case-control study showed that of
46 cases of phocomelia 41 mothers had taken thalidomide and of 300 mothers with normal babies none had taken thalidomide between the fourth and ninth week of pregnancy
Prospective observational cohort studies were quickly made in antenatal clinics where women had yet to give birth; though few, they provided evidence incriminating thalidomide The worst had happened, a trivial new drug was the cause of the most grisly disaster in the short history of modern scientific drug therapy Many thalidomide babies died, but many live on with deformed limbs, eyes, ears, heart and alimentary and urinary tracts.15
The [West] German Health Ministry estimated that thalidomide caused about 10 000 birth deformities in babies, 5000 of whom survived and 1600 of whom would eventually need artificial limbs In Britain there were probably at least 600 live births of malformed children of whom about 400 survived The world total
of survivors was probably about 10 000
Thalidomide had been marketed in [West] Germany in 1956, in Britain in 1958, and in other countries as a sedative and hypnotic and was recommended for use in pregnant women It had not been tested on pregnant animals When it was eventually tested it was at first difficult to induce fetal deformity (until it was used on New Zealand White Rabbits)
Thalidomide, skilfully promoted and credulously prescribed and taken by the public — it was also sold without prescription — achieved huge popularity;
it 'became [West] Germany's baby-sitter' It was a routine hypnotic in hospitals, was even recom-mended to help children adapt themselves to a convalescent home atmosphere and was sold mixed with other drugs for symptomatic relief of pain,
15 For pictures of thalidomide deformities, see British Medical Journal 1962; 2: 646-647 and Journal of the American Medical Association 1962; 180:1106-1114.
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cough and fever In 1960-61 it had become evident
that prolonged use of thalidomide could cause
hypothyroidism and peripheral neuritis The latter
effect was the principal reason why approval for
marketing in the USA, as Kevadon, had been
delayed by the US Food and Drug Administration
Approval had still not been given when the fetal
effects were discovered and so general distribution
was avoided Nonetheless some 'thalidomide babies'
were born in the USA following indiscriminate pre-marketing clinical trials
Thalidomide has anti-inflammatory and immuno-suppressant actions and retains a limited specialist use in, for example, lepromatous leprosy,16 and oral ulceration in AIDS (some cases)
The thalidomide disaster provided the impetus for the introduction of national drug regulatory 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.