THE CHANGING SHAPE OF
PHARMACEUTICAL RISK
PETER
FELDSCHREIBER
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A Brief History
• 120 B.C: Mithradatum/Galene – global panacea,
efficacy and safety trials on condemned prisoners
• 1450: manufacture supervised by 4 inspectors
appointed under Apothecary, Wares, Drugs and
Stuffs Act (c 32 Henry VIII c. 40 for Physicians and
their privileges).
• 1665: The Great Plague; Royal College of
Physician’s advice: ‘..for the cure of the plague and
preventing infection, treat with plaster of galene
applied three times daily…’
• 1746: Criticism of efficacy, last reference in the
London Pharmacopeia
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History (2)
• 1853 – 1871: Following increasing concerns as to
safety of smallpox vaccination, local authorities
employed vaccination officers to ensure quality.
Commons select committee investigating efficiency of
vaccination system recorded concern regarding
transmission of syphilis.
• BMA statement : ‘The duty of the Association, at
once, without any necessary delay is to satisfy the
public that all is being done to discover the means by
which anaesthesia may be rendered safe for the
future.’
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History (3)
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1907: Board of Trade issue manufacturing licenses to control quality of
Salvarsan. Each batch submitted to MRC for approval prior to marketing
1917: Venereal Diseases Act
1922: Salvarsan sub-committee of Parliamentary Select Committee on Patent
Medicines investigate Salvarsan induced jaundice: ‘The Committee hope that a
statement of the rare fatalities and other untoward effects of arsenobenzol may
encourage the communication to the Ministry of Health of details concerning
such accidents for it is only in the light of such information that investigation and
measures to their presentation can be undertaken.’
1925: Therapeutic Substances Act Part 1 introduced regulation of manufacture
of biological substances
1939: Cancer Act; prohibited public advertisements and promotion of drugs in
order to protect sufferers from inadequate or unsuitable treatment and fraudulent
claims of efficacy
1956: Part II added to control, sale and supply of medicinal products. Schedule
1 included sera toxins and antibodies.
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Overview 120 B.C. - 1956
• Predominantly control of quality, although
sporadic references and concerns regarding
safety and efficacy. However latter directed
towards ‘manufacturing defects’.
• No consistent systematic attempt to define
and evaluate intrinsic safety and efficacy of
new medicines even in face of major
developments on pharmacology e.g. insulin,
antibiotics, neurochemical transmitters etc.
No regulatory concept of risk : benefit
assessment
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And then came Thalidomide
• 1953 – 1956: Synthesis and manufacture in
West Germany: ‘
• 1957 Advertisement: ‘Does not damage either
mother or child’
• 1959: neuropathy reported during early use
• 1960: CNS toxicity
• 1961: McBride letter, Australia
• 10,000 babies world wide with phocomelia
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Manufacturer’s response
• Denied any causal relationship despite
the scale of the disaster
• Postulated causes included watching
television, radioactive fall out from
atomic bomb tests
• Recent drug withdrawals have
prompted similar responses
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Regulatory and clinical
responses
• 2nd December 1961: Drug withdrawn from UK
• 9 months later wave of malformations disappeared
• 1962 Joint Sub-Committee of the English and
Scottish Standing Medical Advisory Committees
• Identified need for adequate pharmacology and
safety and efficacy testing before release of new
medicines into general use. Also need for early
detection of adverse effects arising after release and
to keep doctors informed
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1961 - 1963
• UK accept key recommendations:
• Responsibility for experimental animal testing
prior to clinical trials remains with pharma
manufacturer
• Expert advisory body to review evidence and
offer advice on toxicity of new drugs
• June 1963 Committee on Safety of Drugs
formed
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1965 - 1966
• Manufacturers challenge right of CSD to
require evidence of efficacy. Committee
reiterate that for serious diseases failure of
efficacy constitutes unacceptable risk – first
expression of risk : benefit assessment
• Phenacetin: high doses recognised as cause
of renal damage
• Committee recognises problems of drug
interactions: adrenaline interacting with
MAOI anti-depressants
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1966 onwards
• Voluntary reporting of yellow cards and computerised
adverse reactions on-line information systems
• Identified methyl dopa as cause of haemolytic
anaemia
• Pressurised aerosols of broncholdilators for asthma
become prescription only medicines.
• Withdrawal of pronethalol and phenopropazine
• Ibufenac withdrawn due to hepatotoxicity
• 1968 – oral contraceptives induced thromboembolism
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Medicines Act 1968
• Comprehensive measures to replace
most previous legislation re control of
medicines
• Now consistent with European Law
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Scientific developments post
thalidomide
• Greater sophistication in assessing risk :
benefit: improved clinical trial methodology
and statistical techniques
• Evaluation of causality
• Pharmacogenomics – uses genetic
information to predict individual responses to
drugs.
• International harmonisation of clinical trials
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Regulatory Structure and
Function post-thalidomide (1)
• Current framework only 50 years old and has
developed piecemeal.
• Function of the regulator is to:
- protect the public health by allowing only medicines
which have a satisfactory risk : benefit profile to be
marketed and remain so;
- to provide information to prescribers so that these
products can be used safely and effectively;
- not to put unnecessary hurdles in the way of the
development of innovative products
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Regulatory Structure and
Function post-thalidomide (2)
• Regulation must follow science
• Drug development has changed out of all
recognition in the last 50 years
• Regulators now recognise that, at the time of
licensing, the risk-benefit profile may not be
the same as when the drug has been in
extensive use in the population at large. Risk
: benefit has to be assessed iteratively during
its life cycle.
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Ongoing problems and
challenges
• Cox 2 inhibitors: Withdrawal of these, e.g. Vioxx, is an important
watershed in terms of medicine regulation. Emphasises the
importance of mandatory pharmaco-vigilance and risk
minimisation strategies.
• Monoclonal antibodies: Herceptin, now recognise changing riskbenefit depending on indication for use; Cardiotoxicity of
herceptin may be acceptable in advanced breast cancer but use
in early cancer may pose unacceptable risk of cardiac damage.
TGN1412, the Northwick Park catastrophe: need for better preclinical assessment of mechanisms of action and more
appropriately designed pre-clinical studies
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Re-emergence of Thalidomide
• 1998: Approved for complications of leprosy
• Available ‘off – label’ HIV/AIDS related conditions,
autoimmune diseases, cancer – multiple myeloma,
primary brain tumours
• Current research in Crohn’s disease, rheumatoid
arthritis
• Need to monitor exposure in women of child-bearing
age
• Ethical issues in marketing known teratogen
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Lessons to be learnt
• Current regulatory system may have intrinsic defects
of structure and function
• Structure: System may not be able to accommodate
requirements of consumer protection legislation as
regards product liability.
• Function: methodology for evaluating risk : benefit
may not be sufficiently robust for assessment of new
therapeutic modes of action, e.g. monoclonal
antibodies. Need for ‘bespoke’ risk assessment from
earliest stages of drug development
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Improvement of the Regulatory
system
• Two stage approach:
• Objective evaluation of risk : benefit by
scientific experts followed by
• Patient/lay representation in final
approval of marketing authorisation
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Epilogue
• The risk has not changed
• The perception of the risk and risk-benefit of
new medicines is constantly changing
• How can society improve the mechanisms of
understanding and accepting risk so that new,
potentially life saving medicines can be
brought to the population?
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THE CHANGING SHAPE OF
PHARMACEUTICAL RISK
PETER FELDSCHREIBER
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