THE CHANGING SHAPE OF
PHARMACEUTICAL RISK
PETER
FELDSCHREIBER
FOUR
NEW
SQUARE
LINCOLN’S INN
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