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

2. 2 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

3. 3 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.’

4. 4 History (3) 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.

5. 5 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

6. 6 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

7. 7 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

8. 8 Regulatory and clinical responses 2 nd 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

9. 9 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

10. 10 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

11. 11 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

12. 12 Medicines Act 1968 Comprehensive measures to replace most previous legislation re control of medicines Now consistent with European Law

13. 13 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

14. 14 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

15. 15 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.

16. 16 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 risk- benefit 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 pre- clinical assessment of mechanisms of action and more appropriately designed pre-clinical studies

17. 17 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

18. 18 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

19. 19 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

20. 20 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?

21. THE CHANGING SHAPE OF PHARMACEUTICAL RISK PETER FELDSCHREIBER