FOUR NEW SQUARE LINCOLN’S INN. THE CHANGING SHAPE OF PHARMACEUTICAL RISK. PETER FELDSCHREIBER. A Brief History. 120 B.C : Mithradatum/Galene – global panacea, efficacy and safety trials on condemned prisoners
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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.’
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.
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
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
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
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
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.
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
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