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THE DEVELOPMENT RISKS DEFENCE

THE DEVELOPMENT RISKS DEFENCE. DR PETER FELDSCHREIBER FOUR NEW SQUARE, LINCOLNS’ INN and MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY. THE LAW. EC COUNCIL DIRECTIVE ON LIABILITY FOR DEFECTIVE PRODUCTS (85/374/EEC)

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THE DEVELOPMENT RISKS DEFENCE

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  1. THE DEVELOPMENT RISKS DEFENCE DR PETER FELDSCHREIBER FOUR NEW SQUARE, LINCOLNS’ INN and MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY

  2. THE LAW • EC COUNCIL DIRECTIVE ON LIABILITY FOR DEFECTIVE PRODUCTS (85/374/EEC) • CONSUMER PROTECTION ACT 1987:LIABILITY OF ALL WHO HOLD THEMSELVES AS PRODUCERS: • ‘DEFECTIVENESS’ NOT FAULT IS CRITERIA FOR RECOVERY – I.E. REGIME OF STRICT LIABILITY

  3. THE LAW (2) • Article 1:The producer shall be liable for damage caused by a defect in his product • Article 4The injured person shall be required to prove the damage, the defect and the causal relationship between defect and damage….

  4. THE LAW (3) • Article 61. A product is defective when it does not provide the safety which a person is entitled to expect, taking all circumstances into account, including: a) the presentation of the product; b) the use to which it could reasonably be expected that the product would be put; c) the time when the product was put into circulation.2. A product shall not be considered defective for the sole reason that a better product is subsequently put into circulation.

  5. THE LAW (4) • Article 7:The producer shall not be liable as a result of this Directive if he proves:e. ….. that the state of scientific and technical knowledge at the time when he put the product into circulation was not such as to enable the existence of the defect to be discovered – • also CPA section 4(1)f

  6. THE LAW (5) • UK case law as applied to medicines and health care products:A v National Blood Authority [2001] 3 All ER 289- hepatitis contamination of blood productsXYZ v Schering Health Care Ltd [2002] EWHC 1420 – Combined oral contraceptive litigation-even low cardiovascular risk meant defective productWorsley v Tambrands [2000] PIQR P95 – warnings re toxic shock syndrome sufficient to inform what consumers where entitled to expect

  7. THE LAW AND THE SCIENTIFIC EVIDENCE • In the drug development process when does the producer become able to discover the existence of a defect? • In scientific terms when is there sufficient evidence of safety risks to trigger evaluation and awareness of inappropriate risk-benefit of the product?

  8. A BRIEF GUIDE TO DRUG DEVELOPMENT(1) • Pre-clinical in-vitro and animal pharmacology and toxicology-hypothesis of mechanism of action may raise index of suspicion of safety problems: • Vioxx: selective inhibition of COX2 may leave thromboxanes (involved in clotting) in vessel wall unchallenged – risk of myocardial infarction and stroke, but no evidence yet in man.

  9. A BRIEF GUIDE TO DRUG DEVELOPMENT(2) • Phase 1, first studies in volunteers in pharmacokinetics and pharmacodynamics and overt toxicity:- data to evaluate disposition and metabolism in the body and confirm pharmacological mode of action; small numbers; insensitive in detection of potential serious and infrequent side-effects

  10. A BRIEF GUIDE TO DRUG DEVELOPMENT(3) • Phase II: First trials in patients;- objective to find best dose and investigate safety • Phase III- major trials aimed at conclusively demonstrating efficacy – pivotal registration data • Phase IV- post –registration studies for marketing and broader experience of new product

  11. THE DEVELOPMENT OF VIOXX • PRE-CLINICAL PHARMACOLOGY AND TOXICOLOGY • Vioxx: selective inhibition of COX2 may leave thromboxanes (involved in clotting) in vessel wall unchallenged – risk of myocardial infarction and stroke; but no evidence of eventuation of this risk in man at this stage of development programme.

  12. THE DEVELOPMENT OF VIOXX • Phase 1 • Possible to confirm extent of thromboxane production if appropriate tests had been performed, but not possible to confirm clinical implications in terms of cardiovascular and cerebrovascular morbidity and mortality

  13. THE DEVELOPMENT OF VIOXX • Phase II- although small scale studies, possible to evaluate thromboxane effects and surrogate markers for clinical implications • Phase III- studies of sufficient size/statistical power to detect serious adverse events – pivotal studies providing data to evaluate risk:benefit for registration, best pre-licensing mechanism for detecting adverse events but may be insufficient to detect rare/uncommon events

  14. THE DEVELOPMENT OF VIOXX • Phase III continued: • Vioxx Gastro –intestinal Outcomes Trial ‘Vigor’ - Preliminary results in 2000 – more cardiovascular events over 1 year in patients receiving Vioxx than naproxen- unclear whether this indicated harmful effect of Vioxx or beneficial effect of naproxen; need placebo controlled study • Adenomatous Polyp Prevention on Vioxx ‘APPROVe’- prospective randomised placebo controlled study- increase in cardiovascular risk approximately18 months after continuous Vioxx therapy – drug withdrawn 2004

  15. THE DEVELOPMENT OF VIOXX • Issue: when did the producer and the regulator recognise the ‘defect’? • May 1999 – FDA reviewer suggested ‘data seem to suggest thromboembolic events more frequent in patients receiving rofecoxib (vioxx) than placebo • 2000, along with VIGOR trial, study 090 (unpublished) showed significant excess of heart attack and stroke in patients taking Vioxx, as compared with controls. In study 090 excess of events within 6 weeks. In VIGOR event curves divergent by 30 days • Action taken by regulators to amend product licence BUT should Vioxx have been withdrawn several years earlier than it was? • Other studies will provide further evidence but are yet to report

  16. KEY QUESTIONS • Risk benefit evaluation is progressive iterative process throughout all stages of drug development and post marketing. It is a dynamic process. • Risk benefit evaluation assesses known safety against potential benefit. • When does potential benefit become established benefit? At what stage in the development process does this occur? • When, during the development programme, will a company cease to be able to rely on the development risks defence?

  17. What constitutes evidence of risk? • Numerical increases in incidence of side effect might be due to chance • Statistically significant evidence of increased incidence of side effect, i.e less than 5% probability that increase observed due to chance, is still a non-zero probability; extreme statistical significance, e.g. less than 1% or 0.1% still non-zero probability • Absence of numerical trend or statistical significance does not imply absence of risk

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