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)

 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
 THE LAW (2)
 Article 1:

The producer shall be liable for damage caused

by a defect in his product

 Article 4

The injured person shall be required to prove

the damage, the defect and the causal
relationship between defect and damage….
 THE LAW (3)
 Article 6
1. 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.
 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

 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 products

XYZ v Schering Health Care Ltd [2002] EWHC 1420 –

Combined oral contraceptive litigation
-even low cardiovascular risk meant defective product

Worsley v Tambrands [2000] PIQR P95 – warnings re

toxic shock syndrome sufficient to inform what
consumers where entitled to expect
 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?
 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.
 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
 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
 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.
 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
 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
 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
 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
 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?
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