DRUG INDUCED INJURY

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DRUG INDUCED INJURY RISK AND CAUSATION

• PETER FELDSCHREIBERAnd
• ROB HEMMINGS
• And
• LEIGHANN MULCAHY

2
OBJECTIVES

• Outline methods of technical /regulatory
  evaluation of causation
• Medical and statistical principles
• Examine the common ground (if any!) between
  technical and the courts approaches

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The Clinical Drug Development Programme

• Phase 1
• - First in man studies 30 40 healthy subjects
  or patients
• - Risk predicated from findings of preclinical
  animal toxicology/pharmacology studiesPhase2
• First studies in 100 or so patients
• Proof of concept/mechanism of efficacy
• Limited power to detect unexpected /rare
  unforeseen safety related adverse events
• Typically can identify common dose related
  adverse events
• For uncommon events e.g.1 in 100, trial unable to
  differentiate between chance and causal
  relationship.Phase 3
• Pivotal studies 1000s patients with indicated
  disease
• Sufficiently powerful to detect 1in 100 1 in
  1000 events
• Need for rigorous causality assessment
• Study protocols designed to provide pivotal data
  on efficacy and safety

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Determination of Causality

• Is there a reasonable possibility that the
  product is aetiologically related to the adverse
  experience?
• Temporal relationships
• De-challenge / re-challenge information
• Association with underlying disease
• Presence or absence of more likely cause
• Physiological/pathological plausible hypothesis

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Confounding factors

• Recently introduced drugs
• Multiple drug therapy
• Drug withdrawal
• Non drug therapy
• Invasive diagnostic tests and procedures
• Underlying diagnosed and non-diagnosed illness
• Concurrent illnesses
• Note that these factors are interrelated damage
  may be related to both drug and one or more of
  these

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The Courts evaluation of causation

• (1) GENERAL CAUSATIONIs the drug capable of
  causing this kind of damage in the population at
  large or any group of individuals?But
  for/balance of probabilities i.e. relative risk
• Epidemiology (pharmaco-epidemiology) and
  clinical, pathology/pharmacology for mechanism of
  action
• Example XYZ v Schering proof of general
  causation failed since COC3s failed to establish
  relative risk of 21
• Statistical issues Why not absolute frequency?
  What is baseline for comparison - accepted
  standard treatment or placebo?
• Evidential issues Court requires epidemiology
  and pharmacological expertise, but Court must be
  provided with the tools to understand the
  significance of the epidemiology conclusions (Mc
  Tear)

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The Courts evaluation of causation

• (2) INDIVIDUAL CAUSATIONWas the damage to the
  Claimant in fact caused by the drug?But
  for/balance of probabilities test. Can it be
  said that but for administration of the drug, the
  Claimants damage would not have been sustained?
• Evidence epidemiology identifying association
  between drug and damage in population as a whole
  or in particular subgroups pharmacology
  including temporal and dose relationships
  clinical diagnostic features other potential
  causative agents race/sex other therapies
• Example McTear v Imperial Tobacco Attempt to
  prove individual causation using epidemiology
  failed epidemiology cannot provide information
  on the likelihood that an exposure produced an
  individuals condition.
• Statistical issues significance of epidemiology
  data when applied to an individual
  patient/claimant. E.g. Jonny Wilkinson example
  assumption that if 1 in 100 chance of risk
  eventuating and that if 99 did not suffer damage,
  chance in 100th case is 100 and not 1 in 100.
• Evidential issue Court requires both
  epidemiology and clinical/pharmacological
  expertise.

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The Courts evaluation of causation

• (3) FAULT OR PROXIMATE CAUSATION
• If the defect had not existed would the Claimant
  have suffered the damage?
• Either but for test or (possibly) modified
  causation test
• Claimant must prove that but for Ds
  negligence/or the defect in the drug he would not
  have sustained the damage.
• Recovery may be still possible when the but for
  test cannot be established. (Fairchild v
  Glenhaven Funeral Services Barker v Corus).

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The Courts evaluation of causation

• Did the breach of duty on the part of the
  Defendant or the defect in the drug cause or
  materially contribute to the damage suffered
  either by making a material contribution to the
  damage or by materially increasing the risk of
  damage?Limitations on modified approach
• (1) there have to 2 or more potential causes of
  the damage
• (2) they must have the same mechanism but
  impossible for science to prove which cause
  actually caused the damage and
• (3) the defendants liability is limited to its
  contribution to the risk.
• Of particular relevance in damage caused by
  generic drugs administered in chronic conditions
  DES litigation USA Potential Seroxat litigation
  in U.K.
• NB Use of market share as basis for establishing
  causation not yet adopted in UK. Can arguably be
  used to assess extent of contribution to risk?

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Evidential and Statistical Issues in UK litigation

• Gregg v Scott Claimants expert opinion in
  1999 based on contemporaneous published
  statistics prompt treatment would have resulted
  in 84 10 year survival. Delay had reduced this
  to under 50. However before trial new medical
  research revealed difference between ALK positive
  and ALK negative non- hodgkins lymphoma as
  regards survival rates. Rendered original
  statistical epidemiological evidence unusable.
  Experts had to rely on best evidence of relevant
  statistics. On this new basis chance of survival
  less than 50 because Claimant was ALK negative.
• Lord Nicholls The present state of the law is
  crude to an extent bordering on arbitrariness.
  It means that a patient with a 60 chance of
  recovery reduced to a 40 prospect by medical
  negligence can obtain compensation. But he can
  obtain nothing if his prospects were reduced from
  40 to nil. This is rough justice indeed.the
  law must strive to achieve a result which is fair
  to both parties in present day conditions.

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Evidential and Statistical Issues in UK litigation

• XYZ v Schering Health CareAction brought
  against three pharma companies by women claiming
  they had been harmed by COC3S. In Oct 1995 CSM
  warned that such contraceptives carried higher
  risk of venous thrombo-embolism. Manufacturers
  unconvinced. Acrimonious debate followed. Mr
  Justice Mackay impressed by Ken McRaes expert
  opinion (for the industry). McRaes initial
  analysis of one study confirmed increased risk
  but several re-analyses using Cox regression
  analysis enabled the reverse conclusion. On
  basis of this one study judge determined that
  COC3S do not carry increased risk.
• BMJ ....this was a bizarre conclusion. Cox
  regression analysis was developed for prospective
  studies its application in the current context
  is highly controversial and has never been
  subjected to rigorous peer review in the
  statistical literature..

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Evidential and Statistical Issues in UK litigation

• McTear v Imperial TobaccoMrs McTear sought
  damages from Imperial Tobacco in respect of the
  death of her husband from lung cancer caused to a
  material extent by the smoking of cigarettes.
  Although she accepted that the mechanism by which
  tobacco caused lung cancer was not known she
  relied on medical expert evidence of the
  epidemiology between smoking and lung cancer.
  The defendants argued that smoking was not the
  cause of lung cancer and the expert evidence had
  failed to impart to the court a special
  knowledge of epidemiology so it could make its
  own judgement on general causation. Also
  epidemiological evidence could not be used to
  determine individual causation. The Court
  accepted both of these arguments In particular
  Epidemiological arguments could not be used to
  draw conclusions about the cause of disease in an
  individual. The statistical risk of disease in a
  population did not imply a likelihood of disease
  occurrence in an individual.
• Lord Nimmo Smith explicitly criticised the
  statistical evidence.

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The Regulators view

• Objective is to evaluate clinical significance of
  safety signals in the population and to act in
  accordance with the precautionary principle for
  attributing efficacy the conventionally held
  threshold level is statistical significance at
  probability less than 5 i.e. less than 1 in 20
  chance of event occurring not being due to
  chance however action may be taken as regards
  safety with less compelling evidence.
• Evaluates data on basis of absolute frequency,
  not relative risk.
• Assesses both epidemiology statistics and
  pharmacology/pathology data where possible.
  Important to note that the degree of acceptance
  of mechanistic hypotheses changes during drug
  development Vioxx and myocardial infarction
  seroxat akisthisia and suicidal ideation
  thalidomide and nervous system toxicity

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The Courts view

• Objective is to provide just result as regards
  individual claimants and defendants
• Determines causation on much higher threshold
  balance of probabilities/greater than 50
  likelihood
• Uses relative frequency of events and relative
  risk rather than absolute frequency
• Sometimes evaluates causation on basis of
  arbitrarily chosen statistical parameters, e.g.
  10 year survival rate in Gregg and Scott

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Common mistakes by courts/lawyers

• Use of relative risk without regard to absolute
  frequency (e.g. X,Y,Z)
• Applying general epidemiology to individual
  causation and risk (e.g. McTear Badger)

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A Judges View

• for a court of law a fact is proved if the
  court holds that it is more probable than not,
  even if it is only marginally more probable. If
  we stand back, we can see that it is a remarkably
  lax standard. By contrast, scientific experts,
  who do not work under the guiding image of a set
  of scales, require a very much higher standard of
  proof before they hold that something has been
  established for their purposes
• .for my part I would have found it helpful to
  hear expert evidence from a medical statistician.
  More generally, I wonder whether lawyers have
  really woken up to the need for a basic
  understanding of statistics if we are to
  appreciate what many medical and other scientific
  witnesses are saying
  Lord Roger of
  Earlsferry
  Personal Injury Bar
  Association
  Newsletter Issue One 2006