DRUG INDUCED INJURY – RISK AND CAUSATION

DRUG INDUCED INJURY – RISK AND CAUSATION PETER FELDSCHREIBERAnd ROB HEMMINGS And LEIGH–ANN MULCAHY

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

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: 1000’s 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

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

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

The Court’s 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 COC3’s failed to establish relative risk of 2:1 • 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)

The Court’s 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 Claimant’s 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 individual’s 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.

The Court’s 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 D’s 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).

The Court’s 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 defendant’s 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?

Evidential and Statistical Issues in UK litigation • Gregg v Scott: Claimant’s 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.’

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 McRae’s expert opinion (for the industry). McRae’s 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…..’

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.

The Regulator’s 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

The Court’s 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

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)

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

DRUG INDUCED INJURY – RISK AND CAUSATION