Epidemiological uncertainty, causation, and drug product liability.

• Author: Goldberg, Richard
• Position: Technological Innovation and Civil Responsibility

Epidemiological evidence is regularly presented to courts in determining proof of causation in medicinal product liability litigation. Building on the foundations of the author's previous monograph, which supported the use of epidemiological evidence in dealing with problems of proof of causation in alleged cases of adverse drug reactions, this paper revisits this perennial problem of the role of epidemiological evidence in assessing causation in product liability cases in a twenty-first century context, examining recent cases in the United Kingdom, United States, Australia, and Canada. It seeks to determine the extent to which the courts in the highlighted cases have been pragmatic and fair in their interpretation and utilization of epidemiological evidence, from the perspective of both consumers and pharmaceutical manufacturers. The paper examines the apparent tension between the levels of proof required in law and science, including the relationship between levels of statistical significance and the claimant's burden of proof; and it assesses the wisdom of using a doubling of the risk rule as a threshold to any recovery. It explores the ways in which probabilistic methods, including statistical refining with individual risk factors, can be used in conjunction with epidemiological evidence to determine specific causation. The paper supports the view that logistic regression techniques and other forms of statistical refining mechanisms using specific risk factors can and do help in the process of giving quantitative or quasi-quantitative expression to conclusions about the cause of disease in an individual drug product liability claim that is based on epidemiological evidence.

La preuve epidemiologique est regulierement presentee pour demontrer la causalite dans les litiges en matiere de responsabilite pour les produits therapeutiques.

En se fondant sur l'une des monographies precedentes de l'auteur, qui appuie le recours a la preuve epidemiologique pour traiter des difficultes a prouver la causalite dans des affaires portant sur les effets indesirables de medicaments, cet article reexamine, dans le contexte du XXIe siecle, le probleme constant du role de la preuve epidemiologique dans les questions de causalite en matiere de responsabilite du fabricant. Il analyse a cette fin la jurisprudence du Royaume-Uni, des Etats-Unis, de l'Australie et du Canada. Cet article cherche a cerner jusqu'a quel point les tribunaux ont adopte, dans les affaires etudiees, une approche pragmatique et juste en interpretant et en utilisant la preuve epidemiologique, tant du point de vue des consommateurs que de celui des fabricants de produits pharmaceutiques. Il examine la tension entre les niveaux de preuve necessaire dans les domaines scientifique et juridique, y compris la relation entre les niveaux de signification statistique et le fardeau de la preuve du demandeur, et evalue la possibilite d'utiliser la regle de doublement du risque comme seuil pour un recouvrement judiciaire. Il explore les facons dont les methodes probabilistes, telles que l'affinage des statistiques avec des facteurs de risque, peuvent etre utilisees en conjonction avec la preuve epidemiologique afin de determiner la causalite specifique. Cet article avance que les techniques de regression logistique, ainsi que d'autres mecanismes de raffinement statistique se servant de facteurs de risque specifiques, peuvent aider a donner une expression quantitative ou quasi-quantitative aux conclusions portant sur la causalite dans une reclamation en responsabilite pour un produit therapeutique base sur la preuve epidemiologique.

Introduction I. Reconciling the Standards of Proof in Law and Science in the United Kingdom A. Evidence of Causation for Purposes of Science and for Purposes of Law B. Doubling of Risk Theory C. Association Versus Causation D. Teaching Courts Epidemiology E. The Statistical Chance/Personal Chance Dichotomy F. Overcoming the Statistical Chance/Personal Chance Dichotomy: Statistical Refuting Mechanisms Using Specific Risk Factors Conclusions Introduction

Proof of causation in toxic tort litigation is an inherently difficult problem, which regularly requires time-consuming analysis of complex scientific evidence. (1) The difficulties in proving both general causation (whether a product was capable of causing the damage alleged) and specific causation (whether the product did so in the individual case) are magnified in the context of medicinal products. (2) As Harvey Teff and Colin Munro have highlighted:

Drugs are always potentially dangerous due to their toxicity. They are often taken by people who are already ill and who may be unusually susceptible to further ailments. Unlike many other products, they may cause injury in unpredictable ways, depending on the individual user's constitution. They may not be taken according to the instructions. The user may be allergic to a particular drug. Alternatively, what appears to be an allergy may in fact be a toxic reaction. (3) With a multitude of new kinds of drugs emerging as a harvest of the scientific and technological revolutions of both the twentieth and early twenty-first centuries, the cases have become even more complex, demanding much from lawyers and scientific experts on both sides and from judges themselves. (4)

The practical significance of establishing causation in a medicinal product liability case cannot be overstated. In the United Kingdom, whether the claim is in negligence or under the strict liability provisions of the Product Liability Directive, (5) proof of causation will often lead to either a settlement or a successful claim. (6) Conversely, a failure to establish a causal link between a medicinal product and, for example, the alleged medical conditions of claimants, may lead to such claims being struck out as an abuse of the process of the court on the basis that each claim has no real prospect of success. (7)

Epidemiology is defined as "the field of public health and medicine that studies the incidence, distribution and etiology of disease in human populations." (8) Epidemiological evidence is regularly presented to courts in determining proof of causation in medicinal product liability litigation. Building on the foundations of the author's previous monograph, which supported the use of epidemiological evidence in dealing with problems of proof of causation in alleged cases of adverse drug reactions, (9) this paper revisits the perennial problem of the role of epidemiological evidence in assessing causation in product liability cases in a twenty-first century context, examining recent cases in the United Kingdom, United States, Australia, and Canada. In essence, it seeks to determine the extent to which the courts in the highlighted cases have been pragmatic and fair in their interpretation and utilization of epidemiological evidence, from the perspective of both consumers and pharmaceutical manufacturers.

In order to establish factual causation in the context of medicinal product liability, claimants must prove both general causation ("whether a substance is capable of causing a particular injury or condition in the general population") (10) and specific causation ("whether a substance caused a particular individual's injury"). (11) Since epidemiology is based on the study of populations and not individuals, it focuses on the question of general causation rather than specific causation. (12) Epidemiological evidence may identify an association between a drug and a disease, but whether such an association is causal requires an evaluation of the evidence, with emphasis on the extent to which weaknesses of a study's design and implementation compromise its findings and inferences about causation. (13)

The results of epidemiological studies cannot per se conclusively prove specific causation. However, several cases have focused on the role that epidemiological evidence plays in determining proof of specific causation, which is a legal question addressed by courts. (14) This paper explores the ways in which probabilistic methods, including statistical refining with individual risk factors, can be used in conjunction with epidemiological evidence to determine specific causation.

Part IA explores the apparent tension between the levels of proof required in law and science, including the relationship between levels of statistical significance and the claimant's burden of proof. Part IB assesses the wisdom of using a "doubling of the risk" rule as a threshold to any recovery. Notwithstanding the problems with the doubling of risk theory in the United States, its usage appears to be gaining ground in the United Kingdom. Moreover, in particular, the doubling of risk theory has come to recent attention in the context of the utilization and value of epidemiological or statistical evidence alone in determining causation on a balance of probabilities, with discussion by the UK Supreme Court in Sienkiewicz v. Greif. (15) cautious attitude toward the use of the doubling of risk rule in the context of both general and specific causation is seen from the case law explored. In examining the distinction between association and causation, Part IC discerns two main reasons for this judicial scepticism about epidemiological evidence, namely the propriety of drawing causal inferences from observed associations (a general causation issue) and the propriety of drawing causal inferences in individual cases from concededly causal associations observed in samples of populations (a specific causation issue). These reasons are discussed in an analysis of the controversial Scottish case of McTear v. Imperial Tobacco Ltd (16) and the decision of the Federal Full Court of Australia in Merck Sharp & Dohme (Australia) Pty Ltd v. Peterson. (17) In the context of McTear, Part ID discusses the necessity of requiring something more than a doubling of the risk to permit the claimant to recover...