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From Health Law Daily, March 19, 2018

Experts’ opinions on Abilify®’s link to impulse control problems scientifically reliable, admissible

By Jeffrey H. Brochin, J.D.

A federal district court in Florida ruled that the biological plausibility opinions provided by the experts in a multidistrict product liability action against the manufacturers and marketers of Abilify® (aripiprazole), were scientifically reliable as to causation, and were therefore admissible. The court found that the experts’ opinions that Abilify can cause impulse control problems were based on current biochemistry and pharmacological knowledge and that all that was required was a scientific plausibility of causation, not a showing of scientific certainty (In Re: Abilify (Aripiprazole) Products Liability Litigation, March 15, 2018, Rodgers, M.).

Background. In 2002, the anti-psychotic drug Abilify was approved by the FDA for the treatment of schizophrenia. It was subsequently approved for use in patients with bipolar disorder, irritability associated with autistic disorder, Tourette’s Syndrome, and other mental health conditions. In 2010, the first published reports surfaced in medical literature suggesting a possible link between Abilify and pathological gambling. After more published reports followed, as well as hundreds of informal reports from patients and healthcare professionals as to gambling and other impulsive behavior, the scientific community, the FDA, the manufacturers, and public health agencies worldwide took notice and began examining whether Abilify was linked to impulse control disorders.

In 2012, the European Medicines Agency (EMA) required the manufacturers to modify the drug’s product label in Europe to include pathological gambling as a possible "post-marketing undesirable effect." In 2015, Health Canada found an "increased risk" of pathological gambling, as well as hyper-sexuality related to Abilify use, and ordered that the drug’s product monograph be updated to advise of these possible adverse effects. The FDA subsequently initiated a pharmacovigilance review to evaluate whether the potential link between Abilify and impulse control disorders presented a safety issue warranting regulatory action. The review identified an association between Abilify and impulse control disorders.

In the products liability litigation, the manufacturers moved for summary judgment on the issue of general causation—whether Abilify is capable of causing uncontrollable impulses to engage in certain harmful behaviors—necessitating the court’s thorough examination of both sides’ scientific research findings and conclusions offered into evidence.

Expert challenges. The patients’ position centered on how Abilify causes impulse control problems by binding and interacting with two dopamine receptors in the brain in order to produce physiological effects in the form of impulsive behaviors. To establish such causation, they proffered the testimony of five experts, each of whom presented studies in support of the conclusion that Abilify can cause impulsive behaviors. The manufacturers challenged the admissibility of that expert testimony, as to general causation, as unreliable. Specifically, the manufacturers contended that the patients failed to provide reliablescientific evidence demonstrating a statistically significant association between Abilify and impulsive behaviors. They argued that such an omission was a fatal flaw in the patients’ case because their remaining evidence was insufficient as a matter of law, even in the aggregate, to establish general causation.

Determining expert testimony reliability. The court began by reciting the criteria by which expert testimony is admissible: (1) the expert is sufficiently qualified to testify about the matters he intends to address; (2) the methodology used is sufficiently reliable under inquiry; and (3) the testimony assists the trier of fact, through the application of scientific, technical, or specialized expertise, to understand the evidence or to determine a fact in issue. These criteria have been referred to separately as "qualification, reliability, and helpfulness." The party offering the expert has the burden of showing, by a preponderance of the evidence, that each of these requirements has been met, and the court may not evaluate the credibility of opposing experts or the persuasiveness of their conclusions, but rather is limited to ensuring that the fact-finder weighs only sound and reliable evidence.

Reliability of expert testimony on general causation. To prevail in a pharmaceutical products liability case, a plaintiff must establish both general and specific causation through reliable expert testimony: general causation is established by demonstrating, often through a review of scientific or medical literature, that a drug or chemical can, in general, cause the type of harm alleged; and, specific causation is established by showing that exposure to the allegedly toxic drug or chemical actually caused an individual’s injury. Only the issue of general causation—i.e. whether Abilify was capable of causing impulse control disorders, such as impulsive gambling—was at issue in the motions presented to the court.

Primary and secondary methodologies. Because the parties’ experts offered various combinations of primary and secondary methodologies in support of their general causation opinions, the court first set out the scientific and legal principles governing the reliability of each methodology, and in particular focused on epidemiological studies, the branch of science that studies the incidence, distribution, and cause of disease in human populations. The court noted that the first step in establishing causation through epidemiology is to demonstrate that exposure to a drug is associated with a particular disease or adverse effect, and once an association is identified, scientists next determine whether the association represents a true cause-effect relationship between exposure and the disease.

Bradford Hill factors. Any causation inquiry is guided by nine well-established factors, known in the scientific community as the Bradford Hill factors, which include: (1) temporal relationship; (2) strength of the association; (3) dose-response relationship; (4) replication of the findings; (5) biological plausibility; (6) consideration of alternative explanations; (7) cessation of exposure; (8) specificity of the association; and (9) consistency with other knowledge. No one factor is dispositive, and determining whether an association is causal is a matter of scientific judgment. Furthermore, scientists reliably applying the Bradford Hill factors may reasonably come to different conclusions about whether a causal inference may be drawn.

Biological plausibility—not certainty. After restating that the relevant standard in the case was "biological plausibility," not "biological certainty," the court found the patients’ experts’ proposed mechanism of action to be biologically plausible, and that the opinions that Abilify can cause impulse control problems through its effects on dopamine neurotransmission in the brain were scientifically reliable based on current biochemistry and pharmacological knowledge. The court also found that each element of the proposed mechanism of action was adequately supported by peer-reviewed, published scientific literature and sound scientific reasoning. Moreover, the experts’ opinions were consistent with the FDA’s assessment and were based on scientific literature. The expert opinions were found to be admissible.

The case is No. 3:16-md-02734-MCR-GRJ.

Attorneys: Bryan Frederick Aylstock (Aylstock, Witkin, Kreis & Overholtz, PLLC) for Plaintiffs. Anand Agneshwar (Arnold & Porter LLP) for Bristol-Myers Squibb Co. Eric M. Goldstein (Winston & Strawn LLP) for Otsuka America Pharmaceutical Inc. and Otsuka Pharmaceutical Co., Ltd.

Companies: Bristol-Myers Squibb Co.; Otsuka America Pharmaceutical Inc.; Otsuka Pharmaceutical Co., Ltd.

MainStory: TopStory CaseDecisions FDCActNews DrugBiologicNews PLDrugNews SafetyNews FloridaNews

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