A federal appeals court last week affirmed a district court’s grant of summary judgment against plaintiffs who alleged the acne drug Accutane caused inflammatory bowel disease (IBD). Rand v. Hoffmann-LaRoche Inc., 2008 WL 3977611 (11th Cir., 8/26/08). After considering the briefs, the relevant parts of the record, and the opinion by the district court, In re Accutane Prods. Liab., 511 F.Supp.2d 1288 (M.D.Fla .2007), the appeals court concluded that the district court did not abuse its discretion by excluding the plaintiffs’ expert causation evidence and had properly granted summary judgment.

This trial court order dealt with the general causation issue of the IBD cases. General causation is concerned with whether an agent is capable of causing a disease and not whether the agent caused any given individual’s disease. In this case, plaintiffs’ expert, Dr. Fogel, opined that Accutane is a cause of IBD. The issue before the trial court was whether the methodology Dr. Fogel employed in reaching this opinion met the legal standard of reliability set forth in Daubert v. Merrell Dow Pharmaceuticals.

Dr. Fogel pointed to several data sources to support his opinion. First was an alleged analogy to animal and cell culture studies. The court found that Dr. Fogel relied on certain studies of dogs, rats and cell cultures, but had simply ignored the parts of those studies that do not support his opinion, particularly the dose-response relationship. He further drew conclusions not supported by the authors of those studies, said the court. Furthermore, there were other studies, both of dogs and humans, that were contrary to Dr. Fogel’s opinions, but he failed to explain why these other studies have no significance or to otherwise somehow differentiate them from the ones upon which he relied.

On the important issue of dose, the court noted that dose is critical to any evaluation of toxicity of a drug. In fact, dose may be the single most important factor to consider in evaluating whether an alleged exposure caused a specific adverse effect. Indeed, the basic dictum of toxicology as stated by the 16th century physician/philosopher, Paracelsus, was “All substances are poisonous-there is none which is not; the dose differentiates a poison from a remedy.”  An expert who ignores the dose-response relationship casts suspicion on the reliability of his entire methodology. Often low dose exposures -even for many years- will have no consequence at all, since the body is often able to completely detoxify low doses before they do any damage. Furthermore, for most types of dose-response relationships following chronic (repeated) exposure, certain thresholds exist, such that there is some dose below which even repeated, long-term exposure would not cause an effect in any individual.

The expert also tried to rely on defendants’ own internal documents purportedly expressing conclusions on causation. But contrary to Dr. Fogel’s conclusion about these “admissions,” the court determined that the causality assessments referred to by Dr. Fogel did not evidence any conclusion that the adverse events reported were caused by Accutane. Instead, they constituted a synopsis of complaints received by the defendant from various reporters (patient, parent, doctor, or even attorney) regarding their subjective beliefs as to the causes of particular ailments. That is, they reflect the reporter’s opinion as to causality, not the company’s. And they do not necessarily contain information regarding the patient’s medical history, family medical history, or information concerning other risk factors of IBD that would even allow the company to make any legitimate conclusions. While a review of the assessments may possibly support a conclusion that there was an association between Accutane and IBD, an association is not equivalent to causation. This review may serve as a basis for forming an hypothesis, but certainly did not equate with causation.

Lastly, Dr. Fogel relied on anecdotal consumer complaints themselves (“adverse event reports” or “case reports”) reported to the company or the FDA, or published to the medical community. However, these reports concerned events that occurred without any medical controls or scientific assessment. Uncontrolled anecdotal information offers one of the least reliable sources to justify opinions about both general and individual causation, said the court. The reports were unreliable as proof of causation because, in general, the events were not observed in such a way as to rule out coincidence or other potential causes.