Bendectin, Diclegis & The Philosophy of Science

In April of this year, the United States Food and Drug Administration (FDA) approved Diclegis, a combination of doxylamine succinate and pyridoxine hydrochloride for sale in the United States, for pregnant women experiencing nausea and vomiting. See FDA News Release, “FDA approves Diclegis for pregnant women experiencing nausea and vomiting,” (April 8, 2013). The return of this drug to the United States market was held up as a triumph of science over the will of the industry litigation. See Gideon Koren, “The Return to the USA of the Doxylamine-Pyridoxine Delayed Release Combination (Diclegis®) for Morning Sickness — A New Morning for American Women,” 20 J. Popul. Ther. Clin. Pharmacol. e161 (2013).

The sponsor of the drug, Duchesnay USA, wisely did not use the medication’s former name, Bendectin, which was the victim of a litigation industry jihad in the late 1970s through the mid-1990s. The plaintiffs’ lawyers’ war against Bendectin and its United States manufacturer is chronicled in two book-length accounts, and hundreds of articles. See Joseph Sanders, Bendectin on Trial: A Study of Mass Tort Litigation (Ann Arbor 1998); Michael D. Green, Bendectin and Birth Defects: The Challenges of Mass Toxic Substances Litigation (Philadelphia 1996).

As recently approved by the FDA, Declegis is categorized as “Pregnancy Category A,” which means that it is medication indicated for use in pregnant women. Most drugs are not tested in pregnant women in randomized clinical trials for obvious ethical and practical reasons. Perhaps one of the good things that came out of the Bendectin litigation wars was that Bendectin became one of the most intensely studied medications available for pregnant women. Another good thing was the achievement of evidence-based standards for expert witness opinion testimony in federal court. See David Bernstein, “Bendectin is Back” (April 9, 2013).

According to FDA regulations, Category A is defined:

(1) Pregnancy category A. If adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling must state: ‘Pregnancy Category A. Studies in pregnant women have not shown that (name of drug) increases the risk of fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, (name of drug) should be used during pregnancy only if clearly needed.’ The labeling must also contain a description of the human studies. If animal reproduction studies are also available and they fail to demonstrate a risk to the fetus, the labeling must also state: ‘Reproduction studies have been performed in (kinds of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug).’ The labeling must also contain a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child.

21 CFR § 201.57 (c)(9)(i)(A)(1) (April 2012).

A Litmus Test for Philosophy of Science?

The inability to discriminate between valid and invalid science should be a disqualifying characteristic in a putative philosopher of science, or a putative expert, for that matter. Professor Susan Haack, whose writings provide both insight and confusion on the role of science in the law, revealed her robust biases and prejudices in commenting upon the Bendectin litigation. These revelations should raise red flags about her objectivity in commenting on the legal process. See Susan Haack, “Irreconcilable Differences? The Troubled Marriage of Science and Law,” 72 Law & Contemporary Problems 1 (2009).

Haack’s paper on the marital discord was based upon her presentation at the Fourth Coronado Conference, organized by SKAPP (The Project on Scientific Knowledge and Public Policy), an ideological group dedicated to opening the courthouse doors to every quackacademic theory, and shadily funded by the litigation industry of plaintiffs’ lawyers from their left-over spoils from the silicone breast implant litigation. See SKAPP A LOT (April 30, 2010); “Haacking at the Truth – Part Two” (Oct. 31, 2010).

Haack provided examples of “marginal” science and witnesses that are disturb her for biases and prejudices that she perceives in these witnesses. Haack focuses upon Dr. Robert Brent, a toxicologist, who appears to her as Merrell Dow’s expert witness “always ready to testify that Bendectin does not cause birth defects.” Id. At 17. Haack presented no evidence or basis to suggest that Brent was wrong, and indeed, Brent published widely on his views of the subject. Wide publication does not necessarily mean Brent was right, but at least he was willing to subject himself to professional peer review, and post-publication, professional challenges. Still, Haack is distressed that Dr Robert Brent opines with “unwarranted certainty” that Bendectin does not cause birth defects, but she offers no suggestion or support that his certainty was or is misplaced.

In stark contrast, Haack expressed no discomfort with Bendectin plaintiffs’ expert witness, Dr Done, or with the facile ease with which he opined with scientific certainty that Bendectin causes birth defects. Here there really is a great deal of empirical evidence, and along with the FDA’s recent approval of Diclegis for use in pregnant women, the evidence has vindicated Dr. Brent’s views on the safety and efficacy of Bendectin/Diclegis. Dr. Done’s subjective appreciation of “flaws” in some clinical studies does not turn criticism into affirmative evidence in favor of the opinion that he so zealously, and overzealously, advocated in many Bendectin cases, for his own substantial pecuniary benefit. What is remarkable about Haack’s article is that she singles out Dr. Brent in the context of a discussion of “marginal” and “willing” testifying scientists, but she omits any mention of the plaintiffs’ cadre of ready, willing, and somewhat disreputable testifiers. Perhaps even more remarkable is that Haack overlooks that Dr. Done was essentially fired from his university for his entrepreneurial testimonial activities of dubious scientific worth, and that he may well have lied about his credentials. See Michael Green, Bendectin and Birth Defects: The Challenges of Mass Toxic Substances Litigation 280 – 82 (Philadelphia 1996) (citing decisional law in which Done’s lack of veracity was judicially noted).

Of course, what is most remarkable about Haack’s infatuation with Dr. Alan Done and his mosaic theory is that the theory was the concoction of plaintiffs’ lawyer, Barry Nace, and that the theory leads to such a palpably incorrect result. Barry Nace was one of the lead plaintiffs’ counsel in the Bendectin litigation. Nace was also formerly President of the litigation industry’s principal lobbying organization, the American Trial Lawyers Association (now the AAJ). After the second Ninth Circuit Daubert decision, Nace declined to pursue one of his Bendectin cases, and his client sued him. Nace’s attorney moved for summary judgment in August 1998, on grounds that included the assertion that “courts soundly and uniformly reject the notion that Bendectin causes birth defects.” See David Bernstein, “A Day Late and a Dollar Short on Bendectin(June 28, 2005).

This is the same Barry Nace lauded by Michael Green for having devised the notorious matrix theory of scientific evidence (a.k.a. the tsumish theory). Michael D. Green, “Pessimism About Milward,” 3 Wake Forest J. Law & Policy41, 62-63 (2013). Professor Haack sees Nace’s matix theory as the practical application of some of her theories. Susan Haack, “Irreconcilable Differences? The Troubled Marriage of Science and Law,” 72 Law & Contemporary Problems 1, 17 (2009); Susan Haack, “Proving Causation: The Holism of Warrant and the Atomism of Daubertm” 4 J. Health & Biomedical Law 273, 274-78 (2008). Haack’s embrace of the dubious Bendectin causal claims as supported by her matrix theory of causal inference raises the issue why we should credit a theory in the face of such a compelling counter example? As Professor Ronald Allen put the matter, before Bendectin was reintroduced into the United States market this year:

Given the weight of evidence in favor of Bendectin’s safety, it seems peculiar to argue for mosaic evidence from a case in which it would have plainly been misleading.”

Ronald J. Allen and Esfand Nafisi, “Daubert and its Discontents,” 76 Brooklyn L. Rev. 132, 148 (2010). Peculiar indeed. Professor Allen’s point is important for its wide-ranging implications. Methodologies that yield false-positive results are unreliable. Perhaps a methodology can be saved if we could quantify that a given methodology rarely yields such false results, but the matrix theory of Barry Nace and his expert witnesses seems so vague and insubstantial that no one, in all likelihood, could frame a test for the generalized approach. Expert witnesses perhaps should be judged by their track record over time, as well. See David Kaye, “The Experts in Daubert.”[1]

 


[1] Dr. Alan Done (pediatrician, pharmacology, toxicology); Dr. Jay Glasser (biostatistician, epidemiologist); Dr. Adrian Gross (veterinarian); Dr. Stuart Newman (developmental biologist); Dr. Wayne Snodgrass (Assoc. Professor of Pediatrics, Pharmacology, and Toxicology); Dr. Shanna Swan (epidemiologist); Dr. Johannes Thiersch (pathologist and pharmacologist); Dr. John Palmer (Professor of pharmacology).

 

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