Diclegis and Vacuous Philosophy of Science

Just when you thought that nothing more could be written intelligently about the Bendectin litigation, you find out you are right. Years ago, Michael Green and Joseph Sanders each wrote thoughtful, full-length books[1] about the litigation assault on the morning-sickness (nausea and vomiting of pregnancy) medication, which was voluntarily withdrawn by its manufacturer from the United States market. Dozens, if not hundreds, of law review articles discuss the scientific issues, the legal tactics, and the judicial decisions in the U.S. Bendectin litigation, including the Daubert case in Supreme Court and in the Ninth Circuit. But perhaps fresh eyes might find something new and fresh to say.

Boaz Miller teaches social epistemology and philosophy of science, and he recently weighed in on the role that scientific consensus played in resolving the Bendectin litigation. Miller, “Scientific Consensus and Expert Testimony in Courts: Lessons from the Bendectin Litigation,” Foundations of Science (2014) (Oct. 17, 2014) (in press) [cited as Miller]. Miller astutely points out that scientific consensus may or may not be epistemic, that is, based upon robust, valid, sufficient scientific evidence of causality. Scientists are people, and sometimes they come to conclusions based upon invalid evidence, or because of cognitive biases, or social pressures, and the like. Sometimes scientists get the right result for the wrong reasons. From this position he argues that adverting to scientific consensus is fraught with danger of being misled, and that the Bendectin ligitation specifically is an example of courts led astray by a “non-epistemic” scientific consensus. Miller at 1.

Miller is correct that the scientific consensus on Bendectin’s safety, which emerged after the initiation of litigation, played a role in resolving the litigation, id. at 8, but he badly misunderstands how the consensus actually operated to bring closure to the birth defects litigation. Remarkably, he pays no attention to the consolidated trial of over 800 cases before the Hon. Carl B. Rubin, in the Southern District of Ohio. This trial resulted in a defense verdict in March 1985, and judgment that withstood appellate review. Assoc. Press, “U.S. Jury Clears a Nausea Drug in Birth Defects,” N.Y. Times (Mar. 13, 1985). The subsequent litigation turned into guerilla warfare based upon relatively few remaining individual cases in state and federal courts. In one of the state court cases, the trial court appointed neutral expert witnesses, who opined that plaintiffs had failed to make out their causal claims of teratogenicity in human beings. DePyper v. Navarro, No. 83–303467-NM, 1995 WL 788828 (Mich. Cir. Ct. Nov. 27, 1995).

To be sure, plaintiffs’ expert witnesses and plaintiffs’ counsel continued in their campaign to manufacture “reasonable medical certainty” of Bendectin’s teratogenicity, well after a scientific consensus emerged. Boaz Miller makes the stunning claim that this consensus was not a “knowledge-based” consensus because:

(1) the research was controlled by parties to the dispute (Miller at 10);

(2) the consensus ignored or diminished the “value” of in vitro toxicology (Miller at 13);

(3) the consensus relied upon most heavily upon the epidemiologic evidence (Miller at 14);

(4) the animal toxicology research was “prematurely” abandoned when the U.S. withdrew its product from the market (Miller at 15); and

(5) the withdrawal ended the “threat” to public health, and the concerns about teratogenicity (Miller at 15).

Miller’s asserted reasons are demonstrably incorrect. Although Merrell Richardson funded some studies early on, by the time the scientific consensus emerged, many studies funded by neutral sources, and conducted by researchers of respected integrity, were widely available. The consensus did not diminish the value of in vivo toxicology; rather scientists evaluated the available evidence through their understanding of epidemiology’s superiority in assessing actual risks in human populations. Animal studies were not prematurely abandoned; more accurately, the animal studies gave way to more revealing, valid studies in humans about human outcomes. The sponsor’s withdrawal of Bendectin in the United States was not the cause of any abandonment of research. The drug remained available outside the United States, in countries with less rapacious tort systems, and researchers would have, in any event, continued animal studies if there were something left open by previous research. A casual browse through PubMed’s collection of articles on thalidomide shows that animal research continued well after that medication had been universally withdrawn for use in pregnant women. Given that thalidomide was unquestionably a human teratogen, there was a continued interest in understanding its teratogenicity. No such continued interest existed for Bendectin after the avalanche of exculpatory human data.

What sort of inquiry permitted Miller to reach his conclusions? His article cites no studies, no whole-animal toxicology, no in vitro research, no epidemiologic studies, no systematic reviews, no regulatory agency reviews, and no meta-analysis. All exist in abundance. The full extent of his engagement with the actual scientific data and issues is a reference to an editorial and two letters to the editor[2]! From the exchange of views in one set of letters in 1985, Miller infers that there was “clear dissent within the community of toxicologists.” Miller at 13. The letters in question, however, were written in a journal of teratology, which was not limited to toxicology, and the interlocutors were well aware of the hierarchy of evidence that placed human observational studies at the top of the evidential pyramid.

Miller argues that it was possible that the consensus was not knowledge-based because it might have reflected the dominance of epidemiology over the discipline of toxicology. Again, he ignores the known dubious validity of inferring human teratogenicity from high dose whole animal or in vitro toxicology. By the time the scientific consensus emerged with respect to Bendectin’s safety, this validity point was widely appreciated by all but the most hardened rat killers, and plaintiffs’ counsel. In less litigious countries, the drug never left the market. No regulatory agency ever called for its withdrawal.

Miller might have tested whether the scientific community’s consensus on Bendectin, circa 1992 (when Daubert was being briefed in the Supreme Court) was robust by looking to how well it stood up to further testing. He did not, but he could easily have found the following. The U.S. sponsor of Diclegis, Duchesnay USA, sought and obtained the indication for its medication in pregnancy. Under U.S. law, Duchesnay’s new drug application had to establish safety and efficacy for this indication. In 2013, the U.S. FDA approved Bendectin, under the tradename, Diclegis[3], as a combination of doxylamine succinate and pyridoxine hydrochloride for sale in the United States. Under the FDA’s pregnancy labeling system, Diclegis is a category A, with a specific indication for use in pregnancy. The FDA’s review of the actual data is largely available for all to see. See, e.g., Center for Drug Evaluation and Research, Other Reviews (Aug. 2012); Summary Review (April 2013); Pharmacology Review (March 2013); Medical Review (March 2013); Statistical Review (March 2013); Cross Discipline Team Leader Review (April 2013). Given the current scientific record, the consensus that emerged in the early 1990s looks strong. Indeed, the consensus was epistemically strong when reached two decades ago.

Miller is certainly correct that reliance upon consensus entails epistemic risks. Sometimes the consensus has not looked very hard or critically at all the evidence. Political, financial, and cognitive biases can be prevalent. Miller fails to show that any such biases were prevalent in the early 1990s, or that they infected judicial assessments of the plaintiffs’ causal claims in Bendectin litigation. Miller is also wrong to suggest that courts did not look beyond the consensus to the actual evidential base for plaintiffs’ claims. Through the lens of expert witness testimony, both party and court-appointed expert witnesses, courts and juries had a better view of the causation issues than Miller appreciates. Miller’s philosophy of science might be improved by his rolling up his sleeves and actually looking at the data[4].

[1] See Joseph Sanders, Bendectin on Trial: A Study of Mass Tort Litigation (1998); Michael D. Green, Bendectin and Birth Defects: The Challenges of Mass Toxic Substances Litigation (1996).

[2] Robert Brent, “Editorial comment on comments on ‘Teratogen Update: Bendectin’,” 31 Teratology 429 (1985); Kenneth S. Brown, John M. Desesso, John Hassell, Norman W. Klein, Jon M. Rowland, A. J. Steffek, Betsy D. Carlton, Cas. Grabowski, William Slikker Jr. and David Walsh, “Comments on ‘Teratogen Update: Bendectin’,” 31Teratology 431 (1985); Lewis B. Holmes, “Response to comments on ‘Teratogen Update: Bendectin’,” 31 Teratology 432 (1985).

[3] 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).

[4] See “Bendectin, Diclegis & The Philosophy of Science” (Oct 26, 2013).

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