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In re Zofran (Ondansetron) Products Liability Litigation

United States District Court, D. Massachusetts

November 1, 2019

IN RE ZOFRAN ONDANSETRON PRODUCTS LIABILITY LITIGATION This Document Relates To All Actions

          MEMORANDUM AND ORDER ON MOTIONS TO EXCLUDE REGULATORY EXPERTS

          F. DENNIS SAYLOR, IV UNITED STATES DISTRICT JUDGE.

         This is a multi-district litigation (“MDL”) proceeding arising out of product-liability claims that the use of the drug Zofran (ondansetron) by pregnant women caused birth defects in their children.

         Plaintiffs have moved to exclude certain portions of the testimony of the regulatory expert of GlaxoSmithKline LLC (“GSK”), Dr. Dena Hixon. GSK has moved to exclude the testimony of plaintiffs' regulatory expert, Dr. Brian Harvey. For the reasons set forth below, plaintiffs' motion will be denied and GSK's motion will be granted in part and denied in part.

         I. Standard of Review

         Federal Rule of Evidence 702 provides as follows:

A witness who is qualified as an expert by knowledge, skill, experience, training, or education may testify in the form of an opinion or otherwise if:
(a) the expert's scientific, technical or other specialized knowledge will help the trier of fact to understand the evidence or to determine a fact in issue;
(b) the testimony is based on sufficient facts or data;
(c) the testimony is the product of reliable principles and methods; and (d) the expert has reliably applied the principles and methods to the facts of the case. Fed.R.Evid. 702. The adoption of Rule 702 in its present form codified the standard of admissibility for expert testimony that was set forth in Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993). United States v. Diaz, 300 F.3d 66, 73 (1st Cir. 2002).

         Under Rule 702, district courts considering the admissibility of expert testimony must “act as gatekeepers, ensuring that an expert's proffered testimony ‘both rests on a reliable foundation and is relevant to the task at hand.'” Samaan v. St. Joseph Hosp., 670 F.3d 21, 31 (1st Cir. 2012) (quoting Daubert, 509 U.S. at 597). That gatekeeping function requires that the court consider three sets of issues: (1) whether the proposed expert is qualified by “knowledge, skill, experience, training or education”; (2) whether the subject matter of the proposed testimony properly concerns “scientific, technical, or other specialized knowledge”; and (3) “whether the testimony [will be] helpful to the trier of fact, i.e., whether it rests on a reliable foundation and is relevant to the facts of the case.” Bogosian v. Mercedes-Benz of N. Am., Inc., 104 F.3d 472, 476 (1st Cir. 1997) (quoting Fed.R.Evid. 702) (internal quotation marks omitted). “These two requirements-a reliable foundation and an adequate fit-are separate and distinct.” Samaan, 670 F.3d at 31.

         The requirement that an expert's testimony must be based on reliable methods is often the “central focus of a Daubert inquiry.” Ruiz-Troche v. Pepsi Cola of P.R. Bottling Co., 161 F.3d 77, 81 (1st Cir. 1998). In Daubert, the Supreme Court enumerated a non-exhaustive list of factors that a court may consider in undertaking its reliability analysis: (1) whether the scientific theory or technique can be (and has been) tested; (2) whether it has been subjected to peer review and publication; (3) whether it has a known rate of error; (4) whether there are standards controlling its application or operation; and (5) whether it is generally accepted in the relevant scientific community. Daubert, 509 U.S. at 593-94; see also Samaan, 670 F.3d at 31-32.

         Less centrally, but importantly, Rule 702 requires the court to examine whether those methods have been reliably applied. In other words, the court must “ensure that there is an adequate fit between the expert's methods and his conclusions.” Samaan, 670 F.3d at 32 (citing Daubert, 509 U.S. at 591). “This prong of the Daubert inquiry addresses the problem that arises when an expert's methods, though impeccable, yield results that bear a dubious relationship to the questions on which he proposes to opine.” Id. (citing Daubert, 509 U.S. at 591-92).

         In evaluating whether expert testimony will be helpful to the trier of fact, the court must determine whether it is relevant, “not only in the sense that all evidence must be relevant, but also in the incremental sense that the expert's proposed opinion, if admitted, likely would assist the trier of fact to understand or determine a fact in issue.” Ruiz-Troche, 161 F.3d at 81 (citations omitted); see also Cipollone v. Yale Indus. Prods., Inc., 202 F.3d 376, 380 (1st Cir. 2000) (“The ultimate purpose of the Daubert inquiry is to determine whether the testimony of the expert would be helpful to the jury in resolving a fact in issue.”).

         The focus of the inquiry is on the principles and methodology employed by the expert, not the ultimate conclusions. Daubert, 509 U.S. at 595. The court may not subvert the role of the factfinder in assessing credibility or in weighing conflicting expert opinions. Rather, “[v]igorous cross-examination, presentation of contrary evidence, and careful instruction on the burden of proof are the traditional and appropriate means of attacking shaky but admissible evidence.” Id. at 596; see also Ruiz-Troche, 161 F.3d at 85 (admitting testimony notwithstanding a lack of peer-reviewed publications because the opinion rested upon good grounds generally and should be tested by the “adversary process”).

         Expert testimony that is admissible under Rule 702 may nonetheless be excluded under Rule 403 “if its probative value is substantially outweighed by the danger of one or more of the following: unfair prejudice, confusion of the issues, misleading the jury, undue delay, wasting time, or needlessly presenting cumulative evidence.” Fed.R.Evid. 403; see also Daubert, 509 U.S. at 595. Thus, expert testimony that is relevant and that passes muster from a scientific or technical standpoint may nonetheless be excluded if it is likely to be misinterpreted or misused by the jury.

         II. Analysis

         A. Plaintiffs' Motion to Exclude Testimony of Dr. Hixon

         Plaintiffs seek to exclude certain portions of the testimony of GSK's regulatory expert, Dr. Dena Hixon. They contend that her opinions on two topics-determination of teratogenicity (or pregnancy labeling) and pharmacovigilance-should be excluded on the grounds that she is not qualified to render the opinions and that the opinions are based on unsound methodology.

         Dr. Hixon is a medical doctor and a former board-certified obstetrician/gynecologist with thirteen years of clinical experience. She also worked at the Food and Drug Administration (“FDA”) for thirteen years, first as a medical officer within the Center for Drug Evaluation and Research (“CDER”), and then as an advisor on safety issues in the Office of Generic Drugs. For three of those years, she was the primary reviewer of human clinical studies submitted as part of Investigational New Drug (“IND”) applications and New Drug Applications (“NDAs”). She also served on the FDA's Pregnancy Labeling Task Force. That task force assessed pregnancy-related drug-labeling categories, developed the Pregnancy and Lactation Labeling Rule (“PLLR”), and developed FDA guidance documents concerning risk assessment of drugs used in pregnancy. She now works as a regulatory consultant, advising on drug development and regulation for both new and generic drugs, from early development through product approval and post-market surveillance.

         Dr. Hixon produced an expert report in this case on September 21, 2018. Among other things, the report concluded-in what plaintiffs refer to as a “determination of teratogenicity, ” or “pregnancy labeling, ” opinion-that the FDA “appropriately assigned ondansetron Pregnancy Category B in the labeling, based on the data available to GSK and FDA and the applicable regulations.” (Hixon Report at 4). It further concluded-in what plaintiffs refer to as a “pharmacovigilance” opinion-that GSK “appropriately monitored the drug's safety in pregnancy and complied with the regulations in collection, analyzing[, ] and reporting pregnancy-related safety information, ” and that GSK “performed several thorough internal assessments of pregnancy exposure and outcome data.” (Id.).

         Plaintiffs contend that both of those opinions should be excluded on the grounds that they exceed her regulatory experience and lack reliable scientific foundation.

         1. Determination of Teratogenicity (or Pregnancy Labeling) Opinions

         Plaintiffs first object to Dr. Hixon's opinion that Zofran was properly labeled as a pregnancy Category B Drug. Specifically, they contend that (1) her methodology is flawed because one of the Japanese animal studies (Study 424) was never submitted to the FDA and she does not have the expertise to opine on whether the FDA would have found evidence of teratogenicity if that study had been taken into consideration; and (2) her opinions are unreliable because she is not qualified to opine on whether reproductive toxicology animal studies provide evidence of teratogenicity.

         It is undisputed that GSK has never provided a complete version of Study 424 to the FDA. According to plaintiffs, the factfinder will have to rely on expert-witness testimony to assess whether the data from all of the animal studies at issue, when considered in totality, demonstrated sufficient fetal risk such that GSK should have requested a Pregnancy Category C warning. They further contend that Dr. Hixon cannot offer an opinion that the disclosure of Study 424, or any of the other disputed Japanese animal studies, would not have changed the pregnancy category for Zofran without also opining that the study does not show evidence of teratogenicity. Because, they contend, she is not qualified to offer such an opinion, and did not consult with a toxicologist, her opinions as to those topics are unreliable and should be excluded.

         Plaintiffs identify four such “determination of teratogenicity, ” or “pregnancy labeling, ” opinions-that is, “[o]pinions regarding whether the Japanese animal studies provided evidence of teratogenicity and whether their disclosure to FDA would have changed the pregnancy categorization of Zofran”-that they seek to exclude:

(1) “FDA appropriately assigned ondansetron Pregnancy Category B in the labeling, based on the data available to GSK and FDA and the applicable regulations.” (Hixon Report at 4).
(2) “Because data from the studies did not lead to different conclusions regarding safety than the studies that had already been provided to FDA in previous IND and NDA submissions . . ., GSK appropriately determined that the data in these studies did not constitute ‘new' information relevant to safety.” (Id. at 36).
(3) “The evidence must provide a reasonable basis to believe that there is a causal association between the risk and the drug. At no time did such evidence exist, including in reproductive toxicity studies, scientific literature, or GSK's safety database.” (Id. at 36, 72).
(4) “GSK's scientists uniformly concluded that none of the reproductive toxicology studies showed evidence of teratogenicity in animals, and FDA's experts agreed.” (Id. at 72).

         Under the circumstances, the opinions will not be excluded. Dr. Hixon does not claim to determine independently whether the data from reproductive toxicity studies show that Zofran is teratogenic. Instead, she is relying upon the conclusions of GSK's scientists that those studies did not show that Zofran is teratogenic. Starting with that assumption, Dr. Hixon applied what she says are the relevant regulatory standards, which she appears qualified to provide based on her background and training.

         For that reason, the Court will construe Dr. Hixon's opinions (2) and (4) as regulatory opinions conditioned on a specific assumption: the assumption that GSK's experts correctly interpreted the toxicity studies. Of course, if that assumption is incorrect, that would likely undermine her conclusions, if not vitiate them completely.[1] Furthermore, any opinion she expresses must be carefully couched to make clear that she is not testifying (and cannot testify) as to whether the toxicity studies were correctly interpreted.

         As to opinions (1) and (3), GSK contends that they do not turn on a toxicological determination of “non-teratogenicity, ” but are instead based on Dr. Hixon's regulatory analysis of the study reports, FDA standards, and other materials. She appears qualified to deliver those opinions based on her thirteen years of clinical experience as a practicing OB/GYN and her thirteen years of experience at the FDA, including her work on the Pregnancy Labeling Task Force and her role as a team leader in the Office of New Drugs. At the FDA, she directly participated in redeveloping the regulations setting forth the pregnancy categories; worked on guidances concerning pregnancy-related risk assessment; and reviewed NDAs, including the evaluations of pharmacologist/toxicologist reviewers.[2] (Hixon Report at 1). In short, Dr. Hixon is ...


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