In re Zoloft (Sertraline Hydrochloride) Prods. Liab. Litig.

Decision Date02 June 2017
Docket NumberNo. 16-2247,16-2247
Citation858 F.3d 787
Parties IN RE: ZOLOFT (SERTRALINE HYDROCHLORIDE) PRODUCTS LIABILITY LITIGATION Jennifer Adams, et al, Plaintiffs appealing dismissal by order entered April 5, 2016, Appellants
CourtU.S. Court of Appeals — Third Circuit

David C. Frederick [Argued], Derek T. Ho, Kellogg Hansen Todd Figel & Frederick, 1615 M Street, N.W., Suite 400, Washington, DC 20036, Dianne M. Nast, NastLaw, 1101 Market Street, Suite 2801, Philadelphia, PA 19107, Mark P. Robinson, Jr., Robinson Calcagnie Robinson Shapiro Davis, 19 Corporate Plaza Drive, Newport Beach, CA 92660, Counsel for Appellants

Sheila L. Birnbaum, Mark S. Cheffo [Argued], Quinn Emanuel Urquhart & Sullivan, 51 Madison Avenue, 22nd Floor, New York, NY 10010, Robert C. Heim, Judy L. Leone, Dechert, 2929 Arch Street, 18th Floor, Cira Centre, Philadelphia, PA 19104, Counsel for Appellees

Cory L. Andrews, Washington Legal Foundation, 2009 Massachusetts Avenue, N.W., Washington, DC 20036, Counsel for Amicus Washington Legal Foundation

Brian D. Boone, Alston & Bird, 101 South Tryon Street, Suite 4000, Charlotte, NC 28280, David R. Venderbush, Alston & Bird, 90 Park Avenue, 15 th Floor, New York, NY 10016, Counsel of Amicus Chamber of Commerce of the United States

Joe G. Hollingsworth, Hollingsworth, 1350 I Street, N.W., Washington, DC 20005, Counsel for Amicus American Tort Reform Association and Pharmaceutical Research and Manufacturers of America

Before: CHAGARES, RESTREPO and ROTH, Circuit Judges

OPINION

ROTH, Circuit Judge:

This case involves allegations that the anti-depressant drug Zoloft

, manufactured by Pfizer, causes cardiac birth defects when taken during early pregnancy. In support of their position, plaintiffs, through a Plaintiffs' Steering Committee (PSC), depended upon the testimony of Dr. Nicholas Jewell, Ph.D. Dr. Jewell used the "Bradford Hill" criteria1 to analyze existing literature on the causal connection between Zoloft and birth defects. The District Court excluded this testimony and granted summary judgment to defendants. The PSC now appeals these orders, alleging that 1) the District Court erroneously held that an expert opinion on general causation must be supported by replicated observational studies reporting a statistically significant association between the drug and the adverse effect, and 2) it was an abuse of discretion to exclude Dr. Jewell's testimony. Because we find that the District Court did not establish such a legal standard and did not abuse its discretion in excluding Dr. Jewell's testimony, we will affirm the District Court's orders.

I.

This case arises from multi-district litigation involving 315 product liability claims against Pfizer, alleging that Zoloft

, a selective serotonin reuptake inhibitor (SSRI), causes cardiac birth defects. The PSC introduced a number of experts in order to establish causation. The testimony of each of these experts was excluded in whole or in part. In particular, the court excluded all of the testimony of Dr. Anick Bérard (an epidemiologist), which relied on the "novel technique of drawing conclusions by examining ‘trends' (often statistically non-significant) across selected studies." 2

The PSC filed a motion for partial reconsideration of the decision to exclude the testimony of Dr. Bérard, which the District Court denied. The PSC then moved to admit Dr. Jewell (a statistician) as a general causation witness. Pfizer filed a motion to exclude Dr. Jewell, and the District Court conducted a Daubert3 hearing.

The District Court considered Dr. Jewell's application of various methodologies, reviewing his expert report, rebuttal reports, party briefs, and oral testimony. The District Court first examined how Dr. Jewell applied the traditional methodology of analyzing replicated, significant results. While Dr. Jewell discussed many groupings of cardiac birth defects

, he focused on the significant findings for all cardiac defects and septal defects. Dr. Jewell presented two studies reporting a significant association between Zoloft and all cardiac defects (Kornum (2010)4 and Jimenez–Solem (2012)5 ). He also presented five studies reporting a significant association between Zoloft and septal defects (Kornum (2010), Jimenez–Solem (2012), Louik (2007),6 Pedersen (2009),7 and Bérard (2015)8 ). After excluding two studies from its consideration,9 the District Court expressed two concerns with the remaining studies: Jimenez–Solem (2012), Kornum (2010), and Pedersen (2009). First, despite the fact that the remaining studies produced consistent results, the District Court did not consider them to be independent replications because they used overlapping Danish populations. Second, a larger study, Furu (2015),10 included almost all the data from Jimenez–Solem (2012), Kornum (2010), and Pedersen (2009) and did not replicate the findings of those studies. Dr. Jewell did not explain the reasons why this attempted replication produced different results or why the new study did not contradict his opinion.

The court then examined Dr. Jewell's reliance on insignificant results, noting that it was very similar to Dr. Bérard's methodology. The court noted that Dr. Jewell did not provide any evidence that the epidemiology or teratology11 communities value statistical significance12 any less than it has traditionally been understood.13 The court also expressed concern that Dr. Jewell inconsistently applied his "technique" of multiplying p-values14 and his trend analysis.

The District Court critiqued several other techniques Dr. Jewell used in analyzing the evidence. First, Dr. Jewell rejected meta-analyses on which he had previously relied in a lawsuit against another SSRI, Prozac

. The meta-analyses reported insignificant associations with birth defects for Zoloft but not for Prozac. Dr. Jewell rationalized his decision to ignore these meta-analyses because the "heterogeneity"15 within its Zoloft studies was significant; the District Court accepted this explanation but questioned why Dr. Jewell "fails to statistically calculate the heterogeneity" across other studies instead of relying on trends.16 Second, Dr. Jewell reanalyzed two studies, Jimenez–Solem (2012) and Huybrechts (2014),17 both of which had originally concluded that there was no significant effect attributable to Zoloft.18 The District Court questioned his rationale for conducting, and tactics for implementing, this reanalysis. Finally, Dr. Jewell conducted a meta-analysis with Huybrechts (2014) and Jimenez–Solem (2012). The District Court questioned why he used only those particular studies.19

Based on this analysis, the District Court found that Dr. Jewell, tasked with explaining his opinion about Zoloft

's effect on birth defects and reconciling contrary studies, "failed to consistently apply the scientific methods he articulates, has deviated from or downplayed certain well-established principles of his field, and has inconsistently applied methods and standards to the data so as to support his a priori opinion."20 For this reason, on December 2, 2015, the District Court entered an order, excluding Dr. Jewell's testimony, and on April 5, 2016, the court granted Pfizer's motion for summary judgment. The PSC appeals the exclusion of Dr. Jewell and the grant of summary judgment.21

II.22

In general, courts serve as gatekeepers for expert witness testimony. "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," inter alia , "the testimony is the product of reliable principles and methods[ ] and ... the expert has reliably applied the principles and methods to the facts of the case."23 In determining the reliability of novel scientific methodology, courts can consider multiple factors, including the testability of the hypothesis, whether it has been peer reviewed or published, the error rate, whether standards controlling the technique's operation exist, and whether the methodology is generally accepted.24 Both an expert's methodology and the application of that methodology must be reviewed for reliability.25 A court should not, however, usurp the role of the fact-finder; instead, an expert should only be excluded if "the flaw is large enough that the expert lacks the ‘good grounds' for his or her conclusions."26

Central to this case is the question of whether statistical significance is necessary to prove causality. We decline to state a bright-line rule. Instead, we reiterate that plaintiffs ultimately must prove a causal connection between Zoloft

and birth defects. A causal connection may exist despite the lack of significant findings, due to issues such as random misclassification or insufficient power.27 Conversely, a causal connection may not exist despite the presence of significant findings. If a causal connection does not actually exist, significant findings can still occur due to, inter alia , inability to control for a confounding effect or detection bias. A standard based on replication of statistically significant findings obscures the essential issue: a causal connection. Given this, the requisite proof necessary to establish causation will vary greatly case by case. This is not to suggest, however, that statistical significance is irrelevant. Despite the problems with treating statistical significance as a magic criterion, it remains an important metric to distinguish between results supporting a true association and those resulting from mere chance. Discussions of statistical significance should thus not understate or overstate its importance.

With this in mind, we proceed to the issues at hand. The PSC raises two issues on appeal: 1) whether the District Court erroneously concluded that reliability requires replicated, statistically significant findings, and 2) whether Dr. Jewell's testimony was properly excluded.

A.

The PSC argues that the District Court erroneously held that replicated,...

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