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In re Zoloft (Sertraline Hydrochloride) Products Liability Litigation

United States Court of Appeals, Third Circuit

June 2, 2017

IN RE: ZOLOFT (SERTRALINE HYDROCHLORIDE) PRODUCTS LIABILITY LITIGATION Jennifer Adams, et al, Plaintiffs appealing dismissal by order entered Appellants

          Argued on January 25, 2017

         On Appeal from the United States District Court for the Eastern District of Pennsylvania (D. C. Civil Action No. 2-12-md-02342) District Judge: Honorable Cynthia M. Rufe.

          David C. Frederick [Argued] Derek T. Ho Kellogg Hansen Todd Figel & Frederick Mark P. Robinson, Jr. Robinson Calcagnie Robinson Shapiro Davis Counsel for Appellants

          Sheila L. Birnbaum Mark S. Cheffo [Argued] Quinn Emanuel Urquhart & Sullivan Robert C. Heim Judy L. Leone Dechert Counsel for Appellees

          Cory L. Andrews Washington Legal Foundation Counsel for Amicus Washington Legal Foundation

          Brian D. Boone Alston & Bird David R. Venderbush Alston & Bird Counsel of Amicus Chamber of Commerce of the United States

          Joe G. Hollingsworth Hollingsworth Counsel for Amicus American Tort Reform Association and Pharmaceutical Research and Manufacturers of America

          Before: CHAGARES, RESTREPO and ROTH, Circuit Judges.


          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" criteria[1] 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.


         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 Daubert[3] 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 teratology[11] communities value statistical significance[12] any less than it has traditionally been understood.[13] The court also expressed concern that Dr. Jewell inconsistently applied his "technique" of multiplying p-values[14] 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]


         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.


         The PSC argues that the District Court erroneously held that replicated, statistically significant findings are necessary to satisfy reliability. This argument seems to have been originally raised in the motion for reconsideration of Dr. Bérard's exclusion. Explaining its decision to exclude Dr. Bérard, the District Court cited a previous case, Wade-Greaux v. Whitehall Labs, Inc., for the proposition that the teratology community generally requires replicated, significant epidemiological results before inferring causality.[28] The PSC claims that in so doing, the District Court was asserting a legal standard that required replicated, significant findings for reliability.[29] Pfizer contends that the District Court merely made a factual finding about what the teratology community generally accepts.

         Upon review, it is clear that the District Court was not creating a legal standard, but merely making a factual finding. The PSC argues that the District Court must have created a legal standard because it did not cite any sources other than Wade-Greaux to support its assertion that the teratology community generally requires replicated, significant epidemiological findings. However, in its initial exclusion of Dr. Bérard, the District Court noted that it looked to the standards adopted by "other epidemiologists, even the very researchers [Dr. Bérard] cites in her report."[30] Similarly, in its order denying general reconsideration of Dr. Bérard's exclusion, the District Court clarified that it "made this factual finding after review of the published literature relied upon by Dr. Bérard and other experts, as well as its review of the reports and testimony of both parties"[31] and merely used this factual finding as part of its FRE 702 analysis.[32] While the District Court does cite Wade-Greaux, [33] it uses it merely to show "that other courts have made similar findings regarding the prevailing standards for scientists in Dr. Bérard's field."[34]

         Second, the course of the proceedings make clear that the replication of significant results was not dispositive in establishing whether the testimony of either Dr. Bérard or Dr. Jewell was reliable. In fact, the District Court expressly rejected Pfizer's argument that the existence of a statistically significant, replicated result is a threshold issue before an expert can conduct the Bradford-Hill analysis.[35] In doing so, the District Court was clear that it was not requiring a threshold showing of statistical significance. Similarly, the District Court did not end its inquiry after analyzing whether there were replicated, significant results. Instead, the District Court examined other techniques of general trend analysis, reanalysis of other studies, and meta-analysis. Even though it ultimately rejected the application of these techniques as unreliable, it did not categorically reject alternative techniques, suggesting that it did not make a legal standard requiring replicated, significant results.

         For these reasons, we find that the District Court did not require replication of significant results to establish reliability. Instead, it merely made a factual finding that teratologists generally require replication of significant results, and this factual finding did not prevent it from considering other evidence of reliability.[36]


         The second issue on appeal is whether it was an abuse of discretion for the District Court to exclude Dr. Jewell's testimony. Dr. Jewell utilized a combination of two methods: the "weight of the evidence" analysis and the Bradford Hill criteria. The "weight of the evidence" analysis involves a series of logical steps used to "infer[] to the best explanation[.]"[37] The Bradford Hill criteria are metrics that epidemiologists use to distinguish a causal connection from a mere association. These metrics include strength of the association, consistency, specificity, temporality, coherence, biological gradient, plausibility, experimental evidence, and analogy.[38] In his expert report, Dr. Jewell seems to utilize numerous "techniques" in implementing the weight of the evidence methodology. Dr. Jewell discusses whether the conclusions drawn from these techniques satisfy the Bradford Hill criteria and support the existence of a causal connection.[39]

         Pfizer does not seem to contest the reliability of the Bradford Hill criteria or weight of the evidence analysis generally; the dispute centers on whether the specific methodology implemented by Dr. Jewell is reliable. Flexible methodologies, such as the "weight of the evidence, " can be implemented in multiple ways; despite the fact that the methodology is generally reliable, each application is distinct and should be analyzed for reliability. In In re Paoli R.R. Yard PCB Litigation, this Circuit noted that while differential diagnosis-also a flexible methodology-is generally accepted, "no particular combination of techniques chosen by a doctor to assess an individual patient is likely to have been generally accepted."[40] Accordingly, we subjected the expert's specific differential diagnosis process to a Daubert inquiry.[41] We noted that "to the extent that a doctor utilizes standard diagnostic techniques in gathering this information, the more likely we are to find that the doctor's methodology is reliable."[42] While we did not require the expert to run specific tests or ascertain full information in order for the differential diagnosis to be reliable, we did require him to explain why his conclusion remained reliable in the face of alternate causes.[43]

         This standard, while articulated with respect to differential diagnoses, applies to the weight of the evidence analysis. We have briefly encountered the Bradford Hill criteria/weight of the evidence methodology in Magistrini v. One Hour Martinizing Dry Cleaning, a nonprecedential affirmance of the District of New Jersey's exclusion of an expert.[44] The expert followed the weight of the evidence methodology, including epidemiological findings assessed using the Bradford Hill criteria. The District Court acknowledged that although the weight of the evidence methodology was generally reliable, "[t]he particular combination of evidence considered and weighed here has not been subjected to peer review."[45] Similar concerns are arguably present for the Bradford Hill criteria, which are neither an exhaustive nor a necessary list.[46] An expert can theoretically assign the most weight to only a few factors, or draw conclusions about one factor based on a particular combination of evidence. The specific way an expert conducts such an analysis must be reliable; "all of the relevant evidence must be gathered, and the assessment or weighing of that evidence must not be arbitrary, but must itself be based on methods of science."[47] To ensure that the Bradford Hill/weight of the evidence criteria "is truly a methodology, rather than a mere conclusion-oriented selection process . . . there must be a scientific method of weighting that is used and explained."[48] For this reason, the specific techniques by which the weight of the evidence/Bradford Hill methodology is conducted must themselves be reliable according to the principles articulated in Daubert.[49]

         In short, despite the fact that both the Bradford Hill and the weight of the evidence analyses are generally reliable, the "techniques" used to implement the analysis must be 1) reliable and 2) reliably applied. In discussing the conclusions produced by such techniques in light of the Bradford Hill criteria, an expert must explain 1) how conclusions are drawn for each Bradford Hill criterion and 2) how the criteria are weighed relative to one another. Here, we accept that the Bradford Hill and weight of the evidence analyses are generally reliable. We also assume that the "techniques" used to implement the analysis (here, meta-analysis, trend analysis, and reanalysis) are themselves reliable. However, we find that Dr. Jewell did not 1) reliably apply the "techniques" to the body of evidence or 2) adequately explain how this analysis supports specified Bradford Hill criteria. Because "any step that renders the analysis unreliable under the Daubert factors renders the expert's testimony inadmissible, "[50] this is sufficient to show that the District Court did not abuse its discretion in excluding Dr. Jewell's testimony.


         It was not an abuse of discretion for the District Court to find Dr. Jewell's application of trend analysis, reanalysis, and meta-analysis to the body of evidence to be unreliable. Here, we assume the techniques listed are generally reliable and rest on the fact that they were unreliably applied. As stated in In re Paoli, use of standard techniques bolster the inference of reliability;[51] nonstandard techniques need to be well-explained. Additionally, if an expert applies certain techniques to a subset of the body of evidence and other techniques to another subset without explanation, this raises an inference of unreliable application of methodology.[52]

         First, we find no abuse of discretion in the District Court's determination that Dr. Jewell unreliably analyzed the trend in insignificant results. Dr. Jewell applied this technique by qualitatively discussing the probative value of multiple positive, insignificant results. In justifying this approach, he relied on a quantitative method by which one can calculate the likelihood of seeing multiple positive but insignificant results if there were actually no true effect.[53]However, after alluding to this presumably reliable mathematical calculation technique for analyzing trends in even insignificant results, Dr. Jewell did not actually implement it; instead he qualitatively discussed the general trend in the data. In light of the opportunity to actually conduct such quantitative analysis, his refusal to do so- without explanation-suggests that he did not reliably apply his stated methodology.[54]

         Even assuming the reliability of Dr. Jewell's version of trend analysis, Dr. Jewell identified trends and interpreted insignificant results differently based on the outcome of the study. The District Court concluded that Dr. Jewell "selectively emphasize[d] observed consistency . . . only when the consistent studies support his opinion."[55] Dr. Jewell emphasized the insignificance of results reporting odds ratios below 1 but not the insignificance of those reporting odds ratios above 1. He ...

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