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4th Cir.: Statistical significance analysis must be reliable.

Byline: Rebecca M. Lightle

Experts' calculation and application of statistical significance (p-values) must be relevant, reliable, and not likely to confuse jurors. After plaintiffs' expert opinions were excluded, their non-expert evidence was not sufficient to survive summary judgment, and the district court appropriately granted it against all plaintiffs in the multidistrict litigation.<br />Background<br />Pfizer manufactures Lipitor, a drug prescribed to lower patients' cholesterol. In the U.S., Lipitor is commercially available in tablets of 10, 20, 40, and 80 mg.<br />The Plaintiffs in this multidistrict litigation are more than 3,000 women who claim that they developed diabetes as a result of taking Lipitor. They enlisted general and specific causation experts and also retained an expert biostatistician. The district court granted Pfizer's motion to exclude these expert witnesses, leaving the Plaintiffs without their bellwether cases and limited to a subset of patients who had taken an 80 mg dose.<br />The district court then issued a series of show cause orders asking whether any plaintiff in the MDL could submit evidence (expert or otherwise) that would enable her claim to survive summary judgment given the court's prior rulings. In response, one group of plaintiffs submitted evidence that they were not diabetic before taking Lipitor, that they were diagnosed with diabetes after taking Lipitor, and that they lacked certain risk factors that might make them especially likely to develop the disease. Another group simply "dumped boxes upon boxes of documents" on the district court with "no discernment or suggestion as to which documents they claimed precluded summary judgment." The district court determined that neither of these submissions were sufficient to show causation and granted summary judgment against all plaintiffs in the MDL.<br />Excluded statistics expert<br />The district court properly excluded the opinions of the Plaintiffs' expert, Dr. Jewell, as to data used in several clinical trials.<br />Jewell examined blood glucose levels of patients in the trials who had taken Lipitor rather than a placebo. Jewell noted shortcomings of the dataset but nevertheless concluded that it reasonably showed that Lipitor had a statistically significant effect on baseline glucose metabolism. That association, he opined, should have put Pfizer on notice of a possible association between atorvastatin and diabetes.<br />The district court found that Jewell's methodology and application didn't satisfy Daubert v. Merrell Dow Pharm. Inc., 509 U.S. 579 (1993). Jewell's dataset included patients who had only a single elevated blood glucose reading and patients who had an abnormally elevated baseline glucose level at the beginning of the trial. The Plaintiffs had previously said that a single elevated glucose reading was not a reliable indicator of a diabetic patient. The dataset also included patients with elevated baseline levels, which risked introducing confounding variables.<br />The district court concluded that Jewell was simply not qualified to make determinations about which patients' data should have alerted Pfizer to a possible association between its drug and diabetes. Jewell readily admitted that he had no expertise in diabetes, did not "quite know" what new-onset diabetes meant, and was unwilling to testify about the role or use of blood glucose as a surrogate marker for diabetes because he was not a clinician.<br />The district court also questioned how Jewell chose to include or omit results from different tests in his report. Jewell originally performed a "Fisher's exact test," a well-known technique to assess statistical significance for small samples. The test showed a statistically insignificant association between Lipitor and the onset of diabetes. Jewell omitted that result from his initial expert report and instead reported the results using a "mid-p" value. The district court expressed concern that Jewell's test selection was "results driven," and that he "only used [the mid-p] test once the Fisher exact test returned a non-significant result." The district court reasonably concluded that such an approach lacked the hallmark of science properly performed.<br />Finally, the district court was skeptical of Jewell's use of average blood glucose increase as a metric in his analysis. After calculating the average glucose increase among patients with elevated levels in both the treatment and control groups, he reasoned that this average increase could be applied to the group of patients who had taken Lipitor, using his past (potentially flawed) conclusions to support the proposition that patients with glucose elevation were more likely to be in the Lipitor (rather than placebo) groups. The district court found this logic to be flawed, noting that the data actually showed greater increases in blood glucose among placebo-taking patients.<br />Consequently, the district court found that this data was unreliable and had real potential to confuse jurors. The district court properly discharged its gatekeeping duty by considering and ultimately excluding Jewell's opinions and explaining in detail its well-reasoned grounds for doing so.<br />The district court also excluded Jewell's re-analysis of data Pfizer produced from one particular clinical trial. Using a new definition of new-onset diabetes, Jewell concluded that the trial data showed an association between use of Lipitor and an increased risk of diabetes that had not been detected in Pfizer's analysis. The district court again took issue with Jewell's lack of expertise in diabetes and also expressed skepticism about the fact that his case identification, unlike the first analysis, was not blind.<br />The district court repeatedly opined that Jewell (1) wasn't qualified to second-guess the clinicians who selected the diagnostic criteria; (2) didn't even know what criteria they had used; and (3) hadn't adequately justified his decision to replace their criteria with his own.<br />Under Daubert, courts must look to the entire process that produced an opinion to determine whether the expert's work leads to reliable and relevant testimony. Here, even when afforded the opportunity to supplement his report, Jewell did not assuage the district court's justified worries.<br />Excluded general-causation expert<br />The district court also properly excluded the testimony of Dr. Singh. Singh concluded that there was an association between Lipitor and increased risk of diabetes based on a meta-analysis of relevant studies. Singh then used the "Bradford Hill criteria" to conclude that there was a causal association between Lipitor and diabetes at each commercial dose available. Nevertheless, the district court excluded Singh's opinion for each dose except 80 mg, holding that the Bradford Hill analysis was improper at doses where the data didn't reveal a sufficiently strong association between the drug and the disease.<br />One of the central tenets of toxicology is that "the dose makes the poison." The district court determined that this case called for expert opinions broken down by dose because the experts agreed that there is a dose-response relationship. In many cases, substances that might be quite harmful in high doses are innocuous in smaller amounts. Where, as here, each plaintiff took one of only several commercially available doses, clinical data exist that enable an expert to perform a causation analysis at each dose, and experts confirm a relationship between dosage and harm, the district court doesn't abuse its discretion in asking the expert to produce a dose-by-dose analysis.<br />Additionally, because Singh failed to find a statistically significant relationship between Lipitor and diabetes at certain doses, the district court reasonably found that he should not have applied the Bradford Hill factors at the second step.<br />Statistical significance may bear on the question of reliability and must therefore be subjected to the same inquiry as any other scientific evidence. The court declines to establish a bright-line rule requiring experts to rely only on evidence that is statistically significant or else have their opinions excluded. The district court here did not hold to the contrary, but said instead that in the context of a Bradford Hill analysis, a statistician should find a statistically significant association at the method's "step one" before moving on to step two. Because Singh deviated from this norm, the district court concluded that he unreliably applied the Bradford Hill methodology and, thus, his opinion was subject to exclusion.<br />Excluded specific-causation expert<br />Finally, the district court properly excluded the opinion of Dr. Murphy. The focus of Murphy's testimony was whether Lipitor actually caused Plaintiff Hempstead to develop diabetes.<br />While Murphy's report claimed that her methodology is "commonly used," she couldn't identify any organizations or peer-reviewed texts containing it or colleagues who used it to determine the cause of diabetes. She also hadn't personally applied the methodology to her own patients' diabetes. The district court found that Murphy's analysis "offers no data or facts to make the leap from a possibility to a probability that Lipitor was a substantial contributing factor."<br />Murphy identified several factors for which the risk "greatly exceed[ed] the risk of developing diabetes associated with Lipitor." She opined that several of Hempstead's risk factors were significant to the development

of diabetes and others were not. Nevertheless, she concluded that Lipitor ingestion was a substantial contributing factor in causing Hempstead's diabetes. The district court explained: "The powerful evidence that Plaintiff's many other risk factors can independently cause diabetes and cannot be ruled out further undermine Dr. Murphy's testimony."<br />Murphy's report was not entirely void of explanation. She addressed the significant risk factors of age and body mass index by explaining that studies either adjust for those factors or are randomized to control for them, and that those studies nevertheless show an increased risk of diabetes associated with Lipitor. But these explanations (even if true) do not accomplish the specific-causation expert's task: accounting for the development of the disease in a particular plaintiff. That Lipitor may cause an increased risk of diabetes notwithstanding certain other risk factors is insufficient to conclude that the drug was a substantial contributing factor in an individual patient. To hold otherwise would obviate the need for any specific-causation evidence at all.<br />The district court was concerned that Murphy simply concluded that, so long as the patient took Lipitor and developed diabetes, then Lipitor was a substantial contributing factor. She opined that if a "patient was taking the Lipitor and they developed diabetes while on it, ... I would think that it would be a contributing factor." She focused primarily on the fact that the plaintiff took Lipitor close in time to her development of diabetes and also failed to adequately explain the basis for ruling out other contributing factors including some that she herself described as substantial.<br />In sum, Murphy's report appeared to dismiss other possible causes in favor of Lipitor in a cursory fashion. Her conclusions focused almost exclusively on the fact that Hempstead took the drug and later developed the disease, rather than explaining what led her to believe that it was a substantial contributing factor as compared to other possible causes. Daubert requires more.<br />Non-expert evidence<br />Without sufficient expert testimony, the district court did not err in ruling that other evidence of causation was not enough for the Plaintiffs to survive summary judgment.<br />The district court rejected the Plaintiffs' argument that causation could be proven through Pfizer's purported admissions that Lipitor can cause diabetes. Applying an Erie analysis, the district court concluded that "all jurisdictions require expert testimony at least where the issues are medically complex and outside common knowledge and lay experience."<br />There may be cases involving complex issues in which a party admission standing alone can suffice to avoid summary judgment. But we would expect those cases to be rare indeed. The questions presented in this case are complex and manifold, but the evidence at issue isn't especially strong. Most of the proffered statements don't directly support the proposition that Lipitor causes diabetes but instead speak to association rather than causation or focus on blood glucose rather than diabetes. To hand to a jury the evidence here and ask it to evaluate causation would be farcical and result in a verdict steeped in speculation.<br />Summary judgment across cases<br />It was not improper for the district court to enter summary judgment across all cases in the MDL after no plaintiff produced adequate evidence of specific causation in response to the court's show cause orders.<br />There is no inconsistency between the district court's actions and the MDL statute. Here, it was the district court's prerogative to determine whether it could dispose of the cases before it on the merits. At the time of summary judgment, the Plaintiffs were already facing an uphill battle without a general causation expert as to the majority of Lipitor doses, and their specific causation expert for the bellwether trial had also been excluded. After a series of show-cause orders, no plaintiff had come forward with alternative evidence of specific causation that would survive review. The district court thus declined to "essentially disregard the entire course of the MDL proceedings" by recommending remand.<br />These cases involve difficult questions of mathematics and science, wrapped in a complex form of mass litigation. The district court here had to make a number of decisions pursuant to both its "gatekeeper" role imposed by Daubert, as well as its supervisory role as the transferee court in a large multidistrict litigation. The district court discharged those duties meticulously and thoughtfully throughout the litigation.<br />Affirmed.<br />In re: Lipitor Marketing, Sales Practices & Prod. Liability (No II) Litigation MDL 2502, Case No. 17-1140, June 12, 2018. 4th Cir. (Diaz), from DSC at Charleston (Gergel). Derek T. Ho for Appellants; Mark Cheffo for Appellees. VLW No. 018-2-119, 46 pp.

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Author:Lightle, Rebecca M.
Publication:Virginia Lawyers Weekly
Date:Jun 24, 2018
Words:2244
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