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In re Lipitor (Atorvastatin Calcium) Mktg. Sales Practices and Prods. Liab. Litig.

United States District Court, D. South Carolina, Charleston Division

November 20, 2015

IN RE: LIPITOR (ATORVASTATIN CALCIUM) MARKETING, SALES PRACTICES AND PRODUCTS LIABILITY LITIGATION

Page 574

          For Lipitor (Atorvastatin Calcium) Marketing Sales Practices and Products Liability Litigation, In Re: H Blair Hahn, LEAD ATTORNEY, Richardson Patrick Westbrook and Brickman, Mt Pleasant, SC.

         For Plaintiffs' Lead Counsel, Plaintiff: H Blair Hahn, LEAD ATTORNEY, Christiaan A Marcum, Elizabeth Middleton Burke, Richardson Patrick Westbrook and Brickman, Mt Pleasant, SC.

         For Plaintiffs' Liason Counsel, Plaintiff: Mark Charles Tanenbaum, LEAD ATTORNEY, Mark C Tanenbaum Law Office, Charleston, SC.

         For Pfizer Inc, Defendant: Amanda S Kitts, David Eidson Dukes, John Mark Jones, LEAD ATTORNEYS, Nelson Mullins Riley and Scarborough, Columbia, SC; Karin Kramer, LEAD ATTORNEY, Quinn Emanuel Urquhart and Sullivan, San Francisco, CA; Kelly A Evans, LEAD ATTORNEY, Snell and Wilmer, Las Vegas, NV; Lee A Mickus, LEAD ATTORNEY, PRO HAC VICE, Snell and Wilmer, Denver, CO; Lyn Peeples Pruitt, LEAD ATTORNEY, Mitchell Williams Selig Gages and Woodyard, Little Rock, AK; Mara C Cusker Gonzalez, Mark Steven Cheffo, LEAD ATTORNEYS, Lincoln D Wilson, Sheila L Birnbaum, Quinn Emanuel Urquhart and Sullivan, New York, NY; Michael Tucker Cole, LEAD ATTORNEY, Nelson Mullins Riley and Scarborough (Ch), Charleston, SC; Rachel B Passaretti-Wu, LEAD ATTORNEY, PRO HAC VICE, Quinn Emanuel Urquhart and Sullivan, New York, NY; Amy Chung, Lucas Przymusinski, DLA Piper U.S. LLP, New York, NY; Brett M Collings, Theodore VH Mayer, Hughes Hubbard and Reed, New York, NY.

         For McKesson Corporation, Defendant: Emma E Garrison, Habib Nasrullah, Jeremy A Moseley, LEAD ATTORNEYS, Wheeler Trigg O'Donnell LLP, Denver, CO.

         For Greenstone LLC, Defendant: Carole W Nimaroff, George A Tsougarakis, LEAD ATTORNEYS, Brett M Collings, Theodore VH Mayer, Hughes Hubbard and Reed, New York, NY; Mark Steven Cheffo, LEAD ATTORNEY, Quinn Emanuel Urquhart and Sullivan, New York, NY.

         For Pfizer International LLC, Defendant: Carole W Nimaroff, George A Tsougarakis, LEAD ATTORNEYS, Brett M Collings, Theodore VH Mayer, Hughes Hubbard and Reed, New York, NY; Loren H Brown, LEAD ATTORNEY, DLA Piper U.S. LLP, New York, NY.

         For Laura McCammon, Interested Party: John T Lay, LEAD ATTORNEY, Gallivan White and Boyd, Columbia, SC; Joseph D Cohen, LEAD ATTORNEY, PRO HAC VICE, Porter Hedges, Houston, TX.

          OPINION

         Richard Mark Gergel, United States District Judge.

Page 575

         CASE MANAGEMENT ORDER NO. 54

         This Order relates to all cases.

         In this MDL, Plaintiffs allege that Lipitor caused them to develop Type 2 diabetes. To carry their burden, Plaintiffs must prove both general and specific causation. Westberry v. Gislaved Gummi AB, 178 F.3d 257, 263 (4th Cir. 1999). Defendant has moved to exclude the testimony of Plaintiffs' general causation experts. (Dkt. No. 972). In its motion, Defendant also moves to exclude the testimony of Dr. Nicholas Jewell.[1] Dr. Jewell is a statistician. He does not opine on whether Lipitor causes diabetes but offers opinions related to whether particular data show a statistical association between Lipitor and new-onset diabetes.[2] All of Plaintiffs' general causation experts have relied on Dr. Jewell's analysis to some extent in their initial expert reports.

         In Dr. Jewell's initial report, he analyzes (1) data submitted with Lipitor's FDA New Drug Application (NDA), (2) data from the SPARCL trial, and (3) data from the IDEAL and TNT trials. (Dkt. Nos. 972-10, 1247-9, 1247-10). From the outset, Plaintiffs' counsel provided Dr. Jewell with data from the ASCOT trial, but Dr. Jewell did not consider or discuss the ASCOT trial in his initial report. (Dkt. No. 972-7 at 121-22; Dkt. No. 972-10). In his deposition, he testified that " chose not to study the data in ASCOT." (Dkt. No. 972-7 at 120, 123).

         Defendant's experts criticized Dr. Jewell's statistical methodologies and analyses

Page 576

and specifically attacked Dr. Jewell's analysis on the fact that he did not consider the ASCOT trial data. Plaintiff then sought leave from the Court for Dr. Jewell to submit a supplemental and/or rebuttal report addressing Defendant's experts' criticisms and allowing Dr. Jewell to consider and analyze the ASCOT data. " In an abundance of caution, and to ensure this Court ha[d] the best information possible when addressing Daubert motions," the Court allowed Dr. Jewell to submit a supplemental report. (CMO 34, Dkt. No. 869 at 2). In this supplemental report, Dr. Jewell analyzes the ASCOT data, performs additional analysis on the NDA data, and performs some additional analysis of the SPARCL data. (Dkt. Nos. 972-34, 1247-11).

         Defendant specifically attacks Dr. Jewell's analyses of the NDA data and ASCOT data as unreliable. ( See Dkt. No. 972 at 14-15, 34-38, 44-46, 51; Dkt. No. 1247-2 at 27-35; Dkt. No. 1247-5 at 7-8, 12-15, 2; Dkt. No. 1247-6 at 18-19). In briefing, Defendant does not specifically attack Dr. Jewell's statistical analyses of the SPARCL, TNT and IDEAL data but argues that Dr. Jewell has cherry-picked these studies and that such cherry-picking cannot be the basis of a general causation opinion. ( See Dkt. No. 972 at 12-15, 38-43, 53). The Court takes each issue in turn.

         I. Legal Standard

          Under Rule 104(a) and 702, " the trial judge must ensure that any and all scientific testimony or evidence admitted is not only relevant, but reliable." Daubert v. Merrell Dow Pharms., 509 U.S. 579, 589, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993). Thus, the trial court must ensure that (1) " the testimony is the product of reliable principles and methods," that (2) " the expert has reliably applied the principles and methods to the facts of the case," and (3) that the " testimony is based on sufficient facts or data." Fed.R.Evid. 702(b), (c), (d). " This entails a preliminary assessment of whether the reasoning or methodology underlying the testimony is scientifically valid," Daubert, 509 U.S. at 592-93, and whether the expert has " faithfully appl[ied] the methodology to facts." Roche v. Lincoln Prop. Co., 175 Fed.Appx. 597, 602 (4th Cir. 2006)

          Factors to be considered include " whether a theory or technique . . . can be (and has been) tested," " whether the theory or technique has been subjected to peer review and publication," the " known or potential rate of error," the " existence and maintenance of standards controlling the technique's operation," and whether the theory or technique has garnered " general acceptance." Daubert, 509 U.S. at 593-94; accord United States v. Hassan, 742 F.3d 104, 130 (4th Cir. 2014). However, these factors are neither definitive nor exhaustive, United States v. Fultz, 591 Fed.Appx. 226, 227 (4th Cir. 2015), cert. denied, 135 S.Ct. 2370, 192 L.Ed.2d 159 (2015), and " merely illustrate[] the types of factors that will bear on the inquiry." Hassan, 742 F.3d at 130. Courts have also considered whether the " expert developed his opinions expressly for the purposes of testifying," Wehling v. Sandoz Pharms. Corp., 162 F.3d 1158 (4th Cir. 1998), or through " research they have conducted independent of the litigation," Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1317 (9th Cir. 1995) (on remand), and whether experts have " failed to meaningfully account for . . . literature at odds with their testimony." McEwen v. Baltimore Washington Med. Ctr. Inc., 404 Fed.Appx. 789, 791-92 (4th Cir. 2010).

          Rule 702 also requires courts " to verify that expert testimony is 'based on sufficient facts or data.'" E.E.O.C. v. Freeman, 778 F.3d 463, 472 (4th Cir. 2015) (quoting Fed.R.Evid. 702(b)). Thus, " trial

Page 577

judges may evaluate the data offered to support an expert's bottom-line opinions to determine if that data provides adequate support to mark the expert's testimony as reliable." Id. The court may exclude an opinion if " there is simply too great an analytical gap between the data and the opinion offered." Id. " The proponent of the [expert] testimony must establish its admissibility by a preponderance of proof." Cooper v. Smith & Nephew, Inc., 259 F.3d 194, 199 (4th Cir. 2001).

         The Court is mindful that the Daubert inquiry involves " two guiding, and sometimes competing, principles." Westberry v. Gislaved Gummi AB, 178 F.3d 257, 261 (4th Cir. 1999). " On the one hand, . . . Rule 702 was intended to liberalize the introduction of relevant expert evidence," id., and " the trial court's role as a gatekeeper is not intended to serve as a replacement for the adversary system." United States v. Stanley, 533 Fed.Appx. 325, 327 (4th Cir. 2013) cert. denied, 134 S.Ct. 1002, 187 L.Ed.2d 852 (2014). On the other, " [b]ecause expert witnesses have the potential to be both powerful and quite misleading, it is crucial that the district court conduct a careful analysis into the reliability of the expert's proposed opinion." United States v. Fultz, 591 Fed.Appx. 226, 227 (4th Cir.) cert. denied, 135 S.Ct. 2370, 192 L.Ed.2d 159 (2015); accord Westberry, 178 F.3d at 261.

         II. Dr. Jewell's Analysis of the NDA Data

         A. Background on the NDA Data

         Dr. Jewell's first opinion concerns data that Defendant submitted with Lipitor's FDA New Drug Application (NDA). (Dkt. No. 1247-9 at ¶ 6). With its application to the FDA, Defendant submitted an Integrated Summary of Safety (ISS) that summarizes data from 31 completed clinical pharmacology studies and 21 completed clinical studies. (Dkt. No. 1063-8 at 6). Section 5.2.1 and Table 42 group all of the data from the placebo-controlled clinical trials. ( Id. at 118-19). There were seven such placebo-clinical trials, excluding one placebo-controlled trial where all participants had pre-existing Type 2 diabetes. ( See id. at 120; Dkt. No. 1247-9 at ¶ 13). These seven trials included a total of 1,122 participants given various doses of Lipitor and 270 participants given placebo. (Dkt. No. 1063-8 at 119; Dkt. No. 1247-9 at ¶ 13). Dr. Jewell was provided with the data from these seven clinical trials, including patient-level glucose readings.

         Among other things not relevant here, Table 42 reports how many participants in these seven clinical trials had an elevated blood glucose reading during the trials, with elevated glucose defined as > 1.25 ULN [the upper limit of normal]. (Dkt. No. 1063-8 at 119). For most trials, the upper limit of normal was defined as 100 mg/dL such that 1.25 ULN = 1.25 mg/dL.[3] However, there was one trial where ULN was defined as 104 mg/dL such that 1.25 ULN was 130 mg/dL. (Dkt. No. 1063-8 at ¶ 18). Table 42 reports that three (3) of the 270 participants on placebo had an elevated glucose reading " on treatment," i.e. during the trial, and that 37 of the 1,122 participants on Lipitor had an elevated glucose reading on treatment. (Dkt. No. 1063-8 at 119).

         Focusing on the data from these seven clinical trials in the NDA data, Dr. Jewell opined that this data " provide less than optimum information about [Lipitor's] effect on glucose metabolism or new-onset diabetes, because of their short duration, relatively small sample sizes, and the unusual

Page 578

imbalance between the number of participants allocated to placebo and atorvastatin treatment." (Dkt. No. 1247-9 at ¶ 6). Yet, Dr. Jewell mined the data and, after some effort, concluded that " [t]he placebo-controlled data [from the NDA trials] show[] a statistically significant three-fold higher incidence of clinically meaningful abnormal increases in blood glucose measurement greater than 1.25 times the upper limit of normal, a level that, if persistent, is diagnostic for diabetes" and that this glucose data " should have alerted Parke-Davis and Defendant to the possibility of increased risk of new-onset diabetes associated with atorvastatin treatment." (Dkt. No. 1247-9 at ¶ 6). To reach this conclusion, Dr. Jewell improperly engaged in a results-driven methodology, performing, in his words, a " whole lot" of analyses of the data, excluding from his report analyses that he " didn't believe . . . supported . . . being the basis of the kinds of opinions I wanted to put in my summary," [4] (Dkt. No. 1247-8 at 230-31), and conducting multiple statistical tests when the first test did not produce the results that he wanted.

         B. Relative Risk

         Dr. Jewell first looked at adverse event data from these seven clinical trials but could not reach any conclusions from it. Of the 1,392 participants in these trials, only five reported adverse events of diabetes and five others noted an event such as " elevated glucose." [5] (Dkt. No. 1247-9 at ¶ 14). None of these incidents were reported by participants in the placebo group but " it's not a shock . . . given th[e] distribution of participants." [6] (Dkt. No. 1247-8 at 206-07). There are " very few participants" reporting an adverse event of diabetes, so Dr. Jewell " basically lay[s] to rest the hope that one might glean too much from the adverse event [data]." (Dkt. No. 1247-8 at 206).

         Dr. Jewell then turns to glucose measurements. Dr. Jewell " count[ed] the number of individuals who had elevated glucose measurements at any point after baseline" (i.e., during the trial), and compared this number in the groups on Lipitor and the groups on placebo.[7] (Dkt. No. 1247-9 at ¶ 17 (emphasis in original)). Dr. Jewell took the count from Table 42 of the ISS. ( Id. ).

         1. Use of a Single Glucose Measurement

         As an initial matter, whether a single elevated glucose measurement can be used as a proxy for new-onset diabetes (Plaintiffs' alleged injury in this lawsuit) is suspect. Dr. Jewell himself was unwilling to testify about the role or use of blood glucose as a surrogate marker for diabetes because he was not a clinician. (Dkt. No.

Page 579

972-7 at 128). Furthermore, when he used fasting glucose levels as diagnostic of diabetes in other analyses, he defined diabetes as two post-baseline fasting glucose measurements > 125 mg/dL, not one. ( E.g., Dkt. No. 1247-9 at ¶ 146). Indeed, Plaintiffs argue in another context that participants with an elevated glucose reading at baseline are not necessarily diabetic " because a diagnosis of diabetes requires more than a single elevated plasma glucose level." (Dkt. No. 1159 at 12).

         Presumably, Dr. Jewell used a single glucose measurement in his NDA analysis because, at least for some participants, there is only one post-baseline glucose measurement during the controlled trial. ( See Dkt. No. 1247-12 at 59-63). However, when Dr. Jewell examined the IDEAL data and realized that a number of participants would have to be excluded from the analysis because they lacked two post-baseline glucose values, Dr. Jewell chose not to look at glucose measurements at all and chose not to run any statistical analyses using glucose values. (Dkt. No. 1247-9 at ¶ ¶ 95-110). Instead, he only used adverse event reporting. ( Id. ). Nevertheless, with this NDA data, Dr. Jewell not only performed statistical tests based on a single elevated glucose measurement but opined that data based on a single glucose measurement is sufficient to suggest an increased risk of new-onset diabetes. ( See Dkt. No. 1247-9 at ¶ 6 (opining that this glucose data " should have alerted Parke-Davis and Defendant to the possibility of increased risk of new-onset diabetes associated with atorvastatin treatment" )).

         By his deposition testimony, Dr. Jewell lacks the clinical expertise to make any inferences about new-onset diabetes from data regarding a single elevated glucose reading. (Dkt. No. 972-7 at 128). And Plaintiffs state a single elevated glucose measurement is insufficient to infer diabetes. (Dkt. No. 1159 at 12). Therefore, even if the methodological flaws discussed below were not present, the Court would exclude Dr. Jewell's opinion that this data " should have alerted Parke-Davis and Defendant to the possibility of increased risk of new-onset diabetes associated with atorvastatin treatment." (Dkt. No. 1247-9 at ¶ 6).

         2. Including Participants with Elevated Glucose at Baseline

         Dr. Jewell's second methodological flaw in his analysis of the NDA data is that he chose to include participants that had glucose measures above 125 mg/dL at baseline when the study began. ( See Dkt. No. 1247-9 at ¶ 19); see also Reference Manual on Scientific Evidence 216 (3d ed. 2011) (" [F]laws in the data can undermine any statistical analysis." ). Dr. Jewell's analysis starts with the count that three (3) of the 270 placebo participants had " abnormal glucose levels" during the trial and 37 of the 1,122 Lipitor participants had " abnormal glucose levels" during the trial. ( Id. at ¶ ¶ 13, 20). However, 2 of the 3 placebo participants with elevated glucose readings during the trial had baseline glucose levels over 125 mg/dL, and 25 of the 37 Lipitor participants had baseline glucose levels over 125 mg/dL. (Dkt. No. 1247-12 at ¶ 140; Dkt. No. 974-11 at 131). Seven of the 37 with elevated glucose in the Lipitor group had a documented history of diabetes before the trial began.[8] (Dkt. No. 974-11 at 131). Thus, in the

Page 580

NDA Medical Review, the FDA states the following:

The increased incidence of glucose elevations in the atorvastatin-treated participants bears comment. In the placebo-controlled data grouping, of the 37 atorvastatin participants with glucose elevations, 36/37[9] had elevated glucose at baseline, and in 25 of those 36, elevations were > 1.25 X ULN. In addition, 7/37 had a history of diabetes and 2/37 had a history of glucose intolerance.
Similarly, in the all-completed studies grouping, of 185 atorvastatin participants with glucose elevations, 115/185 had a history of NIDDM. 174/185 had baseline values > ULN.
In sum, there is little evidence for an effect of atorvastatin on glucose metabolism.

(Dkt. No. 974-11 at 131) (footnote added).[10]

         There are two ways that failing to exclude participants with elevated baseline glucose is problematic for Dr. Jewell's analysis. First, there is the potential for confounding.[11] In the NDA trials, 5.3% of all participants on Lipitor had at least one glucose measurement above 125 mg/dL before the trial, while only 1.9% of the placebo participants had at least one glucose reading above 125 mg/dL before the trial, and this difference between the two groups was statistically significant. (Dkt. No. 972-36 at ¶ 140). Looking only at the very first pre-trial glucose measurement for each participant, as opposed to all pre-trial glucose measurements, 3.83% of the Lipitor group had an elevated glucose value at this first measurement and only 1.85% of the placebo group had an elevated glucose value at this first measurement, though this difference was not statistically significant.[12] (Dkt. No. 1247-11 at ¶ ¶ 37, 39). This difference has the potential to confound Dr. Jewell's data.

         Second, because Dr. Jewell's analysis includes those with elevated glucose at baseline, it does not compare new cases of elevated glucose, i.e., those participants with elevated glucose due to Lipitor. In

Page 581

other words, the analysis does not test for new-onset diabetes, the subject of Dr. Jewell's opinion, or even new-onset elevated glucose. Dr. Jewell claims that he was only concerned with " clinically meaningful abnormal deviations in glucose" or " assessing whether atorvastatin had a potentially deleterious effect on glucose levels" regardless of baseline characteristics. (Dkt. No. 1247-8 at 235.; Dkt. No. 1247-9 at ¶ 19). He argues that " [w]hether the patient had diabetes, was prediabetic, had elevated blood glucose before the trial is irrelevant to me," (Dkt. No. 1247-8 at 235), because all of these groups could still experience significant increases in their glucose levels. (Dkt. No. 1247-9 at ¶ 19).

         These claims are belied by Dr. Jewell use of this data to support opinions about " the possibility of increased risk of new-onset diabetes," (Dkt. No. 1247-9 at ΒΆ 6 (emphasis added)), and Plaintiffs argument that this NDA data supports the opinion that 10 mg of Lipitor causes new-onset diabetes. (Dkt. No. 1159 at 11-13). However, even assuming that he did want to assess significant changes in glucose levels, regardless of baseline characteristics, this is not what he assessed. He included 100% of the participants that had an elevated glucose measurement during a trial, regardless of whether they actually experienced any significant increase in glucose from baseline. For example, Patient #1 had a baseline glucose measurement of 131 mg/dL and an on-treatment glucose measurement of 133 mg/dL, (Dkt. No. 1247-12 at 59), a change of 2 mg/dL, a change that ...


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