Richard Mark Gergel, United States District Court Judge
CASE MANAGEMENT ORDER NO. 72
This Order relates to all cases.
Richard Mark Gergel, United States District Court Judge
This matter is before the Court on Pfizer's Motion to Exclude Expert Testimony and Claims that Lipitor is Not Effective for and Should Not Be Approved for Primary Prevention in Women, (Dkt. No. 970). For the reasons stated below, the motion is GRANTED IN PART AND DENIED IN PART.
I. Background
All Plaintiffs in this MDL are women who used Lipitor"to lower the LDL cholesterol and triglycerides in the blood and/or as a primary prevention measure to decrease the risk of developing CVD [cardio vascular disease ]." (Dkt. No. 160 at ¶ 17). Plaintiffs generally allege that Lipitor caused their Type 2 diabetes and that Defendant failed to adequately warn them about the diabetes risk associated with
Lipitor. (See generally Dkt. No. 160). Plaintiffs also allege that Lipitor was negligently designed because, among other things, it "was not effective for women as a measure of primary prevention of CVD." (Id. at ¶ 80). Additionally, Plaintiffs allege claims based on the combination of alleged ineffectiveness and alleged dangerousness. (See id. at ¶ 67 (alleging that Defendant was negligent "[i]n its promotion of Lipitor (atorvastatin calcium ) in an overly aggressive, deceitful and fraudulent manner despite the lack of evidence demonstrating its effectiveness in women and despite the evidence as to the product's defective and dangerous characteristics due to its propensity to cause Type 2 Diabetes."); id. at ¶ 80 (alleging the drug was negligently designed because "it contained insufficient, incorrect, and defective warnings," which failed to alert health care professionals and users "of the risks of adverse effects and the lack of benefit for women.")).
At issue in the instant motion are opinions by Plaintiffs' experts that (1) Lipitor is not effective for primary prevention in women, (2) that there is no evidence that Lipitor is effective for primary prevention in women, and/or (3) that Lipitor should not have been approved for primary prevention in women. As an initial matter, Plaintiffs state in briefing that they "do not assert, and their experts do not opine that Lipitor is not effective for primary prevention in women. Rather, these experts opine that there is insufficient evidence to show that Lipitoris effective for primary prevention in women." (Dkt. No. 1046 at 6 (emphasis in original)). However, Plaintiffs do specifically allege in their Master Complaint that Lipitor is " not effective for women as a measure of primary prevention of CVD," (Dkt. No. 160 at ¶ 80 (emphasis added)), and at least some of Plaintiffs' experts state this opinion. (See Dkt. No. 97012 at 155–56 ("Q. Is it your opinion that women with diabetes receive no benefit from [ ] taking Lipitor ? A. Correct.")). Therefore, where applicable, the Court will consider and address both opinions.
Similarly, Plaintiffs state that they "do not allege that Lipitor... should never have been approved for use by women." (Dkt. No. 1046 at 33). While Plaintiffs have not alleged this in their Master Complaint, Dr. Abramson did state this opinion in his deposition. (See Dkt. No. 970–5 at 20 ("I would not have Lipitor be indicated for primary prevention in women."); id. at 20 ("Q.... [Y]ou think that Lipitor prescriptions for women for primary prevention should be an off-label use. Is that right? A. Yes.")). Thus, the Court will address whether Dr. Abramson can testify to this at trial.
Pfizer argues that all of these opinions should be excluded under Fed.R.Evid. 702 and that Plaintiffs' lack of efficacy claims are preempted by federal law. (Dkt. No. 970). In particular, Plaintiffs claim that Defendant's labeling, advertising and promotion of Lipitor are misleading with regard to efficacy in women, and Defendant argues these particular claims are preempted by federal law. The Court will
address the preemption issue first and then turn to Rule 702 and Daubert.
II. Preemption
A. Impossibility Preemption
"A fundamental principle of the Constitution is that Congress has the power to preempt state law." Crosby v. Nat'l Foreign Trade Council, 530 U.S. 363, 372, 120 S.Ct. 2288, 147 L.Ed.2d 352 (2000). Even without an express statutory provision for preemption, the U.S. Supreme Court has held that state law is preempted by federal law when (1) Congress intends federal law to "occupy the field," or (2) where state law conflicts with a federal statute. Id. One variety of conflict preemption is "where it is impossible for a private party to comply with both state and federal law." Id. ; see also id. at 372 n. 6, 120 S.Ct. 2288 ; Oneok, Inc. v. Learjet, Inc., –––U.S. ––––, 135 S.Ct. 1591, 1595, 191 L.Ed.2d 511 (2015) ; Sprietsma v. Mercury Marine, a Div. of Brunswick Corp., 537 U.S. 51, 64, 123 S.Ct. 518, 154 L.Ed.2d 466 (2002). Defendant claims that impossibility preemption is applicable here. In particular, Defendant claims that it could not have complied with any state law duty to change its label with regard to efficacy and still comply with its labeling requirement under federal law. Thus, the Court must determine whether Defendant could change its label to indicate a "lack of benefit for women," as Plaintiffs argue Defendant had a duty to do under state law, and still comply with federal law.
B. FDA Approval Process
The Federal Drug and Cosmetic Act (FDCA) requires drug manufacturers to gain FDA approval before marketing or selling a drug in interstate commerce. 21 U.S.C. § 355(a). To gain FDA approval for a new drug, a manufacturer submits a new-drug application (NDA), and to gain approval for a new indication, a manufacturer submits a supplemental new-drug application (sNDA). See 21 C.F.R. § 314.1, et. seq. Among other things, such applications must include "full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use." 21 U.S.C. § 355(b). Drug manufacturers must also submit proposed labeling, with annotations, to be used with the drug. 21 U.S.C. § 355(b)(1)(F) ; 21 C.F.R. § 314.50(c)(2)(i).
To approve a particular indication for use of a drug, the FDA must determine that there is "substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof" and that "based on a fair evaluation of all material facts," the labeling of the drug is not "false or misleading in any particular." 21 U.S.C. § 355(d). "Substantial evidence" means "evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved." Id. The FDA has discretion to determine "based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness." Id.
"The FDA's premarket approval of a new drug application includes the approval
of the exact text in the proposed label." Wyeth v. Levine, 555 U.S. 555, 568, 129 S.Ct. 1187, 173 L.Ed.2d 51 (2009) (citing 21 U.S.C. § 355 ; 21 C.F.R. § 314.105(b) ). After FDA approval, the manufacturer may sell and distribute the drug without violating federal law as long as it uses the FDA-approved label. In re Celexa & Lexapro Mktg. & Sales Practices Litig., 779 F.3d 34, 36 (1st Cir.2015) (citing 21 U.S.C. §§ 331(c), 333(a), & 352(a), (c) ).
C. Lipitor's Label
In 1996, the FDA approved Lipitor for reducing cholesterol. In 1998, the FDA approved its use by patients with elevated triglycerides, and in 1999, the FDA approved it to increase HDL. At issue in this motion is Lipitor's 2004 indication for use in the primary prevention of cardiovascular disease (CVD). The 2004 indication on the label states:
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL–C, or a family history of early coronary heart disease, LIPITOR is indicated to:
• Reduce the risk of myocardial infarction
• Reduce the risk of stroke
• Reduce the risk for revascularization procedures and angina.
(Dkt. No. 970–28 at 4). The FDA approved Lipitor for this indication based on the ASCOT clinical trial. The FDA approved the use generally, without indication as to gender. However, the FDA-approved label describing the ASCOT study stated that "[d]ue to the small number of events, results for women were inconclusive." (Dkt. No. 970–28 at 18).
D. Changing the Label
There are two ways that a brand name drug manufacturer can change a drug's label that are pertinent here: (1) secure FDA approval or (2) make a change under the Changes Being Effected (CBE) regulations. 21 C.F.R. §§ 314.70(b), 314.70(c)(6)(iii) ; see also In re Celexa, 779 F.3d at 37. The U.S. Supreme Court has held that if a drug manufacturer must obtain FDA approval to take action to comply with state law, then the state law is preempted. PLIVA, Inc. v. Mensing, 564 U.S. 604, 131 S.Ct. 2567, 2571, 180 L.Ed.2d 580 (2011) ( "[W]hen a party cannot satisfy its state duties without the Federal Government's special permission and assistance, which is dependent on the exercise of judgment by a federal agency, that party cannot independently satisfy those state duties for pre-emption purposes."). Thus, the question becomes whether the Defendant could have corrected the alleged labeling deficiency without prior FDA approval by using the CBE regulation. See In re Celexa, 779 F.3d at 41 (stating that the U.S. Supreme Court had drawn a line "between changes that can be independently made using the CBE regulation and changes that require prior FDA approval"); see also Wyeth v. Levine, 555 U.S. at 568, 129 S.Ct. 1187.
Under the CBE regulation, drug manufacturers may change a drug label, without prior FDA approval, "to reflect newly acquired
information ... to accomplish any of the following:
(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c) of this chapter;
(B) To add or strengthen a statement about drug abuse, dependence, psychological effect, or overdosage;
(C) To add or strengthen an instruction about dosage and administration that is intended to increase the safe use of the drug product;
(D) To delete false, misleading, or unsupported indications for use or claims for effectiveness; or
(E) Any labeling change normally requiring a supplement submission and approval prior to distribution of the drug product that FDA specifically requests be submitted under this provision.
21 C.F.R. § 314.70(c)(6)(iii). Plaintiffs claim that Defendant should have changed Lipitor's label regarding efficacy under subsection (D) of this regulation.
Applicable regulations also define "newly acquired information" for purposes of the CBE regulation;
Newly acquired information means data, analyses, or other information
not previously submitted to the agency, which may include (but are not limited to) data derived from new clinical studies, reports of adverse events, or new analyses of previously submitted data (e.g., meta-analyses) if the studies, events or analyses reveal risks of a different type or greater severity or frequency than previously included in submissions to FDA.
21 C.F.R. § 314.3(b) (emphasis added). Thus, any claim that a drug label should be changed based on information previously submitted to the FDA is preempted because the CBE regulation cannot be used to make a label change based on such information. However, claims that a drug label should be changed based on "newly acquired information" not submitted to the FDA are not preempted by federal law. As the First Circuit explained:
To the extent that the underlying policy issue is one of who decides whether and how a drug can be marketed, the line so drawn lets the FDA be the exclusive judge of safety and efficacy based on information available at the commencement of marketing, while allowing the states to reach contrary conclusions when new information not considered by the FDA develops. The CBE regulation, too, covers virtually all situations in which new information indicates new or greater risks, or misleading claims of efficacy. By hinging preemption on the availability of that procedure in a particular case,
Wyeth effectively reserves the launch of new drugs to the expertise of the FDA, but then preserves a wide scope for the states in requiring manufacturers to respond to information not considered by the FDA.
In re Celexa., 779 F.3d at 41.
Here, the FDA approved the Lipitor label based on the ASCOT trial and data. It specifically approved the statement, based on ASCOT, that "[d]ue to the small number of events, results for women were inconclusive." (Dkt. No. 970–28 at 18). To the extent that Plaintiffs claim Lipitor's label should have included different statements about Lipitor's efficacy for primary prevention in women based on the
ASCOT data, those claims are preempted. While Plaintiffs are correct that "new analyses of previously submitted data" are sufficient to invoke the CBE regulation, neither Plaintiffs nor their experts have identified any such "new analyses" of the ASCOT data that should have caused Defendant to change its label. The only "new analysis" of ASCOT efficacy data mentioned by Plaintiffs' experts is Dr. Wells' analysis, which was conducted as a part of this litigation.
The only "newly acquired information" mentioned by Plaintiffs in briefing is the CASHMERE study. (Dkt. No. 1046 at 32). Any claims that Defendant should have changed its label based on the CASHMERE study are not preempted, as the study would be "newly acquired information." Defendant argues that "the results of CASHMERE have no bearing on the primary prevention indications..." (Dkt. No. 1090 at 18). However, such arguments concern the sufficiency of evidence to survive summary judgment, not preemption. Thus, the Court does not address the argument here.
Finally, Plaintiffs argue that "new information about the increased risk of diabetes associated with statins generally, and Lipitor in particular, has continued to accumulate," that "[t]his accumulating information about diabetes and Lipitor has cast the lack of evidence of efficacy in a new light," and that "had Pfizer wished to change its label to make the lack of evidence of efficacy in this group clearer, it could have." (Dkt. No. 1046 at 32). The Court disagrees that new information regarding the risk of diabetes could serve a basis for a CBE label change regarding efficacy. As an initial matter, Pfizer has not claimed that Plaintiffs' failure to warn claims are preempted by federal law, and Plaintiffs are free to argue that "accumulating information about diabetes" should have caused Defendant to add or change warnings regarding diabetes. However, Defendant could not, as Plaintiffs contend, "change its label to make the lack of evidence of efficacy in this group clearer," absent "newly acquired information" that "indications for use or claims for effectiveness" were "false, misleading, or unsupported." 21 C.F.R. § 314.70(c)(6)(iii)(D). In other words, changes to statements regarding efficacy in the label must be based on newly acquired information regarding efficacy.
To hold otherwise would mean that any new information regarding a drug would allow a drug manufacturer, under the CBE regulation, to wholly re-write a drug label, completely divorced from the FDA-approved label, regardless of whether the new information was relevant to particular statements being changed or not. Such an interpretation is contrary to the regulatory scheme of the FDCA and contrary to the CBE regulation itself. Under the CBE regulation, a drug manufacturer can change a label "[t]o delete false, misleading, or unsupported indications for use or claims for effectiveness" when newly acquired information indicates, or " reflect[s] ," that claims of effectiveness are "false, misleading, or unsupported." 21 C.F.R. § 314.70(c)(6)(iii) (emphasis added). Thus, under the CBE regulation, changes to statements regarding efficacy in the label must be based on newly acquired information regarding efficacy.
In sum, to the extent that Plaintiffs claim that a state law duty required Defendant to include different statements on Lipitor's label regarding Lipitor's efficacy for primary prevention in women, based on the ASCOT data or information solely related to the risk of diabetes, those claims
are preempted. To the extent that Plaintiffs claim that a state law duty required Defendant to include different statements on Lipitor's label regarding Lipitor's efficacy for primary prevention in women, based on CASHMERE or other newly acquired information, the claims are not preempted.
E. Advertising and Promotion Claims
Plaintiffs also claim that Defendant should have advertised or promoted Lipitor differently with regard to efficacy. Defendant contends such claims are also preempted.
As an initial matter, any claims that Defendant should have simply stopped selling the drug to women for primary prevention is preempted. The U.S. Supreme Court has explicitly "reject[ed] this ‘stop-selling’ rationale as incompatible with [its] pre-emption jurisprudence," noting that such a rationale would render impossibility preemption "all but meaningless." Mut. Pharm. Co. v. Bartlett, ––– U.S. ––––, 133 S.Ct. 2466, 2477, 186 L.Ed.2d 607 (2013). Plaintiffs appear to concede as much at oral argument and in post-oral argument briefing. (See Dkt. No. 1171 at 108 ("[T]hey don't have to stop selling the drug. I think that's what Bartlett said."); Dkt. No. 1282 at 4–5 ("A judgment grounded in state law that Pfizer's advertising contained untruths not found in the Lipitor label ... [does not] require Pfizer to stop selling Lipitor, or even to stop selling it to women.").
The question remains whether state law claims based upon Defendant's promotion and advertising of Lipitor are preempted by the FDCA. The Court starts with the definition of "labeling," which is fairly broad. For purposes of the FDCA, the term "means all labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article." 21 U.S.C § 321(m). The first clause of this definition "clearly embraces advertising or descriptive matter that goes with the package in which the articles are transported." Kordel v. United States, 335 U.S. 345, 349–50, 69 S.Ct. 106, 93 L.Ed. 52 (1948) ; accord Strayhorn v. Wyeth Pharm., Inc., 737 F.3d 378, 394 (6th Cir.2013). The second clause "plainly includes what is contained within the package whether or not it is ‘upon’ the article or its wrapper or container," but also includes any item that "supplements or explains" article regardless of whether it is
physically attached to the package or container. Id. at 350, 69 S.Ct. 106 ; accord Strayhorn, 737 F.3d at 394.
Thus, labeling under Section 321(m) includes "[b]rochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogs, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, literature, and reprints and similar pieces of printed, audio, or visual matter descriptive of a drug and references published (for example, the "Physicians Desk Reference") for me by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor," 21 C.F.R. § 202.1(f)(2) (emphasis added). Furthermore, the U.S. Supreme Court has explicitly held that "Dear Doctor" letters also qualify as labeling for purposes of the FDCA. Mensing, 131 S.Ct. at 2576. "In essence, virtually all communication with medical professionals concerning a drug constitutes labeling." Del Valle v. PLIVA, Inc., No. CIV.A. B:11–113, 2011 WL 7168620, at *4 (S.D.Tex. Dec. 21, 2011), report and recommendation adopted sub nom. Del Valle v. Qualitest Pharm. Inc., No. CIV. B–11–113, 2012 WL 2899406 (S.D.Tex. June 22, 2012), aff'd sub nom. Lashley v. Pfizer, Inc., 750 F.3d 470 (5th Cir.2014). Thus, Plaintiffs' claims based on promotional material sent to medical professionals are preempted to the same extent as Plaintiffs' claims based on the Lipitor label are preempted. These materials are, in fact, part of Lipitor's labeling.
However, contrary to Defendant's argument, all of its advertising materials are not considered labeling. While promotional materials sent to medical professionals are explicitly defined as "labeling," other advertising is not. See 21 U.S.C. § 352(n) ("This paragraph (n) [regarding advertising] shall not be applicable to any printed matter which the Secretary determines to be labeling as defined in section 321(m) of this title."). Advertisements that are not considered labeling include "advertisements in published journals, magazines, other periodicals, and newspapers, and advertisements broadcast through media such as radio, television, and telephone communication systems." 21 C.F.R. § 202.1(l )(1). In other words, advertising to the general public, as opposed to materials for use by medical professionals, is not considered labeling and, thus, can be changed without the need to invoke the CBE regulation. Defendant has not pointed to any authority stating that a brand name drug manufacturer cannot make any changes to its public advertising without changing the label.
To be sure, such advertising is still highly regulated by the federal government, see 21 C.F.R. § 202.1, and state law cannot require a manufacturer to take action with regard to its advertisements not allowed by federal law. However, Defendant has not pointed to any such conflict here. For example, Defendant notes that a manufacturer's advertisement "shall not recommend or suggest any use that is not in the labeling accepted" by the FDA. 21 C.F.R. § 202.1(e)(4). This restriction speaks only to uses not approved by the FDA. It does not apply here, where the use at issue has been approved by the FDA. Federal regulations also require that drug advertisements "present a true statement of information in brief summary relating to ... effectiveness." 21 C.F.R. § 202.1(e)(1). However, Defendant has not argued that this requirement of federal law conflicts with the actions that Plaintiffs allege Defendant was required to take under state law.
Because Defendant has not shown a conflict between its alleged state law duties and federal law, the Court finds that Plaintiffs' state law claims based on Defendant's advertising to the general public are not preempted.
III. Federal Rule of Evidence 702
A. 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 Pharm., Inc., 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, 113 S.Ct. 2786, 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, 113 S.Ct. 2786 ; 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, ––– U.S. ––––, 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 Pharm. 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 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, ––– U.S. ––––, 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.2015), cert. denied, ––– U.S. ––––, 135 S.Ct. 2370, 192 L.Ed.2d 159 (2015) ; accord Westberry, 178 F.3d at 261.
B. Dr. Wells Reanalysis of ASCOT Data
Dr. Wells is a statistician and was asked to "review statistical aspects of relevant scientific literature and data relating to the efficacy and outcome gender heterogeneity of various atorvastatin studies." (Dkt. No. 970–3 at ¶ 1).
1. Background
ASCOT–LLA tested Lipitor's efficacy in the primary prevention of coronary heart diseases (CHD) in patients with high blood pressure but normal blood lipids. (Dkt. No. 970–29 at 2). The Lipid Lowering Arm of the study included 10,305 patients, aged 40–79 years with at least three other cardiovascular risk factors but normal cholesterol and who had not experienced a cardiovascular event. (Id. ). Participants were randomly assigned to a 10 mg dose of atorvastatin or placebo. (Id. ). The study was stopped early, after a little over 3 years, because "atorvastatin had resulted in a highly significant reduction in the primary endpoint of CHD events compared with placebo and a significant reduction in the incidence of stroke." (Id. at 4). This study was the basis of the FDA's approval of Lipitor for primary prevention.
Because one of the risk factors that allowed participants into the study was "male sex," only 1,942 of the 10,305 participants were women. (Id. at 8, Table 4). While the study showed benefits overall, "no benefit was apparent among [the subgroup] of women." (Id. at 6). Nineteen (19) women on Lipitor and 17 women on placebo experienced a primary endpoint event defined as "non-fatal myocardial infarction and fatal coronary heart disease." (Id. at 8, Table 4). The authors hypothesized "[t]he apparent lack of significant benefit of atorvastatin on the primary endpoint among women may reflect the small number of events they experienced (36 occurrences of the primary endpoint)." (Id. at 8). As to the secondary endpoint of total cardiovascular events and total coronary events, women on Lipitor did have a lower rate of these events, but the difference was not statistically significant. (Id. at 6)
While there was no apparent benefit looking at only at the data for women, the authors also tested for gender heterogeneity and found none. Statistical tests of heterogeneity are used to assess whether the observed difference in results for a particular subgroup is greater than expected to occur by chance. If there is statistically significant heterogeneity for a particular subgroup, researchers do not infer that the overall results of the study apply to that particular subgroup. The ASCOT authors found "no significant interaction between sex and the impact of statin on the primary endpoint." (Id. at 6). In other words, authors did not find any heterogeneity; there was no apparent difference in treatment effect based on gender. (Id. ).
Dr. Wells conducted his own analysis and opines that, "[t]here is significant gender
heterogeneity in the ASCOT trial for all endpoints. In other words, the effectiveness of treatment varied by gender." (Dkt. No. 970–3 at ¶ 3). Dr. Wells reached a conclusion different from the study authors because he used a different statistical test. The ASCOT study prespecified the Cox proportional hazards model, the most commonly used test, to be used to determine heterogeneity. (Dkt. No. 970–14 at 152–53). Dr. Wells used a difference statistical test called the Aalen's linear hazards model.
Dr. Wells opines that the Cox proportional hazards model is not appropriate for use with the ASCOT data. The Cox proportional hazards model assumes that the hazard ratio is constant over time. (Dkt. No. 970–3 at ¶ 7). The Aalen's linear hazards model assumes the ratio varies over time. (Id. at ¶ 8). There are statistical tests that can be run on data sets to determine if the assumptions of the Cox model are true for a particular data set. Dr. Wells ran one of these tests and found that the assumption is not true for the ASCOT data, and therefore opined that the Cox test is not valid. (Id. at ¶ 9). Thus, he applied the Aalen model, and this model showed a significant difference between men and women, indicating that "it is inappropriate to infer that the outcomes for women are similar to the outcomes for men or for the combined population." (Id. at ¶ 10).
Pfizer argues that the Cox proportional hazards model is the "generally accepted method" for testing for heterogeneity whereas the Aalen model is "an obscure statistical model" that is not used "in this context" and that Dr. Wells' analysis reanalysis is "litigation-driven" and should be excluded. (Dkt. No. 1090 at 7, 13).
2. Discussion
The Court finds Dr. Wells' reanalysis admissible under Rule 702. This Court has previously held in this MDL that "courts are appropriately skeptical of post-hoc, reanalyses conducted solely for the purpose of litigation that reach conclusions contrary to peer-reviewed published studies." (CMO 67, Dkt. No. 1412 at 11). However, as the Court stated in CMO 54, "[t]his is not to say that a reanalysis of published data is never admissible." (CMO 54, Dkt. No. 1258 at 32; accord CMO 67, Dkt. No. 1412 at 11). Instead, the expert must provide an explanation for why a reanalysis is warranted, or in the words of the Ninth Circuit, he must "validate" his reanalysis in some way. (Id. ); Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1320 (9th Cir.1995). Dr. Wells has provided such an explanation.
Dr. Wells ran a statistical test used for determining whether the underlying assumption of the Cox proportional hazards model is valid for a particular data set, and he found that the assumption was not valid for the ASCOT data set. (Dkt. No. 970–3 at ¶ 9). Because he found the assumption of the Cox model violated, Dr. Wells turned to a different statistical test, the Aalen model. When asked why others did not also use the Aalen model, Dr. Wells testified that "I think I was the only one to ever cheek the proportional hazards assumption." (Dkt. No. 970–14 at 154). This is a valid reason for conducting a reanalysis. The Aalen model is not one made up by Dr. Wells in this litigation but is one that has been tested and subjected to peer review. While Defendant is correct that the Cox model is more commonly used, the Aalen model is an alternative recognized in peer-reviewed literature. (Dkt. No. 970–3 at 7 n.2). Defendant appears to admit that the Aalen model is "generally accepted" but implies that Dr. Wells has not "establish[ed] an adequate
scientific foundation for using it." (Dkt. No. 1090 at 14–15). However, he has done just that by finding the underlying assumption of the Cox model violated. Therefore, the Court denies Defendant's motion to exclude Dr. Wells' reanalysis of the ASCOT data under Rule 702.
C. Primary Prevention Efficacy Studies
Plaintiffs' experts opine that there is no evidence to support the statement that statins are effective for primary prevention in women. (See, e.g., Dkt. No. 970–3 at ¶¶ 4–5). Thus, it is helpful to review the published studies on this topic before evaluating the experts' opinions.
1. JUPITER
The JUPITER (2008) study included 17, 802 apparently healthy men and women with normal LDL levels but high-sensitivity C-reactive protein levels. (Dkt. No. 970–44 at 2). Participants were from 1,315 sites in 26 countries. (Id. at 3). Participants were randomly assigned to 20 mg of rosuvastatin (Crestor ) or a placebo. (Id. at 2). The study was stopped early because of the CVD benefits of the rosuvastatin. Of the 17,802 participants, 6,801 (38.2%) were women. (Id. at 6). The authors found no evidence of heterogeneity among subgroups. (Id. at 7). "Relative hazard reductions in the rosuvastatin group were similar for women (46%) and men (42%) and were observed in every subgroup evaluated." (Id. ). The reduction in risk was statistically significant for women . (See id. at 10, Figure 2 (showing a confidence interval completely below 1 for women)).
In a separate sex-specific analysis of JUPITER, study authors found a hazard ratio of .54, with a 95% confidence interval of .37 to .8, (p=002), for women with regard to any primary endpoint. (Dkt. No. 970–45 at 4). This is statistically significant and similar to the hazard ratio for men, which was .58 with a confidence interval of .45 to .73. (Id. ). There was also no heterogeneity. (Id. at 5).
2. CARDS
CARDS (2004) tested the efficacy of Lipitor for primary prevention of major cardiovascular events in patients with type 2 diabetes but normal LDL levels. (Dkt. No. 970–42 at 2). The study included 2,838 patients aged 40–75 with type 2 diabetes, no history of cardiovascular disease, an LDL of 4.14 mmol/L or less, a fasting triglyceride of 6.78 mmol/L or less and at least one of the following: retinopathy, abluminuria, current smoking, or hypertension. (Id. ). Participants were randomly assigned to 10 mg of atorvastatin or placebo. The study was terminated 2 years early because of the benefits of Lipitor. (Id. ). Thirty-two percent (32%) of the participants were women. (Id. at 5, Table 1). "Allocation to atorvastatin was associated with at 37% reduction in the incidence of major cardiovascular events (p=.001)." (Id. at 7). "Adjustment for baseline age and sex ... made no difference to the estimate of the treatment effect
(36% risk reduction, p=0.002)." (Id. at 7–8). "Prespecified tests for evidence of heterogeneity of effect were not significant for sex (p=0.59)." (Id. at 8).
3. Mora (2010)
Mora (2010) conducted several meta-analyses of statin therapy for the primary prevention of CVD in women. (Dkt. No. 970–45 at 3). The authors first ran the statistical tests looking only at trials that were "exclusively" primary prevention trials, AFCAPS/TexCAPS, MEGA, and JUPITER. (Id. at 3, 6). They found that "[c]ompared to placebo, statin therapy in women significantly reduced CVD by about one-third." (Id. at 6). The relative risk ratio for women was .63, with a confidence interval of .49 to .82, p