# United States Court of Appeals For the First Circuit

Nos. 11-1904, 11-2096

IN RE: NEURONTIN MARKETING AND SALES PRACTICES LITIGATION KAISER FOUNDATION HEALTH PLAN, INC.; KAISER FOUNDATION HOSPITALS; KAISER FOUNDATION HEALTH PLAN OF COLORADO; KAISER FOUNDATION HEALTH PLAN OF GEORGIA, INC.; KAISER FOUNDATION HEALTH PLAN OF THE MID-ATLANTIC STATES, INC.; KAISER FOUNDATION HEALTH PLAN OF

NORTHWEST; KAISER FOUNDATION HEALTH PLAN OF OHIO,

Plaintiffs, Appellees,

v. PFIZER, INC.; WARNER-LAMBERT COMPANY, LLC,

Defendants, Appellants.

APPEALS FROM THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF MASSACHUSETTS [Hon. Patti B. Saris, U.S. District Judge]

Before Lynch, Chief Judge, Souter, Associate Justice,

* and Lipez, Circuit Judge.

Kathleen Sullivan, with whom Mark S. Che ffo, Katherine A. Armstrong, Quinn Emanuel Urquhart Oliver & Hedges LLP, and Skadden, Arps, Slate, Meagher & Flom LLP were on brief, for appellants. David C . Frederick, with whom Scott K. Attaway, W. Joss Nichols, Caitlin S. Hall, Linda P. Nussbaum, Kel l ogg, Huber,

Hon. David H. Souter, Associate Justice (Ret.) of the * Supreme Court of the United States, sitting by designation.Hansen, Todd, Evans & Figel, P.L.L.C. and Grant & Eisenhofer, P.A.

were on brief, for appellees.

April 3, 2013LYNCH, Chief Judge . This is an appeal from verdicts of

over $140 million, reached by both a jury and a court, compensating Kaiser, a major health plan provider and insurer, for the injury Kaiser suffered by its payment for four categor i e s of off-label Neurontin prescriptions which had been induc ed by a fraudulent

s cheme by Pfizer, the manufacturer of Neurontin. These verdi c t s followed a settlement that Warner-Lambert, a subdivision of Pfizer, had reached in a crimi na l c a s e brought by the United States, in which Warner-Lambert pled guilty to two counts and agreed to pay a $240 million criminal f i ne concerning the off-label marketing of Neurontin; Pfizer agreed to pay an additional $190 million in civil fines. This is one of several related appeals regarding Neurontin, which result in separate opinions, of which this is the lead. We affirm the verdicts for Kaiser. I.

On February 1, 2005, Kaiser Foundation Health Plan, Inc. and Kaiser Foundation Hospitals (together, "Kaiser"), Aetna, Inc. ("Aetna"), and The Guardian Life Insurance Company of America ("Guardian") filed a coordinated complaint in the U.S. District Court in Massachusetts agains t P f izer, Inc. and Warner-Lambert Company (together, "Pfizer"), asserting injury from the fraudulent marketing of Neurontin for off-label uses. The coordinated pla i nt i f fs asserted violations of, inter alia, the Racketeer Influenced and Corrupt Organizations Ac t ( "RICO"), 18 U.S.C.

-3-§ 1962, and the California Unfair Competition Law ("UCL"), Cal Bus.

& Prof. Code § 17200. Ultimately, Kaiser prevailed, but Aetna and Guardian's claims were dismissed on summary judgment, and Aetna's dismissal is the subject of a separate appeal.

In a related case in which we issue a separate opinion, Harden Manufacturing Corporation ("Harden") fil ed a class action compl a i nt on May 14, 2004, in the same court, against Pfizer and Parke-Davis (as a division of Warner-Lambert) on behalf of a broad purported class consisting of "[a]ll entities throughout the United States and its territories who, for purposes other than re s ale, purchased, reimbursed and/or paid for Neurontin for indications not approved by the FDA ('the Class') during the period from January 1, 1994 through the present ('the Class Period')." Harden asserted claims under RICO, as well as state-law claims for common law fraud, violation o f c onsumer protection statutes, and unjust enrichment.

Both the c lass complaint and the coordinated complaint were part of a larger multidistrict litigation ("MDL") concerning the marketing and sale of Neurontin, which was consolidated in the District of Massachusetts in November 2004. In each case, the defendants moved for summary judgment. On January 8, 2010, on defendants' motion the district court dismissed the claims of Guardian and Aetna; the court denied summary judgment as to Kaiser's claims. See In re Neurontin Mktg. & Sales Practices

-4-Litig. (Neurontin Coordinated SJ), 677 F. Supp. 2d 479 (D. Mass.

2010). On December 10, 2010, the court granted summary judgment against all of the Harden purported class pla i nt i f fs except two, whose claims are not relevant to this appeal. See In re Neurontin Mktg. & Sales Practices Litig. (Neurontin Class SJ), 754 F. Supp. 2d 293, 311 & n.4 (D. Mass. 2010).

Beginning on February 22, 2010, the district court held

a jury trial on Kaiser's RI CO c laims against the defendants. On March 25, 2010, after a five-week trial, the jury concluded that "Kaiser prove[d] that Pfizer violated RICO with respect to its promotion of Neurontin for" bipolar disorder, migraine, neuropathic pain, and dosages exceeding 1800 mg per day, and that these

1 "violation[s] of RICO cause[d] Kaiser injury." See In re Neurontin Mktg. & Sales Practices Litig. (Kaiser Findings), No. 04-cv-10739- PBS, 2011 WL 3852254, at *1 (D. Mass. Aug. 31, 2011). The jury awarded Kaiser damages in the amount of $47,363,092, which the court trebled to $142,089,276. Id. The jury also rendered an advisory verdict in favor of Kaiser on its state UCL claim, finding that Pfizer had engaged in fraudulent business acts or practices which caused Kaiser damages with respect to bipolar disorder,

Neuropathic pain is pain caused by damage to the nerves, as 1 opposed to nociceptive pain, which is pain caused by an injury. In re Neurontin Mktg. & Sales Practices Litig. (Kaiser Findings), No. 04-cv-10739-PBS, 2011 WL 3852254, at *3 8 , * 1 n.1 (D. Mass. Aug. 31, 2011). -5-migra i ne , neuropathic pain, and doses over 1800 mg, but no

liability with respect to nociceptive pain.

On November 3, 2010, the district court found in Kaiser's favor on its claims under the UCL, issuing extensive findings of fact and conc l us i ons of law. In re Neurontin Mktg. & Sales Practices Litig., 748 F. Supp. 2d 34 (D. Mass. 2010), amended and superseded by Kaiser Findings, 2011 WL 3852254. The district court ordered defendants t o pay $95,286,518 in restitution, Kaiser Findings, 2011 WL 3852254, at *2, but because this figure reflected the same damage claims encompassed by the jury verdict on Kaiser's RICO claim, the court did not add it to the jury award, id. at *60 n.25. On February 22, 2011, the court entered judgment in favor of Kaiser on its RICO and UCL claims, and on July 27, 2011, the court denied Pfizer's motion for a new trial or, in the alternative, to alter or amend judgment.

On September 20, 2011, Pfizer filed a notice of appeal as to the court's entry of judgment in favor of Kaiser on its RICO and UCL claims, and as to the court's denial of Pfizer's motion for a new trial. This opinion concerns only that appeal. II. We review de novo defendants' contention that Kaiser' s RICO and UCL claims failed as a matter of law, taking the evidence in the light most favorable to the verdict. Tuli v. Brigham & Women's Hosp., 656 F.3d 33, 38 (1st Cir. 2011). Where defendants

-6-cha l l enge the district court's findings of fact, we review these

findings for clear error. Fed. R. Civ. P. 52(a)(6). We begin by setting out the district court's findings of fact and the jury's conclusions. A. The Defendants' Fraudulent Marketing Campaign

Parke-Davis, an operating division of Warner-Lambert Company, developed Neurontin dur i ng the 1980s and early 1990s as 2

an anti-epileptic drug. Kaiser Findings, 2011 WL 3852254, at *5. To secure approval from the Food and Drug Adminis t ra t i on ("FDA") for a drug for a particular indication, a drug manufacturer must submit two favorable double-blind randomized controlled trials ("DBRCTs"). Id. On December 30, 1993, the FDA approved Neurontin

as an adjunctive therapy in the treatment of partial seizures in adults with epilepsy, setting the maximum dose at 1800 mg/day. Id. The FDA found that certain patients taking Neurontin experienced depressive side effects, and the FDA issued a warning to physicians in January 2008 to "[b]e aware of the possibility of the emergence

or worsening of depression, suicidality, or any unusual changes in behavior" resulting from the use of anti-epileptic drugs including Neurontin. Id. (alteration in original) (internal quotation marks omitted). In 1996, Parke-Davis applied to the FDA for approval of Neurontin as a monotherapy for the treatment o f seizures, and

Neurontin's generic name is gabapentin. Kaiser Fi nd i ngs, 2 2011 WL 3852254, at *5. -7-sought an increase in Neurontin's effective dose range and maximum

recommended dose; the FDA rejected this application. Id. at *6.

Pfizer acquired Warner-Lambert in 2000. Id. at *5. In 2001, Pfizer filed an application with the FDA seeking approval of Neurontin for the broad indication of neuropathic pain; after receiving negative feedback from the FDA and non-FDA experts, Pfizer withdrew its application. Id. at *10. The FDA did approve Neurontin for the treatment of post-herpetic neuralgia ("PHN"), a type of neuropathic pain associated with shingles, in 2002. Id.

In 1994, Parke-Davis had estimated that Neurontin would generate $500 million in profits over the duration of its patent. Id. at *6. In order to increase Neurontin's earning potential, Parke-Davis began in 1995 to develop strategies to market Neurontin for off-label conditions -- that is, conditions not included on the official label approved by the FDA. Id. As Parke-Davis was implementing these strategies, Pfizer acquired Warner-Lambert, and so, Parke-Davis. Id. at *5. These marketing strategies apparently worked; in the year 2003, Neurontin sales exceeded $2 billion. Id. at *6. Pfizer's Neurontin team estimated that only about ten percent of Neurontin prescriptions that year were for the FDAapproved on-label uses for epilepsy or PHN, and that more than a third of prescriptions were for the off-label uses of neuropathic pain, migraine or headache, or bipolar disorder.

-8-Both the jury and the district court found that ParkeDavis, Warner-Lambert, and Pfizer had "engaged in the fraudulent marketing of Neurontin" for the trea tment of bipolar disorder, beginning in July 1998, id. at *17; for the treatment of neuropathic pain, beginning in November 1997, id. at *23; for the treatment of migraines, beginning in April 1999, id. at *25; and for doses greater than 1800 mg/day, beginning in November 1997, id. at *28. This fraudulent marketing included, but wa s not limited

3 to, three strategies, each of which included subcomponents: (1) direct marketing (or "detailing") to doctors, which misrepresented Neurontin's effectiveness for off-label indications; (2) sponsoring misleading informational supplements and continuing medical education ("CME") programs; and (3) suppressing negative information about Neurontin whi l e publishing articles in medical journals that reported positive information about Neurontin's offlabel effectiveness. See id. at *12, *17, *18, *25, *28.

The defendants' fraudulent marketing campaign also targeted third-party payors ("TPPs"), including Kaiser, a nonprofit healthcare provider which is also one of the largest health maintenance organizations ("HMOs") i n the United States. Id. at *2. As to these targets, additional mechanisms were used to influence both formulary decisions and prescribing decisions. In

The court and the jury found that Kaiser had not proven that 3 Pfizer fraudulently marketed Neurontin for nociceptive pain. Kaiser Findings, 2011 WL 3852254, at *26. -9-1994, in a memo discussing the promotion of Neurontin as an anticonvulsant, Parke-Davis's marketing team listed Kaiser as second on its list of "Top 10 HMOs Targeted for Neurontin." Id. at *11. In 2004, Pfizer developed an "Operating Plan" for marketing a number of drugs, including Neurontin, to Kaiser; tellingly, the plan featured, as a strategy, "develop[ing] relationships with [decisionmakers affilia t ed with Kaiser] who are not considered whistle blowers." Id. (emphasis added) (internal quotation marks omitted). Pfizer also employed physicians associated with Kaiser to serve on speakers' bureaus and publish misleading articles about Neurontin. Id. B. Kaiser's Management of Neurontin on Its Formularies

Ka i s er is composed of two separate corporations: the Kaiser Foundation Health Plan, which owns six regional health plans and directly provides medical coverage to beneficiaries in California and Hawaii, providing medical insurance to about 8.6 million members; and Kaiser Founda t i on Hospitals, which operates health care facilitie s and pharmacies. Id. at *2. The Kaiser Foundation Health Plan and its subsidiaries do not employ physicians themselves, but have exclusive contractual relationships with regional Permanente Medical Groups ("PMGs"). Id. at *3.

Each PMG has its own Pharmacy and Therapeutics ("P & T") Committee which manages each PMG's formulary, or list o f medications that treating physicians may prescribe. Id.

-10-Representatives from both entities sit on the P & T Committees and

participate in formulary management. Kaiser Foundation Hospitals has a Drug Information Servi c e ("DIS") that researches and communicates information about drugs, including monographs about

new drugs or new drug use s , t o physicians and P & T Committees. Id. DIS monographs summarize available evidence -- including publicly available evidence and unpublished information obtained from pharmaceutical manufacturers -- on drug safety and efficacy, and P & T Committees rely heavily on the s e monographs in making formulary decisions. Id.

PMG formularies may list drugs (1) without restrictions; (2) with restrictions limiting prescribing to a particular group of physicians ; or (3) with guidelines for appropriate prescribing. Id. at *4. Kaiser will pay for off-formulary prescriptions and no prior authorization is required for any prescription. Nonetheless,

an internal Kaiser study found that 95% of prescriptions written by PMG physicians comply with formularies. Id.

After the FDA approved Neurontin for epilepsy in 1993, the P & T Committee of each regional PMG added Neurontin to its formulary, with one regional PMG -- Hawaii -- not adding Neurontin to its formulary until 2000. Id. The Southern California PMG initially restricted prescribing of Neurontin to neurologists. Id. In September of 1997, however, its P & T Committee permitted anesthesiologists to prescribe Neurontin for reflex sympathetic

-11-dystrophy, a particular pain syndrome. Id. In June of 1999, the

Committee removed prescribing restrictions on Neurontin and added guidelines reserving its use for neuropathic pain patients who were unresponsive to or intolerant of other treatments. Id. Then, in September of 1999, the P & T Committee removed all remaining formulary restrictions on Neurontin. Id. at *5. Prescriptions of Neurontin increased dramatically thereafter. Id. at *31.

The district court found that "Kaiser relied on Pfizer's misrepresentations and omissions during the development of drug monographs in both June and September 1999," id. at *29, and that Pfizer's misrepresentations "directly affected decisions about Neurontin's placement on formulary without restrict i ons," id. at *30. C. Physicians' Prescribing Behavior as to Neurontin

The j ury and court found that the prescribing of Neurontin had in fact been causally affected by the fraudulent marketing scheme, which included the sponsorship of CME events attended by physicians and direct marketing to physicians. Id. at *12. Defendants stress that no physician in this case, or in the Neurontin MDL as a whole, testified that he or she prescribed Neurontin because of defendants' fraudulent off-label marketing. Id. at *32. But Kaiser presented other evidence as to causation, and evidence as to why such individual testimony was unreliable.

-12-The primary evidence was the expe r t testimony of Dr.

Meredith Rosenthal, who holds a Ph.D. in health economics from Harvard University and is a professor at the Harvard School of Public Health. Id. Dr. Rosenthal "use[d] aggregate data and statistical approaches to link patterns in promotional spending[ ] 4 to patterns in prescribing for the drug." Id. (internal quotation mark omitted). Her regression analysis found a causal connection between the fraudulent marketing and the quantity of prescriptions written for off-label indications. She also testified as to why Pfizer's proposed physician-by-physician analysis of causation was not a scientifically valid approach to causation.

Dr. Rosenthal used "gold standard" national data on Neuront i n prescriptions, and employed the assumptions that (1) "Kaiser's patient population and physician distribution are similar to the national mix," and (2) "promotional spending on o f f -label marketing wa s the same as the promotional spending on fraudulent off-label marketing." Id. at *32-33. The district court found both assumptions to be reasonable. Id. at *32-33.

As is customary for such experts, Dr. Rosenthal testified that she "assumed that the allegations in the complaint are true" for purposes of conducting her analysis, but offered no view as to

Dr. Rosenthal's promotional spending data included "spending 4 on detailing of doctors, advertisements in professional journals, and the retail value of samples." Kaiser Findings, 2011 WL 3852254, at *32 n.19. -13-whether or not there had been a fraudulent marketing scheme. She

further explained that her assignment was only t o calculate the percentage of prescriptions caused by Pfizer's fraudulent off-label marketing and not to convert that percentage into a damages number for Kaiser, which was the task of another expert witness, Dr. Raymond Hartman, Ph.D.

Dr. Rosenthal explained the difference between correlation and causation and stated that her analysis established causation by performing a regression analysis on sales information against promotional spending on detailing, professional journal advertising, and the retail value of samples, while controlling for other variables. Her analysis excluded the many off-label prescriptions by physicians who received legitimate on-label promotion. She concluded that the " percentage[s] of Neurontin prescriptions that were caused by Pfizer's fraudulent marketing of Neurontin" were, by off-labe l indication, as follows: 99.4% of prescriptions for bipolar d i s order; 70% of prescriptions for neuropathic pain; 27.9% of prescriptions for migraine; and 37.5% of prescriptions for doses over 1800 mg/day. Id. at *33. Thus, three out of ten Neuront in prescriptions written by neurologists for migraine would not have been written or filled but for the alleged misconduct. As for Neurontin prescriptions written by psychiatrists for bipolar disorder between November 1 9 95 and December 2004, 99.4% would not have been written had there been no

-14-f raud . Dr. Rosenthal testified that it was her opinion "to a

reasonable degree of scientific certainty that these calculations

are the best way to estimate the number of pre s c r iptions and the share of prescripti ons that were affected by the alleged misconduct." 5

Turning to Pfizer's insistence that only doctor-by-doctor evidence could prove causation, Dr. Rosenthal testified as to the well-recognized unreliability in the field of healthcare economics of asking doctors individually whether they were influenced by the many methods of off-label marketing. She said that self-reporting from physicians about patterns of practice that may be controversial shows both conscious reluctance and unconscious bias, which lead them to deny being influenced. As a result, it is preferable "[t]o examine objectively the causal association between promotion and sales using
. . . econometric models." Dr. Rosenthal utilized the standard practice of using "aggregate data and . . . statistical approaches to link patterns in promotional spending to patterns in prescribing for the drug." Dr. Rosenthal testified that it was "neither standard nor appropriate to look physician by physician."

In opposition to Dr. Rosenthal's expert testimony, Pfizer introduced the exper t testimony of Dr. Michael C. Keeley, Ph.D.,

These calculations applied to Kaiser as we ll as to other 5 payors across the country. -15-who testified as to alleged flaws in Dr. Rosenthal's methodology.

Dr. Keeley testified that when he re-ran Dr. Rosenthal's regression analysis with different assumptions , he did not find a statistically significant relationship between Pfizer's promotion of Neurontin and prescriptions of Neurontin. Dr. Keeley did not present his own causation or damages model, however. The court rej e cted Dr. Keeley's criticisms and accepted Dr. Rosenthal's calculations. Id. at *58.

The court also found that subsidiary evidence tended to show a causal l i nk. For example, PMG physicians attended conferences where Neurontin wa s promoted for off-label uses, and after one such conference, in May 1999, new starts of Neurontin increased by 62%. Id. at *30. D. Criminal Proceedings and Related Proceedings Against the

Defendants Concerning Neurontin Dr. David Franklin was employed as a medical liaison at Parke-Davis for about five months in 1996; on August 13, 1996, he filed a sealed qui tam action against Parke-Davis under the False Claims Act ("FCA"), 31 U.S.C. §§ 3729-3733. United States ex rel. Franklin v. Parke-Davis, Div. of Warner-Lambert Co., 147 F. Supp. 2d 39, 43-44, 46 (D. Mass. 2001). Frank l i n a lleged that ParkeDavis engaged in a fraudulent scheme to promote off-label uses of Neurontin, and that this campaign caused false claims to be submitted to the Veterans Administration and to the federal government for Medicaid reimbursement. Id. at 43. Franklin's suit -16-remained under seal for more than three years, as the government

considered whether to intervene, and was then unsealed on December 2 1 , 1 9 99, with the government participating only as an amicus curiae. Id. at 46. On June 16, 2 0 0 4 , Franklin, Parke-Davis, Pfizer, and the United States entered into a stipulation of dismissal, under which Franklin received a relator's share of $24,640,000.

On May 13, 2004, the U.S. Department of Justice filed a criminal information charging Warner-Lambert with illegal off-label promotion of Neurontin. Kaiser Findings, 2011 WL 3852254, at *11. Pfizer caused Warner-Lambert to plead guilty to two felony counts of marketing Neurontin for unapproved uses, with Warner-Lambert "expressly and unequivocally admit[ting]" that it promoted the sale and use of Neurontin for neuropa thi c pain, bipolar disorder, and migraine. Id. To be clear, this plea did not admit to fraudulent marketing. Warner-Lambert agreed to pay a $240 million criminal fine, and Pfizer paid $190 million in additional civil fines. Id. News of this action, plea, and settlement caused Kaiser to take certain steps, as described below. E. Kaiser's Actions To Reduce Neurontin Prescriptions

Neurontin prescriptions written by PMG physicians increased dramatically after September 1999 (the fraudulent marketing campaign began in 1997). This notable increase led some Kaiser regions to "examine the i r members' use of Neurontin" and

-17-make efforts to limit it. Id. at *31. By the spring of 2002, the

Northern California PMG had barred Pfizer drug representatives from detailing its physicians regarding Neurontin, and the same PMG's Drug Ut i lization Group ("DRUG") began a campaign to promote only the appropriate use of Neurontin, which other regional PMGs joined. Id. In late 2002, Kaiser learned about Franklin's qui tam action and escalated its efforts to limit prescribing of Neurontin for neuropathic pain, bipolar disorder, migraine, and nociceptive pain. Id. Kaiser shared materials about Neurontin produced by DRUG and the Southern California PMG's Drug Utilization Action Team ("DUAT") with all regional PMGs. The district court found that though Neurontin use continued to increase nationally, Kaiser's efforts to limit its use "resul t [ ed ] in a 33-34% decrease in new starts of Neurontin." Id.

The P & T Committees did not remove Neurontin from their formularies or impose restrictions on its use after learning about the allegations of defendants' fraudulent off-label marke t ing of Neurontin. Favorable information about using Neurontin to treat neuropathic pain remained on Kaiser's website until the eve of trial. Id. at *30. The district court found, however, that Kaiser employees did not know about the full scope of defendants' fraud. Rather , they learned of the full scope of the fraud through (1) discovery in this suit, and (2) the publication, in November of

-18-2009, of an article in the New England Journal of Medicine

reporting defendants' use of scholarly publications to disseminate misleading information about Neurontin. Id. at *31, *7 & n.4. F. Injury and Damages Sustained by Kaiser Due to Defendants'

Fraud The court and the j ury found that Kaiser had suffered bo th injury and quantifiable damages as a result of defendants' actions. After reviewing the evidenc e at trial -- including the results of DBRCTs and other clinical trials, anecdotal accounts of clinical success, regulatory approval in other countries, and expert opinions, id. at *34-45 -- the district court found that "there is no reliable scientific evidence that Neurontin is effective for bipolar disorder, migraine, or at high do s e s," and that although there was evidence that Neurontin was effective in treating some kinds of neuropathic pain, "there is no reliable scientific evidence to support a broad indication of neuropathic pain," id. at *34. The court also found that "PMG physicians would have almost certainly prescribed a l t ernative medication to their patients had they not prescribed Neurontin." Id. at *33.

In add i t i on to Dr. Rosenthal's expert testimony on causation and injury, Kaiser presented testimony by a second

expert, Dr. Hartman, who provided evidence as to the damages

-19-incurred by Kaiser. His analysis used a list of alternative drugs 6 that "were more appropriate for each off-label indication than Neurontin" in order to determine the average cost of the

a l t ernative medications that would have been prescribed in the absence of defendants' fraud. Id. Dr. Hartman then multiplied the quantity of affected prescriptions (as determined by Dr. Rosenthal) by the average excess cost of each Neurontin prescription as compared to alterna t ive medications. Id. He concluded that Kaiser's damages from defendants' fraud totaled $62,457,082, with Kaiser sustaining the following damages from fraud-induced prescriptions for each off-label indication: $17,822,647 for bipolar disorder; $39,774,623 for neuropathic pain; $1,260,464 for migraine; and $3,599,348 for doses over 1800 mg/day. Id. at *34. In fact, the total awarded by the jury was less than this sum.

Dr. Keeley, Pfizer's expert, testified that Dr. Hartman's calculations were flawed be c ause he did not have data that permitted him to determine which alternative drugs would have been prescribed in place of Neurontin. Dr. Keeley did not present his own estimate of Kaiser's damages, however.

P f i z er argued to the jury that Neurontin was effective for the off-label uses at issue, and that as a result, (1) Pfizer's promotional campaign involved no misrepresentations about

This list had been developed by the chairperson of Kaiser's 6 DIS, Dr. Marta Millares. Kaiser Findings, 2011 WL 3852254, at *33. -20-Neurontin's effectiveness; (2) even if Pfizer made

misrepresentations, Kaiser doctors prescribed Neurontin for offlabel uses because it was effective in their clinical experience, not because of Pfizer's misrepresent a tions; and (3) because Kaiser's damages theory was ba s ed on Neurontin's complete ineffectiveness for off-label uses, Kaiser's damages calculations

were invalid if Neurontin was sometimes effective for these uses. The jury rejected Pfizer's arguments and awarded Kaiser $47,363,092 in damages, which the court trebled to $142,089,276. Id. at *1.

Pfizer argued to the d i s trict court that since doctors

c onsider "multiple sources, types, and levels of scientifi c evidence" in making treatment decisions, and the effectiveness of

a drug is a patient-specific inquiry, the court should not confine its analysis of Neurontin's effectiveness for off-label uses to whether DBRCTs demonstrated efficacy. Kaiser responded that DBRCTs

were the "gold-standard for determining efficacy" and that "[l]ower-tier evidence is insufficient, especially in p l a c e of existing DBRCTs."

Pfizer further argued to the court that because Neurontin

was not "completely and categorical ly ineffective" for off-label uses, Pfizer had not misled Kaiser about Neurontin's efficacy and Kaiser had not proved that it suffered economic injury. Pfizer also argued that Dr. Rosenthal's and Dr . Hartman's testimony was flawed and hence not probative of causation or damages. The court

-21-re j e cted Pfizer's arguments and accepted Dr. Rosenthal's and Dr.

Hartman's calculations as the basis for its own damages award of $95,286,518. Id. at *58-60. III.

Pfizer seeks to va c ate the court and jury findings of liability and damages on a number of theories. It argues that Kaiser's claims fail as a matter of law, that the evidence was insufficient, and that ther e were trial errors. At the heart of the appeal is the claim that, as a matter of law, Kaiser cannot meet the RICO or UCL causation requirements, and so Pfizer was entitled to a directed verdict. On appeal, Pfizer does not challenge the conclusions of the jury and district court that it engaged in a fraudulent scheme with respect to its promotion of Neurontin for off-label uses. 7 A. RICO Causation

The civil damages provision of RICO provides that "[a]ny person injured in his business or property by reason of a violation of section 1962 of this chapter may sue therefor . . . and sha ll

As noted, Pfizer argued to the jury and the district court 7 that Neurontin was effective for off

- l abel uses and that Pfizer therefore made no material misrepresentations. It does no t make this argument on appeal. Instead, it argues on appeal only that Neurontin's e f f ectiveness means Kaiser did not prove that it suffered economic injury from paying for off-label prescriptions of Neurontin. Pfizer does state on appeal, in passing, that Kaiser "presented no evidence of fraudulent detailing (sales calls) to PMG doctors," but it does not squarely challenge the district court's contrary finding and, in any event, makes this argument only to attack the "fit" of Kaiser's expert testimony. -22-recover threefold the damages he sustains and the cost of the suit,

including a reasonable attorney's fee." 18 U.S.C. § 1964(c). In relevant part, section 1962 prohibits "any per s on employed by or associated with any enterprise engaged in, or the activities of which affect, interstate or foreign commerce" from "conduct[ing] or participat[ing], directly or indirectly, in the conduct of such enterprise's affairs through a pattern of racketeering activity." Id. § 1 9 6 2 ( c ) . A "racketeering activity" can consist of a wide range of predicate offenses, including, as alleged i n this case, mail and wire fraud, see id. § 1961(1), and a "pattern" of such activity requires at least two racketeering acts, id. § 1961(5).

Our RICO causation analysis is controlled by the Supreme Court' s decisions in Holmes v. Securities Investor Protection Corp., 503 U.S. 258 (1992), and its progeny. See Anza v. Ideal 8 Steel Supply Corp., 547 U.S. 451 (2006); Bridge v. Phoenix Bond & Indem. Co., 128 S. Ct. 2131 (2008); Hemi Grp., LLC v. City of New York, 130 S. Ct. 983 (2010). In Holmes, the Supreme Court held that the civil RICO provision's "by reason of" language c ont ains both but-for causation and proximate causation requirements. 503 U.S. at 268. In our view, these are two quite distinct questions. Here, the harm to Kaiser plainly was foreseeable, and foreseeability is needed for, but does not end the inquiry as to,

The parties apply the same analysis on the proximate 8 causation questions to both Kaiser's RICO claim and its UCL claim, so we proceed on the assumption that this approach is correct. -23-proximate causation. The proximate causa t i on question in this

appeal concerns whether the chain of events between Pfi z er 's misrepresentations and Kaiser's payment for the prescriptions is so attenuated that, for legal and policy reasons, Kaiser's claim for recovery should be denied. The but-for causation question, in contrast, is whether, absent Pfizer's fraud, Kaiser would have paid for fewer off-label Neurontin prescriptions.

Pfizer's primary argument i s that, as a matter of law, there is no proximate causation in this case because there are too many steps in the causal chain connecting its misrepresentations to the injury to Kaiser, particularly because that injury rests on the actions of independent actors -- the prescribing doctors. As to but-for causation, Pfizer argues that its evidence at trial "falsified" Kaiser's theories o f c ausation, and that some of the evidence Kaiser presented to prove but-for causation was inadmissible. We take these arguments in sequence. B. Proximate Causation

In Holmes, the Supreme Court uphe l d entry of summary judgment for the defendant on RICO claims brought by a plaintiff who was subrogated to the rights of others, based on the plaintiff's failure to meet the proximate cause requirement. Id. at 262-64, 271-74. The Holmes plaintiff alleged that the defendant had engaged in an enterprise to manipulate the prices of certain stocks, id. at 261, and complained that this conduct caused the

-24-plaintiff to have to pay the c laims of customers of two brokerdealers that had become insolvent once the fraud was revealed, see id. at 262-63. The Court determined that, even if this plaintiff were allowed to stand in the shoes of a better-situated plaintiff (namely, the customers), the link was t oo remote between the alleged stock manipulation scheme and the harm t o the customers, because that harm was itself contingent on the harm suffered by the broker-dealers who had purchased the manipulated stock. See id. at 271. The only connection between the RICO conduct and the claimed harm was the broker-dealers' insolvency. Id.

The Holmes Court stated that, "[a]t bottom, the notion of proximate cause reflects 'ideas of what justice demands, or of what is administratively possible and convenient.'" Id. at 268 (quoting W. Keeton, et al., Prosser & Ke e t on on Law of Torts § 41, at 264 (5th ed. 1984)). As a result, the Court explained, it was "us[ing] 'proximate cause' to label generically the judicial tools used to limit a person's responsib i l ity for the consequences of that person's own acts." Id.

Because of "the infinite variety of claims that may arise" in which a court must analyze proximate causation, it is "virtually impossible to announce a black-letter rule that will dictate the resu l t in every case." Id. at 272 n.20 (quoting Associated Gen. Contractors of Cal., Inc. v. Cal. State Council of Carpenters, 459 U.S. 519, 536 (1983)) (internal quotation marks

-25-omitted). Instead, the Court set out certain principles, derived

from the common law and from interpretations of analogous statutes, to govern the proximate cause inquiry under RICO.

The Court noted that RICO's civil provision drew it s language directly from the Clayton and Sherman Acts, which had for decades been interpreted as incorporating proximate cause requirements. Id. at 267-68; see Associated Gen. Contractors, 459 U.S. at 531-34. In the antitrust context, the Court had identified

a number of factors that bear on the proximate cause question, including whether the injury was of the sort that the statutes sought to redress, Associated Gen . Contractors, 459 U.S. at 538; the "directness or indirectness of the asserted injury," including whether the "links" in the "chain of causation" were clear or were only "vaguely defined," id. at 540; the identity of the "immediate victims" of the antitrust conduct, id. at 541; whether the injuries complained of may have been caused by "independent factors," id. at 542; and whether the plaintiffs were part of "an identifiable class of persons whose self

- i nterest would normally motivate them to vindicate the public interest in antitrust enforcement," id.

The Holmes Court used various phrases to define what it takes to meet RICO's proximate cause standard, such as "some direct relation be tween the injury asserted and the injurious conduct alleged , " 5 0 3 U.S. at 268, and whether "the link is too remote" between the conduct and the harm suffered, id. at 271. The Court

-26-noted that the proximate cause analysis at common law often

included such a "demand for some direct relation"; that is, proximate cause would be lacking if, as in Holmes, the plaintiff "complained of harm flowing merely from the misfortunes visited upon a third person by the defendant's acts." Id. at 268. Later, in Anza v. I deal Steel Supply Corp., 547 U.S. 451, the Court similarly found proxima t e cause lacking where the RICO conduct alleged had directly harmed a party other than the plaintiff and the plaintiff's alleged injury was only a collateral result of the direct harm. In that case, the defendant's scheme to underpay sales taxes had directly injured the state by depriving it of tax revenue, whereas the plaintiff's al l eged harm related to the competitive effects of the defendant charging lower prices without sales tax. See id. at 458.

Importantly, the Holmes Court also provided three functional factors with which to assess whether proximate cause exists under RICO. First, the Court noted concerns about proof, reasoning that "the less direct an injury is, the more difficult it becomes to ascertain the amount of a p l a intiff's damages attributable to the violation, as distinct from other, independent, factors." 503 U.S. at 269. Second were concerns about administrability and the avoidance of multiple recoveries: "[R]ecognizing claims of the indirectly injured would force courts to adopt complicated rules apportioning damages among plaint i f fs

-27-removed at different levels of injury from the violative acts, to

obviate the risk of mul t ip l e recoveries." Id. Third, the Court focused on the societal interest in deterring illegal conduct and whether that interest would be served in a particular case: "[T]he need to grapple with [the previous two] problems [may be] simply unjustified by the general interest in deterring injurious conduct, sinc e d i rectly injured victims can generally be counted on to vindicate the law as private attorneys general, without any of the problems attendant upon suits by plaintiffs injured more remotely." Id. at 269-70.

Holmes makes it clear that both the directness concern and the three functional factors are part of the proximate cause inquiry. See id. at 271-74. Indeed, the Court warned that its "use of the term 'direct' should merely be understood as a reference to the proximate-cause enquiry that is informed by the concerns" of justice and administrability. Id. at 272 n.20; see id. at 268. Holmes and its successor, Anza, both found a lack of proximate cause when examining the attenuated relationship between the plaintiffs and the direct victim or victims of the alleged fraud. In Bridge v. Phoenix Bond & Indemnity Co., 128 S. Ct. 2131, the Court considered the RICO claims of such direct victims. It also relatedly addressed the question of whether first-party

-28-reliance on a defendant's misrepresentati ons is required under

RICO, and answered that question "no." 9

In Bridge, the plaintiffs alleged that the defendants had engaged in a scheme to make misrepresentations to county tax

authorities in order to win more bids at tax lien auctions than they would have been able to win absent the fraud. See i d . a t 2135-36. The plaintiffs were other bidders at the auctions whose bids had tied with defendants' bids, and whose claimed injury was the deprivation of their fair share of winning bids. Id. at 2136.

A unanimous Court held that first-party reliance is not

an element of proximate cause in a private RICO claim predicated on mail fraud. Id. at 2134. Thus, even where the plaintiffs did not receive the misrepresentations at issue -- the county was the party that had relied on the misrepre s entations -- the plaintiffs had sufficiently alleged proximate causation under RICO. Id. at 2138,

We disagree with Pfizer's argument that "attempting to prove 9 non-party doctors' reliance through inferences from aggregate sales data invokes the 'fraud on the market' doctrine." The fraud-on-the-market doctrine, utilized in securities law, "relieves the plaintiff of the burden of proving individualized reliance on a defendant's misstatement, by permitting a rebuttable presumption that the plaintiff relied on the 'integrity of the market price' which reflected that misstatement." In re PolyMedica Corp . S e c . L i t i g . , 432 F.3d 1, 7 (1st Cir. 2005) (discussing Basic Inc. v . Levinson, 485 U.S. 224 (1988)). While reliance "is an essential element of the § 10(b) private cause of action," Amgen I nc. v. Conn. Ret i rement Plans & Trust Funds,

___ S. Ct. ___, 2013 WL 691001, at *4 (2013) (internal quotation marks omitted), first-party reliance is not an element of a private RICO claim predica t ed on mail fraud, Bridge, 128 S. Ct. at 2134, so the analogy is inapt. -29-2143-44. Here, like the defendants in Bridge, Pfizer argues that

its supposed misrepresentations went to prescribing doctors, and so the causal link to Kaiser must have be en broken. Even putting aside the evidence of Pfizer's direct communications to Kaiser, we think Bridge forecloses this argument. The Bridge Court rejected the attempt to impose a direct reliance requirement on top of the statutory language providing a private right of action under RICO, finding no support for it in the common law. See id. at 2139-41. We likewise find none here.

Bridge also supports the conclusion that Kaiser meets the proximate cause requirement for several additional reasons. First, Bridge held that the plaintiffs there "clearly were injured by [defendant s ' ] scheme," as they lost valuable property they would not otherwise have lost. Id. a t 2 1 3 9 . In so holding, the Court analogized to a business being harmed by misrepresentations made by

a rival to i t s suppliers and competitors but not to the business itself. See id. The Court rejected the argument that no RICO injury could exist in such circumstances. In doing so, it commented on the fact that a business so injured wou ld be "the primary and int ended victim[] of the scheme to defraud." Id. Here, Kais er wa s likewise a "primary and intended victim[] of [Pfizer's] scheme to defraud." Its injury was a "foreseeable and 1 0

In using this language, we do not suggest that a defendant 1 0 can escape R ICO liability to a foreseeably and actually injured plaintiff by saying it did not " i ntend" such a result. Pfizer -30-natural consequence" of Pfizer's scheme, id. at 2144 -- a scheme

that was designed to fraudulently inflate the number of Neurontin prescriptions for which TPPs paid. The evidence that Pfizer had specifically targeted Kaiser for Neurontin sales in general supports the conclusion that Kaiser's injury was a natural consequence of Pfizer's fraudulent scheme, but such evidence was not required, given the mechanisms by which Pfizer's marketing plan operated. As Judge Posner stated in the Bridge case, after remand: "The doctrine of proximate cause . . . protects the ability of primary victims of wrongful conduct to obtain compensation
. . . ." BCS Servs., Inc. v. Heartwood 88, LLC, 637 F.3d 750, 756 (7th Cir. 2011). Here Kaiser was a primary victim.

Further, the Bridge Court saw no risk of multiple recoveries or other policy reasons to limit recovery. See 128 S. Ct. at 2144 (citing Holmes, 530 U.S. 258; Anza, 547 U.S. 451). Nor did it see a "more immediate victim
. . . better situated to sue." Id. So too here: none of the three functional problems that the Holme s test is meant to avoid are present in this case. To the contrary, the functional interests in justice and administrability work in Kaiser's favor. Because Ka i s er was both the natural and foreseeable victim of the fraud and the intended victim of the fraud, there is no risk of duplicative recovery. See id. Neither the individua l phys icians, nor the DIS members, nor the P & T
could not plausibly make such a claim here in any event. -31-Committee members -- the parties to whom Pfizer directly made its

misrepresentations

- - ever paid anything toward a Neurontin prescription, so there is no risk of multiple recoveries due to a suit by another of those actors. Se e Ho lme s , 503 U.S. at 269. 1 1 Kaiser is also in the best po s i t ion to enforce the law because Kaiser is the party that directly suffered economic injury from Pfizer's scheme. See id. at 269-70. And, as we explain below, Kaiser wa s able to present sufficient evidence to ascertain the amount of its damages attributable to Pfizer's conduct. See id. at 269. In our view, Kaiser has met both the direct relationship and functional tests articulated in Holmes and its progeny. We reject Pfizer's core defense that there are too many steps in the causal chain between its misrepre s entations and Kaiser's alleged injury to meet the proximate cause "direct relation" requirement as

a matter of law. Pfizer characterizes this causal relationship as involving at least four steps: Pfizer commun i c ating tainted information about Neurontin to Kaiser's DIS; the DIS producing monographs tha t rely on the misrepresentations; those monographs

There are, of course, o ther potential victims of Pfizer's 1 1 scheme, such a s uninsured individuals who paid for their own prescriptions. But any such injury would be different in kind from Kaiser's injury and could not be considered "multiple" in that respect. At oral argument, Pfizer raised the possibility that premium payers might also sue as victims of Pfizer's scheme, but the question of whether any injury to such payers was proximately caused by this scheme is not before us in this case. -32-influenc ing the PMGs in their formulary decisions; and the

prescribing physicians (who exercise independent medical judgment) acting within the formulary to issue the prescriptions. We think this characterization misconstrues the way in which the Court has framed the direct relation test. Moreover, the adoption of Pfizer's view would undercut the core proximate causation principle of allowing compensation for those who are directly injured, whose injury was plainly foreseeable and was in fact foreseen, and who were the intended victims of a defendant's wrongful conduct. 1 2

The Supreme Court's recent decision in Hemi Group, LLC v . 1 2 City of New York, 130 S. Ct. 983, does not, as Pfizer argues, lead to a contrary conclusion. As an initial matter, that case produced a 4-1-3 decision with no majority on the proximate cause question. See id. at 995 (Ginsburg, J., concurring in part and concurring in the judgment) (providing fifth vote to overturn the decision below,

" [ w]ithout subscribing to the broader range of the Court ' s proximate cause analysis"). But in any event, the f actual situation here is easily distinguished. In Hemi Group, the defendant's alleged RICO conduct was usingthe mails to violate the federal Jenkins Act, which requires outof-state cigarette vendors to report customer informati on to the cus t omers' states of residence. See id. at 987 (plurality opinion). Thus , if the defendant's scheme could even be said to have a foreseen or intended victim, it was New York State (to whom Hemi Group owed the Jenkins Act reports), not the plaintiff New York City. Cf. id. at 990 (identifying the state as a "better situated" plaintiff). Further, Hemi Group raised a policy problem not at issue here: in that case, allowing the city to br i ng wha t was essentially a Jenkins Act claim under the rubric of RICO would have risked "turning RICO into a tax collection statute." Id. at 993 n.2; see id. at 995 (Ginsburg, J., concurring in part and concurring in the judgment) (stating that Justice Ginsburg would have rejected the city's claim because it was an attempt to make an "end-run" around the scope of the Jenk i ns Act). Kaiser's case involves no such unusual policy risk. If anything, the r i s k cut s in the other direction: accepting Pfizer's argument on proxima t e cause as a matter of law woul d e f f ectively preclude TPPs from bringing suit -33-In fact, the causal chain in this case is anything but

attenuated. Pfizer has always known that, because of the structure of the American health care system, physicians would not be the

ones paying for the drugs they pre s cribed. Pfizer's fraudulent marketing plan, meant to i nc rease its revenues and profits, only became successful once Pfizer received payments for the additional Neurontin prescriptions it induced. Those payments came from Kaiser and other TPPs. See Bridge, 128 S. Ct. at 2144 (noting that other auction bidders, not the county officials who immediately relied on defendants' misrepresentations, were the intended victims of defendants' RICO conduct); BCS Servs., 637 F.3d at 756. Kaiser sought only economic recovery in this case, and its economic injury occurred when it paid for fraudulently induced Neurontin prescriptions. 1 3

under RICO as the primary victims of fraudulent off-label drug marketing, and from recovering for their economic injuries. That could mean that no viable plaintiffs would remain to "vindicate the law as private attorneys general." Holmes, 503 U.S. at 269-70. G iven the high costs imposed by fraud in our health care system , and Kaiser's status as a primary victim, this result would not be in the service of either justice or accountability.

While first-party reliance was not needed, the evidence as 1 3 to Kaiser's reliance on Pfizer's misrepresentations was particularly strong, and it came directly from Pfizer itself. Pfizer had specifically identified Kaiser as a potential target for increased Neurontin sales and had developed a five-point plan for promoting Neurontin to Kaiser. That plan included making contact with members of the DIS and the P & T Committees. Kaiser Findings, 2011 WL 3852254, at *11. This strategy shows that Pfizer did not view the various arms within Kaiser as "third and even fourth parties," Hemi Grp., 130 S. Ct. at 992 (plurality opinion); rather, it viewed the Kaiser organization as a single entity to which -34-With respect to the mechanisms by which Pfizer marketed

Neurontin to PMG doctors through detailing and educational programs, Pfizer fraudulently marketed to physicians with the intent that those physicians would write prescriptions paid for by Kaiser. The fraudulent scheme worked as intended, inducing a huge increase in Neurontin prescriptions for off-label uses. Pfizer now argues that because doctors exercise independent medical judgment in making decisions about prescriptions, the actions of these doctors are independent intervening causes. But P f i zer's scheme relied on the expe c t ation that physicians would base their prescribing decisions in part on Pfizer's fraudulent marketing. The fact that some physicians may have consi dered factors other than P f izer's detailing materials in making their prescribing decisions does not add such attenuation to the causal chain as to eliminate proximate cause. Rather than showing a lack of proximate causation, this argument presents a question of proof regarding the total number of prescriptions tha t were attributable to Pfizer's actions. This is a damages question. Cf. Anza, 547 U. S . a t 4 66 (Thomas, J., concurring in part and dissenting in part) ("Proximate

cause and certainty of damages, while both rel a t ed to the plaintiff's responsibility to prove that the amount of damages he

Pfizer could pitch Neurontin in order to create effects that would reach prescribing physicians. -35-seeks is fairly attributable to the defendant, are distinct

requirements for recovery in tort.").

The doctrine of proximate cause, as Judge Posner has noted, "does its work" in situations where

too many unexpected things had to happen between the defendant's wrongdoing and the plaintiff's injury, in order for the injury to occur -- so many unexpected things that the defendant couldn't have foreseen the effect of his wrongdoing and therefore couldn't have been influenced, in deciding how much care to employ in the activity that produced the wrongful act, by the prospect of inflicting such an injury as occurred. BCS Servs., 637 F.3d at 754. Tha t i s not the situation here. Ho lding Pfizer liable will have an effect in deterring wrongful conduct. And the effe c t of that wrongful conduct was clear in foresight, not hindsight. See id. at 755. Upholding the finding of proximate cause here will "protect[] the ability of primary victims of wrongful conduct to obtain compens a t i on; simplif[y] l i tigation; recognize[] the limitations of deterrence . . . and eliminate[] s ome actual or possible but probably minor causes as grounds of legal liabili ty . " I d . at 756. The district court correctly concluded that Kaiser met the proximat e causation requirement. C. But-For Causation

Kaiser introduced several categories of evidence at trial which clearly demonstrated but-for causation. It produced evidence that (1) i t s employees directly relied on Pfizer's -36-misrepresentations in preparing monographs and formularies, which,

in turn, influenced do ctors' prescribing decisions; and (2) Pfizer's fraudulent off-label marketing directed to physicians caused PMG doctors to issue more Neurontin prescriptions than they would have absent such marketing. The latter type of evidence came from Dr. Rosenthal's report as well as inferences from other data. 1 4 Pfizer has argued both that the direct relianc e evidence was insufficient and tha t Dr . Rosenthal's aggregate evidence was inadmissible and insufficient. Pfizer's insufficiency claims rest

on the argument that certain evidence, introduced at trial and considered by the jury and district court, "falsified" Kaiser's theories of causation. We reject both of Pfizer's arguments.

1. But-For Reliance Evidence Kaiser presented ample evidence of the ways in which its reliance on Pfizer's misrepresentations regarding the effectiveness

Kaiser has argued that the district court did not actually 1 4 use the Rosenthal report as evidence of causation, but rather used it only to quantify damages. The district court's findings are not clear on this point. Compare Kaiser Findings, 2011 WL 3852254, at *32 ("To meet its burden of proving causation, plaintiffs offered the testimony of Professor Meredith Rosenthal . . . ."), with id. at *54 (describing causation question as "what misrepresentations and omissions Kaiser and DIS relied on [ , ]
. . . whether that reliance caused Kaiser to suffer injury[, and]
. . . whether or not PMG physicians would have nonetheless prescribed Neurontin to their patients if DIS had not published monographs recommending Neurontin or if the P & T Committees had added guidelines or restrictions to Neurontin's formulary status"). The jury charge on causation and damages did not mention the aggregate evidence one way or another. We will proceed on the understanding tha t the aggregate evidence both went to causation and set the basis for damages. -37-of Neurontin for the four relevant off-label uses met the but-for

causation requirement. Kaiser received Pfizer's misrepresentations through Pfizer's contacts with Kaiser's DIS, which disseminated information throughout the Kaiser organization. See Kaiser Findings, 201 1 WL 3 8 52254, at *3-4. The DIS also relied on publicly available information about Neurontin, id. at *3, which, because of Pfizer's publication strategy, omitted important information about negative study results, see id. at *7-8. A reasonable factfinder could readily conclude that misinformation received by the DIS would be widely disseminated, utilized , and relied upon throughout the Kaiser organization to cause but-for injury. Kaiser specifically presented evidence that the DIS shared with all regions at leas t two monographs that recommended Neurontin for bipolar disorder and that recommended removal of any formulary restrictions on Neurontin. See id. at *28-29. These monographs were compiled without P f i zer having disclosed certain adverse material information. Id. "In making formulary decisions, P & T Committees rely heavily on DIS's monographs," id. at *3, and PMG physicians comply with the formulary at a 95 percent rate, id. at *4. There was also evidence that PMG physicians received and acted upon Pfizer's misrepresentations, both through information sent through the DIS and information provided to them at Pfizer-

-38-sponsored events. For one, when DIS answered physicians' questions

through its inquiry service, DIS relied on half-truths communicated to it by P fizer. See id. at *29. Second, after PMG physicians attended a medical education conference in May 1999, new Neurontin prescriptions increased by 62 percent. Id. at *30. And significantly, when Kaiser conducted the DRUG and DUAT campaigns to reduce Neurontin usage after the negative information about Neuront i n came to light, new prescriptions of Neurontin fell by about 33 percent. At the same time, such prescriptions continued to rise nationally. Id. at *31.

From this evidence, the district court concluded that [t]he publication strategies and the other communications between Pfizer and Kaiser directly affected decisions about Neurontin's placement on formulary without restrictions. In addition, the direct communications to PMG physicians caused Kaiser injury because it reimbursed for Neurontin rather than less costly alternatives. Because Kaiser has a 95% compliance rate with its formulary, formulary restrictions necessarily affect the number of prescriptions written for any given drug. I find that Kaiser was injured as a result of its reliance on Pfizer's intentional misrepresentations and omissions. Id. at *30. This finding was not clearly erroneous. Further, a reasonable jury could have reached the same conclusion.

P f izer argues that Kaiser's DRUG and DUAT campaigns t o reduce prescriptions of Neurontin were not evidence of but-for causation because they were motivated by the desire to contain costs, not by concerns about Neurontin's efficacy for off-label -39-uses. Pfizer also argues that once evidence of the DRUG and DUAT

campaigns is properly discounted, there is no evidence that the Kaiser PMGs took steps to restrict Neurontin on their formularies, which "falsifies" Kaiser's causal theory of direct reliance.

Pfizer d i d present evidence that Kaiser continued to permit and even recommend the prescription of Neurontin for certain off-label uses after it became aware of Pfizer's fraud, as well as evidenc e that Kaiser's efforts to limit Neurontin prescriptions

were driven in part by its cost. But Ka i ser presented evidence that it did not learn the f u l l scope of Pfizer's fraud until November 2009, Kaiser Findings, 2011 WL 3852254, at *31, and that its efforts to limit Neurontin prescrip t i ons were motivated by

concerns about its efficacy for off-label uses. It was within the factfinder's province to weigh thi s evidence. Pfizer's evidence d i d not, as a matter of law or of evidence, "falsify" Kaiser' s theory of reliance upon Pfizer's misrepresentations.

2. Regression Analysis Aggregate Evidence Pfizer relies heavily on its argument that the aggregate statistical evidence presented by Dr. Rosenthal was also insufficient to show causation (or injury) as a matter of law, and was inadmissible as well.

a. Admissibility of Rosenthal Testimony We review a district court's ruling on the admissibility of an expert witness's testimony for abuse of discretion. I n re

-40-Pharm. Indus. Average Wholesale Price Litig. (AWP), 582 F.3d 156,

198 (1st Cir. 2009). Under Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993), expert testimony must have a "reasoning

or methodology" that is "scientifically valid," id. at 592-93, and that methodology must also have a "valid scientific connection to the pertinent inquiry" -- that is, a proper "fit" with the facts of the case, id. at 591-92. Admissibility does not turn on a determi na tion by the trial court of "which of several competing scientific theories has the best provenance," nor does it turn on convincing the trial court that the proffered expert is correct. Milward v. Acuity Specialty Prods. Grp., Inc., 639 F.3d 11, 15 (1st Cir. 2011) (quoting Ruiz-Troche v. Pepsi Cola of P.R. Bottling Co., 161 F.3d 77, 85 (1st Cir. 1998)) (internal quotation mark omitted).

It is clear that Dr. Rosenthal's evidence met several requirements of Federal Rule of Evidence 702. Dr. Rosenthal is a witness with the requisite "knowledge, skill, experience, training,

or education," Fed. R. Evid. 702, and her opinion would assist the trier of fact to understand the evidence or to determine a fact in issue, Fed. R. Evid. 702(a). Yet Pfizer argues that Dr. Rosenthal's testimony should have been excluded, attacking both the methodology and the "fit" of the Rosenthal report.

As t o the methodology, regression analysis is a well recognized and scientifically valid approach to understanding statistical data, and courts have long permitted parties to use

-41-statistical data to establish causal relationships. See, e.g.,

Wards Cove Packing Co., Inc. v. Atonio, 490 U.S. 642, 657-58 (1989) (holding that under Title VII of the C ivil Rights Act of 1964, "specific causation" is shown and a "prima f acie case" is "establish[ed]" when plaintiff identifies a specific employment practice linked to a statistical disparity); Watson v. Fort Worth Bank & Trust, 487 U.S. 977, 994 (1988) (opinion of O'Connor, J.) (explaining that, to establish a prima facie case under Title VII, "[o]nce the employment practice at issue has been identified, causation must be proved; that is, the plaintiff must offer statistical evidence of a kind and degree sufficient to show that the practice in question has caused the exclusion of applicants for jobs or promotions because of their membership in a protected group"); Duren v. Missouri, 439 U.S. 357, 366-67 (1979) (permitting petitioner to establish prima facie violation of fair cross-section requirement of Sixth and Fourteenth Amendments by using "statistics and other evidence" to show that "the underrepresentation of women, generally and on his venire, was due to their systematic exclusion in the jury-selection process"); Times-Picayune Pub. Co. v. United States, 345 U.S. 594, 621 (1953) (in antitrust case, looking to "economic statistics" to determine whether "demonstrably deleterious eff e c t s on competition may be inferred"); In re High Fruc t o se Corn Syrup Antitrust Litig., 295 F.3d 651, 660-61 (7th Cir. 2002) (permitting use of regression analysis to show causation

-42-in antitrust case); Conwood Co., L.P. v. U.S. Tobacco Co., 290 F.3d

768, 794 (6th Cir. 2002) (finding regression analysis " t o be admissible on the issue of causation" in antitrust case (emphasis omitted) (quoting Jahn v. Equine Servs., PSC, 233 F.3d 382, 390 (6th Cir. 2000))).

Pfizer argues that Dr. Rosenthal's analysis is nonetheless unreliable in this instance because it did not account for other factors that may have led a doctor to prescribe Neurontin for off-label use, particularly because the model did not include

a "time trend." Pfizer also argues that the methodology must be 1 5 unsound because the data contradict the results of Dr. Rosenthal's regression in three ways: (1) gabapentin prescriptions continued to grow after October 2004, when marketing spending plummeted as Neurontin lost patent protection; (2) the model improperly controlled for a sp ike in promotional spending in 2003, when Neurontin prescriptions remained relatively flat; and (3) the model attributed 85% of Neurontin prescriptions for nociceptive pain to alleged fraudulent marketing, but the factfinders found that there was no fraudulent marketing for that indication.

The district court acted well within its discretion in concluding that Dr. Rosenthal's methods met the scientific validity

Dr. Rosenthal described a "time trend" as a var i ab le that 1 5 is "introduced to capture some conglomeration of variables believed to have a pattern over time
. . . . [I]t's a hypothetical based on the idea that there are some things [other than promotional spending] over time that drive sales." -43-standard under Rule 702. "So long as an expert's scientific

testimony rests upon 'good grounds, based on what is known,' it should be tested by the adversarial process, rather than excluded f or fear that jurors will not be able to handle the scientific complexities." Milward, 639 F.3d at 15 (citation omitted) (quoting Daubert, 509 U.S. at 590). Pfizer's own expert witness admitted that pe er-reviewed, published studies do not always contain time trends. Moreover, Dr. Rosenthal explained her reason for declining to use a time trend: because the case involved only a single drug (as oppo s ed to other studies involving multiple drugs), the time trend would likely be a confounding variable, because its inclusion would produce results showing that promo t i onal spending had no statistically significant effect on prescriptions -- a conclusion that would not comport with basic economics. Indeed, Pfizer's own documents and testimony show that it expected and believed that off-label marketing of Neurontin would increase off-label prescriptions, and that its marketing had that result. The choice not to use a time trend did not make Dr. Rosenthal's me thodology unreliable.

Pfizer's objections regarding data that allegedly contradict the reliability of the model also do not show that the district court abused its discretion. These objections presented

a question for the jury. The post-October 2004 increase in gabapentin prescriptions does not render the regression ana lys is

-44-inadmissible. Indeed, the increase can be explained by the fact

that gabapentin became a generic drug at that time, and the generic's lower price would be expe c t ed to increase gabapentin sales even though marketing efforts for Neurontin had ceased. This change in circumstances does not negate the causal relationship between marketing and prescriptions that the model revealed for the pre-October 2004 period.

There was also nothing methodologically suspect about Dr. Rosenthal's contro l l ing for a spike in promotional spending in 2003, because that spike wa s likely the result of "strategic interaction" between the marke t i ng efforts for Neurontin and for Pfizer's launch of a new anti-epileptic drug, Lyrica. As Dr. Rosenthal explained, this was the most plausible reason why promotional spending for Neurontin would increase even as it neared the end of its patent life.

Fina lly, Pfizer's argument about the 85% figure for nociceptive pain misunderstands the structure of the model. In conducting her analysis, Dr. Rosenthal assumed

- - at the pla i nt iffs' direction -- that all off-label marketing was fraudulent, then analyzed the relationship between marketing and 1 6 prescriptions. Such an approach to proving injury f rom an underlying assumption of unlawful behavior ( to be proven to the fact-finder) is well accepted in the antitrust context from which
Her analysis excluded the marketing for on-label uses. 1 6 -45-RICO has drawn many of its causation principles. See, e.g.,

Associated Gen. Contractors, 459 U.S. at 528, 535-46 (noting that appellat e court had "properly assumed" that defendant's alleged conduct "might violate the antitrust laws," id. at 528, then going

on to separately evaluate whether pla i nt i f f had sufficiently alleged antitrust injury). Ultimately, Pfizer's attacks on Dr. Rosenthal's methodology were all grist for the trier of fact; they warranted "test[ing ] by the adversarial process, rather than exclu[sion]." Milward, 639 F.3d at 15.

As to the "fit" between Dr. Rosenthal's model and the facts at issue in the case, Pfizer objects that: (1) Dr. Rosenthal did not analyze the effect of the distorted studies or educational events on prescriptions, but rather the effect of promotional spending on prescriptions; (2) she did not analyze the effect of formulary expansion on the number of prescriptions written; (3) the analysis us ed na tional drug utilization data, as opposed to drug utilization data of Kaiser; (4) the analysis assumes all off-label marketing expenditures for Neurontin were for fraudulent marketing; and (5) the diagnostic codes used to determine what condition the drug was prescribed for indicate a patient's primary condition, so Neurontin c ou l d have been prescribed for an on-label use, but appear to be off-label. The basic thrust of Pfizer's argument is that Dr. Rosenthal's analysis does not provide insight into the

-46-quantity of prescriptions written as a result of Pfizer's alleged

fraudulent marketing.

None of these arguments demonstrate that the district court abused its discretion under the "fit" criterion in admitting Dr. Rosenthal's testimony. The use of promotional spending as a variable was a reasonable "fit" to represent Pfizer's fraud because Pfizer t argeted its promotional activities toward PMG physicians and toward Kaiser itself, and the money it spent on promotion helped to implement its fraudulent publication strategy. See Kaiser Findings, 2011 WL 3852254, at *11-28. The analysis did not require Kaiser to quantify the "publication strategy" as distinct from other promotional activities in order to effectively model the causal relationship. In fact, if publications and CME events did exert an effect independent of detailing (for instance, an effect

on decisions about the formulary), the model would have underestimated the impact of the fraud.

Next, the use of national drug data was reasonable, and the district court did not abuse its discretion in so holding. See id. a t * 3 2. Dr. Rosenthal used data that was prepared by independent consulting companies, and this type of data is used by Pfizer itself in its own strategic planning and marketing efforts. Kaiser did not independently keep track of the usage for which each prescription was written, so Dr. Rosenthal used what she considered the be st alternative, derived from national databases that the

-47-district court described as the "gold standard." Id. Pfizer does

not challenge the district court's determination that i t was reasonable to assume that Kaiser's patient population and physician distribution are similar to the nat i ona l mix. See id. The district court also permi s s ib ly found a "fit" in Dr. Rosenthal's use of the databases' diagnostic codes (particularly with respect to bipolar disorder) to determine the percentage of prescriptions written f or each indication. Indeed, Pfizer's own estimate was that bipolar disorder accounted for 14.7 percent of Neurontin prescriptions, which is "quite close" to Dr. Rosenthal's estimate of 16 percent. See id. at *32 n.20.

Finally, that Dr. Rosenthal's report assumed all of Pfizer ' s off-label marketing was fraudulent marketing is not a basis to find that the district court erred in admitting the report. Pfizer is incorrect that this assumption means that Dr. Rosenthal was "assum[ing] the very conclusion she was attempting to prove." Dr. Rosenthal's analysis sought to determine whether Pfizer's marketing had a causal effect on prescribing behaviors, not whether the marketing was in fact fraudulent. Pfizer's objection does not go to the question of whether Dr. Rosenthal's regression had a close enough "fit" to satisfy Daubert; rather, it is a question of damages.

-48-b. Sufficiency of Aggregate Evidence Having found that Dr. Rosenthal's testimony was admissible, we turn to Pfizer's argument that it was insufficient evidence to support the jury's and district court's findings of causation. We reject the argument, while pointing out that her testimony was not the only evidence of but-for causation.

Pfizer insists that Dr. Rosenthal's testimony cannot be credited because it does not take into account the patientspecific, idiosyncratic decisions of individual prescribing physicians. Thus, according to Pfizer, the report was legally insufficient proof of causation. Indeed, Pfizer purports to find support for its position in the district court's rulings entering summary judgment against Aetna and Harden. See Neurontin Class SJ, 754 F. Supp. 2d at 310-11; Neurontin Coordinated SJ, 677 F. Supp. 2d at 485, 494-95.

A tort plaintiff need not "prove a series of negatives; he doesn't have to 'offer evidence which positively exc l ude[s] every other possible cause of the accident.'" BCS Servs., 637 F.3d at 757 (alteration in original) (quoting Carlson v. Chisholm-Moore Ho ist Corp., 281 F.2d 766, 770 (2d Cir. 1960) (Friendly , J . ) ) . "Once a plaintiff presents evidence that he suffered the sort of injury that wou l d be the expected consequence of the defendant's wrongful conduct," the burden shifts to the defendant to rebut this causal inference. Id. at 758.

-49-Pfizer's argument is a repetition of its assertion that

there is an intervening cause -- individual physicians' independent medical judgment -- which precludes a finding of causation based on aggregate evidence. But "the burden of proving an 'intervening cause' -- something which snaps the ' c ausal chain' (that is, operates as a 'superseding cause,' wiping out the defendant's liability) that connects the wrongful act to the defendant's injury

-- is on the defendant." Id. at 757 (citation omitted). Pfizer did offer the testimony of doctors who said that their decisions to prescribe Neurontin were not influenced by Pf i z er 's fraudulent marketing, and the jury and d i s t r i ct court, within their powers, rejected the argument.

Pfizer also argue s that its testimony from doctors who stated that they prescribed Neurontin for off-label uses without relying on Pfizer's misrepresentations "falsified" Kaiser's statistical analysis. Not so. The existence of some doctors who purportedly were not influenced by P fizer's misinformation would not defeat the inference that this misinformation had a significant influence on prescribing decisions which injured Kaiser. Indeed, Dr. Rosenthal noted the scientific invalidity of looking to physician-by-physician accounts of their prescribing decisions. Weighing the individual testimony presented by Pfizer against the aggregate evidence presented by Kaiser was a task for the jury and district court.

-50-Pfizer next argues that the Rosenthal report merely

demonstrated "correlati on " and not "causation." But if Pfizer's i n f ormation could not be expected to affect a single doctor's decisionmaking, the company's cho ice to undertake the marketing

c ampa ign would be inexplicable. Cf. id. at 758 ("The obje c t o f [the defendants'] conspiracies was to obtain liens that would otherwise go to [the plaintiffs and other] bidders -- there could be no other reason for wanting to pack the room in violation of the County's rule. . . . How likely is it that [plaintiffs] lost no bids to bidders who had 13 arms in the room but should have had only three?").

More generally, Pfizer argues that Ka i s er's use of aggregate evidence is precluded by the decisions of other courts in pharmaceutical marketing RICO fraud cases. Pfizer relies on a series of cases that it argues have rejected evi dence like Kaiser's. S e e , e.g., In re Schering Plough Corp. Intron/Temodar Consumer Class Action, 678 F.3d 235 (3d Cir
. 2012); Ironworkers Local Union 68 v. AstraZeneca Pharm., LP, 634 F.3d 1352 (11th Cir. 2011); UFCW Lo c a l 1 7 76 v. Eli Lilly & Co., 620 F.3d 121 (2d Cir. 2010); Se. Laborers Health & Welfare Fund v. Bayer Corp., 655 F. Supp. 2d 1270 (S.D. Fla. 2009). But we dis agree with Pfizer's characterization of these cases and find them either supportive of our result or inapposite. We see no split in authority.

-51-In part i cular, Pfizer leans heavily on the Second

Circuit's decision in UFCW Local 1776 v. Eli Lilly & Co., 620 F.3d 121, which reversed a district court's certification of a class of TPP plaintiffs who claimed that Eli Lilly's fraudulent marketing of Zyprexa caused them to pay an inflated price for that drug and to pay for prescriptions that would not have otherwise been written. Id. at 123, 137. To begin, the district court in Eli Lilly granted class certification on the former (excess pricing) claim, and the Second Circuit reversed on that basis. See id. at 133. By contrast, the claimed injury to Kaiser resembles the latter (excess quantity) theory. The Second Circuit found a lack of but-for causation only on the excess pricing theory, because doctors do not generally consider the price of a drug when they make prescribing decisions. Id. at 133-34. On the other hand , doctors would certainly consider information about the efficacy of a drug when deciding whether to prescribe it for their patients.

As to the excess quantity theory, the Second Circuit de s c r ibed the plaintiffs' aggregate evidence of causation a s involving only an extrapolation from the fact that the number of off-label prescriptions for Zyprexa f e ll after Eli Lilly's fraud became known. S e e i d . at 135. This does not come close to resembling Dr. Rosenthal's evidence, which examined contemporaneous data that reflected what was actually happening with regard to spending and prescriptions while Pfizer's fraud was ongoing.

-52-F i na lly, the Second Circuit specifically noted that, "while [the

excess quantity] theory cannot support class certification, it is not clear that the theory is not viable with respect to individual cla ims by some TPPs." Id. at 136. Kaiser's case, of course, is just such an individual claim by a TPP.

The other cases on which Pfizer relies are distinguishable. The Eleventh Circuit, addressing alleged fraudulent marketing claims involving the drug Seroquel, specifically declined to decide the case on causation grounds. Ironworkers, 634 F.3d at 1359-60. Instead, that court held that the TPP plaintiffs had failed to show economic injury because the prescriptions at issue were merely less cost-effective than the alternatives, rather than being "medically unnecessary or inappropriate." Ironworkers, 634 F.3d at 1360. Kaiser, in 1 7 contrast, staked much of its case on proving that Neurontin was ineffective for the promoted off-label uses, and the district court so found. See Kaiser Findings, 2011 WL 3852254, at *34-45.

The Third Circuit addressed the causation question as a matter of Art i c l e III standing rather than RICO doctrine. In re Schering Plough, 678 F.3d at 246. It also did not address the use

The Eleventh Circuit also decided that the TPPs had assumed 1 7 the risk of paying for all prescriptions of covered drugs, even tho s e induced by fraud, through the process of setting and collecting premiums. Ironworkers, 634 F . 3 d a t 1364. Without commenting on such a theory, we note that neither party in this litigation has raised it. -53-of aggregate evidence at all, finding merely that the TPP plaintiff

in that case had not connected the pharmaceutical company's alleged fraudulent marketing scheme as to two drugs to the TPP's payment for a third drug owned by the same company. Id. at 247-48. The Ninth Circuit, in an unpublished decision, did no t mention aggregate evidence. United Food & Commercial Workers Cent. Pa. & Reg'l Health & Welfare Fund v. Amgen, Inc., 400 F. App'x 255, 257- 58 (9th Cir. 2010). 1 8

Courts' treatment of aggregate evidence is not as Pfizer represents. Earlier we cited to the use of such aggregate evidence to show causation under several causes of action. We see no reason to reach a different conclusion for the specific subset of RICO claims based on fraudulent marketing. IV. At trial, Pfizer argued that it had not committed fraud because Neurontin was effective for the off-label uses at issue. The jury and court rejected the argument, and on appeal Pfizer does not contest the finding of fraud. Nonetheless, it uses the

Further, some courts appear to have conflated the proximate 1 8 and but-for causation inquiries in evaluating aggregate evi dence and the role of doctors' medical judgments. See, e.g., Se. Laborers, 655 F. Supp. 2d at 1280-81 (stating that court was performing proximate cause inquiry, but proceeding to analyze butfor cause question of whether doctors would have prescribed drug at issue in the absence of misrepresentations). And to the extent that some district courts may have endorsed Pfizer's position that aggregate evidence is legally insufficient to prove but-for causation, we disagree, at least on the facts of this case. -54-question of Neurontin's effectiveness to argue that Kaiser failed

to prove that it suffered economic injury. Pfizer contends that because Neurontin was actually effective for the off-label uses at issue, Kaiser suffered no economic injury from paying for prescriptions for these uses. Pfizer claims that the court applied an erroneous burden of proof and an erroneous medical standard in making its findings as to Neurontin's effectiveness. We disagree. 1 9 Pfizer asserts that the district court erroneously shifted the burden of proof to it when the court allowed Kaiser to prove its economic injury by showing that "there is no reliable scientific evidence that Neurontin is effective" for the conditions at issue, Kaiser Findings, 2011 WL 3852254, at *34, rather than requiring Ka iser to show that Neurontin was actually ineffective for these conditions in all cas e s . See, e.g., In re Schering 2 0

Pfizer also advances a somewhat confusing argument about the 1 9 lack of jury instructions on efficacy. Because we decide that, for the purpose of proving injury, Kaiser adequately proved Neurontin's inefficacy for the relevant indications, we ne ed not determine exactly what standard the jury may have used.

Pfizer also argues, briefly, that Kaiser presented another 2 0 theory of injury: that cheaper, alternative drugs could have been used even if Neurontin was effective. Pfizer asserts that this theory has been rejected by numerous courts, citing, for example, Ironworkers, 634 F.3d at 1360; and Dist. 1199P Health & Welfare Plan v. Janssen, L.P., 784 F. Supp. 2d 508, 520 (D.N.J. 2011). Kaiser do e s not explicitly defend the cheaper alternative drug theory in any detail, devoting only one footnote in its bri e f t o the theory and relying on only one case, Desiano v. Warner-Lambert Co., 326 F.3d 339 ( 2 d Cir. 2003), without delving into the trial evidence. Because neither party has properly briefed the is sue , and becaus e we c an dispose of the damages question on the fully briefed effectiveness theory instead, we do not pass on the -55-Plough Corp. Intron/Temodar Consumer Class Action, No.

2:06-cv-5774, 2010 WL 2346624, at *4 (D.N.J. June 9, 2010) ("[A] lack of data or evidence affirmatively proving that a Subject Drug

wa s effective in treating a condition [is] not the same as the actual ineffectiveness of the Subject Drug.").

The district court did not place the burden on Pfizer to show that Neurontin was effective. Kaiser produced expert witnesses and evidence showing that Neurontin was no more effective than placebo for the indications at issue -- i.e., that it was ineffective. See Kaiser Findings, 2 0 1 1 WL 3852254, at *35-45 (reviewing such evidence). Pfizer then produced its own evidence to attempt to rebut Kaiser's evidence.

Pfizer's second argument asserts that the district court rested its conclusion on the FDA approval standard -- two positive DBRCTs showing efficacy -- to determine whether Neurontin was effective, and that this meant the court's conclusion was fatally flawed. Pfizer argues that the proper standard was the standard governing the practice of medicine, not the standard for FDA approval. In clinical practice, Pfizer argues, FDA-type trials

2 1

are not dispo s itive; instead, physicians rely on their own experience, other doctors' positive clinical experiences, and other

"cheaper alternatives" theory.

We acknowledge the brief of amicus curiae Pharmac eut ical 2 1 Research and Manufacturers of America on this issue. -56-evidence. Relatedly, Pfizer argues that Kaiser's use of "negative"

studies to show ineffectiveness was not legally sufficient because such studies do not "establish the drug's inefficacy for treating the condition in all other patients and circumstances."

Kaiser responds that the district court did not frame the issue of ine f fectiveness only in terms of DBRCTs, but rather considered a number of different types of evidence, including clinical trials tha t did not meet the DBRCT requirements and reports of clinical judgments such as case studies. The court was aware of Pfizer's critique of DBRCTs; it was also aware that, due to the plac ebo effect, some patients would report improvements regardless of whether the drug was scientifically effective for their c onditions, making non-DBRCT evidence less probative of effectiveness. Kaiser argues tha t the court properly chose the weight to give each type of medical evidence. Kaiser's is the more accurate description of the record. We conclude that the totality of the evidence supported the district court's ultimate conclusion that Kaiser met its burden of showing that Neurontin was ineffective for the four off-label indications.

Randomized controlled studies like DBRCTs are widely accepted as "ideally suited" for showing causation and as a "good

measure of the treatment effect." D. Kaye & D. Freedman, Reference Guide on Statistics, in Federal Judicial Center, Reference Manual

on S c i entific Evidence 211, 218, 220 (3d ed. 2011). Where, as

-57-here, numerous DBRCTs i ndicate that a drug is ineffective, that

provides powerful scientific evidence of inefficacy, particularly as compared to anecdotal experiences, which can be tainted by the placebo effect. As one witness in this trial testified, "the default position [in medical decisionmaking] is that a drug is ineffective unless it's proven otherwise." Experiments start with

a null hypothesis that the drug is no more effective than placebo. In this case, DBRCTs repeatedly showed that there was not enough evidenc e to reject the null hypothesis for the indications at issue. See Kaiser Findings, 2011 WL 3852254, at *35-45. Pfizer's claimed evidence of Neurontin's efficacy came from less convincing

sources. Thus, the total i ty of the evidence strongly supports a conclusion that Neurontin was not effective for the four off-label conditions as to which the district court and jury found liability. We need not address what the s tandard for efficacy would be if there were no DBRCTs in existence, or if the results of DBRCTs were equivocal, or if there were a different mix of DBRCT and non-DBRCT evidence. V.

Because Kaiser met both causation requirements with legally suffici ent evidence and proved that it suffered economic injury from Pfizer's fraudulent scheme, we move to the separate challenges to the amount of damages awarded. "On that phase of the

-58-c a s e the plaintiff has a more relaxed burden of proof . . . ,

especially if as in this case the defendants' conduct has made it difficult for the plaintiff to prove the precise extent of his damage s ." BCS Servs., 637 F.3d at 759; see also Thermo Electron Corp. v. Schiavone Constr. Co., 958 F.2d 1158, 1166 (1st Cir. 1992). Under such circumstances, damages do not need to be proven "with mathematical cert a i nty, provided an award has a rational basis in the evidence." Thermo Electron, 958 F.2d at 1166 (quoting Jay Edwards, Inc. v. New Eng. Toyota Distrib., Inc., 708 F.2d 814, 819 (1st Cir. 1983)) (internal quotation mark omitted); see Restatement (Second) of Torts § 912 cmt. a. "Otherwise 'the more grievous the wrong done, the less likelihood there wou l d be of a recovery. ' " BCS Servs., 637 F.3d at 759 (quoting Bigelow v. RKO Radio Pictures, Inc., 327 U.S. 251, 265 (1946)).

Pfizer argues that the dist r i c t court erred in its calculation of damages, primarily because Dr. Hartman used a list of alternatives to Neurontin created by Dr. Millares (the chairman of the DIS) but no expert testified that the drugs on the list were at least as effective or as well tolerated as Neurontin. Moreover, Pfizer argues, there was no evidence that PMG doctors would have prescribed those lower-cost alternative drug s but for Pfizer's conduct; indeed, those doctors may have prescribed more expensive drugs instead of Neurontin. Pfizer claims that these assumptions made the estimation of damages too speculative. See Irvine v.

-59-Murad Skin Research Labs, Inc., 194 F.3d 313, 320 (1st Cir. 1999).

Our review of the district cour t ' s admission of Dr. Hartman's testimony i s f or abuse of discretion, AWP, 582 F.3d at 197, and there was none here.

The burden of proof as to damages is lower than that for causation, and the factfinder is afforded a greater deal of freedom to estimate damages where the defendant, as here, has created the risk of uncertainty. See Ocean Spray Cranberries, Inc. v. PepsiCo, Inc., 160 F.3d 58, 63 (1st Cir. 1998). The damages inquiry does not allow a defendant to benefit from the scope of its wrongdoing; thi s is why "[e]ven 'speculation has its place in estimating damages, and doubts should be resolved against the wrongdoer.'" BCS Servs., 637 F.3d at 759 (quoting Mid-Am. Tablewares, Inc. v. Mogi Trading Co., 100 F.3d 1353, 1365 (7th Cir. 1996)).

The district court did not err in accepting Dr. Hartman's methodology for calculating damages. In fact, Pfizer never offered

an alternative: it did not provide its own list of substitute drugs, nor did it offer testimony about the Kaiser list's exclusion of lamotrigine (the only drug Pfizer names on appeal as improperly excluded). VI.

Pfizer raises two other issues on appeal, concerning the district court's denial of Pfizer's motion to transfer venue before trial and its denial of Pfizer's motion for a new trial.

-60-A. Denial of Pfizer's Motion to Transfer Venue The coordinated plaintiffs filed their complaint in the Massachusetts district court on February 1, 2005. More than four years later, on December 4, 2009, Pfizer filed a motion to transfer venue to California pursuant to 28 U.S.C. § 1404.

Pfizer's motion followed more than two months of discussions among the coordinated plaintiffs, the defendants, and the Massachusetts district court regarding the possibility of holding a bellwether trial as to one TPP's claims against the defendants. The court stated on September 18, 2009, that it favored holding a trial on Kaiser's claims, a view joined by plaintiffs on October 2, 2009. Defendants opposed, saying that 2 2 any be l lwe ther trial should not be on Kaiser's claims because "Kaiser is the most atypical of the named TPPs." During none of these discussions did Pfizer suggest that venue should be transferred to California.

On November 12, 2009, the district court ordered that "[t]he trial in the action brought by coordinated plaintiff Kaiser will begin [before it] on February 22, 2010." About a month later, Pfizer moved to transfer venue pursuant to 28 U.S.C. § 1404, arguing for the first time that transfer was favored by (1) Kaiser's residence in California, (2) California's greater interest

While the coordinated plaintiffs represented that they would 2 2 prefer to all proceed to trial at one time, they agreed that if the court were to initially hold only one trial, it should be Kaiser's. -61-in the litigation, (3 ) the greater familiarity of California

federal courts with the California UCL, and (4) the convenience of witnesses. The district court, with years of experience in the case, denied this motion, explaining that (1) Kaiser did not wish to transfer venue; (2) transfer would result in considerable delay

as any transferee judge familiarized herself with the case; and (3) defendants would not be prejudiced, since they had access to videotaped deposition testimony of non-party witnesses. Kaiser Findings, 2011 WL 3852254, at *11 n.6.

On appeal, Pfizer argues that this was error because it

vi o l ated the MDL transfer requirements pursuant to 28 U.S.C. § 1407(a) and the rule of Lexecon Inc. v. Mi lberg We i ss Bershad Hynes & Lerach, 523 U.S. 26 (1998), and because it was an abuse of discretion, in any event, under 28 U.S.C. § 1404.

Pfizer is wrong on the law. Section 1 4 07(a) provides that an action "transferred to any district for coordinated or consolidated pretrial proceedings
. . . shall be remanded by the panel at or before the conclusion of such pretrial proceedings to the district from which it was transferred unless it shall have been previously terminated." The Court held in Lexecon that a district c ourt conducting such pretrial proceedings could not "invoke § 1404(a) to assign a transferred case to itself for trial." 523 U.S. at 28. The coordina t ed plaintiffs filed their complaint in the District of Massachusetts; it was not transferred

-62-to this district for pretrial proceedings, and so § 1407(a) and

Lexecon do not govern here.

There was no abuse of discretion as to § 1404. See Coady

v. Ashcraft & Gerel, 223 F.3d 1, 11 (1st Cir. 2000). Kaiser opposed defendants' motion to transfer, and coordinated plaintiffs Aetna and Guardian were domiciled in New York and Connecticut, respe c t ively. The Massachusetts district court had considerable experience with complex cla ims against defendants arising out of the fraudulent marketing of Neurontin, and coordinated plaintiffs' claims were national in scope, not localized to California. B. Denial of Pfi z er 's Motion for New Trial Based on

Purportedly New Evidence Regarding the Cochrane Review of Neuropathic Pain There was no abuse of discretion in the district court's denial of defendants' March 22, 2 0 1 1 motion for new trial. At trial, Pfizer had presented expert testimony that Neurontin was effective for the broad treatment of neuropathic pain, which relied in part on a 2005 review by the Cochrane Collaboration, an independent organization, that concluded that adequate evidence supported Neurontin's efficacy for neuropathic pain. Kaiser Findings, 2011 WL 3852254, at *42. The district court discounted this testimony because the 2005 Cochrane Review was based on incomplete information, given defendants' suppression of negative information about Neurontin's efficacy for the broad treatment of neuropathic pain. Id. at *42-43.

-63-In 2011, the Cochrane Collaboration published another

review of the effects of gabapentin in treating chronic neuropathic pain. This revised review was "updated with the inclusion of unpublished information made available through litigation" and concluded that "[g]abapentin provides pain relief of a high level in about a third of people who take [it] for pa i n f u l neuropathic pain." The district court denied de fendants' motion for a new trial, explaining that a credible meta-analysis from the Cochrane Collaboration based on the entirety of the sc i entific evidence concerning Neurontin's use in treating broad neuropathic pain was unavailable to defendants at the time of trial only because "Pfizer itself di d not provide the Cochrane Group with all available studies prior to the trial because it fraudulently suppressed these studies." That reason was sufficient. VII. The judgment of the district court is affirmed.

-64-