MEMORANDUM IN SUPPORT OF SEPARATE PRETRIAL ORDER NO. 8933

BARTLE, District Judge.

Plaintiffs Jamie D. Cheek and Valarie Farmer have each filed an action against defendant Wyeth, LLC ("Wyeth")1 alleging that she suffers from primary pulmonary hypertension ("PPH")2 as a result of ingestion of Wyeth's appetite-suppressant drugs fenfluramine, marketed as Pondimin, and dexfenfluramine, marketed as Redux ("Diet Drugs"). Before the court is the motion of Wyeth to enjoin Ms. Cheek and Ms. Farmer from continuing with their lawsuits in the United States District for the District of South Carolina and the Court of Common Pleas of Philadelphia County respectively because of the bar under the provisions of the Diet Drug Nationwide Class Action Settlement Agreement ("Settlement Agreement") and PTO Nos. 1415 and 2383.3 Wyeth has also moved to exclude the testimony of Ms. Cheek's medical experts on causation under Rules 702 and 403 of the Federal Rules of Evidence and Daubert v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 113 S.Ct. 2786, 125 L.Ed.2d 469 (1993).

I.

It is undisputed that Jamie Cheek ingested Diet Drugs for approximately one year. She took the Diet Drug Fenfluramine from October 25, 1995 through June 17, 1996 and from September 11, 1996 to December 29, 1996. She also used the Diet Drug Dexfenfluramine from June 18, 1996 to July 15, 1996. On January 6, 2011, Ms. Cheek filed a lawsuit against Wyeth in the United States District Court for the District of South Carolina claiming, as noted above, that she was suffering from PPH caused by Diet Drugs. The action was transferred to this court for coordinated pretrial proceedings as part of the Diet Drug Multi-District Litigation ("MDL No. 1203").

During discovery, Ms. Cheek produced to Wyeth her complete medical records as well as expert reports by Stuart Rich, M.D. and Lewis Rubin, M.D. which exclude various known conditions as causing her PPH. These physicians opine that the onset of her PPH resulted from her use of Diet Drugs.

Plaintiff Valarie Farmer took the Diet Drug Pondimin for approximately three months in 1997. On June 29, 2011, she was diagnosed with PPH. Thereafter, on July 13, 2011, Ms. Farmer filed suit against Wyeth in the Court of Common Pleas of Philadelphia County alleging that her PPH resulted from her use of Diet Drugs. During discovery, Ms. Farmer produced her medical records and expert reports from Dr. Rubin and Harold Palevsky, M.D. Both determined that Ms. Farmer's PPH was caused by Diet Drugs. Jury selection is scheduled to begin in her case in the state court on September 27, 2012.

In support of its motions, Wyeth first argues that the opinions of plaintiffs' experts fail under the definition of PPH set forth in the Settlement Agreement because they do not exclude idiopathic, that is, unknown causes for plaintiffs' PPH. Wyeth further contends there is no reliable scientific or medical basis for an opinion that Diet Drugs caused Ms. Cheek's PPH when the PPH did not manifest itself until some eleven years after she ceased consumption of Diet Drugs. More specifically, it maintains that there is no reliable scientific evidence that Diet Drugs cause PPH after a latency period of five or more years.

We held a status conference with the attorneys for the parties, at which time they agreed that no evidentiary hearing was necessary and that the pending motions could be decided on the record before the court. On August 23, 2012, this court held oral argument.

II.

This court has previously described the fatal disease known as PPH:

In re Diet Drugs Prods. Liab. Litig., 226 F.R.D. 498, 501 (E.D.Pa.2005).

The Settlement Agreement, with limited exceptions, resolved the claims of those who used Wyeth's diet drugs known as Pondimin and Redux. Those who opted out of the settlement, of course, were not bound by its terms.4 In addition, the PPH claims of persons who ingested Diet Drugs are excluded from the definition of settled claims. Settlement Agreement § VII.B. Such persons may sue Wyeth for PPH in the tort system.5 Id. All other claims against Wyeth for Diet-Drug related injuries are subject to the release and bar provisions of the Settlement Agreement as set forth in PTO No. 1415;

PTO No. 1415 ¶ 7 (Aug. 8, 2000).

To avoid an injunction against proceeding with their PPH claims, plaintiffs must satisfy or at least come forward with evidence to satisfy a three-part definition of PPH under the Settlement Agreement. First, a plaintiff must produce evidence of one of three clinical findings:

Settlement Agreement § I.46.a(1). A plaintiff must also come forward with the following medical records:

Id. at § I.46.a(2). Finally, a plaintiff must have evidence that:

Id. at § I.46.a(3).

Under PTO No. 2383 and PTO No. 3699, a putative PPH plaintiff must initially meet the threshold definition of PPH as set forth in the Settlement Agreement or at least raise a genuine dispute of material fact in this regard. See PTO No. 3699 at 4 (July 6, 2004); PTO No. 2383 at 3 (Feb. 26, 2002). If Wyeth disputes a plaintiff's diagnosis of PPH, it may file a motion to enjoin the plaintiff from proceeding with his or her tort action pursuant to PTO No. 1415. Id. at 6. Wyeth must use its "best efforts" to file such a motion within 60 days of receipt of the plaintiff's medical records. Id. This court then compares the plaintiff's medical records with a checklist based on the definition of PPH in Section 1.46 of the Settlement Agreement, as set forth above. Id. at 7. Such analysis "[i]n most if not all instances ... will not be unduly time consuming." Id. at 8. If plaintiff has not met his or her burden, the court will prohibit the plaintiff from proceeding with a PPH tort claim.7 Id.

Wyeth does not contest that Ms. Cheek and Ms. Farmer have met the criteria set forth in the first two parts of the PPH definition. See Settlement Agreement, § I.46.a(1)-(2). It is also undisputed that the medical experts retained by Ms. Cheek and Ms. Farmer have excluded the other known causes of PPH including those enumerated in the third part of the PPH definition. See id. at § I.46.a(3).

Wyeth asserts, however, that the experts have not excluded "idiopathic" pulmonary hypertension ("IPAH"). IPAH is pulmonary hypertension which results from an unknown cause. According to Wyeth, approximately 300 to 600 Americans develop IPAH each year. Wyeth maintains that to move forward with their actions plaintiffs "must present reliable evidence that their PPH was caused by diet drugs, rather than idiopathic PAH." Such "reliable evidence," Wyeth contends, does not exist because IPAH is "indistinguishable" from Diet-Drug-induced PPH and, as a result, "[t]here is no clinical test that can distinguish between pulmonary hypertension resulting from distant diet drug use as opposed to IPAH."

While an expert can surely opine that the cause of any injury is unknown, it is at least questionable whether an expert can ever really exclude an unknown cause since by definition it is unknown. The Court of Appeals in Heller v. Shaw Industries, Inc., cautioned that an expert is not required under Daubert "to rule out all alternative possible causes of [a person's] illness."8 167 F.3d 146, 156 (3d Cir.1999).

It then quoted Professor Capra, the Reporter to the Advisory Committee on the Federal Rules of Evidence:

Id.; see also In re Asbestos Prods. Liab. Litig., No. 09-69123, 2010 WL 4676563, at *4 (E.D.Pa. Nov. 15, 2010). In any event, evidence excluding idiopathic or unknown causes of PPH is not required under the plain meaning of the Settlement Agreement. The definition of PPH set forth in the Settlement Agreement dictates that those who wish to proceed with a tort claim based on PPH must produce evidence excluding certain "[c]onditions known to cause pulmonary hypertension." Settlement Agreement, at § I.46.a(3) (emphasis added). As discussed above, IPAH is by definition a diagnosis of pulmonary hypertension which arises from an unknown cause. Any interpretation of the Settlement Agreement to require exclusion of conditions unknown, that is, an idiopathic cause or diagnosis, would be "inconsistent with [a] common sense" reading of the Agreement and therefore cannot be adopted by this court. See, e.g., Disabled in Action of Pa. v. Se. Pa. Transp. Auth., 539 F.3d 199, 210 (3d Cir.2008). Under the undisputed facts before us, both Jamie Cheek and Valerie Farmer have satisfied the multi-part definition of PPH as written into Section 1.46 of the Settlement Agreement.

III.

Whether Diet Drugs caused the PPH from which the plaintiffs suffer is a separate issue.9 Each must prove, in addition to the criteria of the Settlement Agreement, that her use of Diet Drugs precipitated the onset of her PPH. As to Valerie Farmer, her lawsuit has never been before this court for pretrial proceedings as part of MDL 1203. It has proceeded and will be tried in the Court of Common Pleas of Philadelphia County where the test for the reliability of an expert's testimony will be determined not under Daubert, but under the Frye test. See, e.g., Commonwealth v. Nazarovitch, 496 Pa. 97, 436 A.2d 170, 172 (1981) (citing Frye v. United States, 293 F. 1013 (D.C.1923)). It is for the state court to decide on the admissibility of the medical opinions of plaintiff's experts and if admissible for the jury to make a finding on causation.

The Cheek case, on the other hand, was transferred here for pretrial proceedings as part of MDL 1203 but will be returned for trial to the transferor court, the United States District Court for the District of South Carolina. See 28 U.S.C. § 1407. Wyeth argues that under Daubert there is no reliable medical or scientific evidence that Diet Drugs can cause an individual to develop PPH eleven years after a patient discontinues use of the drugs, as occurred here with Ms. Cheek. It asserts that there are no epidemiological studies measuring the risk of developing PPH more than five years after an individual has ceased taking Diet Drugs. Wyeth submits that the only such study regarding PPH is the 1996 International Primary Pulmonary Hypertension Study ("IPPHS"). While Wyeth concedes that the IPPHS found that Diet Drugs can cause PPH, it asserts that the IPPHS demonstrates that the risk of developing PPH was no longer statistically significant for patients one year after they discontinued taking Diet Drugs. Wyeth reasons that without any epidemiological study, Ms. Cheeks lacks sufficient scientific evidence to proceed with her lawsuit.

The IPPHS considered 95 patients with PPH in France, Belgium, the United Kingdom, and the Netherlands and compared them with 335 control patients. The study confirmed that Diet Drugs cause PPH and calculated the relative risk, or "odds ratio," of developing PPH for Diet Drug users. Relative risk has been explained as:

Fed. Judicial Ctr., Reference Manual on Scientific Evidence 395 (3d ed.2011).

Overall, the IPPHS determined that individuals who had ingested Diet Drugs had a relative risk of 6.3, meaning that they were 630% more likely to develop PPH than individuals who had not ingested Diet Drugs. The relative risk for recent users was 10.1. In contrast, the study reported that those individuals who had ceased use of Diet Drugs more than one year earlier had a relative risk of 2.4. The study also revealed that the relative risk sharply increased with duration of exposure. While individuals who used Diet Drugs for three months or less had a relative risk of 1.8, those who had used Diet Drugs for longer than three months had a relative risk of 23.1. The study concluded "[t]he risk of primary pulmonary hypertension seems to increase steadily with the quantity of appetite suppressants used, but there has been very little experience with their long-term use in Europe." It acknowledged that "[h]ow fenfluramine and dexfenfluramine may lead to pulmonary hypertension is unknown."

Wyeth asserts that the 2.4 odds ratio did not reach statistical significance because the confidence interval included 1.0. A confidence interval is "a range of possible values calculated from the results of a study.... The width of the confidence interval reflects random error." Reference Manual on Scientific Evidence at 389. "Where the confidence interval contains a relative risk of 1.0, the results of the study are not statistically significant. Id. The confidence interval for the odds ratio for past users in the IPPHS study ranged from 0.7 to 8.2. Therefore, because the boundaries of the confidence interval encompass a relative risk of 1.0, Wyeth asserts that the study is not statistically significant. See id.

Wyeth also relies on the expert opinion of Mitchell Levine, M.D. Dr. Levine is a Professor of Medicine at McMaster University in Ontario, Canada and an Adjunct Professor at the University of Michigan School of Public Health. He is board-certified in the field of internal medicine and specializes in epidemiology and pharmacology, although not board-certified in cardiology or pulmonology. In his expert report, Dr. Levine stated: "I am of the opinion to a reasonable degree of medical and scientific certainty that there is statistically significant scientific support for an association between diet drug exposure and the development of PPH only in patients when symptoms begin within one year after the discontinuation of diet drug use."

In response, Ms. Cheek offers the opinions of Dr. Rich and Dr. Rubin. In his declaration dated July 26, 2012, Dr. Rich opines that the IPPHS was not created to study the latency of Diet-Drug-induced PPH. Dr. Rich was a principal investigator for and a co-author of the IPPHS study. He posits that Wyeth's position "is a distortion of the results" of the IPPHS. In addition, Dr. Rich references several subsequent case studies which support his opinion that Diet Drugs can cause PPH more than ten years after ingestion. While he acknowledges that the risk of developing PPH declines with the passage of time, it is his medical opinion that there is no known cut-off applicable in all cases and that the duration and quantity of a person's Diet Drug use can extend the latency period. Finally, contrary to the opinion of Dr. Levine, Dr. Rich opines that Ms. Cheek's Diet Drug ingestion caused her PPH. In his deposition, Dr. Rubin similarly explained that his opinion was based on not only on the IPPHS, but on medical literature, clinical studies, and a differential diagnosis in reaching his conclusion.

A transferee court presiding over a multi-district litigation may exercise authority over all pretrial proceedings. See In re Patenaude, 210 F.3d 135, 144 (3d Cir.2000). A motion in limine to exclude an expert opinion under Daubert is certainly within the jurisdiction of this court. See, e.g., In re Diet Drugs Prods. Liab. Litig., No. 12-1203, 2001 WL 454586 (E.D.Pa. Feb. 1, 2001); In re Diet Drugs Prods. Liab. Litig., No. 12-1203, 2000 WL 962545 (E.D.Pa. June 28, 2000).

The court has a "gatekeeping" function in connection with expert testimony. See Gen. Electric Co., et al. v. Joiner, 522 U.S. 136, 142, 118 S.Ct. 512, 139 L.Ed.2d 508 (1997); see also Daubert, 509 U.S. at 589, 113 S.Ct. 2786. Rule 702 of the Federal Rules of Evidence provides:

As our Court of Appeals has repeatedly noted, Rule 702 embodies three requirements: qualification, reliability, and fit. Pineda v. Ford Motor Co., 520 F.3d 237, 244 (3d Cir.2008). Wyeth does not question the credentials of Ms. Cheek's experts or the fit of their opinions. Instead, it challenges Ms. Cheek's experts only as to reliability.

To determine reliability, we focus not on the expert's conclusion but on whether that conclusion is "based on the methods and procedures of science rather than on subjective belief or unsupported speculation." Schneider v. Fried, 320 F.3d 396, 404 (3d Cir.2003) (internal quotation marks omitted). Our analysis may include such factors as:

Pineda, 520 F.3d at 247-48.

"[T]he test of reliability is flexible" and this court possesses a broad latitude in determining reliability. Kumho Tire Co. v. Carmichael, 526 U.S. 137, 141-42, 119 S.Ct. 1167, 143 L.Ed.2d 238 (1999). To be reliable under Daubert, a party need not prove that his or her expert's opinion is "correct." In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 744 (3d Cir.1994). Instead:

United States v. Mitchell, 365 F.3d 215, 244 (3d Cir.2004) (quoting Ruiz-Troche v. Pepsi Cola of Puerto Rico Bottling Co., 161 F.3d 77, 85 (1st Cir.1998)).

Daubert does not require that an expert opinion regarding causation be based on statistical evidence in order to be reliable. Matrixx Initiatives, Inc. v. Siracusano, ___ U.S. ___, 131 S.Ct. 1309, 1319, 179 L.Ed.2d 398 (2011). In fact, many courts have recognized that medical professionals often base their opinions on data other than statistical evidence from controlled clinical trials or epidemiological studies. Id. at 1320. Our Court of Appeals has stated, "we do not believe that a medical expert must always cite published studies on general causation in order to reliably conclude that a particular object caused a particular illness." Heller, 167 F.3d at 155. It explained:

Id.

Medical experts are entitled to rely on a differential diagnosis. A differential diagnosis is a process by which a physician rules out alternative causes through review of a patient's medical histories and records, physical examination of the patient, laboratory testing, study of relevant medical literature, and other techniques. See Heller, 167 F.3d at 156; Paoli, 35 F.3d at 758-59. Such technique is generally accepted in the medical community. Heller, 167 F.3d at 156. Our Court of Appeals agrees that opinions based on differential diagnoses should not be excluded under Daubert unless the physician failed to utilize the diagnostic techniques normally relied upon in the medical community or failed to explain why another likely cause did not bring about the plaintiff's illness. Paoli, 35 F.3d at 760.

Ms. Cheek's experts properly rely on the conclusion of the IPPHS that Diet Drugs can cause PPH. Wyeth, we reiterate, does not dispute that point. As discussed above, that study established that the risk of developing PPH increased 630% after ingestion of Diet Drugs. The study need not address the exact circumstances under which Ms. Cheek developed PPH in order to support Dr. Rich and Dr. Rubin's opinions.10 Contrary to Wyeth's assertions, the IPPHS does not establish that an individual cannot develop PPH more than five years after ingestion ends. That study was simply not designed to examine latency. Instead, it included only seven past users and none had ceased use of the drugs for more than five years.

In addition to the IPPHS, plaintiff's experts rely on differential diagnoses made after review of Ms. Cheek's medical records. A differential diagnosis is a reliable method of demonstrating causation under Daubert because such a method "consists of a testable hypothesis," has been peer reviewed, and is generally accepted. See Heller, 167 F.3d at 156; Paoli, 35 F.3d at 758-59. In their diagnoses, Dr. Rich and Dr. Rubin have excluded all other known causes of PPH. They need not exclude unknown or idiopathic causes of PPH in order for their differential diagnoses to be a reliable basis for their opinions. See In re Asbestos, 2010 WL 4676563, at *4. According to Wyeth, an idiopathic origin accounts for only one to two cases of PPH per million people annually. To bolster their differential diagnoses, Dr. Rich and Dr. Rubin also point out that development of PPH after a period of latency is biologically plausible. There are many other causes of the disease that have significant latency periods. For example, PPH caused by connective tissue disease can lay dormant for a period of up to twenty-seven years. Similarly, the latency period for the development of PPH due to a genetic mutation or birth defect is often decades.

Dr. Rich and Dr. Rubin also rely on a large number of case reports which have been published in peer-reviewed journals. In one such study published in 2006 in the American Journal of Respiratory and Critical Care Medicine, "Pulmonary Arterial Hypertension in France: Results from a National Registry," 43% of patients who had ingested appetite-suppressant drugs such as the Diet Drugs experienced a delay of more than five years between their last intake of the drugs and the onset of symptoms of PPH. Similarly, a case study published in the European Respiratory Journal, "Pulmonary Arterial Hypertension Associated with Fenfluramine Exposure: Report of 109 Cases" found the median time between Diet Drug exposure and onset of PPH symptoms to be 4.5 years and reported latency periods of greater than ten years. These case studies can help establish that an expert's opinion is reliable. See Wolfe v. McNeil-PPC, Inc., et al., No. 07-348, 2011 WL 1673805, at *5 (E.D.Pa. May 4, 2011). Case studies are particularly relevant when dealing with rare or newly-discovered diseases, which often have not been the subject of an epidemiological study. See Reference Manual on Scientific Evidence at 474-75. PPH, fortunately, is a rare disease, and it has not been the subject of any epidemiological study on latency.

We further note that Dr. Rubin and Dr. Rich have impressive credentials. Dr. Rich is a board-certified internist and cardiologist who currently serves as a Clinical Professor of Medicine at the University of Chicago. He has studied PPH for over 30 years and has authored most of the leading publications regarding this fatal disease. In addition, Dr. Rich served as a principal investigator for the IPPHS study and co-authored the article describing the results of that study in the New England Journal of Medicine. Dr. Rubin is presently Emeritus Professor of Medicine at the University of California in San Diego. He is board-certified in pulmonary disease and critical care medicine. Like Dr. Rich, he has devoted most of his career to the study of PPH and has authored hundreds of peer-reviewed articles and book chapters pertaining to the disease. Dr. Rubin also worked on the IPPHS study. Together with Dr. Rich, he wrote a textbook on PPH that is considered the authoritative manuscript on the disease and is cited in Section 1.46 of the Settlement Agreement — a document which Wyeth had a hand in drafting. See L.J. Rubin & S. Rich, Primary Pulmonary Hypertension (1997).

Finally, the methods of Ms. Cheek's experts have general acceptance in the medical community. As recently as 2009, the Journal of the American College of Cardiology published the Dana Point Classification for PPH. That classification system identified Diet Drugs as a "definite" risk factor for PPH and included Diet-Drug-induced PPH as a diagnosis for any patient with PPH who did not have a family history of PPH or other known risk factor, without regard to latency. The differential diagnoses conducted by Dr. Rich and Dr. Rubin are in line with this classification system and are the same method used by physicians who deal with PPH, including Ms. Cheek's own treating physicians.

When viewed in totality, the IPPHS coupled with the differential diagnoses performed by these experts, the case reports on which they rely, their credentials, the peer review and publication of their methods, and the general acceptance of their methodology in the medical community demonstrate that the opinions of Dr. Rich and Dr. Rubin are reliable under Daubert. While Wyeth points to various statements of Dr. Rich and Dr. Rubin which one might argue show some inconsistency on the issue of latency, these statements simply go to their credibility and do not undermine the reliability of their methodology in determining causation. See In re Unisys Savings Plan Litig., 173 F.3d 145, 166 (3d Cir.1999). The testimony of Dr. Rich and Dr. Rubin will be of assistance to the trier of fact. See Fed.R.Evid. 702.

The court, of course, expresses no view on whether Ms. Cheek's ingestion of Diet Drugs caused her PPH when her symptoms did not appear until eleven years after she stopped taking those drugs. That is a matter for the jury to decide after hearing from the experts on both sides and considering all other relevant evidence.

IV.

Accordingly, the motion of Wyeth to enjoin Ms. Farmer and Ms. Cheek under PTO Nos. 1415 and 2383 from proceeding with their respective lawsuits will be denied. The motion of Wyeth to exclude the testimony of Dr. Rubin and Dr. Rich in Cheek under Rule 702 of the Federal Rules of Evidence will also be denied.11

PRETRIAL ORDER NO. 8933

AND NOW, this 30th day of August, 2012, for the reasons set forth in the accompanying Memorandum, it is hereby ORDERED that:

(1) the motion of defendant Wyeth, LLC to enjoin plaintiff Valarie Farmer under PTO Nos. 1415 and 2383 from prosecuting her action in Farmer v. Wyeth Pharmaceuticals, Inc., et al., July Term 2011, No. 01174, in the Court of Common Pleas of Philadelphia County, Pennsylvania is DENIED;

(2) the motion of defendant Wyeth, LLC to enjoin plaintiff Jamie D. Cheek under PTO Nos. 1415 and 2383 from prosecuting her action in Cheek v. Wyeth, et al., No. 11-54, in the United States District Court for the District of South Carolina is DENIED; and

(3) the motion of defendant Wyeth, LLC to exclude the expert testimony on the issue of causation of primary pulmonary hypertension proffered by plaintiff Jamie D. Cheek in Cheek v. Wyeth, et al., No, 11-54, in the United States District Court for the District of South Carolina is DENIED.