In re Rezulin Products Liability Litigation

• Decision Date: 14 March 2005
• Docket Number: No. MDL No. 1348, 00 Civ.2843(LAK).,MDL No. 1348, 00 Civ.2843(LAK).
• Citation: 369 F.Supp.2d 398
• Parties: In re: REZULIN PRODUCTS LIABILITY LITIGATION This document relates to: All Cases.
• Court: U.S. District Court — Southern District of New York

369 F.Supp.2d 398

In re: REZULIN PRODUCTS LIABILITY LITIGATION

This document relates to: All Cases.

No. MDL No. 1348, 00 Civ.2843(LAK).

United States District Court, S.D. New York.

March 14, 2005.

Mark P. Robinson, Jr., Kevin F. Calcagnie, Theodore B. Wacker, Edoardo Rigoberto Caldevilla Salvatore, Robinson, Calcagnie & Robinson, Irving H. Greines, Cynthia E. Tobisman, Greines, Martin, Stein & Richland, LLP, Charles A. Mathis, Jr., Christopher V. Tisi, David B. Vermont, Herman, Mathis, Casey, Kitchens & Gerel, LLP, Ramon Rossi Lopez, Steven J. Skikos, John M. Restaino, Jr., Lopez, Hodes, Restaino, Milman & Skikos, Donald C. Arbitblit, Lieff Cabraser Heimann & Bernstein, LLP, Arthur Sherman, Sherman Salkow Petoyan & Weber, Arnold Levin, Levin, Fishbein, Sedran & Berman, Melvyn I. Weiss, Regina La Polla, Milberg Weiss Bershad Hynes & Lerach LLP, for Plaintiffs.

David Klingsberg, Bert L. Slonim, Jan E. Dodd, Pamela J. Yates, Glenn J. Pogust, Jay P. Mayesh, Maris Veidemanis, Steven J. Glickstein, Kaye Scholer LLP, for Pfizer Defendants.

OPINION

KAPLAN, District Judge.

                Table of Contents
                   I. The Legal Backdrop and the Positions of the Parties ....................401
                  II. Proceedings on the Motion ..............................................402
                

                 III. Scientific Background ..................................................402
                      A. Relevant Physiology .................................................402
                         1. Cells ............................................................402
                         2. The Liver ........................................................403
                         3. Mechanisms of Cell Death .........................................404
                      B. Drugs, Toxicity to the Liver, and Rezulin ...........................405
                      C. Patient Population ..................................................406
                      D. Evidence of Causation in Medicine ...................................406
                  IV. The Proposed Testimony .................................................407
                      A. The Experts and Their Opinions ......................................407
                         1. Dr. Smith ........................................................407
                         2. Dr. Reed .........................................................408
                         3. Dr. Julie ........................................................408
                         4. Dr. Day ..........................................................409
                         5. Dr. Bonkovsky ....................................................410
                         6. Summary ..........................................................410
                      B. The Science upon Which the Experts Rely .............................410
                         1. Early Links in the Proposed Causal Chain: The Claim that Rezulin
                             Causes Apoptosis Through Effects on the Mitochondria or the
                             BSEP ............................................................412
                            a. Studies Connecting Rezulin to Apoptosis .......................412
                            b. Studies Connecting Rezulin to Mitochondrial Damage ............413
                            c. Studies Connecting Rezulin to an Effect on the BSEP ...........416
                         2. The Last Link in the Chain: The Claim that Apoptosis from Rezulin
                             Causes Silent Injury ............................................417
                      C. Arguments that Rezulin Can Cause Silent Liver Injury Through
                          Mechanisms Other than Apoptosis ....................................418
                      D. Patients Whose Liver Enzymes Were Not Monitored .....................419
                   V. Law Governing the Admission of Expert Testimony ........................419
                      A. Daubert and Its Progeny .............................................419
                      B. The Daubert Standards Apply to Opinions About General and Specific
                          Causation ..........................................................422
                  VI. Daubert Analysis of the Proposed Testimony .............................423
                      A. Testing and Error Rate, Peer-Review, Publication, Widespread
                          Acceptance .........................................................423
                      B. Independence from Litigation ........................................424
                      C. Consideration of Contrary Evidence ..................................425
                      D. "Fit" and the "Analytical Gap" ......................................426
                         1. The Experts Have No Evidence for the Crucial Link in Their
                             Causal Chain ....................................................426
                         2. The Experts Have Failed To Link the Studies on Mitochondria and
                             the BSEP into Their Causal Chain ................................427
                         3. The Research on Apoptosis in Cell Cultures Does Not "Fit" the
                             Opinion at Issue ................................................428
                            a. Types of Cells ................................................429
                            b. Dose ..........................................................430
                 VII. The Plaintiffs' Argument Concerning Differential Diagnosis..............435
                VIII. Conclusion .............................................................437
                

In 1996, Warner-Lambert Company ("Warner-Lambert"), now owned by Pfizer Inc., announced the development of Rezulin, the trade name of a drug used to treat Type 2 diabetes, a disease affecting approximately 16 million Americans.¹ The United States Food and Drug Administration approved the drug in 1997, and it was administered to 1.92 million people. Following reports that some patients taking Rezulin experienced liver failure resulting in transplant or death, the drug was withdrawn from the market in March 2000.² This led to the commencement of thousands of lawsuits for alleged personal injuries or apprehension of personal injuries in consequence of the ingestion of the drug.³ The federal actions have been consolidated in this Court for pretrial proceedings.⁴

Extensive liability discovery against defendants has been completed. Defendants Pfizer Inc., Warner-Lambert, and Parke-Davis⁵ (collectively, "Pfizer") move, pursuant to Federal Rule of Evidence 702 and Daubert v. Merrell Dow Pharmaceuticals, Inc.,⁶ to exclude "proposed expert testimony that Rezulin can cause a liver injury, or exacerbate a pre-existing liver condition, in the absence of marked elevation of liver enzymes while the patient was taking the medication."⁷ The Plaintiffs' Executive Committee, which is responsible for coordinating the activities of plaintiffs during pretrial proceedings,⁸ retained the experts and is defending this motion.

I. The Legal Backdrop and the Positions of the Parties

Causation in toxic tort cases has two components, general and specific, and the plaintiff must establish both in order to prevail.⁹ "General causation is whether a substance is capable of causing a particular injury or condition in the general population, while specific causation is whether a substance caused a particular individual's injury."¹⁰ As explained in the Federal Judicial Center's Reference Manual on Scientific Evidence:

"General causation is established by demonstrating, often through a review of scientific and medical literature, that exposure to a substance can cause a particular disease (e.g., that smoking cigarettes can cause lung cancer). Specific, or individual, causation, however, is established by demonstrating that a given exposure is the cause of an individual's disease (e.g., that a specific plaintiff's lung cancer was caused by his smoking)."¹¹

Plaintiffs offer the testimony of a number of expert witnesses to prove general causation. As relevant here, they would opine that Rezulin is capable of causing liver injury "silently," that is without markedly elevating liver enzymes, and that such injury is a consequence of a form of liver cell death, known as apoptosis, that the experts assert can be induced by Rezulin.

Pfizer contends that plaintiffs' experts' testimony is insufficiently reliable to satisfy Daubert and Rule 702. It claims that their theories are unsupported by testing and that the potential rate of error therefore cannot be determined. They maintain also that they have not been subjected to peer review and publication and that they do not have widespread acceptance in the scientific community. Furthermore, Pfizer argues that the opinions of plaintiffs' experts are not the product of independent research but were developed solely for this litigation and, finally, that the experts overlook or ignore contrary evidence. The plaintiffs resist these assertions.

II. Proceedings on the Motion

Each side has submitted thousands of pages of expert reports, scientific and medical articles, depositions and other documents in connection with the motion. The Court heard oral argument and then conducted a two-day evidentiary hearing at which three of the plaintiffs' experts and one defense expert testified.¹² The Court then had the benefit of extensive proposed findings of fact from each side and point-by-point responses to each set of proposed findings.

III. Scientific Background

A. Relevant Physiology

1. Cells

The human body consists of cells. The cell has three basic components: the nucleus, the cytoplasm, and the plasma membrane.¹³ The nucleus contains the cell's genetic information.¹⁴ The plasma membrane surrounds the cell and "acts as a selective barrier that enables the cell to concentrate nutrients gathered from its environment and retain the products it synthesizes for its own use, while excreting waste products."¹⁵ The cytoplasm is defined as everything besides the nucleus and cell membrane,¹⁶ and it contains among other things membrane-bound structures known as organelles, of which one type is the mitochondrion (in the plural, mitochondria).¹⁷ The mitochondria sometimes are referred to as the "powerhouse" of the cell¹⁸ because chemical reactions occurring therein produce adenosine triphosphate ("ATP"), the cell's energy currency.¹⁹

2. The Liver

The liver, located in the right...