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In re Rezulin Products Liability Litigation

UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF NEW YORK


July 26, 2006

IN RE: REZULIN PRODUCTS LIABILITY LITIGATION,

The opinion of the court was delivered by: Lewis A. Kaplan, District Judge

(MDL No. 1348)

MASTER FILE

This Document Relates to: 00 Civ. 9168, 00 Civ. 3098, 01 Civ. 6066, 01 Civ. 8171, 01 Civ. 11878, 02 Civ. 1719, 02 Civ. 8395, 03 Civ. 2861, 03 Civ. 2863, 03 Civ. 2864, 03 Civ. 2865, 03 Civ. 2867, 04 Civ. 4916, 04 Civ. 7807, 04 Civ. 8538, 04 Civ. 8539, 04 Civ. 8940, 04 Civ. 8941, 04 Civ. 8942.

MEMORANDUM OPINION

Defendants Pfizer, Inc., Warner-Lambert Company, and Parke-Davis (collectively, "Pfizer") move for an order excluding the proposed opinion testimony of experts in reports submitted by 28 plaintiffs*fn1 and granting summary judgment dismissing those plaintiffs' claims. Pfizer argues that the expert reports are not admissible.

I. Background and Undisputed Facts

A. Procedural History

These actions arise from the use of the prescription diabetes medication Rezulin, formerly manufactured by defendants Warner-Lambert Co. and its Parke-Davis division. The drug was approved by the Food and Drug Administration in 1997 but was withdrawn from the market in 2000 after reports that some patients taking it experienced liver failure*fn2 Thousands of lawsuits for alleged personal injuries ensued. The federal actions, including those at issue here, were consolidated before this Court for pre-trial proceedings by the Judicial Panel on Multidistrict Litigation.*fn3

After extensive discovery, Pfizer moved pursuant to Federal Rule of Evidence 702 and Daubert v. Merrell Dow Pharmaceuticals, Inc.,*fn4 to exclude proposed expert testimony proffered by the Plaintiffs' Steering Committee ("PSC") to the effect that Rezulin can cause so-called silent injury to the liver -- that is, that Rezulin can cause liver injury in the absence of marked elevation of specific liver enzymes while the patient was taking the drug.*fn5 In the Silent Injury opinion, familiarity with which is assumed, the Court analyzed the proposed expert testimony, which was intended to provide a basis for finding general causation,*fn6 and concluded that plaintiffs had not established the reliability of the silent injury theory:

"The theory never has been tested or peer-reviewed, has not been published except by [one proposed expert] after the commencement of this litigation and only then in speculative terms and suspicious circumstances, and has no acceptance outside this litigation. The plaintiffs' experts have ignored information that appears to call crucial aspects of their theory into question. The theory rests on a series of empirically unbridgeable analytical gaps. Most importantly, the experts have not established a sound basis for concluding that Rezulin-induced apoptosis can occur at clinically significant levels and remain silent. Similarly, the experts have failed to show that any mitochondrial changes attributable to Rezulin themselves can cause apoptosis or that any cholestatic injury due to Rezulin's effect on the BSEP would be silent. ". . . The plaintiffs attempt to deal with all of these problems by arguing that the testimony in question could factor into the diagnosis of an individual patient. The plaintiffs' position is that a physician, faced with a patient who took Rezulin and had symptoms of liver disease but no elevated enzymes, could use the opinions of [plaintiffs' experts] and the research they cite to conclude that the patient's injury was caused by Rezulin. The flaw, however, is that a physician must have some reliable basis for believing that a particular substance is capable of causing the injury in question in relevant circumstances before concluding that the substance caused that injury in a particular case. Here, there is no such basis."*fn7

The Court accordingly granted Pfizer's motion to exclude the proposed expert testimony on Rezulin's ability to cause silent liver injury.

The Court later issued a so-called Lone Pine order, which required each plaintiff to consider whether good grounds existed to continue prosecuting his or her claim in light of the Silent Injury and other decisions.*fn8 If a plaintiff concluded that good cause to continue existed, he or she was required to provide an expert report reflecting, among other things, "[w]hether the plaintiff's medical records report that the plaintiff had [specific liver enzyme] levels more than two times the upper limit of normal range while the plaintiff was on Rezulin therapy or within 30 days after the last use of Rezulin" and an "expert's opinion on causation of each claimed injury."*fn9

B. Plaintiffs' Lone Pine Submissions

All 28 plaintiffs whose complaints are the subject of this motion subsequently submitted expert opinions.*fn10 Although each opinion states that the given plaintiff sustained a liver injury attributable to Rezulin, no plaintiff has provided evidence that his or her liver enzyme levels were more than two times the upper limit of normal range while he or she was on Rezulin or within 30 days of ceasing the therapy.*fn11 Most of the plaintiffs rely on opinions from the same handful of experts,*fn12 some of whom were already considered on the previous motion. Their opinions are summarized below.

1. Dr. Glenn Wilson, Ph.D.*fn13

Dr. Wilson, a biomedical scientist*fn14 and professor at the University of South Alabama College of Medicine, opines that Rezulin can injure the mitochondria of cells with which it comes into contact.*fn15 He states that Rezulin reduces blood sugar levels by damaging mitochondria, which then results in "organ toxicity, dysfunction, and failure through apoptosis, necrosis, and impaired ATP (energy) production within the organ."*fn16

In reaching this conclusion, Dr. Wilson relies on a variety of data, including drug class effect information, in vitro cell testing, in vivo animal testing, human clinical trials, and case reports.*fn17 He relies also on an in vitro study he performed on normal human hepatocytes exposed to Rezulin at concentrations of 5 and 50 uM, both with and without the presence of fetal bovine albumin.*fn18 This study found that Rezulin causes cell death in normal human hepatocytes in vitro, even in the presence of albumin, "at [Rezulin] concentrations comparable to those [allegedly] found in vivo in the patients taking Rezulin."*fn19 The mechanism for this toxicity, Dr. Wilson states, is damage to the mitochondria, manifested "as a significant reduction in cellular ATP [] at lower doses and cell death at higher doses."*fn20

This study -- which has not been published, subjected to peer review, or independently validated or duplicated -- did not measure liver enzyme levels or the effect of Rezulin in living humans or animals.*fn21 It was prepared for this litigation and was funded at least in part by the Littlepage law firm.*fn22 Nor does the study address the potential concentration discrepancies discussed in the Silent Injury decision -- whether the concentrations of troglitazone used in this and other studies match the concentrations of the drug to which the outside of the cells in patients actually were exposed -- or the question of how troglitazone is distributed in the liver.*fn23

Finally, Dr. Wilson does not state that Rezulin can cause silent injury to human hepatocytes, by apoptosis or otherwise.*fn24 The Littlepage plaintiffs' lawyers incorrectly suggest that he concludes that "[m]ost importantly, because Rezulin's mechanism of injury is directed at the cell's mitochondria and it causes apoptosis, most of this damage occurs without any easy diagnostic means of detection."*fn25 But Dr. Wilson's report makes no such statement and provides no basis for drawing such a conclusion.*fn26 Rather, he confines his conclusions to the medication's toxicity and mechanism of harming the cell and does not opine on what happens after the cell is harmed.*fn27

2. Dr. Herbert A. Rubin, M.D.*fn28

Dr. Rubin, a board-certified internist specializing in gastroenterology,*fn29 states that Rezulin is a known hepatotoxin causing "a multitude of hepatocellular injuries including, but not limited to, cytolytic hepatitis, steatosis, microvesicular steatosis, apoptosis, and cholestatis."*fn30 He bases his conclusions on internal Pfizer documents, the testimony of Pfizer employees and experts, other experts' testimony, his own experience as a clinician, and the published medical literature.*fn31

In analyzing the cause of the Littlepage plaintiffs' alleged symptoms, he states that the "damage Rezulin causes to liver cells leads to liver cell death via apoptosis. Cell death by apoptosis does not result in the release of [liver enzymes] into the blood stream unless there has been massive liver cell death."*fn32 He does not, however, provide any support for this conclusion about silent liver injury.*fn33

3. Dr. Martyn Smith, Ph.D*fn34

Dr. Smith, a toxicologist, testified at length at the Silent Injury hearing as to his theory that Rezulin can cause apoptosis by either triggering "a cascade of chemical events in which the mitochondria cease functioning normally and release a protein into the cytoplasm that triggers apoptosis" or interfering with the functioning of the bile salt export pump, which leads "to the buildup of toxic bile salts in the cells [which] triggers apoptosis."*fn35 The Court analyzed his opinion and conclusions in the Silent Injury decision, eventually excluding the opinion as evidence that Rezulin can cause liver injury in the absence of marked elevations of liver enzymes while a patient was taking the medication.*fn36

Dr. Smith seeks to avoid that holding via a one-paragraph supplemental declaration that informs the Court that an article he authored was accepted for publication in a toxicology journal in June 2003.*fn37 That information, however, was considered in the Court's analysis in Silent Injury.*fn38 The supplemental declaration thus contains no new information or material relating to Dr. Smith's theories regarding apoptosis.

4. Dr. Neil Julie, M.D.*fn39

Dr. Julie, a medical doctor certified in internal medicine and gastroenterology, is licensed to practice medicine in Maryland.*fn40 He was a witness at the Silent Injury hearing as a potential general causation expert and, as with all the silent injury general causation experts considered at that hearing, his opinion was held inadmissible under Rule 702.*fn41

Dr. Julie's report states that he has "reviewed an extensive amount of the published and unpublished literature regarding Rezulin [] and Rezulin-induced liver disease" and personally has treated "five patients who experienced Rezulin hepatotoxicity."*fn42 He states that it is generally accepted that Rezulin "is a hepatotoxin capable of causing, and has caused in patients exposed to the drug, a spectrum of injuries which can include jaundice, acute liver failure, severe liver injury, end-state liver disease and death"*fn43 and that it can cause apoptosis.*fn44 Dr. Julie does not offer a general causation opinion relating to silent injury.*fn45 Instead, after setting out background on the drug, he goes on to discuss plaintiff Gable's medical history relating to her alleged liver problems and to conclude, supposedly by ruling out "all other likely or reasonable causes," that Gable's cirrhosis was caused by Rezulin.*fn46

5. Dr. Charles L. Mendenhall, M.D., Ph.D.*fn47

Dr. Mendenhall, a medical doctor with two years of specialized training in hepatology, is a Professor Emeritus at the University of Cincinnati College of Medicine.*fn48 He states that the "diagnosis and treatment of injuries to the liver and liver disease have composed the major portion of my professional practice for the past 37 years."*fn49

Dr. Mendenhall states, without providing supporting data, that Rezulin, used in the management of diabetes, was withdrawn from the market due to the "very high incidence of abnormal biochemical tests consistent with liver injury."*fn50 After reviewing the medical records relating to Rezulin use and liver dysfunction of both Chesley plaintiffs, he concludes that "[h]aving reviewed this material in light of my training and experience, utilizing methodology commonly relied upon by hepatologists, it is my opinion, to a reasonable degree of medical certainty, that Rezulin caused" each Chesley plaintiff's liver disease or injury.*fn51 Dr. Mendenhall does not opine as to whether Rezulin can cause silent liver injury or that it did so in the Chesley plaintiffs in particular.*fn52

6. Dr. David A. Rigle, M.D.*fn53

Dr. Rigle is a medical doctor certified in forensic medicine. His report details the Zavesky plaintiff's medical history relating to liver and Rezulin issues, noting that the results of liver enzyme studies were either unavailable or normal.*fn54 After referring to the plaintiff's death from cirrhosis, Dr. Rigle opines that Rezulin "was a significant contributing causative factor in her development of liver failure and her eventual demise."*fn55 He bases this conclusion on the failure of her clinicians to arrive at an alternative diagnosis and on the consistency of her symptoms with those seen in Rezulin toxicity.*fn56 He states that "Rezulin is found to place in motion the pathologic changes that lead to cirrhosis and death early on during the course of treatment and there may be only a mild increase in liver enzymes observed,"*fn57 but provides no support for this conclusion about silent liver injury.

II. Legal Standard

A. Summary Judgment

Summary judgment is appropriate if there is no genuine issue of material fact and the moving party is entitled to judgment as a matter of law.*fn58 The moving party has the burden of demonstrating the absence of a genuine issue of material fact,*fn59 and the Court must view the facts in the light most favorable to the nonmoving party.*fn60 Where the burden of proof at trial would fall on the nonmoving party, it ordinarily is sufficient for the movant to point to a lack of evidence to go to the trier of fact on an essential element of the non-movant's claim.*fn61 In that event, the nonmoving party must come forward with admissible evidence*fn62 sufficient to raise a genuine issue of fact for trial.*fn63

B. Causation

In a product liability case such as these, a plaintiff must prove both general and specific causation as part of his or her prima facie case.*fn64 General causation "bears on whether the type of injury at issue can be caused or exacerbated by the defendant's product," while specific causation addresses "whether, in the particular instance, the injury actually was caused or exacerbated by the defendant's product."*fn65 Further, proof of general causation is a necessary predicate for that of specific causation -- if there is no evidence that a product is capable of causing the kind of harm claimed, then there is no basis to accept evidence that the product in fact did so in a specific case.*fn66

The plaintiffs here do not contest that they must prove both kinds of causation through expert, not lay, testimony.*fn67 This is a requirement in every state in which these plaintiffs have brought their claims.*fn68

III. The Proffered Expert Testimony

As the Court set out in its Silent Injury opinion,*fn69 the admission of scientific or other expert testimony is governed by Federal Rule of Evidence 702:

"If scientific, technical, or other specialized knowledge will assist the trier of fact to understand the evidence or to determine a fact in issue, a witness qualified as an expert by knowledge, skill, experience, training, or education, may testify thereto in the form of an opinion or otherwise, if (1) the testimony is based upon sufficient facts or data, (2) the testimony is the product of reliable principles and methods, and (3) the witness has applied the principles and methods reliably to the facts of the case."

The district court acts as a gatekeeper to ensure that "scientific testimony or evidence admitted is not only relevant, but reliable."*fn70 In other words, the court determines whether the proposed expert will testify as to scientific knowledge that "will assist the trier of fact to understand or determine a fact in issue. This entails a preliminary assessment of whether the reasoning or methodology underlying the testimony is scientifically valid and of whether that reasoning or methodology properly can be applied to the facts in issue."*fn71

In conducting this "flexible" inquiry, a court may consider various factors, such as whether the expert's theory "can be (and has been) tested," whether it "has been subjected to peer review and publication," its "known or potential rate of error," and whether it has "widespread acceptance."*fn72

Further, to meet Rule 702's requirements, the proffered testimony must "fit" the factual dispute at issue -- in other words, it must be "sufficiently tied to the facts of the case that it will aid the jury in resolving a factual dispute."*fn73 As the Court stated in the Silent Injury decision, "[a] district court therefore is not required to admit opinion evidence that is connected to existing data only by the ipse dixit of the expert. A court may conclude that there is simply too great an analytical gap between the data and the opinion proffered."*fn74

Against this background, the Court turns to the admissibility of the proffered testimony of these six experts.

A. Dr. Wilson

The overwhelming majority of Dr. Wilson's report discusses the toxicity of Rezulin and its potentially harmful effects on liver tissue. But the present question is not whether the report is admissible evidence that Rezulin is a hepatotoxin. Most pharmaceuticals are hepatotoxic in some circumstances.*fn75 Instead, the issue is whether Dr. Wilson's report is admissible evidence that Rezulin is capable of causing and in fact caused the Littlepage plaintiffs' particular liver injuries.

Dr. Wilson's report details one new in vitro study on Rezulin's toxicity, which examined normal human hepatocytes exposed to Rezulin at concentrations of 5 and 50 uM, both with and without the presence of fetal bovine albumin.*fn76 This study thus may address some of the potential weaknesses in prior studies identified by the Court in the Silent Injury decision, such as the use of abnormal, non-human, or other tissue cells and the absence of albumin.*fn77 It did not, however, address the potential problems previously identified with prior studies' concentration discrepancies and liver distribution issues.*fn78 Further, the study has not been published or independently validated*fn79 and is a product of this litigation.*fn80

Ultimately, however, the Court need not decide whether this new study is reliable, because it does not relate to the issue here -- whether there is a reliable basis for Dr. Wilson's opinion that Rezulin is capable of causing and in fact caused the Littlepage plaintiffs' particular liver injuries. Dr. Wilson did not measure liver enzyme levels or the effect of Rezulin in living humans or animals in this new study or, indeed, at any time. Contrary to the Littlepage plaintiffs' assertions, his opinion does not state that Rezulin can cause silent injury to human hepatocytes by apoptosis or otherwise.*fn81 The report therefore does not raise a genuine issue of material fact as to general or specific causation of silent liver injury.

B. Dr. Rubin

Unlike Dr. Wilson's report, Dr. Rubin's report does attempt to draw a conclusion as to silent injury causation. The report asserts that "[c]ell death by apoptosis does not result in the release of [liver enzymes] into the blood stream unless there has been massive liver cell death."*fn82

However, it provides no support for this conclusion.*fn83 Without that support, the opinion is identical to those rejected as inadmissible in the Silent Injury analysis. It accordingly is not admissible evidence of general or specific causation.

C. Dr. Smith

Dr. Smith's supplemental declaration informs the Court that an article that he authored was accepted for publication in a toxicology journal in June 2003.*fn84 This article and its publication were considered in the Court's analysis in Silent Injury.*fn85 The supplemental declaration thus contains no new information or material relating to Dr. Smith's theories regarding apoptosis and is not admissible evidence as to general or specific causation. There is no reason to alter the prior conclusion as to the admissibility of his opinion.

D. Dr. Julie

Dr. Julie's specific causation opinion for plaintiff Gable also is inadmissible. In the first instance, evidence of specific causation is irrelevant without evidence of general causation.*fn86 Dr. Julie nowhere offers any opinion as to general causation of silent liver injury.*fn87 Moreover, his differential diagnosis approach was rejected in the Silent Injury decision as a substitute for general causation.*fn88 That conclusion has been affirmed by the Second Circuit.*fn89 Accordingly, Dr. Julie's report is inadmissible.

E. Dr. Mendenhall

Nor does Dr. Mendenhall's report state any opinion as to general causation.*fn90 His specific causation analysis thus is without foundation.*fn91 In addition, like Dr. Wilson, he offers no opinion as to whether Rezulin can cause liver injury without marked elevation of liver enzymes.*fn92 His opinion therefore is inadmissible.

F. Dr. Rigle

This report suffers from the same deficiencies as do those of Drs. Rubin and Mendenhall. Although Dr. Rigle states that "only a mild increase in liver enzymes [may be] observed" when Rezulin causes liver injury,*fn93 he provides no support for this conclusion. It therefore is inadmissible under the Silent Injury decision, as is his differential diagnosis of the specific cause of the Zavesky plaintiff's liver injury.*fn94 The report therefore is inadmissible as evidence of causation.

G. Application to Plaintiffs

1. The Littlepage Plaintiffs

To reiterate, the 25 Littlepage plaintiffs have provided no evidence that any of their liver enzyme levels was more than two times the upper limit of normal range while they were on Rezulin or within 30 days of ceasing the therapy.*fn95 Since they have no evidence that their liver enzyme levels were elevated more than two times the upper limit of normal range while they were taking the medication, they necessarily are relying on the theory that Rezulin can cause liver injury without such enzyme level elevation.

All of the Littlepage plaintiffs rely on the opinions of Drs. Wilson and Rubin and the supplement to Dr. Smith's report. Plaintiff Gable relies also on the report of Dr. Julie. As these expert reports all are inadmissible as evidence of general or specific causation, the Littlepage plaintiffs have failed to come forward with admissible evidence showing a genuine issue of material fact as to causation.

2. The Chesley Plaintiffs

Both Chesley plaintiffs admit that their liver enzyme levels were not greater than two times the upper limit of normal during the relevant time period.*fn96 They rely entirely on a silent injury theory of causation. Each offers only the expert report of Dr. Mendenhall as to specific causation. That report is not admissible evidence of causation. Accordingly, the Chesley plaintiffs also have failed to present admissible evidence demonstrating a genuine issue of material fact as to causation.

3. The Zavesky Plaintiff

The Zavesky plaintiff is deemed to have admitted that her liver enzyme levels did not exceed two times the upper limit of normal during the relevant time period.*fn97 She too therefore relies on a silent injury theory and offers only Dr. Rigle's expert report to establish specific causation. As Dr. Rigle's report is inadmissible, the Zavesky plaintiff has failed to offer admissible evidence showing the existence of a genuine issue of material fact as to causation.

IV. Conclusion

All 28 plaintiffs therefore have failed to provide admissible evidence of general or specific causation of silent liver injury. Without the necessary and admissible expert evidence, there is no genuine issue of material fact as to causation, and summary judgment is appropriate.*fn98

Pfizer's motion for summary judgment is granted*fn99 and the specific plaintiffs' complaints in the cases listed in the caption are dismissed.

SO ORDERED.


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