Full opinion text
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. A. Relevant Physiology. 1. Cells . 2. The Liver. 3. Mechanisms of Cell Death. B. Drugs, Toxicity to the Liver, and Rezulin C. Patient Population. D. Evidence of Causation in Medicine. IV.The Proposed Testimony. A. The Experts and Their Opinions. Lr* 1. Dr. Smith. Ir** 2. Dr. Reed. 3. Dr. Julie. 4. Dr. Day. 5. Dr. Bonkovsky. 6. Summary. B. The Science upon Which the Experts Rely. H 1. Early Links in the Proposed Causal Chain: The Claim that Rezulin Causes Apoptosis Through Effects on the Mitochondria or the BSEP-..'.. a. Studies Connecting Rezulin to Apoptosis. b.. Studies Connecting Rezulin to Mitochondrial Damage. c. Studies Connecting Rezulin to an Effect on the BSEP. 2.' The Last Link in the Chain: The Claim that Apoptosis from Rezulin ' Causes Silent Injury....' C. Arguments that Rezulin Can Cause Silent Liver Injury Through Mechanisms Other than Apoptosis.:.. D. Patients Whose Liver Enzymes Were Not Monitored. V.Law Governing the Admission of Expert Testimony .. A. Daubert and Its Progeny. B. The Daubert Standards Apply to Opinions About General and Specific Causation. 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.426 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 íñe., announced the development of Rezu-lin, the trade name of a drug used to treat Type 2 diabetes, a disease affecting approximately 16 million Americans. 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reports that some patients taking Rezulin experienced liver failure resulting in transplant or death, the drug was withdrawn from the market in March 2000. 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. The federal actions have been consolidated in this Court for pretrial proceedings. Extensive liability discovery against defendants has been completed. Defendants Pfizer Inc., Warner-Lambert, and Parke-Davis (collectively, “Pfizer”) move, pursuant to Federal Rule of Evidence 702 and Daubert v. Merrell Dow Pharmaceuticals, Inc., 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.” The Plaintiffs’ Executive Committee, which is responsible for coordinating the activities of plaintiffs during pretrial proceedings, 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. “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.” 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 plaintiffs lung cancer was caused by his smoking).” Plaintiffs offer the testimony of a number of expert witnesses to prove general causátion. 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 Rezu-lin. 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. 11. 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. 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. The nucleus contains the cell’s genetic information. 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.” The cytoplasm is defined as everything besides the nucleus and cell membrane, and it contains among other things membrane-bound structures known as organelles, of which one type is the mitochondrion (in the plural, mitochondria). The mitochondria sometimes are referred to as the “powerhouse” of the cell because chemical reactions occurring therein produce adenosine triphosphate (“ATP”), the cell’s energy currency. 2. The Liver• The liver, located in the right upper quadrant of the abdomen, is a large organ that plays a central role in the body’s biochemical activity. It metabolizes, or breaks down, a large number of substances, synthesizes essential enzymes, and detoxifies and eliminates a variety of compounds from both within and without the liver. A vein known as the portal vein carries to the liver all blood from the digestive tract, facilitating the liver’s absorption of toxic chemicals that a person has ingested. Most of the liver’s. biochemical functions take place within cells known as hepatocytes, which are the predominant type of cell in the liver. Medicine recognizes many forms of liver disease, including non-alcoholic fatty liver disease (“NAFLD”), described as “fatty liver without inflammation,” and a related condition known as non-alcoholic stea-tohepatitis (“NASH”), described as “fatty liver with inflammation.” These conditions are associated with fibrosis, described as “scarring of the liver” and more precisely as “the presence of excess extracellular matrix.” Fibrosis can lead to cirrhosis, a final stage of liver disease in which “groups of hepatocytes become completely encased by fibrous material, and nodules replace normal lobular organization.” When liver disease is “moderately advanced,” “fibrosis often appears as connective tissue that spans portal and central areas,” a condition known as “bridging fibrosis.” 3. Mechanisms of Cell Death Some of the plaintiffs’ witnesses base their proposed testimony on theories relating to death of liver cells allegedly attributable to Rezulin. There are two basic mechanisms of cell death: necrosis and apoptosis. Experts from both sides agree on their basic features. In necrotic cell death, the cell membrane ruptures, and the contents of the cell are discharged into the surrounding tissue. Among these cellular contents in the liver are enzymes, including alanine amino-transferase (“ALT”) and aspartate amino-transferase (“AST”) (collectively, “transa-minases”). Thus, necrotic cell death in the liver in sufficiently large quantities is accompanied by elevations of liver enzyme concentration in the blood In apoptosis, by contrast, the dying cell shrinks and is engulfed and digested by neighboring phagocytes, described in one of the expert reports as “tissue clean up cells.” Apoptosis sometimes is known as “programmed cell death” or “cell suicide.” Like necrosis, it is “often naturally initiated by the body to eliminate cells that are no longer needed” and is necessary for human survival. Apoptosis in the liver usually is not accompanied by enzyme elevation because the phagocytes typically devour the apop-totic cells before the latter release their contents into blood. Apoptosis in the liver, however, may result in elevated liver enzymes when it takes place on such a scale that the ability of viable cells to remove dying cells is overwhelmed. B. Drugs, Toxicity to the Liver, and Re-zulin Because the liver “is central to the metabolic disposition of virtually all drugs and foreign substances,” liver injury “is a potential complication of nearly every medication that is prescribed.” Experts from both sides agree that liver injury caused by drugs is typically categorized as hepa-tocellular, cholestatic, or mixed based on the pattern of blood test results. Hepato-cellular injury is injury to hepatocytes and is manifested by elevated quantities of transaminases in the blood. Cholestatic injury is injury to the liver’s ability to produce and excrete bile and is manifested by elevated quantities of alkaline phosphatase and bilirubin. The injury is mixed if features of both hepatocellular and choles-tatic injury are present. In general, drugs are either predictable or unpredictable (idiosyncratic) toxins to the liver, or hepatotoxins. Predictable toxins are dose-dependent. Unpredictable toxins, while capable of producing damage at therapeutic doses, do. so rarely. There is no dispute that a small percentage of patients treated with Rezulin developed reversible elevations of ALT of more than three times the upper limit of normal. The mechanism by which Rezulin is toxic to liver cells is not well understood. The defendants’ experts believe that Rezu-lin is an idiosyncratic hepatotoxin, inducing liver injury on an unpredictable basis in a very small number of cases. The plaintiffs’ experts believe that Rezulin can be directly toxic to cells, even though the drug exhibits features of idiosyncratic toxicity. Liver injury attributable to Rezu-lin is predominantly hepatocellular, but the defendants do not dispute, at least for purposes of this motion, that the drug is capable of causing cholestatic or mixed injury. C. Patient Population Type 2 diabetes affects an estimated 16 million Americans. It is associated with obesity, and both obesity and diabetes are associated with NAFLD and NASH. Approximately 50 percent of patients with diabetes have NAFLD. (The prevalence of NAFLD in the general population of the United States was once estimated at 24 percent and is likely higher today.) The percentage of diabetics with NASH is unknown but probably smaller. D. Evidence of Causation in Medicine The expert testimony in this ease purports to be grounded on a number of scientific and medical studies. For the sake of context, the Court briefly reviews principles regarding the applicability of different kinds of scientific and medical research. The “gold standard” for determining the relationship between a drug and a health outcome is the clinical trial. In such investigations, subjects are assigned randomly to one of two groups: one exposed, and the other not exposed, to the drug of interest. Such studies, however, are not always available, at least in part because ethical constraints preclude exposing human beings to agents known or thought to be toxic. Thus, other kinds of evidence often are used to assess whether a drug or agent is related to the risk of developing a certain condition. Chief among these are observational epidemiological studies, in which subjects that were exposed to an agent prior to the investigation are compared with subjects not so exposed. Another type of information used by physicians and medical researchers is the case report, which is a description of a particular patient’s clinical history and symptoms. As explained in the Reference Manual on Scientific Evidence: “Case reports lack controls and thus do not provide as much information as controlled epidemiological studies do. However, case reports are often all that is available on a particular subject.... Causal attribution based on case studies must be regarded with caution. However, such studies may be carefully considered in light of other information available, including toxicological data.” The difficulty with case reports, in other words, is distinguishing between association and causation. Simply because a patient exposed to a particular substance exhibited a set of symptoms does not mean that it was the substance that caused the symptoms. In addition to research on humans, scientists often perform experiments on living animals, such as rats, mice, and monkeys. The advantages of such studies include the fact that they can be conducted as true experiments, with exposure controlled and measured and ethical limitations diminished. Nevertheless, although it is “a basic principle of toxicology and pharmacology” that “a compound causing an effect in one mammalian species [usually] will cause it in another,” extrapolation from animal studies to humans cannot be done uncritically. For one thing, different species have important physiological differences. For another, the high doses often used in animal studies may not correspond to considerably lower concentrations of a drug or other substance to which humans are in reality exposed. Finally, researchers frequently conduct experiments on cell and tissue cultures. These experiments, sometimes referred to as in vitro studies to distinguish them from studies performed in vivo, meaning on live humans and animals, also are subject to the problem of extrapolation. It is not always clear that “one can generalize findings from the artificial setting of tissues in laboratories to whole human beings.” TV. The Proposed Testimony The defendants do not challenge the admissibility of expert testimony to the effect that Rezulin is capable of causing liver injury that results in elevation of liver enzymes. They train their fire only on opinion testimony that the drug is capable of doing so “silently,” that is, without markedly elevating those enzymes approximately concurrently with treatment. The defendants challenge aspects of the opinions of five expert witnesses. Before reviewing the challenged testimony, a preliminary note is in order. The plaintiffs’ counsel at every stage have gone further than their experts. They have formed hypotheses that the experts nowhere mentioned, they have forged connections that the experts stopped short of drawing, and they have portrayed as sturdy hypotheses that the experts espoused hesitantly if at all. None of these elaborations by counsel is relevant. The subject of this motion is the proposed testimony of expert's, not the theories of the lawyers. A. The Experts and Their Opinions 1. Dr. Smith The opinion of Dr. Martyn T. Smith, who testified at the evidentiary hearing, is central to this motion. Dr. Smith is a toxicologist. He holds a Ph.D. and is a professor in the Division of Environmental Health Sciences at the University of California at Berkeley’s School of Public Health. He is not a clinician and has no training in hepatology. Dr. Smith opines that “[a] careful review of all of the literature allows one to conclude to a reasonable degree of scientific probability that [Rezulin] more likely than not ... can damage the liver ‘silently’ because apoptosis does not cause elevation of liver enzymes in serum.” He states “that to a reasonable degree of scientific probability troglitazone can induce apop-totic death of cells in the liver in humans in vivo. ” Dr. Smith offers two major mechanisms by which Rezulin could cause apoptosis. The first involves a cascade of chemical events in which the mitochondria cease functioning normally and release a protein into the cytoplasm that triggers apopto-sis. The second involves the bile salt export pump, or BSEP. The BSEP is a protein in the plasma membranes of hepa-tocytes that pumps bile salt out of the cell. Dr. Smith states that Rezulin can interfere with the functioning of the pump, leading to the build-up of toxic bile salts in the cells and that this condition triggers apop-tosis. 2. Dr. Reed Dr. John C. Reed’s opinion also is a major subject of this motion. Dr. Reed is the president and chief executive officer of the Burnham Institute, a research center in La Jolla, California. He holds an M.D. and a Ph.D. and has described himself as follows: “I don’t consider myself a liver expert or hepatology expert. I consider myself an apoptosis expert.” Dr. Reed testified at the evidentiary hearing. Dr. Reed’s declarations are intended to “address[ ] the evidence that Rezulin (tro-glitazone) induces apoptosis in human and animal cells.” Dr. Reed’s declarations do not say that a Rezulin-induced injury could be silent. His testimony therefore is relevant only to the extent that it provides support for the other experts — principally Dr. Smith — who are willing to draw that conclusion. S. Dr. Julie Neil Julie, M.D., practices gastroenterol-ogy and hepatology in a Maryland suburb of Washington, D.C., and also testified at the evidentiary hearing. His initial declaration is organized for the most part as a set of conclusions, each in the form of a single sentence and each followed by the statement that “[m]y opinions are based upon my education, training and experience as well as my review of the following materials” and then a long list of documents, medical articles, and testimony. The conclusions relevant here are that “Rezulin causes a multitude of hepatocellu-lar injuries including but not limited to ... apoptosis .... ” and “Rezulin liver injury can occur without an elevation of AST and ALT.” The plaintiffs submitted a second declaration from Dr. Julie to address: “the tools a medical doctor should appropriately utilize in order to diagnose a medical condition generally and, more specifically, the use of differential diagnosis [] with respect to a Rezulin-relat-ed hepatic injury, including evidence of studies showing mitochondrial damage and apoptosis caused by Rezulin.” Dr. Julie concludes: “it is my opinion that it would be inappropriate to broadly conclude that a patient did not suffer a drug-induced liver injury from Rezulin simply based upon the absence of a marked elevation in liver enzymes.” In support of this statement, Dr. Julie states among other things that “[a] physician performing a differential diagnosis must consider. ... relevant scientific evidence” of Rezulin’s “toxic effect on mitochondria and its ability to induce cell death via apoptosis.” Dr. Julie acknowledged that his view that Rezulin is toxic to the mitochondria is derived from the opinions of Drs. Smith and Reed and the articles they cite for support. A Dr. Day Dr. Christopher P. Day is a research scientist and practicing hepatologist. He holds an M.D. and a Ph.D. and is a professor at the University of Newcastle upon Tyne in the United Kingdom. His report is concerned mainly with illustrating the varied ways in which Rezulin and other drugs can injure the liver. As relevant here, Dr. Day would testify that “a biologically plausible explanation for why many patients with liver disease post-exposure to troglitazone may not have had significant elevations of their transa-minase levels” is that cells undergoing apoptosis are consumed by surrounding cells. Dr. Day’s declaration further states that cholestasis and mitochondrial injury are “biologically plausible mechanisms for the development of apoptosis in patients exposed to troglitazone.” The Court notes that cholestatic injury normally results in increased bilirubin or alkaline phosphatase and that Dr. Day does not say that apoptosis related to cho-lestasis, if it occurs at all, would not affect bilirubin and alkaline phosphatase levels. Furthermore, Dr. Day does not say that apoptosis related to mitochondrial injury could cause injury without an elevation of transaminases. In other words, Dr. Day does not appear to offer the testimony that the defendants are seeking to exclude, which is the opinion that Rezulin can cause liver injury without an elevation in at least one of the four substances. His testimony therefore is of limited relevance. The Court nonetheless considers it insofar as it could be read to suggest that any injury caused by Rezulin would be silent. 5. Dr. Bonkovsky Herbert L. Bonkovsky, M.D., is a hepa-tologist and a professor at the University of Connecticut Medical School. The thrust of his opinion is that Rezulin “causes a wide spectrum of liver disease.” He states among other things that liver inflammation “such as that caused by Rezulin” can lead to bridging fibrosis and cirrhosis and that “[tjhese injuries have been observed in many cases with either normal or near normal values of ALT.” Dr. Bonkovsky, however, does not say that any such injuries that have been observed were due to Rezulin, nor does he provide any support for the statement that those injuries occurred with normal values of ALT. Elsewhere in his declaration Dr. Bon-kovsky opines that apoptosis and inhibition of the BSEP are plausible mechanisms of injury due to Rezulin. In addition, Dr. Bonkovsky’s opinion reviews some of the research cited in the reports of Drs. Reed and Smith for the proposition that Rezulin can affect the mitochondria. But Dr. Bonkovsky does not attempt to relate these statements, nor does he state that an effect on the mitochondria could cause apoptosis or that any injuries due to inhibition of the BSEP or apoptosis would be silent. He states without significant elaboration that he agrees with the views expressed in Dr. Smith’s report “on the various mechanisms of action associated with Rezu-lin,” but there is no indication that Dr. Bonkovsky intends to testify that Rezu-lin can cause liver injury silently. 6. Summary To the extent the experts would testify that Rezulin can cause “silent” liver injury, they have postulated a causal chain in which Rezulin can affect the mitochondria or the BSEP and thus trigger apoptosis, which would be injurious but silent. A graphical representation of the theory might be useful: B. The Science upon Which the Experts Rely The Court now will review the scientific research that the experts cite in support of their opinions. As will be discussed in a later section, the Court does not necessarily agree that all of the cited studies support the conclusions. The Court’s concern for the time being, however, is to present the experts’ own case. Nonetheless, at certain points in the following discussion, the Court will add its own observations— for example, comments on aspects of the studies, on the nature of the connections between the studies and the expert opinions, or on the absence of certain kinds of evidence — when it believes that additional information is essential to evaluate the testimony in question. As an initial matter, the plaintiffs’ experts cite no studies that say that Rezulin can cause a silent liver -injury. There are no clinical trials and no observational epidemiological studies supporting the plaintiffs’ position. Nor have the plaintiffs pointed to any clinical case in which Rezu-lin was believed to have caused such an injury. Rather, the opinions at issue on this motion are based on studies that the experts say support individual links in their causal chain. In particular, the experts have cited studies that connect Rezu-lin to apoptosis, studies that connect Rezu-lin to mitochondrial damage, and studies that connect Rezulin to an effect on the BSEP. Nearly all of these studies were conducted in vitro. 1. Early Links in the Proposed Causal Chain: The Claim that Rezulin Causes Apoptosis Through Effects on the Mitochondria or the BSEP a. Studies Connecting Rezulin to Apop-tosis The Court begins with studies cited by the experts for the proposition that Rezu-lin caused apoptosis in certain kinds of cells. At the outset, it is important to note that none of these studies dealt with normal human liver cells. The plaintiffs and their experts imply that Kostrubsky et al. (2000), a study that found that Rezulin was toxic to normal human liver cells at certain concentrations, shows that Rezulin produces apoptosis. That study, however, says nothing at all about whether the cell death occurred via apoptosis or necrosis. The same is true of several other studies cited by the plaintiffs and their experts, including Ramachandran et al. (1999). The experts cite one study in which Rezulin was found to cause apoptosis in rat hepatocytes. Toyoda et al. (2001) found that Rezulin produced this effect at concentrations of 15 p.M and above. Furthermore, a Warner-Lambert scientist tentatively reached the same conclusion from the company’s own data. The experts cite four studies in which Rezulin was found to produce apoptosis in human liver cancer cells. Bae and Song (2003), Toyoda et al. (2002), Yoshizawa et al. (2002), and Yamamoto et al. (2001) observed that Rezulin produced this result in a dose-dependent fashion above certain concentrations. In addition, the experts cite a number of studies in which Rezulin at certain concentrations produced apoptosis in cultured cancer cells of other organs. Harris and Phipps (2002) found that troglitazone induces apoptosis in malignant white blood cells. Ohta et al. (2001) observed a similar result in thyroid cancer cells. Tsubouchi et al. (2000) found the same in lung cancer cells. Guan et al. (1999) did so in bladder cancer cells, and Takahashi et al. (1999) and Sato et al. (2000) obtained this result in stomach cancer cells. Finally, Dr. Reed cites a trio of cases on prostate cancer cells, but they did not find that Rezulin produces apoptosis in human cells. Several of the studies on cancer cells examined the effect of Rezulin in concert with other substances. For example, the Kim et al. (2002) study examined the effect on lines of ovarian cancer cells of combining an anti-tumor agent known as TRAIL with troglitazone. The researchers found that troglitazone combined with TRAIL (but neither alone) killed tumor cells; the mechanism was believed to be apoptosis. Similarly, Elstner et al. (1998) found that the combination of troglitazone and another chemical (but neither by itself) caused apoptosis in human breast cancer cells. Finally, the experts cite studies on what Dr. Reed describes as “normal” cells from other organs. Gouni-Berthold et al. (2001) and Okura et al. (2000) obtained results suggesting that troglitazone caused apoptosis in cultures of a type of blood vessel cell taken from ráts and associated with atherosclerosis in humans. YamazaH et al. (2002) and Kawahito et al. (2000) derived a similar result for cultures of a type of cell that destroys the joints of patients with rheumatoid arthritis because it proliferates like a tumor. And Rovin et al. (2002) found that troglitazone induces cell death believed to be apoptotic in a type of kidney cell that proliferates in response to injury but that can cause kidney failure if the proliferation is excessive. b. Studies Connecting Rezulin to Mitochondrial Damage In addition to the studies that show apoptosis from Rezulin, albeit not in normal human liver cells, the experts cite studies showing that Rezulin can affect the mitochondria of liver cells. A preliminary clarification is called for. Toxicity from Rezulin. linked to mitochondrial damage is not necessarily relevant to the silent injury theory. It is uncontested that an injury would not be silent if it occurred by necrosis. The studies on mitochondria are relevant to the silent injury theory set forth in the expert reports only to the extent that those studies can be used to connect Rezu-lin with apoptosis. The experts cite a number of studies in which Rezulin caused morphologic, or structural, changes to mitochondria. Caldwell et al. (2001a) administered normal doses of Rezulin to NASH patients for six months and examined, among other things, their mitochondria. These investigators found that more of the mitochondria had a misshapen and unusually elongated appearance after treatment. They found as well “a decrease in the mean total number of mitochondria ... and an increase in the mean percentage of mitochondria that were enlarged and contained intramito-chondrial crystals ... but neither change was statistically significant.” Although Drs. Smith’s and Reed’s expert reports do not mention it, these researchers looked for evidence of apoptosis. They examined the post-treatment biopsies of five patients with an electron microscope and found that “features of apoptosis (bleb formation, nuclear fragmentation) were not evident.” They then applied a biochemical marker that detects apoptosis and found “[n]o statistically significant difference between the before and after specimens[.]” Apart from Caldwell et al. (2001a), the other mitochondria studies all were performed in vitro. Shishido et al. (2003) applied troglitazone at concentrations up to 50 p,M — the researchers chose that concentration because it had prevented the cells from proliferating without inducing apoptosis in a previous study performed on liver cancer cells — to an immortalized cell line and found “marked enlargement” and other abnormalities in the mitochondria. Tirmenstein et al. (2002) applied the drug to liver cancer cells and found “extensive alterations in mitochondrial morphology.” Several of the studies cited by the experts measured a quantity known as the mitochondrial membrane potential, which is the electrical gradient, or polarization, between the outside and inside of a mito-chondrion. A decrease in this polarization indicates that the mitochondria are not functioning normally. Haskins et al. (2001) found that troglitazone at certain concentrations produced a decrease in the mitochondrial membrane potential in rat hepatocytes and in the hepatocytes of one diabetic human donor, but not in the cells of another diabetic donor. These researchers wrote that “[f]uture studies should address the downstream effects of these changes, since nuclear condensation and apoptosis are observed as late effects that are shared by” troglitazone’s chemical family. Shishido et al. (2003) and Tir-menstein et al. (2002) found that troglita-zone at certain concentrations depolarized the mitochondrial membrane in the'immortalized liver cells and in liver cancer cells, respectively. Dr. Smith’s reports, but not Dr. Reed’s, argue that the above-described effects on the mitochondria link Rezulin to apoptosis. Dr. Smith begins with the statement that “[t]he decline in mitochondrial transmem-brane potential seen in these experiments is called the mitochondrial permeability transition.” Dr. Smith continues: “During the mitochondrial permeability transition, pores in the mitochondrial membrane are opened and [a protein known as] cytochrome c is released into the cytoplasm.... The cell ‘knows’ the cytochrome e should be normally be [sic ] inside the mitochondria, so when it léaks out it acts as a signal telling the cell that the mitochondria are badly damaged, and this stimulates the cell to commit suicide (i.e. apoptosis)[.]” Dr. Smith here cites Ravagnan et al. (2002). That article states that once a cell has been induced to die, “the outer mitochondrial membrane becomes completely permeabilized to proteins, resulting in the leakage of potentially toxic mitochondrial intermembrane proteins” — the authors include cytochrome c in this category — “that orchestrate the degradation phase of apoptosis.” Ravagnan et al. (2002) thus does not say, as Dr. Smith seems to, that mitochondrial change (due to Rezulin or otherwise) alone can be an independent cause" of apoptosis. Rather, the authors view certain mitochondrial changes as themselves products of some prior cause of cell death and as one step in a chain of events that leads to apoptosis. Another article cited by Dr. Smith, Bissell et al. (2001), reflects a similar understanding. A cited study that does agree with Dr. Smith is Kim et al. (2003). These researchers found that the change in permeability of the mitochondrial membrane triggered cell death in rat hepatocytes. This paper, however, reports that the cell will undergo apoptosis — as opposed.to necrosis — only if there is sufficient ATP. The organized death of the cell is a process that consumes energy, and without energy (in the form of ATP), the cell defaults to the necrotic mode of death. Another paper that agrees that the depolarization of the mitochondrial membrane itself can be a cause of cell death is Tirmenstein et al. (2002). This study, however, does not indicate whether the cell death occurs via apoptosis or necrosis, and it specifies that troglitazone leads to a decrease in the amount of ATP in the cell. Furthermore, the concentrations at which troglitazone produced cell death in this study were higher than those at which it began to affect the mitochondria. Dr. Smith continues: “A protein in the cytoplasm, called Bax, then migrates to the mitochondrial membranes and accelerates the apoptotic process by making the mitochondrial membrane even more permeable, thus further releasing even more cytochrome c into the cytoplasm thereby speeding up the apoptotic process[.]” Here Dr. Smith cites Smaili et al. (2001). Those researchers found that a decline in the mitochondrial membrane potential precedes the attachment of Bax to the mitochondria in cells genetically engineered to overproduce Bax. The authors sum up the implications of their research this way: “our results suggest that alterations in mitochondrial energization associated with apoptosis can initiate Bax docking to mitochondria.” The study, in other words, says nothing about whether mitochondrial dysfunction (whether caused by Rezulin or otherwise) is an independent cause of apoptosis. This study, like the research reviewed in Ravagnan et al. (2002), created conditions known to induce apoptosis and then examined the sequence of events within the cell. Dr. Smith concludes: “For TRO induced liver cell apoptosis, this process has recently been studied in detail by Bae and Song.... They found a critical role for Bax and [a protein known as JNK] activation in TRO induced liver cell apoptosis.... TRO ... induced apoptosis that was preceded by activation of JNK ... and increased levels of Bax [and] release of cytochrome c....” Bae and Song (2003), as mentioned above, found that troglitazone causes apoptosis in liver cancer cells. They found as well that TRO increases the levels of proteins associated with apoptosis, including Bax and cytochrome c. They did not, however, examine the mitochondria. c. Studies Connecting Rezulin to an Effect on the BSEP Dr. Smith’s other proposed mechanism through which Rezulin allegedly could cause silent injury involves the BSEP. As with the evidence on mitochondria, and for the same reasons, any effect on the BSEP is relevant to the silent injury theory only to the extent that it connects Rezulin with apoptosis. The experts cite several articles in which Rezulin was found to interfere with the ability of cells to export bile salts. Preminger et al. (1999) reported that troglita-zone interfered with the flow of bile in isolated rat livers. Two studies by Funk et al. confirmed this result in live rats; they found that when troglitazone was administered to rats, there was an increase in the concentration of bile acid in the rats’ blood plasma believed to have been caused by interference with the BSEP. Elevation of bile acid is analogous to elevation of bilirubin; both indicate a cholestatic injury. To connect the presumed effect on the BSEP to apoptosis, Dr. Smith and Dr. Reed cite a group of studies and review articles. All are concerned with elucidating the biochemical mechanisms by which the build-up of bile in the liver can produce apoptosis. 2. The Last Link in the Chain: The Claim that Apoptosis from Rezulin Causes Silent Injury The plaintiffs’ experts have cited no evidence that any apoptosis caused by Rezu-lin can result in a silent injury. That is, the plaintiffs’ experts have offered no evidence that apoptosis caused by Rezulin, if any, occurs at a clinically significant level or, even if it does, that the resulting injury would remain silent. The following exchange occurred during Dr. Smith’s testimony: “The Court: I think ... it is your view ... that doses of Rezulin that have been shown to be cytotoxic in cell studies obviously can be achieved in some human cells. We agree so far? “The Witness: Sure. I agree on it. “The Court: ... [W]hat, if anything, does that tell us on an empirical basis, as opposed to a theological basis, [about] whether achievement of those doses in some undefinable proportion of liver cells has any serious adverse consequences for anybody? ... Isn’t it entirely possible, and indeed probable, that there is some minimal number or proportion of liver cells that have to be killed off before there is any interference with the fiver’s functioning that matters to anybody? “The Witness: That is true. “The Court: Right. Do we know what this, and how it relates to the effect of Rezulin? “The Witness: I don’t think we do know, your Honor.” Dr. Reed testified in a similar way. The following exchange occurred during his cross-examination: “Q. Doctor, you testified that you believe it is possible that Rezulin could be inducing a low level of apoptosis in human fivers, is that correct? “A. Yes, I believe that is possible. “Q.... [D]o you have any study or any data to support that sustained apoptosis has resulted in clinical injury in a patient taking Rezulin? “A. Such a study has not been performed, to my knowledge.” Dr. Reed further testified as follows: “The Court: So just to try to put it in bottom line colloquial terms, even assuming ... everything you and Dr. Smith have said about the capability of Rezulin to induce apoptosis in particular fiver cells at what I will call for the sake of quickness relevant concentrations, we have no empirical data that indicates to us how many or what percentage of the fiver cells are injured in that way in vivo and what the threshold level of injury, in terms of numbers or proportion of liver cells, needs to be before there is any clinical injury to the patient? “The Witness: No, we really don’t know the percentage. All we know is, as I have said, one out of every 50 people has sufficient cell death occurring ... that their transaminase levels rose when they took the drug.” C. Arguments that Rezulin Can Cause Silent Liver Injury Through Mechanisms Other than Apoptosis In addition to the apoptosis theory, the plaintiffs’ counsel have argued that liver injury caused by Rezulin can be silent either because Rezulin suppresses the production of enzymes in the liver or because the enzymes might have been depleted already in a patient with pre-existing liver injury. The logical implication is that even if the apoptosis theory discussed above were unsubstantiated or incorrect, plausible mechanisms by which Rezulin can cause silent liver injury would remain. The problem is that these mechanisms, for the most part, were proposed by the plaintiffs’ counsel, not their experts. To the limited extent that they have been adopted by the experts, they are not supported. The only physiological explanation offered by the plaintiffs’ experts in support of their opinion that Rezulin can cause liver injury silently that requires further consideration is that involving apoptosis. D. Patients Whose Liver Enzymes Were Not Monitored Plaintiffs’ counsel raise the possibility that some people had abnormally elevated liver enzymes while on Rezulin therapy that were not recorded, either because the patient was not tested or was not tested at a time when the enzymes were elevated. The Court recognizes this possibility. But it has no bearing on the present motion, as it does not speak to whether Rezulin can cause liver injury through a mechanism that does not result also in elevated enzymes. V. Law Governing the Admission of Expert Testimony A. Daubert and Its Progeny The standard governing a district court’s determination whether to admit scientific or other expert testimony is familiar. Federal Rule of Evidence 702 provides: “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 (8) the witness has applied the principles and methods reliably to the facts of the case.” This rule incorporates principles established by the Supreme Court in Daubert v. Merrell Dow Pharmaceuticals, Inc. The Court there recognized that district judges have a “gatekeeping” role in which they must ensure that “scientific testimony or evidence admitted is not only relevant, but reliable.” Daubert observed that the relaxation for expert witnesses of the usual requirement of first-hand knowledge presumably “is premised on an assumption that the expert’s opinion will have a reliable basis in the knowledge and experience of his discipline.” For that reason, a trial judge must “make certain that an expert ... employs in the courtroom the same level of intellectual rigor that characterizes the practice of an expert in the relevant field.” A federal district judge faced with a challenge to the admissibility of expert testimony: “must determine at the outset ... whether the expert is proposing to testify 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.” These matters are to be determined by a preponderance of proof. The inquiry is “a flexible one.” In Daubert, the Supreme Court articulated four pertinent factors while leaving open the possibility of others: (1) whether the expert’s theory “can be (and has been) tested;” (2) whether the theory “has been subjected to peer review and publication;” (3) the “known or potential rate of error;” and (4) whether the theory has “widespread acceptance.” Courts have considered other factors as well, including whether an expert’s opinion was developed for litigation and whether the expert has accounted adequately for obvious alternative explanations. In addition, Rule 702’s requirement that the proposed testimony “assist the trier of fact to ... determine a fact in issue” means that the proffered testimony must be “sufficiently tied to the facts of the case that it will aid the jury in resolving a factual dispute.” The Daubert decision recognized that this consideration, which has been described as one of “fit,” “goes primarily to relevance.” 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.” Thus in General Electric Co. v. Joiner, the Supreme Court held that a district court did not abuse its discretion when it excluded the testimony of experts that exposure to polychlorinated biphenyls (PCBs) was likely responsible for the lung cancer of an electrician who was a smoker and had a family history of lung cancer. The Supreme Court found that the animal studies on which the experts relied, which involved exposing infant mice to massive doses of PCBs, “were so dissimilar to the facts presented in this litigation that it was not an abuse of discretion for the District Court to have rejected the experts’ reliance on them.” The Supreme Court likewise did not take issue with the district court’s conclusions that four epidemiological studies were not a reliable basis for the experts’ opinions. In two of the four studies, the authors were unwilling to conclude that PCB exposure had caused cancer in the observed workers. The third study did not even involve PCBs, and the subjects in the fourth had been exposed to numerous carcinogens in addition to PCBs. The Second Circuit’s recent case law follows the logic of Joiner and Daubert. In Amorgianos v. National Railroad Passenger Corp., the Circuit reiterated the familiar principles governing the admissibility of expert testimony and further held that: “[t]o warrant admissibility ... it is critical that an expert’s analysis be reliable at every step.... In deciding whether a step in an expert’s analysis is unreliable, the district court should undertake a rigorous examination of the facts on which the expert relies, the method by which the expert draws an opinion from those facts, and how the expert applies the facts and methods to the case at hand.” In that case the district court was confronted with expert testimony that, among other things, exposure to certain toxic chemicals was a general cause of the type of neuropathy allegedly suffered by the plaintiff bridge painter. The district court “conducted an extremely thorough review of the scientific literature” on which those experts relied. The Circuit found that this review: “was certainly within the broad discretion afforded to the district court under Daubert and its progeny, and did not impinge upon the jury’s function. It is precisely such an undertaking that assures that an expert, when formulating an opinion for use in the courtroom, will employ the same level of intellectual rig- or as would be expected in the scientific community.” The Circuit upheld the district court’s exclusion of the experts. The district court found that the articles cited by at least one of the experts “fail[ed] to ‘fit’ the facts of this case, either in terms of the type and duration of exposure, or the type and duration of the observed effects.” It found it significant as well that this expert “prepared his opinion for litigation, rather than as part of his academic research, and he has not seen fit to share his opinion” with the relevant professional community. The Second Circuit’s most recent pronouncement on the admissibility of expert testimony came last year in Wills v. Amerada Hess Corp, In that case, the Circuit held that a district court did not abuse its discretion when it excluded an expert report theorizing that a sailor’s cancer probably was caused by toxins to which he had been exposed on the defendant’s ships. The district court found that the studies on which the expert had relied did not establish a sufficient link between the toxins and the type of cancer because they were done only on animals and found a significant link only when the animals ingested the chemical, which the sailor had not done. The court was dissatisfied also with the expert’s failure to account adequately for the possibility that the cancer had been caused by the sailor’s smoking and drinking. Finally, the court found that the expert’s novel theory of causation — which the expert admitted was “the product of his own ‘background experience and reading’ ” — failed the Daubert test because it had not been tested or subjected to peer review, there was no known error rate, and it was not generally accepted. B. The Daubert Standards Apply to Opinions About General and Specific Causation As discussed earlier, a plaintiff in a toxic tort case must prove both general causation, that is, that the alleged toxin is capable of causing injuries of the kind suffered by the plaintiff, and specific causation, that is, that the alleged toxin caused the particular plaintiffs injuries. The Daubert requirements apply alike to expert opinions on general and specific causation. Indeed, since Daubert many district courts‘have excluded expert testimony regarding general causation on grounds quite similar to those proposed here. VI. Daubert Analysis of the Proposed Testimony A Testing and Error Rate, Peer-Review, Publication, Widespread Acceptance The challenged testimony in this case does not satisfy any of the core Daubert factors. The theory that Rezulin can cause a liver injury silently never has been tested and necessarily has no error rate. It never has been published or subjected to peer review — aside from an edited version of Dr. Smith’s report, which used more tentative language and which he published in a toxicology journal at the suggestion of a member of its editorial board who also is a paid consultant for the plaintiffs in this litigation. It appears to have no acceptance outside this litigation, let alone widespread acceptance. The plaintiffs argue that' the research linking Rezulin to apoptosis and apoptosis to injury is part of the established scientific literature. The challenged testimony however, is the opinion that Rezulin is capable of causing a silent liver injury. At issue, in other words, is much more than the independent assertions that Rezulin causes apoptosis in some types of cells under some conditions and that excessive apoptosis can be injurious. It is the extrapolation from the existing literature that never has been tested, peer-reviewed, published, or widely accepted. As the Second Circuit has made clear, “it is critical that an expert’s analysis be reliable at every step ... ‘any step that renders the analysis unreliable under the Daubert factors renders the expert’s testimony inadmissible.’ ” B. Independence from Litigation There is likewise no real dispute that the theory that Rezulin can cause a silent liver injury was developed solely in connection with this litigation. The plaintiffs have come forward with no evidence that Dr. Smith ever proposed this idea publicly before, and Dr. Reed admitted at the evi-dentiary hearing that he had not presented the theories in his expert report on the possible mechanisms of Rezulin’s alleged toxicity in any context other than this litigation. C. Consideration of Contrary Evidence A factor that courts have considered in Daubert analyses is whether an expert has accounted adequately for obvious alternative explanations. This is appropriate because any theory that fails to explain information that otherwise would tend to cast doubt on that theory is inherently suspect. By the same token, if the relevant scientific literature contains evidence tending to refute the expert’s theory and the expert does not acknowledge or account for that evidence, the expert’s opinion is unreliable. Accordingly, courts have excluded expert testimony “where the expert selectively chose his support from the scientific landscape.” In this case, the plaintiffs’ experts have ignored a large amount of information that calls many aspects of the silent injury theory into question. Their reports do not mention that the one study that looked for Rezulin-induced apoptosis in humans failed to find it. Caldwell et al. (2001a) administered Rezu-lin to human patients and looked for morphological and biochemical evidence of apoptosis but found none. The expert reports point out that Toyoda et al. (2001) found that Rezulin induced apoptosis in healthy rat hepatocytes. But they do not mention that Kim et al. (2002) — a paper of which Dr. Reed was a coauthor and which he discussed in his declarations — investigated healthy hepato-cytes from cynomologus monkeys and found that Rezulin, alone or in combination with the anti-tumor agent TRAIL, failed to induce1 apoptosis. Rats are much further than monkeys from humans, and Dr. Reed himself regards cells from monkey as a useful alternative to human cells. The expert reports do not mention that four of the studies on cancer cells — including the Kim et al. (2002) study performed in Dr. Reed’s laboratory — compared the effect of troglitazone on the cancer cells to the effect on healthy cells and that, in every such comparison, troglitazone was found to induce apoptosis in the cancer cultures while having no effect on the healthy cells. The expert reports do not mention, in other words, that the reason many researchers were investigating tro-glitazone’s effects on cancer cells and on diseased tissue is that they were actively exploring the possibility that the drug could be an effective therapy for killing or preventing the proliferation of malignant tissue without harming healthy cells. The expert reports do not discuss the fact that the same researchers who found that troglitazone affected the mitochondria in the cells of live humans, immortalized liver cells, and liver cancer .cells either observed no evidence at all of apoptosis or other cell death or, if they did observe cell death, (i) observed it at concentrations higher than the concentrations required to affect the mitochondria, and (ii) did not specify whether the mechanism was apop-tosis. The expert reports did not discuss the fact that Shishido et al. (2003), a study performed on immortalized human liver cells, looked for but could not find cytochrome c, considered a sign of apopto-sis, and believed this absence “suggest[ed] no clear involvement of mitochondria-mediated apoptosis in this in vitro system as previously reported.” The expert reports saw fit to omit that, while Haskins et al. (2001) did find that troglitazone affected the mitochondria in liver cells derived from one diabetic patient, these researchers failed to see this result in the cells derived from another diabetic patient. In other words, the scientists have discussed only the evidence that they believed would advance the plaintiffs’ position. Their reports cannot be said to reflect “the same level of intellectual rigor that characterizes the practice of an expert in the relevant field.” D. “Fit” and the “Analytical Gap” A crucial consideration in evaluating the admissibility of expert testimony is whether the conclusions flow reliably from the premises. As the Supreme Court has explained, “[a] court may conclude that there is simply too great an analytical gap between the data and the opinion proffered.” Or as Judge Becker has explained for the Third Circuit: “[e]ven if an expert’s proposed testimony constitutes scientific knowledge, his or her testimony will be excluded if it is not scientific knowledge for purposes of the case.” This consideration is bound up with the relevancy requirement described in Daubert as one of “fit.” The analytical gap between the research and the conclusions the experts would draw is independently sufficient to warrant exclusion of the testimony in question. The plaintiffs have no evidence for the final link in their causal chain, and they extrapolate from the earlier links in ways the Court finds unreliable. 1. The Experts Have No Evidence for the Crucial Link in Their Causal Chain The experts have no evidence to carry them all the way down their causal chain to silent liver injury. It is worth bearing in mind that some level of apoptosis is entirely normal and occurs all the time in healthy tissue. Drs. Reed and Smith admitted that they have no information on whether therapeutic doses of Rezulin, even assuming they can cause additional levels of apoptosis beyond the normal baseline, can do so to a clinically relevant extent. Furthermore, both sides’ experts and the literature agree that when an insult producing apoptosis is sufficiently serious, the injury or impairment will not be silent. Thus the question is not just whether Re-zulin can cause apoptosis to occur at levels sufficient to cause injury or impairment, but whether it can do so and remain silent. The plaintiffs’ experts have offered no evidence that this is possible. Indeed, nothing in the challenged expert reports gives any indication about the actual capacity of phagocytes (the “clean-up” cells) to absorb the end products of apoptosis — -the precondition to the injury’s hypothesized silence. 11. The Experts Have Failed To Link the Studies on Mitochondria and the BSEP into Their Causal Chain Similarly, the studies on mitochondria have no connection to Rezulin-induced apoptosis. Dr. Smith would opine that (a) Rezulin has been shown to affect the structure and function of the mitochondria, and (b) apoptosis has been shown to involve changes to the mitochondria, and therefore (c) Rezulin can produce apoptosis. This is speculative, and it confuses association with causation. Dr. Smith’s reasoning is logically equivalent to saying that (a) every time John gets hungry he eats, and (b) John eats .whenever he goes to a restaurant, therefore (c) every time John gets hungry, he goes to a restaurant. There are of course plenty of times when John gets hungry and eats at home. So too here. There is not simply the possibility that Rezulin changes the mitochondria without producing apoptosis. There are empirical demonstrations of this in the studies of Caldwell et al. (2001a), Shishido et al. (2003), and Tirmenstein et al. (2002) performed, respectively, on live humans, immortalized human liver cells, and liver cancer cells. The plaintiffs’ experts must have some reliable basis for asserting that Rezulin-induced mitochondrial abnormalities lead specifically to apoptosis, otherwise the mitochondria research does nothing to help them survive this motion. The plaintiffs’ experts have no such basis. Nor is Dr. Smith’s theory rendered reliable by the fact that he, and some of the articles he cites, assert that a change in mitochondrial membrane function itself is an initial cause of, and not just a phenomenon associated with, apoptosis. The fact that there is compelling evidence (which he ignores) in the very studies that he and Dr. Reed cite to the effect that human liver cells — normal, immortalized, and cancerous' — can sustain mitochondrial damage without shriveling up and dying undermines what the plaintiffs’ counsel have described as Dr. Smith’s “one plus one equals two” argument. The BSEP research suffers from the same basic difficulty discussed above. That is, while there are studies to suggest that Rezulin, through a mechanism involving the BSEP, can produce cholestatic injury and that cholestatic injury is associated with apoptosis, there is no reason to believe that any apoptosis caused by BSEP malfunction would be silent. The cholestatic injury that Rezulin produced in rats in the two Funk et al. studies was manifested by the presence in the rats’ blood of products closely associated with bilirubin. For apoptosis associated with cholestasis to be silent, surrounding phagocytes would have to absorb the dying bile salt-filled cells. Can they really do this? The very toxicity to cells of bile and related compounds