SIHARATH v. SANDOZ PHARMACEUTICALS CORP. Nos. CIV.A.195-CV-965TWT, CIV.A.195-CV-3068TWT.
131 F.Supp.2d 1347 (2001)
Bridget Guthrie SIHARATH, Plaintiff, v. SANDOZ PHARMACEUTICALS CORPORATION, Defendant. Bonnie Joyce Rider and Walter Anthony Rider, Plaintiffs, v. Sandoz Pharmaceuticals Corporation, a Delaware Corporation, Sandoz Ltd., a Swiss Corporation, and Sandoz Pharma Ltd., a Swiss Corporation, Defendants.
United States District Court, N.D. Georgia, Atlanta Division.
March 1, 2001.
Dennis P. Orr, Grant J. Esposito, Mayer Brown & Platt, New York City, for Sandoz
Ltd. and Sandoz Pharma Ltd., No. 1:95cv03068.
THRASH, District Judge.
These are two complex products liability actions. In each case, a postpartum woman suffered a stroke after taking a prescription drug manufactured by the Defendant. In its simplest form, the question presented is did the drug cause the strokes? Or, is the temporal association of taking the drug and a subsequent stroke merely coincidental? To begin to answer those questions, the Court must address the recurring issue of what is the quantity and quality of scientific evidence that a plaintiff must present on the issue of medical causation in a world of imperfect scientific knowledge.
Although the cases have not been consolidated, the motions and documentary evidence filed, the expert testimony, and the issues raised are identical in both cases. Consequently, the Court addresses the pending motions of both cases in this single Order. Siharath v. Sandoz Pharmaceuticals Corporation, No. 1:95-CV-965-TWT, ("Siharath") is before the Court on Defendant's Motion to Exclude and for Summary Judgment on Issues of Medical Causation Under Daubert v. Merrell Dow Pharmaceuticals, Inc. [Doc. 68]. Rider v. Sandoz Pharmaceuticals Corporation, No. 1:95-CV-3068-TWT, ("Rider") is likewise before the Court on Defendant's Motion to Exclude and for Summary Judgment on Issues of Medical Causation Under Daubert v. Merrell Dow Pharmaceuticals, Inc. [Doc. 116].
Parlodel® is manufactured by Defendant Sandoz Pharmaceuticals Corporation —now Novartis Pharmaceuticals Corporation.
After a preliminary review of the voluminous record, the Court held a status conference on August 2, 2000, and at that time granted Defendant's request for an evidentiary hearing on its Daubert objections to Plaintiffs' expert testimony on medical causation. Each side was given five hours for direct and cross examination of witnesses and one hour for argument.
II. SUMMARY JUDGMENT STANDARD
Summary judgment is appropriate only when the pleadings, depositions, and affidavits submitted by the parties show that no genuine issue of material fact exists and that the movant is entitled to judgment as a matter of law. Fed.R.Civ.P. 56(c). The court should view the evidence and any inferences that may be drawn in light most favorable to the nonmovant. Adickes v. S.H. Kress and Co.,
Defendant contends that Plaintiffs' experts must be excluded from testifying in this case on the grounds that their expert testimony on medical causation is inadmissible. Expert testimony is admissible only if it satisfies the standards that the United States Supreme Court articulated in Daubert v. Merrell Dow Pharmaceuticals, Inc.,
The first element is competence. The expert must be qualified in his field of expertise. The proponent of expert testimony bears the burden of establishing its admissibility. Wells v. Ortho Pharm. Corp.,
The second element of admissibility is reliability. To be considered reliable, expert testimony on scientific issues must be supported by "scientific knowledge." "The adjective `scientific' implies a grounding in the methods and procedure of science. Similarly the word `knowledge' connotes more than subjective belief or unsupported speculation." Daubert, 509 U.S. at 590, 113 S.Ct. 2786. The Supreme Court in Daubert identified four factors to assist courts in determining whether testimony meets the standard of reliable scientific knowledge: (1) whether the expert's theory can and has been tested; (2) whether it has been subjected to peer review; (3) the known or expected rate of error; and (4) whether the theory or methodology employed is generally accepted in the relevant scientific community. Daubert, 509 U.S. at 593, 113 S.Ct. 2786. These factors, however, are not exhaustive. At its core, the "scientific knowledge" inquiry seeks to determine whether there is "some objective, independent validation of the expert's methodology." Moore v. Ashland Chem., Inc.,
The final element of admissibility, set forth in Daubert, is an appropriate relevance, or "fit," between the expert's opinion and the facts of the case. Daubert, 509 U.S. at 591, 113 S.Ct. 2786; United States v. Gilliard,
In this case, Plaintiffs seek to admit the testimony of five medical experts to support their prima facie requirement of establishing medical causation. To survive Defendant's Motions for Summary Judgment, Plaintiffs must produce evidence that would allow a reasonable jury to find to a reasonable degree of medical certainty that Parlodel® is (1) capable of causing stroke and (2) that Parlodel® did in fact cause their strokes. See, e.g., Joiner v. General Elec. Co.,
Defendant contends that three of Plaintiffs' five experts are not qualified to testify. Defendant also contends that the testimony of all five of Plaintiffs' experts is inadmissible because their testimony is neither scientifically reliable nor relevant. Defendant contends that Plaintiffs' experts' testimony fails to meet the Daubert standards for admissibility because Plaintiffs' experts (1) have failed to provide any evidence, either published or unpublished, that Parlodel® increases one's risk of stroke; (2) rely on uncontrolled and unreliable spontaneous reports and anecdotal case reports as the basis for their opinions; and (3) cannot show that their opinions have an acceptable error rate or are otherwise generally accepted.
Plaintiffs' five experts are as follows. Dr. Kenneth Kulig is a physician who is board certified in toxicology and emergency medicine. He is licensed to practice medicine in Colorado. A practicing physician for more than 20 years, Dr. Kulig received his undergraduate degree from Michigan State in 1972, followed by a M.D. degree from Wayne State Medical School in Detroit in 1978. He completed an internship in internal medicine and a residency in emergency medicine. He then obtained a two-year fellowship in clinical toxicology at the University of Colorado. Thereafter, he became affiliated with both Denver General Hospital and the Rocky Mountain Poison Center. In 1991, he joined Porter Adventist Hospital in Denver where he established a private practice, served as Chairman of its Department of Medicine, and remains to this day as both Chairman of the Pharmacy and Therapeutics Committee and Director of the Porter Regional Toxicology Center. Dr. Kulig also is an associate clinical professor in the Division of Emergency Medicine and Trauma at the University of Colorado
Dr. Dennis Petro is a board-certified neurologist. He received his M.D. degree at Pennsylvania State University. He completed a residency in neurology at Hershey Medical Center in Hershey, Pennsylvania. He became employed by the Food and Drug Administration ("FDA") in Rockville, Maryland, in 1977. While at the FDA, Dr. Petro reviewed drug applications relevant to neurologic disorders, specifically analgesics and drugs of abuse. At the time Dr. Petro began his employment with the FDA, Parlodel® was an investigative drug. After leaving the FDA, Dr. Petro became employed by the New York State Department of Health, but still continued part-time employment with the FDA as a consultant. Later he worked on the development of neurologic drugs while employed by Wyeth Laboratories and then Pfizer Pharmaceuticals. Thereafter, Dr. Petro joined the Nassau County Medical Center on Long Island, New York, to run its Neurologic Department Research Program. From there, he joined Fidia Pharmaceutical Corporation in Washington, D.C. Dr. Petro eventually left Fidia and became a consultant in new drug development. Since 1980, he has served as a member of the American Heart Association's Stroke Council. He also has published at least 16 medical articles in peer-reviewed journals. Defendant does not contest Dr. Petro's qualifications in the field of neurology. It contests only the reliability and relevance of his proposed testimony.
Dr. Subir Roy is a reproductive endocrinologist who serves as a professor in the Department of Obstetrics and Gynecology at the University of Southern California ("USC") School of Medicine. He received his M.D. degree at the University of North Carolina at Chapel Hill. He completed both an internship and residency in obstetrics and gynecology at the Los Angeles County-University of Southern California Medical Center in Los Angeles, California. He then obtained a fellowship in gynecologic endocrinology and infertility from USC and has remained with USC ever since. Dr. Roy served on the FDA's Fertility and Maternal Health Drugs Advisory Committee when it considered the safety of Parlodel® in 1989. In October 1998, he was appointed to a four-year term on the FDA's OB/GYN Devices Advisory Committee. He is board certified by the American Board of Obstetrics and Gynecology. He has been a consultant to such publications as the American Journal of Obstetrics and Gynecology, The Journal of Reproductive Medicine, Obstetrics and Gynecology, and the Journal of the American Medical Association. He himself has published more than 60 peer-reviewed articles. Nevertheless, Defendant contends that Dr. Roy is not qualified by education or experience to render an expert opinion in this case. It also contests the reliability and relevance of his proposed testimony.
Dr. Anthony Guarino is a pharmacologist and toxicologist. He received his Ph.D. in pharmacology in 1966 from the University of Rhode Island. From 1972 to 1980, Dr. Guarino served as the Chief of the Laboratory of Toxicology at the National Cancer Institute in Bethesda, Maryland. From March 1980 to August 1984, he served as a review scientist for the FDA, where he conducted pharmacology and animal toxicology reviews of drugs being offered for clinical investigation and FDA approval. He was responsible for determining, primarily on the basis of animal study data that pharmaceutical manufacturers submitted, whether drugs could be introduced to humans safely and ultimately whether they should be approved for widespread commercial marketing and use. Since 1985, Dr. Guarino has been an adjunct professor of pharmacology at the University of South Alabama College of Medicine in Mobile, Alabama. He also has consulted in the field of drug development
Dr. Maurice N.G. Dukes considers himself to be an adverse drug reaction scientist. No board certification exists for this discipline. Dr. Dukes received his medical degree from St. John's College in England in 1956 and a law degree from Cambridge University in 1957. Following graduation in 1957, Dr. Dukes accepted employment with Richardson-Merrell Pharmaceuticals in its Netherlands office. From 1961 to 1972, he worked at Organon Pharmaceuticals International, eventually obtaining the positions of research manager and assistant research director. In 1972, he became Vice Chairman of the Netherlands National Drug Regulatory Commission, that country's functional equivalent of the FDA. He remained in that position until 1982. Between 1978 and 1982, Dr. Dukes also served as Deputy Member of the European Economic Community's ("EEC") Committee for Proprietary Medicinal Products. In 1982, he left those positions to head the pharmaceuticals program for the World Health Organization's ("WHO") European Regional Office. He left that position in 1991 but continues to consult with the WHO and the World Bank on drug policy. Additionally, Dr. Dukes served between 1985 and 1997 as a professor of drug policy studies at the University of Groningen in the Netherlands. He now serves as an adviser in drug policy studies at the University of Oslo in Oslo, Norway. For years, Dr. Dukes has edited the two internationally recognized standard treatises on drug side effects. Since 1975, he has been the editor-in-chief of Meyler's Side Effects of Drugs. From 1977 to 1996, he served as editor-in-chief of the Meyler's complement, Side Effects of Drugs Annual. He is also the editor-in-chief of the International Journal of Risk and Safety in Medicine and has authored such books as The Effects of Drug Regulation (1985) and Responsibility for Drug-Induced Injury (1988 & 2d ed.1998). He also has authored some 240 papers and journal articles on such issues as pharmaceutical products, drug policy, adverse reactions and drug economics. He remains active in the development and establishment of adverse reaction monitoring systems, particularly in Central and Eastern Europe, Africa, and Southeast Asia. Dr. Dukes has never been a licensed, practicing physician in the United States or any other country. Principally, for that reason, Defendant contends that Dr. Dukes is not qualified by education or experience to render an expert opinion in this case. It also contests the reliability and relevance of his proposed testimony.
Having reviewed the depositions, affidavits, other documentary evidence, and, in the cases of Dr. Kulig and Dr. Dukes, having observed and considered their testimony at the Doubert hearing, the Court concludes that Drs. Kulig, Petro, Roy, Guarino, and Dukes are all well qualified by education and experience to provide an opinion on medical causation in this case. Indeed, Dr. Dukes—whom Defendant most strenuously challenges—is an exceptionally qualified expert on the issue of adverse drug reactions. The fact that he has chosen to spend his professional life in the world of public policy and academics instead of clinical practice in no way reduces his expertise in the field of adverse drug reaction science. Defendant's argument to the contrary minimizes the contributions made to medical science by those who accept the call of public service and selflessly remain in that service throughout the duration of their careers.
The opinion of Plaintiffs' experts regarding medical causation in these cases is that
Plaintiffs' experts admit that bromocriptine does not always act as a vasoconstrictor. They contend that bromocriptine can cause two seemingly anomalous circulation effects, depending on one's "vascular tone." If one's arterial resistance is low, Plaintiffs' experts admit that bromocriptine can cause vasodilation (widening of the blood vessels) and hypotension (low blood pressure). Vasodilation and hypotension are admittedly inconsistent with their theory of causation. If, however, one's arterial resistance is high, Plaintiffs' experts contend that bromocriptine, like other ergot alkaloids, can cause vasoconstriction and hypertension, which can lead to seizures and stroke. The "vascular tone" of Plaintiffs' cerebral arteries at the time of their strokes is completely unknown.
In short, the chain of Plaintiffs' argument is that Parlodel®'s active ingredient is bromocriptine, which is an ergot alkaloid. Ergot alkaloids are a class of drugs that can cause hypertension, seizures and ischemic strokes and, therefore, likely cause hemorrhagic strokes, also. The question before the Court is whether their methodology in constructing this causal chain is based on scientific knowledge that is sufficiently relevant and reliable to assist the trier of fact; or whether Plaintiffs' causal chain instead includes "leaps of faith" and is no more than a hypothesis not adequately supported by the scientific method. See In re Paoli R.R. Yard PCB Litig.,
In Daubert, the Supreme Court "listed four noninclusive factors courts should consider in determining reliability under Rule 702:(1) whether the theory or technique can be tested; (2) whether it has been subjected to peer review; (3) whether the technique has a high known or potential rate of error; and (4) whether the theory has attained general acceptance within the scientific community." Allison, 184 F.3d at 1312 (citing Daubert v. Merrell Dow Pharmaceuticals, Inc.,
B. EPIDEMIOLOGICAL STUDIES
The central question in this pharmaceutical products liability case, just as in Daubert, is the issue of medical causation. The starting point of the Daubert analysis must be consideration of the factors identified by the Supreme Court in that case to determine reliability and relevance. The first of these is whether the theory of causation has been tested. Epidemiology is the medical science devoted to determining the cause of disease in human beings. Epidemiologists employ cohort studies, case-control studies, and ecological studies to determine whether individuals exposed to an agent have a greater risk of developing the disease in question. Bailey, et al., "Reference Guide on Epidemiology," Reference Manual on Scientific Evidence 340-45(2000). In epidemiological terms, the difference in risk of getting the disease is the "relative risk." A relative risk of 1.0 means that the agent has no effect on the incidence of disease. When the relative risk reaches 2.0, the agent is responsible for an equal number of cases of disease as all other background causes. A relative risk of 2.0 implies a 50 percent likelihood that an exposed individual's disease was caused by the agent in question. See, e.g., Hall v. Baxter Healthcare Corp.,
The existence of relevant epidemiological studies can be a significant factor in proving general causation in toxic tort cases. Hall, at 947 F.Supp. at 1403. Indeed, epidemiological studies provide "the primary generally accepted methodology for demonstrating a causal relation between a chemical compound and a set of symptoms or disease." Conde v. Velsicol Chem. Corp.,
Four epidemiological studies have been conducted to investigate a possible association between Parlodel® and stroke. The first study at issue is Kenneth Rothman, An Epidemiologic Evaluation of the Possible Relation Between Bromocriptine, Puerperal Seizures and Strokes (Epidemiologic Resources, Inc. Sept. 30, 1988) (Defendant's Motion to Exclude and for Summary Judgment, Siharath v. Sandoz Pharms. Corp., Ex. 10.) [Doc. 68]; (Defendant's Motion to Exclude and for Summary Judgment, Rider v. Sandoz Pharms. Corp., Ex. 10.) [Doc. 116]. In the hearing, this was referred to as the ERI study. The ERI study, commissioned by Defendant, is the only epidemiologic study using case controls and cohorts that has sought to determine whether a causal relationship exists between Parlodel® and stroke. This study reviewed hospital records of 280,096 postpartum women. Out of a total of ten postpartum strokes in this population, only one occurred in a woman who had taken Parlodel®. Of the 77 controls, only one had been exposed to Parlodel®. The resulting relative risk calculation, at 8.4, was deemed not statistically reliable by the study's investigators. Even Dr. Kulig admitted, "I'm not going to say that this shows the drug causes stroke." (Transcript of Daubert Hearing, at 177.)
Realizing this limitation of the ERI study, Plaintiffs' experts emphasize instead their opinion that the study shows that Parlodel® does cause "late-occurring seizures"—seizures occurring more than 72 hours after delivery. Plaintiffs allege that the relative risk factor of Parlodel®
The second study is HCIA Inc., Postpartum Complications and Parlodel® (October 1995). (Defendant's Motion to Exclude and for Summary Judgment, Siharath v. Sandoz Pharms. Corp., Ex. 12.) [Doc. 68]; (Defendant's Motion to Exclude and for Summary Judgment, Rider v. Sandoz Pharms. Corp., Ex. 12.) [Doc. 116]. This study, also commissioned by Defendant, is commonly referred to as the HCIA study. The study analyzed 533,816 delivery records from 128 hospitals. It tracked postpartum complications and correlated complications with Parlodel® use. The estimated relative risk for stroke associated with bromocriptine use was 1.088, with a confidence interval ("CI") from 0.448 to 2.643. Similarly, the estimated relative risk for seizures associated with bromocriptine use was 1.071, with a CI from 0.406 to 2.829. See Reference Manual at 360 ("A confidence interval is a range of values calculated from the results of a study, within which the true value is likely to fall; the width of the interval reflects random error.") For both preexisting and non-preexisting hypertensive women, the study concluded that there existed a negative association between bromocriptine (0.956 and 0.675 relative risks respectively) and hypertension. As Plaintiffs contend and Defendant admits, the HCIA study may possess methodological flaws that prevent a court from determining that Parlodel® definitely does not cause seizures and stroke, but the study certainly does not support Plaintiffs' theory of causation that Parlodel® does cause seizures and hemorrhagic stroke.
The third study is R.M.C. Herings and B.H.C. Stricker, Bromocriptne and Suppression of Postpartum Lactation, Pharmacy World & Sci. 17:133-37 (1995). (Defendant's Motion to Exclude and for Summary Judgment, Siharath v. Sandoz Pharms. Corp., Ex. 13.) [Doc. 68]; (Defendant's Motion to Exclude and for Summary Judgment, Rider v. Sandoz Pharms. Corp., Ex. 13.) [Doc. 116]. This study is often referred to as the Herings-Stricker study. In this study, investigators compared hospital admission and drug use of 2,130 women to identify the existence of ischemic heart disease, hypertension, and cerebrovascular events such as stroke before, during and after use of Parlodel® for postpartum lactation. The study found that no women whatsoever were admitted to hospitals for any of these conditions during the presumed exposure period or in the following two months. Plaintiffs question the methodology of this study on a number of grounds, including that the sample size was too small for an accurate epidemiological study. That may be, but the study also does not support Plaintiffs' theory that Parlodel® causes hemorrhagic stroke and seizures.
The fourth study is Andrea D. Witlin, et al., Postpartum Stroke: A Twenty-Year Experience. (Defendant's Motion to Exclude and for Summary Judgment, Siharath v. Sandoz Pharms. Corp., Ex. 11.) [Doc. 68]; (Defendant's Motion to Exclude
In short, neither the ERI study, the HCIA study, nor the Herings-Stricker study shows any statistically significant relationship between Parlodel® and stroke. The unpublished Witlin study found that bromocriptine was negatively associated with postpartum stroke, but it is unpublished and questions surround its actual intended purpose. As Dr. Kulig stated, "there is no good epidemiology on the subject." (Transcript of Daubert Hearing, at 281.) Plaintiffs' experts concede that no epidemiological study shows a statistically significant association between Parlodel® and stroke. The epidemiological studies either show no relationship or a negative relationship between the drug and stroke. Unable to rely upon the epidemiological studies as support for their causation opinions, Plaintiffs' experts predictably are critical of the conclusion that the studies prove Parlodel® is safe for postpartum women. None of the epidemiological studies are perfect; all have their flaws. It is important to recall, however, that the burden is on Plaintiffs to show that well-conducted epidemiological studies do show a statistically significant relationship between Parlodel® and seizures and stroke. It is not Defendant's burden to show the lack of such relationship.
Plaintiffs' well-taken criticisms of the epidemiological studies does not satisfy their burden of proof. See Glastetter v. Novartis Pharmaceutials Corp.,
The lack of epidemiological studies supporting Plaintiffs' claims creates a high bar for Plaintiffs to surmount with respect to the reliability requirement, but it is not automatically fatal to Plaintiffs case. If other reliable scientific knowledge exists, Plaintiffs may overcome this evidentiary gap in their case. Epidemiological evidence is not the only legally sufficient proof for establishing a prima facie case of medical causation. In a pre-Daubert case, the Eleventh Circuit stated that:
Wells v. Ortho Pharm. Corp.,
Epidemiology often is difficult to conduct. Additionally, ethical issues abound. "[O]ne cannot ethically experiment on human beings, exposing them to near certainty of some number of deaths, simply to satisfy some evidentiary standard." Globetti v. Sandoz Pharms. Corp.,
Joiner v. General Elec. Corp.,
C. CASE REPORTS
In the absence of statistically significant epidemiological studies to support their general causation theories, Plaintiffs' experts rely most heavily on case reports. Case reports are a form of anecdotal evidence where one event is reported as following another. Reference Manual at 91. Defendant's response to the reliance upon case reports is twofold. First, it contends that the specific case reports relied upon by Plaintiffs are not cases where Parlodel® caused hemorrhagic stroke in postpartum women. Second, it contends that case reports in general do not satisfy the requirements of the scientific method sufficient to establish general causation. Following much thought and careful review of the case reports, relevant case law, and numerous scholarly articles, the Court agrees on both counts.
Dr. Dukes, Plaintiffs' principal adverse drug reactions expert, emphasized in his affidavit a number of Sandoz case reports as evidence for his opinion that Parlodel® causes strokes:
(Affidavit of M.N.G. Dukes, M.D., M.A., L.L.M., at ¶¶ 36-37 (emphasis in original).) After looking at the adverse reaction reports themselves, the Court must conclude that this is a considerable overstatement of the case. This should be apparent from a brief examination of the reports relied upon by Dr. Dukes.
In paragraph 36 of his affidavit, Dr. Dukes states that Sandoz concluded that bromocriptine had probably caused an ischemic stroke in a woman five days after she began taking the drug. This woman, however, (1) was 62 years old; (2) was not postpartum; (3) had suffered from hypertension for 12 years; (4) suffered from acromegaly, a life-threatening pituitary disease that Dr. Dukes admits can lead to stroke; (5) was taking bromocriptine to reduce the size of a tumor (an approved indication); and (6) was also taking cortisone. (Plaintiffs' Ex. 125.) The case report emphasizes that her stroke was "[p]robably due to hypotension," not hypertension. The initial adverse drug report states only that it was possible, not probable, that the adverse event was due to Parlodel®. A subsequent, more detailed analysis in the case report likewise states that causality "is difficult to ascertain" and that it is only "possible" that Parlodel® "may be related to ischaemic cerebral infarction." Additionally, even if it can be said that bromocriptine probably caused this woman's stroke, it should be noted that this is the only stroke that Sandoz's Drug Monitoring Centre has ever concluded as "probably" having been caused by bromocriptine. Dr. Dukes has written that "[s]ometimes an adverse development may be a complication of the primary disease which is being treated rather than a complication of drug therapy." M.N.G. Dukes, et al., Responsibility for Drug-Induced Injury: A Reference Book for Lawyers, the Health Professions and Manufacturers 43 (2d ed.1998). This case report may be a good example of this process.
Dr. Dukes refers in paragraph 37 of his affidavit to a 23 year old German woman who took Parlodel® for three months and suffered from hypertension and cerebellar incoordination. As Defendant's counsel elicited from Dr. Dukes on cross-examination at the Daubert hearing, however, this patient was not postpartum; was taking Parlodel® to treat a pituitary adenoma, which itself can lead to hypertension and incoordination; and suffered from multiple sclerosis, a condition for which cerebellar incoordination is a classic symptom. (Plaintiffs' Ex. 57.) Also, the adverse event report stated only that it was "possible" that Paroldel® was causally related to her hypertension and incoordination. Mere possibility does not establish medical causation. Although an adverse case report is not required to "rule out" every other possibility to have some reliability, it should do more than just fail to rule out the alleged cause. It should provide a source for "ruling in" the alleged cause. A finding that Parlodel® "probably" caused a particular adverse event may add needed evidence to a causation theory. A finding that it only "possibly" caused the adverse event does not.
Dr. Dukes refers next in paragraph 37 of his affidavit to a 22 year old French woman who took Parlodel® to suppress postpartum lactation. She later developed hypertension and convulsions. (Plaintiffs' Ex. 60.) Dr. Dukes, however, fails to mention in his affidavit that the patient was hypertensive before delivery; that her hypertension decreased after taking Parlodel®; and that she suffered from postpartum eclampsia, which can lead to seizures and stroke. See generally Steven J. Kittner, et al., Pregnancy and the Risk of Stroke, New Eng. J. Med. 768-74 (1996)
Dr. Dukes also refers to a 20 year old Arkansas woman who took Parlodel® to suppress postpartum lactation and later developed hypertension. Dr. Dukes says that her symptoms improved after being taken off the drug, but the case report notes that she continued to suffer from hypertension for another four to five days. (Plaintiffs' Ex. 61.) This fact raises questions about the dechallenge (stopping use of the drug by the patient) aspect of this report, which is what Dr. Dukes emphasizes. Dr. Dukes discussed additional case reports in his affidavit. Defense counsel effectively discredited these additional case reports as evidence of a relationship between Parlodel® and postpartum stroke. See Transcript of Daubert Hearing, at 108-19 (referring to Plaintiffs' Exs. 126, 127, 25 & 168). Thus, Defendant has raised serious questions about Dr. Dukes' analysis of these case reports.
Additionally, Dr. Dukes stated during the Daubert hearing that the value of adverse drug reports varies greatly, depending on the quantity, nature and content of the reports. (Transcript of Daubert Hearing, at 20.) He explained that in determining whether a sufficient quantity exists, one should ask how many reports have been received. In determining the nature of the reports, one should ask whether the reactions are what one might expect of the drug, the drug type and the dosage. In determining whether the content of the reports is sufficient, Dr. Dukes provided a chart at the hearing listing four questions that can assist in this analysis:
The adverse drug reports in this case lack the requisite quantity, nature and content. From 1980 to 1994, millions of women took Parlodel®. The modest number of case reports associating the drug with stroke or even postpartum hypertension is not what would be expected if there was a significant increased risk. Only one report exists that links Parlodel® to a stroke, and in that case the patient suffered from an underlying condition that itself can cause stroke. No other patient in any case reports suffered any form of stroke. The other patients instead suffered non-cerebral effects such as hypertension and myocardial infarction. Many of the case reports cited involved patients who were not postpartum. One case report involved a patient who was dechallenged but continued to suffer from hypertension for another four to five days. In short, Plaintiffs' have not pointed to a single case report involving a postpartum woman who suffered a hemorrhagic stroke. Accordingly, even if case reports could be used to establish general causation, the Court would have to conclude that they are insufficient to do so in this case. The case reports simply lack the quantity, nature and content that Dr. Dukes himself claims is necessary for case reports to provide reliable scientific information about causation.
The fact of the matter is that even if relevant case reports existed, they cannot establish general causation:
Casey v. Ohio Medical Products,
Adverse reaction reports and other case reports are generated by the clinical process of "differential diagnosis." Differential diagnosis is a patient-specific process of elimination that medical practitioners use in an attempt to identify the "most likely" cause of a set of signs and symptoms from a list of possible causes. Differential diagnosis, however, does not by itself unequivocally prove the cause, even for the particular patient. Nor can the process establish general causation. In re Breast Implant Litig.,
Hall v. Baxter Healthcare Corp.,
Both of Plaintiffs' experts who testified at the Daubert hearing recognize the severe limitations of case reports and differential diagnosis in establishing general causation. Dr. Kulig admitted the limitations in the following exchange:
(Transcript of Daubert Hearing, at 193.) Case reports can establish only specific causation. Testimony regarding specific causation, however, is irrelevant unless general causation is established. Hall, 947 F.Supp. at 1413. Accordingly, given the limits of case reports in establishing general causation, as recognized by Plaintiffs' experts, the Court must conclude that Plaintiffs' reliance upon case reports as a substitute for epidemiology cannot withstand the scrutiny that Daubert requires.
The court in Globetti v. Sandoz Pharmaceuticals Corporation,
D. EFFECTS OF OTHER ERGOT ALKALOIDS
Plaintiffs' experts also rely on adverse effects of drugs other than bromocriptine, but within the same class, to support their hypothesis that Parlodel® causes seizures and stroke. They allege that the effects of bromocriptine are similar to those of other ergot alkaloids, a family of naturally occurring and semi-synthetic compounds. Defendant contends that this reliance raises serious questions of "fit." The Court agrees. In general, "[t]estimony extending general conclusions about similar drugs does not meet Daubert's requirements of reliability." Brumbaugh v. Sandoz Pharm. Corp.,
B. Berde & H.O. Schild, Ergot Alkaloids and Related Compounds 2 (emphasis in original).
In Mitchell v. Gencorp, Inc.,
Likewise, Plaintiffs' experts in this case cannot show that bromocriptine, the active ingredient in Parlodel®, affects the body in a manner similar to other ergot alkaloids. Plaintiffs' argument in this regard is as follows: Parlodel®'s active ingredient is bromocriptine. Bromocriptine is a semi-synthetic ergot alkaloid. Ergot alkaloids are a class of drugs that can cause vasoconstriction. Vasoconstriction can lead to hypertension, seizures and ischemic strokes. Hemorrhages are another type of stroke, so it is possible that they also are caused by Parlodel®. As in Mitchell, this argument suffers from a number of flaws. As mentioned above, bromocriptine cannot be assumed to cause the same effects as other ergot alkaloids. Bromocriptine differs physically from the other ergot alkaloids in several respects, most notably the addition of a bromine atom. It is accepted in the scientific and medical community that bromocriptine is not always a vasoconstrictor. It can be a vasodilator depending upon vascular tone. No evidence exists that other ergot alkaloids cause such peculiar effects. This scientific fact supports both the finding that small
Additionally, even if scientific support did exist for the Plaintiffs' conclusion that bromocriptine acts like other ergot alkaloids, Plaintiffs have presented no evidence that ergot alkaloids cause hemorrhagic strokes. There is evidence only that they may cause ischemic strokes. See, e.g., Goldfrank's Toxicologic Emergencies 754 (6th ed. 1998) ("In more serious cases, severe peripheral vasoconstriction may produce ischemic changes including angina, myocardial infacrction, cerebral ischemia, and mesenteric ischemia."). Dr. Kulig states that in his clinical experience drugs that cause ischemia can also cause hemorrhage, but he cites as examples only cocaine and methamphetamine, two highly dangerous drugs that no expert has claimed are similar to bromocriptine or any other ergot alkaloid. (Transcript of Daubert Hearing, at 166.) Furthermore, no epidemiology or even learned treatises link ergot alkaloids to hemorrhagic strokes. (Transcript of Daubert Hearing, at 212). Significant physiological distinctions exist between ischemic and hemorrhagic strokes. Ischemic strokes are caused by lack of blood flow to the brain. Hemorrhagic strokes are caused by the rupture of a blood vessel in the brain. The treatises list only cerebrovascular ischemia among the cerebral risk factors for ergot alkaloids. For all of the above reasons, Plaintiffs' experts' argument that bromocriptine is akin to other ergot alkaloids has not been supported by sufficient reliable scientific evidence in the record. Consequently, the Court cannot adopt Plaintiffs' conclusion that bromocriptine's effects can be extrapolated from the effects of other ergot alkaloids.
E. FOOD AND DRUG ADMINISTRATION DETERMINATIONS
Plaintiffs next contend that Food and Drug Administration findings and conclusions support their experts' causation opinions. On August 24, 1994, the FDA issued the following statement:
59 Fed.Reg. 43347, 43351 (Aug. 24, 1994).
Plaintiffs contend that this statement by the FDA supports the reliability of their experts' testimony. Plaintiffs' contention, however, ignores the lower standard of proof for agency determinations based upon a risk-utility analysis than the standard of proof required for the imposition of tort liability.
Mitchell v. Gencorp, Inc.,
F. ANIMAL STUDIES
Plaintiffs' experts also rely on animal studies to support their causation opinions. Defendant questions the reliability, or "fit," of these studies. Extrapolations from animal studies to human beings generally are not considered reliable in the absence of a credible scientific explanation of why such extrapolation is warranted. Hall v. Baxter Healthcare Corp.,
A few courts have been more amenable to the use of animal studies in proving causation, at least pre-Daubert. See In re Paoli R.R. Yard PCB Litig.,
Bell v. Swift Adhesives, Inc.,
There are basically three animal studies relied upon by Plaintiffs as evidentiary support for their theory that Parlodel® causes hemorrhagic strokes. These studies are (1) a Sandoz study conducted on the hind limb of a dog to determine bromocriptine's vasoconstrictive properties (Plaintiffs' Ex. 113); (2) a Sandoz study that assessed the effect of bromocriptine on the carotid artery of three mongrel dogs (Plaintiffs' Ex. 191); and (3) a group of Sandoz studies performed on pithed animals (Plaintiffs' Exs. 18, 19, 20, 21 & 210). As shown below, however, none of these studies establish that Parlodel® causes stroke in humans — or even in animals, for that matter. Even Dr. Kulig stated that he "wouldn't make the leap to stroke." (Transcript of Daubert Hearing, at 254 (emphasis added)). Furthermore, all of these animal studies have methodological flaws that prevent any conclusion that they "fit" with Plaintiffs' causation theory.
The Bertholet and Sutter study of the "hind-limb" of a dog (Plaintiffs' Ex. 113) attempted to determine, by injecting bromocriptine
The "carotid artery" study (Plaintiffs' Ex. 191) attempted to determine the effects of bromocriptine on the carotid artery of a dog. Plaintiffs emphasize that the study concluded that bromocriptine is capable of increasing vascular resistance by 177 percent. (Transcript of Daubert Hearing, at 157-58.) Plaintiffs contend that this fact clearly establishes that bromocriptine is a vasoconstrictor. Plaintiffs' experts, however, admit that this study does not demonstrate that bromocriptine causes stroke. (Transcript of Daubert Hearing, at 262.) The most they can say is that a drug that can cause vasoconstriction of the carotid artery should be "high on the suspicious drug list" for causing stroke. (Transcript of Daubert Hearing, at 262.) Suspicion, however, does not constitute the reasonable degree of medical certainty required to establish prima facie causation. Additionally, Defendant has provided a very persuasive argument that this study is of limited significance. According to Defendant, the study shows only that vascular resistance increased, not that blood vessels constricted or dilated. Any number of other factors could have caused the change in blood flow. Simply put, a change in resistance may occur regardless of a change in the artery. Analogizing to decreased pressure that one might experience in the shower when additional water faucets are turned on, Defendant's expert Dr. Engelman explained how in the carotid artery study the dog's cardiac output already was rapid, blood pressure dropped, and consequently the flow into the carotid artery dropped, resulting in an increase in resistance. Dr. Engelman convincingly explained that Plaintiffs' experts' simply conclude that the increase in resistance was caused by vasoconstriction, but that was not necessarily the case at all. All anyone really knows is that there was an increase in resistance in the study. The reason is unknown. That vasoconstriction occurred is simply a hypothesis, not an actual scientific finding.
Furthermore, Defendant noted that the flow probe in the study was placed only at the common carotid artery before it branches, with one branch going to the brain and the other going to the rest of the head. Consequently, there was no way for the researchers to measure the flow in either of these two branches. Dr. Engelman explained that typically when blood pressure falls, the body seeks to preserve blood flow to the heart and the brain. One, therefore, would have expected in this study for the carotid artery branch to the rest of the head to have contracted to preserve blood flow to the brain via the other branch. Because of the manner in which the carotid artery study was conducted,
Plaintiffs also contend that a number of studies conducted on pithed animals (Plaintiffs' Exs. 18, 19, 20, 21 & 210) show that bromocriptine can cause severe vasoconstriction. Pithed animals have had their central nervous system obliterated. The pithed animal studies at issue include rats, mice, dogs, cats and rabbits. Plaintiffs argue that vasoconstriction in these experiments was so severe that the tails of rats and mice became deprived of blood and fell off, as did the ear margins of dogs. Nevertheless, Plaintiffs' experts admit that they do not know whether these tests are predictive of human outcomes. (Transcript of Daubert Hearing, at 265.) It also is true that pithing an animal causes dramatic effects that otherwise would not be seen. As Defendant's expert, Dr. Engelman, testified, a pithed animal is one in which the brainstem is destroyed by inserting a probe or needle into the foramen magnum (the hole at the back, lower portion of the skull) and then moving the probe back and forth and up and down until the lower portion of the brain has been destroyed. This portion of the brainstem is the area where regulatory reflexes control the body's cardiovascular system. Consequently, destroying this regulatory mechanism renders an animal extremely sensitive to any change in blood pressure. Any drug that might affect blood pressure, whether to increase or decrease it, will thus magnify that change tremendously. (Transcript of Daubert Hearing, at 334.) Plaintiffs' expert, Dr. Dukes, has written that "[a]nimal studies can sometimes prove embarrasingly [sic] misleading, even where matters as serious as effects on pregnancy ... are concerned." M.N.G. Dukes et al., Responsibility for Drug-Induced Injury: A Reference Book for Lawyers, the Health Professions and Manufacturers 38 (2d ed.1998). The methodology of using pithed animals to determine cardiovascular effects such as blood pressure seems less than reliable. Given the possible magnifying effects of pithing on blood pressure, the pithed animal studies are of limited, if any, utility. Because causation must be based on scientific knowledge allowing for a reasonable degree of medical certainty rather than mere "leaps of faith," the Court must conclude that the animal studies do not assist Plaintiffs in satisfying the requirements of Daubert.
G. LEARNED TREATISES
Plaintiffs also rely on a number of medical treatises that they contend support their causation theory. Plaintiffs cite medical treatises stating the following:
These excerpts from the treatises, however, do not provide sufficient support for Plaintiffs' causation theory. The statements in the treatises are clearly based on case reports and, therefore, provide no more support than the case reports themselves. See Glastetter v. Novartis Pharms. Corp.,
H. TOTALITY OF THE EVIDENCE
Plaintiffs have produced an enormous mass of evidence about Parlodel®. Prior to Daubert, the Court in all likelihood would have said that it is the function of the jury to evaluate the relevance and reliability of Plaintiffs' expert testimony. The command of Daubert, however, is that scientific testimony must be based upon scientific methodology. In concluding that Parlodel® causes seizures and hemorrhagic strokes, Plaintiffs' experts have not relied upon reliable scientific methodology. This would be a different case if there was at least some support for the causal hypothesis in the peer-reviewed epidemiological literature, a predictable chemical mechanism, general acceptance in learned treatises and other scientific literature of a causal relationship, a plausible animal model, and dozens of well-documented case reports involving postpartum women with no other risk factors for stroke. In such a case, the totality of the evidence would be enough to satisfy the demands of Daubert. In this case, no epidemiological studies support Plaintiffs' causation theory. Plaintiffs have not established that all ergot alkaloids cause vasoconstriction and strokes. Although the FDA has removed its indication of Parlodel® for postpartum lactation, this decision was based upon a risk-utility analysis rather than a finding using scientific methodology that Parlodel® causes strokes. The standard by which the FDA deems a drug harmful is much lower than is required in a court of law. The FDA's lesser standard is necessitated by its prophylactic role in reducing the public's exposure to potentially harmful substances. The animal studies that Plaintiffs rely on do not "fit" because the reliability of extrapolating them to the human situation has been forcefully and effectively challenged by Defendant. The excerpts from learned treatises that Plaintiffs cite are merely based on case reports and, therefore, provide no more assistance
Plaintiffs' causal chain also is seriously flawed. The chain of Plaintiffs' argument is that Parlodel®'s active ingredient is bromocriptine, which is an ergot alkaloid, and ergot alkaloids are a class of drugs that can cause hypertension, seizures and ischemic strokes and, therefore, likely cause hemorrhagic strokes. Three scientifically unwarranted "leaps of faith" exist in this causal chain. First, a serious question exists whether bromocriptine is like other ergot alkaloids since it generally causes hypotension rather than hypertension. Second, even if Parlodel® can occasionally cause hypertension, Plaintiffs have not established that it can cause hypertension so severe as to cause seizures and stroke in humans. Third, even if Parlodel® can cause hypertension severe enough to cause stroke in humans, Plaintiffs have not shown that it causes hemorrhagic stroke. Plaintiffs have identified no epidemiological or animal studies, or even case reports, where Parlodel® was deemed to have caused a hemorrhagic stroke. Additionally, all medical evidence presented in this case on other ergot alkaloids establishes only that they may cause ischemic stroke. As discussed, ischemic strokes and hemorrhagic strokes are distinct and have different modi operandi. Ischemic strokes are caused by a reduction in blood flow to the brain. Hemorrhagic strokes are caused by a rupture to a blood vessel in the brain. Perhaps there is a reasonable extrapolation of ischemic strokes to hemorrhagic strokes, but Plaintiffs never fully explained it on their own or even when the Court raised the issue during the Daubert hearing. (Transcript of Daubert Hearing, at 39, 85, 165-66.) As Judge Becker of the Third Circuit has explained, expert testimony must be supported by "good grounds" at each step of the causal chain; and any step that renders their analysis unreliable also renders the testimony inadmissible. In re Paoli R.R. Yard PCB Litig.,
In short, Plaintiffs' case is not based on reasonable medical certainty, or "probabilities." It instead is based merely on "possibilities." This fact is vividly shown by the following exchange:
(Transcript of Daubert Hearing, at 267.) The inability of Dr. Kulig — as well as Plaintiffs' other experts — to answer this question in the affirmative requires this Court to exclude the experts' testimony and grant summary judgment in favor of Defendant. Experts must do something more than just "rule out" other possible causes. They must explain how they were able to "rule in" the product in question. If all an expert does is rule out other possible causes, he or she may fail to
As Defendant's expert, Dr. Buchholz explained at the Daubert hearing, doctors every day seek to determine causes of injury and illness and make patients healthier. In their eternal quest for "the answer," however, doctors sometimes believe that they have found a cause when they have not necessarily done so. Doctors in their day-to-day practices stumble upon coincidental occurrences and random events and often follow human nature, which is to confuse association and causation. They are programmed by human nature and the rigors and necessities of their clinical practices to conclude that temporal association equals causation, or at least that it provides an adequate proxy in the chaotic and sometimes inconclusive world of medicine. This shortcut aids doctors in their clinical practices because their most important objective day-to-day is to help their patients and "first, do no harm," as their Hippocratic oath requires. Consequently, "[t]hey make a leap of faith. And then in retrospect they build a bridge constructed of other anecdotal evidence, in some cases totally unrelated about heart attacks in older men and things like that and animal data, a bridge to help lead others across the chasm." (Transcript of Daubert Hearing, at 429.) The Court does not question Dr. Kulig's honest conviction that Parlodel® causes stroke or think that he is deliberately peddling "junk science." The Court also does not question that the methodology Dr. Kulig discussed at the Daubert hearing serves him well every day in the clinical practice of medicine. Dr. Kulig obviously is an exceptionally qualified practitioner, and the Court found him to be a very credible witness in this regard. Unfortunately, his clinical impression is not the sort of scientific methodology that Daubert demands.
Basically, Plaintiffs seek to survive Defendant's Motions to Exclude and for Summary Judgment by emphasizing that they have employed the same methodology as is applied by doctors throughout the world in their clinical practices. Plaintiffs argue that they have used the best methodology available for this case. That may be so, but their methodology does not satisfy the requirements of Daubert. They have not provided sufficient, reliable scientific evidence to support a jury finding of legal causation. As Dr. Bucchholz explained:
(Transcript of Daubert Hearing, at 396-97 (emphasis added).)
Plaintiffs' counsel and their expert witnesses have done the best they could with the data available from the scientific literature and the Defendant's internal studies. If Daubert established a "best efforts" test, they unquestionably would have passed that test. Nevertheless, it appears that their "testimony is based more on personal opinion than on scientific knowledge." Allison v. McGhan Med. Corp.,
Finally, the Court should not be too eager to make leaps of faith from a pharmaceutical manufacturer's basic research. Defendant continually researched whether an association exists between Parlodel® and hypertension, seizures, myocardial infarctions, and strokes. It attempted to determine whether the correlation of these conditions and Parlodel® use was a causal occurrence or rather only a chance occurrence. They never were able to establish causation. If this Court were to lower the Daubert standard based on anecdotal, temporal evidence obtained from Sandoz case reports, unfounded extrapolations, and leaps of faith, the Court would create an unintended disincentive for pharmaceuticals companies to engage in ongoing research as to their products' safety and efficacy. Such an "ostrich in the sand" approach would in the long run make pharmaceutical products more risky, not safer.
In an attempt to prohibit the presentation of "junk science" to the trier of fact, perhaps Daubert has raised the bar for admissibility of expert testimony too high. Maybe there should be a middle ground between the Daubert standard and a standard that would allow sympathetic plaintiffs with catastrophic injuries to recover against pharmaceutical manufacturers based upon nothing more than speculation and conjecture. It is not, however, for this Court to seek that middle ground. This Court's duty is to apply the law as it exists today. And Daubert requires reliable science to support scientific opinion. "Striking the appropriate balance may sometimes be a difficult task." Allison, 184 F.3d at 1321. In some cases, no reliable science exists. Unfortunately for Plaintiffs, it appears to the Court that this is one of those cases. As Judge Posner has written, "the courtroom is not the place for scientific guesswork, even of the inspired sort. Law lags science; it does not lead it." Rosen v. Ciba-Geigy Corp.,
For the reasons set forth above, the Court in Siharath GRANTS Defendant's Motion to Exclude and for Summary Judgment on Issues of Medical Causation Under Daubert v. Merrell Dow Pharmaceuticals, Inc. [Doc. 68], DENIES AS MOOT Defendant's Motion for Partial Summary Judgment on Warning Claims [Doc. 69-1], DENIES AS MOOT Defendant's Motion for Partial Summary Judgment on Fraud and Negligent Misrepresentation [Doc. 69-2], DENIES AS MOOT Defendant's Renewed Motion for Summary Judgment on the Statute of Limitations [Doc. 69-2], DENIES AS MOOT Defendant's Motion for Oral Argument on its Renewed Motion for Summary Judgment on the Statute of Limitations [Doc. 126], DENIES AS MOOT Defendant's Motion for Leave to Amend its Answer to Plead Federal Preemption [Doc. 133-1], DENIES AS MOOT Defendant's Motion for a Briefing Schedule [Doc. 133-2], and DENIES AS MOOT Defendant's Motion for Oral Argument on its Federal Preemption Defense [Doc. 133-3]. The Clerk is directed to enter judgment for the Defendant.
Similarly, the Court in Rider GRANTS Defendant's Motion to Exclude and for Summary Judgment on Issues of Medical Causation Under Daubert v. Merrell Dow Pharmaceuticals, Inc. [Doc. 116], DENIES AS MOOT Defendant's Motion for Partial Summary Judgment on Warning Claims [Doc. 117-1], DENIES AS MOOT Defendant's Motion for Partial Summary Judgment on Fraud and Negligent Misrepresentation [Doc. 117-2], DENIES AS MOOT Defendant's Motion for Leave to Amend its Answer to Plead Federal Preemption [Doc. 177-1], DENIES AS MOOT Defendant's Motion for a Briefing Schedule [Doc. 177-2], and DENIES AS MOOT Defendant's Motion for Oral Argument on its Federal Preemption Defense [Doc. 177-3]. The Clerk is directed to enter judgment for the Defendants.
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