Opinion ID: 2341867
Heading Depth: 1
Heading Rank: 4

Heading: reliability and relevance of causation evidence

Text: An appellate court's standard of review relative to a ruling on the reliability of scientific evidence under Daubert is whether the ruling is supported by substantial evidence. Id. at 917. The ruling as to the relevance of the scientific evidence is reviewed under an abuse of discretion standard. Id. Appellants maintain that the scientific evidence relied on by the Gundersons' causation experts, specifically case reports, animal studies, and chemical analogies, was unreliable and/or not relevant because it did not prove that Parlodel causes seizures in women taking the drug for postpartum lactation suppression (PPLS). Appellants argue that such evidence is merely anecdotal and that the only reliable method of proving that Parlodel causes seizures in such women is an epidemiological study. It was established at trial that there were two epidemiological studies looking at postpartum women taking Parlodel for PPLS, the HCIA study commissioned by Sandoz, and the ERI study, also commissioned by Sandoz and conducted by Dr. Rothman from Epidemiology Resources, Inc. (ERI). The evidence established that the HCIA study had been rejected by the scientific community because some patients were not trackable, and there were apparent misclassifications within the study. Even an epidemiologist from Sandoz conceded that the HCIA study was too flawed to be considered. Shortly after Parlodel was approved by the FDA for PPLS in 1981, the FDA began receiving a significant amount of adverse drug reports of women experiencing headaches, hypertension, heart attacks, seizures, and strokes after taking the drug for PPLS. The ERI study was commissioned by Sandoz in 1986 to allay concerns of the FDA that Parlodel was responsible for causing strokes and seizures in women taking the drug for PPLS. The final report from the ERI study released in 1988 concluded that women taking Parlodel for PPLS had only a 1.61% greater risk of having a seizure than women not getting the drug, which is considered statistically insignificant. At trial, three of Appellees' experts, Dr. George Nichols, Dr. Kenneth Kulig and Dr. Dennis Petro, seriously criticized the final report from the ERI study because it was apparent to them that the risk rate of seizure for that population had been lowered from 2.86% (which is considered statistically significant) due to changing the data analyzed to exclude women with a history of seizures and women who had also taken a related drug, ergonovine, regardless of whether that drug was known to be in the woman's system at the time of the adverse event. In fact, the Gundersons offered into evidence a letter to ERI from Sandoz requesting that it recut the data on late-onset seizures in the final report on the ERI study. The final report on the ERI study was subsequently rejected for publication by three peer review journals because it was misleading and discounted the positive association between Parlodel and seizures. Dr. Kulig and Dr. Petro testified that the ERI study actually supported their opinion that Parlodel can cause seizures late in the postpartum period (more than seventy-two hours after delivery). The Gundersons' causation experts also relied on the myriad of case reports of women experiencing postpartum seizures after taking Parlodel for PPLS. The case reports filed with the FDA, known as adverse drug reports (ADRs), are filed by many sources, including hospitals, physicians, and the patients who took the drugs. The ADRs are relied on by the FDA after the drug is approved and released into the marketplace to monitor whether there are side effects or adverse reactions to the drug that did not show up in the initial clinical trials of the drug. Under federal regulations, drug companies that receive information about an adverse drug reaction that involves one of their drugs are required to report the reaction to the FDA. The package insert for Parlodel listed eighty-nine cases of hypertension, seventy-two seizures, and thirty strokes when the drug was used for PPLS. Several case reports were contained in peer-reviewed medical literature as support for statements that Parlodel has been known to cause vasoconstriction and possibly seizure, stroke and heart attacks. At least two of the case reports indicated that the adverse symptoms disappeared when Parlodel was withdrawn and then reappeared when Parlodel was reintroduced. Dr. Petro testified that these cases of de-challenge/re-challenge were considered substantially better evidence of a causal relationship than an adverse reaction alone. The Gundersons offered into evidence an internal Sandoz document from 1982 in which Sandoz acknowledged that it had received ten to twelve reports of seizures in patients given Parlodel during the postpartum period and stated, From our side, we felt that these cases were probably related to episodes of hypertension, which we know can occur under Parlodel in such patients. In another internal Sandoz memorandum from 1982, Dr. William Westlin, Director of the Medical Services Department at Sandoz, responded as follows to reports of adverse reactions to Parlodel: In view of my recent conversation with Dr. Weiner at FDA, I think we should give this report serious consideration. I am beginning to think that there is some association between seizures, hypertension, and Parlodel therapy in the postpartum period, even though it is rare and is, at present, unexplainable. Dr. Petro testified that case reports are some evidence of an association between a drug and a particular reaction, but not definitive evidence. Although Parlodel is known to lower blood pressure by dilating blood vessels, the Gundersons' causation experts also relied on animal studies wherein Parlodel was shown to cause the paradoxical effect of vasoconstriction. One study in particular, a hind leg study on dogs, indicated that low initial vascular resistance, which women typically experience after giving birth, permits vasoconstriction, which could account for why women in a postpartum state are more susceptible to seizures from Parlodel. Dr. Petro also cited a toxicology study on rats in which the rats experienced seizures when given high doses of Parlodel. Appellants contend that the animal studies offer no proof that Parlodel causes seizures in humans, thus, are scientifically unreliable under Daubert . Dr. Nichols, Dr. Petro and Dr. Kulig all testified that they looked at animal studies on Parlodel and found them insightful on the issue of causation. Dr. Kulig testified that animal reactions to drugs are relevant because they reflect a reaction that a human may have to the drug. Appellants also assert that evidence of the properties of the general class of drugs within which Parlodel is contained, ergot alkaloids, was not scientifically relevant or reliable. Dr. Kulig, a physician specializing in emergency medicine and medical toxicology, testified that it is a well known and proven fact that ergot alkaloid drugs can cause vasoconstriction, hypertension, and convulsive seizures, which supported his opinion that the Parlodel caused the hypertensive episode which resulted in Mary Gunderson's fatal seizure. Appellants maintain that the general propensities of the broad class of ergot alkaloid drugs cannot be analogized to Parlodel because of the diversity amongst the different ergot drugs. The trial court ruled at the January 19, 2004 hearing that although the individual pieces of evidence at issue (case reports, ADRs, animal studies and chemical analogies, articles in medical textbooks and scientific publications) may not by themselves definitively prove that Parlodel causes postpartum seizures in women, when considered together as an aggregate body of evidence with scientific underpinnings, it is reliable enough evidence to put before the jury in this case. We agree. The four factors that a court may look at in determining the reliability of an expert's testimony include, but are not limited to: (1) whether a theory or technique can be and has been tested; (2) whether the theory or technique has been subjected to peer review and publication; (3) whether, with respect to a particular technique, there is a high known or potential rate of error and whether there are standards controlling the technique's operation; and (4) whether the theory or technique enjoys general acceptance within the relevant scientific, technical, or other specialized community. Goodyear Tire and Rubber Co. v. Thompson, 11 S.W.3d 575, 578-79 (Ky.2000) (citing Daubert, 509 U.S. at 592-94, 113 S.Ct. at 2796-97, 125 L.Ed.2d at 482-83). A trial court's reliability analysis under Daubert is not limited to the above factors and should be tailored to the particular facts and science in the case. Miller, 146 S.W.3d at 918-19. The Daubert factors are simply a way of distinguishing between science and pseudo-science. Id. at 919. In applying Daubert to the type of evidence relied on by the causation experts in the instant case, a number of courts in Parlodel cases from other jurisdictions have rejected the evidence other than epidemiological studies (case reports, ADRs, animal studies, temporal association between ingestion of Parlodel and adverse event, hypertensive properties of ergot alkaloids, FDA withdrawal of approval of Parlodel's indication for PPLS) as scientifically unreliable. Rider v. Sandoz Pharm. Corp., 295 F.3d 1194 (11th Cir. 2002) (postpartum stroke case); Glastetter v. Novartis Pharm. Corp., 252 F.3d 986 (8th Cir.2001) (postpartum stroke case); Dunn v. Sandoz Pharm. Corp., 275 F.Supp.2d 672 (M.D.N.C.2003) (postpartum stroke case); Soldo v. Sandoz Pharm. Corp., 244 F.Supp.2d 434 (W.D.Pa.2003) (postpartum stroke case); Caraker v. Sandoz Pharm. Corp., 188 F.Supp.2d 1026 (S.D.Ill.2001) (postpartum stroke case); Hollander v. Sandoz Pharm. Corp., 95 F.Supp.2d 1230 (W.D.Okla.2000), affirmed and remanded on other grounds, 289 F.3d 1193 (10th Cir.2002) (causation expert's testimony rejected in postpartum stroke case); Brumbaugh v. Sandoz Pharm. Corp., 77 F.Supp.2d 1153 (D.Mont.1999) (causation expert's testimony rejected in postpartum seizure case). However, we view those cases, as the court did in Globetti v. Sandoz Pharmaceuticals Corporation, 111 F.Supp.2d 1174, 1180 (N.D.Ala. 2000) (expert testimony that Parlodel caused plaintiffs acute postpartum heart attack found to be sufficiently reliable), as incorrectly requiring scientific certainty, which was not intended by Daubert . The court believes that in those cases the Daubert standard was applied incorrectly, creating too high a standard of admissibility. Both of these cases seem to equate Daubert's reliability with scientific certainty, which is far from what the Supreme Court intended in Daubert . Science, like many other human endeavors, draws conclusions from circumstantial evidence when other, better forms of evidence is not available.... [O]ne cannot practically conduct an epidemiological study of the association of Parlodel with postpartum AMI. Moreover, one cannot ethically experiment on human beings, exposing them to the near certainty of some number of deaths, simply to satisfy some evidentiary standard. Id. at 1180. The Globetti court adjudged that much of the same type of evidence relied on by the causation experts in the instant case was scientifically reliable under Daubert . Although defendant is correct that there is no epidemiological study showing an increased risk of AMI [acute myocardial infarction] associated with bromocriptine, there is more than adequate evidence of a scientific nature from which a reliable conclusion can be drawn about the association. While an epidemiological study may be the best evidence, Daubert requires only that reliable evidence be presented, and that evidence here consists of animal studies, the medical literature reviews, the ADRs reported to the FDA, the general acceptance of the association reflected in several medical texts, the Larrazet experiment, and Dr. Waller's observations in the Avers case. These all are recognized and accepted scientific methodologies, used for assessing the possible side-effects and hazards associated with particular drugs and the causes of disease. The fact that Mrs. Globetti's AMI was caused by her ingestion of Parlodel can be reliably inferred from the facts known about the vasoconstrictive effect of bromocriptine. Id. at 1179; see also Kuhn v. Sandoz Pharm. Corp., 270 Kan. 443, 14 P.3d 1170 (2000) (expert testimony that Parlodel caused woman's postpartum seizure, cerebral edema and death ruled admissible). Likewise, the court in Brasher v. Sandoz Pharmaceuticals Corporation, 160 F.Supp.2d 1291, 1296 (N.D.Ala.2001) (even without epidemiological study establishing causation and with other possible explanations for strokes, experts' opinions that Parlodel caused postpartum strokes found to be sufficiently reliable), ruled that this type of evidence was reliable and rejected a requirement of scientific certainty relative to causation evidence: Daubert does not require proof to a scientific certainty, or even proof convincing to the trial judge. The trial judge is not required to find that the proffered opinion is scientifically correct, but only that it is trustworthy because it is tied to good scientific grounds. What Daubert does require is that the expert's opinion be based on sound methodologies of the type used by experts in the field in which the opinion is offered. There can be little question that scientists routinely use animal studies, case reports, and pharmacological comparisons of similar classes of drugs to infer conclusions, which are expressed in peer-reviewed journals and textbooks. Unquestionably, epidemiological studies provide the best proof of the general association of a particular substance with particular effects, but it is not the only scientific basis on which those effects can be predicted. In science, as in life, where there is smoke, fire can be inferred, subject to debate and further testing. We believe the scientific evidence on which the Gundersons' causation experts based their testimony was sufficiently reliable in the present case and that there was substantial evidence supporting the court's ruling of reliability in this case. While Dr. Petro admitted that epidemiological evidence is the gold standard for determining causation, the Gundersons' causation experts, including Dr. Petro, testified that they also relied on other scientific evidence to assess causation. Each of the disputed pieces of evidence considered by the Gundersons' experts (case reports, animal studies, and general chemical properties of ergot drugs) had scientific underpinnings, was derived from recognized scientific methodologies, and was shown to have general acceptance within the scientific community as a factor tending to show that Parlodel causes postpartum seizures. As for the relevancy of the causation evidence at issue, relevance is determined by evaluating whether [that] reasoning or methodology properly can be applied to the facts in issue. Daubert, 509 U.S. at 592-93, 113 S.Ct. at 2796. The consideration of relevance has been described as one of `fit.' Thompson, 11 S.W.3d at 578 (quoting Daubert, 509 U.S. at 591, 113 S.Ct. at 2796, 125 L.Ed.2d at 481-82). We deem the case reports, animal studies, and general chemical properties of ergot drugs to be relevant scientific evidence that would assist the jury in making the determination of general causation in this casewhether Parlodel was capable of causing a postpartum seizure. Both Dr. Kulig and Dr. Petro testified that they considered this type of evidence (among other evidence as shall be discussed below) because it tended to show how the ingestion of Parlodel would have affected a postpartum woman and that it was capable of causing a fatal seizure. Accordingly, the trial court did not abuse its discretion in its relevancy ruling.