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In re Accutane Litigation

Superior Court of New Jersey, Appellate Division

July 28, 2017

IN RE: ACCUTANE LITIGATION

          Argued March 7, 2017

         On appeal from the Superior Court of New Jersey, Law Division, Atlantic County, Case No. 2 71 (MCL).

          Bruce D. Greenberg and David R. Buchanan argued the cause for appellants (Seeger Weiss, LLP, Lite, DePalma, Greenberg, LLC, and Weitz & Luxenberg, PC, attorneys; Mr. Buchanan and Peter Samberg, of counsel; Mr. Buchanan, on the briefs).

          Paul W. Schmidt (Covington & Burling, LLP) of the District of Columbia bar, admitted pro hac vice, argued the cause for respondents Hoffman LaRoche, Inc. and Roche Laboratories, Inc. (Gibbons PC, Dughi Hewit & Domalewski, PC and Mr. Schmidt, attorneys; Michelle M. Bufano, Natalie H. Mantell, Russell L. Hewit, Mr. Schmidt and Michael X. Imbroscio (Covington & Burling, LLP) of the District of Columbia bar, admitted pro hac vice, of counsel; Ms. Bufano, on the brief).

          Hollingsworth LLP, attorneys for amicus curiae Pharmaceutical Research and Manufacturers of America (Gregory S. Chernack, of counsel and on the brief).

         The parties have not filed briefs in A-0910-16.

          Before Judges Reisner, Koblitz and Sumners.

          OPINION

          REISNER, P.J.A.D.

         Plaintiffs, in these 2076 multicounty litigation (MCL) products liability cases, alleged that they developed Crohn's disease [1] as a result of taking Accutane (isotretinoin), a prescription acne drug manufactured by defendants Hoffman-La Roche Inc. and Roche Laboratories Inc. (collectively Roche or defendants). After a Kemp[2] hearing, the trial court issued a February 20, 2015 order granting defendants' omnibus motion to bar plaintiffs' experts - Dr. David Madigan, a statistician, and Dr. Arthur Kornbluth, a gastroenterologist - from testifying, among other things, that the epidemiology studies on which the defense relied were flawed and unreliable, and that Accutane can cause Crohn's disease. The trial court also directed the parties to prepare an order listing the lawsuits affected by the ruling, and subsequently issued a May 8, 2015 order dismissing 2076 MCL claims with prejudice. Plaintiffs appeal from those orders.[3]

         On this appeal, plaintiffs primarily contend that the trial court misapplied its discretion in finding that the methodologies Madigan and Kornbluth used were scientifically unreliable and inadmissible. After reviewing the record, we reverse the orders on appeal and remand this case to the trial court.

         We agree with plaintiffs that the trial court went beyond its gatekeeping function, as set forth in Rubanick v. Witco Chemical Corp., 125 N.J. 421, 449 (1991), Landrigan v. Celotex Corp., 127 N.J. 404 (1992), and Kemp, supra, 174 N.J. at 412.[4] The trial court took too narrow a view in determining whether the experts were using accepted scientific methodologies to analyze the evidence, and improperly determined the weight and credibility of the experts' testimony. Among other things, the judge inappropriately condemned the experts for relying on relevant scientific evidence other than epidemiological studies, despite their plausible explanations for doing do.[5] Consequently, we conclude that the trial court mistakenly exercised discretion in barring the experts' testimony.

         In reaching our conclusion, we emphasize that we are not placing this court's imprimatur on plaintiffs' experts or on their opinions. The experts on both sides are highly reputable scientists, who view the evidence differently. We find no basis to describe plaintiffs' experts pejoratively as "hired guns, " any more than the defense experts are "hired guns." Their testimony should not have been barred because their analyses emphasized different evidence and produced different conclusions than those reached by the defense experts. The fact that plaintiffs' experts found certain evidence to be critically important did not constitute improper "cherry picking, " because they provided plausible scientific explanations for their choices. See State v. Dreher, 302 N.J.Super. 408, 464 (App. Div. 1997) ("Expert testimony should not be excluded merely because it fails to account for some condition or fact that the opposing party considers relevant.").

         We are not predicting whether a jury will find plaintiffs' experts - or defendants' experts - credible or persuasive. That is not our role, as it was not the trial court's role in the Kemp hearing. See Hisenaj v. Kuehner, 194 N.J. 6, 24 (2008) (N.J.R.E. 104 hearings "are intended to determine admissibility, not credibility."). We only hold that, on the record created in the Kemp hearing in this case, the plaintiffs' experts provided well-explained scientific reasons for analyzing the available evidence differently from the defense experts, and for relying more heavily on different evidence than the defense experts relied on.

         Accordingly, plaintiffs are entitled to present the experts' testimony at trial.

         I

         This case cannot be viewed in a vacuum. It is one in a long series of mass tort litigations concerning Accutane.[6] We need not review the history in detail, as it is set forth in a series of previous unpublished opinions issued by different panels of this court. We summarize only what is important to this case.

         For more than a decade, the same trial judge had handled the Accutane cases. To some extent, that judge's familiarity with the prior litigation, and with the multiplicity of scientific issues involved, may have shaped the way the parties and their experts prepared for the current litigation.[7] The first judge's rulings no doubt also shaped the parties' litigation strategies.

         In particular, during the course of the litigation, the first judge determined that the opinions of plaintiffs' experts, based on the same types of evidence relied on by plaintiff's experts in this case, would be admissible as scientifically reliable. We affirmed that determination in McCarrell I, supra, A-3280-07, [8]finding that animal studies, case reports, analogous medications, and other evidence relied on by plaintiffs' experts, were types of evidence accepted in the scientific community.[9]

         In the present case, defendants contend that the existence of epidemiological studies now precludes reliance on the other types of evidence on which plaintiff's experts had previously relied. However, the studies on which defendants rely are not the controlled clinical trials that the Federal Judicial Center's Research Manual on Scientific Evidence calls "the gold standard" of scientific evidence. Rather they are observational studies that depend on the collection of information from databases or from patient questionnaires. Plaintiffs' experts testified that the studies are biased and otherwise flawed. We conclude that plaintiffs should be entitled to present that testimony at trial, along with their affirmative evidence in support of their case.

         II

         We begin with some background as to Accutane, the epidemiological studies of the drug, and relevant scientific principles of epidemiology.

         A. Accutane

         In 1982, the Food and Drug Administration (FDA) approved defendants' application to market Accutane, the brand name for isotretinoin, "to treat recalcitrant nodular acne that has not responded to other regimens." Kendall I, supra, 209 N.J. at 180. The drug is a retinoid, derived from vitamin A, and is very effective in treating severe acne. Ibid. It is well established that Accutane "has a number of known side effects, including dry lips, skin and eyes; conjunctivitis; decreased night vision; muscle and joint aches; elevated triglycerides; and a high risk of birth defects if a woman ingests the drug while pregnant." Ibid. There is also some evidence that Accutane, which was originally studied for use in treating cancer, has an effect on the gastrointestinal tract.

         The MCL cases concern the alleged propensity of Accutane to cause IBD, a chronic disease which primarily manifests as one of two diseases: Crohn's disease or ulcerative colitis. Id. at 18081. Although both ulcerative colitis and Crohn's disease share the same core symptoms, including abdominal pain, frequent and often bloody bowel movements, and rectal bleeding, there are differences in the clinical presentation of the disease and the triggers statistically associated for developing it, which include family history, infections, frequent use of some antibiotics, smoking, and possibly the use of oral contraceptives and nonsteroidal anti-inflammatory drugs. Id. at 181.

         The peak onset of the disease occurs during adolescence-the same period that individuals are likely to have been prescribed Accutane. Ibid. For both diseases there may be a significant latency effect (the time from the exposure to the trigger for IBD to the first symptom of the disease) and a prodromal period (the time from the first symptom of the disease to diagnosis).

         B. Epidemiological studies

         For the first six years of this MCL litigation, from 2003 to 2009, there were no epidemiological studies regarding Accutane and IBD. In previous trials, the plaintiffs were permitted to present expert testimony that relied on animal studies, human clinical studies, case reports, class effects, published scientific literature, causality assessments, and biological plausibility. McCarrell I, supra, slip op. at 86; Kendall I, supra, slip op. at 85-86; Sager, supra, slip op. at 20.

         The first two epidemiological studies (Crockett and Bernstein), [10] were published in 2009 and in 2010, finding no statistically significant increased risk of developing Crohn's disease from the use of Accutane, although the Crockett study found ulcerative colitis is associated with exposure to the drug. The Crockett and Bernstein studies were addressed in expert testimony in Gaghan, McCarrell II, and Rossitto. In Kendall II, the expert witnesses addressed four new epidemiological studies (Etminan, Alhusayen, Fenerty, and Racine).[11] After the trial in Kendall II, two additional studies were published (Rashtak and Sivaraman).[12] The epidemiological studies vary in whether they show that Accutane increases or decreases the risk of developing Crohn's disease. However, with one exception, none of them demonstrates a statistically significant increased risk of developing Crohn's disease from exposure to Accutane. One small study (Sivaraman) did find a statistically significant increased risk. However, when the study authors adjusted the study results for antibiotic use, the results were no longer statistically significant. Plaintiffs' experts questioned the appropriateness of that adjustment.

         C. Epidemiology

         In understanding the epidemiological studies, it is first helpful to define the methodology used in conducting such studies and the relevant terms, as testified by the experts at the hearing and as set forth in the Federal Judicial Center, Reference Manual on Scientific Evidence 549, 555 (3d. ed. 2011) (Reference Manual or Manual).[13] "Epidemiology is the field of public health and medicine that studies the incidence, distribution, and etiology of disease in human populations." Id. at 551. "Epidemiology assumes that disease is not distributed randomly in a group of individuals and the identifiable subgroups, including those exposed to certain agents [such as prescription drugs], are at increased risk of contracting particular diseases." Ibid. Epidemiological studies identify agents that are associated with an increased risk of a disease in groups of individuals, but "is not equivalent to causation." Id. at 552.

         There are two types of epidemiological studies: experimental and observational. Id. at 555. Experimental studies, or double-blind randomized control trials, in which one group is exposed to an agent and the other is not, are "considered the gold standard for determining the relationship of an agent to a health outcome or adverse side effect." Ibid. There are, however, no Accutane experimental studies because although such studies have the potential to provide higher quality evidence, they cannot ethically be conducted if researchers suspect that a drug's side-effects are harmful. Id. at 555-56.

         Instead, all of the Accutane epidemiological studies to date are less rigorous observational studies, which are considered to be the next best available evidence. Id. at 556. There are two types of observational studies: 1) a case-control study, which measures and compares the frequency of exposure in the group with the disease (cases) and a similar group without the disease (controls); and 2) a cohort study, which compares a group of exposed and unexposed individuals over a period of time. Id. at 557-59. In these studies, researchers "observe" individuals who have already been exposed to the drug and compare them to a group of individuals who have not. Id. at 555-56.

         Unlike experimental studies in which risk factors can be controlled, observational studies generally focus on individuals living in a community, "for whom characteristics other than the one of interest, such as diet, exercise, exposure to other environmental agents, and genetic background, may distort a study's results." Id. at 556. "[T]he Achilles' heel of observational studies is the possibility of differences in the two populations being studied with regard to risk factors other than exposure to the agent." Ibid.

         Epidemiological studies commonly express the strength of association between exposure to a drug and a disease in numerical terms as: 1) "relative risk" (RR), the ratio of the incidence rate of a disease in exposed individuals to the risk among the unexposed; or 2) "odds ratio" (OR), the ratio of the odds that an individual with the disease was exposed to the drug to the odds that an individual without the disease was exposed. Id. at 56669.[14] An RR of 1.0 means that the relative risk is equal to the "null hypothesis, " that is, that the risk in individuals exposed to Accutane is the same as the risk in unexposed individuals, or that Accutane use is not associated with an increased risk of developing Crohn's disease. Id. at 567. If the RR is greater than 1.0, the risk in exposed individuals is greater than the risk in unexposed individuals. Ibid. For example, an RR of 1.5 means that an exposed individual has a 50% greater chance of contracting Crohn's disease. If the RR is less than 1.0, the exposed group has a decreased risk of contracting the disease. Ibid. Thus, an RR of .32 represents a 68% reduction in risk, which might mean that the drug had a protective effect on developing the disease.

         The OR or RR is, however, only an estimate of the true value. Determining whether an association identified in an epidemiological study is causal "requires an understanding of the strengths and weaknesses of the study's design and implementation, as well as a judgment about how the study findings fit with other scientific knowledge." Id. at 553. An assessment must be made of the power of the study to detect associations, the role of chance, and what sources of error might have produced a false result, including sampling variability, bias, and confounding variables (extraneous variables that may affect result). Id. at 566-97.

         Therefore, a showing of an increased relative risk for Crohn's disease does not automatically prove that Accutane use creates a higher risk of developing the disease because the discrepancy between the exposed and unexposed groups could be the product of chance as a result of random sampling error. Id. at 553. In determining whether a relative risk greater than 1.0 is a true association or the result of random error, researchers consider whether the association is statistically significant. Id. at 628. In making that assessment, researchers calculate a p-value, which "represents the probability that an observed positive association could result from random error even if no association were in fact present." Id. at 576. The p-value quantifies the statistical significance of a relationship; the smaller the p-value the greater the likelihood that associations determined in a study do not result from chance. Id. at 626. The most commonly used p-value is .05, that is for example, that there is a 5% chance that the relative risk could have occurred by random error. Id. at 57677.

         A more sophisticated approach, which was used in the studies at issue in this case, involves calculating a confidence interval (CI):

A confidence interval is a range of possible values calculated from the results of a study. If a 95% confidence interval is specified, the range encompasses the results we would expect 95% of the time if samples for new studies were repeatedly drawn from the same population. . . . The advantage of a confidence interval is that it displays more information than significance testing. "Statistically significant" does not convey the magnitude of the association found in the study or indicate how statistically stable that association is. A confidence interval shows the boundaries of the relative risk based on selected levels of . . . statistical significance. . . . [T]he confidence interval reveals the likely range of risk estimates consistent with random error.
[Id. at 580.]

         If, for example, a study reveals a RR of 1.5, which represents an elevated risk of developing Crohn's disease, that result might or might not be considered statistically significant, depending on the boundaries of the confidence interval. If the CI includes 1.0 (the null hypothesis, meaning that taking Accutane neither increases nor decreases the risk of developing Crohn's disease), then the 1.5 result is said not to be statistically significant. However, if the CI is entirely above 1.0, for example if it ranges from 1.2 to 3.2, then the 1.5 RR would be considered statistically significant. Id. at 580-81.

         In assessing whether the failure of a study to find a statistically significant association was exonerative of the drug or simply inconclusive, scientists consider the "power" of a study, or "the probability of finding a statistically significant association of a given magnitude (if it exists) in light of the sample sizes used in the study." Id. at 582. "The power of a study depends on several factors: the sample size; the level of statistical significance specified; the background incidence of disease; and the specified relative risk that the researcher would like to detect." Ibid. The higher the power of the study the less likely it will show a false negative. Ibid. For example, a study with a likelihood of .25 of failing to detect a true RR of 2.0, has a power of .75, meaning the study has a 75% chance of detecting a true RR of 2.0. Ibid. On the other hand, a study with low power has a greater likelihood of failing to detect a significant relative risk, even though such a risk exists. "With large numbers [of individuals included in the study group], the outcome of the test is less likely to be influenced by random error, and the researcher would have greater confidence in the inferences drawn from the data." Id. at 57 6.

         Under the proper circumstances, researchers can increase the power of a series of studies by conducting a meta-analysis, which involves pooling the results of different studies, some of which are small and lack statistical power, to arrive at a single figure to represent the totality of the studies. Id. at 608. The Manual indicates, however, that a meta-analysis may produce an unreliable result.

The appeal of a meta-analysis is that it generates a single estimate of risk (along with an associated confidence interval), but this strength can also be a weakness, and may lead to a false sense of security regarding the certainty of the estimate. A key issue is the matter of heterogeneity of results among the studies being summarized. If there is more variance among study results than one would expect by chance, this creates further uncertainty about the summary measure from the meta-analysis. Such differences can arise from variations in study quality, or in study populations or in study designs. Such differences in results make it harder to trust a single estimate of effect; the reasons for such differences need at least to be acknowledged and, if possible, explained. People often tend to have an inordinate belief in the validity of the findings when a single number is attached to them, and many of the difficulties that may arise in conducting a meta-analysis, especially of observational studies such as epidemiologic ones, may consequently be overlooked.
[Ibid.]

         III

         We next address the parties' conflicting testimony on the subjects of gastroenterology and epidemiology. As background, the following chart[15] summarizes the epidemiological studies at issue in this case:

STUDY

DATABASE AND SUBJECTS

NO. OF SUBJECTS

RR for CD at CI 95%

ACCUTANE EXPOSURE PRIOR TO DIAGNOSIS

STUDY RESULTS

Bernstein 2009 manuscript (case-control)

Canadian Health Ins.

21, 500 (total) 1118 (CD)

1.15 (0.61-2.02)

2.6 years

Positive association (increased risk), but not SS

Crockett 2010 manuscript (case-control)

US Health Ins. (55 million)

29, 000 (total) 3664 (CD)

0.68 (0.28-1.68)

0.89 (0.32-2.52)

1 year

2 year

Negative association (decreased risk) Negative association (decreased risk)

Etminan 2013 manuscript (case-control) (meta-analysis)

US Health Ins. (women who had taken oral contraceptives)

45, 000 (total) 1103 (CD)

1.05 (0.5501.98)

0.91 (0.37-2.25)

0.75 (0.46-1.24)

1 year

Positive unadjusted association Negative adjusted association (decreased risk) Negative association (meta-analysis)

Racine 2014 manuscript (case-control)

French Health Ins. (47 million)

44, 000 (total) 2829 (CD)

0.45 (0.24-0.85)

1 to 2 years

SS protective association (reduced risk)

Alhusayen 2013 manuscript (cohort)

Canadian Database (4.5 million)

46, 922 (treated with Accutane)

1.17 (0.90-1.52)

1 year

Positive association (increased risk), but not SS

Sivaraman 2014 abstract/ poster (case-control)

US Patient Questionnaire from three clinics

509 (total)

5.6 (1.1-28.0)

4.8 (0.3-70)

unknown

Positive unadjusted association and SS for CD

Positive adjusted association, but not SS for CD

Fenerty 2013 abstract/ power-point (case-control)

Marketscan Medicaid Database

176, 889 (total) 324 (CD)

For IBD

0.57 (0.28-1.16)

Not reported for CD

Negative association for IBD (decreased risk)

Rashtak 2014 manuscript (cohort)

Mayo Clinic patients

1078 (total)

For IBD 0.28 (0.10-0.79)

Not reported for CD

Negative association for IBD (decreased risk)

         A. Gastroenterology experts

         1. Dr. Asher Kornbluth

         Plaintiffs' expert, Dr. Kornbluth, was a highly qualified expert who was board-certified in internal medicine and gastroenterology and was a professor of medicine at Mount Sinai, the preeminent hospital for IBD. He had specialized in Crohn's disease for twenty-seven years, conducted research on IBD, conducted clinical trials on several drugs intended for use in the management of IBD, treated between 5, 000 and 10, 000 patients with Crohn's disease, been retained as a consultant to pharmaceutical companies, and published more than 100 articles on IBD in peer-reviewed scientific journals, textbooks, and other publications.

         Kornbluth opined that Accutane can cause Crohn's disease in humans. In reaching that conclusion, Kornbluth relied on his personal experience in treating thousands of patients with the disease. Additionally, he relied on some of the same evidence that Dr. David Sachar, a previous plaintiffs' expert, had relied on in seven previous Accutane trials in this MCL docket, [16]including animal studies, case reports, class effects of Vesanoid, biological plausibility, scientific articles, internal studies, causality assessments, and epidemiological studies. However, as more fully discussed infra, both Dr. Kornbluth and Dr. Madigan testified that most of the epidemiological studies done to date were fundamentally flawed, thus warranting greater reliance on other forms of scientific evidence.

         Evidence of an Association

         In accord with what he testified was the established scientific methodology, Kornbluth first considered whether there was an association between Accutane and Crohn's disease. In making that determination, he reviewed scientific articles, MedWatch reports, epidemiological studies, and causality assessments, which he found reflected a strong association between Accutane and Crohn's disease.

         a. Scientific articles

         Kornbluth reviewed articles published in peer-reviewed scientific journals, many of which analyzed a single anecdotal case report, which he found supported a finding that there was an association between Accutane and Crohn's disease.[17] For example, an article by Reddy and several colleagues reported that of the approximately four or five million people that took Accutane between 1997 and 2002, the FDA received eighty-five reports of IBD. Using the Naranjo ADR probability scale, the authors found that "4 cases (5%) scored in the 'highly probable' range for isotretinoin as the cause of IBD, 58 cases (68%) were 'probable, ' 23 cases (27%) were 'possible, ' and no cases were doubtful." Reddy, supra note 17, at 1571. The authors concluded that "isotretinoin appears to be a potential precipitant of IBD." Id. at 1572.

         b. MedWatch reports

         Kornbluth next reviewed a series of MedWatch reports, reports which are made by physicians, patients and others to the FDA listing among other information, a description of the adverse event and whether it abated after the patient stopped using Accutane and returned after reintroduction (referred to as challenge/dechallenge/rechallenge). He found that if corrected for underreporting, the number of MedWatch reports suggested a strong association between Accutane and Crohn's disease.

         c. Epidemiological studies

         Kornbluth also reviewed six observational epidemiological studies (Bernstein, Crockett, Alhusayen, Etminan, Racine, and Sivaraman), only one of which (Sivaraman) found a statistically significant positive association (before adjustment for antibiotic use) between Accutane and Crohn's disease, one found a statistically significant negative association (Racine) and no study concluded that Accutane use presents an increased risk for developing Crohn's disease.[18] Kornbluth opined that despite "significant flaws" in five of those studies that distorted the results, the studies nonetheless provided some evidence of an association between Accutane and Crohn's disease.

         Kornbluth relied on the unadjusted results of the Sivaraman study, which was summarized in a published abstract (not manuscript form), and selected by the American College of Gastroenterology to be presented as a poster at their annual conference to enable peers and colleagues to discuss the findings with the researchers. In that small study (509 patients), the authors initially found a statistically significant association between Accutane and Crohn's disease: that the risk of developing the disease was more than five times higher in the group exposed to Accutane. The authors collected data using a questionnaire, which included information about use of antibiotics, family history of IBD, and smoking, thereby accounting for confounding variables. The authors then "adjusted" the analysis to remove subjects who had taken antibiotics, which Kornbluth said still yielded a "very striking increased risk" of developing Crohn's disease from Accutane use, although the adjusted sample size was too small to demonstrate statistical significance. The authors concluded that "isotretinoin exposure does not appear to confer risk for Crohn's disease independent of antibiotic exposure." Kornbluth and Madigan both questioned the basis for the adjustment the authors made.[19]

         Kornbluth opined that the results of the other five studies (Bernstein, Crockett, Alhusayen, Etminan, and Racine), were inconclusive because they: failed to account for the prodrome (see section 1 below); were insufficiently "powered"; or contained design flaws that biased or distorted the results to show a reduced risk of developing Crohn's disease. Nonetheless, Kornbluth found that the studies were informative in determining causation, noting that four of the studies (Bernstein, Etminan (unadjusted), Alhusayen, and Sivaraman) found a positive association between the drug and the disease.

         1. Prodrome

         Kornbluth opined that four of the studies (Crockett, Alhusayen, Etminan, and Racine) had not followed patients for long enough to detect an effect from Accutane exposure and thus had failed to account for the prodrome of Crohn's disease, that is, the delay between the time of the first or early symptoms and the diagnosis. He opined, based on his decades of experience as a treating gastroenterologist, that the average prodrome for Crohn's disease was from two to four years. He found support for that opinion in several studies, including: 1) the Pimentel study, [20] a referral-based study (45 of the 66 subjects had Crohn's disease), in which the authors found the mean prodrome for Crohn's disease was 6.9 years; and 2) the Barratt study, [21] in which the authors found the mean prodrome was four years. He distinguished the findings of a larger study by Chouraki[22] in which the authors found a three-month prodrome, based upon the selection of the patients for the study and the use of patient charts as opposed to patient questionnaires, as used in the Barratt and Pimentel studies.

         Kornbluth explained that because the prodrome for Crohn's disease is two to four years, a study that looks back only one-year from diagnosis would not capture patients who developed Crohn's disease from Accutane exposure 366 days to four years after taking the drug. He noted, for example, that in the Crockett study the odds ratio increased from 0.68 (one-year analysis) to 0.89 (two-year analysis), which he said was likely a result of capturing more patients who had developed the disease. Similarly, the Bernstein study, which looked back approximately 2.6 years, found a positive association between Accutane and Crohn's disease, which Kornbluth opined may also have resulted from capturing more Crohn's disease patients than the other shorter studies. He found that these four studies were not designed to accurately account for all of the Accutane patients who had developed Crohn's disease, thereby distorting the results. He opined that if the studies had been designed to account for the long prodrome, the results would have shown a greater increased risk of developing Crohn's disease.[23]

         2. Power

         Next, Kornbluth opined that three of the studies (Bernstein, Crockett, and Etminan), were insufficiently powered to detect a statistically significant association; in other words, that the sample size was not large enough to make a definitive conclusion as to whether there was a statistically significant risk. For example, in the Bernstein study, a large case-control study using a Canadian database, the study population only comprised 1118 Crohn's disease cases out of a control population of 19, 419. He calculated that the "power" of the Bernstein study was low (about 25% to 30%), that is, there was only a 25% to 30% chance of detecting a statistically significant association (greater than 2%) between Accutane and Crohn's disease. He explained that 80% power was appropriate for a study. He opined that if these studies had not been underpowered, the results would have been statistically significant for an increased risk of developing the disease.

         However, Kornbluth admitted that where individual studies are underpowered to detect outcomes, studies can be pooled using a meta-analysis, to increase the power to detect a risk. One such study was done by Etminan, which combined the Bernstein, Crockett, Etminan (case-control study) and Racine studies, and found a pooled RR of .75 with a CI of 0.46 to 1.24, indicating no increased risk of developing Crohn's disease. Another study was done by Goodman, defendants' expert, as discussed more fully infra, who found a pooled RR of 0.87 with a CI of 0.59 to 1.28, or, again, no statistically significant increased risk of developing Crohn's disease. However, Kornbluth, like Madigan, rejected the results of these meta-analyses, explaining that a meta-analysis using underpowered and flawed studies (as he said existed in this case), which did not account for the prodrome, are not informative and should not be relied upon by scientists in determining causation.

         3. Design flaws

         Kornbluth also found the results of the five studies were inconclusive because they had design flaws, including differences in the populations and the failure to account for confounding variables. For example, he opined that the Bernstein study, a Canadian study, was flawed because of the differences in recommended doses between the United States (higher dose) and Canada (lower dose). He expected that given that difference there would be far fewer cases of Crohn's disease in Canada thereby decreasing the relative risk ratio. Similarly, there were differences in recommended doses ...


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