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In Re: Avandia Marketing

January 3, 2011

IN RE: AVANDIA MARKETING,SALES AVANDIA PRACTICES AND PRODUCTS LIABILITY LITIGATION


The opinion of the court was delivered by: Hon. Cynthia M. Rufe

Rufe, J.

ALL ACTIONS THIS DOCUMENT RELATES TO MEMORANDUM OPINION AND ORDER

Presently before the Court are GlaxoSmithKline LLC's (GSK's) Motions to Exclude the Testimony of Plaintiff Steering Committee's Expert Witnesses Eliot A. Brinton, M.D.,*fn1 Nicholas

P. Jewell, Ph.D.,*fn2 and Allan D. Sniderman, M.D.,*fn3 Plaintiffs' responses thereto, and GSK's replies. The Court has reviewed each expert's report and held a Daubert hearing to hear argument and testimony regarding the admissibility of the expert testimony on September 20 -22, 2010. For the reasons set forth below, the Court will deny the motions to exclude the testimony of Drs. Brinton, Sniderman, and Jewell.

Factual Background

Plaintiff intends to offer Drs. Brinton, Jewell and Sniderman, among other experts, as generic expert witnesses for civil actions in MDL No. 1871. Their testimony will cover the alleged health risks involved in taking the drug Avandia, which is manufactured by GSK. GSK challenges the admissibility of this evidence, asserting that the experts used unreliable methods to reach their conclusions that Avandia may cause myocardial infarction in diabetic patients taking it to control their blood sugar.

Standard of Review

Federal Rule of Evidence 702 reads:

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

The Third Circuit has distilled this rule to two essential inquiries: 1) is the proffered expert qualified to express an expert opinion; and 2) is the expert opinion reliable?*fn4 In this case, GSK primarily challenges the reliability of the opinions.

Under the Third Circuit framework, the focus of the Court's inquiry must be on the experts' methods, not their conclusions. Therefore, the fact that Plaintiffs' experts and defendants' experts reach different conclusions does not factor into the Court's assessment of the reliability of their methods.*fn5 The experts must use good grounds to reach their conclusions, but not necessarily the best grounds or unflawed methods.*fn6

Here, the scientific question the experts are addressing is whether there is a reasonable degree of scientific certainty that Avandia can cause myocardial infarctions. To meet the Daubert standard, the experts must demonstrate that they have good grounds for their causation opinion (i.e. the opinion is based on methods and procedures of science, not subjective belief) and a reasonable degree of scientific certainty regarding their causation opinion.*fn7

Expert evidence must be relevant and reliable to be admissible. The Court must consider:

1) whether the expert's theory can be tested; 2) whether studies have been subject to peer review and publication; 3) the potential for error in a technique used; and 4) the degree to which a technique or theory (but not necessarily a conclusion) is generally accepted in the scientific community.*fn8 In cases such as this one, where the allegation is that a chemical (Avandia) causes a medical condition (myocardial infarction) experts should rely primarily on epidemiological studies to test their theory that the drug causes the disease. Double-blind randomized control trials, and particularly monotherapy trials comparing Avandia use to a placebo, are the "gold standard" of epidemiology. The best studies are designed and powered to test the outcome of interest (e.g., in this case, the most telling trial would be designed and have adequate subjects needed to study the impact of Avandia on the heart, not its effectiveness in managing blood sugar or other outcomes).*fn9

Discussion

1. General Issues

Epidemiological Methods

The research on safety risks from Avandia use falls into three categories: 1) randomized control trials ("RCTs"), such as RECORD, DREAM, and ADOPT; 2) meta-analyses, such as NISSEN, SINGH, and MANUCCI; 3) and observational studies (such as the Harvard and Michigan studies).*fn10

GSK argues that randomized control trials are the "gold standard" for epidemiological research, and that Plaintiffs' experts can find no support for their position in the RCTs conducted because the association between Avandia and myocardial infarction did not reach statistical significance in any of the RCTs. Therefore, GSK argues, the experts cannot rule out the possibility that the association was due to chance alone. In addition, GSK argues, none of the RCTs found Avandia to be associated with a statistically significant increase in atherosclerosis, which Plaintiffs' experts agree is the principal cause of myocardial infarction.

GSK also argues that Plaintiffs' experts do not give adequate weight to the findings of the RECORD study, which was a large RCT designed and carried out by GSK specifically to compare the cardiovascular safety of Avandia to that of Actos (a competitor medication in the same class). The RECORD study found no statistically significant increase in myocardial infarction, cardiovascular hospitalization or death.

Similarly, GSK argues that Plaintiffs improperly disregard the findings of the ADOPT and DREAM trials. Both are RCTs designed to test to the efficacy of Avandia for glycemic control, not its safety, and in both the association between Avandia and myocardial events approached but did not reach statistical significance.

Plaintiffs' experts each made specific criticisms about the RCT study designs and pointed out issues which complicate interpretation of the data, such as concurrent use of statins and a high drop out rate. These will be discussed in detail below. The experts also explained that when both the treatment group and the control group have a high background risk of myocardial infarction by reason of being diabetic, a large number of subjects is needed to adequately test whether Avandia is associated with an increased risk of myocardial infarction. If the sample size is too small to adequately assess whether the substance is associated with the outcome of interest, statisticians say that the study lacks the power necessary to test the hypothesis. Plaintiffs' experts argue, among other points, that the RCTs upon which GSK relies are all underpowered to study cardiac risks.

To overcome the problem of underpowered studies, researchers may combine data from several studies into a meta-analysis. The NISSEN meta-analysis combined 42 clinical trials, including the RECORD trial and other RCTs, and found that Avandia increased the risk of myocardial infarction by 43%, a statistically significant result (p = .031). Plaintiffs point out that all the data used by Dr. Nissen in his meta-analysis came from GSK's own clinical trial registry. The NISSEN study was peer reviewed and published in the New England Journal of Medicine. Although GSK criticizes Plaintiffs' experts for relying on the NISSEN study, and notes that meta-analysis generally can be unreliable, GSK points out no specific flaws or limitations in the design or implementation of the NISSEN meta-analysis, and the NISSEN results have been replicated by other researchers. For example, the SINGH meta-analysis pooled data from four long-term clinical trials, and also found a statistically significant increase in the risk of myocardial infarction for patients taking Avandia.*fn11 GSK and the FDA have also replicated the results of NISSEN through their own meta-analyses.

GSK argues that Plaintiffs' experts place too much reliance on meta-analysis (and particularly the NISSEN and SINGH studies), as meta-analysis is better for generating hypotheses than for testing them. While this may be true, the Court notes that if a statistically significant finding in a meta-analysis generates a hypothesis that Avandia is associated with a significant risk of heart attack, it may then become unethical to proceed with RCT of that substance, especially given the number of test subjects which would be required to adequately power a RCT to study whether Avandia causes heart attacks. Therefore, in some cases the science must proceed based upon less rigorous methods. This does not mean that inferences about causation cannot be made; it simply means that the expert must more carefully examine possible sources of bias or confounding and other factors which may make the study a weak indicator of causation.

Additionally, GSK argues that Plaintiffs' experts rely too heavily on observational studies, in which patients are not randomly assigned to treatment groups, and hence the patients for whom Avandia is prescribed may be different in some important ways from those in the control group who take another drug or no drug. One must carefully consider sources of bias, confounding, and alternative mechanisms.

Making Conclusions about Causation and the Bradford-Hill Criteria Bradford-Hill criteria are used to assess whether an established association between two variables actually reflects a causal relationship.*fn12 Because these criteria are so well established in epidemiological research, it appears that the experts often consider these factors without citation to Bradford-Hill. When making causal inferences from associations between exposure to a chemical or drug and a disease outcome, the relevant Bradford-Hill criteria are: temporal relationship between the exposure and the outcome; the strength of the association between the exposure and the outcome; the dose-response relationship; replication of findings; the biological plausibility of or mechanism for such an association; alternative explanations for the association; the specificity of the association; and the consistency with other scientific knowledge. An expert need not consider or satisfy every criteria in order to support a causal inference. GSK argues that the Plaintiffs' experts equate association with causation and fail to apply the Bradford-Hill criteria when making causal inferences. The Court will examine this assertion in detail in the sections that follow.

Although GSK asserts that a plausible biological mechanism to explain any association is one of the weaker Bradford-Hill criteria, GSK goes on to argue that Plaintiffs' experts lack a reliable theory for and proof of a biological mechanism of action. Specifically, they argue that the research on Avandia does not show that it causes a ...


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