For GSK, the other shoe dropped in the Avandia multi-district litigation, on January 13, 2011, when the presiding judge denied the defense challenge to plaintiff’s expert witness specific causation opinions, in the first case set for trial. Burford v. GlaxoSmithKline, PLC, 2011 WL 135017 (E.D.Pa. 2011).
In the MDL court’s opinion on general causation, In re Avandia Marketing, Sales Practices and Product Liability Litigation, 2011 WL 13576 (E.D. Pa. 2011), Judge Rufe determined that she was bound to apply a “Third Circuit” approach to expert witness gatekeeping, which focused on the challenged expert witnesses’ methodology, not their conclusions. In Burford, Judge Rufe, citing two Third Circuit cases were decided after Daubert, but before Joiner, repeats this basic mistake. Burford, 2011 WL 135017, *2. Remarkably, the court’s opinion in Burford recites the current version of Federal Rule of Evidence 702, which states that the court must analyze expert witnesses’ conclusions for being based upon “sufficient facts or data,” as well as for being “the product of reliable principle and methods.” The statute mandates consideration of the reliability and validity of the witness’s conclusions, if those conclusion are in his testimony. This Rule, enacted by Congress in 2000, is a statute, and thus supersedes prior case law, although the Advisory Notes explain that the language of the rule draws heavily from the United States Supreme Court’s decisions in Daubert, Joiner, and Kumho Tire. The Avandia MDL court ignored both the post-Daubert decisions of the Supreme Court, as well as the controlling language of the statute, in gatekeeping opinions on general and specific causation.
Two expert witnesses on specific causation were the subject of GSK’s challenge in Burford: Dr. Nicholas DePace and Dr. Judy Melinek. The court readily dispatches Dr. Melinek, who opines that Mr. Burford’s fatal cardiac event, which she characterizes as a heart attack, was caused by Avandia because Avandia causes heart attacks. The court correctly noted that this inference was improper because risk does not equal causation in a specific case.
As one well-known epidemiologist has put it:
“An elementary but essential principal that epidemiologists must keep in mind is that a person may be exposed to an agent and then develop disease without there being any causal connection between exposure and disease.”
* * *
“In a courtroom, experts are asked to opine whether the disease of a given patient has been caused by a specific exposure. This approach of assigning causation in a single person is radically different from the epidemiologic approach, which does not attempt to attribute causation in any individual instance. Rather, the epidemiologic approach is to evaluate the proposition that the exposure is a cause of the disease in a theoretical sense, rather than in a specific person.”
Kenneth Rothman, Epidemiology: An Introduction 44 (Oxford 2002)(emphasis added).
In addressing the admissibility of Dr. DePace’s expert opinion, however, the MDL Court is led astray by Dr. DePace’s handwaving about having considered and “ruled out” Mr. Burford’s other risk factors.
To be sure, Dr. DePace has some ideas about how Avandia may, plausibly, cause heart attacks. In particular, Dr. DePace identified three plausible mechanisms, each of which would have had been accompanied by some biomarker (elevated blood lipids, elevated Lp-PLA2, or hypoglycemia). This witness, however, could not opine that any of these mechanisms was in operation in producing Mr. Burford’s fatal cardiac event. Burford, at *3.
Undaunted, Dr. DePace opined that he had ruled out Mr. Burford’s other risk factors, but his opinion, even from Judge Rufe’s narrative is clearly hand waving and dissembling. First, everyone, including every middle age man, has a risk of heart attack or cardiac arrest, although that risk may be modified – increased or lowered – by risks or preventive factors. Mr. Burford had severe diabetes, which in and of itself, is a risk factor, commonly recognized to equal the size of the risk from having had a previous heart attack. So Mr. Burford was not at baseline risk; indeed, he started all his diabetes medications with the equivalent risk of someone who had had a heart attack already.
Dr. DePace apparently opined that Mr. Burford’s diabetes, his blood sugar level, was well controlled. The court accepted this contention at face value, although the reader of the court’s opinion will know that it is rubbish. Although the court does not recite any blood sugar levels, its narrative of facts includes the following course of medications for Mr. Burford:
- June 2004, diagnosed with type II diabetes, and treated with metformin
- April 2005, dose of metformin doubled
- August 2005, Avandia added to double dose of metformin
- December 2005, Avandia dose doubled as well
- June 2006, metformin dose doubled again
- October or November 2006, sulfonylurea added to Avandia and metformin
This narrative hardly suggests good control. Mr. Burford was on a downward spiral of disease, which in a little over two years took him from diagnosis to three medications to try to control his diabetes. Despite adding Avandia to metformin, doubling the doses of Avandia, doubling and then quadrupling doses of metformin, Mr. Burford still required yet another, third medication, to achieve glycemic control. Of course, an expert witness can say anything, but the federal district court is supposed to act as a gatekeeper, to protect juries and parties from their ipse dixit. Many opinions will be difficult to evaluate, but here, Dr. DePace’s opinion about glycemic control in Mr. Burford comes with a banner headline, which shouts “bogus.”
The addition of a third medication, a sulfonylurea, known to cause hypoglycemia (dangerously low blood sugar), which in turn can cause cardiac events and myocardial infarction, is particularly troubling. See “Sulfonylurea,” in Wikipedia January 24, 2011. Sulfonylureas act by stimulating the pancreas to produce more insulin, and the sudden addition of this medication to an already aggressive regime of medication clearly had the ability to induce hypoglycemia in Mr. Burford. Dr. DePace notes that there is no evidence of an hypoglycemic event, which is often true in diabetic patients who experience a sudden death, but the gatekeeping court should have noticed that Dr. DePace’s lack of evidence did not equate to evidence that the risk or actual causal role (of hypoglycemia) was lacking. Again, the trial court appeared to be snookered by an expert witness’s hand waving. Surely gatekeepers must be made of sterner stuff.
Perhaps the most wrongheaded is the MDL court’s handling, or its failure to handle, risk as causation, in Dr. DePace’s testimony.
In his deposition, Dr. DePace testified that a heart attack in a 49 year-old man was “very unusual.” Such a qualitative opinion does not help the finder of fact. A heart attack is more likely in any 49 year-old man than in any 21 year-old man, although men of both ages can and do suffer heart attacks. Clearly, a heart attack is more likely in a 49-year old man who has had diabetes, which has required intensive medication for even a semblance of control, than in a 49 year-old man who has never had diabetes. Dr. DePace’s opinions fail to show that Mr. Burford had no base-line risk in absence of one particular medication, or that this base-line risk was not operating to produce, sufficiently, his alleged heart attack.
Rather than being a high-risk group with respect to his Avandia use, according to the FDA’s 2007 meta-analysis, Mr. Burford and other patients on “triple therapy” (Avandia + metformin + sulfonylurea), would have had an odds ratio of 1.1 for any myocardial ischemic event, not statistically significant, as a result of their Avandia use. Mr. Burford’s additional use of an ACE-inhibitor, along with this three diabetic medications, would place him into yet another sub-subgroup. Whatever modification or interaction this additional medication created in combination with Avandia, the confidence intervals, which were wide for the odds ratio of 1.1, would become extremely wide, allowing no meaningful inference. In any event, the court in Burford does not tell us what the risk was opined to be, and whether there were good data and facts to support such an opinion. Remarkably absent from the court’s opinion in Burford is any consideration of the actual magnitude of the claimed risk (in terms of a hazard ratio, relative risk, odds ratio, risk difference, etc.) for patients like Mr. Burford. Further absent is any consideration of whether any study showing risk has further shown the risk to be statistically different from 1.0 (no increased risk at all).
As Ted Frank has noted on PointofLaw Forum, the Avandia MDL raises serious questions about the allocation of technical multi-district litigation cases to judges in the federal system. “It is hard to escape the conclusion that the MDL denied GSK intellectual due process of law” (January 21, 2011). The Avandia experience also raises questions about the efficacy of the Federal Judicial Center’s program to train judges in the basic analytical, statistical, and scientific disciplines needed in their gatekeeping capacity.
Although the Avandia MDL court’s assessment that Dr. DePace’s opinion was suboptimal, Burford at * 4, may translate into GSK’s ability to win before a jury, the point of Rule 702 is that a party should not have to stand trial on such shoddy evidence.