Remember that Nissen and Wolski said that they used the Peto method,1 but, “The patron saint of meta-analysis, Richard Peto, who helped bring the approach back from what we used to dismiss as ‘unplanned pooling,’ stressed approaches that would avoid bias . . . .”2
This post considers whether Nissen and Wolski avoided bias in their meta-analysis1 of rosiglitazone (Avandia; GlaxoSmithKline).
“Bias” is a serious charge. Is it justified?
Let us begin by consulting Steven Nissen, himself. Dr. Nissen has blasted “Flaws, Bias, Misinterpretation and Fraud in Randomized Clinical Trials.”3 Some of his dishonorable mentions included:
- Use of unblinded study designs
- Errors of omission (selective reporting of results)
- Type I (particularly multiplicity) and Type II error
Let’s see how many of those applied to Nissen and Wolski’s own meta-analysis.1
To begin with, Nissen and Wolski were unblinded, meaning they knew what effects their choices of studies would have: “. . . this was not a blinded effort and the results were obtained with full knowledge of the effect of various analytic decisions on the outcome by the analysts.”2 In fact, they included the DREAM (Diabetes REduction Assessment With ramipril And rosiglitazone Medication) study in their meta-analysis because it suggested an increase in acute myocardial infarctions (heart attacks).
. . . in his presentation at the July 2010 AC [advisory committee of the Food and Drug Administration] meeting, Nissen made it clear that it was DREAM, with its adverse trends on AMI [acute myocardial infarction] as well as other endpoints (especially CHF [congestive heart failure]), that provoked the meta-analysis.2
Interestingly, Nissen uses his own unblinded study1 to contrast with the unblinded RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) study.3
- Unblinded study? Check one.
Nissen and Wolski1 selectively chose studies to include, from among those that met their inclusion criteria,4 with the full knowledge of the impact that these choices would have upon the outcome: “Nonetheless, it must be recognized that there was potential bias in its development (or at least the analysis was done with knowledge of what would emerge) . . . .”2
- Ascertainment bias? Check another.
I devoted a whole post to Nissen and Wolski’s1 strange omissions, in Strange Omissions in Nissen’s Avandia Analysis, January 31, 2014. Suffice it to say that
There were, in fact, studies available to Nissen and to the public, which met Nissen’s inclusion criteria, but which he failed to include in his meta-analysis. Nissen’s meta-analysis was thus biased by its failure to have conducted a complete, thorough review of the medical literature for qualifying RCTs [randomized controlled trials].4
- Errors of omission? Check another one.
I devoted another whole post to Nissen and Wolski’s results depending upon the errors of multiple comparisons (multiplicity), in More Concerns With Nissen’s Avandia Analysis, January 29, 2014. In brief, the more comparisons beyond one, the greater the bias toward finding a difference that does not really exist. Nissen and Wolski reported eight. Apparently, Dr. Nissen did not pay much attention to his own graph of the effect of multiple comparisons.
- Errors due to multiplicity? Check one more.
Interestingly, although Dr. Nissen makes much of pharmaceutical sponsorship as being sufficient to prove bias,5 his list did not mention bias from sponsorships. However, he did claim that “Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor tax deduction is received.”3 This claim is not what it appears to be. As will be seen in an upcoming post, Dr. Nissen’s hypocrisy in this. Apparently, he has never been supported by GlaxoSmithKline, but
“. . . Steven Nissen has acknowledged that his work is supported by many GlaxoSmithKline competitors including Pfizer, AstraZeneca, Sanofi-Aventis, Eli Lilly and the Japanese drug company called Takeda, which makes the diabetes drug Actos that competes directly with Avandia.”6
- Sponsorship bias? Add another.
While Dr. Nissen acknowledged limitations with the analysis, “his concern was mainly about the true magnitude of the risk, not whether or not the risk was present or absent.”2 Dr. Nissen did not mention it in his list,3 but it is bias, nonetheless.
- Bias toward a particular outcome? Add a very big one.
How important were these biases to the results? Considering “the fragility of their findings,”7 even a small effect from bias would devastate Nissen and Wolski’s meta-analysis–without considering all of the other profound flaws in their study.
In commenting on the Nissen meta-analysis, Psaty and Furburg7 noted that the weaknesses of the study were substantial and that “a few events either way might have changed the findings for myocardial infarction or death from cardiovascular causes. In this setting, the possibility that the findings were due to chance cannot be excluded.”1
Six different types of bias in just one study, four of which Dr. Nissen, himself, puts on a par with fraud, flaws, and misinterpretations.3
Maybe Dr. Nissen thinks that what is good for randomized controlled trials is too good for a meta-analysis1 that was merely based upon randomized controlled trials.
Or, maybe he is just biased.
© 2014 Myron Shank, M.D., Ph.D.8
2 Temple Robert. Memorandum to Janet Woodcock: Data on Rosiglitazone, August 8, 2010. http://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm226066.pdf
3 Steven Nissen. Flaws, bias, misinterpretation and fraud
in randomized clinical trials. http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=3132
4 Schachtman Nathan A. Learning to embrace flawed evidence–the Avandia MDL’s Daubert opinion. Schachtman Law January 10th, 2011. http://schachtmanlaw.com/learning-to-embrace-flawed-evidence-the-avandia-mdls-daubert-opinion/
5 Sullivan Thomas. Nissen relationships with industry: CME, professional societies and red dresses. Policy and Medicine March 18, 2010. http://www.policymed.com/2010/03/nissen-relationships-with-industry-cme-professional-societies-and-red-dresses.html (The reader is strongly encouraged to read this revealing article about Steven Nissen’s character and credibility.)
6 Milloy Steven. Junk science: diabetes drug scare or scam? FoxNews.com June 10, 2007. http://www.foxnews.com/story/2007/06/10/junk-science-diabetes-drug-scare-or-scam/
8 I served: in the speaker program for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, Chicago, Illinois, August 7, 1999; as a consultant for Takeda Pharmaceuticals America, Inc. and Eli Lilly and Company, “Current Update and Discussion of the Glitazone Class of Oral Antidiabetics,” January 3, 2001; on Avandia Regional Advisory Panels in Cleveland, Ohio (February 4, 1999), Toledo, Ohio (September 15, 1999), San Juan, Puerto Rico (February 2000), and Beverly Hills, California (April 2000); as a preceptor for SmithKline Beechum, Lima, Ohio (June 23-25, 1999); and in a “Meet-the-Specialist,” SmithKline Beecham, Lima, Ohio, (2000). In 2000, SmithKline Beechum merged with GlaxoWellcome, to form GlaxoSmithKline. Before it became impractical to continue prescribing rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline), I prescribed both it and pioglitazone (ACTOS, ACTOSPlusMet, DuetAct; Takeda).