It should be understood that, in 2006, the Food and Drug Administration (FDA) had the results of a meta-analysis, performed by GlaxoSmithKline, which suggested possible increases in cardiovascular risks with rosiglitazone (Avandia, Avandamet, Avandaryl; GlaxoSmithKline),2 a year before Nissen and Wolski’s controversial article.1 In fact, the Food and Drug Administration (FDA) had requested patient-level data for these studies and was already conducting its own meta-analysis.2 The Food and Drug Administration’s meta-analysis included studies that were different from those used by Nissen and Wolski2 and had occurred independently of Nissen and Wolski.
Most of the component studies in the Food and Drug Administration’s analysis were of less than six months duration–not very long for cardiovascular (“heart attack,” anginal chest pain, stroke, and sudden death) outcomes. As with the group of studies included by Nissen and Wolski, none had been designed to evaluate cardiovascular risk, so they had lacked plans for studying cardiovascular events. Instead, adverse events that were captured in case report forms had been classified using often vague terms (such as “chest pain,” without any laboratory or electrocardiogram (EKG) evidence that the heart was the cause).2 Without adjudication (tracking down and examining the appropriate original data), it is impossible to know what these reports really meant. As noted in my December 18, 2013 post, “Steven Nissen and The Not-So-Great Avandia Controversy,” Nissen and Wolski did not do this; however, the Food and Drug Administration did. When compared with placebo (an inactive lookalike), Avandia showed possible increases both in ischemic heart disease (“heart attacks” and anginal chest pain) and in ischemic heart disease plus strokes, but not when compared with active drugs.2 There was a possible increase in ischemic heart disease, but not ischemic heart disease plus strokes, in the combination of studies comparing Avandia either to placebos or to active drugs.2
So long as its results were compatible with his own, Dr. Nissen does not seem to have had any complaints with the Food and Drug Administration’s analyses. As we will see in future posts, however, that changed, once its results no longer supported his agenda. In spite of the glaring shortcomings in Nissen and Wolski’s meta-analyses,1,3 as compared both to another meta-analysis of the same data,4 published a mere five months after their first meta-analysis and to those of the Food and Drug Administration,2 Dr. Nissen has stubbornly clung to his conclusions.
Dr. Nissen has also viciously attacked the Food and Drug Administration for continuing with its planned evaluations of Avandia. Why? If it was only because he knew that his own conclusions would not be confirmed, why does he not seem to have ever lashed out at Diamond and others?4 The fact that his ongoing vitriol seems to be targeted against the Food and Drug Administration, but apparently not Diamond’s group, gives credence to speculations that Dr. Nissen fully expected Avandia to be his ticket to the top Food and Drug Administration position. Whether or not he ever sought a formal position, Dr. Nissen seems preoccupied with controlling the Food and Drug Administration. At any rate, evidence will be reviewed that Dr. Nissen’s motives may be suspect on multiple levels.
© 2013 Myron Shank, M.D., Ph.D.
2 Parks Mary H. Introduction memorandum. Readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes Trial (RECORD): Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee June 5—6, 2013. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm354859.pdf