Next month, the FDA will hold a two-day meeting to discuss the results of a clinical trial for the Avandia diabetes pill, three years after the agency greatly restricted use of the controversial drug. And Steve Nissen, who co-authored a meta-analysis that several years ago found increased cardiovascular risks with the GlaxoSmithKline pill, believes the FDA has a hidden agenda for convening the session.
“The most likely explanation: the leadership of the division of the FDA responsible for drug regulation, the Center for Drug Evaluation and Research, is seeking to avoid accountability for its role in the Avandia tragedy,” he writes in a provocative op-ed in Forbes. Nissen, by the way, is head of cardiology at the Cleveland Clinic.
The meeting, which the agency had ordered, will reassess a clinical trial called RECORD that was, in part, the heated focus of a contentious 2010 FDA panel meeting held to review the Avandia safety record. At the time, both the drugmaker and the FDA were under considerable pressure in the midst of growing public outcry over patient safety and the disclosure of clinical trial data.
In his essay, Nissen notes that Glaxo had secretly conducted an analysis in 2005 and 2006, and concluded its pill increased the risk of heart attacks and related events by about 30 percent. Initially, Glaxo withheld the data from the FDA, but did inform the agency of the findings. But in 2007, his meta-analysis was published, which “intensely embarrassed” the FDA, he maintains.
“Since 2006, CDER has expended considerable taxpayer dollars trying to absolve itself of responsibility for this inexplicable error in judgment that cost many lives. In 2010, CDER and Glaxo saw an opportunity clear Avandia of any cardiovascular hazard and scheduled an FDA Advisory Committee meeting to exonerate the drug,” he writes.
And Glaxo was widely criticized for its handling of the trial. Some FDA scientists claimed the study was flawed and undercounted cardiovascular events. And both the US Senate Finance Committee and the Journal of the American Medical Association chastised Glaxo for attempting to undermine its own scientific steering committee and squelching unfavorable results (more here).
The most significant development at the meeting was a presentation by FDA reviewer Thomas Marciniak, who discussed how the RECORD trial was biased. “For example,” Nissen writes, “the trial was unblinded, meaning that physicians and patients were aware which drug each patient was taking. Even Glaxo was unblinded" (here is the Marciniak review).
“Incredibly, whenever a study site reported a clinical event, GSK and its contract research organization knew immediately which drug the patient was receiving. Marciniak’s review showed that events occurring in Avandia patients were changed or deleted, sometimes months after they should have been reported and counted. These and many other flaws make the RECORD trial totally unreliable.”
Just the same, the FDA ordered Glaxo (GSK) to convene an independent group of scientists to review the RECORD trial. “During the course of the FDA’s review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings,” the agency wrote in its September 2010 announcement (here it is).
Since then, you may recall, the FDA restricted Avandia use to only Type 2 diabetics who are unable to benefit from other diabetes medications. The agency also announced a Risk Evaluation & Mitigation Strategy, or REMS, in which patients have to enroll in an Avandia access program and the diabetes pill will only be available by mail from certified, participating pharmacies (see this).
But Nissen claims the upcoming meeting is a disastrous attempt at face saving. “The CDER leadership refused to accept the conclusion of regulators around the world and its own advisory committee that Avandia is hazardous,” he writes. “…These agency officials hope to show that the RECORD trial really did ‘prove’ that Avandia is safe. If the RECORD trial was reliable, the logic goes, then the 2006 decision by CDER to conceal the risks of Avandia did not represent a dereliction of its public duty.”
However, he points out that Glaxo was allowed to prepare the materials for the reanalysis, which was conducted by scientists at Duke University, which he maintains undermines the independence of the process. “The CDER leadership of any responsibility for ignoring the public health hazard of Avandia,” he concludes. “The current effort is intended to ‘whitewash’ the Avandia scandal and rewrite history.”
He adds, by the way, that he requested an opportunity to speak at the meeting, but was denied.
As a practical matter, the review is unlikely to alter the commercial standing of the pill. The cardiovascular risks, which have generated countless negative headlines over the past six years, and subsequent FDA restrictions have assured that many physicians have become more cautious about prescribing the drug. As Nissen notes, only 3,000 or so patients use Avandia these days.
Just the same, the hearing is likely to revisit not only the Avandia imbroglio, but also serve as an unfortunate reminder of the sort of business practices that have plagued the pharmaceutical industry. The Avandia scandal, you may recall, became a prime example of a drugmaker being widely accused of failing to disclose unflattering data and factored into a $3 billion settlement Glaxo reached last year with the US Department of Justice (read more here).