February 22, 2010 (Silver Spring, Maryland) — A new senate report has rekindled debate about the cardiovascular safety of GlaxoSmithKline's diabetes agent, rosiglitazone (Avandia), and severely condemns the company's handling of events over the past few years .
The 342-page document--released over the weekend by Sen Max Baucus, chair of the Committee on Finance, and Sen Chuck Grassley--details a two-year investigation into rosiglitazone by US Senate Committee on Finance investigators, and concludes that there are "serious health risks associated with Avandia."
It also criticizes the FDA's role in deciding the fate of this drug, questioning the structure of the agency, because those who make decisions about drug approvals are often in charge of the people who judge drug safety. It calls for a separate, independent pharmacovigilance unit to be established.
Finally, the senators express concern about an ongoing clinical trial, Thiazolidinediones Intervention with Vitamin D Evaluation (TIDE), which is comparing rosiglitazone with a rival drug pioglitazone (Actos; Takeda) in type 2 diabetes patients at risk for cardiovascular disease.
Whistleblowers Interviewed, TIDE Condemned
This story first came to light in a New York Times article on Friday night by Gardiner Harris , and on Saturday the senators issued a press release about their new report .
Spokesperson for Sen Grassley, Jill Kozeney, told heartwire that the report was ready before the NYT story appeared and that "she could not speak" to how the newspaper obtained it. Asked whether the press release was issued in response to the story, she said, "we issue press releases all the time."
The report reviewed more than 250 000 pages of documents provided by GSK, the FDA, and several research institutes. Its investigators also interviewed numerous people at GSK and the FDA, as well as "anonymous whistleblowers."
It alleges that GSK knew about a risk of myocardial infarction with rosiglitazone for "several years" prior to the 2007 New England Journal of Medicine paper that first raised the concerns ; that the company failed to sufficiently warn patients and the FDA of the dangers; that it actively attempted to discredit any research showing rosiglitazone in a poor light, including the intimidation of independent physicians; and that it tried to downplay findings that competing agent pioglitazone might reduce cardiovascular risk.
Following the 2007 NEJM study, which linked rosiglitazone to a 43% greater risk for MI, a black-box warning was added to the US labeling for Avandia, stating that it was associated with an increased risk of myocardial ischemic events, such as angina or myocardial infarction, but that, "in their entirety, the available data on the risk of myocardial ischemia are inconclusive."
In the wake of this new labeling, the FDA mandated a new study to compare the cardiovascular risks of rosiglitazone and other diabetes drugs. The result was the ongoing TIDE trial, but in their press release, the senators express concern about this, noting that FDA documents they reviewed show that FDA safety officials said in 2008 that any head-to-head trial of the two thiazolidinediones would be "unethical and exploitative." After reviewing the protocol for TIDE, one wrote that "the safety of the study itself cannot be assured and is not acceptable," the senators say.
However, the trial has been allowed to proceed and there appear to be no references to these warnings from the safety officials in the consent form given to patients currently enrolling in TIDE, the report claims.
We will now await the response from the FDA before we consider whether to start enrolling patients in TIDE.
A TIDE investigator based in Denmark, Dr Henning Beck-Nielson (Odense University Hospital, Denmark), told heartwire that his institution has not yet enrolled any patients in TIDE and "we will now await the response from the FDA before we consider whether to start."
Call for Independent Safety Unit
Central to the complaints about the FDA made by the senators is the fact that those who judge drug safety work under the same umbrella as the people who make decisions about drug approvals.
In a letter sent to FDA commissioner Dr Margaret Hamburg on February 18, 2010 alerting her to their report, and reproduced in their press release, Sens Baucus and Grassley say: "It doesn't make any sense to have these experts, who study the drugs after they have been on the market for several years, under the thumbs of the officials who approved the drug in the first place and have a natural interest in defending that decision. The Avandia case may be the most alarming example of the problem with this set-up."
The senators call for a separate, independent safety unit to be established to avoid any inherent conflicts of interest.
Dr Marcia Angell, former editor of the NEJM, told Alicia Mundy of the Wall Street Journal  that the authority to ask for a drug withdrawal should be given to the safety reviewers, not to the Office of New Drugs.
But "veteran FDA officials have resisted such a separation as cumbersome and said the people who review a drug when it is new are best-equipped to assess problems with it," writes Mundy.
GSK Denies All; FDA to Consider Findings
Not surprisingly, GSK denies the senators' claims in a statement also issued on Saturday .
"The Staff Report of the Senate Committee on Finance . . . cherry-picks information from documents, which mischaracterizes GlaxoSmithKline’s comprehensive efforts to research Avandia and communicate those findings to regulators, physicians, and patients," it states.
"The safety and effectiveness of Avandia is well characterized in the label approved by the FDA. Contrary to the assertions in the report . . . the scientific evidence simply does not establish that Avandia increases cardiovascular ischemic risk or causes myocardial ischemic events," the company asserts.
In the meantime, an FDA spokesperson told the WSJ that commissioner Hamburg will meet "with FDA scientists and outside experts to gain a full understanding and awareness of all of the data and issues involved. The FDA takes very seriously concerns and issues raised in the recent inquiry."
The paper also reports that the agency plans to call a meeting of an outside advisory committee in the next few months to look at recent information on the drug, which GSK reports as having sales of $1.2 billion in 2009.
GSK, however, insists that everything is continuing according to plan: "The assessment of the safety of Avandia is continuing now with . . . TIDE, which was mandated by the FDA. The protocol . . . was developed with and approved by the FDA [and] has also been approved by an independent review board and appropriate safety boards."
The company also denies that it has tried to silence dissent: "When GSK believes that statements made by others don't accurately present information on its products or its actions, GSK corrects inaccuracies and misstatements."
Heartwire from Medscape © 2010 Medscape, LLC
Cite this: New Senate Report Puts Avandia Safety in Spotlight Again - Medscape - Feb 22, 2010.