CardioExchange Archive

Battle lines are being drawn two weeks before a highly unusual two-day FDA advisory committee meeting to discuss the contentious diabetes drug rosiglitazone (Avandia, GlaxoSmithKline [GSK]). This will be the second time an FDA panel has wrestled with the fate of the drug and expectations have been that the discussion will once again be heated.

But at least one source of fierce criticism won’t be participating in the panel. Steve Nissen, who originally raised concerns about the drug and who has remained the most consistent critic of the drug, will not participate in the deliberations or present to the committee. Early on Thursday, Nissen contributed a blog post on Forbes accusing the FDA of stacking the committee in favor of rosiglitazone. The FDA leadership, he says, is trying to use the meeting to “whitewash” its reputation:

The ostensible purpose of the June 5-6 Advisory Committee meeting is to consider the ‘re-adjudicated’ RECORD trial. However, this time the meeting seems systematically designed to absolve the drug of harm and the CDER leadership of any responsibility for ignoring the public health hazard of Avandia. The current effort is intended to ‘whitewash’ the Avandia scandal and re-write history. Certain respected and independent members of 2010 Advisory Committee have been recused from the 2013 meeting. I requested the opportunity to present an independent analysis to the Committee, but was denied and offered a 5-minute statement in the ‘open public hearing.’

Keen observers should compare the roster of this new committee to the 2010 hearings to determine which participants have been re-invited and which have not. Similarly, assess whether prominent drug safety experts within FDA, such as Dr. David Graham, are listed as speakers or excluded. Finally, will any GSK consultants address the panel?”

By the end of the day on Thursday both the FDA and GSK had published responses to Nissen. Here is the FDA’s explanation for why it did not invite Nissen to present at the meeting:

During the planning of the upcoming June 2013 AC meeting on rosiglitazone, Dr. Nissen contacted FDA staff and requested that he be invited as a guest speaker. To clarify the basis for his request, FDA staff asked Dr. Nissen to summarize what he proposed to present to the committees. Dr. Nissen indicated that he would summarize all of the available data on the CV safety of rosiglitazone; discuss the limitations of an attempt to readjudicate an old clinical trial; review any discrepancies between the adjudicated RECORD trial and the investigator-reported events; and discuss the public health implications of any decision to remove restrictions on the use of rosiglitazone.

FDA staff reviewed Dr. Nissen’s proposed topics and concluded they did not warrant a slot as an FDA guest speaker. The content of his proposed topics is expected to be covered by other speakers as agency staff plan to summarize the available data on the cardiovascular safety of rosiglitazone at the committee meeting, and multiple FDA speakers will address their review of the readjudication of RECORD trial based on the study reports submitted to the Agency.

FDA staff provided information to Dr. Nissen on how to request time to speak during the open public hearing portion of the meeting. Thus, Dr. Nissen was offered the same opportunity that is available to all members of the public interested in sharing their perspectives and opinions. It is our current understanding that Dr. Nissen has declined this opportunity.”

GSK said that “many inaccuracies exist in Dr. Nissen’s commentary and need to be addressed.” The company specifically denied the multitude of reports over the years that it had suppressed negative data about rosiglitazone. The GSK response offers one potentially very important piece of news. The main focus of the June 5-6 hearing will be the re-adjudication of the RECORD trial performed by the Duke Clinical Research Institute. No public disclosure of the results of the re-adjudication have been made, and in the normal course of events the details of the re-adjudication, along with the rest of the committee’s briefing documents, would appear two days before the start of the hearing on the FDA website. But FDA staff, advisory panel members, and the drug sponsor (GSK) have almost certainly already seen the re-adjudication. In its statement, GSK flatly states that the re-adjudication confirms the safety of rosiglitazone:

The RECORD study is the largest clinical trial designed to evaluate the cardiovascular safety of Avandia. The study conclusions have now been confirmed through a re-examination by one of the leading independent institutions in the country (Duke Clinical Research Institute). In the accepted hierarchy of evidence generation, the results of a randomized, controlled clinical trial usually take precedence over other forms of evidence such as meta-analysis and observational studies. Despite some limitations of trial design, including the open label nature of the study, RECORD remains the only randomized trial of cardiovascular outcomes for Avandia at this time. The confirmation of the RECORD results by the independent re-examination support a positive risk/benefit profile for Avandia for the treatment of type 2 diabetes in appropriate patients.”

It remains to be seen whether this is more RECORD spinning or an accurate summary of the Duke re-adjudication.

In sharp contrast to these posts, the American College of Cardiology sent a letter earlier in the week to the FDA that acknowledges the heated controversy without taking a controversial position or inflaming passions. The ACC acknowledges “that the events that triggered the FDA’s request for readjudication of the RECORD clinical trial data is atypical, but the College agrees that it exposed some concerns regarding the long-term safety of drugs and how it is studied and monitored, both before and after approval.” The ACC cites the rosiglitazone controversy as a perfect reason to utilize the ACC’s experience with registries to enhance safety monitoring.

Relevant Links:

• Steve Nissen: The Hidden Agenda Behind The FDA’s Avandia Hearings
• The FDA Responds To Steve Nissen’s Criticism Of Upcoming Avandia Meeting
• Glaxo Alleges Errors In Nissen’s Critique Of FDA’s Handling Of Avandia
• ACC  Letter to the FDA

Partial Rosiglitazone/RECORD Chronology

• Rosiglitazone goes on the RECORD, but is it a hit? (June 5, 2009)
• Senate releases Avandia report, GSK responds to attacks (February 20, 2010)
• More Avandia action: Nissen secretly recorded GSK execs, FDA announces safety review (February 22, 2010)
• Avandia again: Nissen and JAMA editors spin RECORD round and round (March 23, 2010)
• EHJ editors rebuffed GSK efforts to suppress Nissen editorial on rosiglitazone (April 30, 2010)
• Tightening the noose yet again on Avandia(June 28, 2010)
• NEJM editors were “not fully aware” of GSK and Merck manipulation of Avandia and Vytorin DSMBs (July 7, 2010)
• 5 different ways of spinning RECORD (July 9, 2010)
• NY Times: GSK concealed negative Avandia study (July 13, 2010)
• Live Blog of the 2 Day Panel (Part 1, Part 2, Part 3, Part 4) (July 13-14, 2010)
• Avandia aftermath: who are the winners and losers? (July 16, 2010)
• 2 Avandia panel members found to have received money from GSK and Takeda (July 20, 2010)
• FDA puts TIDE on “partial clinical hold” (July 21, 2010)
• BMJ papers increase pressure on Avandia (September 7, 2010)
• 2 FDA rebels criticize inclusion of Avandia defenders on July advisory panel (September 13, 2010)
• FDA keeps Avandia on market, re-adjudicates RECORD, halts TIDE; EMA suspends Avandia marketing (September 23, 2010)
• FDA Announces Details of Severe New Restrictions on Rosiglitazone (May 18, 2011)
• FDA Schedules Another 2 Day Avandia Advisory Panel (April 12, 2013)