After two days of deliberation an FDA advisory panel today recommended that the severe restrictions (REMS) placed on rosiglitazone (Avandia,
The key to restoring at least some of rosiglitazone's tarnished reputations was the re-adjudication of the RECORD trial by the Duke Clinical Research Institute (DCRI). Despite an attempt by Tom Marciniak, an FDA reviewer acting on his own initiative, to question the reliability of the re-adjudication, the rest of the FDA and the panel members all expressed praise for DCRI's work. The panel endorsed the FDA's perspective that the re-adjudciation of the trial had been well performed, thus confirming the integrity of the original analysis.
But it would be a mistake to conclude that assurance of the integrity of the RECORD data leads to the conclusion that rosiglitazone is safe. Over the course of the two-day meeting panel members continually stated their belief that the underlying flaws of RECORD-- especially its open-label, noninferiority design and a large amount of missing data-- ensured that it could never definitively dispel the cloud of uncertainty over rosiglitazone's safety. DCRI's Ken Mahaffey, who was in charge of the re-adjudication, conceded under questioning that although no significant misconduct was observed in the trial, RECORD did not provide strong evidence demonstrating the safety of rosiglitazone. But the DCRI analysis did allay the 2010 fears that RECORD may have been even more severely compromised due to misconduct, incompetence, or fraud.
On the second day of the meeting panel members spent a significant amount of time considering the impact of the current rosiglitazone REMS, which resulted in a greater than 99% reduction in the use of the drug in the US, and asked the FDA about possible modifications of the severe REMS. It was clear that most members wanted to see rosiglitazone become more easily available though they seemed wary about removing all restrictions. The general sentiment of the committee was that the restrictions on rosiglitazone should be loosened but not entirely removed. But the committee could reach no agreement about how to achieve this goal.
Conspicuous by his absence at the panel meeting was Steve Nissen, whose original meta-analysis helped ignite the Avandia controversy and who was a vocal presence at the 2010 advisory panel meeting. Nissen had earlier announced that the FDA had not invited him to present his results to the panel (except as a speaker during the public access portion of the meeting). Nissen provided the following statement:
Little practical impact. Despite maximal efforts by FDA to convince the panel to remove restrictions, the majority voted to continue restricted access. If FDA loosens the requirements, a few additional patients may receive the drug, but effectively, Avandia is gone, which is a good thing.
I disagree with the findings regarding RECORD. Duke used the dossiers supplied by GSK to re-adjudicate. It was a foregone conclusion that they would get a similar answer.
We have three sources of data regarding Avandia. The meta-analyses, include FDA's, show an increased risk of heart attack ranging from 40 to 80%. The observational data virtually all show an increased hazard for MI. The outlier is RECORD and it was a fatally flawed trial, completely unblinded to patients, physicians and GSK.
I'm relieved that Avandia will remain restricted and continue to doubt the wisdom of spending taxpayer dollars to try to resurrect this drug.
GSK issued its own statement. James Shannon, GSK’s Chief Medical Officer, said:
“We appreciate the committee’s thorough examination of the RECORD results and will continue to work with the FDA as it considers the recommendation of the committee. We continue to believe that Avandia is a safe and effective treatment option for type 2 diabetes when used for the appropriate patient and in accordance with labelling.”
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)
- Spinning RECORD: Battle Over Rosiglitazone Heats Up Two Weeks Before Crucial FDA Meeting (May 24, 2013)
- Independent Re-Adjudication Of RECORD Confirms Safety Of Rosiglitazone (May 29, 2013)
- With One Big Exception FDA Reviewers Back More Benign View Of Avandia Trial (June 3, 2013)
