Avandia's Future Still Bleak?
By Kristina Fiore, Staff Writer, MedPage Today
Published: June 07, 2013
An FDA panel recommendation to loosen restrictions on the controversial diabetes drug rosiglitazone (Avandia) isn't likely to affect how -- or whether -- doctors prescribe it, according to experts interviewed by MedPage Today.
Clinicians are wary not only of the agent and its unclear risks of cardiovascular complications, but of the thiazolidinedione (TZD) class in general -- and the fact that several alternatives now exist makes it hard to justify prescribing agents that have clouded safety profiles, they said.
"I think the world has already made its judgment that this is not a safe drug, and changing the labeling a little bit is not going to change its use," Steven Nissen, MD, of the Cleveland Clinic and the most vocal critic of rosiglitazone's risks, told MedPage Today.
"The reality is that the drug is essentially gone from the marketplace," Nissen said. "Most other countries in the world have banned the drug entirely."
He noted that only about 3,000 patients in the U.S. currently take rosiglitazone, and although that number might go up a a little bit given a potential loosening in its currently restricted access, it will "still be a drug used by only a handful of people," Nissen said.
Fernando Ovalle, MD, of the University of Alabama at Birmingham, said clinicians are no longer keen on using TZDs, given risks such as heart failure, bone fractures, and weight gain.
"When Avandia and Actos first came out, we had a more limited number of choices for diabetes," Ovalle told MedPage Today. "Now we have a series of other agents that seem to be effective and safe, as best we can tell ... and our tolerance for the side effects of these drugs has decreased."
"Based on the increasing availability of other anti-diabetic therapy such as the dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) agonists, other options are available to improve glucose control," Robert Rosenson, MD, of the Icahn School of Medicine at Mount Sinai Hospital in New York City, told MedPage Today. "For my patients, I would not consider prescribing rosiglitazone."
Significance of the RECORD Trial
Some experts have questioned the FDA's reliance on a single study -- albeit one of the only large-scale randomized, controlled trials of cardiovascular safety with the drug -- in its decisions on the medication. Nissen has pointed out several design flaws in RECORD, including the fact that it was open-label and unblinded.
"Everybody knew which patients got Avandia and which got the comparator," he said. "Once that happened, the integrity of the trial was destroyed and it can never be resurrected."
Nissen also pointed out the fact that other meta-analyses, including one of the FDA's own by Thomas Marciniak, MD, head of the FDA's Division of Cardiovascular and Renal Products, have found an increased risk of MI among patients on the drug.
Marciniak also offered a critique of the readjudication of the RECORD trial during the FDA hearing, noting that even though it was conducted by Duke Clinical Research Institute, it could not be independent because it was financially backed by rosiglitazone maker GlaxoSmithKline.
"You have a company that still faces billions in lawsuits providing files to Duke for adjudication. What do you think the outcome is going to be?" Nissen said. "Marciniak is pointing out to the committee that no matter how high the integrity of Duke, if you put a company in charge of providing files, you can't get independent analysis."
Ralph Brindis, MD, MPH, of Northern California Kaiser Permanente and past president of the American College of Cardiology, agreed that the most recent review by Marciniak was at odds with the final Duke analysis used by FDA.
"We appreciate the discordance in their own organization on how to analyze the data," he told MedPage Today during the hearing.
But not all researchers have been as concerned about the RECORD data.
"Although RECORD had an open-label design and the cardiovascular event rates were lower than expected, it was prospective, multicenter, and included blinded endpoint adjudication," Cecilia Low Wang, MD, of Anschutz Medical Campus at the University of Colorado Denver, told MedPage Today, adding that "selecting the right patients for TZD therapy is key."
Brindis noted that one of the most important lessons learned from the rosiglitazone advisory committee hearing is the need for several revisions in trials going forward to investigate the safety of diabetes drugs, including the need for better coordination of study endpoints.
How the Panelists Voted
During the hearing, 20 of 26 panelists voted to remove or modify rosiglitazone's highly restrictive label and distribution system.
Five panelists voted to keep the risk evaluation and mitigation strategy (REMS) as it is, and one voted to remove the drug from the market.
Of the 20 panelists who voted to loosen restrictions on the drug, 13 called for modification of the REMS and seven voted to remove the REMS entirely.
Rosiglitazone is currently limited to patients who cannot achieve glycemic control on other medications and who can tolerate the potential MI risks.
The FDA has no regulatory deadline by which it has to make a final decision on rosiglitazone.
Begin forwarded message:
Bone Effects of Rosiglitazone in HIV-Infected Patients with Lipoatrophy
Bone Effects of Rosiglitazone in HIV-Infected Patients with Lipoatrophy
FDA places more restrictions on GSK's Avandia, Pioglitazone - NATAP
May 20, 2011 - The FDA says that patients and healthcare providers must now enroll in a special programme in order to prescribe and receive Avandia
FDA Adds Boxed Warning for Heart Attacks to Anti-Diabetes Drug
From the FDA, Nov 14, 2007. The U.S. Food and Drug Administration
FDA says again: Rosiglitazone does not up CV risk
June 6 2013 Miriam Tucker
Silver Spring, MD - An extensive analysis by the US Food and Drug Administration (FDA) concludes that the much-discussed diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) does not increase the risk for adverse cardiovascular outcomes.
The data were discussed on the first day of a two-day joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, being held to determine the future of rosiglitazone in the US , and supports the findings of a recent readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial.
The data were discussed on the first day of a two-day joint meeting of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, being held to determine the future of rosiglitazone in the US .
Since September 2010, rosiglitazone's use there has been severely restricted due to cardiovascular safety concerns. At the time it imposed the restrictions, the FDA also called for an independent readjudication of GlaxoSmithKline's RECORD study, the only randomized trial of the drug to specifically examine CV outcomes.
Presentations yesterday were broadly supportive of the readjudication finding, although several concerns remain, many pertaining to the initial trial design. Today the two advisory committees will vote on what to do next with rosiglitazone.
DCRI accused of not being independent, mishandling data
The multicenter, open-label RECORD trial randomized 4447 patients with type 2 diabetes who were poorly controlled (HbA1c 7.9%), despite treatment with metformin or a sulfonylurea, to either rosiglitazone or a combination of metformin plus a sulfonylurea. The study met its primary end point, to show noninferiority with regard to composite end points of CV death and CV hospitalizations (hazard ratio 0.99, 95% CI 0.85-1.16) .
Presentations on the first day of the new hearing were given by the FDA, GlaxoSmithKline, and by the Duke Clinical Research Institute (DCRI), which conducted the RECORD readjudication with data provided by GlaxoSmithKline.
In the morning, Dr Thomas A Marciniak (FDA Division of Cardiovascular and Renal Products) delivered a personal critique of the RECORD readjudication, in which he stated that the DCRI's review was not independent because the institution was paid by GlaxoSmithKline. He also accused the DCRI of "extreme mishandling" of the data and cited methodological flaws of the original trial.
Marciniak, who had delivered a similar assessment of RECORD at a July 2010 FDA advisory committee hearing on the safety of rosiglitazone, when he was among the reviewers, was this time speaking only for himself and not on behalf of the FDA.
Irrespective of analysis, findings "reassuring"
Subsequent presenters yesterday included Dr Kenneth W Mahaffey, the DCRI's associate director, and Dr Robert Bigelow (DCRI), who summarized the readjudication, which involved 22 reviewers at eight organizations.
Readjudication of a total 2223 events revealed no significant event risks for the rosiglitazone group (2220 patients) compared with those receiving sulfonylureas and/or metformin (2227). The hazard ratios were 0.95 for the composite end point of CV death, MI, or stroke; 0.90 for CV death; 1.13 for MI; 0.79 for stroke; and 0.86 for all-cause death. None of those were statistically significant.
Numerous sensitivity analyses to account for missing data did not change the conclusion, that the results "were consistent with originally published RECORD results," said Mahaffey.
A series of detailed FDA presentations essentially backed up the DCRI's conclusion, despite numerous discrepancies between the original trial analysis and the readjudication in the attribution of causes of death.
"Irrespective of the specific analysis selected, the hazard ratio is in the favorable to neutral range, which seems reassuring," said Dr Ellis F Unger, director of the FDA's Office of Drug Evaluation 1.
However, several presenters and panel members expressed concern about one major limitation of RECORD that the readjudication could not address: it was an open-label trial, which introduces the potential for bias.
This was done out of necessity, because the "rescue medication," insulin, is contraindicated for use with rosiglitazone in Europe. It would have been impractical to blind the study subjects with multiple daily sham injections, noted Dr Karen Murry Mahoney (FDA Division of Metabolism and Endocrinology Products).
Another concern, raised by two panel members, related to the possible treatment effect of statins, which were used more often in the rosiglitazone patients. That topic will be discussed further today.
Panels will vote today on what to do with rosiglitazone
Rosiglitazone was pulled from the European market in 2010 at the same time the US imposed restrictions. In the US, it is available only under a risk evaluation and mitigation strategy (REMS), which limits its use to patients who were already taking it or to new patients for whom no other glucose-lowering agents are acceptable.
Since the REMS was imposed, the number of patients using rosiglitazone has dropped dramatically from 117 349 in 2009 to 3405 during 2011-2013.
Today, the two advisory panels will be asked to vote on whether to keep the current REMS program as is, modify it, remove it and allow freer use of rosiglitazone, or remove rosiglitazone from the US market.