Avandia's future murky after FDA panel vote

The type 2 diabetes drug, already under a black-box warning, is examined again as more questions about its safety are raised.

By — Posted July 26, 2010

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Some physician organizations are recommending that doctors make no sudden changes in their prescribing of Avandia after a Food and Drug Administration panel, for a second time, raised safety questions about the diabetes drug. However, unlike in its first review, the panel did not issue a clear recommendation to the FDA about what it should do as a result of the findings.

"Don't do anything different now than you did before the [July 13-14] hearing," said Alan J. Garber, MD, PhD, treasurer of the American Assn. of Clinical Endocrinologists. He said changes might be recommended for physicians when the FDA issues a decision, which is usually based on the advisory panel's recommendation. However, observers are wondering what the FDA will decide, since the panel gave no unanimous recommendation.

The FDA first put a black-box warning on Avandia (rosiglitazone) in 2007, when research came to light that GlaxoSmithKline's type 2 diabetes drug increases the risk for a heart attack, a leading cause of death among diabetics. Issues regarding Avandia cropped up again recently as more evidence questioned Avandia's safety and whether the company withheld data that would have pointed out problems with the drug.

To address the issues, an FDA advisory panel reviewed scientific data and information on the safety and efficacy of Avandia during a two-day meeting July 13 and 14 in Gaithersburg, Md.

The 33-member panel voted 18-6, with some abstentions, that there are "significant safety concerns" that Avandia raises the risk of heart attack and chest pain. The panel also voted 21-3 that Avandia's risk was higher than that of Actos (pioglitazone), a similar drug manufactured by Takeda Pharmaceuticals.

However, the panel was less clear on what to do about Avandia than it was in 2007, when it voted 20-3 that the drug increased the risk of heart attacks but voted 22-1 that it should stay on the market with a black-box warning about the risk.

In the July 14 vote, 12 panel members recommended that Avandia be taken off the market. Ten others said its black-box warning should be enhanced and additional restrictions added to its use, which could include requiring special physician and patient education on the medication.

Seven voted for the warning merely to be enhanced, without restrictions on its prescription. Three said it should be sold with warnings unchanged. One member abstained.

The experts also recommended that GSK continue the Thiazolidinedione Intervention With Vitamin D Evaluation, or TIDE, trial, which compares Avandia and Actos.

But on July 21, the FDA announced that the TIDE trial had been placed on partial clinical hold, meaning no new patients can be enrolled until the agency gives further notice.

The FDA instructed GSK to update investigators, institutional review boards and ethics committees involved in the trial about new safety information presented at the advisory committee meeting. The manufacturers also were asked to discuss the deliberations and votes of that meeting.

GSK said in a statement that it would comply with the FDA's request and suspend enrollment of new patients. Those who already are enrolled can continue in the trial, according to the manufacturer.

"We are committed to working with the FDA in the best interest of diabetic patients," said Ellen Strahlman, MD, GSK's chief medical officer, in a statement.

Timing of decision unclear

The FDA's decision on whether Avandia will remain on the market could take weeks or months, the agency said. While the FDA often follows advisory panel recommendations, it is not required to do so, and experts said that given this panel's vote, it was difficult to tell what the FDA will decide.

In a joint statement, the Endocrine Society, the American Diabetes Assn. and the American Assn. of Clinical Endocrinologists said they would provide physicians detailed information interpreting the FDA's decision when it is issued.

The American Heart Assn. stressed that patients should not change or stop medication without first consulting a health professional. The association recommends that metformin be physicians' first choice of medical treatment for type 2 diabetes patients, particularly among those who are obese. Several studies have shown that particular drug helps with glycemic control and reduces cardiac events in obese patients, said Denver endocrinologist Robert Eckel, MD, past president of the American Heart Assn. and professor of medicine at the University of Colorado School of Medicine.

Patients who have achieved recommended hemoglobin A1c control on a drug in the thiazolidinedione class, such as Avandia, can continue taking the medication, according to the heart association. But doctors uncomfortable with using this class of drugs can replace it with another diabetes medication.

Dr. Eckel encouraged physicians to examine the data that relates to Avandia, diabetes and heart disease, and make an educated choice about whether to prescribe the drug.

Information has been published about Avandia that might not be favorable, "but the science isn't there to take it off the market," Dr. Eckel said.

Mounting concern

Nearly 24 million people, or about 8% of the U.S. population, had diabetes in 2007, according to the most recent data from the Centers for Disease Control and Prevention. Of those cases, 90% to 95% were type 2 diabetes.

Avandia was licensed by the FDA in 1999 to help control blood-sugar levels in this large group of diabetic patients. Concern was raised when a meta-analysis published June 14, 2007, in the New England Journal of Medicine found that the medication increases heart attack and cardiovascular death risk by 43% and 64%, respectively.

The findings prompted the FDA to add a black-box warning -- the strongest the agency issues -- about heart attack risk in 2007. Later that year, an FDA advisory committee recommended that the drug remain on the market, and the agency followed the recommendation.

Since then, evidence has continued to accumulate about safety concerns with Avandia.

In February of this year, a Senate Finance Committee report accused GlaxoSmithKline of withholding data that show safety problems with the drug. Internal GSK documents in the report show debate on whether an interim analysis manuscript, published July 5, 2007, in the New England Journal of Medicine, might misrepresent the RECORD study's results. The long-term RECORD study was the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes trial.

In response to the committee findings, an editorial was published in the March 24/31 Journal of the American Medical Association that said journal editors should require an independent analysis of industry-sponsored trial data by an academic statistician before publishing results. A NEJM spokeswoman said at the time that her journal does employ biomedical statisticians to review manuscripts and seeks clarifications and revisions from authors when needed.

GSK said in a statement that the JAMA editorial and commentary "unjustly challenge the motives of physician scientists seeking to inform diabetes treatment and patient safety, and mischaracterize the RECORD study on rosiglitazone."

Regarding the Senate Finance Committee report, GSK said that it "fails to present an accurate, balanced, or complete view of the currently available information on Avandia." The company also rejected "any allegations of concealing safety information or acting inappropriately on behalf of patients."

Additionally, a study was posted online June 28 in JAMA that found that Avandia, when compared with Actos, was associated with an increased risk of stroke, heart failure, and all-cause mortality in patients age 65 and older.

GSK rejected these conclusions and maintained that the medication is safe. After the most recent recommendation by the federal advisory committee in July, GSK said that it would continue to work with the FDA in the best interest of diabetes patients.

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External links

"Rosiglitazone Evaluated for Cardiovascular Outcomes -- An Interim Analysis," New England Journal of Medicine, July 5, 2007 (link)

"Ensuring Integrity in Industry-Sponsored Research," Journal of the American Medical Association, March 24/31 (link)

"Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes," New England Journal of Medicine, June 14, 2007 (link)

"Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone," Journal of the American Medical Association, online June 28 (link)

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