FDA News

FDA panel recommends new safety labeling for Onglyza

An FDA advisory panel recommended label changes for the diabetes drug Onglyza after results from a cardiovascular outcomes trial revealed an increased risk for heart failure.

The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 14-1 Tuesday in favor of including new safety information for Onglyza (saxagliptin, AstraZeneca). The recommendation follows EMDAC review of the results of the SAVOR trial, which found a 27% increase in the rate of hospitalization for heart failure, as well as an increase in all-cause mortality, in patients who had taken the drug.

The majority of the panel opted not to vote in favor of more serious actions, including label changes with restricted distribution of the drug or withdrawing saxagliptin from the market. The panel also voted 13-1 (with one abstention) that the SAVOR trial demonstrated that saxagliptin has an acceptable CV risk profile.

Researchers for the SAVOR trial analyzed data from 16,492 patients with type 2 diabetes for 2 years who had an established risk or high risk for CVD. During the course of the prospective, randomized, double blind, placebo-controlled trial, 493 patients assigned saxagliptin (6%) were hospitalized or died of heart failure vs. 432 patients (5.3%) assigned a placebo (HR = 1.14; 95% CI, 1-1.3).

“There is a public health implication of this finding — a substantial number of subjects with hospitalization for heart failure events, regardless of treatment assignment, had recurrent events and/or died during the trial,” the researchers wrote. “A safety signal for heart failure was not previously observed in the saxagliptin clinical program.”

Approved by the FDA in 2009, saxagliptin is part of a class of diabetes drugs known as DPP-IV inhibitors used to control glucose levels in patients. Since 2008, the FDA has required agents in that class to undergo additional studies to examine their safety after concerns of a link between the drugs and an increased risk for heart failure.

Speaking on behalf of AstraZeneca, Jay S. Skyler, MD, MACP, of the University of Miami Miller School of Medicine, said the trial findings can be managed in the context of an updated label with new patient safety information. Saxagliptin, he said, remains an effective glucose-lowering agent with a low risk for hyperglycemia and no weight gain.

“There are always going to be side effects,” Skyler told the committee. “We always need to weigh risk vs. benefit.”

Some panelists said the findings were difficult to interpret and called for more long-term studies, noting that the SAVOR trial included only participants who were already at a high risk for heart disease and may not apply to all patients with type 2 diabetes.

Speaking during the public comment portion of the meeting, Robert Ratner, MD, FACP, FACE, chief science and medical officer for the American Diabetes Association, questioned the SAVOR trial results, calling the outcome the result of “data drenching” that does not take typical patients into account.

“We have to ask ourselves what is clinically significant as opposed to statistically significant,” Ratner said. “No definitive conclusions can be drawn from these observations.”

Some consumer advocates, however, found the heart failure risk to be too great. Bonnie Arkus, RN, consumer member of the EMDAC, voted the drug be withdrawn.

“As a consumer, I feel the risk–benefit is just not there,” said Arkus, who also voted that the drug does not have an acceptable CV risk profile. “The heart failure question … what is causing this is baffling. It’s just too much of a risk to take this drug as a consumer.”

Addressing the panel, consumer health advocate Sidney Wolfe, MD, also said label changes are not enough. He asked that the drug be recalled.

“This drug has no unique benefits whatsoever,” said Wolf, founder of Public Citizen’s Health Research Group. “And, what appear now to be some unique risks.”

The panel’s recommendations are nonbinding, although the FDA often follows its suggestions.

Robert J. Smith, MD, chair of the EMDAC and a professor of endocrinology at Brown University’s Alpert Medical School, said label changes that reflect the actual data may be difficult.

“There are challenges in how to handle the labeling in connecting it to the actual data,” Smith said after the vote. “The three issues most significant for me are the heart failure risk, and … what I would call unresolved risks regarding pancreatitis and renal effects.

“One of the things that make the labeling challenging is we do know that risk goes up with certain groups of patients, but the risk is not limited to those subgroups,” Smith said. “This doesn’t lend itself to simply nonuse in certain patients … so that requires some careful thought in how the labeling is done.” – by Regina Schaffer

 

An FDA advisory panel recommended label changes for the diabetes drug Onglyza after results from a cardiovascular outcomes trial revealed an increased risk for heart failure.

The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) voted 14-1 Tuesday in favor of including new safety information for Onglyza (saxagliptin, AstraZeneca). The recommendation follows EMDAC review of the results of the SAVOR trial, which found a 27% increase in the rate of hospitalization for heart failure, as well as an increase in all-cause mortality, in patients who had taken the drug.

The majority of the panel opted not to vote in favor of more serious actions, including label changes with restricted distribution of the drug or withdrawing saxagliptin from the market. The panel also voted 13-1 (with one abstention) that the SAVOR trial demonstrated that saxagliptin has an acceptable CV risk profile.

Researchers for the SAVOR trial analyzed data from 16,492 patients with type 2 diabetes for 2 years who had an established risk or high risk for CVD. During the course of the prospective, randomized, double blind, placebo-controlled trial, 493 patients assigned saxagliptin (6%) were hospitalized or died of heart failure vs. 432 patients (5.3%) assigned a placebo (HR = 1.14; 95% CI, 1-1.3).

“There is a public health implication of this finding — a substantial number of subjects with hospitalization for heart failure events, regardless of treatment assignment, had recurrent events and/or died during the trial,” the researchers wrote. “A safety signal for heart failure was not previously observed in the saxagliptin clinical program.”

Approved by the FDA in 2009, saxagliptin is part of a class of diabetes drugs known as DPP-IV inhibitors used to control glucose levels in patients. Since 2008, the FDA has required agents in that class to undergo additional studies to examine their safety after concerns of a link between the drugs and an increased risk for heart failure.

Speaking on behalf of AstraZeneca, Jay S. Skyler, MD, MACP, of the University of Miami Miller School of Medicine, said the trial findings can be managed in the context of an updated label with new patient safety information. Saxagliptin, he said, remains an effective glucose-lowering agent with a low risk for hyperglycemia and no weight gain.

“There are always going to be side effects,” Skyler told the committee. “We always need to weigh risk vs. benefit.”

Some panelists said the findings were difficult to interpret and called for more long-term studies, noting that the SAVOR trial included only participants who were already at a high risk for heart disease and may not apply to all patients with type 2 diabetes.

Speaking during the public comment portion of the meeting, Robert Ratner, MD, FACP, FACE, chief science and medical officer for the American Diabetes Association, questioned the SAVOR trial results, calling the outcome the result of “data drenching” that does not take typical patients into account.

“We have to ask ourselves what is clinically significant as opposed to statistically significant,” Ratner said. “No definitive conclusions can be drawn from these observations.”

Some consumer advocates, however, found the heart failure risk to be too great. Bonnie Arkus, RN, consumer member of the EMDAC, voted the drug be withdrawn.

“As a consumer, I feel the risk–benefit is just not there,” said Arkus, who also voted that the drug does not have an acceptable CV risk profile. “The heart failure question … what is causing this is baffling. It’s just too much of a risk to take this drug as a consumer.”

Addressing the panel, consumer health advocate Sidney Wolfe, MD, also said label changes are not enough. He asked that the drug be recalled.

“This drug has no unique benefits whatsoever,” said Wolf, founder of Public Citizen’s Health Research Group. “And, what appear now to be some unique risks.”

The panel’s recommendations are nonbinding, although the FDA often follows its suggestions.

Robert J. Smith, MD, chair of the EMDAC and a professor of endocrinology at Brown University’s Alpert Medical School, said label changes that reflect the actual data may be difficult.

“There are challenges in how to handle the labeling in connecting it to the actual data,” Smith said after the vote. “The three issues most significant for me are the heart failure risk, and … what I would call unresolved risks regarding pancreatitis and renal effects.

“One of the things that make the labeling challenging is we do know that risk goes up with certain groups of patients, but the risk is not limited to those subgroups,” Smith said. “This doesn’t lend itself to simply nonuse in certain patients … so that requires some careful thought in how the labeling is done.” – by Regina Schaffer