A federal advisory committee voted 9 to 6 on July 19 that a first-of-its-kind diabetes drug should not be approved for use because of safety concerns, including a possible increased risk of breast and bladder cancers….
The advisory committee to the FDA said that while the drug, dapagliflozin, had some attractive features as a treatment for type 2 diabetes, there were too many unanswered questions about safety and in which type of patients it should best be used.
The drug, being developed by Bristol-Myers Squibb and AstraZeneca, could become the first to work to lower blood sugar by causing it to be excreted in the urine. Many other companies are in a heated race to develop similar drugs, which are called SGLT2 inhibitors.
Dr. David M. Capuzzi, a professor at Thomas Jefferson University and a member of the committee, who voted ‘no,’ stated that, “While I really liked the concept, we just don’t have enough right now, in my opinion, to ensure safety and efficacy and how to use it.”
The FDA is not bound to follow the advice of its committees, and it has often said that when a vote is close it pays more attention to the discussion than to the final tally. Still, it would be highly unusual for the agency to immediately approve a drug after a negative vote. The agency is supposed to make a decision by Oct. 28.
Some doctors on the committee said that there was a need for new drugs and that dapagliflozin would be useful in treating type 2 diabetes.
One reason, they said, was that its mechanism of action was different from many other diabetes drugs, which work by affecting the supply or use of insulin. That could make it easier to combine dapagliflozin with other drugs. Also, since so many calories are excreted through the urine, dapagliflozin causes a small weight loss while many other diabetes drugs cause weight gains.
“Finding anti-diabetic agents that are weight-neutral is going to be a huge advance,” said Dr. Ellen W. Seely, an endocrinologist at Harvard Medical School and Brigham and Women’s Hospital, who voted in favor of approval. “Although there is a scare factor to the word ‘cancer’,” she said, diabetes “is a devastating disease.”
Several committee members said they could have voted either way.
“I changed my mind about four times in the last 10 seconds,” said Erica H. Brittain, a statistician at the National Institutes of Health who voted ‘no.’
The biggest safety concern was that in clinical trials, patients who got the drug were more likely to develop breast and bladder cancers than those in the control groups.
About 0.4 percent of women taking the drug got breast cancer, compared with 0.1 percent of the women in the control groups. About 0.3 percent of men getting the drug got bladder cancer, compared with about 0.05 percent of men in the control groups.
The numbers were very small, however, making it hard to draw definitive conclusions. Bristol-Myers and AstraZeneca argued that many of the cancers occurred too soon to have been caused by the drugs. Still, some committee members said the imbalance could not be overlooked. “The breast and bladder cancers, I can’t dismiss as being irrelevant or minor,” said Dr. Doris B. Strader of the University of Vermont.
Another safety concern was that there was one case of liver damage probably caused by the drug. And some committee members said Bristol-Myers and AstraZeneca had not done enough studies of how exactly the drug affected the kidneys. Some also said the clinical trials did not include enough minorities and very old patients, demographics that are prone to diabetes.
The committee members agreed that more study of the possible cancer risks and other safety questions would be needed. Those who voted ‘no’ mainly believed that the studies needed to be done before approval, even though that might delay approval by years.
Those who voted yes tended to think it would be impossible to do large enough studies to rule out the cancer risk before approval. Rather they said the studies could be done after approval, in part by observing the effects of the drug as it is used.