He said it is vital that all new diabetes therapies be carefully scrutinized for CV risk, though, because CVD is the leading cause of morbidity and mortality among patients with diabetes. Even so, postmarketing surveillance may be adequate for some diabetes therapies if there is no CV safety signal during phase 1 through phase 3 studies.

“You may impede development if all new diabetes drugs must undergo exactly the same requirement for completion of very large cardiovascular outcome trials prior to FDA approval,” said Dr. Hiatt.  “For example, our recent review of liraglutide suggested that it may be more important to understand potential imbalances in breast cancer with the drug.” 


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Up for Discussion

Currently, there is considerable debate over whether diabetes therapies in development should have a higher bar for CV safety than other medications.  A case-by-case decision may be more appropriate, according to some experts.

Fernando Ovalle, MD, who is the director of the Comprehensive Diabetes Center at the University of Alabama Birmingham, said the requirements need to be more individualized and based on the particular drug being tested. He said this will help avoid unnecessary delays in the approval of potentially beneficial drugs.

“Although well intentioned, I think the FDA reaction following the rosiglitazone controversy went a little too far and I think it is now time to reassess the need for such a rigid, one-size-fits-all, blanket policy when it comes to evaluating the cardiovascular safety of diabetes drugs,” Dr. Ovalle told Endocrinology Advisor.  “There are other important safety considerations as well as cost-effectiveness considerations. So, we need to keep in mind the bigger picture.”

Parag Joshi, MD, MHS, who is a Clinical Fellow in Cardiovascular Diseases at Johns Hopkins Hospital, Baltimore, Maryland, said we are now in a new era in terms how diabetes therapies are viewed. 

“We used to think changing numbers and improving blood sugar levels was enough and that was the goal,” Dr. Joshi said in an interview with Endocrinology Advisor. “But, of course, what we care about is preventing heart attacks and kidney failure and all the things that come with diabetes.”

He said this is not a black and white issue and it is not simply a matter of the FDA putting unnecessary restraints on the development of diabetes therapies. 

“You really can’t hold diabetes drugs to a different standard. The pendulum may have swung a little too far. However, outcome data matters. This idea of requiring more studies is really a gray zone right now. It costs a lot of money to conduct these studies,” said Dr. Joshi. 

Janet McGill, MD, who is a professor of medicine in the division of endocrinology, metabolism and lipid research at Washington University School of Medicine, St. Louis, Missouri, agreed with Dr. Joshi. She said the costs of newer diabetes therapies may be significantly higher than in the past due to the current guidance of the FDA. 

“The requirement of a cardiovascular safety trial for drugs that do not show an adverse cardiovascular signal adds significant cost to the development program, which is passed along to the patients in the form of higher drug costs,” said Dr. McGill.

References:

  1. U.S. Food and Drug Administration. Guidance for Industry Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071627.pdf. Published December 2008. Accessed September 2014.
  2. Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med. 2007;356:2457-2471.