In a warning letter, the FDA upbraided Merck & Co. for failing to conduct a promised animal study of pancreatitis risk associated with its diabetes drug sitagliptin (Januvia, Janumet).
The company "failed to comply with the approved timetable and ... failed to show good cause for not conducting the additional testing required to further assess whether a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin, represents a public health risk," according to the Feb. 17 letter, made public this week.
Under an earlier agreement with the FDA, Merck was supposed to have completed the study and submitted results to the agency by June 15, 2011.
Merck said Wednesday that it would submit a final design for the study within 30 days and begin it in six months. "Merck is fully committed to complying with FDA's requirement and is confident that the company will complete the requirement within the time frame outlined in the Feb. 17 letter," according to a company statement.
Increased risk of acute pancreatitis has been a longstanding concern with the incretin class of diabetes drugs, including exenatide (Byetta), linagliptin (Tradjenta), and liraglutide (Victoza) as well as sitagliptin. Several studies have shown higher rates of acute pancreatitis in patients taking these drugs, and labeling for the drugs includes statements about the possible increased risk.
The FDA had required Merck to conduct the rodent study when it approved use of sitagliptin in combination with glitazone drugs for diabetes in February 2010. Specifically, the agency called for a three-month study of pancreatitis risk in a diabetic rodent model.
Merck's initial design proposal was rejected by the FDA as inadequate, and the firm never submitted a revised protocol.
Instead, the company said it would provide data from a separate, investigator-initiated study in mice.
Those data were finally submitted in January 2012, but the agency determined that they did not satisfy its original requirements, according to the warning letter. It noted that Merck had not secured the FDA's approval ahead of time to use this study in place of the originally agreed-upon study.
Furthermore, the letter said, Merck never gave a good reason for missing the deadlines spelled out in the original agreement and subsequent exchanges.
"As a result, you are more than 20 months late in achieving the June 15, 2010, final protocol submission milestone and more than eight months late in achieving the final protocol submission milestone in the timetable, and you have not demonstrated good cause for these delays," the letter said.
Failure to submit a final protocol for the three-month rodent study within 30 days and to win the agency's approval and initiate it within six months would expose Merck to a fine of $250,000 and other unspecified actions.