FDA Flexes New Enforcement Muscle; Issues Warning Letter for Failure to Meet Required Postmarketing Study Milestone Dates

February 28, 2012

By Kurt R. Karst –      

Among the Warning Letters FDA posted on its website this week, one in particular caught our attention – a February 17, 2012 Warning Letter to Merck Sharp and Dohme Corp. (“Merck”) citing a violatation of FDC Act § 505(o)(3).  FDA’s enforcement action against Merck appears to be the first of its kind citing the new authority Congress granted FDA under the FDA Amendments Act of 2007 (“FDAAA”).

The products at issue in the Warning Letter are Merck’s antidiabetic drugs Januvia® (sitagliptin) Tablets, approved under NDA No. 021995 on October 16, 2006, and Janumet® (sitagliptin/metformin HCl) Tablets, approved under NDA No. 022044 on March 30, 2007.  Based on reports of pancreatitis associated with the use of sitagliptin in FDA’s Adverse Event Reporting System database, including two cases of necrotizing pancreatitis, FDA invoked its authority under FDC Act § 505(o) to require Merck to conduct a postmarketing study (“PMR”) to investigate the safety issue.  Specifically, as a condition of approving NDA supplements for Januvia® and Janumet®, Merck agreed to conduct PMRs 1602 and 1603, described as a “3-month pancreatic safety study in a diabetic rodent model treated with sitagliptin.”  FDA documented the agreement in approval letters (here and here) with the following timetable:

Final Protocol Submission: June 15, 2010
Study Completion Date: March 15, 2011
Final Report Submission: June 15, 2011

FDC Act § 505(o)(3) states that FDA may “require a responsible person for a drug to conduct a postapproval study or studies of the drug, or a postapproval clinical trial or trials of the drug, on the basis of scientific data deemed appropriate by the Secretary, including information regarding chemically-related or pharmacologically-related drugs.”  A PMR is intended to “assess a known serious risk related to the use of the drug involved,” “assess signals of serious risk related to the use of the drug,” and “identify an unexpected serious risk when available data indicates the potential for a serious risk.”  FDC Act § 505(o)(3)(E)(ii) requires sponsors to periodically report to FDA on the status of a PMR.  A violation of FDC Act § 505(o) is a basis for misbranding under FDC Act § 502(z), and may result in civil monetary penalties under FDC Act § 303(f)(4) of $250,000 per violation, with the potential for significant additional penalties for a continuing violation.  In April 2011, FDA issued guidance on the Agency’s implementation of FDC Act § 505(o)(3). 

Animal studies are not generally viewed as particularly onerous PMRs and, while Merck attempted to submit results of studies to address the PMR, none of those study designs had been agreed upon by FDA.  FDA implies that the conducted studies did not reach sufficient levels of exposure to properly evaluate the safety concern.  If FDA was looking to set out an example of its willingness to enforce 505(o), Merck’s failure to even submit a draft protocol and get FDA buy-in for a study that FDA likely views as a fairly simple 3-month rodent study made it easy for them.  After some wrangling between Merck and FDA that is laid bare in the Warning Letter, and a November 2011 Failure to Repond letter FDA issued to Merck, FDA had apparently had enough.  “You have not provided an adequate explanation for the cause of the delay of either of the milestones in the timetable for completion of the postmarketing requirement, nor did you propose to revise the agreed-upon timeline,” writes FDA in the Warning Letter.  “[Y]ou are more than 20 months late in achieving the June 15, 2010 final protocol submission milestone and more than 8 months late in achieving the final protocol submission milestone in the timetable, and you have not demonstrated good cause for these delays.”

As a result, FDA concludes that Merck’s products are misbranded and threatens the company with civil monetary penalties:

Under section 502(z) of the Act [21 U.S.C. 352(z)], your product is considered misbranded because you are in violation of a [PMR] established under section 505(o)(3) of the Act.  You have failed to comply with the approved timetable and periodic report submissions of section 505(o)(3)(E)(ii) of the Act 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.

Failure to promptly correct this violation may result in regulatory actions by the FDA without further notice.  These actions include, but are not limited to, civil money penalties.  Other federal agencies may take this Warning Letter into account when considering the award of contracts.  In addition, civil money penalties under section 303(f)(4) of the Act [21 U.S.C. 333(f)(4)] could be levied for a maximum of $250,000 per violation, with the possibility of additional penalties if the violation continues uncorrected.

Is the Merck Warning Letter a sign of a new enforcement move by FDA?  Only time will tell.  Interestingly, just days after FDA issued the February 17th Warning Letter to Merck, the Agency issued what can now be viewed as a prescient “Notice to Industry” stating, among other things: “Once FDA notifies a drug sponsor of the need for a postmarketing study or clinical trial, the company is required to provide a timetable for completion, including study milestones, and periodic status reports on progress toward completion of the PMRs.  If a company fails to comply with the timetable, FDA is authorized to take enforcement action against the company, unless the company can demonstrate good cause for the failures.”


  • News Release – Merck Provides Information on FDA Post-Marketing Requirement for Sitagliptin