Over the last several years I have read in the trade press reports on post approval commitments of companies with respect to clinical studies and the frequency at which they have been initiated. The reports vary but they appear to be in the 20-30% range. What does that mean?
We all know the situation. We make our submission and in the negotiations in the last several weeks we deal with
- Label approval. We wrestle with the inclusion of efficacy, wanting as broader claim as possible, and reduced or minimised safety warnings. Often we just accept what we are goven.
- Manufacturing inspections. We negotiate the various responses to the inevitable observations at the pre-approval inspection. We make some illogical commitments just to get the license.
- CMC submission. We argue for adequacy of the submission, often agreeing to outlandish requests because we are so close to approval.
- Clinical data. After the advisory panel recommendation for approval, we negotiate with the agency with respect to the adequacy of the efficacy and safety package. We often commit to Phase 4 studies to further gather data to demonstrate safety in a larger patient pool and other studies.
Then we get approval and we are off to the market. But in the years following approval, we are supposed to perform these post approval studies mentioned in point 4 above. The reports I mentioned earlier are that only 20-30% of these commitments are actually acted upon after about 2 years. I do not mean completed since these studies may take much longer but actually initiated. This sounds like an abysmal record.
But up until now I have not seen any report of action by the agency against these recalcitrant companies. That is until now. On February 17 of 2012, FDA issued a warning letter to Merck, Sharp and Dohme on the lack of follow through for some animal studies that were committed to as part of the approval for Januvia® and Janumet®. The complete response letter was issued late in 2009 with an observation that the post marketing Pharmacovigilance studies were not sufficient to assure safety of the product. They required a further animal study to be performed post approval. A timetable was agreed to with protocol approvals and study report completion dates. These were to be completed by June 2011. As of February 2012, the studies had not been submitted. Thus the FDA has labeled the product as misbranded and required response with data or further action will occur.
The Warning Letter describes the details of the rationale and the commitment and then goes on to document the events that lead up to the situation. It presents interesting reading.
This does represent another facet of Commissioner Hamburg’s tougher enforcement.