FDA has just published a report on how well companies are doing in regard to PMCs and PMRs. These are FDA requirements put in place at the time of approval (usually) of a new product that the companies agree to do. See the full report here.
This document summarized a recently released review of the status of these PMCs and PMRs for the fiscal years 2013 (ending September 30, 2013 and September 30, 2014 respectively. Evidently, there is a lag of about two years to get the data compiled and summarized for these reports.
Post-Marketing Requirements (PMRs) & Post-Marketing Commitments (PMCs)
A PMR is a study or clinical trial of a product that the company is required by statute or regulation to do after approval. A PMC is also a study or trial, but which is not required to be done by law, rather by a written agreement with the FDA. FDA can require these for various reasons:
- To assess a serious risk, signals of serious risk or to identify an unexpected serious risk if available data indicates the potential for this.
- To study certain new drugs for pediatric populations where there is insufficient data.
- For accelerated approvals of products, studies or trials may be required to verify and describe the predicted effect or other clinical benefit of the products.
- For drugs approved only on the basis of animal efficacy since human trials were not ethical or feasible.
FDA realized that these studies are not necessarily easy or feasible to do. They allow for modifications and changes as the study goes along if necessary. Each study has a “lifecycle” which tracks how it is going and allows for problems that might delay completion. Below is a figure from the report showing the possible lifecycles. Note that there are basically three paths: Ongoing, Delayed, and Terminated such that a study is either 1) completed with or without delay and fulfilled or 2) “released” (terminated).
“Pending” means the trial has not yet started but is not yet delayed based on the promised date. “Delayed” means the study is behind schedule. “Terminated” means the study was ended before completion but a final report has not been submitted yet to FDA. “Fulfilled” means that the final report was submitted and that the requirement or commitment has been fulfilled. A study is “released” if the study is no longer feasible, would no longer provide useful information or the NDA has been withdrawn.
Companies must submit an annual report on the status of each PMC and PMR within 60 days of the anniversary of the product’s approval. The report must provide a description of the PMC/PMR, a completion schedule and the current status. It should also note when the completion and submission of the final study report are expected.
This report includes data on 1464 studies/trials (1204 PMRs and 260 PMCs) established from March 2005 to September 2013. An audit of the status of the studies was done by FDA. The results can be summarized as follows showing the status of the studies and trials as of the end of each fiscal year:
|Submitted to FDA
As the table shows, many of the pending studies were released, fulfilled or ongoing. More interestingly, this shift table shows the status of particular categories during the period from 2013 to 2014:
The shift table shows the status as of Sept 2013 in the left-hand column and then the status of those studies a year later (Sept 2014). Thus for the status of the pending, look at the first row marked pending and read across. Of the 670 pending studies as of 2013, by a year later, only 413 are now pending (not started yet), 107 are now started and ongoing, 41 delayed, one terminated, 23 submitted and 59 done and fulfilled. And finally, 26 released from the commitment or requirement. Look at the other rows to see where each category in the 2013 totals (in the last column) are in 2014. The good news is that 124 studies were fulfilled and 49 submitted.
There are multiple other tables in the report that slice and dice the data by NDA/BLA, type of approval (Accelerated approval, animal efficacy, Pediatric Research Equity Act, etc.).
All PMRs Since 2008
Another table shows the evolution of the status of CDER PMRs since the establishment of the program.
This table is somewhat more sanguine. There have been, since the second year of the program, between 200 and 250 new CDER PMRs per year. The number pending has risen steadily since 2009 and the number ongoing has dropped to a low of 9% in 2014. The number released and fulfilled (successes) has dropped.
For CBER, there have been far fewer PMRs and PMCs per year with most still pending and several ongoing as of 2014. The data, due to smaller sample size, is more scattered but not too different from the CDER results.
This is a little less satisfying. For fiscal year 2013 and 2014 about 500 annual reports were due each year. Only about 60% were received on time; some 18-21% were received late and, surprisingly, 18-21% were never received at all. See table 4 in the document.
FDA: Interestingly, the FDA does not state their conclusions beyond noting that “The data show that over time, PMRs and PMCs are progressively completed and fulfilled.”
Author: The results appear mixed. Clearly, the FDA is requiring PMRs and PMCs and companies are agreeing to them – largely because they don’t have much choice. Not agreeing might delay or prevent approval by the FDA. The data suggests that many of the proposals are very difficult to put in place and start up.
As of 2014, some 670 were pending – the protocol has not even been finalized and put in place. 228 were ongoing and 107 were delayed (late). Even the annual reports run at only 60% on time with ~20% late and ~20% never submitted(!). It’s not clear that the companies are devoting sufficient time, money and resources to these studies. This is evidenced, in particular, by the late annual reports.
It also appears that FDA has not pushed harder on these studies. The long lag time for start-up is in contrast to studies the companies perform to get drug approval. There is usually a lot of management pressure to finalize the protocol, recruit investigators and get the study going asap. Investigators who fail to enroll are often dropped and replaced quickly. Clearly, companies have more incentive to complete trials destined for the NDA submission and approval than to do trials after marketing. A cynical person might note that many of these post-approval studies can only bring bad news…
It would not be surprising if FDA, at some point, starts cracking down on these studies and pushes for faster completion.
Take-Aways for Companies:
- Enter into PMRs and PMCs in good faith. Don’t make extravagant promises that you know are unlikely to be fulfilled. At some point you may be penalized for not doing them. In general, FDA will negotiate such that realistic and doable studies result.
- Assign adequate resources in terms people and money to complete them.
- Re-evaluate periodically. Everyone who does trials knows that there are usually multiple amendments to tweak the study as it goes along to improve areas that don’t work well or make the studies more doable. Same here. FDA understands that the trials may need to be altered as one goes along and clinical use of the newly approved product shows the original PMC/PMR proposal is not quite on target.
- By all means, complete and submit the annual reports. This is a promise made to the federal government and should be kept at a rate of 100%. No excuse for non-submission.
- Keep a dialogue with the FDA if there are issues or if the situation changes. As always, try to maintain a good relationship with FDA and all regulators. It’s in the best interests of everyone, particularly the patients.