Update On Postmarket Study Commitments: It’s Not What You Count, But How You Count It

  • February 6, 2012

By Bob Roth

Several years ago, we became interested in the trend towards new drug approvals with defined sponsor postmarket commitments. These commitments were FDA-mandated, sponsor-agreed plans for conducting postmarket studies, directed at specific gaps in the drug data package. The majority of new drugs approved today carry commitments for post-approval work. Many such commitments are plans to study the drug in particular patient groups of interest (for example, pediatric patients, patients with various organ dysfunctions, or patients taking concomitant medications of interest) such that the drug can be utilized more rationally and safely. Other post-approval agreements, however, can be considered more pivotal. These include studies that evaluate true clinical outcomes in cases of accelerated drug approvals, which had been based on surrogate rather than clinical endpoints. Of course, after approval of a given drug, a number of possible outcomes may occur with regard to the postmarket plans: studies can be conducted and completed in a timely fashion; studies can be temporarily delayed then initiated later; planned postmarket studies may instead be eliminated for scientifically valid reasons and with FDA acceptance; or sponsors may simply renege on their study commitments.

Based on data from the time period 2002-2005, I published an article documenting rather limited success in fulfilling these requirements. At the time of evaluation, 50-60% of planned NDA studies and 20-30% of planned BLA studies had not been initiated without meeting criteria for acceptable delay, and only 20-30% of existing commitments had been completed (data published in the 2006 FDLI Update, which can be provided to interested readers upon request). Now, several years later, I noticed a Federal Register notice (76 FR 47213) which summarized more updated information, and was interested to learn if progress had been made. The more recent data presentation is a composite over an undefined time period, not year-by-year as in our previous data evaluation, and therefore a direct comparison of current data to our previous findings is not possible. However, it still is possible to contrast the take-home messages from the earlier and more current data. With regard to the 76 FR 47213 presentation, three items in particular caught my attention.

First, recent regulation in the Food and Drug Administration Amendments Act of 2007 which pertain to the issue of sponsor post-approval commitments, makes a sensible distinction between enforceable commitments, termed postmarking requirements, and non-enforceable postmarking commitments (agreed upon but not required investigations). At the time of the Federal Register notice there were approximately equal numbers of enforceable and unenforceable approval agreements. Somewhat surprisingly, postmarket requirements and postmarket commitments were nearly identically “on-schedule.” On-schedule in this context consists of studies that have been completed and submitted, ongoing, or are actively pending initiation. The majority of requirements and commitments were categorized as on-schedule; only 9-16% of drug application plans and 12-23% of biologics application plans were not on-schedule.

Second, it was surprising to note that pediatric studies, which are required under the Pediatric Research and Equity Act (PREA) but often deferred pending completion of other studies in adult populations, were most commonly on-schedule: 22 such studies were characterized as completed, 26 ongoing and 217 pending, with only 39 studies delayed and thus considered off-schedule. Similarly, postmarket required studies on the basis of accelerated approvals were also most commonly on-schedule: 8 NDA/ANDA/BLA studies were completed, 19 were ongoing and 9 pending, with only 7 delayed and thus off-schedule. Although the Federal Register notice does not explicitly define the timeliness of a sponsor’s plans for a post-approval study, i.e., whether the schedule milestones for satisfying the commitment are truly reasonable, the published results are encouraging.

Third, the most recent evaluation shows that only 6-8% of postmarket required NDA studies have been completed and submitted whereas concluded commitments ranged between 18-30% in the earlier evaluation. Pending studies (those not yet initiated but not yet qualifying as delayed) now are extremely common (70% of NDAs and 61% of BLAs) whereas in the earlier analysis these represented 50-60% of NDAs and 20-32% of BLAs.

To my eye, the data do not suggest that drug sponsors are now proceeding any faster through their post-approval obligations than a decade ago. The principal table of the 76 FR 47213 presentation, showing 88-91% of post-approval obligations “on-target”, is perhaps a bit more informative method for evaluating progress on postmarket commitments than previous approaches.

Bob Roth is Vice President and Worldwide Medical Director at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please contact us.