Postmarketing commitments for novel drugs and biologics approved by the US Food and Drug Administration: a cross-sectional analysis

Abstract

Background Postmarketing commitments are clinical studies that pharmaceutical companies agree to conduct at the time of FDA approval, but which are not required by statute or regulation. As FDA increasingly adopts a lifecycle evaluation process, greater emphasis will be placed on postmarket evidence as a component of therapeutic evaluation. Therefore, the objectives of this study were to determine how often postmarketing commitments agreed upon by pharmaceutical companies at first FDA approval lead to new clinical trials and to establish the characteristics and rates of completion and dissemination of postmarketing commitments. Methods For new drugs and biologics approved in 2009–2012, we used public FDA documents, ClinicalTrials.gov, and Scopus, to determine postmarketing commitments and their characteristics known at the time of FDA approval; number subject to reporting requirements, for which FDA is required to make study status information available to the public (“506B studies”), and their statuses; and rates of registration and results reporting on ClinicalTrials.gov and publication in peer-reviewed journals for all clinical trials. Results Among 110 novel drugs and biologics approved by the FDA between 2009 and 2012, 61 (55.5%) had at least one postmarketing commitment at the time of first approval. Of 331 total postmarketing commitments, 33 (10.0%) were for new clinical trials; 27 of these were 506B studies subject to public reporting requirements, of which 12 (44.4%) did not have a recent (i.e., up-to-date) or closed (i.e., fulfilled or released) status provided publicly by the FDA. Although two postmarketing commitments were insufficiently described in FDA records to perform searches on ClinicalTrials.gov, nearly all (28, 90.3%) of the 31 remaining postmarketing commitments for new clinical trials were registered on ClinicalTrials.gov. Among the registered trials, 23 (23 of 28, 82.1%) were classified as completed or terminated, of which 22 (95.7%) had reported results. When considering all 29 completed or terminated clinical trials, registered or unregistered on ClinicalTrials.gov, only half (14, 48.3%) were published in peer-reviewed journals. Conclusions While only 15% of postmarketing commitments agreed to by pharmaceutical companies at the time of FDA approval were for new clinical trials, these trials were nearly always registered with reported results on ClinicalTrials.gov. However, only half were published, and despite FDA public reporting requirements, recent status information was often unavailable for 506B studies. Electronic supplementary material The online version of this article (10.1186/s12916-019-1344-3) contains supplementary material, which is available to authorized users.

Reporting of Study Participant Demographic Characteristics and Demographic Representation in Premarketing and Postmarketing Studies of Novel Cancer Therapeutics

“…Two investigators (JJS and JDW) identified all PMRs and PMCs outlined in the original approval letters available in the Drugs@FDA database. 14 , 15 , 16 …”

“…Given that many PMRs and PMCs did not have results reported on ClinicalTrials.gov, we also searched the Scopus database for publications (Elsevier) using a previously described approach. 14 , 15 , 19 …”

“…There are some concerns with postmarketing requirements (PMRs) and postmarketing commitments (PMCs), including that many are not associated with improvements to gaps in the foundation of clinical evidence present at the time of FDA approval. 14 , 15 , 16 However, to our knowledge, there is no evidence evaluating whether postmarketing studies for cancer therapeutics are associated with improved representation of women, older adults, or racial/ethnic minority groups, compared with premarketing studies. To address these knowledge gaps, we characterized and compared the quality of demographic data reporting and demographic representation of patients enrolled in premarketing studies vs postmarketing studies evaluating novel cancer therapeutics approved by the FDA between 2012 and 2016.…”

Generating comparative evidence on new drugs and devices after approval

“…According to a recent evaluation of FDA approvals from 2009 to 2012, the vast majority of post-marketing commitments, which are not required by any statute or regulation, were for non-clinical studies. 18 Often, post-marketing studies required by regulatory agencies are insufficiently described and do not contain enough information to characterise important study design features such as comparators, randomisation, and endpoints. 19 This is partly because postmarketing studies are rarely underway (or even designed) at the time of market entry.…”

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009–2018

“…[15][16][17] Previous analyses of new therapeutics approved from 2009 to 2012 found that postmarketing requirements and commitments outlined at approval rarely require new prospective cohort studies, registries, or clinical trials, even though these are important sources of clinical evidence for understanding therapeutic efficacy and safety. 18,19 Furthermore, new clinical studies from postmarketing requirements and commitments are inconsistently completed and disseminated, [18][19][20][21] despite generous timelines. 22 Given the opportunity for postmarketing requirements and commitments to promote the generation of clinical evidence for therapeutics, particularly with respect to safety and efficacy for original approved indications, it is important to understand the studies FDA has outlined in postmarketing requirements and commitments, the indications they investigate, and whether they are intended to generate safety and/or efficacy data.…”