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

Abstract

Background/Aims The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics (“therapeutics”). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018. Methods We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated. Results From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1–4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1–4)) to 2018 (median: 2 (interquartile range: 1–3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications. Conclusions The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.

Comparison of Duration of Postapproval vs Pivotal Trials for Therapeutic Agents Granted US Food and Drug Administration Accelerated Approval, 2009-2018

“…This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. For each therapeutic agent, we used previously described approaches to identify pivotal and postapproval trials designed to confirm efficacy, 3 , 4 , 5 classify postapproval trials as either new or ongoing at the time of approval, 4 identify FDA-established postapproval trial results reporting deadlines, 4 , 6 and locate ClinicalTrials.gov registrations and publications. 4 We used FDA labels/letters and medical reviews, ClinicalTrials.gov registrations, and publications to identify pivotal and postapproval trial primary outcomes and the timing of their ascertainment (ie, median duration of follow-up or response for event-driven trials).…”

Feasibility of Using Real-world Data to Emulate Postapproval Confirmatory Clinical Trials of Therapeutic Agents Granted US Food and Drug Administration Accelerated Approval

“…We used the Drugs@FDA database to identify all FDA-required postapproval confirmatory trials for new molecular entity drugs and biologics that were regulated by the FDA Center for Drug Evaluation and Research and granted accelerated approval between 2009 and 2018. 5 For all postapproval confirmatory trials designed to verify efficacy, we reviewed study descriptions, ClinicalTrials.gov information, and abstracts of publications to determine the proportion of trials for which the (1) clinical indication, (2) at least 80% of the clinical inclusion and exclusion criteria, (3) the comparator, and (4) the primary end point(s) could be routinely ascertained from RWD using previously described methods (eTable in the Supplement ). 3 These characteristics were considered unlikely to be routinely ascertained from observational data if researchers would find it difficult to develop a computable phenotype using available RWD sources.…”

Analysis of Supportive Evidence for US Food and Drug Administration Approvals of Novel Drugs in 2020

“…An in-depth follow-up, using methods set by published studies of earlier time periods, could investigate whether these PMRs and PMCs would answer questions left by limited preapproval evidence, timeliness of completion, and whether the FDA takes appropriate action based on the results of PMRs and PMCs. [32][33][34]…”