U.S. Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018

Abstract

Background/Aims: The U.S. Food and Drug Administration (FDA) outlines clinical studies as postmarketing requirements and commitments to be fulfilled following FDA approval of new drugs and biologics ("therapeutics"). As regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy, yet little is known about how often clinical studies are outlined or the indications they investigate. To assess FDA's use of postmarket clinical studies to generate evidence of therapeutic safety and efficacy, we characterized FDA postmarketing requirements and commitments for new therapeutics approved from 2009-2018. Methods: We conducted a cross-sectional study of all novel therapeutics, including small molecule drugs and biologics, receiving original FDA approval from 2009-2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of FDA postmarketing requirements and commitments for new therapeutics at original approval, including types of studies outlined, indications to be investigated, and clinical evidence to be generated. Results: From 2009-2018, FDA 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 nor commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median = 2 (IQR, 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not significantly change from 2009 (median 2 (IQR, 1-4)) to 2018 (median 2 (IQR, 1-3); P = .54). 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: Most therapeutics are approved by FDA with at least 1 postmarketing requirement or commitment for a clinical study, which outline investigations of safety or efficacy for both approved and unapproved indications. However, the median number of 2 clinical studies outlined has remained relatively constant over the last decade, despite increasing emphasis on lifecycle evaluation of approved therapeutics.

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 …”

“…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] Among this sample of premarketing and postmarketing studies, we excluded studies that evaluated only the therapeutics' safety, pharmacokinetics and pharmacodynamics, bioavailability, dose escalation, or drug interactions (eTable 1 in the Supplement). Additionally, Phase 1 studies, extension studies, expanded access studies, and studies that included patients with a different indication or only healthy patients were excluded.…”

“…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.…”

“…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 . 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.…”