Abstract
Objectives
To evaluate the use of postmarketing requirements under the FDA Amendments Act (FDAAA) and postmarketing commitments issued by the US Food and Drug Administration (FDA), for new drugs approved from 2016 to 2024, and to determine rates of study completion and changes in drug labelling resulting from these studies.
Design
Cross sectional evaluation of postmarketing studies.
Setting
All new drugs and their associated indications approved by the FDA's Center for Drug Evaluation and Research, 1 January 2016 to 31 December 2024.
Population
420 drugs approved by the FDA for 567 indications, associated with 913 FDAAA postmarketing requirements and 434 postmarketing commitments.
Main outcome measures
Drug characteristics associated with issuance of FDAAA postmarketing requirements and issuance of postmarketing commitments, rates of study completion and on-time completion, and proportion of studies leading to changes in drug labelling.
Results
More than two thirds of drugs (n=287, 68.3%) had at least one FDAAA postmarketing requirement and 42.9% (n=180) had at least one postmarketing commitment. Indications with an orphan designation were more likely to have an FDAAA postmarketing requirement (63.3% v 48.6%; absolute difference 14.7%, 95% confidence interval (CI) 6.7% to 22.8%), as were indications approved with an expedited programme (59.6% v 48.1%; absolute difference 11.5%, 2.7% to 20.3%). Similarly, postmarketing commitments were more likely to be issued for indications with an orphan designation (47.0% v 33.6%; absolute difference 13.4%, 5.4% to 21.4%) and those using expedited approval programmes (47.9% v 23.8%; absolute difference 24.1%, 16.2% to 32.1%). Among studies due by the end of 2024, 73.4% (95% CI 69.2% to 77.3%; n=345) of FDAAA postmarketing requirements and 81.5% (76.3% to 86.1%; n=212) of postmarketing commitments were completed, although only 33.4% (29.1% to 37.9%) (n=157) and 36.2% (30.3% to 42.3%) (n=94), respectively, were completed on time. Of the 311 fulfilled FDAAA postmarketing requirement studies, 63.3% (n=197) resulted in at least one labelling change, most often in the section on use in specific populations and clinical pharmacology. Fewer postmarketing commitment studies (n=94, 49.7%) resulted in changes in drug labelling, with most changes found in the clinical pharmacology and clinical studies sections.
Conclusions
FDAAA postmarketing requirements and postmarketing commitments are important regulatory tools for generating postapproval evidence, particularly for drugs approved with orphan designation or under expedited programmes. Although a large proportion of studies resulted in changes in drug labelling, delays in completion were common, highlighting the need to ensure effective oversight and timely study completion and reporting.
Keywords: Therapeutics, Clinical trial
WHAT IS ALREADY KNOWN ON THIS TOPIC
The US Food and Drug Administration (FDA) increasingly relies on postmarketing requirements and commitments to address evidentiary uncertainties at the time of approval
With the enactment of the FDA Amendments Act (FDAAA) in 2007, FDAAA postmarketing requirements were established as a central mechanism for postapproval evidence generation across drug types and indications
Assessment of the regulatory impact of FDAAA postmarketing requirements and postmarketing commitments is limited
WHAT THIS STUDY ADDS
Among all new drugs approved between 2016 and 2024, more than two thirds had at least one FDAAA postmarketing requirement and nearly half had a postmarketing commitment
Postmarketing studies were issued more frequently for drugs with orphan designation or approved with expedited programmes, where premarket evidence was often more limited
A substantial proportion of completed studies resulted in regulatory action, with 63% of FDAAA postmarketing requirements and 50% of postmarketing commitments resulting in changes in drug labelling
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
These findings show that postmarketing studies are commonly used by the FDA, particularly for drugs with more limited premarket evidence, and frequently generate information that alters prescribing information
For regulators and clinicians, the results highlight the importance of strengthening oversight and public reporting to ensure that emerging evidence is rapidly integrated into drug labels and real world decision making
Introduction
The US Food and Drug Administration (FDA) has increasingly adopted a more flexible approach to drug approvals, allowing some new drugs to enter the market based on more limited evidence.1 In recent years, expanded use of expedited programmes by the FDA has resulted in more drugs being approved with fewer pivotal trials and with surrogate endpoints as indicators of efficacy.2 Although this approach allows patients to access promising treatments sooner, greater uncertainty about the safety and efficacy of a drug at the time of market entry is introduced, because surrogate endpoints do not directly show clinical benefit. To manage these uncertainties, the FDA often requests additional evidence to be collected to further evaluate a product's safety, efficacy, or appropriate use.3 These postmarketing studies are intended to confirm clinical benefit or uncover risks not fully understood at approval, contributing to ongoing assessment of the benefits and risks of a drug as part of a lifecycle evaluation process.4,5
Before enactment of the FDA Amendments Act (FDAAA) in 2007, the FDA could issue postmarketing requirements under three specific authorities. These authorities were: the Accelerated Approval Program (1992), whereby the FDA could approve new drugs for serious and life threatening diseases on the basis of surrogate markers with requirements for postmarket trials to confirm efficacy; the Animal Efficacy Rule (2002), allowing the FDA to approve drugs based only on animal efficacy data and require further postmarket evaluation in specific circumstances; and the Pediatric Research Equity Act (PREA, 2003), which authorises the FDA to require paediatric postmarket studies for some drugs approved for adults and considered relevant to paediatric populations. The enactment of FDAAA was motivated by a series of drug safety events and intended to give the FDA a new authority to require drug manufacturers to conduct postmarket safety studies across approval and indication types.3,5 To answer concerns about the FDA's previous monitoring of postmarketing requirements, FDAAA also stipulated specific mechanisms for study oversight, including provision of timetables with study milestone dates, and submission of annual reports on study status.
At the same time, FDAAA redefined postmarketing commitments to represent studies agreed on, but not legally required, between sponsors and the FDA.3,6 Postmarketing commitments represent an important regulatory tool, enabling the FDA to request postmarket efficacy data to complement safety studies required under FDAAA.5,7–9 Similar to FDAAA postmarketing requirements, postmarketing commitments can be issued broadly and are not tied to an approval pathway (ie, Accelerated Approval Program) or patient population (ie, PREA). Unlike FDAAA postmarketing requirements, however, which are legally enforceable and subject to penalties for non-compliance (including civil monetary penalties), postmarketing commitments are voluntary agreements and are not bound by the same statutory enforcement mechanisms.
A focused assessment of FDAAA postmarketing requirements and postmarketing commitments would provide valuable information on how the FDA uses these regulatory provisions in combination to generate postapproval safety and efficacy data for new drugs across approval pathways. Although several previous analyses have evaluated postmarketing requirement studies, most have provided assessments in aggregate across the different postmarketing requirement types or focused on those issued under the Accelerated Approval Program or under PREA.7,10–13 Also, limited information is available on regulatory activities resulting from these studies, including labelling additions related to postapproval study outcomes.11–13 Accordingly, our objective was to evaluate FDAAA postmarketing requirements and postmarketing commitments for new drugs approved by the FDA from 2016 to 2024, including assessment of the types of studies issued, rates of study completion, and changes in labelling resulting from the studies.
Methods
Study design and sample
We conducted a cross sectional evaluation of postmarketing studies for all new drugs approved by the FDA's Center for Drug Evaluation and Research between 1 January 2016 and 31 December 2024.14 For each drug, we identified all postmarketing requirements and commitments with reporting requirements under section 506B of the Food, Drug, and Cosmetic Act associated with the drug indications, including original and supplementary indications, approved up to 31 December 2024. Postmarketing commitments subject to reporting requirements under section 506B are studies on clinical safety, clinical efficacy, clinical pharmacology, and non-clinical toxicology, reflecting situations where more evidence is required after approval, and exclude studies on chemistry, manufacturing, and production controls that may also be issued as postmarketing commitments.15,16 Only postmarketing commitments with reporting requirements (representing about a quarter of all postmarketing commitments8) were included in the analysis. Information on postmarketing requirements and commitments was obtained from FDA approval letters, which are available in the FDA's online Drugs@FDA database and list all postmarketing requirements and commitments issued at the time of approval, together with brief study descriptions.17 To identify postmarket studies issued by the FDA after the indication approval date, we searched the FDA's Postmarketing Requirements and Commitments Database for studies associated with the indications in our study sample.18
Characteristics of drug indications and postmarketing studies
For each indication associated with an FDAAA postmarketing requirement or postmarketing commitment study, we recorded the approval date, therapeutic area (based on the Anatomical Therapeutic Chemical classification), orphan designation status (granted to drugs intended for the treatment of rare diseases affecting <200 000 people in the US), and whether an expedited approval pathway (ie, programmes such as Priority Review, Breakthrough Therapy, or Fast Track, which are designed to facilitate earlier patient access to treatments for serious conditions) was used.
For all FDAAA postmarketing requirements and postmarketing commitments, the FDA provides a standard and mutually exclusive categorisation for the type of clinical trial or study (online supplemental methods). This categorisation was used to classify postmarketing requirements and commitments as clinical trials (eg, primary efficacy trials), clinical studies (eg, epidemiological studies), or other study types (eg, laboratory studies). Based on the study descriptions and types, we assigned a temporality label to indicate whether the study represented a new study, completion of an ongoing study, or whether further analysis was conducted based on existing data. Finally, we extracted information on study due dates to determine planned study durations, defined as the time from approval of the indication to due date for the study report.
Determination of study status
We queried the FDA's Postmarketing Requirements and Commitments Database to determine the status of studies and the date when the final status was assigned. The status of a study could be pending (study has not yet started), ongoing (study is in progress), delayed (study has not met expected timelines), submitted (final study report has been submitted), fulfilled (study obligations are considered satisfied), or released (sponsor has been released from the obligation to conduct the study).19 The FDA also has a category of terminated, although no studies in our sample had this designation. Because information on studies that are fulfilled or released are removed from the database after a year, we retrieved quarterly archived versions of the database (available through the FDA's website) to identify the final status of studies along with status dates. Also, through a Freedom of Information Act request, we obtained nine archived databases that were not publicly available, as well as submission dates for 87 FDAAA postmarketing requirement and postmarketing commitment studies missing from the datasets.
Studies were considered complete when submitted. Observed study duration was defined as the time from approval of the indication to study submission. Studies were tracked until they were fulfilled or released, or until the end of our observation period on 31 December 2024. For drugs that were discontinued (n=16), if the postmarketing requirement or commitment had not been submitted or fulfilled at the time of discontinuation, we censored follow-up on the discontinuation date.
Identification of labelling changes and other regulatory outcomes
To determine whether the postmarketing studies contributed to a labelling change, for indications associated with at least one fulfilled postmarketing study, we searched the FDA's safety related labelling changes database to identify updates to safety information and also reviewed labels manually to extract information on all types of changes in drug labelling changes.20 All label changes up to 31 December 2024 were included. A postmarketing study was considered to have resulted in a labelling change if any result from the study was added. We collected information on all changes in drug labelling associated with a study, noting the sections of the label that had been changed and defining the number of labelling changes as the number of sections in the label that had been modified.
Other regulatory outcomes that were considered included issuance of a new postmarketing study to investigate study results, Risk Evaluation and Mitigation Strategy (REMS) modifications, and FDA safety communications.21 New postmarketing studies were those that were issued after the approval date of the indication and referenced the findings from the earlier study as rationale for the new postmarketing requirement. For all drugs in the study cohort, we reviewed REMS in the REMS@FDA database to identify those with modifications triggered by postmarketing requirement or commitment studies.22 We also investigated whether any fulfilled postmarketing requirements were associated with FDA Drug Safety Communications, available on the FDA's website.23
Statistical analysis and visualisation
We used descriptive statistics to characterise FDAAA postmarketing requirement and postmarketing commitment studies and to evaluate study completion and outcomes. Evaluation of completion of a study was performed on the subset of studies with due dates by 31 December 2024, to deal with censored study follow-up periods. Changes in drug labelling and other regulatory outcomes were evaluated only for studies that had been fulfilled by 31 December 2024. We used χ2 tests to assess the characteristics of indications associated with postmarketing requirement and commitment studies, as well as the characteristics of postmarketing studies associated with study completion, completion on time, and addition of labelling changes. Absolute differences in proportions with 95% confidence intervals (CI) were calculated to estimate the magnitude of differences based on orphan status and use of expedited programmes. Observed study completion times for postmarketing requirement and commitment studies were compared with planned completion times with two complementary approaches. Kaplan-Meier curves were used to visualise time-to-completion distributions, with studies not yet completed by 31 December 2024 treated as censored. Separately, we used the Wilcoxon signed rank test to compare planned versus observed completion dates among studies with observed completion times only (ie, excluding censored studies), because this test is appropriate for paired data and allows evaluation of whether completion occurred later than originally planned. To visualise the relation between postmarketing study types and corresponding changes in drug labelling, we constructed Sankey diagrams showing the specific label sections that had been modified. For studies resulting in multiple labelling changes, all modified sections were included and linked to the study.
All statistical tests were performed with R version 4.4.1 and were two tailed, with a significance threshold of P<0.05. Results are reported in accordance with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for observational research.24
Patient and public involvement
Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of this research because this was a secondary analysis of publicly available regulatory data.
Results
Study cohort
Between 1 January 2016 and 31 December 2024, the FDA approved 420 drugs for 567 indications. These indications were associated with 1386 postmarketing requirements, including 913 (65.9%) FDAAA postmarketing requirements, 355 (25.6%) paediatric postmarketing requirements under PREA, 115 (8.3%) postmarketing requirements associated with the Accelerated Approval Program, and three (0.2%) postmarketing requirements under the Animal Efficacy Rule. Also, 434 postmarketing commitments were issued for these indications.
At the drug level, 287 (68.3%) drugs were associated with at least one FDAAA postmarketing requirement, whereas 180 (42.9%) had at least one postmarketing commitment. At the indication level, 317 (55.9%) indications were linked to at least one FDAAA postmarketing requirement and 228 (40.2%) to at least one postmarketing commitment (median 2.0 (interquartile range (IQR) 0-3.0) FDAAA postmarketing requirement studies and median 0 (0-2.0) postmarketing commitment studies issued for each drug).
Indications with FDAAA postmarketing requirements and postmarketing commitment studies
Issuance of FDAAA postmarketing requirements was associated with several characteristics of drug indications, including product type, orphan designation status, use of expedited programmes, and therapeutic area (table 1). Indications with an orphan designation were more likely to have an FDAAA postmarketing requirement, with 63.3% (n=178) of orphan indications assigned an FDAAA postmarketing requirement compared with 48.6% (n=139) without orphan status (absolute difference 14.7%, 95% CI 6.7% to 22.8%). Similarly, among indications approved based on an expedited programme, 59.6% (n=230) were associated with an FDAAA postmarketing requirement compared with 48.1% (n=87) based on traditional approvals (absolute difference 11.5%, 95% CI 2.7% to 20.3%; P=0.01). Use of FDAAA postmarketing requirements varied across therapeutic areas, with the highest rates seen for cardiovascular drugs (n=11; 84.6%) and alimentary tract and metabolism drugs (n=34; 77.3%), and the lowest for sensory organ agents (n=3; 25.0%) and drugs in the various category (n=5; 20.0%).
Table 1. Characteristics of indications with FDA Amendments Act (FDAAA) postmarketing requirements and indications with postmarketing commitments, 2016-24.
| Total No of indications (n=567) |
FDAAA postmarketing requirement studies | Postmarketing commitment studies | |||||
|---|---|---|---|---|---|---|---|
| Indications with at least one postmarketing requirement (n=317) |
Indications without a postmarketing requirement (n=250) |
P value | Indications with at least one postmarketing commitment (n=228) |
Indications without a postmarketing commitment (n=339) |
P value | ||
| Product type: | |||||||
| Small molecule | 384 (67.7) | 233 (60.7) | 151 (39.3) | 0.001 |
150 (39.1) | 234 (60.9) | 0.47 |
| Biologic | 183 (32.3) | 84 (45.9) | 99 (54.1) | 78 (42.6) | 105 (57.4) | ||
| Orphan designation: | |||||||
| Yes | 281 (49.6) | 178 (63.3) | 103 (36.7) | <0.001 |
132 (47.0) | 149 (53.0) | 0.002 |
| No | 286 (50.4) | 139 (48.6) | 147 (51.4) | 96 (33.6) | 190 (66.4) | ||
| Use of an expedited programme: | |||||||
| Yes | 386 (68.1) | 230 (59.6) | 156 (40.4) | 0.01 |
185 (47.9) | 201 (52.1) | <0.001 |
| No | 181 (31.9) | 87 (48.1) | 94 (51.9) | 43 (23.8) | 138 (76.2) | ||
| Expedited programme type: | |||||||
| Accelerated Approval | 94 (16.6) | 58 (61.7) | 36 (38.3) | 0.26 | 55 (58.5) | 39 (41.5) | <0.001 |
| Breakthrough Therapy | 161 (28.4) | 96 (59.6) | 65 (40.4) | 0.30 | 95 (59.0) | 66 (41.0) | <0.001 |
| Fast Track | 178 (31.4) | 120 (67.4) | 58 (32.6) | <0.001 | 82 (46.1) | 96 (53.9) | 0.07 |
| Priority Review | 350 (61.7) | 211 (60.3) | 139 (39.7) | 0.01 | 172 (49.1) | 178 (50.9) | <0.001 |
| Therapeutic area: | |||||||
| Antineoplastic agents | 197 (34.7) | 90 (45.7) | 107 (54.3) | <0.001 |
125 (63.5) | 72 (36.5) | <0.001 |
| Immunomodulating agents | 74 (13.1) | 50 (67.6) | 24 (32.4) | 28 (37.8) | 46 (62.1) | ||
| Nervous system | 60 (10.6) | 42 (70.0) | 18 (30.0) | 11 (18.3) | 49 (81.7) | ||
| Anti-infectives for systemic use | 48 (8.5) | 32 (66.7) | 16 (33.3) | 19 (39.6) | 29 (60.4) | ||
| Alimentary tract and metabolism | 44 (7.8) | 34 (77.3) | 10 (22.7) | 17 (38.6) | 27 (61.4) | ||
| Various | 25 (4.4) | 5 (20.0) | 20 (80.0) | 3 (12.0) | 22 (88.0) | ||
| Blood and blood forming organs | 24 (4.2) | 11 (45.8) | 13 (54.2) | 8 (33.3) | 16 (66.7) | ||
| Dermatologicals | 20 (3.5) | 8 (40.0) | 12 (60.0) | 4 (20.0) | 16 (80.0) | ||
| Musculoskeletal system | 15 (2.7) | 11 (73.3) | 4 (26.7) | 1 (6.7) | 14 (93.3) | ||
| Cardiovascular system | 13 (2.3) | 11 (84.6) | 2 (15.4) | 1 (7.7) | 12 (92.3) | ||
| Systemic hormonal preparations | 13 (2.3) | 6 (46.2) | 7 (53.8) | 2 (15.4) | 11 (84.6) | ||
| Sensory organs | 12 (2.1) | 3 (25.0) | 9 (75.0) | 2 (16.7) | 10 (83.3) | ||
| Other* | 22 (3.9) | 14 (63.6) | 8 (36.4) | 7 (31.8) | 15 (68.2) | ||
Data are number (%) unless indicated otherwise.
Other includes therapeutic groups representing <2.0% of all indications, including antiparasitic products and insecticides (n=9; 1.6%), respiratory system (n=8; 1.4%), and genitourinary system and sex hormones (n=5; 0.9%).
Assignment of postmarketing commitments followed a similar pattern to postmarketing requirements (table 1). Postmarketing commitments were more likely to be issued for indications with an orphan designation, with 47.0% (n=132) of orphan indications associated with a postmarketing commitment versus 33.6% (n=96) without orphan status (absolute difference 13.4%, 95% CI 5.4% to 21.4%). Use of an expedited programme was also linked to postmarketing commitments, with 47.9% (n=185) of indications approved by an expedited programme receiving a postmarketing commitment compared with 23.8% (n=43) of indications without (absolute difference 24.1%, 95% CI 16.2% to 32.1%). Across therapeutic areas, use of postmarketing commitments ranged from 63.5% (n=125) for antineoplastic drugs to 6.7% (n=1) for musculoskeletal system agents.
Study characteristics
About two fifths (37.5%, n=342) of the FDAAA postmarketing requirements consisted of clinical trials and a fifth (20.0%, n=183) of clinical studies (table 2). The median planned duration was 3.3 years (IQR 1.7-6.6). Among postmarketing commitments, 62.7% (n=272) were clinical trials, including 38.3% (n=166) primary efficacy trials. Planned study durations were slightly shorter than for FDAAA postmarketing requirements, at 2.3 years (IQR 1.1-4.8).
Table 2. Characteristics of FDA Amendments Act (FDAAA) postmarketing requirement and postmarketing commitment studies.
| Study type | FDAAA postmarketing requirement studies (n=913) | Postmarketing commitment studies (n=434) |
|---|---|---|
| Clinical trial: | 342 (37.5) | 272 (62.7) |
| Primary efficacy clinical trial | 0 | 166 (38.3) |
| Primary safety clinical trial | 117 (12.8) | 6 (1.4) |
| Pharmacokinetic or pharmacodynamic clinical trial | 109 (11.9) | 28 (6.5) |
| Other clinical trial* | 116 (12.7) | 72 (16.6) |
| Clinical study: | 183 (20.0) | 18 (4.2) |
| Epidemiological study | 181 (19.8) | 18 (4.2) |
| Meta-analysis or pooled analysis of observational studies | 2 (0.2) | 0 |
| Other study type: | 388 (42.5) | 144 (33.2) |
| Laboratory or in vitro study | 173 (18.9) | 107 (24.7) |
| Animal study | 125 (13.7) | 6 (1.4) |
| Other | 90 (9.8) | 31 (7.1) |
| Temporality: | ||
| New study | 756 (82.8) | 257 (59.2) |
| Ongoing study | 88 (9.6) | 144 (33.2) |
| Additional analysis of existing data | 69 (7.6) | 33 (7.6) |
| Median (IQR) planned study duration (years) | 3.3 (1.7-6.6) | 2.3 (1.1-4.8) |
Data are number (%) unless indicated otherwise.
Other clinical trials include: meta-analysis or pooled analysis of previous clinical trials, drug interaction or bioavailability trials, immunogenicity trials, thorough Q-T clinical trials, pharmacogenetic or pharmacogenomic trials, dose-response clinical trials, safety outcomes trials, and dosing trials.
IQR, interquartile range.
Completion of studies
Among the 470 FDAAA postmarketing requirements due by 31 December 2024, 345 (73.4%) were completed but only 157 (33.4%) were completed on time (table 3). Among studies completed late, the median delay beyond the due date was 0.5 years (IQR 0.3-0.9). We found no differences in the percentage of studies that were completed or completed on time based on orphan designation, although use of expedited approval pathways was associated with a higher rate of completion on time (35.4% v 21.7%; absolute difference 13.7%, 95% CI 2.9% to 24.5%).
Table 3. Completion of FDA Amendments Act (FDAAA) postmarketing requirement and postmarketing commitment studies due by 31 December 2024.
| FDAAA postmarketing requirement studies | Postmarketing commitment studies | |||||
|---|---|---|---|---|---|---|
| No of studies due by 31 December 2024 | Completed | Completed on time | No of studies due by 31 December 2024 | Completed | Completed on time | |
| All studies | 470 | 345 (73.4) | 157 (33.4) | 260 | 212 (81.5) | 94 (36.2) |
| Orphan designation: | ||||||
| Yes | 321 | 233 (72.6) | 108 (33.6) | 140 | 114 (81.4) | 44 (31.4) |
| No | 149 | 112 (75.2) | 49 (32.9) | 120 | 98 (81.7) | 50 (41.7) |
| P value | — | 0.63 | 0.95 | — | 1 | 0.11 |
| Use of expedited programme: | ||||||
| Yes | 401 | 296 (73.8) | 142 (35.4) | 222 | 183 (82.4) | 81 (36.5) |
| No | 69 | 49 (71.0) | 15 (21.7) | 38 | 29 (76.3) | 13 (34.2) |
| P value | — | 0.73 | 0.04 | — | 0.50 | 0.93 |
| Study type:* | ||||||
| Clinical trial | 223 | 167 (74.8) | 78 (35.0) | 157 | 128 (81.5) | 61 (38.9) |
| Clinical study | 14 | 3 (21.4) | 0 (0) | 4 | 4 (100) | 1 (25.0) |
| Other | 233 | 175 (75.1) | 79 (33.9) | 99 | 80 (80.8) | 32 (32.3) |
| P value | — | <0.001 | 0.01 | — | 0.94 | 0.21 |
| Temporality: | ||||||
| New study | 366 | 257 (70.2) | 110 (30.1) | 143 | 106 (74.1) | 46 (32.2) |
| Ongoing study | 61 | 53 (86.9) | 32 (52.5) | 97 | 88 (90.7) | 44 (45.4) |
| Additional analysis of existing data | 43 | 35 (81.4) | 15 (34.8) | 20 | 18 (90.0) | 4 (20.0) |
| P value | — | 0.01 | 0.003 | — | 0.003 | 0.03 |
Data are number (%) unless indicated otherwise.
Based on US Food and Drug Administration categorisation of clinical trials (eg, primary efficacy trials), clinical studies (eg, epidemiological studies), or other study type (eg, laboratory studies).
For postmarketing commitment studies, 212 (81.5%) of 260 studies due by 31 December 2024 were completed, which was significantly higher than for FDAAA postmarketing requirements (73.4%; absolute difference 8.1%, 95% CI 2.0% to 14.3%). Among these studies, 94 (36.2%) were completed on time (no significant difference compared with postmarketing requirements). Among postmarketing commitment studies that were delayed, the median delay beyond the due date was 0.6 years (IQR 0.3-1.0).
Figure 1 compares the cumulative incidence of study completion based on originally planned versus observed completion dates for FDAAA postmarketing requirement and postmarketing commitment studies. For both FDAAA postmarketing requirements and postmarketing commitments, studies were completed significantly later than expected (Wilcoxon signed rank test, P<0.001 for both). For FDAAA postmarketing requirement studies, at two years, 31.7% of studies were planned to be completed compared with 27.5% actually completed. The difference increased over time and by five years, 65.2% were planned to be completed versus 54.9% observed to be completed. Similarly, for postmarketing commitment studies, at two years, 45.2% of studies were planned to be completed whereas 36.8% were observed to be completed. By five years, 77.2% were planned to be completed and 72.2% were actually completed.
Figure 1. Cumulative incidences of study completion based on planned versus observed study completion dates for FDA Amendments Act (FDAAA) postmarketing requirement studies (top) and postmarketing commitment studies (bottom).
Changes in drug labelling
Among the 311 FDAAA postmarketing requirements that were fulfilled by 31 December 2024, 197 (63.3%) resulted in changes in drug labelling, corresponding to 112 of 146 (76.7%) indications with a fulfilled postmarketing requirement (table 4). FDAAA postmarketing requirement studies conducted for indications with an orphan indication were more likely to result in a labelling change (68.4% v 53.3%; absolute difference 15.1%, 95% CI 3.7% to 26.6%), although no difference was seen for the use of expedited programmes (P=0.83). Study type was also associated with changes in drug labelling, with 73.4% (n=113) of clinical trials resulting in labelling changes compared with 50.0% (n=1) of clinical studies (P<0.001). In terms of study temporality, ongoing studies at the time of approval had the highest percentage of labelling changes (70.6%, n=36) and analysis of existing data the lowest (31.4%, n=11; P<0.001).
Table 4. Changes in drug labelling resulting from FDA Amendments Act (FDAAA) postmarketing requirement and postmarketing commitment studies.
| FDAAA postmarketing requirement studies | Postmarketing commitment studies | |||||
|---|---|---|---|---|---|---|
| No of fulfilled studies | Labelling change | P value | No of fulfilled studies | Labelling change | P value | |
| All studies | 311 | 197 (63.3) | — | 189 | 94 (49.7) | — |
| Orphan designation: | ||||||
| Yes | 206 | 141 (68.4) | 0.01 |
100 | 42 (42.0) | 0.03 |
| No | 105 | 56 (53.3) | 89 | 52 (58.4) | ||
| Use of expedited programme: | ||||||
| Yes | 265 | 169 (63.8) | 0.83 |
163 | 77 (47.2) | 0.13 |
| No | 46 | 28 (60.8) | 26 | 17 (65.4) | ||
| Study type:* | ||||||
| Clinical trial | 154 | 113 (73.4) | <0.001 |
117 | 67 (57.2) | 0.01 |
| Clinical study | 2 | 1 (50.0) | 1 | 0 (0) | ||
| Other | 155 | 83 (53.5) | 71 | 27 (38.0) | ||
| Temporality: | ||||||
| New study | 225 | 150 (66.7) | <0.001 |
97 | 45 (46.4) | <0.001 |
| Ongoing study | 51 | 36 (70.6) | 75 | 47 (62.7) | ||
| Additional analysis of existing data | 35 | 11 (31.4) | 17 | 2 (11.8) | ||
Data are number (%) unless indicated otherwise.
Based on US Food and Drug Administration categorisation of clinical trials (eg, primary efficacy trials), clinical studies (eg, epidemiological studies), or other study type (eg, laboratory studies).
The 197 FDAAA postmarketing requirements resulted in 227 changes in drug labelling. Figure 2 shows the association between FDAAA postmarketing requirement study types and drug labelling sections that were modified. The study types contributing the largest number of changes were pharmacokinetic or pharmacodynamic clinical trials (n=49; 21.6%, 95% CI 16.5% to 27.6%), laboratory or in vitro studies (n=46; 20.2%, 15.3% to 26.2%), other clinical trials (n=30; 13.2%, 9.2% to 18.2%), and animal studies (n=30; 13.2%, 9.2% to 18.2%). Changes were most frequent in the sections on use in specific populations (n=58; 25.6%, 95% CI 20.1% to 31.7%), followed by sections on clinical pharmacology (n=49; 21.6%, 16.5% to 27.6%) and drug interactions (n=37; 16.3%, 11.8% to 21.9%).
Figure 2. Relation between FDA Amendments Act (FDAAA) postmarketing requirement (top) and postmarketing commitment (bottom) study types and the resulting changes in drug labelling. Top=311 postmarketing requirement studies corresponding to 227 labelling changes. Bottom=189 postmarketing commitment studies associated with 129 labelling changes. The width of each band is proportional to the number of studies contributing to each type of labelling change. Labelling changes are shown in descending order based on frequency.
Postmarketing commitment studies were less likely to lead to changes in drug labelling compared with FDAAA postmarketing requirements, with 94 of the 189 fulfilled postmarketing commitments resulting in a change (63.3% v 49.7%, respectively; absolute difference 13.6%, 95% CI 4.7% to 22.5%). This finding corresponded to 66 of 114 (57.9%) indications with a fulfilled postmarketing commitment study. Unlike FDAAA postmarketing requirements, postmarketing commitments were more likely to result in labelling changes for indications without orphan designation (42.0% v 58.4%, absolute difference 16.4%, 2.3% to 30.5%). Both study type and temporality were associated with changes in drug labelling, with 57.2% (n=67) of clinical trials leading to labelling changes compared with none of the clinical studies (P=0.01), and 62.7% (n=47) of ongoing studies compared with 11.8% (n=2) of analyses of existing data (P<0.001).
We found 129 changes in drug labelling associated with the postmarketing commitment studies (figure 2). Most labelling changes resulted from primary efficacy clinical trials (n=37; 28.7%, 95% CI 21.3% to 37.0%), followed by laboratory or in vitro studies (n=24; 18.6%, 12.6% to 26.7%), and pharmacokinetic or pharmacodynamic clinical trials (n=24; 18.6%, 12.6% to 26.7%). The sections most likely to be modified were clinical pharmacology (n=32; 24.8%, 17.9% to 33.1%), followed by clinical studies (n=25; 19.4%, 13.3% to 27.7%) and drug interactions (n=19; 14.7%, 9.4% to 22.3%).
Other regulatory outcomes
As well as changes in drug labelling, FDAAA postmarketing requirements were associated with other regulatory outcomes. For two drugs, ibalizumab-uiyk and remdesivir, additional FDAAA postmarketing requirements were issued that were related to the findings from the original FDAAA postmarketing requirements. For the drug pexidartinib, the REMS was revised to update educational materials to align with the label changes resulting from the FDAAA postmarketing requirement. Finally, for the drug duvelisib, an FDA Drug Safety Communication was issued relating to study findings showing a possible increased risk of death and serious side effects associated with the use of the drug. Postmarketing commitment studies did not result in any other regulatory outcomes.
Discussion
Principal findings
In this evaluation of 420 new drugs approved between 2016 and 2024, the FDA requested postmarketing studies for a substantial proportion of products, with 68% approved with FDAAA postmarketing requirements and 43% with postmarketing commitments. These requirements were more common for drugs with orphan indications and those approved through expedited pathways, underscoring the role of postmarketing studies in complementing limited preapproval data with additional evidence.25 Although FDAAA introduced provisions to promote timely completion of postmarketing requirements, only about a third of studies were completed on schedule. Many FDAAA postmarketing requirement and postmarketing commitment studies, however, contributed to regulatory actions, with 63% of postmarketing requirements and 50% of postmarketing commitments resulting in changes in drug labelling. Because the FDA increasingly relies on postmarketing studies to deal with uncertainties in expedited approvals, these findings highlight the central role of FDAAA postmarketing requirements and postmarketing commitments in generating critical postapproval evidence. The findings also emphasise the ongoing need for timely completion of studies and effective regulatory oversight to ensure that the benefits and risks of new drugs are fully understood across the product lifecycle.
Comparison with other studies
Our analysis builds on previous assessments of postapproval studies by providing a focused evaluation of FDAAA postmarketing requirements and postmarketing commitments and the regulatory outcomes generated from these studies. FDAAA postmarketing requirements represented a large proportion of all postmarketing requirements issued by the FDA, consistent with analyses of drugs approved during earlier periods.26,27 Overall, about two thirds of postmarketing requirements came from the authority granted under FDAAA, underscoring its broad use by the agency. A substantial number of FDAAA postmarketing requirement and postmarketing commitment studies, however, were not submitted on time. An analysis of drugs approved from 2013 to 2016 reported that only 13% of FDAAA postmarketing requirements and 18% of postmarketing commitments were completed by their deadline.26 In our sample, about a third of studies met their due dates, suggesting either improved adherence to timelines or changes in study requirements that may have facilitated completion. The difference between planned and observed completion dates was relatively small (about six months) although delays likely vary by study type and may have different implications depending on the objectives of the study and evidence needs. This duration aligns with previous findings,26 emphasising the need to assess both the frequency and magnitude of submission delays to fully understand the extent of non-compliance.
An important contribution of this analysis is in furthering our understanding of the regulatory activities and outcomes associated with FDAAA postmarketing requirement and postmarketing commitment studies. We found that a large proportion of indications underwent labelling changes based on these studies. Changes were more likely for orphan indications, but not for those drugs approved through expedited programmes. Labelling updates to sections on warnings and precautions and adverse reactions may be particularly important in informing risk-benefit discussions between clinicians and patients and guiding monitoring strategies. Nonetheless, many studies did not result in changes in drug labelling, and the FDA provides neither details on their findings nor insights into the agency's evaluation of the reports. Moreover, whether these studies produced the information originally intended, particularly about the supplementation of preapproval data and the resolution of uncertainties about clinical benefit and safety, is not clear. Notably, only 3% of labelling changes from FDAAA postmarketing requirements and 19% from postmarketing commitments affected the clinical studies section of the label, which is where key evidence on the safety, efficacy, and optimal use of a drug in patient populations is typically presented.
Without additional information on study protocols or the FDA's internal reviews of the submitted study reports, further analysis of the factors associated with labelling changes or other regulatory outcomes was not possible. The lack of publicly available information on the conduct and findings of FDAAA postmarketing requirements and postmarketing commitments also hinders a full understanding of the evidence generated by these studies. Previous work underscored this gap insofar as about 25% of prospective FDAAA postmarketing requirement studies and clinical trials were not registered on ClinicalTrials.gov and did not have publicly reported study results.27 For patients and clinicians, the absence of such data in the drug label and the literature limits the ability to make fully informed treatment decisions and may undermine trust in the completeness and transparency of the available evidence.
Comparison with the European regulatory setting
In the European regulatory setting, the European Medicines Agency (EMA) similarly mandates postapproval evidence generation through a framework of postauthorisation measures.28 These measures are designed to deal with residual uncertainties about benefit-risk and are integral to the EMA's lifecycle approach to oversight of medicinal products.29,30 Similar to the FDA's use of postmarketing requirements and postmarketing commitments, these obligations are frequently applied to drugs approved through accelerated or conditional pathways. A comparative evaluation of advanced therapy medicinal products authorised by both the FDA and EMA found that the EMA imposed 53 postapproval studies compared with 27 FDA postmarketing requirements, with only 15 (28.3%) of the EMA imposed obligations fulfilled as of December 2023 and none of those required by the FDA.31 In another analysis, among postapproval studies associated with 21 medicines granted conditional marketing authorisation in the European Union between 2006 and 2014, half were completed on time whereas the remainder were submitted about nine months later than their agreed timelines.32 Although most obligations were ultimately fulfilled, less than a third of medicines converted to standard marketing authorisation within a year of the expected period. Similarly, in an analysis of oncology drugs approved by the EMA from 2004 to 2014, nearly 80% were approved with associated postmarketing study obligations. After a median follow-up of eight years, 40% of studies were ongoing or delayed, and only half of the requirements for new clinical studies had been completed on time. Despite these delays, 80% of drugs with outstanding requirements were ultimately granted permanent marketing authorisation.33 Together, these findings parallel those observed under the FDA's postmarketing framework: both agencies rely extensively on postapproval studies to confirm therapeutic benefit and further characterise safety, but both have persistent challenges with timely study completion and transparency about how these data inform subsequent regulatory decisions.
Recommendations
To enhance transparency and facilitate more meaningful use of postmarketing study data, opportunities exist to improve FDA reporting practices and data infrastructure. Limited information is available on some key aspects of FDAAA postmarketing requirements and postmarketing commitments, such as the rationale for requesting studies, details on study design and characteristics, and study findings and outcomes. The FDA also does not provide information on factors leading to study release or other regulatory activities related to the conduct and completion of postmarket studies. Previous analyses have reported the lack of study specific information that is available on postmarketing requirements. We also found that some documents were inconsistently posted and difficult to obtain even through Freedom of Information Act requests.27 At a minimum, the FDA should consider providing summary data on the results of all completed FDAAA postmarketing requirements and postmarketing commitments together with a description of their rationale for the resulting regulatory action. Improved public access to study specific materials would allow researchers and clinicians to better understand the intent, design, and outcomes of postmarketing studies, assess the quality and rigour of the evidence generated, and evaluate how this evidence fills gaps that presumably prompted postmarketing requirements and commitments and informs regulatory decisions and clinical practice.
Also, a centralised, drug level repository is crucially needed that links drugs to their associated postmarketing requirements and commitments, and provides additional details and updates on requested studies. This information could include descriptions of study rationales, quarterly updates on study status, links to submitted reports, and summaries of labelling changes and other resulting regulatory actions. Although the FDA is required to submit an annual report to the Federal Register summarising the status of postmarketing requirement and commitment studies, these reports provide only aggregate data on ongoing and submitted postmarketing requirements and commitments for the previous fiscal year.6 Using the currently available FDA data sources, linking drugs to their postmarket studies and identifying resulting regulatory actions requires extensive manual searches and data collection across multiple document types and datasets. A more robust and integrated data infrastructure is essential to enable comprehensive tracking of postmarketing studies, support timely evaluation of emerging evidence, and ensure regulatory decisions are transparent, data driven, and accessible to all stakeholders.
Limitations of this study
This study had several limitations. Firstly, our cohort was restricted to drugs approved from 2016 onwards; products approved from the enactment of FDAAA in 2008 to 2015 were excluded. Hence our findings are not necessarily reflective of all FDAAA postmarketing requirements and postmarketing commitments, and our data did not support comprehensive analyses of trends since the enactment of FDAAA. Secondly, information on reasons for study delays or other aspects of the conduct of trials, such as adherence to agreed study designs and outcomes, was not publicly available. Thirdly, because the FDA does not formally report on the evidence generated from FDAAA postmarketing requirement and postmarketing commitment studies, other regulatory actions may have been taken that we could not capture with the outcomes that were assessed in this study.
Conclusions
Postmarketing studies have an essential role in the FDA's lifecycle evaluation of newly approved drugs, particularly in the context of expedited approvals and orphan indications where premarket evidence may be more limited. Our findings reinforce the potential value of FDAAA postmarketing requirements and postmarketing commitments in generating clinically meaningful data, as evidenced by the high rate of associated changes in drug labelling. The persistent delays in study completion and limited public access to key study level information, however, are significant challenges for independent evaluation of postapproval evidence and their role in complementing preapproval requirements. Improving the transparency, consistency, and accessibility of data related to FDAAA postmarketing requirements and postmarketing commitments is necessary to fully realise their potential in informing regulatory decisions and clinical practice. Establishing a centralised, comprehensive, and publicly accessible infrastructure for tracking postmarketing studies would enhance accountability, enable more effective oversight, and promote a deeper understanding of how postapproval evidence adds to the safety and effectiveness information of drugs.
Supplementary material
Footnotes
Funding: This work was funded by a grant from Arnold Ventures (grant No 24-10849). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability free text: All data were extracted from publicly available sources.
Ethics approval: In accordance with the Common Rule, this study was exempt from institutional board review given that human participants were not involved.
Data availability statement
Data are available upon reasonable request.
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