Abstract
This cohort study investigates delays in Pediatric Research Equity Act–required studies and issuance of noncompliance letters by the Food and Drug Administration.
Introduction
The Pediatric Research Equity Act (PREA) was implemented in 2003 to expand prescribing information for pediatric patients by allowing the US Food and Drug Administration (FDA) to require that sponsors perform pediatric studies for certain new drugs.1 Prior research assessing this policy found that only approximately one-third of PREA studies were completed after a median of 7 years, resulting in prolonged periods of potential off-label use in pediatric populations.2 While the FDA monitors PREA study progress, it can issue noncompliance letters only after sponsors fail to meet final study submission deadlines. We performed a longitudinal analysis evaluating PREA study delays and issuance of noncompliance letters.
Methods
In accordance with the Common Rule, this cohort study was exempt from institutional review board review given that human participants were not involved. The study followed the STROBE reporting guideline. We reviewed all novel drugs approved by the FDA Center for Drug Evaluation and Research from 2015 to 2019 and identified pediatric postmarket studies required under the PREA using approval letters in the Drugs@FDA database. The study period allowed for a minimum of 5 years of follow-up through December 31, 2024. We collected study characteristics from study descriptions in approval letters (eMethods in Supplement 1). To determine whether a study was delayed during trial conduct, we examined study statuses using the FDA Postmarketing Requirements and Commitments Database.3 For all studies that had been delayed, we determined whether a PREA noncompliance letter was issued.4
We used χ2 tests and t tests to compare studies with and without delays. Analyses were conducted in R Studio version 2024.12.1 + 563 (RStudio). A 2-sided P value < .05 was considered statistically significant.
Results
Among 220 novel drugs approved by the FDA between 2015 and 2019, 62 drugs (28.2%) had a total of 137 pediatric studies required under the PREA at the time of approval. Most studies were primary efficacy (64 studies [46.0%]) or safety (55 studies [40.1%]) studies, and they were concentrated across a few therapeutic areas, with approximately one-half studying nervous system agents (39 studies [28.5%]) or antiinfectives (30 studies [21.9%]) (Table).
Table. Pediatric Research Equity Act–Required Study Characteristics.
| Characteristic | Total studies, No. (column %) (N = 137) | Studies by delay status, No. (row %) | P value | |
|---|---|---|---|---|
| Ever delayed (n = 65) | Never delayed (n = 72) | |||
| Drug type | ||||
| Small molecule drug | 105 (76.6) | 53 (50.5) | 52 (49.5) | .28 |
| Biologic | 32 (23.4) | 12 (37.5) | 20 (62.5) | |
| Study type | ||||
| Primary efficacy study | 63 (46.0) | 32 (50.8) | 31 (49.2) | .74 |
| Primary safety study | 55 (40.1) | 24 (43.6) | 31 (56.4) | |
| Primary PK/PD study | 19 (13.9) | 9 (47.4) | 10 (52.6) | |
| Youngest pediatric age group | ||||
| Neonate (0 to <1 mo) | 18 (13.1) | 9 (50.0) | 9 (50.0) | .43 |
| Infant (1 mo to <2 y) | 26 (19.0) | 11 (42.3) | 15 (57.7) | |
| Early childhood (2 to <6 y) | 21 (15.3) | 10 (47.6) | 11 (52.4) | |
| Late childhood (6 to <12 y) | 48 (35.0) | 26 (54.2) | 22 (45.8) | |
| Adolescent (12 to <18 y) | 20 (14.6) | 9 (45.0) | 11 (55.0) | |
| Unspecified | 4 (2.9) | 0 (0.0) | 4 (100.0) | |
| Therapeutic areaa | ||||
| Nervous system | 39 (28.5) | 13 (33.3) | 26 (66.7) | .003 |
| Anti-infectives for systemic use | 30 (21.9) | 12 (40.0) | 18 (60.0) | |
| Alimentary tract and metabolism | 25 (18.2) | 21 (84.0) | 4 (16.0) | |
| Immunomodulating agents | 13 (9.5) | 7 (53.9) | 6 (46.1) | |
| Hematologic agents | 11 (8.0) | 5 (45.5) | 6 (54.5) | |
| Otherb | 19 (13.9) | 7 (36.8) | 12 (63.2) | |
Abbreviation: PK/PD, pharmacokinetic/pharmacodynamic.
Based on the Anatomical Therapeutic Chemical classification system.
Other includes all therapeutic groups constituting less than 3% of the total study count: dermatologicals (4 studies [2.9%]), cardiovascular (4 studies [2.9%]), various (4 studies [2.9%]), respiratory system (3 studies [2.2%]), systemic hormonal preparations (3 studies [2.2%]), and antiparasitic products, insecticides, and repellents (1 study [0.7%]).
There were 65 studies (47.4%) pertaining to 34 drugs (54.8%) that experienced delays. Delays did not differ significantly by drug type, study type, or age group but varied by therapeutic area, ranging from 13 studies (33.3%) of nervous system agents to 21 studies (84.0%) of alimentary tract drugs (P = .003). Studies with delays took a mean of 2.2 years (95% CI, 1.12-3.20 years; P < .001) longer to complete than those without delays.
The FDA issued noncompliance letters for 9 studies that failed to meet final submission deadlines (13.8% of studies with delays). Of these, 2 studies were subsequently completed while 7 studies remained delayed after a median (range) of 4.1 (0.68-4.76) years after the letter.
Discussion
In this retrospective cohort study of pediatric studies required under the PREA, delays in study completion were common, with nearly half delayed during study conduct. Noncompliance letters were provided for a few delayed studies after they missed reporting deadlines, although most remained delayed years after the letter was issued. A study limitation is the lack of publicly available information on factors contributing to delays and on potential interactions between the FDA and sponsors beyond letters.
Enforcement activities may be more effective if available to the FDA when initial study milestones are missed. In addition, while the FDA has the authority to impose financial penalties for sponsors not complying with adult postmarket study requirements, it is legally prohibited from doing so for pediatric studies.5 A bill was introduced in the US Congress in 2023 to remove this exemption and align enforcement tools across pediatric and adult policies.6 Although the bill was not enacted, our findings underscore the critical need for this and other legislative reforms to increase timely and rigorous conduct of pediatric drug trials.
eMethods.
eReferences.
Data Sharing Statement
References
- 1.Pediatric Research Equity Act of 2003, PL 108-155, 108th Cong (2003). Accessed March 31, 2025. https://www.congress.gov/108/plaws/publ155/PLAW-108publ155.pdf
- 2.Hwang TJ, Orenstein L, Kesselheim AS, Bourgeois FT. Completion rate and reporting of mandatory pediatric postmarketing studies under the US Pediatric Research Equity Act. JAMA Pediatr. 2019;173(1):68-74. doi: 10.1001/jamapediatrics.2018.3416 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.US Food and Drug Administration . Postmarketing requirements and commitments: searchable database. Accessed June 6, 2025. https://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm
- 4.US Food and Drug Administration . PREA non-compliance letters. Accessed June 6, 2025. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/prea-non-compliance-letters
- 5.US Food and Drug Administration . Guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. 2011. Accessed September 26, 2025. https://www.federalregister.gov/documents/2011/04/01/2011-7707/guidance-for-industry-on-postmarketing-studies-and-clinical-trials-implementation-of-section-505o3
- 6.Innovation in Pediatric Drugs Act of 2023, HR 6664, 118th Congress (2023). Accessed March 21, 2025. https://www.congress.gov/bill/118th-congress/house-bill/6664/text
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods.
eReferences.
Data Sharing Statement