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Table 1.  Characteristics of Published and Unpublished Trials
Characteristics of Published and Unpublished Trials
Table 2.  Safety and Efficacy Data Available in Unpublished Trial Reportsa
Safety and Efficacy Data Available in Unpublished Trial Reportsa
1.
Jones  CW, Handler  L, Crowell  KE, Keil  LG, Weaver  MA, Platts-Mills  TF.  Non-publication of large randomized clinical trials: cross sectional analysis.   BMJ. 2013;347:f6104. doi:10.1136/bmj.f6104 PubMedGoogle ScholarCrossref
2.
Sachs  AN, Avant  D, Lee  CS, Rodriguez  W, Murphy  MD.  Pediatric information in drug product labeling.   JAMA. 2012;307(18):1914-1915. doi:10.1001/jama.2012.3435 PubMedGoogle ScholarCrossref
3.
Pica  N, Bourgeois  F.  Discontinuation and nonpublication of randomized clinical trials conducted in children.   Pediatrics. 2016;138(3):e20160223. doi:10.1542/peds.2016-0223 PubMedGoogle Scholar
4.
Gordon  D, Taddei-Peters  W, Mascette  A, Antman  M, Kaufmann  PG, Lauer  MS.  Publication of trials funded by the National Heart, Lung, and Blood Institute.   N Engl J Med. 2013;369(20):1926-1934. doi:10.1056/NEJMsa1300237 PubMedGoogle ScholarCrossref
5.
National Institutes of Health. US National Library of Medicine. ClinicalTrials.gov. Glossary of common site terms. Accessed March 3, 2021. https://clinicaltrials.gov/ct2/about-studies/glossary
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    Research Letter
    Pediatrics
    April 14, 2021

    Evaluation of Publication of Pediatric Drug Trials

    Author Affiliations
    • 1Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
    • 2Pediatric Therapeutics and Regulatory Science Initiative, Computational Health Informatics Program, Boston Children’s Hospital, Boston, Massachusetts
    • 3Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
    JAMA Netw Open. 2021;4(4):e215829. doi:10.1001/jamanetworkopen.2021.5829
    Introduction

    Nonpublication of clinical trials compromises the integrity of scientific evidence and represents a breach in ethical obligations to trial participants.1 Timely publication of trials in the medical literature is especially important for pediatric trials, which are often challenging to conduct because of small participant pools and unique ethical and practical considerations. Pediatric trials frequently fill critical gaps in medical knowledge. Many medications used in pediatric populations, for example, have not been formally tested in children; therefore, essential data on pediatric safety and efficacy are not available.2 To increase our understanding of publication practices for pediatric studies, we assessed the rate of publication of pediatric drug trials. We also examined the information that was lost when trials were not published.

    Methods

    We performed a cross-sectional evaluation of pediatric trials registered in ClinicalTrials.gov. Trials were included if they examined a drug intervention in children younger than 18 years; had a randomized trial design; were registered between January 1, 2014, and June 30, 2016; and were completed or discontinued by June 30, 2018.3 This date was selected to allow a minimum of 2 years from trial end to publication of trial findings. The study was deemed exempt from institutional review board approval by the institutional review board at Boston Children’s Hospital because it did not involve human participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    We considered a trial published if results were reported in a peer-reviewed medical journal.4 Publications were identified through searches in PubMed, GoogleScholar, Embase, and company websites. If no publication was found, we searched for trial reports in conference abstracts, press releases, thesis documents, trial registries, and preprint servers. We also contacted investigators to inquire about trial status and availability of trial results. Reports from unpublished studies were reviewed for findings on mortality, adverse events, and efficacy of the drug intervention. Data analysis was performed from August 28, 2020, to October 30, 2020. We used SciPy, version 1.5.0 (Python Software Foundation) to perform χ2 tests and Mann-Whitney tests, with statistical significance prespecified at a 2-sided P < .05.

    Results

    Among 189 pediatric drug trials, academic institutions were the most common funding source (92 trials [48.7%]), and most (120 trials [63.5%]) included an international trial site (Table 1). Seventy-nine trials (41.8%) remained unpublished after a median follow-up period of 3.6 years (interquartile range, 3.0-4.8 years). These studies accounted for 8395 of 24 338 pediatric participants (34.5%). Publication rates at 2 and 4 years were 33.3% (63 of 189 trials) and 71.7% (109 of 152 trials), respectively.

    Thirty trials (15.9%) were discontinued, and 6 of 30 discontinued trials (20.0%) and 104 of 159 completed trials (65.4%) were published (P < .001). The most frequent reasons for discontinuation were insufficient patient enrollment (10 trials [33.3%]), scientific reasons (8 trials [26.7%]), and business decisions (5 trials [16.7%]).

    Trial reports were identified through online searches (n = 38) and email correspondence (n = 11) for 49 of the 79 unpublished trials (62.0%) (Table 2).5 Of these trials, 2 (4.1%) included deaths, 14 (28.6%) included serious adverse events, and 31 (63.3%) included nonserious adverse events. Efficacy data for the investigational drug were available in unpublished reports for 43 trials (87.8%). For the entire cohort of 79 unpublished trials, safety or efficacy data were available for a total of 44 unpublished trials (55.7%).

    Discussion

    In this sample of pediatric drug trials, two-thirds remained unpublished 2 years after trial end, representing considerable loss of scientific information and inefficiency in research practices. More than half of unpublished trials generated safety and efficacy findings, which were largely inaccessible to clinicians and the scientific community.

    A limitation of our study is that trial reports were available for only 62% of unpublished trials, and results may not be representative of all unpublished studies. Nonetheless, our findings point to the need for additional efforts and incentive mechanisms to ensure that pediatric trials are published in a timely fashion and that participation by children in clinical trials contributes to advances in clinical care.

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    Article Information

    Accepted for Publication: February 23, 2021.

    Published: April 14, 2021. doi:10.1001/jamanetworkopen.2021.5829

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Srivastava A et al. JAMA Network Open.

    Corresponding Author: Florence T. Bourgeois MD, MPH, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (florence.bourgeois@childrens.harvard.edu).

    Author Contributions: Ms Srivastava and Dr Bourgeois had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Both authors.

    Acquisition, analysis, or interpretation of data: Both authors.

    Drafting of the manuscript: Srivastava.

    Critical revision of the manuscript for important intellectual content: Bourgeois.

    Statistical analysis: Both authors.

    Supervision: Bourgeois.

    Conflict of Interest Disclosures: Dr Bourgeois reported being a co-director of the Harvard-MIT Center for Regulatory Science. No other disclosures were reported.

    Funding/Support: This study was supported by grant 1017627 from the Burroughs Wellcome Fund (Dr Bourgeois) and by the Harvard-MIT Center for Regulatory Science.

    Role of the Funder/Sponsor: The Burroughs Wellcome Fund and the Harvard-MIT Center for Regulatory Science had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Jones  CW, Handler  L, Crowell  KE, Keil  LG, Weaver  MA, Platts-Mills  TF.  Non-publication of large randomized clinical trials: cross sectional analysis.   BMJ. 2013;347:f6104. doi:10.1136/bmj.f6104 PubMedGoogle ScholarCrossref
    2.
    Sachs  AN, Avant  D, Lee  CS, Rodriguez  W, Murphy  MD.  Pediatric information in drug product labeling.   JAMA. 2012;307(18):1914-1915. doi:10.1001/jama.2012.3435 PubMedGoogle ScholarCrossref
    3.
    Pica  N, Bourgeois  F.  Discontinuation and nonpublication of randomized clinical trials conducted in children.   Pediatrics. 2016;138(3):e20160223. doi:10.1542/peds.2016-0223 PubMedGoogle Scholar
    4.
    Gordon  D, Taddei-Peters  W, Mascette  A, Antman  M, Kaufmann  PG, Lauer  MS.  Publication of trials funded by the National Heart, Lung, and Blood Institute.   N Engl J Med. 2013;369(20):1926-1934. doi:10.1056/NEJMsa1300237 PubMedGoogle ScholarCrossref
    5.
    National Institutes of Health. US National Library of Medicine. ClinicalTrials.gov. Glossary of common site terms. Accessed March 3, 2021. https://clinicaltrials.gov/ct2/about-studies/glossary
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