Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents Over Three Decades, 1995-2017: Cross-Sectional Analysis

Objective To evaluate whether characteristics of pivotal efficacy trials supporting US Food and Drug Administration (FDA) approval of novel therapeutic agents have changed over the past three decades. Design Cross-sectional study. Setting and population Publicly available data on novel therapeutics approved by the FDA between 1995-1997, 2005-2007, and 2015-2017. Main outcome measures Use of randomization, blinding, types of comparators and primary endpoints, number of treated patients, and trial duration in pivotal trials supporting novel therapeutic approval, both individually and aggregated by each indication approval. Analyses were repeated stratifying by use of orphan designation and use of special regulatory programs. Results There were 273 novel therapeutics approved by the FDA in these 3 periods (107 in 1995-1997, 57 in 2005-2007, 109 in 2015-2017), representing 339 indications (157, 64, and 118, respectively). Overall, the proportion of indication approvals supported by at least 2 pivotal trials decreased (80.6% in 1995-1997, 60.3% in 2005-2007, 52.8% in 2015-2017; p<0.001). The proportion supported by only single-arm pivotal trials increased (4.0% in 1995-1997, 12.7% in 2005-2007, 17.0% in 2015-2017; p=0.001), as did the proportion supported by at least one pivotal trial of 6 months’ duration (25.8% in 1995-1997, 34.9% in 2005-2007, 46.2% in 2015-2017; p=0.001). When stratified by use of special regulatory programs, pivotal trial characteristics changed over time in divergent ways, both individually and when aggregated by indication approvals. Conclusion More recent FDA approvals of novel therapeutics were based on fewer pivotal trials, with less rigorous designs but longer trial durations. These findings reinforce the importance of FDA’s strategy for requiring ongoing evaluation of therapeutic safety and efficacy after approval. What is already known on this topic What this study adds ### Competing Interest Statement All authors have completed the Unified Competing Interest form (available on request from the corresponding author) and declare: In the past 36 months, Ms. Zhang received research support as a scholar in the Yale-Mayo Clinic FDA CERSI (U01FD005938) and from the Laura and John Arnold Foundation. In the past 36 months, Mr. Puthumana received a student research grant provided by the Yale School of Medicine Office of Student Research (National Institutes of Health training grant T35DK104689). Dr. Downing is currently employed by Bain Capital Life Sciences, a venture company. His participation in this work took place during his postgraduate training in internal medicine at the Brigham & Women’s Hospital. In the past 36 months, Dr. Krumholz was a recipient of a research grant, through Yale, from Medtronic and the U.S. Food and Drug Administration to develop methods for post-market surveillance of medical devices; was a recipient of a research grant with Medtronic and Johnson & Johnson, through Yale, to develop methods of clinical trial data sharing; was a recipient of a research agreement, through Yale, from the Shenzhen Center for Health Information for work to advance intelligent disease prevention and health promotion; collaborates with the National Center for Cardiovascular Diseases in Beijing; received payment from the Arnold & Porter Law Firm for work related to the Sanofi clopidogrel litigation and from the Ben C. Martin Law Firm for work related to the Cook IVC filter litigation; chairs a Cardiac Scientific Advisory Board for UnitedHealth; is a participant/participant representative of the IBM Watson Health Life Sciences Board; is a member of the Advisory Board for Element Science, the Advisory Board for Facebook, and the Physician Advisory Board for Aetna; and is the founder of Hugo, a personal health information platform. In the past 36 months, Dr. Shah has received research support through Mayo Clinic from the Food and Drug Administration to establish Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938); the Centers of Medicare and Medicaid Innovation under the Transforming Clinical Practice Initiative (TCPI); the Agency for Healthcare Research and Quality (R01HS025164; R01HS025402; R03HS025517); the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R56HL130496; R01HL131535); the National Science Foundation; and the Patient Centered Outcomes Research Institute (PCORI) to develop a Clinical Data Research Network (LHSNet). In the past 36 months, Dr. Ross has received research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from Medtronic, Inc. and the Food and Drug Administration (FDA) to develop methods for postmarket surveillance of medical devices (U01FD004585), from the Food and Drug Administration to establish Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), from the Blue Cross Blue Shield Association to better understand medical technology evaluation, from the Centers of Medicare and Medicaid Services (CMS) to develop and maintain performance measures that are used for public reporting (HHSM-500-2013-13018I), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164), and from the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International and to establish the Collaboration for Research Integrity and Transparency (CRIT) at Yale. ### Clinical Trial Not applicable ### Funding Statement This project was not supported by any external grants or funds. ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Not Applicable Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Yes Data will be posted publicly upon publication.