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Table 1.  Novel Therapeutic Agents Approved 2011-2015
Novel Therapeutic Agents Approved 2011-2015
Table 2.  US Food and Drug Administration Disagreements Over New Drug Approvals, Populations Indicated, and the Parameters of Approval by Subject, Leadership, and Discipline (Total Instances)a
US Food and Drug Administration Disagreements Over New Drug Approvals, Populations Indicated, and the Parameters of Approval by Subject, Leadership, and Discipline (Total Instances)a
1.
21 U.S.C. § 355. Title 21: Food and Drugs, Chapter 9—Federal Food, Drug, and Cosmetic Act Subchapter V, Drugs and Devices Part A, Drugs and Devices Sec. 355, New Drugs. Enacted January 7, 2011. Accessed June 17, 2020. https://www.govinfo.gov/app/details/USCODE-2010-title21/USCODE-2010-title21-chap9-subchapV-partA-sec355
2.
Kesselheim  AS, Avorn  J.  Approving a problematic muscular dystrophy drug: implications for FDA policy.   JAMA. 2016;316(22):2357-2358. doi:10.1001/jama.2016.16437PubMedGoogle ScholarCrossref
3.
Downing  NS, Aminawung  JA, Shah  ND, Krumholz  HM, Ross  JS.  Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.   JAMA. 2014;311(4):368-377. doi:10.1001/jama.2013.282034PubMedGoogle ScholarCrossref
4.
Wallach  JD, Egilman  AC, Dhruva  SS,  et al.  Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis.   BMJ. 2018;361:k2031. doi:10.1136/bmj.k2031PubMedGoogle ScholarCrossref
5.
Regulations.gov. Comment on the Food and Drug Administration (FDA) Notice: new drugs regulatory program modernization—improving approval package documentation and communication. Published August 27, 2019. Accessed September 17, 2019. https://www.regulations.gov/document?D=FDA-2019-N-2012-0010.
6.
Herder  M, Morten  CJ, Doshi  P.  Integrated drug reviews at the US Food and Drug Administration: legal concerns and knowledge lost.   JAMA Intern Med. 2020. doi:10.1001/jamainternmed.2020.0074PubMedGoogle Scholar
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    Research Letter
    Health Policy
    July 24, 2020

    Disagreements Within the US Food and Drug Administration Regarding Approval of Novel Therapeutic Agents, 2011-2015

    Author Affiliations
    • 1Schulich School of Law, Dalhousie University, Halifax, Nova Scotia, Canada
    • 2New York University School of Medicine, New York, New York
    • 3Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut
    • 4Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
    • 5Health Law Institute, Schulich School of Law, Dalhousie University, Halifax, Nova Scotia, Canada
    • 6Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
    JAMA Netw Open. 2020;3(7):e209498. doi:10.1001/jamanetworkopen.2020.9498
    Introduction

    Thirty days after a novel therapeutic agent, a new molecular entity, or original biologic is approved, the US Food and Drug Administration (FDA) must publicly disclose its approval package, including scientific reviews completed by FDA disciplines (eg, pharmacology, statistical, and medical reviewers) and any available assessments by agency leadership.1 Although reports of internal disagreement have surfaced,2 it is unclear how often such disagreements occur. Disagreements document differing points of view or engaged discussion and may, thus, capture important scientific debates or signal challenging decisions within the agency. We sought to determine the frequency of disagreements within the FDA regarding approval of novel therapeutic agents.

    Methods

    This cross-sectional study did not require institutional review board approval or patient informed consent because it was based on publicly available information and involved no patient records, in accordance with 45 CFR §46. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.

    Between May and September 2019, we identified all approval packages for novel therapeutic agents approved by the FDA from January 2011 to December 2015 using the Drugs@FDA database. Disagreements were defined as instances where multiple reviewers and/or leadership (whether part of the same discipline or not) disagreed about approving a drug, the indicated patient population (eg, patient age), and/or the parameters of the drug’s approval (eg, postmarketing requirements). We searched for disagreements in 2 ways. First, we reviewed the Summary Review, the Office Director Memo, the Cross-Disciplinary Review, and the Medical Review, which tend to describe the recommendations and disagreements. Second, we used key word searches to identify disagreements located elsewhere in the package. The data were extracted by 1 author (A.M.); uncertain cases were resolved through discussion with 2 or 3 other authors (M.H., J.D.W., and A.D.Z.). The frequency of disagreements within and between different disciplines and/or FDA leadership (eg, Division Director) was recorded and tabulated using Excel software version 16.31 (Microsoft Corp). Data analysis was performed from June to November 2019.

    Results

    From 2011 through 2015, the FDA published 174 approval packages for novel therapeutic agents (Table 1). The most common therapeutic areas were cancer (46 agents [26.4%]) and infectious diseases (27 agents [15.5%]); 72 agents (41.4%) were first in class, and the FDA was the first major regulatory agency to approve the drug for 118 agents (67.8%).

    Forty-two (24.1%) approval packages contained at least 1 disagreement: 12 (6.9%) included a disagreement about whether to approve a drug, 10 (5.7%) disagreed over the patient population for which the drug was indicated, and 35 (20.1%) disagreed regarding the parameters of approval, including 20 about postmarketing requirements, safety warnings, or risk evaluation and management strategies, and 15 about other issues, such as drug label phrasing.

    Of 155 instances of disagreement, 18 (11.6%) were among reviewers within the same discipline, whereas 137 (88.4%) occurred between different disciplines and/or leadership. The most frequently involved parties were medical reviewers (27 cases [17.4%]), members of agency leadership (eg, the Division Director; 33 cases [21.3%]), the Cross-Discipline Team Lead (23 cases [14.8%), and the Office Director (19 cases [12.3%]) (Table 2). Among the 12 disagreements regarding approval, 11 were approved with a postmarketing requirement or risk evaluation and management strategy.

    Discussion

    Among all approval packages for novel therapeutics approved by the FDA from 2011 to 2015, disagreements were common over new drug approvals, populations indicated, and the specific parameters of the approval. Given the complexity of determining drug safety and efficacy and the challenge of extrapolating to broad populations from a limited number of small, narrowly defined clinical trials,3 disagreements within the FDA are not surprising and likely represent differing points of view that may inform pharmacovigilance efforts, as well as public discourse.4

    Our study was limited to disagreements recorded within approval packages. Where disagreements may be unrecorded, our analysis may underestimate their prevalence. We also did not assess whether disagreements were discussed by advisory committees or associated with particular outcomes (eg, safety warnings discovered after approval).

    Nevertheless, our findings have important implications for the FDA’s recent move to publish only integrated reviews in lieu of reviews by each discipline and agency leadership.5 It raises questions about whether disagreements within the agency will continue to be published in compliance with the law.1,6

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    Article Information

    Accepted for Publication: April 14, 2020.

    Published: July 24, 2020. doi:10.1001/jamanetworkopen.2020.9498

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 MacGregor A et al. JAMA Network Open.

    Corresponding Author: Matthew Herder, JSM, LLM, Health Law Institute, Schulich School of Law, Dalhousie University, 6061 University Ave, 3rd Floor, Rm 329, PO Box 15000, Halifax, NS B3H 4R2, Canada (matthew.herder@dal.ca).

    Author Contributions: Ms MacGregor and Mr Herder 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: MacGregor, Zhang, Wallach, Herder.

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

    Drafting of the manuscript: MacGregor, Wallach, Herder.

    Critical revision of the manuscript for important intellectual content: All authors.

    Obtained funding: Herder.

    Administrative, technical, or material support: MacGregor, Zhang.

    Supervision: Herder.

    Conflict of Interest Disclosures: Dr Zhang reported receiving research support through the Collaboration for Research Integrity and Transparency at Yale University from the Laura and John Arnold Foundation and the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program. Dr Wallach reported receiving research support through Yale University from the Laura and John Arnold Foundation and the US Food and Drug Administration (grant U01FD00593) outside the submitted work. Dr Ross reported receiving research support through Yale from Johnson and Johnson to develop methods of clinical trial data sharing; from Medtronic, Inc, and the US Food and Drug Administration (FDA) to develop methods for postmarket surveillance of medical devices; from the Centers of Medicare & Medicaid Services to develop and maintain performance measures that are used for public reporting; from the FDA to establish a CERSI at Yale University and the Mayo Clinic; from the Blue Cross Blue Shield Association to better understand medical technology evaluation; and from the Laura and John Arnold Foundation. Mr Herder reported being a member of the Patented Medicine Prices Review Board, Canada’s national drug price regulator, and receiving honoraria from the Board for his service. No other disclosures were reported.

    Funding/Support: This project was supported by an external grant from the Canadian Institutes of Health Research (CIHR PJT 156256).

    Role of the Funder/Sponsor: The funder 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.
    21 U.S.C. § 355. Title 21: Food and Drugs, Chapter 9—Federal Food, Drug, and Cosmetic Act Subchapter V, Drugs and Devices Part A, Drugs and Devices Sec. 355, New Drugs. Enacted January 7, 2011. Accessed June 17, 2020. https://www.govinfo.gov/app/details/USCODE-2010-title21/USCODE-2010-title21-chap9-subchapV-partA-sec355
    2.
    Kesselheim  AS, Avorn  J.  Approving a problematic muscular dystrophy drug: implications for FDA policy.   JAMA. 2016;316(22):2357-2358. doi:10.1001/jama.2016.16437PubMedGoogle ScholarCrossref
    3.
    Downing  NS, Aminawung  JA, Shah  ND, Krumholz  HM, Ross  JS.  Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012.   JAMA. 2014;311(4):368-377. doi:10.1001/jama.2013.282034PubMedGoogle ScholarCrossref
    4.
    Wallach  JD, Egilman  AC, Dhruva  SS,  et al.  Postmarket studies required by the US Food and Drug Administration for new drugs and biologics approved between 2009 and 2012: cross sectional analysis.   BMJ. 2018;361:k2031. doi:10.1136/bmj.k2031PubMedGoogle ScholarCrossref
    5.
    Regulations.gov. Comment on the Food and Drug Administration (FDA) Notice: new drugs regulatory program modernization—improving approval package documentation and communication. Published August 27, 2019. Accessed September 17, 2019. https://www.regulations.gov/document?D=FDA-2019-N-2012-0010.
    6.
    Herder  M, Morten  CJ, Doshi  P.  Integrated drug reviews at the US Food and Drug Administration: legal concerns and knowledge lost.   JAMA Intern Med. 2020. doi:10.1001/jamainternmed.2020.0074PubMedGoogle Scholar
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