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Viewpoint
Health Care Policy and Law
March 2, 2020

Integrated Drug Reviews at the US Food and Drug Administration—Legal Concerns and Knowledge Lost

Author Affiliations
  • 1Health Law Institute, Schulich School of Law, Dalhousie University, Halifax, Nova Scotia, Canada
  • 2Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  • 3Engelberg Center on Innovation Law & Policy, New York University School of Law, New York
  • 4Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore
JAMA Intern Med. Published online March 2, 2020. doi:10.1001/jamainternmed.2020.0074

When the US Food and Drug Administration (FDA) approves a new drug, federal law requires public disclosure of the review documents prepared by scientific disciplines (eg, clinical, toxicology, statistical) during the review.1 These scientific reviews are published on the FDA Drugs@FDA website (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm). In many cases, the data and analyses contained in those reviews have proved useful to public health.

A well-known example involves the Celecoxib Long-term Arthritis Safety Study (CLASS), which was published in 2000.2 The article reported that after long-term follow-up (6 months), treatment with celecoxib (Celebrex) “was associated with a lower incidence of symptomatic ulcers and ulcer complications combined”2(p1247) compared with ibuprofen and diclofenac, thus offering support for the claim that celecoxib was a safer alternative to other nonsteroidal anti-inflammatory agents. The CLASS trial was funded by celecoxib’s manufacturer and authored by its employees and academic researchers who were also consultants to the manufacturer.2 However, independent researchers used the FDA’s publicly available scientific reviews to question the safety claim for celocoxib.3 They found that:

the published CLASS trial differs from the original protocol in primary outcomes, statistical analysis, trial duration, and conclusions. In particular, the unpublished data [in an FDA scientific review] show that by week 65, celecoxib was associated with a similar number of ulcer complications as diclofenac and ibuprofen.3(p2398)

In June 2019, the FDA announced that individual scientific reviews were being replaced by integrated reviews.4 Rather than each scientific discipline writing its own review, the disciplines will collectively generate an integrated review—a “collaborative document with input from clinical, clinical pharmacology, biostatistics, toxicology reviewers, and other disciplines based upon the issues raised by the application.”4 The FDA stated that the move is intended to “enhance clarity of [FDA] assessments regarding the benefits and risks for new drug products, and improve…communication about the basis for new drug approvals.”4 However, in our view, integrated reviews are unlikely to achieve the agency’s stated goals and likely to introduce new problems. In this Viewpoint, we elaborate on the concerns expressed in a public comment5 to the FDA that was drafted and organized by 2 of us (M.H. and P.D.) and signed by 54 academics and researchers.

At times, the sheer volume of information in FDA scientific reviews has effectively buried important safety information.6 Nonetheless, it is doubtful that physicians and others who prescribe medications have the time to examine these documents—however integrated—for clinically relevant information. If the agency’s goal is to better communicate a drug’s risks and benefits of use to clinicians, other tools, such as the Drug Facts Box, a proposal that the agency has had multiple opportunities to adopt, are more likely to be effective.7

The replacement of individual FDA scientific reviews with integrated reviews also has public health implications because information that many researchers find essential may be lost. Individual drug reviews typically contain a variety of important information that never appears in published articles, such as details from clinical trial protocols and statistical analysis plans, complete sets of efficacy end points and adverse events, analyses of the same data by the FDA and the study sponsor, details about postmarketing study requirements, and each individual FDA reviewer’s view on the application’s approvability (reviewers can disagree). An enormous amount of research has been based on these reviews, as explained in the public comment.5 The signatories to the comment argued that the loss of granularity and detail in integrated reviews may negatively affect systematic reviews, research on the processes for drug development and approval, and the creation of decision-making tools for consumers, physicians, and other medical professionals.

Furthermore, the replacement of individual reviews with integrated reviews could open the agency to legal challenges. Recognizing the importance of the public disclosure of FDA drug approval documents following a series of regulatory failures, such as the issues with rofecoxib (Vioxx) and valdecoxib (Bextra),8 Congress enacted a law in 2007 that required the publication of drug approval documents.1 Specifically, federal law requires the FDA to publish a:
summary review that documents conclusions from all reviewing disciplines about the drug, noting any critical issues and disagreements with the applicant and within the review team and how they were resolved, recommendations for action, and an explanation of any nonconcurrence with review conclusions.1
The law also stipulates that a “scientific review of an application is considered the work of the reviewer and shall not be altered by management or the reviewer once final.”1 Thus, the 2007 law assumed the preparation of individual scientific reviews and was explicit about the need for these reviews to be published in an unaltered form.

Courts have yet to rule on whether integrated reviews are consistent with the applicable federal law. One reason is that a court challenge is most likely to occur after the FDA fully implements the use of integrated reviews. However, if integrated reviews were to contain only a single assessment of a drug, this would arguably fail to comply with the law’s mandate to disclose the “conclusions from all reviewing disciplines.”1 Additionally, if FDA scientists no longer generate individual scientific reviews but instead coauthor a single integrated review, that could constitute a prohibited alteration of each individual reviewer’s work. If, during the development of an integrated review, disagreements among reviewers are minimized or omitted altogether, that, too, could violate federal law. It may also run counter to the FDA Equal Voice initiative,9 a set of practices the agency established in 2008 to ensure that dissenting views within drug review teams are considered during the drug approval process. Among other things, the Equal Voice initiative requires that dissenting views be documented, preserved, and published and that supervisors who overrule individual reviewers or reviewing disciplines document and publish their reasons for doing so.

The FDA’s first use of the integrated review format—for the approval in 2019 of an HIV drug (dolutegravir/lamivudine [Dovato])—highlights some of these problems. The agency published no individual scientific reviews because none were written. Federal law only requires publication of any “[d]ocuments generated…related to review of the application.”1 If individual scientific reviews are never written in the first place, there is nothing to publish—a troubling loophole in the 2007 law that was not appreciated at the time.

In summary, the FDA’s long-standing practice of generating and publishing individual scientific reviews has been a great service to public health, largely because of the detail contained in these reviews. Despite the importance of individual scientific reviews, the FDA is phasing them out. Although implementing the use of integrated reviews will take time, there is no indication that the agency plans to revisit its decision. If the FDA’s aim is to circumvent its legal obligation to prepare and publicly disclose individual scientific reviews, congressional action or litigation may be needed. For the FDA to earn and maintain public trust, its decision-making processes should be transparent and prioritize the public release of detailed, comprehensive, and unredacted information. The agency can best meet its goal of improving public and clinician understanding of its review process by creating better summaries of its individual scientific reviews, not by replacing them.

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Article Information

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

Published Online: March 2, 2020. doi:10.1001/jamainternmed.2020.0074

Conflict of Interest Disclosures: Mr Herder reported receiving honoraria from the Patented Medicine Prices Review Board (Canada’s national drug pricing regulator). Dr Morten reported receiving personal fees from Yale University’s Collaboration for Research Integrity and Transparency, which has received grant funds from Arnold Ventures. Dr Doshi reported receiving grants from the Laura and John Arnold Foundation, American Association of Colleges of Pharmacy, the Patient-Centered Outcomes Research Institute, the Cochrane Methods Innovation Fund, and the UK National Institute for Health Research; receiving travel funds from the European Respiratory Society and Uppsala Monitoring Centre; and serving as an editor at The BMJ and as an unpaid member of the Reagan-Udall Foundation for the US Food and Drug Administration.

Funding/Support: This work was supported by grant CIHR PJT 156256 from the Canadian Institutes of Health Research (Mr Herder).

Role of the Funder/Sponsor: The Canadian Institutes of Health Research 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.
Food and Drug Administration Amendments Act of 2007, 21 USC §355(l).
2.
Silverstein  FE, Faich  G, Goldstein  JL,  et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.  JAMA. 2000;284(10):1247-1255. doi:10.1001/jama.284.10.1247PubMedGoogle ScholarCrossref
3.
Hrachovec  JB, Mora  M.  Reporting of 6-month vs 12-month data in a clinical trial of celecoxib.  JAMA. 2001;286(19):2398. doi:10.1001/jama.286.19.2398PubMedGoogle Scholar
4.
Regulations.gov. New drugs regulatory program modernization: improving approval package documentation and communication. https://www.regulations.gov/document?D=FDA-2019-N-2012-0001. Accessed September 17, 2019.
5.
Doshi  P, Herder  M, Alexander  GC,  et al. Re: docket No. FDA-2019-N-2012 (“New Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication”). https://www.regulations.gov/contentStreamer?documentId=FDA-2019-N-2012-0010&attachmentNumber=1&contentType=pdf. Accessed November 27, 2019.
6.
Schwartz  LM, Woloshin  S.  Lost in transmission—FDA drug information that never reaches clinicians.  N Engl J Med. 2009;361(18):1717-1720. doi:10.1056/NEJMp0907708PubMedGoogle ScholarCrossref
7.
Schwartz  LM, Woloshin  S.  The Drug Facts Box: improving the communication of prescription drug information.  Proc Natl Acad Sci U S A. 2013;110(suppl 3):14069-14074. doi:10.1073/pnas.1214646110PubMedGoogle ScholarCrossref
8.
Kesselheim  AS, Mello  MM.  Confidentiality laws and secrecy in medical research: improving public access to data on drug safety.  Health Aff (Millwood). 2007;26(2):483-491. doi:10.1377/hlthaff.26.2.483PubMedGoogle ScholarCrossref
9.
Center for Drug Evaluation and Research. Equal voice: discipline and organizational component collaboration in scientific and/or regulatory decisions. https://www.fda.gov/media/79353/download. Accessed December 3, 2019.
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