Disagreements Within FDA About Novel Drug Approvals Common

Among FDA approval packages for novel therapeutic agents from 2011 and 2015, disagreements were common over new drug approvals, populations indicated, and the specific parameters of the approval, according to a JAMA Network Open study.

The study aimed at determining how often internal disagreements occur within the FDA over the approval of novel therapeutic agents.

They identified all approval packages for novel therapeutic agents approved by FDA from January 2011 to December 2015 using the FDA drug approval database and found that 42 or 174 approval packages contained at least one disagreement. 

Nearly seven percent (6.9 percent) included a disagreement about whether to approve a drug, while 5.7 percent disagreed over the patient population for which the drug was indicated.

Additionally, 35 of the packages included disagreements about the parameters of approval, which included 20 about post-marketing requirements, safety warnings, or risk evaluation and management strategies. 

The remaining packages included other concerns, such as drug label phrasing, researchers noted. 

Eighteen of the 155 disagreements were among reviewers within the same discipline, while 137 were between different disciplines or leadership. 

The groups most involved were medical reviewers, members of agency leadership, the cross-discipline team lead, and the office director. 

The disagreements highlight differing points of view on a novel therapeutic agency, as well as engaged discussions going on among FDA leaders about the drug. Importantly, the disagreements document important scientific debates or indicate challenging discussions within the agency, researchers stated.

But the frequency of these disagreements may have implications for the FDA’s latest push to publish only integrated reviews.

Thirty days after a novel therapeutic agent or a biologic is approved, FDA must publicly disclose its approval package, such as scientific reviews completed by the agency and any available assessments by agency leadership.

“It raises questions about whether disagreements within the agency will continue to be published in compliance with the law,” researchers stated.

Last year, FDA introduced its “integrated review for drug marketing applications” which directly supports scientific leadership, integrated assessment, operational excellence, knowledge management, and benefit-risk monitoring.

The agency explained that the motivation behind the change was to modernize its New Drug Regulatory Program.

“The guiding principles of this initiative are issue-focused assessments, enhanced communication both within the review team and with the applicant, and stronger interdisciplinary collaboration,” FDA said in a statement. 

“We believe that the format and content of the new integrated review will provide a clearer description of our analysis of the scientific issues raised by the application and will more effectively communicate the basis for the regulatory decision.”

But many major universities and healthcare companies are calling on FDA to not implement its new integrated review process because of the potential challenges it may present. 

“These developments represent fundamental threats to the U.S. drug-evaluation process,” Benjamin N. Rome, MD, and Jerry Avorn, MD, professors at Harvard University, said in a perspective piece published in the New England Journal of Medicine. 

“Advocating that the FDA should quickly approve drugs without randomized trial data runs counter to the idea of evidence-based medicine and risks further undermining the public’s understanding of and faith in the drug-review process, which requires “substantial evidence” of safety and efficacy based on adequate and well-controlled trials before a drug can be marketed.” 

Health technology company, Flatiron, noted that some valuable information may be lost in FDA’s proposed review process and urged them to ensure they share key insights.

“We note that the new document is considerably shorter than the original, which suggests that some potentially useful content may be lost in the new format. We urge FDA to ensure that highly valuable insight into reviewers’ thinking is retained in the new integrated review format,” Flatiron said in an official letter to FDA.