Industry calls for revisions of FDA’s REMS draft guidance

Industry stakeholders say the US Food and Drug Administration’s (FDA) draft guidance calling for a REMS logics model requires major changes to make it workable, claiming the guidance is too broad and lacking clarity.

The Pharmaceutical Research and Manufacturers of America (PhRMA) offered the most strident criticism of the guidance and said FDA is exceeded its statutory authority in the guidance and misread the law establishing the REMS program.

The agency received five comments in response to the draft guidance, issued in May 2024, which proposed the use of a common logic model principles adapted for use in a REMS to provide applicants with a recommended systematic, structured approach to designing and implementing a REMS. (RELATED: FDA unveils draft guidance on REMS logic models, Regulatory Focus 6 May 2024)

The REMS program itself is a drug safety program that requires FDA to implement specific safety measures that go beyond the labeling requirement; the program is codified by Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) which authorizes FDA to require a REMS if FDA determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks.

PhRMA: Guidance is ‘untethered’ to the statute

In comments to the agency, PhRMA said the guidance is “very broad and appear untethered to—and even inconsistent with—both statutory provisions regarding FDA’s REMS authority and existing regulatory processes for REMS submissions.”

PhRMA asserts that Section 505-1 of FDCA requires FDA to consider certain factors when determining whether a REMS is necessary to ensure that a drug’s benefits outweigh its risks. These include the estimated size of the population likely to use the drug involved, the seriousness of the disease or condition that is to be treated with the drug, the expected benefit of the drug with respect to such disease or condition, the expected or actual duration of treatment with the drug, the seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug, and whether the drug is a new molecular entity.

Yet the draft guidance “does not address how the substantive discussion regarding the logic model aligns with these statutory provisions. This approach leaves several key legal questions unclear as a result, and FDA should revise the Draft Guidance to ensure its consistency with the statute.”

PhRMA also asserts that the draft guidance focuses on new REMS following the logic model, as opposed to existing REMS where the logic model may be less directly relevant and is unclear whether the recommendations apply to existing programs.

The group said it is also unclear how FDA envisions the logic model will be integrated into regulatory submissions.

PhRMA, REMS consortium say guidance is too broad

Both PhRMa and the REMS Industry Consortium (RIC) complained that the guidance was too broadly written.

PhRMA said that several of the draft’s recommendations are “overly broad.” One is the recommendations that sponsors conduct a “care gap assessment” in the design phase which involves “identifying the discrepancies in risk mitigation between clinical trial protocols, best practices, and the actual care that is provided and or anticipated to be provided in clinical practice.”

PhRMA said that “this description is very broad, particularly given the substantial heterogeneity in clinical practice patterns, environments, and delivery models in the U.S. To the extent FDA expects this assessment be used to determine if a REMS is warranted, the recommendation exceeds what is relevant under the statutory standard.”

RIC also wanted more clarity on which events would trigger a logic model analysis and whether this could be triggered by the submission of a new drug application (NDA) or a modification of an existing REMS program.

“Although FDA recommends the Logic Model be used throughout the REMS life cycle to support continuous evaluation and program improvement, specific triggering events are not discussed.”

RIC was established in September 2021 to discuss and establish a set of best practices for drugs that are subject to a REMS and is comprised of 25 companies that commercialize or anticipate commercializing prescription drugs or biologic products subject to REMS, and eleven industry partners that provide technology and other service provider solutions for REMS programs.

RIC also suggested more flexibility in the logic model. The group said it was “concerned” that the guidance “appears to promote the use of specific data inputs across all REMS programs without considering program differences or maturity, availability of data, and the differences in impact the healthcare environment may have on a REMS program. RIC recommends that FDA clarify that the Logic Model is flexible, and state which parts of the Logic Model would be universally recommended versus only appropriate in specific circumstances.”

Support for logic model

Yet some members of the academic community supported FDA’s move to standardize the REMs in their comments.

The guidance “provides great clarity to systematically designing, implementing, and evaluating an FDA risk evaluation and mitigation strategy (REMS) program. The need for a structured approach was well-defined, and the utility of frameworks for providing guidance regarding carrying out REMS is indisputable,” wrote Maya Roytman and Elaine Morrato of Loyola University Chicago.

They added that “the proposed FDA REMS logic model possesses strengths in coherently unifying elements of implementation science models into a single framework to inform REMS development and execution.”

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Industry calls for revisions of FDA’s REMS draft guidance

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