FDA finalizes guidance on considerations for evaluating drug’s benefits and risks

The US Food and Drug Administration (FDA) has finalized guidance that clarifies how the benefits and risks of a drug or biologic factored into the agency’s decisions on whether to approve a new drug application (NDA) or biologics license application (BLA).

The document also addresses how patient experience data may be used to inform benefit-risk assessments and the best time for sponsors to interact with FDA to discuss benefit-risk information in their applications.

The guidance was developed in accordance with goals set in the Prescription Drug User Fee Act of 2017 (PDUFA VI) under the FDA Reauthorization Act of 2017 and the 21st Century Cures Act and finalizes a draft guidance issued in September 2021 (RELATED: FDA draft guidance outlines criteria for conducting benefit/risk assessments, Regulatory Focus 1 October 2021).

The final guidance contains minor revisions from a draft to incorporate public comments. FDA said that “changes from the draft to the final guidance include clarifying language on FDA's approach to benefit-risk assessment of new drugs and biologics, clarifying language on important considerations for FDA's premarket benefit-risk assessment of drugs and biologics, clarifying language on activities that occur in premarket development that inform benefit-risk assessment, and other editorial changes.”

In one modification, the finalized version contains a list of examples of conditions that would support FDA’s decision to approve applications. One condition is identifying a subpopulation where the drug’s benefits would outweigh the risks if, even if this is not the case in a broader population.

FDA will use the following criteria to assess a drug’s benefit-risk profile:

The therapeutic context in which the drug will be used, including the nature and severity of the disease the drug is intended to prevent or treat and whether the patients’ needs are being met by currently available treatments.

The evidence submitted in the premarket application or evidence generated in the postmarket setting. Sources of data can include clinical data, non-clinical data, patient experience data, product quality information, adverse events, and epidemiologic data.

Uncertainties about the drug’s benefits and risks. FDA states that “although uncertainty can be reduced through careful study design and conduct, some uncertainty in the body of evidence available at the time of regulatory decision-making is inevitable, e.g., the frequency of rare serious adverse events or whether the drug’s effectiveness persists in long-term use.”

The regulatory options to manage risks, such as adding information in the labeling on contraindications or adding a boxed warning.

FDA states that “therapeutic context plays an important role in FDA’s assessment of the acceptability of uncertainty.” For example, for drugs intended to treat serious diseases with unmet needs, the agency may accept greater risk and also may tolerate higher risks for rare disease treatments “where the prevalence of disease, and consequent limitations of study size, can limit the precision of safety and efficacy characterizations.”

FDA is working to better incorporate the patient’s voice into drug development and evaluation through its Patient-Focused Drug Development (PFDD) initiative. The agency states that “different types of patient experience data can inform nearly every aspect of FDA’s benefit-risk assessment, including many of the considerations.” This includes therapeutic context, such as the impact of the disease and its treatment and the patient’s perspectives about available treatments and unmet medical needs.

As such, the agency states that “collecting robust patient input on the symptoms or other aspects of their condition that matter most to patients can inform and strengthen the rationale for endpoint selection, development of COAs, and the overall benefit-risk assessment.”

Sponsors are advised to evaluate a drug’s benefit-risk early in development, such as identifying patients who are more likely to experience greater expected benefit or less likely to experience serious adverse events of the drug.

FDA states that the End of Phase 2 (EOP2) meeting is the best time for sponsors to schedule a meeting to discuss benefit and risk considerations as this can influence the design of phase 3 studies in terms of study design, selection of appropriate patient populations, and clinically meaningful endpoints.

FDA said the sponsor’s NDA or BLA is a “critical source of benefit-risk information.” This information is derived from the integrated summary of the benefits and risks of the drug in the proposed labeling.

The summary should address the magnitudes of the treatment effects, comparing the pending drug to an approved drug and estimate the statistical uncertainty around the magnitudes of the most important benefits and risks.

Sponsors were advised to consult the International Council on Harmonisation’s (ICH) M4E(R2) guidance on how to present this benefit-risk information in the Common Technical Document (CTD) adopted in June 2016.

Final guidance

FDA finalizes guidance on considerations for evaluating drug’s benefits and risks

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