October 05, 2021

Weighing Benefits and Risks: New Draft Guidance Offers Insights on FDA Decision-Making

In late September, the Food and Drug Administration (FDA) released a draft guidance on benefit-risk assessments for drugs and biological products. The draft guidance includes considerations the agency uses when weighing the potential benefits and risks of candidate therapies when conducting reviews. Of particular interest to many in the health policy community is the inclusion of information on how patient experience data factors into the benefit-risk assessment.

Beginning with the Prescription Drug and User Fee Act (PDUFA) V (Fiscal Years 2013-2017), the FDA has been honing its structured approach to using a benefit-risk assessment when making regulatory decisions. Under PDUFA VI, the agency began requiring the use of a benefit-risk framework — a table summarizing benefits, risks, uncertainties  and evidence — in review packages for all approved therapies. This has proved to be a useful way of capturing the key points the agency weighs when deciding whether to approve a therapy, especially when there is a close balance between benefits and risks.

The draft guidance notes that benefit-risk should be considered throughout the drug development lifecycle and can be used by the FDA when reviewing many elements of a proposed therapy, including:

  • The therapeutic context in which the treatment will be used
  • The evidence of benefits and risks submitted by the sponsor
  • The uncertainties about benefits and risks
  • The options available to the FDA to reduce uncertainties and risks such as post-market study requirements or labeling content

The newly published draft guidance offers insight on how the FDA considers therapies that may carry significant risks. In cases where that treatment offers clear, meaningful benefits or has clear advantages over currently approved treatments, those benefits may outweigh the risks. In other cases, the FDA may consider subpopulations and determine that the benefits to them outweigh the risk even if the same is not true for the broader population.

The guidance also touches on how the FDA deals with uncertainty when conducting benefit-risk assessments. Examples of uncertainty in this context include limits on understanding of the patient population, differences between clinical studies and the anticipated real-world use of a therapy, questions about how the therapy may interact with other drugs and lack of clarity on the meaningfulness of the potential benefits of the therapy. According to the draft guidance, the FDA may tolerate greater uncertainty for a therapy for a serious disease with high unmet medical needs, including those that may be going through the accelerated approval pathway. The draft guidance notes that uncertainty is especially common in candidate therapies for rare diseases and the FDA may use more regulatory flexibility when making decisions on products to treat such diseases. Such interpretations of therapeutic context by the FDA provide important insights for developers in terms of potential latitude in application review for new entities addressing critical unmet needs, provided the standard of substantial evidence is satisfied. Conversely, several citations in the draft guidance convey that for new agents which are for preventive indications or are being studied for treatment of prevalent disorders with established, acceptable benefit risk profiles for available therapies are unlikely to have regulatory flexibility accorded.

Since the benefit-risk framework was introduced, many in the patient advocacy community have been keenly interested in learning more about how patient experience data (PED) factors into the assessment. This draft guidance offers insight on that but stops short of encouraging sponsors to collaborate with patient groups to collect PED. Per the draft guidance, PED is critically important when it comes to collecting robust patient input on aspects of their condition that matter most in order to identify unmet medical needs, define the target population for a therapy, inform the assessment of clinical relevance of endpoints and inform the development of clinical outcome assessments (COAs). FDA notes that during premarket review, the agency indicates in review documentation if relevant patient experience data were submitted as part of the application and whether relevant information was not submitted but still informed the FDA review. The draft guidance also includes content on patient preference information and when it may be most appropriate for use.

The draft guidance emphasizes the importance of benefit-risk considerations throughout the drug development lifecycle, beginning in the earliest stages. The document notes that benefit-risk planning is most valuable in cases where a challenging benefit-risk assessment is expected because the benefit is expected to be modest or highly uncertain or when serious adverse events are anticipated. In terms of sponsors discussing prospective benefit-risk considerations with the FDA, the draft guidance indicates that this is typically most appropriate during the End of Phase 2 meeting. This discussion can inform the design of Phase 3 studies, especially when greater certainty about benefits and risks are needed before the drug can be considered for approval. The draft guidance notes that earlier discussions of benefits and risks, such as when considering the clinical meaningfulness of benefits or risks before proceeding to first-in-human studies. The FDA also encourages sponsors to have early interactions with the agency if they are considering collecting patient experience data as a part of their drug development program.

Of note, the draft guidance also addresses post-approval benefit-risk considerations, which are important to sponsors in terms of capturing dynamic, evolving information post-launch, such as with exposed populations commercially having features which may differ in demographics and concurrent medications when compared to the more limited criteria in clinical trial enrollment. Such conditions may often focus on safety findings and thus balanced benefit risk reassessments are vital in preserving fair representation of all safety and efficacy data.

This draft guidance, especially the content on patient experience data and the critical role it plays in a drug development program, dovetails with the patient-focused drug development (PFDD) guidance series the FDA has been developing as another requirement under PDUFA VI and the 21st Century Cures Act. Comments on the draft guidance are due November 30 and can be submitted via the public docket.

This draft guidance document is an important step in increasing transparency of the FDA’s decision-making processes. It gives sponsors, patient advocacy organizations and other stakeholders a view into how the FDA is using the relatively new benefit-risk assessment process and raises helpful points for considering benefits and risks in a drug development program.

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