I used to think of a Benefit Risk Assessment as part of a marketing application. However, FDA’s recent guidance, Benefit-Risk Assessment for New Drug and Biologic Products, published in October 2023, clearly highlights the role that Benefit-Risk Assessments play throughout the lifecycle of a product, not only at the time of New Drug Application (NDA) or Biologic Licensing Application (BLA) review. Benefit-risk planning should be done early in product development and continue into the post-marketing setting. In this guidance, FDA recommends that, at a minimum, benefit-risk planning be a topic at an End of Phase 2 (EOP2) meeting as this can influence the design of phase 3 studies.

Benefit-risk planning in early development can add value by helping to ensure that the patient populations included in studies, endpoints studied, and data collected throughout the program support the continued development and subsequent approval of the product. As new data are generated, benefit-risk planning may suggest changes in the program as a result of the emerging efficacy and safety profile. This may be particularly important in cases where the efficacy data may be preliminary or modest, or where there are other factors that may make the clinical results less robust, such as the use of single-arm studies to support Accelerated Approval.

In cases where safety may be an issue (e.g., when significant or concerning side effects have been seen or are expected based on pharmacological class, mechanism of action, or non-clinical safety findings), the Benefit-Risk Assessment proves a very useful tool. It is important to consider whether risks can be outweighed by benefits in the patient populations being studied or if one needs to further limit the target populations. Other considerations are the availability of other therapies, a greater benefit in a sub-set of the population, or the need for a black box warning or Risk Evaluation and Mitigation Strategy (REMS) plan.

As development progresses, and the sponsor begins to prepare a marketing application, there are other opportunities for interaction with FDA to discuss benefit‑risk considerations.  The recent guidance also provides considerations on benefit-risk assessments that inform regulatory decision-making in the post-marketing setting.

The guidance indicates that FDA’s benefit-risk assessment of a product takes into account the following features:

  • The therapeutic context in which the agent will be used;
  • The evidence to support the benefit-risk assessment;
  • The uncertainties about the agent’s benefits and risks;
  • FDA’s regulatory options to manage risks and reduce uncertainties such as contraindications, limitations of use, boxed warnings, and warnings and precautions in the product labeling or a Medication Guide or REMS.

Important in the FDA’s assessment is the consideration that a safety profile that is acceptable in a population with a serious or life-threatening condition and/or a condition for which there are no therapeutic options, may not be acceptable in a population with a more chronic condition or where there are other therapeutic options.

FDA has increasingly recognized that patient experience data can help inform a development program and the benefit-risk assessment; they suggest that patient experience be integrated into trial design and data analysis.

How studies are designed, the patient populations included in pivotal studies, and the efficacy and safety data generated to support the marketing application can have a significant impact on the FDA’s benefit-risk assessment during an application review. Other information to be considered include whether the indication represents an unmet medical need, dose(s) being studied, key trial design features, study endpoints, and risk mitigation practices incorporated into the clinical program.

The guidance also provides details as to what the FDA would like to see in the benefit-risk section of a marketing application. This is of particular importance to those of us working in the regulatory field, and supporting our sponsors in meeting these criteria is one of PROMETRIKA’s strengths. The analyses included in the Integrated Summary of Efficacy (ISE) and Integrated Summary of Safety (ISS) inform the Benefit-Risk Assessment; thus, they must be carefully planned to include the information, noted below, that FDA wishes to see in the Integrated Summary of Benefits and Risks:

  • A summary of the important benefits and risks identified in the development program and a description of the clinical importance of those benefits and risks, including the following:
    • Discussion of the magnitude of the treatment effects. 
    • Whether the treatment effect clinically meaningful, and on what considerations is this decision is based.
    • Time course and durability of the effects, as well as the interdependence of endpoints.
  • Estimates of the statistical uncertainty around the magnitudes of the most important benefits and risks (e.g., with confidence intervals).
  • Discussion of additional sources of uncertainty about benefits and risks (e.g., untested risk management strategies).
  • Potential differences between aspects of the clinical trial and expected real-world use (e.g., population, adherence, safety monitoring).
  • In some instances, a graphical or tabular summary of results for the most important benefits, side by side or juxtaposed with important risks (e.g., the benefits and risks identified in a value tree), may be helpful. 

FDA points out that sponsors may want to use these same considerations when presenting this type of product-specific information to FDA advisory committees.

In their review of marketing applications, FDA uses the Benefit-Risk Framework shown below, in their integrated reviews, which are posted on-line after approval.


Evidence and Uncertainties

Conclusions and Reasons

Analysis of Condition



Current Treatment Options






Risk and Risk Management



Conclusions Regarding Benefit-Risk

The last part of the guidance discusses the use of a benefit-risk assessment in the post-marketing setting. The FDA has expressed a preference for receiving updated safety and efficacy data in the Periodic Benefit-Risk Evaluation Report (PBRER) format rather than the older Periodic Adverse (Drug) Event Report (PADER or PAER). As suggested by the title, the PBRER allows the agency to focus on a continuous evaluation of the benefits and risks of the product after approval for marketing.

As new data are generated, benefit-risk planning may suggest changes in the program as a result of the emerging efficacy and safety profile.

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