FDA Guidance on Benefit-Risk Assessment

The U.S. Food and Drug Administration (FDA) has published a draft guidance to clarify how considerations about benefit-risk assessment (BRA) are integrated into the agency´s pre- and postmarket decisions for marketing applications of new drugs and biologics. In this regulatory context the agency is making an informed judgment as to whether the benefits outweigh the risks under the conditions of use described in the product labeling. 

According to the FDA, BRA takes into account the extensive evidence of safety and effectiveness submitted, as well as many other factors, including the nature and severity of the condition the product is intended to treat or prevent, the benefits and risks of other available therapies for the condition, and risk management tools that might be necessary to ensure that the benefits outweigh the risks.

Examples of regulatory options to reduce and manage risks include the following:

• Clinical studies (pre- or postmarket) to further characterize safety, effectiveness, or dose response;
• Additional product quality information;
• Postmarket observational studies
• Enhanced pharmacovigilance;
• Labeling content (e.g., limitations of use);
• Risk evaluation and mitigation strategies (REMS).

FDA´s Benefit-Risk Framework for New Drugs

FDA’s tool for conducting and communicating BRAs is the Benefit-Risk Framework (BRF). The BRF provides a structured, qualitative approach for identifying, assessing, and communicating important considerations which factor into the BRA.

Following the framework, activities during development are:

• BRA planning (carried out by the sponsor), beginning in early development,
• Interactions between sponsor and FDA (e.g. via formal meetings),
• Collecting patient experience data,
• Conducting additional analyses (e.g. estimation of important clinical benefit or risk outcomes, modeling of benefit and risk outcomes or public health outcomes that could be expected in the real-world setting (see also FDA´s draft guidance on Real-World Data), integrating benefits and risks in a combined analysis),
• Presenting benefit-risk considerations in marketing applications (e.g. description of the clinical importance of key benefits and risks, estimates of the statistical uncertainty, presentation of a graphical or tabular summary of results, discussion of additional sources of uncertainty).

BRA Lifecycle Approach / Periodic Benefit-Risk Evaluation Reports

The agency considers BRA as a lifecycle approach, acknowledging that understanding of both the product’s benefits and risks often change over time as new information about the product’s effectiveness or safety becomes available. According to the FDA, sponsors may find a structured approach (guided by the BRF or ICH´s guidance for industry E2C(R2) + Q&As) useful to support generation and evaluation of new information and decisions made regarding the new information. Moreover, the ICH E2C(R2) guideline on Periodic Benefit-Risk Evaluation Report provides recommendations on developing an optional Periodic Benefit-Risk Evaluation Report (PBRER).

However, sponsors should not wait for a periodic safety update to report a potentially serious safety concern. New information about a potential serious safety concern that could have an impact on a drug’s benefit-risk profile should be communicated promptly to FDA.

More information is presented in FDA´s draft guidance on Benefit-Risk Assessment for New Drug and Biological Products.