The Prescription Drug and User Fee Act (PDUFA), first enacted in 1992, was put in place to ensure timely FDA approval or licensure decisions of New Drug Applications (NDAs) and Biologics License Applications (BLAs). To streamline this decision-making process, the FDA developed a structured benefit-risk assessment framework designed to highlight uncertainties about a drug’s safety and efficacy in the indicated population and where new findings, as they become available in the post-market setting, can be incorporated into the framework. The FDA began implementing this framework into their regulatory review processes and documentation in 2012 after the 5^th authorization of PDUFA (PDUFA V), and as part of their commitments under PDUFA VI, the FDA developed and finalized a guidance document for industry on this benefit‑risk assessment for new drug and biological products.

When assessing the benefit-risk profile of a product under review, the FDA considers the following:

• extensive evidence of product quality, safety, and effectiveness submitted by a sponsor in an NDA or BLA, or generated in the post-market setting,
• patient experience data (as required by the 21st Century Cures Act of 2016),
• potential consequences to public health (eg, misuse or disease transmission),
• the implications of the condition the drug is intended to treat or prevent and the current treatment landscape for the condition,
• uncertainties about the product (e.g., its effectiveness in the real-world population and its long‑term safety), and
• any necessary risk management tools to ensure the benefits of the product outweigh the risks.

The benefit-risk paradigm is intended to guide a sponsor’s development program by reducing uncertainties and minimizing risk. A product’s benefit-risk profile is assessed throughout product development by designing the integrated product development strategy, collecting and analyzing data, and refining the development plan for the most successful outcome (clinically and statistically meaningful outcomes). In theory, the activity of developing the benefit-risk framework may initiate when drafting the Target Product Profile (TPP); however, in practice, the structured framework typically initiates as part of key message development for the purpose of developing the overall marketing application including the package insert (i.e., the product labeling) and Module 2.5 Clinical Overview (Guidance for Industry:  ICH M4E(R2)). Regardless, sponsors are encouraged to build the framework throughout development, starting with drafting the TPP early and developing the framework throughout each phase of development.

To ensure the most appropriate data are collected throughout development to support the benefit-risk assessment of the product, Sponsors should incorporate benefit-risk planning early in development, ideally at the preclinical stage. Our experts at Rho can help you implement benefit-risk planning at whatever stage of development you are with your product. To help you better understand how to approach the benefit-risk paradigm, we will provide future blog posts further describing the structured benefit-risk framework, key messages for the framework, and risk management and mitigation.

Kimberly Koehn, Ph.D., Regulatory Scientist, has 10 years of experience in writing and editing scientific documents and publications across a variety of chemistry, biological, clinical, and regulatory fields. At Rho, she leads and manages regulatory and scientific authoring teams and has participated in the authoring and preparation of modules for regulatory submissions (IND, NDA, BLA, etc.), briefing packages to support regulatory meetings, clinical study protocols and reports, and other regulatory documents.