Benefit-Risk Framework: PDUFA VI Goals Outlined

Regulatory NewsRegulatory News | 30 March 2018 |  By 

With an aim to better explain how a drug’s benefits and risks inform regulatory decision-making, FDA said Friday it expects to draft guidance on the topic by the end of June 2020.

As outlined in the latest Prescription Drug User Fee Act (PDUFA VI) commitment letter, this draft guidance will: Illustrate the application of the benefit-risk framework throughout a drug's lifecycle, "using a case study approach, if appropriate," discuss interactions between a sponsor and FDA during development to understand the severity of disease and the extent of unmet medical need, and discuss appropriate approaches to communicate publicly the agency’s thinking on a benefit-risk assessment.


The Benefit-Risk Framework (BRF) has two key elements for new drug applications (NDAs) and biologics license applications (BLAs): The “Benefit-Risk Dimensions” portion and the “Benefit-Risk Integrated Assessment.”

The dimensions portion outlines the critical elements (“Analysis of Condition, Current Treatment Options, Benefit, and Risk and Risk Management”) that factor into the assessment. The table includes columns for outlining evidence and uncertainties, as well as the conclusions and reasons for each.

The Benefit-Risk Integrated Assessment, meanwhile, provides a succinct explanation and rationale for the regulatory recommendation or decision. The assessment demonstrates “how evidence and uncertainties about a drug’s benefits and risks are considered in the context of the severity of the condition and the current medical needs for patients,” FDA said.

And after conducting patient-focused drug development meetings in over 20 disease areas, the agency said it concluded that patient input can: “1) inform the clinical context and provide insights to frame the assessment of benefits and risk; and 2) provide a direct source of evidence regarding the benefits and risks, if methodologically-sound data collection tools could be developed and used within clinical studies of an investigational therapy.” FDA last June said it was developing guidance to enable more widespread development of such patient experience data to inform regulatory decision-making. 

In July 2017, FDA published guidance to industry entitled M4E(R2): The CTD – Efficacy Guidance for Industry, which integrates the ICH guidelines on presenting benefit-risk information in an applicant’s submission.

Beginning last August, under the 21st Century Cures Act, FDA had to “make public a brief statement regarding the patient experience data and related information, if any, submitted and reviewed as part of the application.” FDA said the revised primary clinical review template now incorporates a section on “Patient Experience Data.”  
In September 2017, a contractor studied the use of BRFs and found that 87% of relevant review documents covered in the assessment cohort contained a BRF. FDA staff opinions about including the BRF into the review process “were mixed, but most staff saw some value,” the report says. Seventy-five percent of FDA staff interviewed "stated that the BRF has some value in (1) organizing and documenting their thinking about benefit-risk or (2) documenting a concise view of the review and recommendation. Twenty-five percent (25%) of FDA staff interviewed believed that the BRF is primarily used to communicate benefit-risk assessment externally.”

What’s Coming

In addition to the draft guidance, FDA’s incorporation of the BRF into the review processes and templates for new drug review will continue over the next five years, and FDA said it will also explore how to enhance the use of the BRF as an internal review tool earlier in the NDA/BLA review process.

Other commitments include revising and publishing relevant Manuals for Policies and Procedures (MAPPs) and Standard Operating Practices and Procedures (SOPPs) to incorporate benefit-risk assessment approaches, in addition to a second evaluation of the implementation of the BRF beginning in 2021.

FDA also said it has committed to convening public meetings in the third quarter of FDA’s fiscal year (April – June), each year beginning in FY 2019, on progress toward implementing resource capacity planning and modernized time-reporting capabilities.

Benefit-risk assessment in drug regulatory decision-making: Draft PDUFA VI Implementation Plan (FY 2018-2022)

Public Workshops on Benefit-Risk Considerations

Resource Capacity Planning & Modernized Time Reporting Implementation Plan


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