Benefit-Risk: BIO Comments on Food and Drug Administration Prescription Drug User Fee Act VI Benefit-Risk Implementation Plan

May 31, 2018

Re: Docket No. FDA-2018-N-1010: Food and Drug Administration Prescription Drug User Fee Act VI Benefit-Risk Implementation Plan.

Dear Sir/Madam:

The Biotechnology Innovation Organization (BIO) thanks the Food and Drug Administration (FDA or Agency) for the opportunity to submit comments regarding the Prescription Drug User Fee Act VI Benefit-Risk Implementation Plan.

BIO is the world's largest trade association representing biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial, and environmental biotechnology products.

General Comments:

BIO supports the FDA's continued efforts to evaluate and improve upon the clarity of the complex and critical process of benefit-risk assessment (B/R assessment) throughout the lifecycle of drug evaluation. While BIO commends the FDA for the great progress in implementing the benefit-risk framework (B/R framework), especially as it relates to transparency and communication of benefit-risk assessments (B/R assessment), additional work is needed to continue to advance and improve upon the current FDA B/R framework. In order to continue to advance the science of B/R assessments and the ability of the framework to inform regulatory decision making, BIO believes that there should be increased emphasis and guidance on the utilization of the B/R framework as a decision support tool, implemented earlier in development, rather than just to support communication following a regulatory decision. For example, the FDA has identified additional opportunities to advance their B/R work, through: (1) incorporation of patient experience into drug development, evaluation, and review and (2) exploration of more quantitative approaches to inform B/R assessments in targeted cases, we ask that these efforts be highlighted as steps toward using the B/R framework as a decision support tool.

As the B/R framework relates to patient experience data, BIO believes that clear guidelines regarding how the FDA will synthesize information, how review division will utilize this information at the reviewer level, and how this process will be systematically implemented across the agency would be beneficial to all stakeholders. Specifically, we ask the FDA to clarify how they will incorporate patient perspective into the B/R assessment. It will be important for the FDA to provide information regarding how the Agency expects to use patient engagement meetings, real world data, and patient experiences in their understanding of what risks are acceptable to patients.

Additionally, further emphasis should be placed on defining the methodology to develop the B/R assessment, which could include implementing consistent definitions and tools (both qualitative and quantitative) for FDA reviewers to use when assessing medical products. BIO also suggests that this be done, to the extent possible, in alignment with other international regulatory authorities, including the European Medicines Agency.[1] Such standardized definitions could assist FDA reviewers in answering questions such as how to define an important benefit, how to define an important risk, how to determine in which situations risk minimization or pharmacovigilance activities are required to further mitigate or characterize a risk, measuring a patient’s risk tolerance, and how B/R assessments inform the indication for which the product is ultimately approved. Such activities could include a methods tool kit or catalog with case studies, standards for methods application, information regarding the adaptation and application to post-marketing assessments, as well as information regarding use of quantitative B/R assessment approaches. In the B/R implementation plan, we encourage FDA to clearly outline how they plan to advance and define the specific methodology for developing B/R assessments at FDA, for example, as part of the decision-making context. In addition to implementing consistent definitions and tools for FDA reviewers, BIO asks the FDA to consider updating its Manual of Policies and Procedures and providing training to reviewers to ensure consistent methodology and approaches to B/R assessment across therapeutic areas, Divisions, and Centers.

Communication around the B/R Assessment and the B/R Framework:

BIO applauds FDA for its strides to more clearly communicate the B/R framework with all stakeholders. In order to continue to advance these efforts, BIO encourages the FDA to consider developing a mechanism that allows for easier location of B/R information on the FDA’s website by either flagging or linking to the B/R assessment in FDA review documents. Additionally, as it currently stands, the B/R assessment grid in FDA reviews is followed by a tabular listing of what patient experience data was included in the marketing application, and where it is located. Moving forward, BIO believes that the patient experience data that influenced the B/R grid should to be integrated, or cross-referenced, and made more accessible for patients and providers.

BIO also asks the FDA to consider using structured B/R assessments routinely within the framework of product-specific Advisory Committees. For example, BIO encourages the FDA to include the B/R framework, developed in collaboration with or in addition to a B/R framework developed by the Sponsor, in Advisory Committees briefing materials, rather than waiting until the end of the FDA’s review. We believe that Including the B/R assessments in the Advisory Committee briefing materials may help lead discussion during the Advisory Committee meetings.

Finally, we also ask the FDA to consider moving from a post-approval summary of B/R considerations to a more active use of a specific B/R framework throughout drug development. To this end, the FDA could engage with sponsors during IND or pre-NDA/BLA milestone meetings and allow for discussion of the B/R assessment at other set time points. Such a discussion would benefit both the FDA and Sponsors when deciding whether to advance a particular compound into later stage development.

BIO appreciates this opportunity to submit comments regarding FDA’s Prescription Drug User Fee Act VI Benefit-Risk Implementation Plan; we would be pleased to provide further input or clarification of our comments, as needed.