The Pharmaceutical Research and Manufacturers of America’s Benefit-Risk Action Team expects to complete pilot testing of a framework for conducting benefit-risk assessments by the end of 2011.

The framework provides a structured and systematic method for considering information needed to weigh a medical product’s benefits and risks.

BRAT’s goal is to give companies, regulators and other stakeholders a means to organize, interpret and communicate information about many outcomes, accounting for heterogeneity and uncertainty, in order to facilitate benefit-risk decisions.

To do this, the framework defines a set of processes to select, organize, interact with, summarize, display and communicate the data relevant to a benefit-risk decision (see chart, Also see "Six Steps To Benefit-Risk Assessment" - Pink Sheet, 12 September, 2011.).

“The FDA framework really emphasizes communicating the rationale behind the decision, whereas the BRAT framework provides a set of processes and tools that can actually help you get to a decision.” – Eli Lilly’s Rebecca Noel

The framework does not quantify the overall benefit-risk ratio, but focuses on both qualitative and quantitative analysis of the individual benefit and risk outcomes.

By utilizing a framework, “sponsors and regulators could realize increased predictability, consistency and transparency of decisions” and this would facilitate communication of decisions to patients and health care providers, according to PhRMA.

Thirteen drug companies are participating in the BRAT pilot program, Firms selected the products to be evaluated, with no limitations set on class type or where the product is in its life cycle.

BRAT, which previously tested the framework on three make-believe drugs, will use real-world experiences from the pilot test to further refine the framework and drive its uptake and adoption by companies and regulators, Rebecca Noel, a research scientist at Eli Lilly and member of BRAT, reported during a recent ParagonRxWebinar.

The European Medicines Agency and FDA are developing frameworks as well, but BRAT does not view those as competitive.

BRAT, FDA Frameworks Complementary

“We see them really as being collaborative,” Noel said, since they come at the issue from different perspectives. “The FDA framework really emphasizes communicating the rationale behind the decision, whereas the BRAT framework provides a set of processes and tools that can actually help you get to a decision and then also communicate it.”

In the past, FDA has shown little interest in a framework so the fact that FDA is looking at one now is a step forward, Noel said, noting that when BRAT began its work in 2007 and approached the agency, officials were not enamored of the idea.

FDA indicated an interest in using a framework in spring of 2010 with a presentation by OND director John Jenkins on regulatory decision-making.

Compared to BRAT’s extensive information organizational platform, Jenkins presented a more limited framework. The simple grid he suggested calls for consideration of how the severity of the condition, unmet medical need, clinical benefit, risk and risk management contribute to the favorable or unfavorable side of the benefit-risk ledger and/or are non-contributory (see chart, “Fill In The Blanks: FDA’s Potential Qualitative Benefit-Risk Framework”).

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[Click link to view full-size chart.]

Jenkins had noted that a framework needs to provide a “big picture” of the issues relevant to a regulatory decision, describe the benefit-risk implications of the evidence and support structured discussions of the issues involved in assessments.

The agency continues “to further develop the framework and evaluate its usefulness to FDA reviewers while reviewing a drug application,” FDA told “The Pink Sheet.”

Industry user fees will facilitate that development as the agency and drug companies have agreed to a benefit-risk component as part of the next Prescription Drug User Fee Act (Also see "PDUFA V Agreement Set In Four Areas, But Broad FDA/Industry Talks Continue" - Pink Sheet, 7 March, 2011.).

Putting A Framework Into Decision-Making

The agency will utilize PDUFA funds to optimize its benefit-risk framework and incorporate it into the new drug approval process. A draft plan for achieving this goal is to be issued for public comment by the end of 2012.

The plan will lay out FDA’s approach for putting a framework into practice throughout a drug’s lifecycle.

The agency will conduct two public workshops on benefit-risk considerations from the regulator’s perspective. The first, to be held by late 2014, will be informational, covering various methods and frameworks and their application to regulatory decision-making. The second will focus on lessons learned in implementing frameworks at regulatory agencies.

FDA will convene another set of public meetings to receive patient input on how much risk they are willing to take for a given disease.

Four meetings per year will be held throughout PDUFA V. Each will discuss a different disease, its severity and the current state of the treatment armamentarium. Following the first two meetings, FDA will develop a proposal for incorporating patient perspectives into its decision-making (Also see "PDUFA V: Patients’ Opinions Could Get Formal Role In Review Decisions" - Pink Sheet, 20 December, 2010.).

By Cathy Dombrowski

PhRMA Testing Pilot Framework For Structured Benefit-Risk Assessment

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