Harmonizing BRAT

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  • 08/27/2012

The Pink Sheet reports that “An international group of regulators and drug companies have agreed in principle to a framework that sets out eight steps for assessing a drug’s benefits and risks and could set the stage for a global approach to evaluating drugs.”

The framework will not result in uniform decisions across countries, but rather will provide a structure for the benefit-risk assessment process as a number of efforts are underway to make the exercise more methodical and to develop systematic ways for regulators and sponsors to present, communicate and discuss drug data.

Methodologies to reach decisions may vary, but “if everybody follows those same basic eight steps, … any new method that you come up with to develop or to assess benefit-risk should be internationally acceptable because they follow these general eight-step principles,” Lawrence Liberti, executive director of the Centre for Innovation in Regulatory Science, explained in an interview.

The Eight-Step Benefit-Risk Assessment Framework can be found here.

A task force of representatives from eight regulatory agencies and six international pharmaceutical companies, organized by CIRS through its Unified Methodologies for Benefit-Risk Assessment initiative, endorsed the framework following a June 21-22 workshop held in Washington, D.C., to discuss global harmonization of the benefit-risk assessment process. FDA Senior Advisor Murray Lumpkin and GlaxoSmithKline Inc. Senior VP-Global Clinical Safety and Pharmacovigilance Frank Rockhold co-chaired the workshop of regulators, academics and industry representatives.

The CIRS-mediated effort is separate from the International Conference on Harmonization, a long-standing initiative to coordinate regulatory standards between the U.S., Europe and Japan. FDA recently put ICH periodic benefit-risk evaluation standards into draft guidance for post-market safety reporting

While the eight steps coming out of the CIRS effort create structure, the methodology for benefit-risk decision-making will not be uniform soon, if ever. A common lexicon should be developed, according to a synopsis of the meeting, which was not open to the public. But agencies vary in their weighting of benefit-risk parameters and there are regional differences in regulatory and cultural viewpoints, making uniformity difficult.

With general agreement on the framework, stakeholders now can focus their attention on developing those methodologies. “Time should be allowed for pragmatic methodological approaches to be developed, including adequate timing for feedback on best practices to emerge,” the synopsis says.

Four agencies that make up the Consortium on Benefit-Risk Assessment – Swissmedic, Health Canada, Singapore’s Health Sciences Authority and Australia’s Therapeutic Goods Administration – pilot-tested the methodology using information from applications for a drug they previously approved.

The BRAT process was pilot-tested by 13 companies during various stages of drug development. A case study of its application to evaluate Johnson & Johnson/Bayer HealthCare AG’s rivaroxaban found that such methodology can add rigor and transparency to decision-making and is easily used in regulatory settings, such as advisory committee meetings, according to the workshop synopsis.

FDA is field testing its benefit-risk framework with six products. With the FDA approach, reviewers list evidence/uncertainties and conclusions/reasons for five decision factors in a grid format and then analyze the implications. The factors are severity of condition, unmet medical need, clinical benefit, risk and risk management.

(FDA committed to a structured benefit-risk assessment framework for the drug review process as part of PFUFA V.)

Among FDA initiatives in this area is a basic roadmap to be used by patient groups interested in development of patient-reported outcome measures in a specific disease area.

The European Medicines Agency has a benefit-risk assessment methodology that it considers a simple qualitative tool. PrOACT-URL identifies the problem, determines the objective, considers the alternatives and their consequences (presented in tabular form) and makes tradeoffs through swing-weighting of the events. Sensitivity analysis determines the level of uncertainty.

On the developer’s side of the table, Diana Hughes, a vice president in Pfizer Inc.’s primary care business unit, suggested industry form a consortium with the mission of gaining a perspective on unmet medical need and patient experience. Companies should continue collaborating with advocacy groups and develop patient educational programs to elicit information on the most relevant aspects of a disease and advance a common approach to valuing and weighting benefit and risk, she said.

Workshop participants concluded that rules of engagement must be set to avoid any misperceptions of conflict-of-interest during interactions with patients, and that such interactions are consistent, scheduled and balanced. Patients would benefit from education on the inherent nature of uncertainty in benefit-risk decisions, according to the workshop.


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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