Benefit-Risk Assessment Framework Moves Toward Global Harmonization

PhRMA shifts further development of its structured benefit-risk assessment framework to the European organization CIRS, which has relationships with regulators in Europe, the U.S. and elsewhere that can drive the framework’s adoption for the drug approval process.

The Pharmaceutical Research and Manufacturers of America is transferring its framework for risk-benefit assessment to the Centre for Innovation in Regulatory Science Ltd. for further development on the road to harmonization of how companies and regulators evaluate drugs.

The transfer, announced Jan. 30, helps consolidate efforts to bring consistency to benefit-risk assessments across the globe. London-based CIRS, whose funding includes dues from 22 pharmaceutical companies, will now be responsible for technical work on the PhRMA framework, as well as its own structured approach to benefit-risk assessment, which was pilot-tested by regulatory agencies in Canada, Australia, Singapore and Switzerland.

The full benefit of a framework will not be seen unless both regulators and drug makers adopt the concept. Because of its relationships with regulators in Europe, the U.S., and elsewhere, CIRS is well-positioned to “drive the regulatory adoption and the adoption by industry of a structured approach to the assessment of benefit and risk,” PhRMA Vice President Sascha Haverfield-Gross explained in an interview.

PhRMA now can focus its attention on converting a benefit-risk provision of the FDA/industry agreement on Prescription Drug User Fee Act reauthorization into a systematic assessment during new drug reviews (Also see "PDUFA V Agreement Set In Four Areas, But Broad FDA/Industry Talks Continue" - Pink Sheet, 7 Mar, 2011.).

A framework facilitates benefit-risk assessment, PhRMA VP Haverfield-Gross says. “It structures it. It makes it more transparent. It facilitates discussions between not only regulators and sponsors, but also the communication of how a benefit-risk decision was reached.”

The goal, Haverfield-Gross said, is “to have a process, a scientific process that relies on input from all relevant parties – patients, health care providers, the regulated industry, academia, as well as regulators – [to] come up with the approach that is best to be implemented in the U.S. and implement that by the end of PDUFA V.”

Eventually, he said, “it would be beneficial if there was a harmonized approach to benefit-risk assessment across all major regions. But I think that is a future step that would follow the implementation of a framework in the U.S.”

The final form that FDA’s benefit-risk framework will take remains unclear. It will be determined by the agency with public input through a series of meetings and workshops during the fiscal 2013-18 timeframe of PDUFA V.

Haverfield-Gross voiced expectations that the new approach will facilitate the regulatory review and approval process and communications about a therapy’s benefits and safety.

“Transparency of the process and predictability are cornerstones of an efficient regulatory system. I expect that the implementation of a structured approach to the assessments of benefits and risks will actually positively influence the efficiency of the review process in the U.S.,” he said.

Designing A Flexible Framework

The PhRMA framework, developed by the Benefit-Risk Action Team (BRAT), provides a set of processes to select, organize, interact with, summarize, display and communicate data relevant to a benefit-risk decision on medical products (Also see "PhRMA Testing Pilot Framework For Structured Benefit-Risk Assessment" - Pink Sheet, 12 Sep, 2011.). The CIRS framework also has six steps.

The first order of business for CIRS will be to examine the components of the two frameworks to identify the strengths and weaknesses of each.

The BRAT framework is “a wonderful visualization tool and allows categorization of benefit-risks in ways that other methodologies, maybe, are not so strong at,” CIRS Executive Director Lawrence Liberti told “The Pink Sheet.” This visualization is critical to communicating the assessment to different stakeholders, he said.

The CIRS approach, on the other hand, is more descriptive and verbal and has a robust electronic methodology to document decisions, he explained. Tying elements from both together “will provide for a robust flexible approach to benefit-risk assessment,” he said.

Liberti expects a number of methodologies to be available to conduct the assessments. Ideally, he said, drug makers and regulators can choose the ones suitable to the task.

CIRS will work to evolve the frameworks “by developing and incorporating the strongest elements of each, engaging key stakeholders and integrating feedback from real-world experience with these structured approaches.” The organization will consider the approaches being developed by the European Medicines Agency and FDA, as well. “We’re looking to bring those together in the sense of being able to provide a forum for discussion about their commonality and their differences,” Liberti said.

“The goal would be that all of the stakeholders can agree on appropriate frameworks and methodologies so that they have a common platform for conversation and discussion of benefits and risks,” he added.

A framework does not replace expert judgment, Haverfield-Gross stressed. What it does is “it facilitates the process. It structures it. It makes it more transparent. It facilitates discussions between not only regulators and sponsors, but also the communication of how a benefit-risk decision was reached between regulators and sponsors, as well as health care providers and patients.”

Real-World Test Results To Come

Both the BRAT and CIRS frameworks have had real-world testing, the former by industry and the latter in the regulatory setting. The results, which are still being analyzed, will inform CIRS’ efforts going forward.

Thirteen companies completed pilot-tested the BRAT framework at the end of 2011. They had the option of employing it wherever it might be useful, Haverfield-Gross said, noting that this “structured approach to benefit-risk assessment can be applied broadly across the entire spectrum of pharmaceutical development.”

Evaluations of the CIRS framework by HealthCanada, Australia’s Therapeutic Goods Administration, Health Sciences Authority of Singapore and SwissMedic, using real products, concluded recently. The results are being analyzed and the process for disseminating them will be decided during a June meeting of a consortium of the four countries, Liberti reported.

To gather stakeholder input, CIRS will conduct a workshop focused on patient concerns during the week of April 23 in the London area; the organization’s annual workshop with regulators and industry will be held the week of June 18 in Washington.

CIRS is part of the Intellectual Property and Science business of Thomson Reuters, but is operated as an independent company for the sole support of its members’ activities and is funded from membership dues, related activities and grants.