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Frame work

How FDA is using and improving benefit-risk frameworks in new drug reviews

A little over four years into its implementation, FDA’s structured benefit-risk framework appears to be meeting its objectives of creating transparency into its approval decisions.

The agency began to incorporate the framework templates into its reviews of drugs and biologics in 2013. The standardized approach is intended to focus reviews more explicitly on the trade-offs between benefits and risks, increase transparency around the factors driving decisions, make reviews of similar products more consistent, and explain and resolve disagreements within the agency.

BioCentury’s review of published frameworks for 70 products approved since mid-2015 shows most divisions consistently present the benefits and risks under consideration, identify reasons for uncertainty around them and, in the event that agency personnel disagreed, highlight factors that tipped the scales (see “Framework Use by FDA Division”).

Among the six Center for Drug Evaluation and Research (CDER) offices included in the review, the Office of Drug Evaluation I (ODE I), which houses the divisions of neurology, psychiatry, and cardiovascular and renal products, stands out for using the framework to discuss the relative weight of benefits and risks that went into complicated decisions. In three cases, the frameworks were used to document the agency’s rationale for why individual patient preferences should drive the final benefit-risk calculation.

FDA plans to improve the frameworks by adding more structured and quantitative analyses, and increasing the incorporation of patient perspectives and preferences into the documents.

In the latter case, industry, academia and advocacy groups have begun working to develop and validate tools to include more formal patient preference data in the frameworks.

One bottleneck is FDA’s ability to hire experts who can interpret the resulting data, as people with the appropriate statistical background are scarce and also highly desired by industry.

Figure: Framework use by FDA division

BioCentury analyzed the use of structured benefit-risk frameworks by FDA reviewers for 70 new drugs and biologics approved before October 2017. Among the six offices at CDER included in the survey, the Office of Hematology and Oncology Products (OHOP) reviewed 22 of the products. The Office of Drug Evaluation III (ODE III) reviewed 15 while ODE I reviewed 13. The latter stood out for more frequently using the frameworks to document when reviewers disagreed about approvability (four products), incorporating quantitative analyses of benefits or risks (three products) or deeming patients to be the final arbiters of whether the benefits outweigh the risks to them (three products). OAP = Office of Antimicrobial Products; Source: FDA website

First look

All of the frameworks published so far were used in reviews of NMEs and original BLAs. In September, the agency began using the framework in sNDAs and sBLAs.

The framework template asks reviewers to evaluate

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