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FDA benefit-risk frameworks for drug approval

In a recent study published in Therapeutic Innovation and Regulatory Science, researchers conducted a systematic review of the decision factors communicated by FDA in all benefit-risk frameworks associated with novel drug approvals.

Drug approval

Authorisation of human drugs and biologics by the FDA involves an assessment of whether the drug is effective and whether the benefits of the drug outweigh its risks. In order to do this, interdisciplinary review teams evaluate large volumes of scientific and clinical data to come to a regulatory decision. Typically, at this stage, the body of evidence available is imperfect. Therefore, the team have to use scientific and regulatory judgement.

Benefit-risk frameworks

The FDA and several other drug regulatory bodies utilise systematic, structured and qualitative approaches for regulatory decision-making. Although there are similarities, no single approach is used by all regulators. The FDA’s approach is found in the benefit-risk framework. It was developed by the Center for Drug Evaluation and Research, and the Center for Biologics Evaluation and Research. It was phased into new drug reviews for the centres between 2013 and 2017.

The benefit-risk framework is fundamentally a discussion regarding:

  • Therapeutic context – clinical characteristics of the condition, population impacted, currently available treatments and also the degree of unmet medical needs
  • What is known about the benefits and risk of the drug under review
  • An integrated assessment of the benefit-risk balance
  • The need for risk management
  • The regulatory decision

The benefit-risk framework consists of questions to help guide the review team through the decision-making process. It also provides a mechanism for documenting uncertainties and identifying and resolving disagreements.

Systematic review

This paper explores how the benefit-risk framework has been used by FDA teams to communicate approval decisions. They conducted a systematic review for benefit-risk frameworks published (n=237) for novel drug approvals between 2017 and 2018 (n= 104).

The team found that the majority of novel drug approvals, 76% in 2017 and 86% in 2018, had benefit-risk frameworks that described a condition that was severe or life-threatening and had an unmet medical need. They specifically described this overlap as an ‘urgent’ context. Additionally, they found that 58% of approvals in 2017 and 68% of approvals in 2018 reported issues related to establishing the benefit of a novel drug. Importantly, serious safety concerns or limitations assessing safety profile were also discussed in benefit-risk frameworks for 64% of approvals in 2017 and 56% of approvals in 2018. Overall, just over a third of all novel drug approvals have benefit-risk frameworks that describe an urgent therapeutic context (38% in 2017 and 37% in 2018).


The majority of novel drugs approved were considered ‘urgent’. This finding is not unexpected due to industry-wide trends focussed on novel drug development in serious, rare diseases. This paper highlights the utility of having a structured, descriptive benefit-risk assessment tool to display and communicate key decision factors. Such a mechanism supports the diversity of drug approval decisions made by the FDA. Moreover, the team note that the FDA is continuing to develop qualitative frameworks and is exploring decision analysis techniques that could support assessment of complicated issues.

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