FDA draft guidance outlines criteria for conducting benefit/risk assessments

Regulatory NewsRegulatory News | 01 October 2021 |  By 

The US Food and Drug Administration (FDA) issued a draft guidance on Wednesday that aims to shed light on how it assesses the benefits and risks of new drugs in deciding whether to approve them. The guidance also describes how companies can present benefit and risk information in their applications to increase chances of approval.
The guidance also addresses how sponsors can collect patient experience data to inform their benefit/risk assessments. It was developed in accordance with commitments made under the Prescription Drug User Fee Act of 2017 (PDUFA VI) under the FDA Reauthorization Act of 2017 and under the 21st Century Cures Act.
“The intent of this guidance is to provide drug sponsors and other stakeholders with a clearer understanding of how considerations about a drug’s benefits, risks, and risk management options factor into certain FDA pre- and postmarket regulatory decisions about new drug applications (NDAs) submitted under the Federal Food, Drug and Cosmetic Act (FD&C Act) and biologics license applications,” according to the Federal Register announcement of the availability of the draft guidance.
FDA officials offered an early glimpse of the forthcoming guidance in a May 2019 workshop with industry. (RELATED: Reassessing Benefit-Risk: FDA Preps for New Guidance, Regulatory Focus 16 May 2019)
FDA uses the following four factors in assessing a proposed new drug’s benefits and risks:
  • The therapeutic context in which the drug will be used, including the nature and severity of the proposed indicated condition for the drug.  “Therapeutic context is particularly important in cases where it is necessary to determine whether a serious risk associated with the drug is outweighed by its demonstrated benefit;” the agency will also take into account whether a proposed indication is preventative, and whether patient needs are met by medicines that are currently available.
  • The evidence submitted in the premarket application, or evidence generated in the postmarketing setting that informs the agency’s understanding of the drug’s benefits and risks. Clinical and nonclinical data together with patient experience data, safety reports, and epidemiologic data, among others, are all sources FDA will consider.
  • Uncertainties about the drug’s benefits and risks. Here, FDA acknowledges that “some uncertainty in the body of evidence available at the time of regulatory decision-making is inevitable”
  • Regulatory options, such as requiring additional clinical study or product quality information, or postmarket actions such as observational studies, that FDA can use to reduce uncertainties and manage risks.
These factors are captured in a benefit-risk framework for new drug review. FDA uses this framework is a structured way to capture qualitative information during review of new drug applications (NDAs) and biologics license applications (BLAs) to support their decision-making in reaching benefit-risk assessments.
The benefit-risk grid assesses evidence and uncertainties for reviewers’ analysis of the condition, identification of current treatment options, and benefit and risk/risk management for the proposed therapy. For each dimension, the grid allows room for the review to outline conclusions drawn and a justification for those conclusions.  Finally, the reviewer summarizes conclusions regarding the benefit-risk balance.
FDA has been steadily integrating this benefit-risk framework into actions taken both by the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER), according to the draft guidance.
The agency noted that the sponsor’s NDA or BLA is “a critical source of benefit risk information.” As part of an NDA submission, the sponsor must provide “an integrated summary of the benefits and risks of the drug, including a discussion of why the benefits exceed the risk under the conditions stated in the labeling.”
In addition, the following information may facilitate FDA’s benefit-risk assessment:
  • A discussion of the “magnitudes of effects and treatment effects (difference between drug and comparator)” FDA also provides guidance on how both continuous and binary outcome measures should be addressed.
  • The “estimates of the statistical uncertainty around the magnitudes of the most important benefits and potential risks (e.g., with confidence intervals)”
  • A graphical or tabular summary of the most important benefits alongside the risk.
A table in the draft guidance provides examples of the factors that FDA will consider in assessing each dimension of its benefit-risk framework; these important considerations range from understanding public health implications of an indicated disease or condition, to such drug characteristics as dosing regimen, to how a product quality issue could affect a drug’s effectiveness.
Leveraging patient experience data
The guidance also discusses how sponsors can use patient experience data to help in their benefit-risk assessments. If collected early in the development program, the data can “help identify unmet patient needs and define the target patient population.”
During a March 2018 workshop addressing patient-focused drug development, FDA and industry officials pointed to several existing barriers in collecting and incorporating patient experience data for purposes of drug development, such as the lack of a methodological framework for identifying what measures are the most important to patients. (RELATED:  FDA Invites Draft Guidance on Patient-Focused Drug Development, Regulatory Focus, 20 March 2018).
Patient preference information (PPI) is one type of patient experience data that sponsors may submit, according to the draft guidance. “PPI may be useful to sponsors at various stages of drug development, including informing the therapeutic context, identifying endpoints, and informing benefit-risk assessment. It can be collected for a specific drug development program, or more broadly within a therapeutic area.”
The use of PPI data is recommended when there are “significant” treatment risks or uncertainty about the drug’s benefits or when patients’ views on the benefits and risks “vary considerably within a population;” an approach that uses PPI can also be useful when patients’ views on the benefits are expected to differ from healthcare professionals.
PPI would be considered in FDA’s assessment of a drug’s efficacy and safety, although such data would not be enough to overcome “significant safety issues or lack of therapeutic benefit.”
The deadline for public comment is 29 November 2021.
FDA officials gave an early glimpse of the guidance in a May 2019 workshop with industry. (RELATED: Reassessing Benefit-Risk: FDA Preps for New Guidance, Regulatory Focus, 16 May 2019)
FDA also partnered with Duke University’s Robert J. Margolis Center for Health Policy to offer a public meeting that gathered stakeholder input on applying FDA’s benefit-risk framework throughout the human drug lifecycle and explored best approaches to communicating FDA’s benefit-risk assessment framework. (RELATED: Public Meeting to Address FDA’s Benefit-Risk Assessments, Regulatory Focus, 23 April 2019).
FDA guidance
FDA announcement


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