Guest Column | February 11, 2022

Clinical Trials: FDA Proposes Benefit-Risk Assessment For New Drug And Biological Products

By Mark Durivage, Quality Systems Compliance LLC

Expert NetworkThe FDA’s Center for Devices and Radiological Health (CDRH) recently released a draft guidance, Benefit-Risk Assessment for New Drug and Biological Products. The guidance illustrates how a drug’s benefits, risks, and risk management options factor into certain premarket and postmarket regulatory decisions that the FDA makes about new drug applications (NDAs) submitted under section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as well as biologics license applications (BLAs) submitted under section 351(a) of the Public Health Service Act (PHS Act) for drug sponsors of clinical trials and other stakeholders.

The benefit-risk assessment is a qualitative one involving subjective judgment that weighs data and information about the drug’s benefits and risks and considers uncertainties within a specific therapeutic and regulatory context. There may be situations where additional benefit-risk analyses may add value early in the drug development process. The FDA will consider additional benefit-risk analysis as one component of the overall benefit-risk assessment and regulatory decision-making process.

Benefit-risk planning includes the identification of patients, data collection, selection of a primary efficacy endpoint, using active controls to establish the benefit-risk profile, demonstration of benefit in a specific subpopulation, required sample size and duration of a clinical trial, evaluating a potential adverse event(s), and risk mitigation activities to prevent or monitor anticipated serious adverse events. Structured benefit-risk planning is defined as a purposeful activity carried out by the sponsor to incorporate consideration of the product’s benefit-risk assessment throughout the drug development life cycle. Adopting a life cycle approach to benefit-risk planning can help improve product safety and efficacy, as the product’s benefits and risks often change over time as new information about the product’s effectiveness or safety becomes available.

Benefit-risk assessment by the FDA for the approval of new drugs incorporates broad public health considerations for the target patient population and others, such as risks related to misuse, accidental exposure, or disease transmission. It comprises a case-specific, multidisciplinary assessment of science and medicine, considering the therapeutic context in which the drug will be used versus currently available treatments, evidence submitted in the premarket application and/or generated during postmarket surveillance, uncertainties about the drug’s benefits and risks, and the FDA’s regulatory options to manage risks and reduce uncertainties.

Details Of The Proposed Guidance

The proposed guidance expresses the CDER’s and the Center for Biologics Evaluation and Research’s (CBER) current thinking regarding benefit-risk assessments, which now includes how patient experience will be used when considering the benefit-risk assessment. Patient experience data can aid critical aspects of a drug development program and the benefit-risk assessment. As part of the Patient-Focused Drug Development and Science of Patient Input initiatives, the FDA is working to advance the development and use of systematic approaches to better incorporate the patient’s voice into drug development and evaluation. Patient preference information (PPI) is another type of patient experience data. PPI is useful to sponsors at various stages of drug development, including the therapeutic context, identifying endpoints, and benefit-risk assessment. The patient experience with their disease or condition provides invaluable feedback regarding medical treatment outcomes throughout the drug’s life cycle.

The proposed FDA guidance on benefit-risk assessment also discusses how sponsors can inform the FDA about the benefit-risk assessment through the design and conduct of a development program, as well as how sponsors may present benefit-risk information in the marketing application. During the development of an NDA or BLA, sponsors can discuss the benefit-risk considerations with the FDA and the FDA’s regulatory decision-making in the postmarket setting.

The FDA’s Benefit-Risk Framework provides a structured, qualitative approach for identifying, assessing, and communicating the factors influencing the benefit-risk assessment (see Figure 1, Benefit-Risk Framework Model).

The first two rows in Figure 1 demonstrate the dimensions of the assessment concerning the therapeutic context (Analysis of Condition and Current Treatment Options), followed by the product-specific rows for the assessment of Benefit and Risk and Risk Management.

The columns distinguish two important inputs to each dimension: the Evidence and Uncertainties that are most relevant to the benefit-risk assessment and the Conclusions and Reasons centered on the evidence and the potential impact of the findings for each dimension.

The Conclusions Regarding Benefit-Risk overview integrates the Evidence and Uncertainties about the drug’s risk-benefit considering the context of the severity of the condition and the unmet needs of the patient.

Figure 1 Benefit-Risk Framework Model

The benefit-risk assessment carefully considers the strength and quality of the evidence available and considers remaining uncertainties. Trial design during product development stages can help identify and avoid uncertainties.

Communication between the sponsor and the FDA regarding the benefit-risk assessment in clinical trials is typically conducted at the end of the Phase 2 study, which can help influence the design of Phase 3 studies, including decisions on study design, selection of appropriate patient populations, enrichment strategies, clinically meaningful endpoints, trial duration, dose-response assessment, and trial sizes. Effectively communicating the drug’s benefits, risks, and uncertainties is important to the benefit-risk assessment that supports regulatory decision-making as part of the sponsor’s NDA or BLA. It is the sponsor’s responsibility to clearly articulate the benefits and risks of the drug, including a discussion of why the benefits exceed the risks.

The sponsor should consider supplementing the benefit-risk assessment by describing the clinical importance of key benefits and risks, including estimates of the statistical uncertainty around the magnitudes of the most important benefits and potential risks, adding a graphical or tabular summary of results, and discussing additional sources of uncertainty about benefits and/or risks.

The proposed guidance is consistent  with the International Council for Harmonization’s (ICH) guidance for industry The Common Technical Document (CTD)—Efficacy (ICH M4E(R2)) (July 2017).


Recent changes in organization, structure, and philosophy at the FDA are a positive sign for the pharmaceutical and biologics industry, with programs like the Benefit-Risk Assessment for New Drug and Biological Products encouraging reminders of that fact. Utilizing patient experience data and patient preference data will help the sponsor and the FDA ensure the Benefit-Risk Assessment considers all stakeholders. Further expanding the channels of communications between manufacturers and the FDA will hopefully build the public’s trust and confidence in the safety and efficacy of new and existing drugs.

About the Author:

Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC, an ASQ Fellow, and SRE Fellow. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications including CRE, CQE, CQA, CSQP, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. Durivage resides in Lambertville, Michigan. Please feel free to email him with any questions or comments.