FDA’s Benefit-Risk guidance: How Benefit-Risk is assessed in new medicines

by | Dec 4, 2023 | Regulatory Affairs

The Food and Drug Administration (FDA) recently published guidance detailing how it assesses benefit-risk when evaluating new drug applications (NDAs) and biologics license applications (BLAs).

How is Benefit-Risk assessed?

Suffice to say, weighing up the purported benefits of a medicine, against the potential risks and side effects is a complex task. Regulators must weigh up all the uncertainties and determine which trade-offs are reasonable with each individual medicinal product assessed. Different subject matter experts will have differing opinions, and fundamentally, regulators must weigh the evidence presented by the sponsor against the current treatment landscape (which also differs from country to country).

The process for determining benefit-risk isn’t standardised across the global board of regulatory authorities. There’s no boilerplate template for evaluating a drug for approval because each NDA/BLA or—in Europe—each new marketing authorization application (MAA) is qualitatively assessed on a multidimensional, case-by-case basis.

However, guidance explaining how the FDA determines a medicine’s benefit-risk is invaluable to medicine developers. When you know what’s expected throughout your product development, and how those expectations will be evaluated in relation to your product’s benefit-risk, you can make informed decisions.

As we’ve said before: forewarned is forearmed.

Therefore, the latest guidance from the FDA is refreshing because it details the medicine benefit-risk assessment process through the lens of the agency.

So, to summarize the FDA Benefit-Risk guidance:

What the FDA considers when assessing benefit-risk

Therapeutic context1

Considerations for the disease you are targeting, including:

  • The nature and severity of the disease,
  • if your product aims to diagnose, prevent or treat, and
  • currently available treatment options.

If your drug or biologic has serious or life-threatening side effects, but its proposed indication is for a rare disease with no currently approved therapeutic alternatives, the FDA may deem the greater risk associated with your product more acceptable given the current therapeutic landscape.

Conversely, the FDA may be less tolerant of serious side effects associated with your product if precedent therapies are already approved with lesser risks.

The evidence you submit1

The documents you submit as part of your NDA/BLA make up in large part, the FDA’s benefit-risk assessment.

So, it stands to reason that the more robust your evidence submitted in the form of clinical, non-clinical quality and patient-specific data, the easier you make the evaluation process for the FDA regulators reviewing your dossier.

Patient experience data1

The FDA makes it quite clear in this guidance the value it places on patient experience, stating that:

“Patients are experts in the experience of their disease.” 1

And that patients are:

“…the ultimate stakeholders in the outcomes of medical treatment.” 1

The FDA looks specifically at whether relevant patient experience data has been included in your NDA/BLA documentation. Ultimately, the FDA will consider patient perspectives in its judgement of your product’s benefit-risk, which could have implications for your development strategy, e.g., your endpoint selection.

Consequently, the FDA’s guidance suggests that – in addition to traditional clinical relevance – sponsors will be expected to consider patient-focused outcome measurements in the rationale for choosing endpoints.


The FDA remarks that uncertainties regarding benefits and risks are “inevitable”.1 However, uncertainty is a consideration that requires careful assessment and expert regulatory judgment by the FDA.

Some uncertainties listed in the FDA guidance include:1

  • Limits on scientific understanding of the patient population,
  • aspects of your development program or study design (e.g., controls, endpoints and representation of your trial population),
  • limited information collected from patients,
  • proposed risk management strategies that you haven’t studied in clinical trials, and
  • reliability of your estimated benefit-risk due to statistical uncertainty, missing trial data, how accurately you minimised confounding or bias in your clinical trials, etc.

So, it’s in your best interests to prove to the FDA that you designed your product’s development program to collect the most robust data in every measurable aspect as it relates to the disease and populations you are targeting—in particular, as it pertains to the specific uncertainties listed in the guidance.

Regulatory options

The FDA employs several methods to reduce the level of uncertainty when assessing a product’s benefit-risk, including:1

  • Amendments and additions to your product labelling (boxed warnings, limitations of use and additional contraindications),
  • requiring additional clinical safety and/or efficacy studies before approval or in the post-marketing setting, and/or
  • additional clinical studies in sub-populations.

FDA benefit-risk framework1

DimensionsEvidence & uncertaintiesConclusions & reasons
Analysis of condition  
Current treatment options  
Risk & risk management  
Benefit-risk conclusions  
  1. The framework considers the therapeutic landscape to include analyses of the condition itself and current treatment paradigms.
  2. Then, the medicinal product is evaluated to analyse the purported benefits and risks, as well as the strengths and limitations of the evidence regarding safety and risk management activities.
  3. Regulators then weigh the evidence supplied, against each of the dimensions, to determine the strengths and uncertainties.
  4. The conclusions incorporate all aspects within the table to evaluate benefit-risk based on the evidence, any uncertainties, the condition’s severity, and the unmet needs of the patient population you are targeting.

Pre-market activities to consider when assessing benefit-risk

The FDA guidance lists the aspects of your development strategy that can impact the benefit-risk assessment, including:1

  • How you defined your target population and any sub-populations,
  • how you identified the unmet need of your target population,
  • how you selected doses for your clinical trials,
  • how you defined key aspects of your clinical study design(s),
  • how you chose your study endpoints, and
  • how you mitigated risks in your clinical trial(s).

Development activities the FDA considers when assessing benefit-risk

1: Are you including benefit-risk planning during drug development?

The FDA encourages medicine developers to “purposefully”1 consider a product’s benefit-risk throughout development. This is especially important if you become aware that:1

  1. your drug or biologic may not have a significant benefit compared to already approved therapies, or
  2. your drug or biologic causes serious adverse events/reactions.

Identifying uncertainties and including benefit-risk planning early in development is important because uncertainties can crop up at any stage. If you have specific benefit-risk planning in place, you can proactively amend your strategy throughout development.

Our expertise lies in helping you to interrogate the data you have, and then provide expert advice on how to position the benefits and risks in the context of your regulatory engagements.

 2: Have you been interacting with the FDA during your drug’s development?

This is interesting because although this is an FDA guidance, this consideration directs you as a medicine developer, to the implications of regulatory interactions with the FDA during development.

Specifically, the FDA guidance highlights the importance of having an End of Phase 2 (EOP2) meeting, as this will generally be at a critical period in your development when potential safety concerns present themselves in your preclinical or early clinical data.

This is also the stage in development when you may be designing your pivotal clinical trial to support an NDA/BLA filing. So, getting feedback from the FDA on the design of your pivotal trial could impact the benefit-risk assessment when you file your NDA/BLA.

3: Have you been including patient experience data?

Again, we see the FDA reiterate the importance of patient experience data needing to be incorporated into your development design.

And again, it’s reiterated that patient experience data will play a role in determining how clinically relevant your chosen endpoints are.

How patient experience data is considered by the FDA:1

  • considered in the clinical relevance of endpoint selection,
  • identify unmet patient needs and intended patient population, and
  • patient preference information: which attributes of your product are important to patients?

4: Have you conducted additional analyses?

Certain analyses may be important with regard to the benefit-risk assessment in cases where there are a lot of uncertainties in your development and/or product, or when you become aware of benefit-risk issues later on in development.

The FDA guidance lists some of the additional analyses you can conduct:1

  • Estimate further benefit/risk outcomes that weren’t measured in your clinical trial(s),
  • modelling studies for benefit-risk that you might expect in a real-world setting, and/or
  • combined analyses integrating benefits and risks or incorporating information about benefit and risk trade-offs.

5: How do you plan to present your drug’s benefit-risk considerations when you file your NDA/BLA?

Essentially, the main source of information the FDA will use to determine the benefit-risk assessment of your product is your NDA/BLA dossier.

This will include your ‘Integrated summary of the benefits and risks of the drug.’1

The FDA guidance lists specific information you can provide to make the benefit-risk assessment easier for regulators, including:1

  • Discuss the gravity of the treatment effects, clinical meaningfulness and the nature of effects of your product,
  • discuss statistical uncertainty in magnitude of the most important benefits/risks, and
  • discuss any differences in the clinical trials vs real-world use of your product.


The FDA guidance on Benefit-Risk signals a shift towards a more structured and patient-centred approach to evaluating a medicine’s benefit-risk assessment.

The FDA offers clear guidance on how the Benefit-Risk Framework is used to evaluate different dimensions of your product and the medical condition you are targeting. Using the Benefit-Risk Framework, the FDA also instructs you on what is expected of you as a medicine developer to integrate benefit-risk evaluation throughout your development programme.

How Somerville Development Partners can help

We have supported numerous regulatory submissions and can advise how to use the data you have available to best effect – whether as company positions in a briefing book or as a discussion of the data in Module 2.

We will:

  1. Build a foundational understanding of your product and data, so that we can act as a strategic partner and proactively look out for your best interests,
  2. support specific deliverables (agency interactions, marketing applications, PRIME, BTD and others), and
  3. support you in developing a longer-term regulatory strategy which takes account the regulatory precedent and therapeutic space.

Get in touch

We welcome the opportunity to discuss scientific advice and regulatory strategy with you!



Nicole Brooks, Regulatory Consultant / Copywriter


The Food and Drug Administration (2023). Benefit-Risk Assessment for New Drug and Biological Products. Guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/benefit-risk-assessment-new-drug-and-biological-products