Benefit-Risk 
Assessment for New 
Drug and Biological 
Products 
Guidance for Industry 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 
October 2023 
Clinical/Medical 
 
 
   
Benefit-Risk 
Assessment for New 
Drug and Biological 
Products 
Guidance for Industry
 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
and/or 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
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Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances    
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research (CBER) 
Center for Drug Evaluation and Research (CDER) 
 
October 2023 
Clinical/Medical  
  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  FDAS APPROACH TO THE BENEFIT-RISK ASSESSMENT OF NEW DRUGS 
AND BIOLOGICS ........................................................................................................................ 3 
A.  Regulatory Background ................................................................................................................ 3 
B.  FDAs Benefit-Risk Framework ................................................................................................... 7 
III.  IMPORTANT CONSIDERATIONS FOR FDAS PREMARKET BENEFIT-RISK 
ASSESSMENT OF DRUGS AND BIOLOGICS ....................................................................... 9 
A.  Overview of Important Considerations ....................................................................................... 9 
B.  The Impact of Uncertainty on Benefit-Risk Assessment .......................................................... 11 
C.  The Role of Patient Experience Data in FDAs Benefit-Risk Assessment .............................. 12 
IV.  ACTIVITIES THAT OCCUR IN PREMARKET DEVELOPMENT THAT 
INFORM BENEFIT-RISK ASSESSMENT ............................................................................. 14 
A.  Structured Benefit-Risk Planning During Drug Development ................................................ 14 
B.  Appropriate Interactions Between a Sponsor and FDA During Drug Development to 
Inform Benefit-Risk Planning ............................................................................................................. 17 
C.  Collecting Patient Experience Data During Development to Inform Benefit-Risk Assessment
  18 
D.  Conducting Additional Analyses to Inform Benefit-Risk Assessment .................................... 19 
E.  Presenting Benefit-Risk Considerations in the Marketing Application .................................. 20 
V.  BENEFIT-RISK ASSESSMENT CONDUCTED IN THE POSTMARKET 
SETTING ..................................................................................................................................... 22 
  Contains Nonbinding Recommendations 
 
Benefit-Risk Assessment for New Drug and Biological Products 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
The intent of this guidance is to clarify for drug2 sponsors and other stakeholders how 
considerations about a drugs benefits, risks, and risk management options factor into certain 
premarket and postmarket regulatory decisions that the Food and Drug Administration (FDA or 
Agency) makes about new drug applications (NDAs) submitted under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(b) as well as biologics 
license applications (BLAs) submitted under section 351(a) of the Public Health Service Act 
(PHS Act).3  This guidance first articulates important considerations that factor into the Center 
for Drug Evaluation and Researchs (CDER) and the Center for Biologics Evaluation and 
Researchs (CBER) benefit-risk assessments, including how patient experience data4 can be used 
to inform the benefit-risk assessment.  It then discusses how sponsors can inform FDAs benefit-
risk assessment through the design and conduct of a development program, as well as how they 
may present benefit and risk information in the marketing application.  It also discusses 
 
1 This guidance has been prepared by the Office of Strategic Programs in the Center for Drug Evaluation and 
Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug 
Administration. 
2 For the purposes of this guidance, unless otherwise specified, all references to drugs include human drug products 
and biological products other than drug products or biological products that also meet the definition of a device in 
section 201(h) of the FD&C Act (21 U.S.C. 321(h)). 
 
3 For the purposes of this guidance, biologics license applications and BLAs refer to BLAs submitted under section 
351(a) of the PHS Act (42 U.S.C 262(a)).  BLAs submitted under section 351(k) of the PHS Act (i.e., applications 
for biosimilar or interchangeable biosimilar products) are outside the scope of this guidance. 
 
4 The term patient experience data includes data that (1) are collected by any persons (including patients, family 
members and caregivers of patients, patient advocacy organizations, disease research foundations, researchers, and 
drug manufacturers), and (2) are intended to provide information about patients experiences with a disease or 
condition, including: (A) the impact (including physical and psychosocial impacts) of such disease or condition, or a 
related therapy on patients lives; and (B) patient preferences with respect to treatment of such disease or condition.  
This definition is found in section 569C(c) of the FD&C Act, (codified at 21 U.S.C. 360bbb-8c) and is referred to in 
section 3002 of the 21st Century Cures Act, which directed FDA to issue certain guidance documents regarding the 
collection of patient experience data (see section 3002(b) of the 21st Century Cures Act). 
  1 Contains Nonbinding Recommendations 
 
opportunities for interaction between FDA and sponsors to discuss benefit-risk considerations in 
connection with the development of an NDA or BLA.  This guidance concludes with additional 
considerations on benefit-risk assessments that inform regulatory decision-making in the 
postmarket setting.   
 
This guidance pertains to benefit-risk assessments made to support certain regulatory decisions 
about NDAs or BLAs, from premarket approval through the postmarket setting.  This includes 
decisions regarding any regulatory requirements for approval, such as inclusion of a boxed 
warning in approved labeling, postmarketing study requirements and commitments, and risk 
evaluation and mitigation strategies (REMS).5  These regulatory decisions are made in 
accordance with specific, applicable legal and regulatory authorities and criteria.6  This guidance 
touches on some of these authorities but does not attempt to list or address them all.   
 
This guidance does not directly address other regulatory decisions that may occur throughout the 
drug development lifecycle, such as decisions regarding first-in-human trials of an 
investigational new drug and expanded access applications,7 which also may require FDA to 
consider information about the benefits and risks of an investigational or marketed drug for its 
proposed use.  However, the concepts discussed in this guidance may also be relevant to these 
other types of decisions.  
 
The Agency developed this guidance document in accordance with goals associated with the 
sixth authorization of the Prescription Drug User Fee Act (PDUFA VI) under Title I of the FDA 
Reauthorization Act of 20178 and requirements under section 3002(c)(8) of the 21st Century 
Cures Act to issue guidance relating to using relevant patient experience data and related 
information to inform regulatory decision-making.9  This guidance draws from, and is consistent 
with, the International Council for Harmonizations (ICH) guidance for industry M4E(R2): The 
Common Technical Document (CTD)Efficacy (ICH M4E(R2)) (July 2017).10 
 
 
5 More information on REMS is available at FDAs Risk Evaluation and Mitigation Strategies REMS web page, 
available at https://www.fda.gov/drugs/drug-safety-and-availability/risk-evaluation-and-mitigation-strategies-rems. 
 
6 See, e.g., sections 505-1 and 505(o)(3) of the FD&C Act (REMS and PMRs, respectively), 21 CFR 201.56, and 21 
CFR 201.57 (labeling). 
 
7 More information on expanded access is available at FDAs Expanded Access web page: 
https://www.fda.gov/news-events/public-health-focus/expanded-access. 
 
8 This guidance satisfies the goal under section I.J.2.c. of the PDUFA Reauthorization Performance Goals and 
Procedures Fiscal Years 2018 Through 2022 (goals letter) to publish guidance on benefit-risk assessment for new 
drug and biological products, available at https://www.fda.gov/industry/prescription-drug-user-fee-
amendments/pdufa-vi-fiscal-years-2018-2022. 
 
9 This guidance addresses a requirement in section 3002(c)(8) of the 21st Century Cures Act, available at 
https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf. 
 
10 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
  2 Contains Nonbinding Recommendations 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.   
 
 
II.  FDAS APPROACH TO THE BENEFIT-RISK ASSESSMENT OF NEW DRUG 
AND BIOLOGICAL PRODUCTS 
 
A.  Regulatory Background 
 
Under the FD&C Act, for a new drug to be approved for marketing in the United States, FDA 
must determine that the drug is safe and effective for use under the conditions prescribed, 
recommended, or suggested in the products labeling.11  The demonstration of effectiveness 
under this standard requires substantial evidence that the drug will have the effect it purports or 
is represented to have.12, 13  Because all drugs can have adverse effects, the demonstration of 
safety requires a showing that the benefits of the drug outweigh its risks.   
 
Benefit-risk assessment is thus integrated into FDAs regulatory review of marketing 
applications for new drug and biological products.14  Broadly speaking, benefit-risk assessment 
in FDAs drug regulatory context is making an informed judgment as to whether the benefits 
(with their uncertainties) of the drug outweigh the risks (with their uncertainties and approaches 
 
11 See section 505(d) of the FD&C Act.  Under section 351 of the PHS Act (42 U.S.C. 262) licenses for biological 
products have been issued only upon a showing that the products are safe, pure, and potent.  Potency has long 
been interpreted to include effectiveness (21 CFR 600.3(s)).  FDA has also generally considered substantial 
evidence of effectiveness to be necessary to support licensure. 
 
12 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)).  The substantial evidence standard refers to both the 
quality and the quantity of the evidence that the drug will have benefit.  See the May 1998 guidance for industry 
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.  The Agency has also 
published a draft guidance for industry on this topic entitled Demonstrating Substantial Evidence of Effectiveness for 
Human Drug and Biological Products (December 2019).  When final, this guidance will represent the FDAs 
current thinking on this topic. 
 
13 Biological products are subject to provisions in both the FD&C Act as well as the PHS Act.  Biologics license 
applications have to meet applicable requirements in the PHS Act to ensure the continued safety, purity, and potency 
of the product (see section 351 of the PHS Act; see also 21 CFR parts 600, 601, and 610). 
 
14 Section 905 of the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law 112-144), 
amends section 505(d) of the FD&C Act by requiring FDA to: 
implement a structured risk-benefit assessment framework in the new drug approval process to 
facilitate the balanced consideration of benefits and risks, a consistent and systematic approach to 
the discussion and regulatory decision-making, and the communication of the benefits and risks of 
new drugs.  Nothing in the preceding sentence shall alter the criteria for evaluating an application 
for premarket approval of a drug. 
 
  3 Contains Nonbinding Recommendations 
 
to managing risks) under the conditions of use described in the approved product labeling.15  
Making an informed judgment that a drug has a favorable benefit-risk assessment requires 
determining that the drugs benefits and risks are sufficiently characterized and that the benefits 
to the intended population will outweigh the risks if the product is approved.  FDAs benefit-risk 
assessment of a product for its proposed indication is a case-specific determination that requires 
a thorough assessment of the extensive evidence of safety and effectiveness submitted by a 
sponsor in an NDA or BLA, as well as a thorough understanding of the data gaps.  It also 
requires careful consideration of a complex set of factors, including the nature and severity of the 
condition the drug is intended to treat or prevent, the benefits and risks of other available 
therapies for the condition, and any risk management tools that might be necessary to ensure that 
the benefits of the drug outweigh its risks.  
 
The benefit-risk assessment for a new drug can be straightforward in cases when a drugs benefit 
is established as clinically meaningful and the drugs safety profile is well-characterized with no 
serious risks identified.  The benefit-risk assessment becomes more challenging in cases where 
the potential for serious risks is identified or expected to exist, e.g., risks that are life-threatening 
or associated with significant morbidity.  In cases where serious risks are anticipated, certain 
findings may nevertheless weigh in favor of a favorable benefit-risk assessment.  The following 
are illustrative examples of circumstances that may support FDAs determination in support of 
approval in such cases:  
 
  Demonstrating direct and meaningful benefit of the drug on the most important clinical 
outcomes for a serious or life-threatening disease or condition.   
 
  Determining that the drug represents a specific important advantage over currently 
available therapies (e.g., is effective in patients who do not respond to available therapies, 
or treats an important clinical outcome not addressed by current therapies).  
  
  Demonstrating that adequate measures can be implemented to mitigate risks in the 
postmarket setting.   
 
  Identifying a subpopulation (e.g., characterized by age, disease severity, genetic, 
pathophysiologic, or medical history) for whom the benefits outweigh the risks even if 
they do not do so in a broader population, and then targeting the drugs labeled indication 
to that population.   
 
  Determining that a lower dose of the drug, compared to a higher dose, maintains 
meaningful benefit to patients, with a more acceptable risk profile.   
 
  Determining that patients and their providers can adequately assess the drugs benefit 
(e.g., symptom relief) early in the course of treatment such that a patient who is not 
 
15 This definition is consistent with principles outlined in ICH M4E(R2), including the ICH definition of terms such 
as key benefit and key risk.  
 
  4 Contains Nonbinding Recommendations 
 
obtaining meaningful benefit can discontinue treatment and thereby reduce exposure to 
the risk. 
 
At times, there may be a tension between FDAs benefit-risk assessment, which takes into 
account the intended patient population as a whole, versus the individual assessment that a 
healthcare provider and patient may make considering a patients specific circumstances and 
condition.  For example, FDA may conclude that if a drug were to be approved, the expected 
frequency of serious adverse events in the overall intended population would outweigh the 
demonstrated benefits of the drug, even if some patients might be willing to accept such risks 
when considering their individual circumstances.  This determination may occur, for example, 
when the beneficial effects of a drug are modest or highly variable in the population and 
prediction or mitigation of serious, irreversible adverse events is difficult.  However, when it is 
possible to identify patients who are most likely to experience the greatest benefit, the least risk, 
or both, the benefit-risk assessment for the intended population is more likely to be found 
favorable.  In such a situation, the product labeling would need to adequately describe the 
benefits and risks, including the differences in response across the approved subpopulations, as 
appropriate, thereby facilitating individual benefit-risk treatment decision-making by healthcare 
providers and patients.  
 
In certain circumstances, FDAs benefit-risk assessment incorporates broader public health 
considerations for both the intended patient population and others.  For example, in the review of 
drugs, including vaccines, to diagnose, prevent, or treat communicable diseases, risks related to 
disease transmission are important considerations.  Similarly, for drugs identified as controlled 
substances, 16 FDAs benefit-risk assessment incorporates considerations such as risks related to 
misuse or accidental exposure in the intended population and in other populations who may have 
access to the drug.  
 
FDAs benefit-risk assessment comprises a case-specific, multi-disciplinary assessment of 
science and medicine, which considers: 
 
  The therapeutic context in which the drug will be used, including the nature and 
severity of the disease or condition the drug is intended to prevent, treat, cure, mitigate, 
or diagnose, and how well patients needs are being met by currently available 
treatments.  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.  Greater risk may be more acceptable if there are no available 
therapies or when a specific important unmet need had been identified, for example, in 
 
16 For example, FDAs draft guidance for industry Opioid Analgesic Drugs: Considerations for Benefit-Risk 
Assessment Framework (June 2019), explains that, because of the widespread misuse and abuse of prescription 
opioid analgesic drugs, for this class of drugs, FDA . . . considers the broader public health effect of opioid analgesic 
drugs; this involves consideration of the risks related to misuse, abuse, opioid use disorder, accidental exposure, and 
overdose, for both patients and others.   When final, this guidance will represent the FDAs current thinking on this 
topic.   Section 3001 of the SUPPORT for Patients and Communities Act (Public Law 115-271) recognizes that 
FDA may incorporate the risks of misuse and abuse of a controlled substance (as defined in section 102 of the 
Controlled Substances Act (21 U.S.C. 802)) into the benefit-risk assessments under subsections (d) and (e) of 
section 505 of the FD&C Act (21 U.S.C. 355), section 510(k) of the FD&C Act (21 U.S.C. 360(k)), or section 
515(c) of the FD&C Act (21 U.S.C. 360e(c)), as applicable.   
  5 Contains Nonbinding Recommendations 
 
patients who do not respond to available treatments.  FDA is likely to have a lower 
tolerance for potential serious risks or toxicities when a drug is intended to treat 
conditions for which many treatment options with lesser risks are available, or when it 
evaluates preventative medicines, where the intended population may be healthy people.  
 
  The evidence submitted in the premarket application and/or generated in the postmarket 
setting that informs FDAs understanding of the benefits and risks of the drug.  Sources 
of evidence include clinical data, non-clinical data, patient experience data, product 
quality information,17 spontaneous reports of adverse events, and epidemiologic data.  
Such data may have been collected specifically to address questions regarding the 
benefits and risks of the drug or routinely collected from a variety of real-world 
sources.18 
 
  The uncertainties about the drugs benefits and risks.  Although uncertainty can be 
reduced through careful study design and conduct, some uncertainty in the body of 
evidence available at the time of regulatory decision-making is inevitable, e.g., the 
frequency of rare serious adverse events or whether the drugs effectiveness persists in 
long-term use.  With appropriate consideration of this uncertainty, the Agency uses 
scientific assessment and regulatory judgment to determine whether the drugs benefits 
outweigh the risks, and whether additional measures or additional data are needed and 
able to address or mitigate this uncertainty.  Uncertainty in the benefit-risk assessment is 
discussed further in section III.B below. 
 
  FDAs regulatory options to manage risks and to further reduce uncertainties.  
Examples of regulatory options to manage risk include, but are not limited to, product 
labeling (e.g., adding contraindications, limitations of use, a boxed warning, warnings 
and precautions in the Prescribing Information, requiring a new (or updating an existing) 
Medication Guide) or REMS. Examples of regulatory options to reduce uncertainties 
include, but are not limited to, requirements for additional clinical studies conducted 
premarket or postmarket to further characterize safety, effectiveness, or dose-response, 
generally or in a specific sub-population; additional product quality information; and 
postmarket observational studies. 
 
 
 
17 For more information on benefit-risk principles applied by FDA when conducting product quality-related 
assessments of chemistry, manufacturing, and controls (CMC) information, see the draft FDA guidance document 
for industry Benefit-Risk Considerations for Product Quality Assessments (May 2022) available at: 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/benefit-risk-considerations-product-
quality-assessments.  Additionally, MAPP 5015.13  Quality Assessment for Products in Expedited Programs 
(December 2022) available at: https://www.fda.gov/media/162786/download describes considerations and 
flexibilities for products that address unmet medical needs in the treatment of serious or life-threatening conditions. 
 
18 More information on real world data (RWD) and real-world evidence (RWE) is available in the December 2018 
Framework for FDA's Real-World Evidence Program at https://www.fda.gov/media/120060/download, and in 
FDA guidance documents on RWD and RWE available at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents. 
 
  6 Contains Nonbinding Recommendations 
 
   
B.  FDAs Benefit-Risk Framework 
 
FDAs vehicle for conducting and communicating its benefit-risk assessments is the Benefit-
Risk Framework for new drug review.19  The Benefit-Risk Framework (Figure 1) provides a 
structured, qualitative approach for identifying, assessing, and communicating the important 
considerations that factor into the benefit-risk assessment:   
 
  The first two rows in Figure 1 outline the important dimensions of the assessment 
concerning the therapeutic context, including 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 pertinent to the benefit-risk assessment and the Conclusions 
and Reasons based on the evidence and its strength, and the potential significance of the 
findings for each dimension.  Evidence and uncertainties are relevant not only to the 
benefits and risks of the drug but also to the analysis of condition and current treatment 
options.   
 
  Finally, the Conclusions Regarding Benefit-Risk overview integrates the evidence and 
uncertainties about the drugs benefits and risks and considers them in the context of the 
severity of the condition and the patients current unmet needs.   
 
19 Information on development of the Benefit-Risk Framework is provided in FDAs 2013 PDUFA V 
Implementation Plan, Structured Approach to Benefit-Risk Assessment in Drug Regulatory Decision-Making, 
available at https://www.fda.gov/media/84831/download and FDAs 2018 PDUFA VI Implementation Plan, 
Benefit-Risk Assessment in Drug Regulatory Decision-Making, available at 
https://www.fda.gov/media/112570/download. 
  7 Contains Nonbinding Recommendations 
 
Figure 1.  FDAs Benefit-Risk Framework for New Drug Review 
 
 
 
FDA currently includes the Benefit-Risk Framework in its NDA and BLA review training, 
processes, and templates to support the conduct and communication of its benefit-risk 
assessment.  CBER incorporates benefit-risk assessment through interdisciplinary review, and 
since 2013 has integrated the Benefit-Risk Framework into its clinical review template for its 
new BLA and supplement assessments.  CDER has integrated the Benefit-Risk Framework into 
its clinical review and decisional memo templates since 2015.  In 2019, as part of the New Drugs 
Regulatory Program Modernization,20 CDER developed a new integrated review process and 
template21 for its marketing application (NDA and BLA) assessments.  This template includes 
interdisciplinary, issue-based sections that highlight important issues and address their impact on 
benefit and risk.  The template also presents the Benefit-Risk Framework as a component of 
section 1., Executive Summary.22, 23  
 
20 More information on the New Drugs Regulatory Program Modernization is available at: 
https://www.fda.gov/drugs/regulatory-science-research-and-education/modernizing-fdas-new-drugs-regulatory-
program. 
 
21 This new process and template was announced in the Federal Register of June 27, 2019 (84 FR 30733), New 
Drugs Regulatory Program Modernization: Improving Approval Package Documentation and Communication, 
available at https://www.federalregister.gov/documents/2019/06/27/2019-13751/new-drugs-regulatory-program-
modernization-improving-approval-package-documentation-and. 
 
22 Information on how the Benefit-Risk Framework is incorporated into the review process is available in FDAs 
2018 PDUFA VI Implementation Plan, Benefit-Risk Assessment in Drug Regulatory Decision-Making, available 
at https://www.fda.gov/media/112570/download. 
 
23 Publicly-available review documentation for approved NDAs and BLAs is available on FDAs website: at 
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm (drugs and biologics); https://www.fda.gov/vaccines-
blood-biologics/vaccines/approved-vaccine-products (vaccine products); https://www.fda.gov/vaccines-blood-
 
  8 Contains Nonbinding Recommendations 
 
 
FDAs thinking on a drugs benefits and risks is often a topic discussed at product-specific 
advisory committee meetings.24  FDA may use the Benefit-Risk Framework to communicate 
important considerations on the drugs benefit-risk assessment to the committee or to the public. 
 
 
III.  IMPORTANT CONSIDERATIONS FOR FDAS PREMARKET BENEFIT-RISK 
ASSESSMENT OF DRUG AND BIOLOGICAL PRODUCTS 
 
A.  Overview of Important Considerations 
 
As evident from the multiple dimensions of the Benefit-Risk Framework, FDAs benefit-risk 
assessment integrates many different considerations.  Table 1 provides examples of 
considerations that may be included in an assessment.  These examples are not intended to be a 
full or comprehensive list of all considerations.  The relevance and relative importance of any 
consideration depends on the specific details of the application. 
 
Table 1: Examples of Important Considerations for FDAs Premarket Benefit-Risk 
Assessment of NDAs, BLAs, and Efficacy Supplements 
Benefit-Risk  Important Considerations 
Framework   
Dimension 
Analysis of   Context of use for proposed indication: intended medical use, intended patient 
Condition  population, aspects of the condition that the treatment is targeting (e.g., symptom 
burden)  
 Aspects of the indicated condition that are most relevant to, or have the greatest impact 
on, the intended population (e.g., incidence, duration, disease progression, morbidity, 
symptoms, impact on patient functioning, mortality, health-related quality of life, 
important differences in outcome or severity in subpopulations) 
 Public health implications of the disease 
Current   Understanding of current FDA-approved treatments and standard of care, including 
Treatment  their efficacy, safety, tolerability, and other limitations (e.g., subpopulations who do 
Options  not respond to or do not tolerate treatment, curative versus palliative intent) 
 Effectiveness and safety of other interventions used for the intended population, such 
as drugs used off-label or nondrug interventions 
 Patients medical need for a new therapy in terms of efficacy, safety, tolerability, 
burden of existing treatments, etc. 
Benefit   Strengths/limitations of clinical trials, including design, and potential implications for 
assessing drug efficacy  
 Clinical relevance of the study endpoints: ability to measure or predict clinical 
outcomes of importance to patients  
 Description of the clinical benefits, including but not limited to: 
 
biologics/approved-blood-products/approved-new-drug-applications-ndas-and-abbreviated-new-drug-applications-
andas-supporting-documents (blood products); and https://www.fda.gov/vaccines-blood-biologics/cellular-gene-
therapy-products/approved-cellular-and-gene-therapy-products (cellular and gene therapy products) 
 
24 More information on FDAs advisory committees is available at: https://www.fda.gov/advisory-committees. 
  9 Contains Nonbinding Recommendations 
 
Benefit-Risk  Important Considerations 
Framework   
Dimension 
o Nature of the effect (e.g., survival, slowing disease progression, reduction of serious 
outcomes, reduction of symptoms, relevance of symptomatic benefit to patients) 
o Effect size and associated uncertainty (e.g., a confidence interval), including an 
interpretation of clinical importance  
o The distribution of treatment effects in the clinical trial population (e.g., presence of 
patients who experience a more substantial benefit such as long-term survival or 
marked improvement in symptoms, even if the mean response is modest)   
o Time course and durability of effect 
o Benefit attributed to the drug when studied in combination with other therapies 
o Defined subpopulations achieving a greater magnitude of benefit  
 Benefit to a subpopulation where there is a specific unmet need (e.g., patients who 
have not responded adequately to available therapies) 
 Generalizability of the demonstrated benefits to all populations likely to be prescribed 
the drug (e.g., older patients or patients with co-morbidities not extensively studied in 
the clinical trials)   
 Important characteristics of the drug (e.g., a less burdensome dosing regimen, dosing 
preparation, or route of administration)  
Risk and Risk   Strengths/limitations of the evidence regarding safety, and potential implications for 
Management  assessing drug risks (e.g., due to limited database size and/or exposure duration, 
missing important subpopulations) 
 Observed adverse events or safety signals and their clinical importance, including: 
o Severity of the adverse event, the likelihood of its occurrence, reversibility, and the 
estimate of the effect size and its uncertainty (e.g., a confidence interval) 
o Ability to predict, monitor for, and/or prevent the adverse event 
o Impact of adverse events on drug tolerability and/or adherence, and the potential 
consequences 
 Level of certainty for a causal association between drug exposure and risk  
 Potential impact of product quality issue(s) that could negatively impact the drugs 
safety or effectiveness, including quality considerations that would need to be 
monitored postmarket  
 Anticipated differences in safety that could occur in postmarketing compared with the 
clinical trial setting (e.g., because of less likelihood of appropriate monitoring, or use in 
patients who may be at higher risk of the safety event) 
 Potential for misuse or accidental exposure, and associated adverse consequences  
 Likely effectiveness of proposed approaches to managing risks (e.g., evidence from 
clinical trials that steps can be taken to reduce the risk) 
Conclusions   Overall conclusions about the quality and strength of evidence and the remaining 
Regarding  uncertainties regarding benefits and risks  
Benefit-Risk   How therapeutic context affects the assessment of benefits, risks, and uncertainties  
 Relative importance of the benefits and risks in the overall indicated population, which 
also considers patient perspectives 
 The time course over which the benefits and risks occur (e.g., considering adverse 
events that may occur shortly after initiation for benefits that may take years to accrue) 
 Ability of patients and providers to clearly assess the drugs benefits or risks (e.g., by 
assessing their symptom relief, monitoring for a biomarker change), thereby informing 
treatment decisions (e.g., to discontinue drug if adequate response is not achieved)   
  10  Contains Nonbinding Recommendations 
 
Benefit-Risk  Important Considerations 
Framework   
Dimension 
 Whether patients more or less likely to experience serious adverse events are also more 
or less likely to experience meaningful benefit (e.g., if adverse events reflect on-target 
pharmacology) 
 Whether the benefits and risks can be adequately communicated in product labeling to 
support informed individual benefit-risk assessments by patients and providers 
 Whether certain labeling (e.g., adding contraindications, limitations of use, a boxed 
warning, warnings and precautions in the Prescribing Information; requiring a new (or 
updating an existing) Medication Guide) and/or REMS is necessary to support a 
favorable benefit-risk assessment 
 Whether a postmarketing study or clinical trial is necessary to assess a known serious 
risk, a signal of a serious risk, or to identify an unexpected serious risk when available 
data indicates the potential for a serious risk. 
 
B.  The Impact of Uncertainty on Benefit-Risk Assessment 
 
FDAs benefit-risk assessment carefully considers the strength and quality of the evidence 
available and takes remaining uncertainties into account in every dimension of the Benefit-Risk 
Framework.  Uncertainties that can affect benefit-risk assessments may include, but are not 
limited to: 
 
  Limits on scientific understanding of the patient population and natural history of the 
condition, e.g., due to heterogeneity of disease manifestations and progression in the 
patient population, or lack of identification of risk factors or prognostic biomarkers. 
 
  Aspects of the program or study design, such as the subgroup representation and diversity 
of the trial population, choice of controls, endpoints, and data sources, as well as any 
anticipated differences between the investigational and real-world use. 
 
  Reliability of the estimates of benefit or risk based upon variability in estimated effects 
due to sampling (i.e., statistical uncertainty), issues with trial conduct (e.g., missing data, 
poor study protocol compliance), or adequacy of measures taken to minimize study bias 
or confounding (e.g., randomization, blinding). 
 
  Limited understanding of the effects of the drug that may be used in combination with 
existing therapies (e.g., potential beneficial adjunctive effect, potential for adverse drug-
drug interactions). 
 
  Proposed risk management strategies, such as patient monitoring, that have not been 
studied in clinical trials, or that have been studied in clinical trials but would be 
potentially difficult to implement in practice. 
 
  Limited information collected from patients on disease burden and unmet medical needs, 
meaningfulness of potential benefits, and acceptability of risk tradeoffs and uncertainty. 
  11  Contains Nonbinding Recommendations 
 
 
  Introduction of a novel technology or control strategy in the drugs manufacturing 
process, or other potential issues regarding the product quality, formulation, or 
manufacturing. 
 
Many sources of uncertainty can be anticipated and potentially avoided with careful attention to 
trial design and trial conduct during product development stages, as discussed further in section 
IV.  At other times, uncertainties become apparent only after the trial evidence has been 
generated, such as the appearance of an unexpected safety signal.  In such cases, identifying 
information to address these uncertainties becomes particularly important to support the benefit-
risk assessment. 
 
Therapeutic context plays an important role in FDAs assessment of the acceptability of 
uncertainty.  For a drug intended to treat a serious disease with unmet needs, FDA may accept 
greater uncertainties about benefit or risk at the time of approval, for example through the 
accelerated approval pathway.25  In other situations, such as in the case of a drug that is intended 
to treat a non-serious disease and for which other therapeutic options exist, FDA would not be 
likely to accept as much uncertainty regarding either benefit or risk.   
 
A higher degree of uncertainty is common in drug development programs for rare diseases, 
where the prevalence of disease, and consequent limitations of study size, can limit the precision 
of safety and efficacy characterizations.  FDA recognizes that when a drug is developed to treat 
serious diseases for which there are few or no approved therapies, greater uncertainty or greater 
risks may be acceptable provided that the standard for substantial evidence of effectiveness has 
been met.  In the case of serious rare diseases, FDA may thus exercise regulatory flexibility by 
accepting clinical trials that have smaller sample sizes.  Accepting smaller sample sizes for 
serious rare diseases places even greater importance on maximizing the trials potential to 
provide interpretable scientific evidence about the drugs benefits and risks in order to be 
respectful of patients willingness to participate in clinical trials.  Patient contribution is 
optimized in clinical trials (and particularly in small sample size studies) by minimizing bias and 
maximizing precision with trial design features such as randomization, blinding, enrichment 
procedures, and adequate trial duration.26  
 
C.  The Role of Patient Experience Data in FDAs Benefit-Risk Assessment 
 
FDA recognizes the importance of enabling meaningful patient input to inform drug 
development and regulatory decision-making, including in the context of FDAs benefit-risk 
assessment.  Patients are experts in the experience of their disease or condition, and they are the 
ultimate stakeholders in the outcomes of medical treatment.  Different types of patient 
 
25 For more information about accelerated approval, see FDAs guidance for industry Expedited Programs for 
Serious ConditionsDrugs and Biologics (May 2014), available at the FDA guidance web page. 
 
26 For further discussion of this issue, see FDAs draft guidance for industry Rare Diseases: Common Issues in Drug 
Development (January 2019) in particular, section VII., available at the FDA guidance web page.  When final, this 
guidance will represent the FDAs current thinking on this topic.   
  12  Contains Nonbinding Recommendations 
 
experience data can inform nearly every aspect of FDAs benefit-risk assessment, including 
many of the considerations outlined in Table 1, throughout the drug lifecycle.  For example: 
 
  Therapeutic context, such as: 
o  Impact of the disease and its treatment on the patient 
o  Patients perspectives about available treatments and unmet medical needs 
o  Enhanced understanding of the natural history of the disease or condition, 
including progression, severity, chronicity 
  Potential benefits that are most meaningful 
  Acceptability of benefit and risk tradeoffs and uncertainty 
  Value and burden of risk mitigation efforts  
  Information needs that could be addressed through patient education or communications 
 
As part of the Patient-Focused Drug Development27 and Science of Patient Input28 initiatives, 
FDA is working to advance the development and use of systematic approaches to better 
incorporate the patients voice into drug development and evaluation and has developed a series 
of methodological guidances29 on these approaches.  A primary component of this guidance 
series is to provide a patient-focused outcome measurement approach to clinical outcome 
assessment (COA)30 selection and/or development for clinical trials, including patient-reported 
outcomes (PROs).  Collecting robust patient input on the symptoms or other aspects of their 
condition that matter most to patients can inform and strengthen the rationale for endpoint 
selection, development of COAs, and the overall benefit-risk assessment.  
 
 
27 More information on patient-focused drug development, including a list of condition-specific meeting reports is 
available at https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-
development. 
 
28 More information on the Science of Patient Input initiative is available at https://www.fda.gov/vaccines-blood-
biologics/development-approval-process-cber/center-biologics-evaluation-and-research-patient-engagement-
program. 
 
29 More information on FDAs patient-focused drug development guidance series is available at 
https://www.fda.gov/drugs/development-approval-process-drugs/fda-patient-focused-drug-development-guidance-
series-enhancing-incorporation-patients-voice-medical. 
 
30 Clinical outcome assessment (COA): Assessment of a clinical outcome can be made through report by a clinician, 
a patient, a non-clinician observer, or through a performance-based assessment.  There are four types of COAs: 
patient-reported outcome (PRO), clinician-reported outcome (ClinRO) measures, observer-reported outcome 
(ObsRO), and performance outcome (PerfO).  See, e.g., FDA guidance for industry, FDA staff, and other 
stakeholders Patient-Focused Drug Development: Collecting Comprehensive and Representative Input (June 2020). 
 
  13  Contains Nonbinding Recommendations 
 
If a methodologically sound and fit-for-purpose31 data collection tool(s) is used to collect patient 
experience data in a drug development program, the collected data can provide direct evidence 
regarding the benefits and risks of the drug and their importance to patients.  During premarket 
review, FDA indicates in review documentation whether relevant patient experience data are 
submitted as part of the application, and whether relevant information was not submitted in the 
application but has informed FDA review nonetheless.32  
 
As discussed in section II, FDA must balance the perspectives of patients with the judgments it 
must make regarding overall benefit-risk of a drug to the patient population.  Even if some 
patients may derive benefit from a drug and express the desire for access to a drug, FDA would 
not approve the drug if it concludes that the drug would lead to more harm in the indicated 
population overall  for example, if the drug is associated with significant risk, benefit is likely 
to be minimal for most patients, and there is no way to identify those individuals who might have 
a greater extent of benefit (through the use of biomarkers, baseline characteristics, patient 
history, etc.).  Nonetheless, FDA carefully weighs and considers the patient perspective 
including available patient experience data.  When patients indicate that a benefit is important to 
them in the treatment of their condition, this informs FDAs assessment of the extent of benefit.  
 
 
IV.  ACTIVITIES THAT OCCUR IN PREMARKET DEVELOPMENT THAT 
INFORM BENEFIT-RISK ASSESSMENT 
 
Decisions and activities undertaken by sponsors in the development of their drugs, and the 
evidence generated to support their marketing applications, can have a significant impact on the 
Agencys benefit-risk assessment.  Examples of decisions and activities that may have bearing 
on a benefit-risk assessment include defining the intended patient population and relevant 
subpopulations, identifying unmet needs for these patients, selecting dose(s) for clinical trials, 
defining key features of trial design, selecting study endpoints, and incorporating risk mitigation 
practices into the clinical trial.  It is important to note that these decisions and activities are also 
important in supporting any benefit-risk assessment the sponsor considers within their own drug 
development program.  
 
A.  Structured Benefit-Risk Planning During Drug Development 
 
For the purposes of this guidance, structured benefit-risk planning is defined as a purposeful 
activity carried out by the sponsor to incorporate consideration of the products benefit-risk 
assessment throughout the drug development lifecycle.  Benefit-risk planning is most valuable in 
 
31 Fit-for-purpose: a conclusion that the level of validation associated with a medical product 
development tool is sufficient to support its context of use.  This definition is consistent with the definition of this 
term in the FDA guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug Development: 
Collecting Comprehensive and Representative Input (June 2020). 
 
32 Section 3001 of the 21st Century Cures Act (21 U.S.C. 360bbb-8c (b)(1)) states: Following the approval of an 
application that was submitted under section 355(b) of this title or section 262(a) of title 42 at least 180 days after 
December 13, 2016, the Secretary shall make public a brief statement regarding the patient experience data and 
related information, if any, submitted and reviewed as part of such application. 
  14  Contains Nonbinding Recommendations 
 
cases where a challenging benefit-risk assessment can be reasonably anticipated, either because 
the extent of benefit is expected to be modest or is highly uncertain, or when serious adverse 
events of the drug can be anticipated (e.g., based on a suspected class effect, understanding of the 
mechanism of action, and/or early-phase or non-clinical safety findings).  In cases where serious 
risks are anticipated, it is important to consider whether the risk can be outweighed by a benefit 
of sufficient certainty, magnitude, and clinical relevance to patients.  The goal of benefit-risk 
planning would be to direct drug development toward reducing important uncertainties and to 
increase the likelihood of establishing a favorable benefit-risk assessment of the submitted NDA 
or BLA.  This could be accomplished, for example, by targeting a population that has a higher 
likelihood to benefit from the product (which may require limiting the population to those 
patients who are anticipated to obtain a greater benefit, or who have a greater unmet need), by 
careful selection of doses and endpoints, incorporating risk mitigation practices into the clinical 
trial, or by demonstrating that benefits outweigh the risks to the patient population.  
 
Benefit-risk planning by the sponsor, beginning early in development, can add value by helping 
to ensure that the clinical trial data and other supporting information collected are best suited to 
support the benefit-risk assessment.  Such planning can also support reexamination of the drugs 
benefit-risk assessment and inform potential changes in the development program as new 
evidence is generated throughout development.  In addition to supporting premarketing 
development and evaluation, planning for postmarket benefit-risk assessment during the 
premarket stage can inform approaches to collecting additional information in the postmarket 
setting to further reduce uncertainties. 
 
Benefit-risk planning includes identifying, as early as possible, the most important potential 
benefits and risks of the drug, so that they can be carefully evaluated.  This planning also 
includes careful consideration of how to focus the development program to best inform the 
eventual benefit-risk assessment.  Examples that illustrate this concept include, but are not 
limited to: 
 
  Identification of patients (e.g., utilizing a predictive biomarker or other patient 
characteristics) who are more likely to experience greater expected benefit or less likely 
to experience serious adverse events of the drug, thereby supporting determination of an 
intended population for whom the drug may have a more favorable benefit-risk 
assessment.    
 
  Collection of sufficient data throughout development to inform dose-exposure-response 
relationships for both efficacy and safety/tolerability and integrating this information to 
identify doses that can optimize benefit relative to risk and inform dosing 
recommendations.  
 
  Selection of a primary efficacy endpoint that is a direct measure of how a patient feels, 
functions, or survivesor is a surrogate endpoint for which the relationship between an 
effect on the surrogate endpoint and the clinical outcome of interest is well understoodin 
order to obtain a reliable estimate of and reduce uncertainty about direct patient benefit, 
especially when serious risks may be associated with the drug. 
 
  15  Contains Nonbinding Recommendations 
 
  Using an active control arm in circumstances when it may be critical to ensure that the 
drug does not have an unacceptable benefit-risk assessment compared to an approved, 
alternative therapy. 
 
  Enriching a trial to enable the assessment of benefit in a specific subpopulation (e.g., 
patients who do not respond to or who do not tolerate a standard of care treatment).33 
 
 
  In planning the sample size and duration of a clinical trial, consideration of not only the 
efficacy assessment, but also the degree of precision that will be provided for evaluating 
an anticipated serious risk. 
 
  Prospective collection of data to evaluate a potential serious risk, such as by actively 
ascertaining the occurrence and nature of the adverse event of interest using targeted case 
report form prompts and/or independent adjudication. 
 
  Implementation of appropriate risk mitigation measures into the clinical trial with the 
ability to prevent or monitor for anticipated serious adverse events - in particular, 
measures that can feasibly be implemented if the drug were approved, to provide 
sufficient evidence that the risks can be adequately managed post-approval. 
 
  Determining whether there may be a need for additional patient experience data, possibly 
including patient preference information (see section IV.C.), and additional analyses (see 
section IV.D.) to inform the benefit-risk assessment; if so, developing appropriate data 
collection and analysis plans. 
 
Benefit-risk planning can take many forms throughout the product lifecycle.  For benefit-risk 
planning in the premarket setting, the ICH guidance for industry M4E(R2), section 2.5.6, may 
provide a useful starting point for sponsors.  For benefit-risk planning in the postmarket setting, 
the July 2016 ICH guidance for industry ICH E2C(R2) Periodic Benefit-Risk Evaluation Report 
(PBRER) (ICH E2C(R2)), section 3.18, may provide a useful starting point.34  In addition, 
various qualitative structured approaches and supporting tools tailored for drug development and 
evaluation (e.g., value trees, effects tables, forest plots) have been developed and may be useful 
to support sponsors benefit-risk planning, assessments, and communications with FDA.35  The 
 
33 For more information on developing enrichment strategies that can be used in clinical investigations intended to 
demonstrate effectiveness (and in some cases safety) of human drugs and biological products, see the FDA guidance 
for industry Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological 
Products (March 2019) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/enrichment-strategies-clinical-trials-support-approval-human-drugs-and-biological-products  
 
34 Both of these guidances are available at the FDA guidance web page. 
 
35 Examples are discussed in Hughes, D, E Waddingham, S Mt-Isa, A Goginsky, E Chan, GF Downey, CE 
Hallgreen, KS Hockley, J Juhaeri, A Lieftucht, MA Metcalf, RA Noel, LD Phillips, D Ashby, and A Micaleff, 2016, 
Recommendations for Benefit-Risk Assessment Methodologies and Visual Representations, Pharmacoepidemiol 
Drug Saf, 25(3):251-262.  
 
  16  Contains Nonbinding Recommendations 
 
optimal timing, scope, and level of effort of benefit-risk planning may vary depending on the 
sponsors expectation of the degree of complexity regarding the eventual benefit-risk assessment 
of the marketing application.   
  
B.  Appropriate Interactions Between a Sponsor and FDA During Drug 
Development to Inform Benefit-Risk Planning 
 
FDA can provide insight and regulatory perspective that can inform a sponsors benefit-risk 
planning appropriate to the issues identified at a particular stage of development.  The End of 
Phase 2 (EOP2) meeting is typically a critical timepoint where discussions with FDA on benefit 
and risk considerations may be especially important and can influence the design of phase 3 
studies in ways that can enhance the characterization of the drugs benefits and risks, including 
decisions on study design, selection of appropriate patient populations, enrichment strategies, 
clinically meaningful endpoints, trial duration, dose-response assessment, and trial sizes.  
Thoughtful planning can also enhance the assessment of risk needed to support informed benefit-
risk assessment.  These discussions at EOP2 can be particularly important when preclinical, early 
clinical, or other data identify a potential safety issue that would require greater certainty about 
the drugs benefits and/or risks to support approval. 
 
Although it is important to discuss benefit-risk planning at EOP2, in some situations there may 
be earlier points in a products development when communication between the Agency and the 
sponsor regarding benefit and risk considerations and/or benefit-risk planning would be useful.  
These communications could involve, for example, deliberations regarding the clinical 
meaningfulness of a purported benefit or concern for non-clinical safety signals.  They could also 
involve considerations on the best design to characterize benefits and risks where the population 
is limited or vulnerable, such as for rare or serious diseases or pediatric populations.   
 
Typically, discussion of benefit-risk considerations and benefit-risk planning occurs within the 
standard processes for formal meetings between FDA and sponsors.36  Sponsors can add 
benefit-risk considerations as a proposed agenda item and provide specific questions and 
relevant supplementary information in the meeting package.  Examples of relevant information 
may be a program-wide safety and/or benefit-risk assessment plan, if utilized by the sponsor, or a 
proposal for collecting patient preference information to inform additional benefit-risk analyses, 
if planned (see sections IV.C and IV.D).  The type of input that FDA can provide on benefit and 
risk considerations and/or benefit-risk planning depends on the product, indication, patient 
population, current therapeutic context, stage of product development, and uncertainties 
associated with the benefit, risk, or other development issues.  FDAs input on these topics may 
evolve as more information becomes available throughout development.  FDAs final premarket 
benefit-risk assessment is based on complete information submitted as part of an NDA or BLA. 
 
 
36 See FDAs draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (December 2017), available at the FDA guidance web page.  When final, this guidance will represent the 
FDAs current thinking on this topic. 
 
  17  Contains Nonbinding Recommendations 
 
C.  Collecting Patient Experience Data During Development to Inform Benefit-
Risk Assessment  
 
Patient experience data can help inform critical aspects of a drug development program, and 
benefit-risk assessment more broadly.  For example, patient experience data collected early in the 
development program can help identify unmet patient needs and define the intended patient 
population.  Patient experience data can also inform the assessment of the clinical relevance of 
the study endpoints, that is, to help identify endpoints that measure or predict clinical outcomes 
of importance to patients.  FDA encourages sponsors who are considering collecting and utilizing 
patient experience data as part of their evaluation of effectiveness or safety to have early interactions 
with FDA during the design phase of such studies and obtain feedback from the relevant FDA 
review division on appropriate research design and any applicable regulatory requirements.   
 
In addition to PROs and some other COAs (described in section III. C.), patient preference 
information (PPI)37 is another type of patient experience data.  PPI captures the value that 
patients place on important attributes (e.g., benefits and risks) of the medical product.  PPI is not 
the same as PROs, which measure how patients feel and function.  Well-designed and well-
conducted PPI studies can elicit which attributes are important to patients, how important they 
are, and what tradeoffs patients are willing to make between attributes.  
 
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.  
PPI may be best suited to inform regulatory decision-making when: (1) significant risks of 
treatment or uncertainty about risks exist relative to the expected benefits; (2) patients views 
about the most important benefits and risks vary considerably within a population; and/or (3) 
when patients views as to the most important benefits are expected to differ from those of 
healthcare professionals.  If available, PPI would be considered within the context of FDAs 
assessment of the drugs efficacy and safety to the patient population, although it would not, for 
example, overcome lack of substantial evidence of effectiveness. 
 
Use of a carefully planned, fit-for-purpose PPI study design can increase the ultimate usefulness 
of the PPI.  Before using any approach, sponsors should consider its utility, complexity, the 
extent to which the approach can address the research question and the interpretability of the 
results.  FDA encourages sponsors and other groups who are planning to conduct a patient 
preference study with the goal of informing the benefit-risk assessment to communicate with the 
applicable review division early in the development of the study.  When included in a regulatory 
submission, PPI should be collected through a formal study with pre-specified protocols and 
analysis plans and should include a broad and representative sample of patients.  Additional 
information about patient preference study considerations may be found in section IV. of FDAs 
 
37 Patient preference information (PPI): Assessments of the relative desirability or acceptability to patients of 
specified alternatives or choices among outcomes or other attributes that differ among alternative health 
interventions.  The methods for generating PPI may be qualitative, quantitative, or mixed methods.  For further 
discussion, see FDAs guidance for industry, FDA staff, and other stakeholders Patient-Focused Drug 
Development: Collecting Comprehensive and Representative Input (June 2020). 
 
  18  Contains Nonbinding Recommendations 
 
guidance for industry Patient Preference InformationVoluntary Submission, Review in 
Premarket Approval Applications, Humanitarian Device Exemption Applications, and De Novo 
Requests, and Inclusion in Decision Summaries and Device Labeling (August 2016).38  
 
D.  Conducting Additional Analyses to Inform Benefit-Risk Assessment 
 
Benefit-risk assessment inevitably involves a qualitative, subjective judgment by the Agency that 
weighs data and information about the drugs benefits and risks and considers uncertainties 
within a specific therapeutic and regulatory context.  A qualitative, descriptive approach to 
benefit-risk assessment (e.g., completion of the Benefit-Risk Framework) will be adequate in 
many cases.  In some circumstances, additional benefit-risk analyses to help inform the overall 
benefit-risk assessment may add value.  This may occur in situations involving complex 
tradeoffs between the drugs expected benefit and risks, and/or situations involving significant or 
unexpected uncertainties regarding the drugs benefits and risks.  Although additional benefit-
risk analyses may add value in some situations, they are likely not necessary in all 
circumstances, and such analyses cannot overcome significant issues in a development program, 
such as inadequate assessment of risk mitigation in the clinical trial.   
 
Additional analyses can take various forms, for example: 
 
  Estimation of important clinical benefit and/or risk outcomes that were not directly 
measured or sufficiently assessed in the clinical trial (e.g., estimation of potential long-
term clinical benefit by extrapolating from trial results involving a validated primary 
surrogate endpoint). 
 
  In certain situations (e.g., diagnostics), modeling of benefit and risk outcomes or public 
health outcomes that could be expected in the real-world setting, accounting for aspects 
regarding the patient population or setting of use that may extend upon the clinical trial 
setting (e.g., the public health impacts of false negative diagnoses). 
 
  Integrating benefits and risks in a combined analysis and/or incorporating information 
about desirability of outcomes and tradeoffs between benefits and risks (e.g., based on 
patient preference studies or other published studies).  
 
Some situations where conducting additional benefit-risk analyses may add value can be 
anticipated early in development, notably in the case of a drug expected to have a serious risk.  In 
such cases, consultation with FDA and careful planning early in drug development can increase 
the potential value of the benefit-risk analysis by ensuring that appropriate information is 
collected through studies, trials, or other approaches.  Pre-specification of benefit-risk analysis 
and relevant data collection can also ensure transparency, reduce potential for bias (e.g., 
confirmation bias), and facilitate interpretation of results.   
 
 
38 See section IV., Recommended Qualities of Patient Preference Studies.  This guidance for industry was released 
by FDAs Center for Devices and Radiological Health (CDRH) and CBER. 
  19  Contains Nonbinding Recommendations 
 
Additional benefit-risk analyses, such as those listed above, can also be useful in cases where 
unanticipated benefit-risk issues arise late in the development program or in the postmarket 
setting (e.g., from a new safety signal arising in pivotal trials, from an analysis showing a 
subpopulation at potentially greater risk, or as new safety data becomes available post-approval).  
However, the utility of additional benefit-risk analysis in such instances may be limited if the 
data critical for analysis (e.g., data necessary to estimate important benefit and risk outcomes or 
tradeoffs) are not fit-for-purpose, or if the data cannot be collected through appropriately 
designed studies within the time frame available to the relevant regulatory decision.   
 
There are many approaches to conducting additional benefit-risk analyses, and numerous reviews 
of methodology are available.39  This guidance does not prescribe specific approaches for 
sponsors to follow.  The appropriate method(s) will depend on the benefit-risk issue and the 
information available.  The interpretability and usefulness of results rests on the validity and 
robustness of the selected method, the fitness-for-purpose of the data used, and the adequacy of 
support for the underlying assumptions used in the selected method, all of which should be fully 
reviewable by the Agency.   
 
Generating rigorous evidence to inform FDAs benefit-risk assessment calls for careful planning 
and should involve prospective interaction with FDA early in the development of the analysis 
plan (see section IV.B.).  To support these interactions, sponsors are recommended to provide 
documentation including scientific justification for selection of methodology, plans for data 
collection, and analysis plans.  When final analysis results are submitted, the documentation 
should include sufficient information allowing FDA to evaluate the strength of the methodology 
and the quality of the data, and to verify the analysis results (see section IV.E.).  
 
The output of additional benefit-risk analyses is typically not useful in isolation for regulatory 
decision-making.  FDAs decision that a drugs benefit-risk assessment is favorable may be 
informed by the additional analyses, but is not determined by such results, and takes into account 
other assessments and information that bear on a detailed understanding of both benefit and risk.  
 
E.  Presenting Benefit-Risk Considerations in the Marketing Application  
 
The effective communication by sponsors of the drugs benefits, risks, and uncertainties is 
important to informing the benefit-risk assessment that supports regulatory decision-making.  A 
critical source of benefit-risk information is the sponsors NDA or BLA.  As part of an NDA 
submission, the sponsor must provide [a]n integrated summary of the benefits and risks of the 
drug, including a discussion of why the benefits exceed the risks under the conditions stated in 
labeling (see 21 CFR 314.50(d)(5)(viii)).  The ICH M4E(R2) guidance, revised in 2016 and 
adopted by FDA as a guidance for industry in July 2017, provides recommendations on the 
presentation of benefit-risk information in premarket applications.40  In addition, in light of the 
considerations described in section III. above, inclusion of the following information in the 
 
39 Mt-Isa, S, M Ouwens, V Robert, M Gebel, A Schacht, and I Hirsch, 2015, Structured Benefit-Risk Assessment: A 
Review of Key Publications and Initiatives on Frameworks and Methodologies, Pharm Stat, 15(4):324332. 
40 See the discussion of CTD section 2.5.6. in FDAs guidance for industry M4E(R2): The CTDEfficacy (July 
2017). 
  20  Contains Nonbinding Recommendations 
 
sponsors integrated summary of the benefits and risks, as appropriate, may facilitate FDAs 
benefit-risk assessment: 
 
  Summary of the important benefits and risks identified in the development program and a 
description of the clinical importance of those benefits and risks, including: 
 
o  Discussion of the magnitudes of the treatment effects.  For binary outcomes, this 
includes providing treatment effects on both the absolute difference and relative 
scales.  For continuous outcomes, this includes providing the treatment effect on the 
pre-specified summary measure (e.g., the mean at a specific time point), context on 
the assessment scale, mean baseline values, and exploration of the distribution of 
outcomes in the treatment groups. 
 
o  Clinical meaningfulness of the treatment effect, including the clinical importance of 
benefit of a particular magnitude, understanding of meaningful within-patient change, 
and patient input on its importance. 
 
o  Exploration of the nature of effects (e.g., consideration of time course and durability 
of the drugs effect, interdependence of endpoints).  
 
  Estimates of the statistical uncertainty around the magnitudes of the most important 
benefits and risks (e.g., with confidence intervals).  
 
  Discussion of additional sources of uncertainty about benefits and/or risks (e.g., untested 
risk management strategies). 
 
  Potential differences between aspects of the clinical trial and expected real-world use 
(e.g., population, adherence, safety monitoring). 
 
  In some instances, a graphical or tabular summary of results for the most important 
benefits side by side or juxtaposed with important risks (e.g., the benefits and risks 
identified in a value tree).  Example techniques include forest plots and effects tables.41  
Care should be taken to ensure that such presentations provide a complete and balanced 
picture of benefits and risks that is easily interpretable.  This includes, for example, 
ensuring that all important benefit and risk outcomes are included and clearly indicating 
when multiple endpoints used to assess the same benefit or risk outcome are presented. 
 
These same considerations may be useful for sponsors when considering how to present this type 
of information at product-specific advisory committee meetings. 
 
 
 
41 For additional examples, see: Hughes, D, E Waddingham, S Mt-Isa, A Goginsky, E Chan, GF Downey, CE 
Hallgreen, KS Hockley, J Juhaeri, A Lieftucht, MA Metcalf, RA Noel, LD Phillips, D Ashby, and A Micaleff, 2016, 
Recommendations for Benefit- Risk Assessment Methodologies and Visual Representations, Pharmacoepidemiol 
Drug Saf, 25(3):251-262. 
  21  Contains Nonbinding Recommendations 
 
V.  BENEFIT-RISK ASSESSMENT CONDUCTED IN THE POSTMARKET 
SETTING 
 
Benefit-risk assessment does not end with FDAs approval of a drug.  FDA considers a drugs 
benefit-risk assessment over the drugs lifecycle, acknowledging that our understanding of both 
the drugs benefits and risks often changes over time as new information about the products 
effectiveness or safety becomes available.  When FDA considers a drugs benefits and risks and 
uncertainties in the postmarket setting, it does so in light of new information that is available 
post-approval.  Postmarket evidence to inform benefit-risk assessments can come from a diverse 
set of sources, such as the medical literature, postmarketing studies, adverse event reports, 
medication error reports, product quality reports, REMS assessment reports, patient experience 
data, and in some cases, from new data obtained from drugs of the same class.  This information 
can be collected for specific purposessuch as for a postmarketing study requirement or for 
REMS assessmentsor it can be generated through routine pharmacovigilance.  In some cases, 
uncertainty about serious safety concerns identified in the premarket review may decrease over 
time as the body of evidence builds (including from postmarketing clinical trials, studies, and 
surveillance).  In other cases, a new safety signal may emerge in the postmarketing setting, 
especially for rare adverse events that were not observed in pre-approval clinical trials.   
 
FDA may conduct a structured benefit-risk assessment, guided by the Benefit-Risk Framework 
(see section II.B), when new information emerges that warrants a reexamination of the benefit-
risk assessment of the marketed drug under the current requirements for approval.  Examples of 
regulatory decisions that may be informed by such assessments include addition, modification, or 
release of a REMS, initiation or release of postmarketing study requirements, requesting or 
requiring labeling changes (e.g., addition, revision, or removal of a boxed warning), and, rarely, 
marketing withdrawal.42  FDAs benefit-risk assessment in the postmarket setting generally takes 
into account the considerations discussed in Table 1, as relevant, and additionally may consider 
the strength of the evidence evolving in the postmarket setting, remaining uncertainties about the 
drugs benefits and risks, how the drug is used in the postmarket setting, the evolving therapeutic 
context, and the availability of alternative treatments. 
 
Considering a products lifecycle during benefit-risk planning can help inform sponsors 
postmarketing activities and decisions.  Sponsors may find a structured approach, guided by the 
Benefit-Risk Framework or the principles described in the July 2016 guidance for industry ICH 
E2C(R2) useful to support the generation and evaluation of new information and decision-
making in light of new information. 
 
Periodic reporting is an important mechanism for sponsors to communicate information to FDA 
that can inform benefit-risk assessment over the drugs lifecycle.43  The ICH guidance for 
industry E2C(R2) provides recommendations on developing a Periodic Benefit-Risk Evaluation 
Report (PBRER), which provides an alternative reporting format that may be used in place of the 
 
42 As noted above, these regulatory decisions are made in accordance with specific, applicable legal and regulatory 
authorities and criteria, most of which are not discussed in this guidance. 
 
43 Sponsors are required to submit certain adverse event reports to FDA (see 21 CFR 314.80 and 600.80).   
 
  22  Contains Nonbinding Recommendations 
 
periodic postmarketing safety report described in 21 CFR 314.80(c)(2) and 600.80(c)(2)) with 
the objective to: 
 
[P]resent a comprehensive, concise, and critical analysis of new or emerging information 
on the risks of the medicinal product and on its benefit in approved indications, to enable 
an appraisal of the products overall benefit-risk profile.44 
 
FDAs November 2016 guidance for industry Providing Postmarketing Periodic Safety Reports 
in the ICH E2C(R2) Format (Periodic Benefit-Risk Evaluation Report) recommends the 
procedures that sponsors should follow if they wish to submit a PBRER.45  If sponsors wish to 
submit a PBRER, FDA recommends that sponsors follow the format described in the most 
current version of the ICH E2C guidance for industry.   
 
Sponsors, however, should not wait for a periodic safety update to report a potentially serious 
safety concern.  New information about a potential serious safety concern that could have an 
impact on a drugs benefit-risk profile should be communicated promptly to FDA. 
 
44 See ICH E2C(R2), page 2. 
 
45 To submit the PBRER in lieu of submitting the periodic adverse drug experience report or periodic adverse 
experience report as required under 21 CFR 314.80(c)(2) or 600.80(c)(2), applicants must request a waiver under 
314.90(a) or 600.90(a), respectively. 
 
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