Regulatory spotlight
PRO guidance
Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims
PRO instruments must demonstrate content validity through patient input and qualitative research, ensuring the instrument measures concepts relevant to the population and condition being studied.
Sponsors must confirm the reliability, construct validity, and ability to detect change for the PRO instrument before use in confirmatory clinical trials.
Statistical analysis plans should address multiplicity, handling of missing data, and cumulative distribution function comparisons to interpret clinical trial results.
Modifications to PRO instruments (e.g., format changes, population adaptations) require evidence that measurement properties are preserved.
Electronic PRO systems must comply with regulatory requirements for data integrity, security, and investigator access.
Recommendations
Develop and validate PRO instruments early in the clinical development process, ensuring alignment with the clinical trial’s endpoint model.
Document all stages of instrument development, including qualitative input from patients, pilot testing, and cognitive interviews.
Use clear and consistent administration procedures, whether paper-based or electronic, to minimize variability and missing data.
Define responder thresholds using anchor-based methods and consider presenting cumulative distribution functions to interpret treatment benefits.
Address cultural and linguistic adaptation of PRO instruments by ensuring equivalent content validity and measurement properties across versions.
Regulatory Considerations
Include detailed descriptions of the PRO instrument, its conceptual framework, and scoring algorithms in regulatory submissions.
Ensure PRO instruments used in clinical trials comply with FDA requirements for record-keeping, data security, and source data accessibility.
Plan for the FDA to review all modifications to PRO instruments, including changes in administration mode or population.
Address missing data in clinical trial protocols and statistical analysis plans, ensuring prespecified handling rules.
Provide evidence that PRO instruments reliably measure the intended concepts across all study populations and data collection methods.
Some summaries are generated with the help of a large language model; always view the linked primary source of a resource you are interested in.
“A PRO is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. The outcome can be measured in absolute terms (e.g., severity of a symptom, sign, or state of a disease) or as a change from a previous measure. In clinical trials, a PRO instrument can be used to measure the effect of a medical intervention on one or more concepts (i.e., the thing being measured, such as a symptom or group of symptoms, effects on a particular function or group of functions, or a group of symptoms or functions shown to measure the severity of a health condition).
Generally, findings measured by a well-defined and reliable PRO instrument in appropriately designed investigations can be used to support a claim in medical product labeling if the claim is consistent with the instrument’s documented measurement capability. The amount and kind of evidence that should be provided to the FDA is the same as for any other labeling claim based on other data. Use of a PRO instrument is advised when measuring a concept best known by the patient or best measured from the patient perspective. A PRO instrument, like physician-based instruments, should be shown to measure the concept it is intended to measure, and the FDA will review the evidence that a particular PRO instrument measures the concept claimed. The concepts measured by PRO instruments that are most often used in support of labeling claims refer to a patient’s symptoms, signs, or an aspect of functioning directly related to disease status. PRO measures often represent the effect of disease.”
– Section II (Background), p. 2, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, Final, 2009 (FDA)
“The evaluation of a PRO instrument to support claims in medical product labeling includes the following considerations:
• The population enrolled in the clinical trial
• The clinical trial objectives and design
• The PRO instrument’s conceptual framework
• The PRO instrument’s measurement properties
Because the purpose of a PRO measure is to capture the patient’s experience, an instrument will not be a credible measure without evidence of its usefulness from the target population of patients. Sponsors should provide documented evidence of patient input during instrument development and of the instrument’s performance in the specific application in which it is used (i.e., population, condition). An existing instrument can support a labeling claim if it can be shown to reliably measure the claimed concept in the patient population enrolled in the clinical trial.”
– Section III (Evaluation of a PRO Instrument), p. 3, Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, Final, 2009 (FDA)
Condition-specific meeting reports
Condition-Specific Meeting Reports and Other Information Related to Patients’ Experience
Patient experience data provides critical context for regulatory review by illuminating disease burden, unmet medical needs, and the aspects of a condition that matter most to patients.
A systematic approach is necessary to ensure patient experience data is robust enough for regulatory consideration, moving beyond anecdotal evidence to scientifically rigorous data collection.
Early engagement between sponsors and the FDA is a key factor for successfully incorporating patient perspectives into a drug development program.
The value of patient-reported outcomes (PROs) and other clinical outcome assessments (COAs) is highly context-dependent, varying significantly across different diseases and patient populations.
Recommendations
Drug sponsors should leverage the FDA’s meeting process to discuss their strategies for collecting and submitting patient experience data early in the development lifecycle.
Sponsors should utilize the repository of meeting reports as a learning resource to understand best practices and common challenges in patient-focused drug development for specific conditions.
Patient advocacy groups should actively participate in these discussions to ensure the full spectrum of patient experiences is captured and communicated to both regulators and developers.
Researchers should develop and validate novel tools and methodologies for capturing and analyzing patient experience data that are meaningful for both clinical and regulatory purposes.
Regulatory Considerations
Patient experience data is a key component of the benefit-risk assessment, providing evidence that can inform regulatory decisions regarding a drug’s approval and labeling.
The FDA’s review of patient experience data is guided by a commitment to patient-focused drug development, as mandated by the 21st Century Cures Act and supported by user fee agreements like PDUFA.
The scientific rigor of data collection and analysis is paramount; for patient experience data to be influential, it must meet high standards of validity and reliability.
Transparency is a core principle, and the publication of these meeting reports is intended to provide clear examples of how patient input can be effectively integrated into regulatory submissions.
Some summaries are generated with the help of a large language model; always view the linked primary source of a resource you are interested in.
“An alphabetical listing of condition-specific meeting reports and other information related to patients’ experience. These meetings include FDA-led Patient-Focused Drug Development (PFDD) meetings, Externally-led PFDD meetings, and Patient Listening Sessions.”
– FDA, 2025
Remote data acquisition
Digital Health Technologies for Remote Data Acquisition in Clinical Investigations
There is a need for comprehensive validation and verification processes for DHTs.
Ensuring data security and privacy is a significant concern.
Usability issues for diverse populations need to be addressed.
There is a lack of clarity on whether certain DHTs meet the definition of a device under the FD&C Act.
The guidance does not establish legally enforceable responsibilities.
Recommendations
Ensure DHTs are fit-for-purpose for clinical investigations.
Implement robust data security measures to protect participant information.
Conduct usability evaluations to ensure DHTs can be used by intended populations.
Engage with FDA early to discuss the use of DHTs in clinical investigations.
Develop a risk management plan to address potential issues with DHT use.
Regulatory Considerations
Verification and validation should be addressed regardless of device classification.
Sponsors should ensure compliance with data protection and privacy regulations.
FDA evaluates DHT data based on endpoints, medical products, and patient populations. Sponsors can engage with FDA’s Q-Submission Program for feedback on DHT usage in clinical trials.
Sponsors should understand the legal implications of using DHTs in clinical investigations.
The guidance provides recommendations but does not establish legally enforceable responsibilities.
Some summaries are generated with the help of a large language model; always view the linked primary source of a resource you are interested in.
“Novel endpoints based on data captured by DHTs may provide opportunities for additional insight into participant function or performance that was previously not easily measurable (e.g., tremors). While it is possible to measure some aspects of function or performance during participant visits to the clinic at a point in time, the use of DHTs potentially provides for their measurement over a longer time period and in different settings.
When justifying a novel endpoint using data captured by the DHT, sponsors should address the following:
- Whether the endpoint reflects how a participant feels, functions, or survives.
- Whether a biomarker serving as a surrogate endpoint will predict or will be reasonably likely to predict clinical benefit.
- Whether the effect of the intervention as captured by the novel endpoint is meaningful to the target patient population for the medical product being evaluated.
- How the endpoint relates to other endpoints that are intended to reflect the same concept and have been used to support a marketing authorization for a similar indication. In the absence of related endpoints, evidence from other sources of information (e.g., literature or input from stakeholders and experts) may support use of the endpoint.
- Whether the novel endpoint is a well-defined and reliable measure of disease severity or health status (e.g., mild, moderate, or severe) to allow assessment of disease modification or progression.
- When an existing medical product has already received marketing authorization based on evidence from a study using an established endpoint for the disease or condition of interest and the concept being evaluated by the novel endpoint is similar, it may be useful to determine whether the effect of that existing medical product (positive control) can be detected using the novel endpoint.”
– Section IV.D (Evaluation of Endpoints Involving Data Collected Using DHTs), p. 16, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA).
“This section outlines general considerations for justifying endpoints (e.g., primary, secondary, exploratory) measured using data collected from DHTs, but does not address any disease-specific endpoints. The principles that guide development of endpoints based on data captured by DHTs are the same as the principles for developing endpoints captured by other means. Sponsors should obtain input from interested parties (such as patients, caregivers, clinicians, engineers, statisticians, and regulators) to ensure that the endpoint is both clinically meaningful and the data are adequately captured by the DHT. Sponsors should discuss their plans for endpoint development with the relevant review division. See appendix B for an example of justifying an endpoint using a DHT.”
– Section IV.D (Evaluation of Endpoints Involving Data Collected Using Digital Health Technologies), p. 15, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA).
“A precise definition of an endpoint typically specifies the type of assessment(s) made (e.g., activity level, average heart rate, sleep quantity and quality), the timing of those assessments, the tool(s) used for the assessment(s), and other details, as applicable, such as if (and if so, how) multiple assessments for a trial participant will be combined.”
– Section IV.D (Evaluation of Endpoints Involving Data Collected Using Digital Health Technologies), p. 15, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA).
PFDD 1: Comprehensive and representative input
Patient-Focused Drug Development: Collecting Comprehensive and Representative Input
Patient experience data encompass a range of inputs, including symptom burdens, treatment impacts, patient preferences, and views on unmet medical needs.
These data inform all stages of medical product development, from discovery to post-market use.
Quantitative methods (e.g., surveys) provide numerical insights, while qualitative methods (e.g., interviews) offer in-depth understanding. Mixed methods combine both for a fuller perspective.Social media and verified patient communities present novel data collection opportunities but require consideration of verification and representativeness challenges.
Probability sampling (e.g., stratified random sampling) is emphasized for generalizability, while non-probability methods (e.g., convenience sampling) are useful for exploratory research. Representativeness ensures that patient input reflects the diversity and heterogeneity of the target population.
Data collection should adhere to good clinical practices and regulatory standards.
Research protocols should address missing data, quality assurance, and confidentiality.
Early collaboration with the FDA is recommended to align on study designs and regulatory requirements.
Recommendations
Define clear research objectives and determine specific research questions before selecting data collection methods.
Use probability sampling methods whenever feasible to ensure representativeness of the target population.
Address data quality through rigorous planning, data management, and adherence to FDA-supported standards.
Incorporate diverse perspectives by including underrepresented patient populations, tailoring methods to specific subgroups as needed.
Leverage existing data sources, such as patient registries and literature, to complement primary data collection efforts.
Regulatory Considerations
Data submitted to FDA should include clear documentation of the study protocol, intended use, and data collection methodologies.
Researchers must comply with human subject protection regulations (e.g., 21 CFR Parts 50 and 56) and good clinical practice guidelines.
For data intended to support regulatory submissions, adherence to FDA-supported data standards (e.g., CDISC) is strongly encouraged.
Missing data should be addressed through pre-planned strategies and summarized in the study report.
Patient experience data must meet methodological rigor to ensure their reliability and relevance for regulatory decision-making.
Some summaries are generated with the help of a large language model; always view the linked primary source of a resource you are interested in.
“Patient experience data include the experiences, perspectives, needs, and priorities of patients related to:
- The signs and symptoms patients experience and how these signs and symptoms affect their day-to-day functioning and quality of life
- The course of their disease over time, including the effect the disease has on patients’ day-to-day function and quality of life over time, and the changes that patients experience in their symptoms over time
- Patients’ experience with the treatments for their disease: the symptoms and burdens related to treatment
- Patients’ views on potential disease or treatment outcomes and how they weigh the importance of different possible outcomes
- How patients view the impact of the disease, treatment, and outcomes, and their view of potential tradeoffs between disease outcomes and treatment benefits and risks
The patient experience in a medical product development context incorporates their journey throughout the course of their disease or condition, including patient views, feelings, needs, actions, preferences, and interactions (e.g., clinical trials, home life, social life) with respect to their disease and its treatment (Wolf et al. 2014; McCarthy et al. 2016).”
Section I.B (Patient Experience Data), p. 4, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
“You should examine previously conducted studies and other relevant research literature and consult subject matter experts (e.g., clinicians, social scientists, patients, advocates, caregivers) to help determine the most appropriate questions and to decide:
• Which methods are better suited to meet your research goals and provide evidence to support your research questions
• The design of study materials (e.g., study protocol, interview guides, coding dictionary; refer to Guidance 2 for more details).”
– Section II.B (Defining the Research Objectives and Questions), p. 8, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
“For the collection of patient experience data, FDA recommends direct reports from patients, unless they are unable to reliably report on the concept of interest (e.g., young children, individuals with cognitive problems). The ability to provide self-report also depends on the methods used to elicit the input and the complexity of the concepts. Methods of data collection can be tailored to specific situations and patient groups, for example by eliciting patient experience through play and drawings from young children.
When collection of direct patient experience is limited, valuable, but distinct, information may still be obtained from caregivers, patient advocates, clinicians, and others.”
– Section II.C.2 (Determining Who Will Be Providing Patient Experience Data), p. 9, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
“When studying patient experience, it is important to obtain patient experience data that are not only relevant, objective, and accurate, but also representative of the target population. Sufficient representation may depend on the characteristics of the target population, the disease or condition under study, and the intended use of study results. In this document, the term representative or representativeness can be interpreted in the following ways.
(1) A sample is representative of the target population if statements made about patient experience based on data from the sample of patients are generalizable to the target population. In principle, probability sampling schemes enable you to obtain such representative samples and often arise in the context of quantitative studies. However, if there are subgroups of patients from the target population that are not adequately represented in your study sample, your ability to generalize your research findings to the target population may be limited, even if you use a probability sampling scheme.
(2) A sample is representative of the target population to the extent that patients in the study sample consist of individuals with various characteristics that approximate the heterogeneity of characteristics in the target population. If your sample does not reflect the broad range of patient characteristics of the target population, patient experience results may not be representative of the target population. Thus, statements made about patient experience based on data from the study are not necessarily generalizable to the target population. Whether this is acceptable depends on the research objectives. If your research objective is to generate hypotheses or tools to collect patient experience data, this extent of representativeness may be sufficient. It also may be possible to attain generalizability through weighting to account for the over-sampling (or under-sampling) of certain subpopulations if the sample is obtained with known sampling probabilities.”
– Section II.E.2 (Representativeness), p. 15, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
Human Subjects Protection
“Research involving access to patient information or directly engaging with patients requires careful consideration of federal, state, and local laws, and institutional polices for the protection of human subjects. Because this guidance focuses on sampling methods for collecting patient experience data through a variety of research contexts (including, but not limited to, clinical trials, observational studies, advisory boards, public meetings) a full discussion of the laws that may apply to these collection methods is beyond its scope.
Research subject to FDA regulations must satisfy the requirements for informed consent at 21 CFR part 50 and the Institutional Review Board (IRB) requirements at 21 CFR part 56. Research supported or conducted by the Department of Health and Human Services must satisfy the requirements at 45 CFR part 46. FDA recommends that researchers work with their IRBs and Health Insurance Portability and Accountability Act Privacy Boards to determine which laws may apply. FDA also recommends that research involving patient information be conducted in accordance with the principles of good clinical practice, including the ICH Guidelines.”
– Section III.B (Human Subjects Protection), p. 19-20, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
“Data collection methods can include: Interviews, Focus groups, Facilitated discussions at meetings, Observational methods, Documents (e.g., medical charts), Survey instruments, Audiovisual materials, Social media and verified patient communities, Digital health technologies.
Each of these data collection methods generates different types of data, each of which has its own advantages and limitations. Additional details, including potential advantages and limitations of each method, are discussed.”
– Section III.D (Collecting Data), p. 20, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
“This document has provided an overview of methods to collect robust, meaningful, and sufficiently representative patient input to inform medical product development and regulatory decision-making. The proposed methods presented serve only as a basis for dialogue in the evolving and growing discipline of the science of patient input. If you are considering collecting patient experience data, FDA encourages you to have early interactions with FDA and obtain feedback from the relevant FDA review division on appropriate research design and any applicable regulatory requirements.”
– Section IV (Conclusions), p. 28, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
“Endpoint: A precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question. A precise definition of an endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used, and possibly other details, as applicable.”
– Appendix 2 (Glossary), p. 36, Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, Final, 2020 (FDA)
PFDD 2: What is important to patients
Patient-Focused Drug Development: Methods to Identify What Is Important to Patients
Qualitative Methods: One-on-one interviews provide in-depth individual insights, while focus groups capture diverse perspectives through participant interaction.
Approaches such as Delphi panels and observational methods can complement interviews and focus groups in understanding patient experiences.
Quantitative Methods: Surveys provide structured, quantifiable data and are effective for large populations.
Careful design of questions and response options minimizes bias and improves data quality.
Mixed Methods:Combining qualitative and quantitative techniques enhances understanding and validates findings.
Sequential and concurrent designs can address complex research questions and improve robustness.
Barriers to Self-Report: Special adaptations may be needed for patients with disabilities, pediatric populations, or those with language or cultural differences.
Proxy reporting by caregivers is sometimes necessary but may introduce bias.
Social Media: Useful for real-time or retrospective insights into patient perspectives. Limitations include lack of verified identities and potential bias in user demographics.
Recommendations
Choose data collection methods aligned with research objectives and the target population.
Use open-ended questions for qualitative research to elicit unbiased responses; avoid leading or judgmental prompts.
Pilot test interview guides, surveys, and response options to ensure clarity and relevance.
Integrate cultural and linguistic adaptations for diverse populations in multinational studies.
For mixed-method research, establish clear objectives for combining qualitative and quantitative components and address conflicting findings systematically.
Regulatory Considerations
Data collected through qualitative or quantitative methods must meet regulatory standards for integrity and reliability when submitted to the FDA.
Screening and exit interviews should not interfere with the integrity of ongoing clinical trials; use trained third-party interviewers where appropriate.
Researchers should follow ethical standards and federal regulations when using social media data, ensuring informed consent and data privacy.
Some summaries are generated with the help of a large language model; always view the linked primary source of a resource you are interested in.
“The methods described in this document can be used to elicit what is important to patients, which may in turn help inform understanding of disease/condition and clinical trial design. It may also help the generation and use of patient experience data, including clinical outcome assessments and patient preference information, to inform benefit-risk assessment.”
– Section I (Purpose and Scope of Guidance 2), p. 2, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients, Final, 2022 (FDA)
“Research to understand what matters most to patients living with a disease or condition to guide medical product development should begin with a characterization of the disease or condition and currently available therapies. Before conducting studies in patients, which may involve their caregivers as well, literature reviews, consultation with relevant subject matter experts, and other information sources should be used to develop targeted research questions and select appropriate methods to identify what matters most to patients regarding their experience with their disease or condition.”
– Section II (Background Research), p. 3, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients, Final, 2022 (FDA)
“Qualitative research methods, such as interviews and focus groups, are typically used to obtain a deeper understanding of the patient experience by generating in-depth information about the experiences, perspectives, priorities, preferences, and feelings of patients and others, in their own words.”
– Section II (Overview of Methods), p. 3-4, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients, Final, 2022 (FDA)
“One-on-one interviews offer opportunities to explore topics in-depth at an individual level using probing questions.”
– Section III.A.1 (One-on-One Interviews), p. 4, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients, Final, 2022 (FDA)
“Focus groups allow for participant interaction and can capture a range of perspectives within a population in a shorter time frame.”
– Section III.A.3 (Choosing Between One-on-One Interviews and Focus Groups, In-Person or Remote), p. 5, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients, Final, 2022 (FDA)
“There is no single preferred qualitative method for all uses and research questions. The method selected should be suitable for the research objective(s) and question(s).”
– Section III (Qualitative Research Methods), p. 4, Patient-Focused Drug Development: Methods to Identify What Is Important to Patients, Final, 2022 (FDA)
PFDD 3: Fit-for-purpose clinical outcome assessments (COAs)
Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments
The guidance applies to four types of Clinical Outcome Assessments (COAs): Patient-Reported Outcomes (PROs), Observer-Reported Outcomes (ObsROs), Clinician-Reported Outcomes (ClinROs), and Performance Outcomes (PerfOs). A COA is considered fit-for-purpose when the validation evidence is sufficient to support its context of use (COU). To determine if a COA is fit-for-purpose, sponsors must clearly describe the Concept of Interest (COI) and the COU, and present sufficient evidence to support a clear rationale for the COA’s proposed interpretation and use. The rationale for using a COA should include up to eight components, such as justification for the COA type, capturing the important parts of the COI, appropriate administration and scoring, minimal influence from irrelevant factors or measurement error, and correspondence with the Meaningful Aspect of Health (MAH). The most direct assessment of how a patient feels or functions (MAH) should be used as the COI whenever possible.
Recommendations
Sponsors should use the Roadmap to Patient-Focused Outcome Measurement to guide the selection, modification, or development of a COA. The process begins with understanding the disease/condition (including patient perspectives) and conceptualizing clinical benefits and risks (defining the MAH, COI, and COU). When feasible, existing COAs are generally preferred, especially for well-established COIs, as this approach is often the least burdensome. If an existing COA is modified or used in a different context, additional evidence (e.g., cognitive interviews, psychometric studies) must be collected to justify its fitness for the new context of use. For new COA development, sponsors should involve patients, document all steps, and generally avoid using the new COA for the first time in a registration (pivotal) trial; a standalone observational study or early phase trial is recommended for evaluation.
Regulatory Considerations
Sponsors are encouraged to interact early and throughout medical product development with the relevant FDA review division to ensure COAs are appropriate for the intended COU. Sponsors should communicate their proposed COA-based endpoint approach, including the MAH, COI, COA type/name/score, and the final COA-based endpoint, ideally using the suggested format. The type and amount of evidence required to support the rationale for a COA’s use is weighed against the degree of uncertainty regarding that part of the rationale. For ClinROs, it is recommended to use an assessor masked to treatment assignment and study visit for primary endpoints, if feasible. FDA strongly discourages proxy-reported measures for concepts known only to the patient (e.g., pain) and recommends using an ObsRO to measure observable behaviors instead when the patient cannot self-report.
Recommendations
Clearly define the concept of interest and its context of use to ensure COAs align with trial objectives.
Use conceptual and measurement frameworks to communicate how COAs measure patient experiences and generate interpretable scores.
Leverage existing COAs where possible, modifying them only when justified, and document all modifications rigorously.
Ensure COAs are accessible and inclusive, incorporating features like large fonts, touch interfaces, or audio assistance for diverse populations.
Conduct early engagement with FDA to discuss COA selection, development, and validation plans.
Regulatory Considerations
Fit-for-purpose validation requires evidence of conceptual alignment, scoring reliability, and sensitivity to clinically meaningful changes.
Digital health technologies used for COAs must comply with FDA’s guidance on data integrity, usability, and technical performance.
COAs intended for regulatory submissions must be developed and validated before pivotal trials to avoid jeopardizing trial outcomes.
Modifications to COAs or scoring methods during trials necessitate justification and revalidation.
Sponsors should submit comprehensive documentation on COA development, including scoring algorithms and item tracking matrices.
Some summaries are generated with the help of a large language model; always view the linked primary source of a resource you are interested in.
“This guidance is intended to help sponsors use high quality measures of patients’ health in medical product development programs. Ensuring high quality measurement is important for several reasons: measuring what matters to patients; being clear about what was measured; appropriately evaluating the effectiveness, tolerability, and safety of medical products. Findings from high quality measures may help support regulatory decision-making in a variety of contexts. For example, findings based on a well-defined and reliable COA-based endpoint in an appropriately designed and conducted investigation may be used to support a claim in medical product labeling if the claim is consistent with the findings and the COA’s documented measurement capabilities.”
– Section I.B (Purpose and Scope of PFDD Guidance 3), p. 3, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“Patients and caregivers have been increasingly integrated as stakeholders in the development and evaluation of medical products.”
– Section I.B (Purpose and Scope of PFDD Guidance 3), p. 4, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“Clinical benefit is defined as “a positive effect on how an individual feels, functions, or survives”. To provide clinical benefit, a medical product should affect a meaningful aspect of health (MAH), i.e., some aspect of feeling or functioning in daily life that is important to patients (Walton et al. 2015). In a clinical trial, we study the effect of a medical product on a MAH by estimating a treatment effect on an endpoint that is thought to reflect the MAH.
To precisely describe the role of a COA in a clinical study, sponsors should propose to FDA how they intend to interpret scores from a COA (i.e., what they believe the score measures), how scores will be used to reflect the MAH (e.g., to construct an endpoint), and the context in which scores will be used. In other words, the sponsor’s proposal should explicitly reference the MAH, the concept of interest (COI; see section II.B.2) and the context of use (COU; see section II.B.3). For COAs with multiple domains and related scores, the domain of interest (and particular score) should be clearly stated.
Having established the COA measures something meaningful, the construction of the COAbased endpoint should preserve the meaningfulness. Using COAs to construct trial endpoints is discussed in PFDD Guidance 4, Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making (April 2023).”
– Section II.B (The Role of COAs), p. 7, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“The identification of concepts of interest that are both appropriate for, and important to, a given target population in CDER and CBER decision-making is described in Guidance 2 of this series. Such identification may involve qualitative research with patients, caregivers and clinical experts. For some diseases or conditions, important concepts of interest might have already been identified and used in previous studies based on input from patients, caregivers, clinical experts, and other sources. In such cases, sponsors should reference and summarize the prior work done when justifying their choice of concept(s) of interest.
In a clinical trial, it is important to carefully select concepts that:
• Reflect an aspect of health that is important to patients, i.e., a MAH
• Have the potential to demonstrate a clinically meaningful effect of the investigational treatment within the time frame of the planned clinical trial, when measured adequately and incorporated into an endpoint.”
– Section II.B.2 (The Concept of Interest for Measurement), p. 8, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“The concept of interest is what is specifically measured by a COA to help understand how a medical product affects a MAH. Depending on the intervention, the intent of treatment may be, for example, to improve a symptom(s) or a specific function (e.g., ambulation); delay or avoid further worsening of a symptom(s) or further loss of a specific function; prevent the onset of a symptom or a loss of a specific function; or restore a specific function. Sponsors might also want to assess whether aspects of how patients feel and/or function could be negatively impacted by receipt of the intervention (i.e., harms).”
– Section II.B.2 (The Concept of Interest for Measurement), p. 7, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“This section describes a general Roadmap to patient-focused outcome measurement in clinical trials. Sponsors and COA developers are not required to use this approach, and it may not fit every development program, but it has worked well for several COAs in many contexts of use. FDA recommends sponsors seek FDA input as early as possible and throughout medical product development to ensure COAs are appropriate for the intended context of use.”
– Section III (A roadmap to patient-focused outcome measurement in clinical trials), p. 10, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“The first step involves considering the manifestations and natural history of the disease or condition; important patient subpopulations; the clinical environment in which patients with the condition seek care; and patient and/or caregiver perspectives on the disease, its impacts, and therapeutic needs and priorities. One important outcome of this step is understanding and summarizing the important signs, symptoms, and health impacts patients with the disease or condition might experience.”
– Section III.A.1 (Understanding the Disease or Condition), p. 12, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, Final, 2025 (FDA)
PFDD 4: Incorporating COAs into endpoints
Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making
COA-based endpoints should reflect meaningful patient health aspects and support clear treatment effect inferences.
Selection of endpoints requires a well-supported rationale, including evidence of their importance to patients.
Use of MSD and MSR approaches enhances the interpretation of treatment effects by linking COA scores to meaningful patient experiences. Proper anchors (e.g., global impression of severity) are essential for validating these approaches.
Frequency and timing of COA data collection must align with disease characteristics and study objectives.
Adjustments for potential practice effects and assistive device use are critical for robust outcome measurement.
Proper handling of missing data and sensitivity analyses ensure valid conclusions from COA-based endpoints.
Continuous, ordinal, and dichotomized endpoints require tailored statistical methods for analysis.
Early engagement with the FDA is crucial for aligning study designs and COA approaches with regulatory expectations.
Recommendations
Engage patients and caregivers early to identify meaningful endpoints and assess potential barriers to COA use.
Use anchor-based methods to validate COA scores and define meaningful thresholds for interpretation.
Develop and pilot test study protocols to ensure COA reliability, usability, and alignment with regulatory requirements.
Implement strategies to reduce participant burden, such as concise COA instruments and patient-friendly data collection methods.
Submit comprehensive documentation, including endpoint justification and scoring rationale, to FDA for feedback before trial initiation.
Regulatory Considerations
Endpoints must be supported by evidence of their fit-for-purpose status and alignment with the trial’s objectives.
COAs used in digital or adaptive formats must meet FDA’s standards for usability and data integrity.
Trials with nonrandomized designs require robust measures to mitigate bias in COA-based endpoint analysis.
Thresholds for MSD or MSR must be prespecified and justified with empirical evidence.
Sponsors must follow FDA guidance for submitting COA-based data, ensuring compliance with electronic data standards.
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“FDA encourages stakeholders to interact early with FDA and obtain feedback from the relevant FDA review division when considering the collection of patient experience data related to the burden of disease and the benefits, burdens, and harms of treatment. FDA recommends that stakeholders engage with patients and other appropriate subject matter experts (e.g., clinical and disease experts, qualitative researchers, survey methodologists, statisticians, psychometricians, patient preference researchers) when designing and implementing studies to evaluate the burden of disease and treatment, and perspectives on treatment benefits and risks.”
– Section I.A (Overview of the Series of FDA Guidance Documents on Patient-Focused Drug Development), p. 2, Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making, Draft, April 2023 (FDA)
“Generally, endpoints that are based on COAs should (1) reflect an aspect of the patient’s health that is meaningful; and (2) be capable of supporting an inference of treatment effect within the context of the planned clinical trial.”
– Section II.A.1 (Selecting and Justifying Endpoints), p. 4, Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making, Draft, April 2023 (FDA)
“FDA recognizes that constructing and selecting trial endpoint(s) often involves weighing the strengths and limitations of different approaches. Early in the planning of a clinical trial, sponsors should provide to FDA a well-supported rationale for the selection of the endpoint(s) by explaining why each endpoint is informative for the trial context.”
– Section II.A.1 (Selecting and Justifying Endpoints), p. 5, Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making, Draft, April 2023 (FDA)
“In regulatory decision-making, FDA evaluates how well results of a COA-based endpoint correspond to a treatment benefit that is meaningful to patients. For endpoints based on COAs intended to reflect how patients feel or function (see Section I.B), sponsors should provide supporting evidence to justify the meaningfulness of an observed treatment benefit. Section III discusses what supporting evidence is recommended, how it could be collected, and how it can be applied to help interpret the trial results. FDA strongly recommends that sponsors seek FDA input as early as possible regarding the evaluation of meaningful treatment benefit.”
– Section III (Evaluating the meaningfulness of treatment benefit), p. 18, Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making, Draft, April 2023 (FDA)
Scope of PFDD guidances
The FDA’s Patient-Focused Drug Development (PFDD) Guidance Series “is intended to facilitate the advancement and use of systematic approaches to collect and use robust and meaningful patient and caregiver input that can better inform medical product development and regulatory decision making.”
While the PFDD series provides this key framework, different FDA centers emphasize distinct guidances in their assessments. For instance, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) currently utilize PFDD 1 and 2. In contrast, the Center for Devices and Radiological Health (CDRH) uses Principles for Selecting, Developing, Modifying, and Adapting Patient Reported Outcome Instruments for Use in Medical Device Evaluation, for patient-reported outcomes. All centers are also preparing for the implementation of PFDD 3 (finalized Oct 2025) and the forthcoming PFDD 4, which will together replace the older 2009 guidance on Patient-Reported Outcome Measures.
More resources to guide you
Once you’ve read the guidances, explore these best practices from the field:
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