Regulatory spotlight
We offer selected excerpts from relevant guidances below, to help you get oriented and understand their significance. It is your responsibility to fully examine and interrogate these guidances in detail. Click through on individual resource links to be taken to the primary source material.
Clinical trials with decentralized elements
Conducting Clinical Trials With Decentralized Elements
Coordination challenges with multiple locations in DCTs.
Variability in data collection across decentralized locations and remote tools.
Challenges in implementing certain statistical approaches in DCTs.
Need for DHTs to be accessible and suitable for all trial participants.
Ensuring compliance with local laws and regulations.
Recommendations
Develop clear protocols for integrating decentralized elements into clinical trials, specifying remote and in-person activities.
Use digital health technologies (DHTs) and electronic systems to streamline data acquisition, informed consent, and investigational product tracking.
Provide training for all stakeholders, including trial personnel, local health care providers, and participants, on decentralized processes.
Implement robust safety monitoring plans to address adverse events in decentralized settings.
Ensure compliance with local and international laws governing telehealth, data privacy, and investigational product use.
Regulatory Considerations
Maintain compliance with FDA requirements under 21 CFR parts 312 and 812 for drug and device trials, respectively.
Document all trial activities and data flows in trial protocols and data management plans, ensuring traceability and integrity.
Ensure informed consent processes meet FDA standards and provide clear communication to participants about decentralized trial activities and data handling.
Address investigational product accountability by documenting IP distribution, storage, and return or disposal.
Design electronic systems for decentralized trials to comply with 21 CFR part 11 requirements for data reliability, security, and confidentiality.
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.
“Sponsors should ensure that DHTs used in a DCT are available and suitable for use by all trial participants… Sponsor-provided DHTs should be available as an option… Sponsor-provided telecommunication services should also be made available as needed so that participants who have no or limited access to these services are not excluded from the clinical investigation.”
– Section III.C (Digital Health Technologies), p. 6, Conducting Clinical Trials With Decentralized Elements, Final, 2024 (FDA)
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.
“The design and operation of the DHT and other technologies should be considered to determine if the DHT is fit-for-purpose. DHT design (e.g., material, size, weight, appearance, portability) and ease of use may influence whether trial participants will use the DHT for the duration of the clinical investigation and in the manner described in the protocol. These factors may be particularly important for DHTs that are wearable, where comfort and convenience may influence a trial participant’s ability and willingness to use the DHT for the duration specified in the protocol.”
– Section IV.A.3 (Design and Operation of DHTs and Other Technologies), p. 9, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA)
“To assist the Agency in understanding the sponsor’s plans for consistent data collection during the clinical investigation, sponsors should describe features that impact usability, such as the user interface, and how the DHT is worn, operated, and maintained… Sponsors should describe how access to the DHT or the data collected from it is controlled to ensure privacy and security.”
– Section IV.B (Digital Health Technology Description in a Submission), p. 10, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA)
“Sponsors should evaluate the advantages and disadvantages of allowing trial participants to use their own DHTs (e.g., continuous glucose monitors) and/or other technologies (e.g., general-purpose computing platforms such as smartphones and tablets) for remote data acquisition in a clinical investigation. Allowing participants to use their own DHTs or other technologies with which they are already familiar may potentially reduce the burden of using additional DHTs or other technologies provided by the sponsor. However, allowing participants to use their own DHTs may not be appropriate for DHTs that are customized or highly specialized for specific uses (e.g., actigraphy with algorithms customized for participants with a specific movement disorder).
Sponsor-provided DHTs or other technologies to support their operation should be available as an option to ensure that participants who do not bring their own are not excluded from the clinical investigation for that reason. Sponsor-provided telecommunication services should also be made available as needed so that participants who have no or limited access to these services are not excluded from the clinical investigation.”
– Section IV.A.4 (Use of a Participant’s Own DHT and/or Other Technologies), p. 10, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA)
“Usability evaluations should be conducted to demonstrate that the DHT can be used as intended by the trial population, without errors or problems. Usability evaluations are a critical component in confirming the suitability of the DHT in the proposed clinical investigation. Usability evaluations should be tailored to the risks and complexities associated with each DHT to be used in a clinical investigation. Usability evaluations should assess if the design of the DHT will allow participants in the clinical investigation to use the proposed DHT as directed in the trial protocol.”
– Section IV.C.3 (Usability Evaluations), p. 14, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA)
“Usability evaluations are important to ensure proper use of the DHT so that measurements obtained from DHTs used in remote settings are accurate and precise. Usability evaluations support the accuracy, completeness, and consistency of measurements as well as ongoing participant engagement throughout the duration of the clinical investigation. Findings from the usability evaluations can be used to improve the design and functionality of the DHT, to improve ease of use, and to inform the instructions for use and training provided to trial participants and trial personnel.”
– Section IV.C.3 (Usability Evaluations), p. 14, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Final, 2023 (FDA)
“Usability Evaluation: The sponsor may consider conducting usability evaluations to assess whether the intended population for the clinical investigation will be able to use the DHT as directed in the protocol. In designing these evaluations, the sponsor should consider the following:
- Is the DHT appropriately designed for use by the intended population for the clinical investigation of the drug, including older adult patients and/or their caregivers (if applicable)? For example, will trial participants wear the DHT correctly?
- How frequently should the DHT be charged and are there any expected challenges with the participant’s charging practices?
- How will participants transmit data from the DHT to the investigator or sponsor?”
Appendix B (Example of Selecting a Digital Health Technology for a Clinical Investigation and Justifying the Endpoint for Which It Is Used), p. 34, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, December 2023 (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.
“A portion or all of the target population may benefit from accessibility features and universal design³¹ considerations. Usability testing is recommended for accessibility features for a COA under certain situations (e.g., event-triggered data collection; see guidance for industry and FDA staff Applying Human Factors and Usability Engineering to Medical Devices (February 2016) for guidance on CDRH decision-making).”
— Section III.C.4 (COA Accessibility and Universal Design), p. 17, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 2025 (FDA)
“Respondents who feel fatigued or over-burdened during an assessment might not provide data reflective of the underlying disease or the impact of treatment. Evidence from cognitive interviews and/or usability testing may provide insight as to whether a COA might lead to fatigue and/or burden.”
— Section IV.F.3 (Respondent Fatigue or Burden Does Not Overly Influence Assessment of the Concept of Interest), p. 30, Patient-Focused Drug Development: Selecting, Developing, or Modifying Fit-for-Purpose Clinical Outcome Assessments, October 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.
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.
“In many instances, such as when a COA is planned to be frequently measured (e.g., event-triggered data collection) or when the COA is complex and potentially burdensome, sponsors might consider seeking input from members of the patient community to ensure that the planned length of the trial and timing of COA assessments is feasible and as convenient as possible for the patients and/or caregivers.”
– Section II.A.3 (Clinical Trial Duration and Timing of Assessments for COA-Based Endpoints), p. 15, Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making, Draft, 2023 (FDA)
“To demonstrate respect for the patients and/or caregivers who participate and maximize the quality and completeness of information collected in a clinical trial, sponsors should consider ways to minimize the burden of participation and increase the convenience and value of participation to patients and/or caregivers. Early engagement with patient communities (see PFDD Guidance 1) and the involvement of patient representatives in the development of a clinical trial can improve the patient-centeredness of trial procedures and assessments… A failure to evaluate and address potential issues with burden or fatigue can result in a trial with greater missing data, poorer quality data… and/or more dropout.”
– Section IV.A.7 (Minimizing Participant Burden), p. 38, Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints for Regulatory Decision-Making, Draft, 2023 (FDA)
Q-Submission Program
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program
Pre-Submissions (Pre-Subs) allow submitters to obtain FDA feedback on specific questions before submitting formal IDEs, 510(k)s, PMAs, or other applications. Early feedback can improve submission quality and streamline the review process.
Submission Issue Requests (SIRs) provide a mechanism for addressing issues raised in FDA hold letters (e.g., 510(k) deficiencies) to help expedite resolutions.
Study Risk Determinations help sponsors clarify whether clinical studies are significant risk (SR), non-significant risk (NSR), or exempt from IDE regulations.
Informational Meetings are non-feedback sessions aimed at familiarizing FDA staff with new devices or sharing updates on ongoing development.
The program encourages timely submissions, including supplements for ongoing discussions and amendments to update materials.
Recommendations
Clearly define the purpose and goals of the Q-Sub in the submission to facilitate effective FDA review.
Include specific, well-formulated questions that focus on a limited number of topics to ensure actionable feedback.
For Pre-Subs, align planned testing and submissions with FDA guidance and include detailed device descriptions, testing protocols, and relevant background information.
Use SIRs to discuss proposed solutions to deficiencies raised in FDA hold letters, focusing on timely resolution.
Draft and submit meeting minutes promptly (within 15 days of meetings) to ensure accurate documentation of FDA feedback.
Regulatory Considerations
Submitters should adhere to the timelines specified for different Q-Sub types, including 70 days for Pre-Sub feedback or 21 days for SIRs submitted promptly after a hold letter.
Q-Subs should include all relevant regulatory history and references to prior FDA communications to streamline the review process.
FDA feedback through the Q-Sub program is non-binding and based on the information available at the time; subsequent submissions must align with the provided feedback to maintain consistency.
Informational Meeting requests should clearly state that feedback is not expected and may be used to track interactions outside other formal Q-Sub types.
Confidentiality of Q-Subs is maintained in compliance with FDA’s disclosure regulations and the Freedom of Information Act (FOIA).
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.
“Human Factors Questions
- Is the human factors test protocol, submitted in Attachment 1, adequate to collect safety data to support our future marketing submission?
- Is the attached use-related risk analysis plan adequate? Does the Agency have any additional critical tasks that we should consider?
- Is the proposed test participant recruitment plan for the human factors validation testing appropriate?”
– Appendix 2 (Example Pre-Sub Questions), p. 34, Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program, Final, May 29, 2025 (FDA)
Human factors and usability engineering
Applying Human Factors and Usability Engineering to Medical Devices
HFE/UE is essential for identifying and mitigating use-related risks that could compromise device safety or effectiveness.
Preliminary analyses, such as task and fault tree analyses, help identify critical tasks and use-related hazards early in device development.
Human factors validation testing must represent realistic use scenarios, include diverse user populations, and focus on critical tasks with potential for serious harm.
Residual risks that remain after validation testing must be justified in terms of the device’s overall benefits and risk management measures.
Effective risk management prioritizes design modifications over labeling or training as the primary method for addressing use-related hazards.
Recommendations
Incorporate HFE/UE into all stages of device development to address use-related hazards through design improvements.
Conduct comprehensive risk analyses to identify and prioritize critical tasks that may lead to serious harm if performed incorrectly.
Design human factors validation testing to reflect real-world conditions and involve representative user populations.
Address use-related risks primarily through design modifications, with labeling and training as secondary measures.
Submit detailed HFE/UE documentation in premarket applications to facilitate FDA review and approval.
Regulatory Considerations
Submit human factors validation testing data as part of premarket applications for devices where use-related errors could result in serious harm.
Risk management processes must align with standards such as ANSI/AAMI/ISO 14971 and IEC 62366, ensuring comprehensive hazard identification and mitigation.
Conduct additional validation testing if modifications to a marketed device impact user interactions or introduce new risks.
For actual-use testing, ensure compliance with Investigational Device Exemption (IDE) requirements where applicable.
Manufacturers should maintain detailed records of HFE/UE processes, which must be available for FDA review upon request.
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.
Requires manufacturers to address user needs and intended use during the design process. Includes design input, verification, and validation activities that ensure human factors and usability are assessed through systematic processes, including use error risk analysis and testing with representative users in actual or simulated use environments.
– FDA, 2017
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.
Once you’ve read the guidances, explore these best practices from the field:
Industry spotlight
Gathers real-world examples, case studies, best practices, and lessons learned from peers and leaders in the field relevant to this section. Use these insights to accelerate your work and avoid common pitfalls.