Findings
Evaluating patient outcomes on a case-by-case basis within individual drug programs is an inefficient use of resources and creates regulatory unpredictability. This approach frequently leads to redundant efforts to validate the same assessment tools across different development programs. The lack of a standardized, transparent process for accepting Clinical Outcome Assessments (COAs) hinders the development and use of novel, patient-centric endpoints, ultimately slowing the delivery of therapies that address outcomes that matter most to patients.

Recommendations
Developers of COAs, including patient groups, academic researchers, and pharmaceutical sponsors, are encouraged to collaborate with the FDA through the qualification program. This engagement should occur early to ensure that the measures are developed with sufficient rigor to meet regulatory standards. Stakeholders should leverage the program to validate a wide range of COAs, particularly Patient-Reported Outcomes (PROs), making them publicly available to advance patient-focused drug development across the entire industry and reduce redundant validation work.

Regulatory Considerations
The COA Qualification Program offers a formal regulatory pathway for the FDA to review and accept a COA for a specific Context of Use (COU). This qualification is separate from the review of an individual drug application, making the validated tool accessible for any sponsor to use in their clinical trials without re-adjudicating the COA's fitness for that purpose. Qualification requires a comprehensive submission demonstrating the measure is well-defined and reliable, ensuring that it appropriately captures the patient's experience or functional status.

Findings
Patient-centeredness is a key criterion, with higher importance assigned to endpoints identified by patients as meaningful.
The tool includes predefined weighting criteria to ensure that endpoints addressing unmet needs are prioritized.
A structured rating scale facilitates the comparison of novel endpoints across different therapeutic areas.
Digital measurement technologies, such as wearables and ePROs, are increasingly considered viable novel endpoints.
The tool provides a standardized approach to endpoint selection but requires user input to tailor scores to specific trial needs.

Recommendations
Clinical researchers should use the tool to systematically evaluate novel endpoints before incorporating them into study designs.
Weighting criteria should be adapted based on the specific therapeutic area and patient population to reflect real-world priorities.
Endpoint selection should incorporate regulatory and scientific considerations to ensure alignment with study objectives.
Digital health technologies should be leveraged where appropriate to support novel endpoint validation and implementation.
Stakeholder engagement, including patient advocacy groups, should be integrated into the endpoint selection process.

Regulatory Considerations
Novel endpoints should align with FDA and regulatory body expectations for evidence generation and validation.
The tool does not replace regulatory guidance but can serve as a structured framework for early-phase endpoint assessment.
Sponsors should document endpoint selection rationale in submissions to regulatory agencies.
Digital health endpoints should comply with data integrity and privacy regulations, including HIPAA and GDPR.
Ongoing validation and post-market evidence generation may be required for novel digital endpoints used in pivotal trials.

Findings
Developing a novel endpoint requires an iterative and patient-centered approach, beginning with defining the study population and relevant health aspects.
Concepts of interest (COIs) must be specific, measurable, and clinically meaningful, with input from patients and caregivers.
Endpoint validation includes defining meaningful change, ensuring content validity, and demonstrating the ability to detect change.
Digital tools must meet criteria for usability, analytic validity, and tolerability within the target population.
Regulatory engagement and alignment throughout the process are critical to endpoint acceptance.

Recommendations
Define the study population and context of use (COU) early to guide endpoint and technology selection.
Identify meaningful health aspects (MHA) and concepts of interest (COI) with input from patients and clinicians.
Select and validate DHTs based on performance, usability, and their ability to capture meaningful data.
Establish meaningful change thresholds and validate endpoints in real-world settings.
Engage with regulators at every stage to align endpoints with evidentiary and regulatory standards.

Regulatory Considerations
Define and validate meaningful change thresholds that reflect treatment benefits for regulatory acceptance.
Ensure DHTs meet analytic validity standards, including accuracy, reliability, and reproducibility.
Demonstrate content validity, ensuring that endpoints accurately reflect the intended COI across the full range of anticipated data.
Align with regulatory requirements to incorporate validated endpoints into pivotal trials.
Address usability, data privacy, and compliance concerns to meet regulatory and operational standards.

Findings
D-PPAC (daily tool) and C-PPAC (weekly tool) are hybrid tools combining subjective patient inputs with objective activity monitor outputs, offering comprehensive insights into PA levels.
Psychometric validation indicates reliability, with high internal consistency and construct validity, though test-retest reliability is limited to specific trials.
Both tools are sensitive to changes in physical activity, but interpretation is limited in patients with very severe COPD or significant comorbidities.
Minimal important difference (MID) thresholds were identified for domains and total scores, though their clinical meaningfulness remains under investigation.
The tools' interchangeability within trials is limited due to differing score ranges and measurement approaches.

Recommendations
Apply D-PPAC in trials where daily monitoring of physical activity is a primary endpoint.
Use C-PPAC in trials requiring supportive outcome data or when minimizing patient burden is critical.
Train investigators and patients thoroughly to ensure high compliance with both tools.
Further refine the total score derivation methodology to enhance interpretability and clinical relevance.
Expand validation efforts to include patients with broader comorbidity profiles and greater PA limitations.

Regulatory Considerations
Restrict the tools' use to the validated activity monitors (Actigraph G3TX and Dynaport MoveMonitor) until further assessments are conducted.
MID thresholds should be used with caution, considering their limited precision and potential variability across different populations.
The use of these PRO tools in regulatory submissions must align with EMA's guidance for COPD, ensuring endpoints align with study objectives.

Findings
Concerns about data accuracy, particularly variability in measurements across different age groups and devices.
Issues with data provenance, as raw data from wearables are often transformed and filtered before storage, making comprehensive analysis difficult.
Regulatory challenges due to lack of specific FDA guidance for clinical trials using wearables and mobile devices.

Recommendations
Improve data accuracy through standardized approaches and expert recommendations.
Enhance data provenance by developing methods to trace data lineage and ensure transparency in data processing.
Develop specific FDA guidance for the use of wearables and mobile devices in clinical trials.
Implement robust security measures to protect data integrity and privacy.
Follow the ePRO Consortium's recommendations for device suitability in clinical trials.

Regulatory Considerations
The need for FDA guidance specific to clinical trials using mHealth technologies.
Sponsors' responsibility to validate the reliability of mHealth technology in capturing and transmitting data.
Security vulnerabilities in devices, necessitating adherence to privacy standards and robust security protocols.

Findings
There is uncertainty regarding the regulatory acceptability of data collected from wearable devices.
There is a lack of specific regulatory guidance on implementing wearables in clinical trial protocols.
The need for evidence to demonstrate the appropriateness and clinical relevance of new endpoints derived from wearable data.

Recommendations
Identify essential properties of fit-for-purpose wearables and propose evidence needed to support their use.
Extend the FDA's definition of a PerfO to include unsupervised settings.
Ensure that any wearable device adheres to basic properties important to clinical trials, such as source data control, traceability, and security.
Provide evidence supporting the reliability, validity, and interpretability of data generated by wearable devices.

Regulatory Considerations
Market clearance/certification is not a requirement for device selection in clinical trials if evidentiary considerations are satisfied.
The need for a robust framework for adopting wearables in regulatory trials despite the lack of specific guidance.
The evidence needed to support a device and its endpoint depends on the ultimate use of the endpoint.

Findings
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.