Findings
Only a small number of novel digital measures have matured into regulatory qualification or efficacy endpoints.
Demonstrating that digital measures are meaningful to patients is a key challenge.
There is resistance from sponsors due to uncertainty about the value of DHT-derived endpoints in regulatory discussions.
Patient experiences are highly heterogeneous, making it difficult to generalize meaningful aspects of health.
Challenges exist in defining clinical significance and classifying digital measures as COAs vs biomarkers.

Recommendations
Engage patients and caregivers in facilitated discussions to incorporate their voices.
Determine the best method for gathering patient input on a case-by-case basis.
Engage patients to inform evidence needs, implementation, and value delivery.
Return summarized health data to participants to motivate and encourage communication with clinicians.

Regulatory Considerations
Understand the FDA's recent guidance on patient engagement in drug development.
Recognize the shift in evidence rigor required by the FDA for demonstrating meaningfulness.
Provide evidence that DHTs are usable, acceptable, and clinically relevant.
Utilize early engagement channels like CPIM and pre-LOI programs offered by the FDA.

Findings
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.

Findings
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.

Findings
Sponsors must weigh the study benefits of PTs against potential burdens such as usability challenges, frequent reminders, or the need for connectivity and device maintenance.
Factors such as geography, socioeconomics, cultural practices, and technical literacy must be addressed to ensure PT accessibility across diverse patient populations.
Sponsors need to protect patient privacy by adhering to data protection standards and ensuring informed consent materials clearly communicate how data will be used and stored.
Effective maintenance, training, and 24/7 support systems for patients and sites are critical to ensure smooth operation and minimize disruptions.
Providing value to participants, such as progress feedback or gamification elements, can improve the patient experience and adherence.

Recommendations
Design Patient-Centric Materials: Simplify patient-facing materials, tailoring them to low health and technical literacy levels, and ensure patient input is incorporated during the design phase.
Identify and address geographic, socioeconomic, and cultural barriers to technology adoption to ensure inclusivity.
Offer multi-format training for patients and caregivers, provide troubleshooting guides, and ensure 24/7 multilingual technical support.
Safeguard patient data and inform patients of all potential risks associated with PTs. Develop backup plans for device failures or power outages.
Assess how PTs affect daily living, including comfort, usability, and the time required for setup and routine use, to minimize intrusion.

Regulatory Considerations
Ensure adherence to GDPR, HIPAA, and other relevant data protection laws. Clearly communicate privacy and data use details in consent forms.
Validate PTs for safety and suitability in the target population and ensure compliance with regulatory standards for medical devices.
Ensure that consent forms clearly describe PT functionality, benefits, and limitations in accessible language.
Global Adaptability: Account for regional laws, infrastructure limitations, and language requirements to ensure PT compatibility and regulatory compliance across geographies.

Findings
There is a gap in developing robust and meaningful outcome measures based on DHTT sensor data.
A major challenge is integrating vast amounts of sensor data into meaningful clinical outcome measures.
There is no clear pathway for developing these outcome measures, indicating a need for standardized methods.

Recommendations
Develop roadmaps for data-centric and patient-centric digital outcome measures.
Integrate patient insights into the development of outcome measures.
Ensure statistical robustness and validity in digital outcome measures.
Encourage scientific discourse to reach a consensus on digital outcome measure development.
Combine subjective and objective data for comprehensive patient assessment.

Regulatory Considerations
The field relies on guidance from regulatory authorities like the FDA and EMA.
Regulatory frameworks need to keep pace with the fast-moving nature of DHTTs.
There is a need for consensus on digital outcome measure development that respects established methods.

Findings
Scarcity of reliable and frequent ground truth labels in real-world conditions.
Challenges in extracting clinically meaningful information from digital device data.
Lack of standardized methods for data collection, storage, organization, curation, and analysis.
Issues with participant diversity and digital literacy affecting patient engagement and adherence.
Need for alignment on methods to establish reliability and validity of DHT measures.

Recommendations
Focus on clinically meaningful outcomes for patients in PD drug development.
Build consensus on data and metadata standards for data exchangeability.
Develop open-source platforms for analysis across device types and studies.
Engage early and often with regulatory agencies via consortia.
Align with FDA review divisions and utilize EMA qualification methodologies.

Regulatory Considerations:
Align with regulatory science pathways to ensure scientific rigor and clinical validity.
Engage with regulatory agencies like FDA and EMA early in the process.
Adhere to standardized data collection and analytical approaches.

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.