Findings
Establishing cross-sector consortia does not guarantee success without a unified objective and stakeholder buy-in. A neutral, independent facilitator is a key element for successful governance in many collaborative platforms. Many consortia lack consistent methods for storing critical data, meeting minutes, and regulatory briefing packages, which creates barriers after project completion. Regulatory success depends heavily on the early development of a strategy that defines the necessary evidence to validate innovative methodologies. Successful examples include the qualification of biomarkers for polycystic kidney disease and type 1 diabetes, as well as imaging measures for Alzheimer’s disease.

Recommendations
Consortium members should develop an initial regulatory strategy during the project scoping and planning phases. Teams must explicitly define the context of use for any proposed tool to articulate exactly what decisions the output will inform. A robust data strategy should be implemented early, including formal agreements for data use, standardization, and sharing that remain in place in perpetuity. Consortia must prioritize sustainability plans to ensure data and active databases remain available for research and regulatory use after funding expires. Projects should integrate regulatory science expertise from the start to cover both EU and US frameworks.

Regulatory Considerations
Regulators require individual patient-level data that is fully curated, standardized, and presented through formal submissions like qualification applications. Formal regulatory endorsement ensures a tool can be trusted for consistent interpretation in drug development and marketing authorization evaluations. Early engagement with agencies such as the FDA and EMA is essential to gain feedback on novel methodologies and align study designs with regulatory expectations. Specific pathways like the EMA Qualification of Novel Methodologies and the FDA Qualification Process for Drug Development Tools should be utilized. Regulatory qualification may require ongoing access to databases to support the long-term use of the methodology.

Findings
Regulatory Acceptance is Complex: Gaining regulatory acceptance for endpoints derived from Digital Health Technologies (DHTs) is a lengthy, multifaceted, and costly process that requires a global strategy and early health authority consultation.
"Fit-for-Purpose" is Key: A DHT's clearance or approval as a medical device does not automatically ensure it is fit-for-purpose in a clinical trial; its intended use must align with the specific context of use (COU) in the study.
Meaningfulness is a Hurdle: Demonstrating the clinical meaningfulness of novel digital endpoints, especially for abstract concepts like cognitive decline in Alzheimer's Disease, remains a significant challenge for regulatory acceptance.
International Harmonization is Lacking: Differences in regulatory requirements for DHT validation between major health authorities can delay or prevent the successful implementation of digital measures in global clinical trials.
Technology Changes Pose Risks: Software and hardware updates to DHTs during a clinical trial can have significant implications, potentially invalidating study results if not managed through a predetermined change-control plan.

Recommendations
Engage Health Authorities Early and Often: Sponsors should conduct multiple consultations with major health authorities (e.g., FDA, EMA) early in the development process to align on the Concept of Interest (COI), COU, and the validation roadmap.
Develop a Comprehensive Regulatory Strategy: A global regulatory strategy should be an integral part of the overall development plan, tailored to the program's objectives and endpoint hierarchy.
Establish "Fit-for-Purpose" Criteria: Before selecting a DHT, sponsors should establish the minimum technical and performance specifications required for the specific COU to guide the selection of a fit-for-purpose device.
Create a Conceptual Framework: For novel endpoints, sponsors should develop a conceptual framework that visualizes how the DHT-derived measure relates to meaningful health concepts and patient experiences.
Plan for Change and Missing Data: Sponsors should establish predetermined change-control plans with manufacturers to manage DHT updates and create risk management plans to minimize and handle missing data from remote acquisition.

Regulatory Considerations
Distinct Pathways in US vs. EU: The US FDA uses a risk-based approach for DHTs that are medical devices, while in Europe, CE marking for the intended COU is generally expected by the EMA.
Qualification is an Option, Not a Requirement: Both the FDA and EMA offer voluntary qualification programs for Drug Development Tools (DDTs), which can validate a DHT for a specific COU across multiple drug programs, though the process is resource-intensive.
Scientific Advice for Individual Programs: For DHTs used within a single drug development program, engaging with health authorities through scientific advice meetings is a more targeted and confidential pathway for gaining feedback and agreement.
Data Privacy and Security are Paramount: Sponsors must ensure that the collection, transfer, and storage of personal data via DHTs comply with all applicable regulations, such as GDPR in the EU, including cybersecurity and data transfer measures.

Findings
Product development firms are hesitant to increase DHT use despite regulatory support.
Conventional hardware-based technologies are preferred over newer digital tools.
Operational barriers contribute to the low adoption of DHTs in product development trials.

Recommendations
Reduce operational barriers to facilitate DHT adoption.
Provide additional regulatory clarity to encourage DHT use.
Encourage the incorporation of more DHTs and patient-centric endpoints in clinical trials.

Regulatory Considerations
The FDA's guidance on DHT use is evolving and not yet fully formalized.
There is a need for harmonization between US and non-US regulatory agencies.
The impact of recent regulatory support may take years to be fully realized.

Findings
There is a lack of alignment in concepts, definitions, and terminology related to digital health technologies, which hinders global drug development programs.
Different regulatory agencies interpret common terms like "monitoring" differently, leading to confusion and inconsistency.
The classification of digital measures impacts evidentiary requirements and regulatory acceptance, but detailed guidance on these requirements is lacking.

Recommendations
Align terminology and definitions across stakeholders to ensure consistency in understanding and communication.
Reuse existing terms where possible to avoid unnecessary complexity.
Focus on what is measured rather than how it is measured to streamline regulatory processes.
Encourage companies and regulators to reflect on and adopt a common lexicon within their organizations.
Move quickly to address critical questions about evidence needed for validation of digital measures.

Regulatory Considerations
Regulatory authorities should apply consistent standards for all endpoints, regardless of data acquisition methods.
The classification of DHTs as medical devices or not will impact their regulatory pathway and requirements.
There is a need for dialogue with regulators to clarify source data requirements for data acquired by DHTs.

Findings
The adoption of BYOD in clinical trials has been accelerated by the COVID-19 pandemic and supportive regulatory guidance, which now recognize it as an acceptable means for remote data collection. Studies have shown high measure completion and equivalent data quality between provisioned devices and BYOD, supporting its use in diverse patient populations. Key challenges to BYOD implementation include ensuring data equivalence across a wide variety of personal devices, managing participant technical support, and addressing data privacy and security concerns. The choice between native apps and web-based solutions involves trade-offs in usability, data security, and operational complexity.

Recommendations
Sponsors should develop a clear BYOD strategy that considers the target patient population, the complexity of the required data collection, and the global regulatory landscape. A robust training and support plan is essential for both participants and site staff to ensure proper device use and troubleshooting. Sponsors should work with technology vendors to ensure their platforms are user-friendly, secure, and capable of handling data from a variety of devices. It is crucial to establish clear communication channels for participants to report technical issues and receive timely assistance.

Regulatory Considerations
Both the FDA and EMA have issued guidance that supports the use of BYOD in clinical trials, provided that data integrity, security, and privacy are maintained. Sponsors must be able to demonstrate the equivalence of data collected via BYOD with data from provisioned devices. All BYOD solutions must comply with relevant data protection regulations, such as GDPR and HIPAA. The regulatory submission should include a clear description of the BYOD strategy and a justification for its use in the trial.

Findings
Standard assessments lack sensitivity in early stages of neurodegenerative diseases.
Challenges with the validity and quality of RMT measurements.
Issues related to equity and inclusion in deploying digital tools.
Importance of considering feasibility, acceptance, usability, and ecological validity of digital endpoints.

Recommendations
Develop regulatory strategies early on.
Ensure equity and inclusion in deploying digital tools.
Address challenges related to the validity and usability of digital endpoints.
Promote public-private partnerships to address privacy and security concerns.
Involve patients and stakeholders in the design and implementation of digital tools.

Regulatory Considerations
Acceptance of digital endpoints by regulatory authorities is crucial.
Validation with current gold standards and clinically meaningful legacy endpoints.
Ensure data security and privacy.

Findings
Limited number of drugs approved using DHT data for labeling claims.
Lack of clarity on definitions and regulatory pathways for DHT-derived endpoints.
Challenges in global studies due to varying definitions among regulatory authorities.
Fine line between using DHT-derived measures for therapy response and quality of life assessments.

Recommendations
Create clear definitions for DHT-derived tools and measures.
Define specific evidentiary criteria for DHT-based tools.
Leverage precompetitive public-private partnerships to advance DHT development.
Utilize existing regulatory pathways like the iSTAND pilot program.

Regulatory Considerations
Need for harmonized global definitions and pathways for DHT-derived measures.
Use of existing programs like the iSTAND pilot program to integrate new digital measures.
Clear guidance from FDA and EMA for qualifying biomarkers or COAs in drug development.

Findings
The US regulatory landscape is more suitable for promoting innovation in digital health compared to Europe.
Traditional regulatory approaches are not keeping pace with technological advancements.
There is a lack of specific guidance on the use of wearables and software in clinical drug trials.
The US has a more advanced regulatory framework for drug development tools than Europe.

Recommendations
Use approved solutions or consider early qualification of drug development tools.
Engage early with FDA and EMA to define evidentiary standards and regulatory pathways.
Ensure correct regulatory classification of digital tools.
Engage early with regulatory authorities to navigate the regulatory landscape.

Regulatory Considerations
Digital tools must be fit-for-purpose for their intended use.
Sponsors must ensure conformity with GxP and local data privacy and cybersecurity laws.
Data from digital tools must deliver reliable data with tangible clinical benefits.
The context of use drives the benefit-risk assessment and evidentiary criteria for regulatory acceptability.

Findings
A need for additional regulatory clarity specific to DHT-derived endpoints.
The official clinical outcome assessment qualification process is impractical for the biopharmaceutical industry.
A lack of comparator clinical endpoints.
A lack of validated DHTs and algorithms for concepts of interest.
A lack of operational support from DHT vendors.

Recommendations
Engage key stakeholders early.
Incorporate DHT-derived endpoints in early-phase trials and observational studies.
Invest in COA development initiatives.
Engage technology manufacturers early in the development process.

Regulatory Considerations
The EMA published a Q&A document on DHT use in clinical trials.
The FDA released guidance on collecting patient data remotely using DHTs.
The FDA established the Digital Health Center of Excellence to facilitate early regulatory engagement.

Findings
Regulatory frameworks differ across regions, with the FDA focusing on digital health technologies and the EU emphasizing digital methodologies under MDR.
Determining whether a DHT qualifies as a medical device depends on its intended use and functionality, necessitating region-specific evaluations.
Health authority engagement can occur through FDA pathways like Critical Path Innovation Meetings (CPIM) and EMA’s Innovation Task Force (ITF).
Verification and validation of DHTs are crucial to ensure reliability and compliance with regulatory requirements in clinical trials.
Cybersecurity and compliance with privacy laws, such as GDPR, are mandatory considerations for DHT implementation.

Recommendations
Engage Regulators Early: Utilize FDA, EMA, or MHRA pathways (e.g., CPIM, ITF) during early development to align on requirements and mitigate risks.
Conduct thorough assessments to determine if a DHT qualifies as a medical device under regional regulations.
Implement robust validation and verification processes to confirm that DHTs are fit-for-purpose in clinical investigations.
Ensure compliance with GDPR, HIPAA, and other relevant data protection standards to safeguard patient information.
Adhere to GCP guidelines, including the ALCOA+ principles, to maintain data credibility and patient safety throughout the trial.

Regulatory Considerations
FDA Regulations: Evaluate DHTs under the FDA’s framework for medical devices, including exemptions under 21 CFR Part 812 and the Digital Health Software Precertification Program.
EU MDR/IVDR: Comply with MDR for medical devices and IVDR for in-vitro diagnostics, ensuring alignment with Annex VIII for software classification.
UK MHRA Guidance: Reference MHRA’s flowcharts for determining if a software qualifies as a medical device and ensure compliance with UK-specific regulatory requirements.
Global Harmonization Efforts: Consider global standards, such as ICH E6 (R2) and GHTF/IMDRF guidelines, to align multinational clinical trials.
Leverage pathways like EMA’s qualification process for novel methodologies and FDA’s DDT qualification program for broader acceptance of digital endpoints.

Findings
The qualification process addresses both clinical and non-clinical methodologies, encouraging iterative interaction between the EMA and applicants to refine the methods.
Early engagement through preparatory meetings and informal discussions enhances the alignment of methodologies with regulatory expectations.
Public consultations ensure that qualified methodologies reflect scientific consensus and address broader stakeholder concerns.
The process includes provisions for updating qualifications based on emerging scientific evidence or technological advancements.
A multidisciplinary qualification team ensures comprehensive evaluation of methodologies within their scientific and regulatory contexts.

Recommendations
Engage with the EMA early in the development of novel methodologies to align on procedural and scientific expectations.
Provide comprehensive documentation, including study protocols, analytical validations, and clinical data, to support qualification requests.
Prepare for iterative reviews and potential public consultations to address gaps and enhance methodological robustness.
Include systematic reviews and meta-analyses to support claims about the utility and validity of the methodologies.
Use the qualification advice or opinion to build trust and transparency with stakeholders and regulatory bodies.

Regulatory Considerations
Adhere to EMA’s procedural guidelines for submission via the IRIS platform, ensuring compliance with data submission and review timelines.
Consider the applicable legal and regulatory frameworks, including Medical Devices Regulation and ICH guidelines, when developing and validating methodologies.
Address potential updates to methodologies during development through a risk-based management approach to maintain regulatory alignment.
Ensure the qualification process is informed by public consultation and international regulatory collaboration, where applicable.
Submit detailed impact assessments for changes to methodologies that may affect the reliability or applicability of the generated data.

Findings
SV95C provides a reliable and sensitive measure of maximal ambulation, addressing limitations of traditional assessments like the 6MWT.
Real-world data collection via wearable devices enhances accuracy and reflects true ambulatory capabilities.
Longitudinal studies confirmed SV95C's ability to detect disease progression and response to corticosteroid treatments.
Correlations with existing clinical outcome assessments (6MWT, NSAA, and 4SC) validate SV95C’s construct validity.
Patients and caregivers support the use of wearable devices in clinical trials, emphasizing reduced burden and improved trial attractiveness.

Recommendations
Use SV95C as a primary endpoint in DMD clinical trials to monitor maximal stride velocity in real-world conditions.
Incorporate SV95C alongside traditional endpoints to ensure comprehensive assessment of therapeutic efficacy.
Establish training protocols for patients and caregivers to optimize compliance with device usage.
Expand normative data for SV95C in younger and more diverse patient populations.
Conduct further research on meaningful change thresholds (MCTs) to refine clinical relevance.

Regulatory Considerations
Ensure SV95C is included as a primary endpoint with supporting secondary endpoints (e.g., muscle strength assessments) for consistency.
Validate wearable devices used for SV95C measurement to meet regulatory standards for accuracy and reliability.
Address variability and standardize protocols for data collection to ensure regulatory compliance.
Collect additional longitudinal data to strengthen the predictive value of SV95C for regulatory submissions.
Incorporate privacy and data security measures to comply with data protection regulations, including anonymization and encryption.