Findings
Traditional, site-based clinical trials often create significant burdens for participants, which can hinder recruitment, retention, and the enrollment of diverse populations.
A lack of early and sustained patient engagement in trial design can lead to research protocols that are misaligned with patient needs and endpoints that are not meaningful to them.
The underrepresentation of diverse racial, ethnic, and other demographic groups in clinical trials limits the generalizability of study results and can perpetuate health disparities.
Emerging digital health technologies (DHTs) and real-world data (RWD) present significant opportunities to make clinical trials more efficient, patient-centric, and inclusive, but their adoption has been inconsistent.

Recommendations
Sponsors and research teams should engage patients and patient advocacy groups as active partners throughout the entire clinical trial lifecycle, from design to dissemination.
Decentralized clinical trial (DCT) elements should be incorporated to reduce patient burden, improve access for diverse populations, and enhance the quality of data collection.
Trial sponsors must develop and implement proactive strategies to enhance the diversity and inclusion of trial participants to ensure results are applicable to all patient populations.
Novel endpoints derived from DHTs should be developed and validated to capture more objective, real-world measures of how patients feel, function, and survive.
Multi-stakeholder collaboration between industry, academia, patient groups, and regulators is essential to address systemic challenges and improve the clinical trial enterprise.

Regulatory Considerations
Early and frequent communication with regulators, such as the FDA, is critical when implementing novel approaches like DCTs or developing new digital endpoints for pivotal trials.
Regulatory frameworks must support the use of innovative technologies and trial models while ensuring data integrity, reliability, and patient safety.
The use of a single Institutional Review Board (IRB) for multi-site trials is a key regulatory-supported mechanism for streamlining ethics review and increasing trial efficiency.
When using DHTs and decentralized methods, robust plans for data quality, privacy, and security are necessary to meet regulatory standards for trial data submission.

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
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.

Findings
The need for rigorous verification and validation of DHT-generated measurements before they can be relied upon for safety, efficacy, or effectiveness.
The risk of widening health inequities due to disparities in access to healthcare and technology.
Challenges in ensuring data quality, privacy, and security.
The necessity for improved interoperability to facilitate data sharing.
The requirement for developing AI and machine learning algorithms for real-time data evaluation.

Recommendations
Improve the reach and effectiveness of DHTs, particularly among marginalized groups.
Develop and validate AI and machine learning algorithms for real-time evaluation of DHT data.
Ensure systematic protections for data privacy and security.
Enhance interoperability to unlock the full potential of DHTs.
Engage with stakeholders, including patients, to create efficient pathways for DHT adoption.

Regulatory Considerations
Compliance with rapidly changing digital health policies.
Utilization of FDA guidance documents and tools for understanding digital health regulations.
Consideration of regulatory oversight as DHTs become more integral to clinical trial design.

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.

Key Principles (Findings)
The core principle of the Critical Path Innovation Meeting (CPIM) program is that early, non-binding communication between the FDA and innovators can accelerate the development of new Drug Development Tools (DDTs). The program is designed to be a collaborative, scientific discussion, not a formal regulatory review of a specific product. A key finding from the program's existence is that a dedicated forum to discuss emerging science—outside the context of a specific drug application—is critical for advancing regulatory science and modernizing the drug development process.

Recommendations for Stakeholders
The program implicitly recommends that innovators (from industry, academia, etc.) proactively seek the FDA's perspective on novel methodologies and technologies. Stakeholders are encouraged to request a CPIM to discuss potential biomarkers, novel clinical outcome assessments (COAs), innovative clinical trial designs, and other new tools. The goal is for sponsors to gain a better understanding of the FDA's thinking on a particular topic, which can help guide their development efforts and de-risk future regulatory submissions.

Regulatory Considerations
A CPIM is an informal, non-binding scientific discussion and does not replace formal regulatory meetings like pre-IND or End-of-Phase meetings. The advice provided by the FDA during a CPIM does not constitute a regulatory decision or a commitment for a future approval pathway. The program is part of the FDA's broader "Critical Path Initiative" and is intended to promote innovation by enhancing communication. Any outcomes or suggestions from a CPIM are for informational purposes to help guide the development of novel tools and approaches.

Reference list only.

Findings
Novel digitally-derived endpoints can provide more reliable data, increase trial efficiency, and enhance patient centricity.
Selecting appropriate outcome measures that are meaningful to patients and clinicians is critical to success.
Developing these endpoints requires a resource-intensive, systematic approach to meet stakeholder needs.
Demonstrating validity and utility of novel endpoints poses unique challenges, especially for new measures without established validation standards.
Sharing lessons learned and promoting transparency can advance the field by enabling collaboration and establishing standards.

Recommendations
Focus on measures that are meaningful to patients and clinically relevant by incorporating both patient and clinician perspectives.
Select technology after identifying the appropriate outcome to ensure alignment between the technology and trial objectives.
Engage with regulators early and often to ensure endpoint acceptance and alignment with regulatory requirements.
Include digitally-derived endpoints in early-phase trials and observational studies to validate their fit-for-purpose status.
Encourage knowledge sharing and collaboration among stakeholders to establish shared standards and accelerate adoption.

Regulatory Considerations
Engage with FDA, EMA, or other regulatory bodies during early stages of endpoint development to gather critical input.
Use established regulatory frameworks, such as Investigational New Drug (IND) or Investigational Device Exemption (IDE), for guidance on endpoint use in pivotal trials.
Validate technologies to meet performance characteristics, ensuring outputs correspond to clinical concepts of interest.
Include digitally-derived endpoints in exploratory studies to build evidence for their regulatory approval.
Reference resources such as the FDA and EMA guides for navigating endpoint-related regulatory interactions.

Findings
Traditional RCTs face high costs, long timelines, recruitment challenges, and lack of diversity.
Recruitment efficiency in stroke trials has decreased over the past 25 years.
Digital tools for stroke prevention often lack quality and interactive functionality.
Decentralized RCTs present challenges in data quality and require validation.
Regulatory and compliance requirements vary significantly across regions.

Recommendations
Adopt decentralized RCTs with a patient-centric approach.
Leverage digital technologies to improve trial efficiency and participant experience.
Ensure participant engagement and education in trial design.
Provide high-quality training and support for decentralized procedures.

Regulatory Considerations
Collaborate with regulatory agencies early in trial design.
Compliance with varying international standards is necessary.
Rapid evolution of technology outpaces regulatory changes.
Cross-border data standards and privacy rules must be observed.

Findings
Meaningful outcome measures should align with patient priorities and clinical relevance, emphasizing aspects of health that impact daily life.
Digital tools must demonstrate value over traditional methods in capturing outcomes, especially in remote or decentralized contexts.
Questions about therapeutic benefit and endpoint sensitivity must address how these measures reflect patient improvements or disease progression.
Stakeholder collaboration is critical to selecting and validating concepts of interest and corresponding outcome measures.
Challenges include ensuring data privacy, operational feasibility, and addressing potential gaps in endpoint validation.

Recommendations
Engage patients and caregivers to identify meaningful aspects of health and concepts of interest relevant to their daily lives and goals.
Collaborate with clinicians to determine the clinical validity and utility of proposed measures and tools for endpoint development.
Ensure that DHTs selected for measurement add value beyond traditional methods and are feasible for clinical and real-world use.
Incorporate payer perspectives to align outcome measures with cost-benefit evaluations and reimbursement criteria.
Use the question bank as a flexible guide, adapting it to the specific needs and context of individual clinical trials.

Regulatory Considerations
Ensure endpoints and their measures meet regulatory standards for clinical relevance and sensitivity to therapeutic changes.
Align outcome measures with accepted core sets (e.g., COMET database) and validate them through stakeholder engagement.
Address concerns related to data privacy, scalability, and operational feasibility in the use of DHTs for endpoint development.
Plan for regulatory engagement to demonstrate the robustness of digitally-derived endpoints in pivotal clinical trials.
Provide evidence to support the incorporation of novel endpoints into regulatory and payer frameworks for decision-making.

Findings
Digitally-derived endpoints must align with trial goals, reflect the concept of interest (COI), and demonstrate clinical relevance.
Validation involves both verification of the digital tool's performance and ensuring the endpoint measures what it claims to measure.
Early-phase trials should assess usability, tolerability, and data privacy to ensure tools are operationally feasible for the intended population.
Regulatory alignment on endpoints, including their ability to demonstrate meaningful change, is critical before pivotal trials.
Statistical analysis plans must account for the unique aspects of digital endpoints, such as data quality and missing data considerations.

Recommendations
Define target populations and meaningful aspects of health (MAH) early in development to guide endpoint selection.
Conduct gap assessments of existing endpoints and propose clinically meaningful differences for patient outcomes.
Validate digital tools through verification (e.g., accuracy, reliability) and usability studies specific to the intended population.
Engage with regulators to align endpoints with evidentiary requirements for pivotal trials and label claims.
Prepare statistical plans and supporting evidence to justify the inclusion of digitally-derived endpoints in pivotal trials.

Regulatory Considerations
Verification and validation of DHTs should meet FDA and EMA standards, ensuring endpoints are fit-for-purpose and clinically relevant.
Align endpoints with regulatory requirements, demonstrating meaningful change that reflects treatment benefit.
Compile evidence of clinical validation, including how endpoints detect meaningful changes during treatment.
Address privacy, scalability, and operational feasibility to meet regulatory expectations for pivotal trials.
Consult regulatory guidance documents, such as FDA’s draft guidance on DHTs for remote data acquisition and EMA's methodologies for drug development.