Findings
Value-Based Metrics: Digital endpoints should directly measure meaningful outcomes for patients, emphasizing health-related quality of life and real-world relevance.
Technical Validation: Validation must ensure device reliability, data security, and usability in real-world settings while addressing potential confounders like environmental variability.
Clinical Validation: Rigorous evaluation should assess tolerability, differences between patients and controls, repeatability, correlation with traditional metrics, and responsiveness to disease changes.
Regulatory Challenges: Clear guidelines for digital endpoints are lacking, but early engagement with FDA or EMA can streamline the qualification process.
Collaboration Needs: Greater collaboration across stakeholders, including patients, regulators, and industry, is essential to standardize methodologies and share data effectively.

Recommendations
Engage Early with Regulators: Begin discussions with agencies like FDA and EMA to align on endpoint requirements, definitions, and validation approaches.
Adopt Patient-Centric Design: Collaborate with patients and advocacy groups to ensure digital endpoints are relevant, tolerable, and user-friendly.
Standardize Validation Processes: Follow a structured framework that includes technical validation, clinical evaluation, and regulatory case-building.
Invest in Data Sharing and Harmonization: Create shared databases and metadata standards to integrate findings across studies and devices, reducing duplication.
Encourage Open Science: Promote transparency and collaboration among researchers, industry, and regulatory bodies to accelerate innovation.

Regulatory Considerations
Regulatory Alignment: Align endpoints with EMA and FDA guidance to meet evidentiary standards for qualification and integration into clinical trials.
Iterative Validation: Conduct iterative validation studies, integrating feedback from regulatory interactions and stakeholder collaborations.
Privacy and Compliance: Ensure data privacy and security compliance, particularly when leveraging wearable and mobile technologies for home-based monitoring.
Address Real-World Variability: Provide evidence that real-world variability does not significantly bias results and demonstrate endpoint reliability across diverse populations.
Build Regulatory Confidence: Use validated endpoints in exploratory or secondary roles initially to build evidence for their adoption as primary endpoints.

Findings
There is a need for a deeper understanding of biomarker dynamics in response to tcVNS for real-time physiological monitoring.
PPG amplitude is identified as a superior biomarker compared to heart rate for predicting responses to tcVNS.
Current digital health technologies may benefit from exploring beyond standardized waveforms for tcVNS applications.

Recommendations
Focus on PPG amplitude as a primary biomarker for real-time tcVNS systems.
Consider latency in clinical monitoring7 and closed-loop system design.
Explore multimodal closed-loop systems utilizing signals other than ECG and PPG.

Regulatory Considerations
Use of FDA-approved devices like gammaCore for tcVNS.
Ensure user safety during stimulation by varying parameters appropriately.

Findings
Digital measures must align with patient-defined meaningful aspects of health to ensure relevance and impact.
Continuous patient engagement is essential to identify meaningful concepts, validate measures, and refine endpoints.
The proposed framework—MAH, COI, Outcome, Endpoint—helps structure the development process, ensuring alignment with patient priorities.
Existing tools like the 6-minute walk test lack specificity and meaningfulness for many patients, highlighting the need for patient-centered digital alternatives.
Regulatory guidance emphasizes the importance of meaningful, patient-focused endpoints in clinical trials to support treatment evaluation and labeling claims.

Recommendations
Continuously involve patients in defining MAHs, COIs, outcomes, and endpoints to ensure relevance and usability.
Use the MAH-to-Endpoint framework to systematically develop measures that align with patient needs and clinical goals.
Select outcomes that demonstrate a clear relationship with MAHs and COIs, supported by patient and clinical validation.
Work collaboratively with patient advocacy groups, regulators, and researchers to harmonize development efforts and prioritize meaningful measures.
Ensure technology choices are driven by patient needs and clinical relevance, not the capabilities of available tools.

Regulatory Considerations
Ensure digital measures comply with regulatory expectations for meaningfulness, clinical relevance, and evidence generation.
Provide robust evidence linking MAHs, COIs, outcomes, and endpoints to support regulatory submissions.
Validate Endpoints Rigorously: Demonstrate that digital endpoints reliably reflect patient outcomes and provide value in clinical trial contexts.
Include Statistical Plans: Define how endpoints will be analyzed, ensuring alignment with trial protocols and regulatory frameworks.
Use patient-reported anchors to validate the clinical meaningfulness of changes in digital measures.

Findings
Early and iterative engagement with EMA helps developers refine data generation plans, identify multidisciplinary expertise, and ensure the adequacy of early-stage data.
Clearly defining the concept of interest, context of use, and clinically meaningful change is essential for qualifying digital measures.
Comprehensive documentation should cover benefit-risk impacts, reliability, and validity of digital health technologies, avoiding overly detailed technical specifications that could invalidate qualification during updates.
Risk assessments of technology changes and updates, akin to approaches used for manufacturing changes, are crucial during regulatory reviews.
Support for collaborative groups, such as consortia and trade associations, helps aggregate and harmonize data to progress regulatory applications.

Recommendations
Establish early contact with EMA to align on regulatory requirements, optimize data generation, and ensure continuity in assessment teams.
Identify the digital technology's impact on benefit-risk assessment, specifying its purpose as a novel measure or alternative to traditional methods.
Provide evidence of reliability, accuracy, repeatability, and clinical validity, ensuring sufficient detail for regulatory assessment without risking qualification during updates.
Conduct comprehensive risk assessments for changes to technology or software, following principles of ICH guidelines (Q8, Q9, Q10, Q12).
Develop user manuals and training materials to optimize implementation in clinical trials and ensure patient compliance.

Regulatory Considerations
EMA’s Remit: Focus on aspects affecting the benefit-risk assessment of medicinal products, while providing high-level information on unrelated technical parameters.
Alignment with MDR and GDPR: Ensure digital tools comply with applicable legal frameworks, including medical device regulations and data protection requirements.
Treat software and technology updates with a risk-based framework, evaluating their impact on clinical data validity and performance.
Collaborate with consortia to aggregate diverse data sources for confidential regulatory discussions, maximizing evidentiary value.
For medical devices, ensure CE marking or equivalent regulatory compliance before marketing, though it is not required during development.

Findings
1. Challenges related to patient privacy and lack of sufficient validation for digital endpoints.
2. Lack of transparency in endpoint calculations and operational challenges.
3. Added complexities due to software version changes and regulatory unknowns.

Recommendations
1. Increase patient-centricity and reduce patient burden through digital health technologies.
2. Foster collaboration among pharmaceutical companies, regulators, academia, and technology companies.
3. Embrace innovation and ensure senior leadership support for digital health initiatives.
4. Utilize real-time data access to enrich clinical trial data sets.
5. Implement outpatient sampling to augment decision-making processes.

Regulatory Considerations
1. Request feedback from regulatory agencies as part of the development plan for outpatient sampling.
2. Consider the FDA's guidance on bioanalytical method validation for dried blood sampling.
3. Note examples of regulatory acceptance of digital biomarkers as primary or secondary endpoints.

Findings
Operational inefficiencies in participant recruitment and data acquisition inflate costs and extend timelines.
Disparities in access to research due to geographic and mobility constraints limit participant diversity.
Many digital biomarkers require further validation for use in clinical trials.
Heightened need for security measures to protect against data breaches in digital trials.
Opportunities exist to improve clinical trials using real-world data from EHRs and IoT technologies.

Recommendations
Leverage existing technologies and research platforms to transform clinical trials.
Develop partnerships with technology and computational communities.
Create standard protocol templates for automation in recruitment, retention, and data collection.
Develop validation models for new devices and analyses using existing trials.
Invest in the next generation workforce in medicine, technology, and clinical research.

Regulatory Considerations
Address data privacy and security concerns in digital trials.
Provide guidance for IRBs on consenting requirements, reporting, and oversight in digital trials.
Develop empirical research on the risks and benefits of digital trials.
Educate IRBs on digital technology and its implications for clinical trials.

Findings
The COVID-19 pandemic has highlighted the need for decentralized clinical trials (DCTs) due to the closure of traditional trial sites.
There is a lack of a national electronic medical system, which poses a challenge for digital risk minimization.
The current regulatory framework is not fully equipped to handle the rapid advancements in digital health technologies.

Recommendations
Increase the adoption and integration of decentralized clinical trials (DCTs) to ensure continuity of research during disruptions.
Develop a national electronic medical system to support digital health initiatives and improve data integration.
Enhance collaboration between regulatory bodies and technology developers to create flexible and adaptive regulatory frameworks.
Encourage the use of real-world data and digital endpoints in clinical trials to improve efficiency and relevance.
Promote patient engagement and input in the development and implementation of digital health technologies.

Regulatory Considerations
The need for standardization and integration of digital health technologies across different platforms and systems.
The importance of developing regulatory guidelines that can adapt to the rapid pace of technological advancements.
The necessity for collaboration between regulatory bodies and standards development organizations to ensure effective oversight of digital health technologies.

Findings
Rigorous evaluation of digital biomarkers is currently lacking, which is necessary for their effective and safe use.
No speech measure has been comprehensively evaluated across verification, analytical validation, and clinical validation.
There is a wide variability in the speech features analyzed across studies, indicating a lack of standardization.

Recommendations
Conduct systematic and rigorous evaluation of digital biomarkers to ensure accurate measurement.
Develop comprehensive evaluations across all necessary categories for speech measures.
Standardize the analysis of speech features across studies.
Apply the recommendations for speech-based biomarkers to other novel digital biomarkers.

Regulatory Considerations
Not mentioned

Findings
Clinical trials often have unmet measurement needs, where traditional endpoints may not adequately characterize disease progression, treatment response, or new disease phenotypes.
Traditional trial designs can create a high patient burden, which can negatively impact the adoption of new measures by both clinicians and patients.
Clinical trials face significant operational challenges, including the risk of disruption, slow enrollment, poor medication adherence, and difficulty making early go/no-go decisions.
There is a need to improve the predictability rates for advancing new products from early-phase trials to pivotal trials.

Recommendations
Select digital measures to address specific unmet needs, such as to increase sensitivity in detecting disease worsening, characterize treatment response in subpopulations, or identify new disease phenotypes.
Prioritize digital measures that are well-received by clinicians and patients by demonstrating lower patient burden and higher patient relevance.
Deploy digital measures to improve trial efficiency and speed by reducing dependence on clinic visits, enabling earlier go/no-go decisions with higher resolution data, or improving medication adherence.
Use digital measures in early-phase trials to improve the probability of success for advancing new products to pivotal trials.
Consider digital measures that provide remote, continuous physiological insight to enable better oversight and remote management of trial participants.

Regulatory Considerations
When selecting a digital endpoint, a key consideration is whether the measure will increase the likelihood of regulatory approval or support a broader label claim.
A digital measure can strengthen a regulatory submission by generating more complete and patient-centric information that demonstrates the benefit of a new therapy.

Findings
The MDR/IVDR enhance the focus on cybersecurity for devices incorporating electronic programmable systems and software. Cybersecurity risk is inherently linked to patient safety and effectiveness; manufacturers must reduce all risks, including security risks with safety impacts, to an acceptable level. The management of security risks should be integrated into the product's overall Risk Management System. Due to the rapid change in the threat landscape, security maintenance is a critical, ongoing requirement across the entire product lifecycle. Other EU legislation, such as GDPR (data protection) and the NIS Directive (network security), also apply in parallel.

Recommendations
Manufacturers must follow a "Secure by design" strategy throughout the Design and Development phase, adopting a "Defense-in-Depth strategy". This includes:
Risk Management: Conduct a Security Risk Assessment (using techniques like Threat Modelling) to identify vulnerabilities and their potential impact on safety and effectiveness.
Risk Control: Prioritize mitigating risks in this order: eliminate/reduce risks through safe design; take adequate protection measures (e.g., encryption, authentication, alarms); provide information for safety and training .
Minimum IT Requirements: Clearly set out the minimum hardware, IT network, and IT security requirements for the device's operating environment and communicate these in the Instructions for Use. Devices should be as autonomous as possible in terms of security and avoid sole reliance on the operating environment.
Vigilance: Establish a robust Post-Market Surveillance (PMS) System to actively collect information, review data, and timely implement corrective actions (e.g., security updates/patches) for security vulnerabilities and incidents throughout the device's lifespan. Manufacturers must report all serious incidents and Field Safety Corrective Actions (FSCA).

Regulatory Considerations
Manufacturers must ensure that technical documentation includes information demonstrating conformity with all general safety and performance requirements, including justification and verification/validation of security solutions. Instructions for Use must include information on residual risks related to IT security and detailed instructions for secure installation, configuration, operation, and deployment of security updates. The entire process is a continuous, iterative cycle, requiring regular updates to technical documentation, risk management, and clinical evaluation

Findings
There is a lack of research on patient perspectives regarding the use of digital health technologies in clinical trials.
Digital health technologies offer opportunities to reduce participant burden and streamline operations but require effective engagement strategies.
Protocols need to address safety signals and data contexts not covered by traditional designs.

Recommendations
Engage patients and research sites early and often in planning digital health trials.
Ensure that outcome measurements meaningful to patients are identified before selecting digital health technologies.
Conduct feasibility or pilot studies with representative patient populations prior to trial launch.
Provide thorough descriptions of digital health technologies in informed consent documents.
Ensure sites have appropriate infrastructure and training for digital health trials.

Regulatory Considerations
Protocols should address safety signals not previously observed with traditional designs.
Communicate clearly about data confidentiality risks to participants.
Ensure informed consent documents provide clear guidance on expectations and responsibilities.

Findings
There are significant risks associated with connected sensor technologies that exceed current evaluation capabilities, including validation, security practices, data rights and governance, utility and usability, and economic feasibility.
Existing evaluation frameworks are inadequate for the unique challenges posed by digital health technologies.
The regulatory environment for digital specimens is not well-established, leading to ambiguity in oversight.

Recommendations
Develop a systematic and standardized evaluation framework for connected sensor technologies.
Implement a connected sensor technology label to improve transparency and decision-making.
Encourage innovation and modern regulatory oversight through updated guidelines.
Address the evolving distinction between regulated and unregulated digital health technologies.
Enhance communication infrastructure to make information more accessible to stakeholders.

Regulatory Considerations
The regulatory environment for digital health technologies is evolving, with a need for modern oversight.
There is ambiguity in the regulation of digital specimens, requiring clearer guidelines.
The FDA has issued guidances to encourage innovation and efficient oversight.