Findings
Widespread use of mobile technologies in clinical trials is impeded by perceived challenges.
Scientific and technical challenges affect decision-making around using mobile technology for data capture.
Concerns include choosing appropriate technology, data collection and analysis, ensuring data authenticity, and designing protocols.

Recommendations
Use CTTI's framework for mobile technology selection to assist sponsors.
Conduct feasibility studies prior to launching trials.
Engage with regulatory authorities early to discuss endpoint appropriateness and validation processes.
Secure data generated by mobile technologies using recommended practical approaches.
Optimize data quality to minimize variability and ensure robust conclusions.

Regulatory Considerations
Engage with the FDA early in the trial design process.
Ensure data integrity and security throughout the data life cycle.
Maintain open dialogue with regulatory authorities regarding trial-specific strategies for data collection and sharing.

Findings
Software functions for administrative support of healthcare facilities, general wellness, and maintaining electronic patient records are excluded from FDA regulation if they meet specific criteria under section 520(o)(1) of the FD&C Act.
MDDS software functions for transferring, storing, converting formats, and displaying data are not devices unless they include interpretive or analytical features.
Wellness-related software functions that are unrelated to disease diagnosis or treatment (e.g., tracking fitness or sleep) are no longer regulated as devices.
Software functions associated with certified health IT under ONC Health IT Certification are not considered devices, provided they are not intended for interpretation or diagnosis.
Software involving clinical alerts, prioritization of patient information, or medical decision support remains subject to FDA oversight under section 520(o)(1)(E).

Recommendations
Clearly define software functions to assess whether they fall under the excluded categories outlined in section 520(o)(1) of the FD&C Act.
For software functions that combine device and non-device functionalities, ensure that only device-related functionalities are included in FDA regulatory submissions.
Maintain compliance with general FDA requirements for software that still meets the definition of a device, particularly those with interpretive or decision-support capabilities.
Align product labeling and marketing claims with the revised guidance to accurately reflect whether software functions meet the exclusion criteria.
Use the latest FDA-recognized consensus standards to assess compliance for any software functions still considered devices.

Regulatory Considerations
Non-device software functions under section 520(o)(1) are excluded from FDA regulation, but any interpretive or analytical capabilities must still comply with device requirements.
Software functions certified under ONC Health IT Certification are not devices unless intended for analysis or diagnosis.
Hardware associated with MDDS functions remains subject to FDA regulation, but non-device MDDS software functions are excluded from oversight.
FDA continues to regulate functions that prioritize patient-related information or trigger clinical alerts under section 520(o)(1)(E).
Software combining device and non-device functions must clearly delineate each functionality’s regulatory status to avoid unnecessary oversight of non-device components.

Findings
A systematic approach is needed to assess the quality and utility of digital biomarkers.
Challenges exist in ensuring patient privacy and autonomy with remote monitoring.
Evaluating the validity and fit-for-purpose of digital biomarkers is difficult due to the interplay among hardware, sensors, and algorithms.
Cybersecurity challenges pose risks to privacy and safety.
Transparency of algorithms and interoperability of components are necessary for a safe digital biomarker ecosystem.

Recommendations
Promote transparency of algorithms used in digital biomarkers.
Ensure interoperability of components with open interfaces.
Establish strong incentive structures for the safe and effective use of digital biomarkers.
Continuously collect data and handle modifications over time in a learning digital health system.
Encourage collaboration among industry, researchers, regulators, clinicians, and patients.

Regulatory Considerations
The FDA's regulatory process can address modular components of digital biomarkers.
The FDA is piloting a pre-certification program for streamlined product approvals.
New frameworks are emerging for security, ethics, and informed consent challenges in digital phenotyping technologies.

Findings
The probability of receiving an irregular pulse notification was low, indicating a gap in detection sensitivity.
The study was not designed to assess the algorithm as a screening tool, highlighting a need for further research in this area.
The paroxysmal nature of atrial fibrillation presents challenges in interpreting notifications, suggesting a gap in understanding the condition's episodic nature.

Recommendations
Conduct further research to understand the implications of irregular pulse notifications.
Explore the potential for digital health technologies to engage users with healthcare systems.
Investigate the use of smartwatches and similar devices as population screening tools.
Develop methods to improve the accuracy and reliability of health monitoring algorithms.
Enhance user engagement and follow-up after receiving health notifications.

Regulatory Considerations
Ensure data privacy and consent in large-scale digital health studies.
Address the accuracy and reliability of health monitoring algorithms.
Consider the implications of using consumer-owned devices for health monitoring.

Findings
Lack of regulatory guidance on validating precision and reliability of DHT data.
Challenges in managing large, complex datasets without appropriate processing.
Insufficient integration of DHTs into existing clinical trial standards.

Recommendations
Develop a metadata set to improve data interpretability and exchangeability.
Encourage standard development organizations to extend existing standards for DHTs.
Ensure that none of the proposed metadata is compulsory, allowing flexibility based on application and resources.

Regulatory Considerations
Meet additional regulatory standards for medical devices.
Utilize guides like the FDA's Clinical Trials Transformation Initiative for data capture.
Align metadata standards with regulatory requirements to facilitate approval.

Findings
SV95C is a promising secondary endpoint for evaluating drug efficacy in ambulant DMD patients aged 5 and above.
The wearable device provides continuous, objective measurements, overcoming the limitations of episodic tests like the 6MWT, which are influenced by patient motivation and clinic settings.
The system demonstrates strong correlation with existing endpoints (e.g., 6MWT, NSAA), but further longitudinal data are needed to establish it as a primary endpoint.
Variability in SV95C decreases significantly with longer recording durations, with 180 hours recommended as optimal.
Combining SV95C with other gait variables could enhance sensitivity to change and predictive capacity for disease progression.

Findings
SV95C is a promising secondary endpoint for evaluating drug efficacy in ambulant DMD patients aged 5 and above.
The wearable device provides continuous, objective measurements, overcoming the limitations of episodic tests like the 6MWT, which are influenced by patient motivation and clinic settings.
The system demonstrates strong correlation with existing endpoints (e.g., 6MWT, NSAA), but further longitudinal data are needed to establish it as a primary endpoint.
Variability in SV95C decreases significantly with longer recording durations, with 180 hours recommended as optimal.
Combining SV95C with other gait variables could enhance sensitivity to change and predictive capacity for disease progression.

Regulatory Considerations
SV95C requires validation in conjunction with traditional endpoints (e.g., 6MWT, NSAA) to support regulatory submissions.
Device and software updates must be accompanied by bridging data to ensure consistent measurement properties.
Patient data privacy and security must comply with regulatory standards, including encryption of recorded data and limited researcher access to identifiers.
Future applications of SV95C as a primary endpoint will require expanded normative datasets and stronger correlation with clinically meaningful outcomes.
Incorporate SV95C in early-phase exploratory trials to build a robust case for its clinical relevance in pivotal studies.

Findings
Organizational challenges such as risk-averse corporate culture and lack of strategy hinder PT adoption.
Business-related challenges include unclear ROI and limited willingness to invest.
External challenges involve regulatory implications and technology landscape issues.
Internal disconnections within companies lead to inefficiencies in PT initiatives.

Recommendations
Improve understanding and communication between all clinical trial stakeholders.
Engage with sites and patients to inform trial design.
Address internal disconnections within companies to facilitate PT adoption.
Develop a clear business case for PT to encourage investment.
Enhance training and support for technology use in clinical trials.

Regulatory Considerations
Lack of specific guidance for PT use in clinical trials.
Geographic variability in regulations and interpretations.
Privacy and security concerns related to data management.

Findings
FDA requires OUS clinical investigations to comply with GCP, ensuring the credibility and accuracy of data and protecting human subjects.
Statements on GCP compliance and supporting information are mandatory for OUS data submissions.
Waivers are permitted in circumstances where GCP compliance is unattainable or where local regulations differ significantly from FDA requirements.
Investigations must demonstrate that OUS data are applicable to U.S. populations and medical practices.
Sponsors must provide robust documentation, including investigator qualifications, site descriptions, IEC reviews, and informed consent processes.

Recommendations
Ensure clinical investigations adhere to GCP standards, including IEC review and informed consent, for all OUS clinical data submitted to FDA.
Include detailed supporting information in submissions, such as investigator qualifications, facility descriptions, protocols, and data summaries.
Clearly identify any deviations from GCP and justify how data integrity and subject protection were maintained.
Use FDA’s Pre-Submission Program to discuss potential challenges with GCP compliance or data validation before submission.
Retain all required records for at least two years after FDA’s decision on the application or submission.

Regulatory Considerations
FDA evaluates OUS clinical data on a case-by-case basis, considering the adequacy of GCP compliance and supporting documentation.
For significant risk device investigations, sponsors must provide the most comprehensive documentation, while non-significant risk and exempt devices require less detailed information.
Waivers may be granted when justified by public health considerations or when local laws prohibit compliance with specific FDA requirements.
FDA retains the right to inspect clinical sites or review source documents to validate data integrity and compliance with GCP.
Sponsors must ensure that OUS data are valid and relevant to the U.S. population and medical practice.

Findings
Rapid development of digital biomarkers through sensors and personal devices.
Lack of established standards for evaluating digital biomarkers.
Challenges in handling large volumes of data, including missing data and outliers.

Recommendations
Improve the quality and reproducibility of research supporting biomarker use.
Ensure rigorous methodology in biomarker assessment.
Foster collaboration across disciplines for biomarker development.
Develop standards for linking digital phenotypes to traditional outcomes.
Address data handling challenges in digital health technologies.

Regulatory Considerations
Substantial validation work required for FDA approval of biomarkers.
Importance of rigorous scientific evidence for regulatory approval.
Need for collaboration in regulatory science to advance biomarker development.

Findings
Variability in imaging acquisition, display, and interpretation methods across different clinical sites can increase endpoint measurement errors, potentially compromising a trial's ability to achieve its objectives.
Standard imaging procedures used in routine medical practice are often insufficient for clinical trials, which require greater standardization to reduce variability and ensure the interpretability of results.
In open-label trials, site-based image interpretation is vulnerable to bias because knowledge of a patient's clinical status can influence assessments.
Technical factors such as equipment upgrades, software changes, and inconsistent image quality can introduce errors and undermine the consistency of imaging data collected in multicenter trials.
Lack of consistency in image reader training and performance can lead to significant variability in endpoint measurements, reducing the precision of the treatment effect estimate.

Recommendations
Sponsors should develop and implement trial-specific imaging process standards, detailed in a document called an imaging charter, that go beyond routine medical practice.
Use a centralized image interpretation process to enhance the credibility of image assessments, ensure consistency, manage reader performance, and reduce variability.
Image readers should be blinded to treatment assignments and, in most cases, to other clinical data to prevent bias in the primary endpoint assessment.
Standardize all critical imaging procedures, including equipment settings, subject preparation, image acquisition protocols, site qualification processes, and ongoing quality control monitoring.
Establish clear procedures for image data transfer, quality assessment, locking, and archiving to maintain data integrity and ensure a verifiable audit trail.

Regulatory Considerations
Sponsors are encouraged to submit the imaging charter to the FDA for review, as compliance with the charter is an important part of verifying the trial's data integrity.
The use of investigational imaging equipment, software, or interpretation tools in a clinical trial must comply with all applicable FDA regulations, including investigational device exemption (IDE) requirements.
Imaging source data and records must be retained for a minimum of two years after a marketing application is approved or an investigation is discontinued, as specified in 21 CFR 312.
The final report submitted to the FDA for review should thoroughly document all imaging processes that took place during the trial, from acquisition and interpretation to data transfer.
The clinical protocol and consent forms must describe all imaging-related risks to subjects, such as radiation exposure, for review by institutional review boards (IRBs).

NA

Findings
Digital technologies face challenges across scientific, clinical, technological, business, ethical, and regulatory domains.
Current testing paradigms are inadequate for identifying meaningful changes in early-stage Alzheimer's disease.
Complex digital tools may not be suitable for all trial participants due to varying technology, motor, or cognitive skills.
Ethical issues such as privacy, data sharing policies, and informed consent are significant concerns.
The regulatory path for digital medical devices is unclear and needs further development.

Recommendations
Develop more sensitive and specific diagnostic tools for early-stage Alzheimer's disease.
Create adaptable and user-friendly digital tools suitable for diverse populations.
Address ethical concerns by establishing clear privacy and data sharing policies.
Engage with regulatory bodies early to understand the regulatory landscape.
Integrate digital tools into clinical trials alongside traditional measures to advance the field.

Regulatory Considerations
The regulatory path for digital medical devices is currently unclear and needs clarification.
Developers should follow design control methods and ensure compliance with relevant regulations.
Early engagement with regulatory agencies is recommended to speed up development and approval processes.