Findings
Long and Unpredictable Timelines: The COA Qualification Program is lengthy and unpredictable, with an average qualification time of six years. Nearly half of all submissions experience review times that exceed the FDA's own published targets.
Low Qualification and Uptake: As of October 2024, only seven COAs (8.1% of those listed) have been qualified, and only three of those have been used to support the benefit-risk assessment of new medicines. No COAs submitted after the passage of the 21st Century Cures Act in 2016 have been qualified.
Limited Regulatory Impact: Qualified COAs are consistently designated for "exploratory use" and have never been accepted as a primary endpoint in a clinical trial. In contrast, some non-qualified COAs have been used as key endpoints and included in drug labels, questioning the utility of the formal qualification pathway.
Discrepancy Between FDA Centers: There is a notable difference in how COAs are qualified between the drug (CDER/CBER) and device (CDRH) centers. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was qualified by CDRH for use as a primary or secondary endpoint, while for drugs, it was only qualified as an "exploratory" measure.

Recommendations
Increase Transparency of Timelines: The FDA should publish its actual, historical review timelines for COA qualification so that drug developers can better plan and integrate these tools into their development programs.
Clarify the Use of Qualified COAs: The FDA should clearly articulate how and when qualified COAs can be used as primary or secondary endpoints to support regulatory decision-making and provide a clear pathway for updating a COA's status from "exploratory" to a key endpoint.
Publish Best Practices: Both sponsors and the FDA should be encouraged to publish their experiences with the qualification program to share best practices and learnings with the broader drug development community.
Create a List of Accepted Endpoints: The FDA should create and maintain a public list of qualified COAs that can be used as surrogate endpoints to support drug approval decisions, thereby increasing their utility and adoption.

Regulatory Considerations
"Qualified as a Measure" Ambiguity: The FDA's practice of qualifying COAs as "measures" for "exploratory use" creates regulatory uncertainty for sponsors, as it implies that significant additional evidence is still needed before the tool can be relied upon for a key endpoint.
Qualification is Not Required: The analysis shows that COAs can be accepted for regulatory decision-making and included in drug labels without going through the formal qualification program, suggesting that qualification is not a prerequisite for use as a reliable endpoint.
Unclear Path to Endpoint Progression: The current DDT guidance does not specify the process for upgrading a COA's qualification status (e.g., from exploratory to a primary endpoint) after additional data has been generated, which hinders its evolution and broader use.

Findings
Clinically Acceptable Performance: A clinical study demonstrated that the weekly AFib burden estimates from the Apple AFib History Feature were in close agreement with a reference ECG patch, with an average difference of just 0.67%. The vast majority of measurements had paired differences within ±10% of the reference device.
Generalizable Across Subgroups: The device's accuracy was similar across various subgroups, including different sexes, races, ages, and skin tones.
Performance Post-Ablation is Uncertain: In a small subgroup of patients with a prior cardiac ablation, the device's performance, while still strong, showed slightly more variability and exceeded a pre-specified acceptance criterion. The study was not designed or powered to demonstrate equivalent performance in this specific group.
Technical Limitations Exist: The feature only provides a retrospective weekly estimate and does not give specific timestamps or durations of AFib episodes. It also does not detect other atrial tachyarrhythmias, like atrial flutter.

Recommendations
Appropriate Use: The document implicitly recommends using the tool precisely within its qualified context of use—as a secondary, not primary, endpoint for comparing AFib burden between study arms in cardiac ablation device trials.
Supplemental Data Collection: For studies involving patients who have had a prior ablation, it would be beneficial to assess the tool alongside other methods of determining AFib burden to better characterize its performance in this population.
Define Study-Specific Endpoints: Investigators using the tool are responsible for defining and justifying their specific study designs and what constitutes a clinically significant reduction in AFib burden.

Regulatory Considerations
MDDT Qualification: The Apple AFib History Feature is officially qualified by the FDA as a Medical Device Development Tool (MDDT), which reduces the burden on device developers, as they no longer need to independently justify its methodology for collecting weekly AFib burden estimates in their clinical studies.
Secondary Endpoint Only: A key limitation for its regulatory use is its qualification only as a secondary endpoint. It cannot, by itself, be used to evaluate the primary safety and effectiveness of cardiac ablation devices. This is partly because FDA typically requires the inclusion of any atrial tachyarrhythmia (not just AFib) for defining ablation success in pivotal studies.
Not a Replacement for Primary Endpoints: The tool's utility is intended to provide supplemental data and help better understand post-treatment AFib burden; it is not meant to replace more clinically well-defined primary endpoints.

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.

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).