Findings
Cytokine Release Syndrome (CRS) is a common and potentially life-threatening adverse event of immunotherapies, particularly in Oncology, complicating patient care and increasing healthcare costs. Standard-of-care inpatient monitoring for CRS is manual, intermittent, costly, and restrictive, providing an incomplete view of the syndrome’s development and progression. The use of Digital Health Technologies (DHTs) for continuous, remote monitoring of vital signs (like heart rate, respiratory rate, skin temperature, SpO2, and activity) can capture early indicators of CRS up to two hours earlier than standard episodic monitoring. This ability to collect multivariate continuous data is valuable for informing robust model development for CRS risk prediction.

Recommendations
Investigators should deploy DHTs available today to monitor vital signs and symptoms currently observed in the hospital setting, but in an outpatient or home environment. The goal is to develop Early Warning Products that assess the probability of developing CRS, providing clinical decision support. Product developers should follow a strategic roadmap that outlines milestones for building products that are clinically relevant and commercially viable. Researchers should use a common set of digital clinical measures to gather high-quality datasets and ensure comparability across studies to build more robust predictive models. Predictive algorithms should be built on a robust reference measure for analytical validation and be clinically validated with sufficient data.

Regulatory Considerations
The resources are designed to help developers build products that are clinically appropriate, regulatory-acceptable, and commercially viable. Future regulatory submissions for CRS de-risking products will benefit from aligning with this industry-wide dialogue that is being built in collaboration with the FDA. Developing a robust CRS safety biomarker could enhance the safety profile of clinical trials, increase trial access, and streamline regulatory decision-making, possibly through a qualification pathway. Products that aim for a higher level of autonomy, such as a Diagnostic that redefines current CRS grading classes, may require very high clinical evidence and likely stringent regulatory review.

Key Principles (Findings)
The central principle of the DDT Qualification Programs is to create a formal pathway for the FDA to conclude that a specific tool is well-suited for a particular Context of Use (COU) in drug development. A key finding, as reflected in the program's design, is that qualification de-risks drug development by allowing a tool to be used in any regulatory submission for its qualified COU without needing to be re-validated each time. The program is designed to foster stakeholder collaboration, encouraging the development of tools that can benefit the entire research community, thereby reducing the burden on individual sponsors.

Program Activities (Recommendations)
The structure of the DDT programs serves as a series of recommendations for tool developers:
Engage Early and Collaboratively: The programs are designed to provide a framework for early and ongoing scientific collaboration with the FDA to facilitate the development of new tools.
Follow a Staged Process: Developers are guided through a multi-stage process, typically involving a Letter of Intent, a Qualification Plan, and a Full Qualification Package, to systematically build the evidence needed for qualification.
Seek Public Qualification: The ultimate recommendation is to achieve public qualification for a DDT, which makes the tool available for broad use and integrates it into the regulatory review process, expediting future drug development.

Regulatory Considerations
The DDT Qualification Programs are a formal regulatory framework established under the 21st Century Cures Act. A "qualified" DDT has a specific regulatory status; it can be relied upon to have a specific interpretation and application in drug development and regulatory review for its stated Context of Use (COU). This qualification is publicly available and allows the tool to be included in Investigational New Drug (IND), New Drug Application (NDA), or Biologics License Application (BLA) submissions without the FDA needing to reconsider its suitability. This creates a more efficient and predictable regulatory compliance pathway for sponsors who use the qualified tool.

Key Principles (Findings)
This guidance establishes that the eSTAR platform will become the mandatory format for the electronic submission of medical device Pre-Submissions to the FDA. A key principle is that a properly completed eSTAR submission is considered a 'complete' submission, which allows it to bypass the traditional Refuse-to-Accept (RTA) process and instead undergo a more focused technical screening within 15 days. The structure of the eSTAR template is designed to align with the FDA's internal review memo, creating a more efficient and consistent review process. The guidance also makes it clear that while eSTAR use is currently voluntary, it will become required for Pre-Subs at least one year after this guidance is finalized.

Recommendations for Industry
The primary recommendation for industry is to familiarize themselves with and begin voluntarily using the eSTAR platform for Pre-Submissions in advance of the mandatory deadline. The guidance recommends that submitters use the structured, dynamic PDF to ensure all necessary elements of a complete submission are included, thereby facilitating a smoother and more efficient review. For certain types of follow-up communications, such as submitting meeting minutes or presentation slides, the guidance recommends they continue to be submitted as an eCopy rather than through the eSTAR template.

Regulatory Considerations
This guidance is issued under the authority of the Federal Food, Drug, and Cosmetic (FD&C) Act, which mandates the transition to electronic-only submissions. Upon finalization, the requirement to use the eSTAR template for Pre-Subs will be a binding regulatory requirement. The guidance outlines a specific technical screening process for eSTAR submissions that will replace the RTA process. If a submission fails this screening, it will be placed on hold, and the review clock will restart upon receipt of the corrected information. The document also specifies certain types of submissions, such as appeals and withdrawal requests, that will be exempt from the mandatory eSTAR requirement.

NA

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
The database provides a transparent and accessible way for the public to track the progress of various Drug Development Tools (DDTs) through the FDA's qualification pipeline. This includes biomarkers, clinical outcome assessments, and animal models. The information available, such as submission status and supporting documentation, offers insight into the types of tools being developed and the evidence required for their qualification. The platform reveals that a wide range of tools are in development across numerous therapeutic areas, highlighting active areas of research and innovation in drug development.

Recommendations
Stakeholders in the drug development ecosystem are encouraged to utilize this database to inform their research and development strategies. By reviewing the status of existing DDT submissions, sponsors can identify opportunities for collaboration, avoid duplicative efforts, and better understand the evidentiary requirements for tool qualification. Prospective tool developers should use the database to learn from successful submissions and to align their own development plans with FDA expectations.

Regulatory Considerations
This database is a direct implementation of the transparency provisions of the 21st Century Cures Act. The public availability of this information is intended to foster trust and collaboration in the DDT qualification process. By providing a clear view of the regulatory journey of various tools, the FDA aims to standardize the qualification process and encourage the development and use of novel, validated tools in drug development. Users of the database should be aware that the information reflects the status of a DDT at a particular point in time and that the qualification process is an iterative one.

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
The development and evaluation of medical devices require scientifically plausible and reliable tools for collecting data to support regulatory submissions. A lack of standardized, pre-vetted tools can lead to inefficiencies and unpredictability in the device development and review process. The qualification of development tools can be applied across a wide range of device areas, including cardiovascular, neurology, imaging, and cybersecurity. The evidence required for tool qualification must be robust enough to support its intended context of use.

Recommendations
Tool developers, medical device sponsors, research organizations, and academic institutions are encouraged to voluntarily submit proposals to the MDDT program to qualify their tools. Submissions should include a detailed description of the tool, a clearly defined context of use (COU), specific performance criteria, and a comprehensive plan for collecting evidence to validate the tool's performance and scientific plausibility. Collaboration in developing tools and supporting evidence is recommended to pool resources and increase the acceptance of qualified tools.

Regulatory Considerations
The MDDT program is a formal regulatory mechanism for the FDA to qualify tools that can be used to support assessments of medical device safety, effectiveness, or performance. Once a tool is qualified for a specific context of use, the FDA accepts assessments from that tool in support of regulatory submissions without needing to re-evaluate the tool's suitability. The program recognizes four main categories of tools: Non-clinical Assessment Models (NAM), Biomarker Tests (BT), Clinical Outcome Assessments (COA), and an "Other" category for tools that do not fit the primary classifications.

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
The guidance applies to four types of Clinical Outcome Assessments (COAs): Patient-Reported Outcomes (PROs), Observer-Reported Outcomes (ObsROs), Clinician-Reported Outcomes (ClinROs), and Performance Outcomes (PerfOs). A COA is considered fit-for-purpose when the validation evidence is sufficient to support its context of use (COU). To determine if a COA is fit-for-purpose, sponsors must clearly describe the Concept of Interest (COI) and the COU, and present sufficient evidence to support a clear rationale for the COA's proposed interpretation and use. The rationale for using a COA should include up to eight components, such as justification for the COA type, capturing the important parts of the COI, appropriate administration and scoring, minimal influence from irrelevant factors or measurement error, and correspondence with the Meaningful Aspect of Health (MAH). The most direct assessment of how a patient feels or functions (MAH) should be used as the COI whenever possible.

Recommendations
Sponsors should use the Roadmap to Patient-Focused Outcome Measurement to guide the selection, modification, or development of a COA. The process begins with understanding the disease/condition (including patient perspectives) and conceptualizing clinical benefits and risks (defining the MAH, COI, and COU). When feasible, existing COAs are generally preferred, especially for well-established COIs, as this approach is often the least burdensome. If an existing COA is modified or used in a different context, additional evidence (e.g., cognitive interviews, psychometric studies) must be collected to justify its fitness for the new context of use. For new COA development, sponsors should involve patients, document all steps, and generally avoid using the new COA for the first time in a registration (pivotal) trial; a standalone observational study or early phase trial is recommended for evaluation.

Regulatory Considerations
Sponsors are encouraged to interact early and throughout medical product development with the relevant FDA review division to ensure COAs are appropriate for the intended COU. Sponsors should communicate their proposed COA-based endpoint approach, including the MAH, COI, COA type/name/score, and the final COA-based endpoint, ideally using the suggested format. The type and amount of evidence required to support the rationale for a COA's use is weighed against the degree of uncertainty regarding that part of the rationale. For ClinROs, it is recommended to use an assessor masked to treatment assignment and study visit for primary endpoints, if feasible. FDA strongly discourages proxy-reported measures for concepts known only to the patient (e.g., pain) and recommends using an ObsRO to measure observable behaviors instead when the patient cannot self-report.

Recommendations
Clearly define the concept of interest and its context of use to ensure COAs align with trial objectives.
Use conceptual and measurement frameworks to communicate how COAs measure patient experiences and generate interpretable scores.
Leverage existing COAs where possible, modifying them only when justified, and document all modifications rigorously.
Ensure COAs are accessible and inclusive, incorporating features like large fonts, touch interfaces, or audio assistance for diverse populations.
Conduct early engagement with FDA to discuss COA selection, development, and validation plans.

Regulatory Considerations
Fit-for-purpose validation requires evidence of conceptual alignment, scoring reliability, and sensitivity to clinically meaningful changes.
Digital health technologies used for COAs must comply with FDA’s guidance on data integrity, usability, and technical performance.
COAs intended for regulatory submissions must be developed and validated before pivotal trials to avoid jeopardizing trial outcomes.
Modifications to COAs or scoring methods during trials necessitate justification and revalidation.
Sponsors should submit comprehensive documentation on COA development, including scoring algorithms and item tracking matrices.

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
A comprehensive catalogue of over 340 symptoms and impacts was identified across ten symptom domains and two functional impact domains. Strongest evidence for relevance in early disease was found for tremor, fine motor dexterity, gait, stiffness, and slowed movements. Common non-motor symptoms include cognitive alterations, mood changes such as anxiety or depression, sleep disturbances, fatigue, and urinary dysfunction. Significant variability exists in how these concepts are currently measured and classified in literature, often confounding symptoms with functional impacts. There is a notable lack of diversity in existing research, with over 93% of qualitative data originating from white populations in the US, UK, and Canada.

Recommendations
Researchers and clinicians should utilize the proposed Domain-Category-Concept-Experience schema to ensure consistency and parsimoniousness in outcome selection. Selection of concepts for clinical trials should be evidence-based, focusing on those demonstrated to be both prevalent and bothersome to patients. Future research must prioritize the inclusion of culturally, racially, and geographically diverse populations to ensure the model's universal applicability. Stakeholders should adopt lay-friendly terminology, such as using ""slow movements"" instead of ""bradykinesia,"" to better reflect the patient perspective. Continuous re-evaluation of the model is necessary to maintain alignment with emerging biological staging systems for neuronal synuclein disease.

Regulatory Considerations
The consensus model was developed to align specifically with FDA guidance on patient-focused drug development (PFDD) to support regulatory-ready endpoints. Meaningful aspects of health should be identified through direct patient report to satisfy evidentiary requirements for ""fit-for-purpose"" clinical outcome assessments. Evidence-based SOFT report cards provide a transparent method for justifying the selection of concepts of interest in regulatory submissions. Early engagement with agencies is encouraged to ensure selected endpoints are sensitive to treatment effects and reflect what matters most to patients. Harmonization of concept definitions is a critical prerequisite for the successful qualification of new drug development tools.