Findings
Digital endpoints must not only support regulatory approval but also provide evidence that meets payer expectations for reimbursement and value-based care. The lack of early engagement with payers and health technology assessment (HTA) agencies is a key barrier to the adoption of digital clinical measures. Digital measures can enhance value-based care models by capturing patient-centered outcomes, reducing healthcare costs, and improving early disease detection. The scalability and generalizability of digital endpoints remain challenges, particularly for diverse populations and real-world healthcare settings. Technical and systematic barriers—such as data heterogeneity, stakeholder knowledge gaps, and inconsistent regulatory-payer alignment—are slowing the adoption of digital endpoint data for reimbursement decisions.

Recommendations
Pharma and medical product developers should engage early with payers and regulators to ensure digital endpoints align with reimbursement expectations. Payers and HTA bodies should establish clear evidence thresholds for digital endpoint validation, ensuring consistency in market access decisions. Digital endpoints should be validated against health-related quality of life (HRQoL) measures and patient-reported outcomes (PROs) to demonstrate clinical relevance. Real-world evidence (RWE) should be incorporated into clinical trials alongside digital endpoints to strengthen reimbursement applications. Stakeholders should prioritize scalable, patient-centered digital measures that capture disease progression over time and across different care settings.

Regulatory Considerations
Integrated Evidence Plans (IEPs) should be developed early to align digital endpoint evidence with regulatory and payer requirements. Digital endpoints should be assessed through multi-stakeholder collaboration, ensuring validation across pharmaceutical, regulatory, and reimbursement frameworks. Payers and regulators should work together to create aligned pathways for digital measure acceptance, reducing delays in market access. Data security, privacy, and interoperability must be addressed to support regulatory approval and patient trust in digital health solutions. The industry should leverage international regulatory-payer collaboration models, such as the HTA-EMA partnership and the FDA Payor Communication Task Force, to accelerate global digital endpoint adoption.

Findings
Existing guidelines lack pragmatic application and systematic approach for device selection.
Device choice is dependent on measurement objectives, user population, and available resources.
Current frameworks do not systematically consider verification, validation, feasibility, and protocol design.
Rapid obsolescence of digital devices due to technological advancements.
Need to incorporate social/psychological factors into device selection.

Recommendations
Develop a practical guide with a systematic approach for selecting wearable devices.
Use five core criteria: continuous monitoring capability, device suitability and availability, technical performance, feasibility of use, and cost evaluation.
Prioritize feasibility of use to ensure user needs are incorporated into the selection process.
Adapt guide criteria to accommodate novel innovations.
Foster clarity and transparency in decision-making among researchers, HCPs, and device users.

Regulatory Considerations
Follow FDA guidance for digital health technology usage in clinical investigations.
Consider CTTI recommendations for improving clinical trial quality and efficiency.
Use ePRO Consortium's factors for device suitability in regulatory trials.
Apply international guidelines for specific measurements when available.

Findings
Regulatory inconsistencies across different FDA divisions and international jurisdictions create inefficiencies in the approval process for digital health products.
Lack of alignment between regulatory approval and payer reimbursement requirements poses a significant barrier to commercialization and widespread adoption of digital health innovations.
There are limited regulatory pathways for novel digital health products, including AI-enabled solutions, requiring new frameworks to address iterative software development and real-world data integration.
Existing health technology assessment (HTA) models do not fully accommodate digital health technologies, limiting their inclusion in reimbursement decisions.
Industry stakeholders emphasize the need for clearer guidelines on cloud-based infrastructure, third-party AI model validation, and digital health interoperability.

Recommendations
FDA and international regulatory bodies should improve coordination to establish standardized approval processes and consistent clinical evidence requirements.
New regulatory pathways should be introduced for AI-driven and software-based digital health products, considering their unique lifecycle and iterative development models.
Greater transparency and communication between FDA divisions should be established to ensure consistent decision-making and regulatory interpretations across centers.
Policymakers should prioritize payer alignment strategies, incorporating real-world evidence (RWE) to streamline reimbursement and market access processes.
The digital health industry should collaborate with regulators to create standardized best practices for AI validation, cloud security, and digital biomarker evaluation.

Regulatory Considerations
FDA should clarify the evidentiary standards for AI-enabled medical devices and establish predefined change control plans for software updates.
Digital health products should adhere to globally recognized standards such as HL7 for interoperability and ISO regulations for data security.
Market access pathways must integrate pricing and reimbursement considerations to facilitate the commercial viability of digital health technologies.
The use of real-world data (RWD) should be expanded in regulatory decision-making, supporting the approval and post-market surveillance of digital health innovations.
Regulatory frameworks should be updated to accommodate cloud-based health platforms, addressing issues such as data privacy, operational security, and compliance with HIPAA and GDPR.

Findings
Regulation exists to ensure the safety and effectiveness of digital health products and to protect the public from potential risks. Engaging with the FDA throughout product development, even though it may seem burdensome, offers valuable benefits such as shared understanding of requirements, faster outcomes, enhanced efficiency in the review process, and built trust with regulators and the public. Working with the FDA is crucial for understanding a device's risk classification and applicable regulatory requirements.

Recommendations
Developers should follow a three-step approach for successful interaction:
EARLY: Start interacting with the agency as early as possible in development, ensuring the intended use and some basic product functionalities are defined.
OFTEN: Maintain communication, especially if new product features, design changes, or changes to how the product will be used occur, to ensure the FDA's advice remains accurate.
TRANSPARENT: Be honest and upfront about the product, evidence, testing plans, and data.
For both "non-written" (meetings) and "written" communications, best practices include:
Preparation: Define the purpose, have specific goals and questions, and prepare a well-planned meeting package (including supporting documentation and data) in advance.
Format and Tone: Select the right type of interaction for the goal, use a professional tone, and communicate clearly, concisely, and with proper formatting.
Follow-up: Respond to all FDA requests promptly and accurately, as delays can result in regulatory action.

Regulatory Considerations
Manufacturers must be familiar with and in compliance with relevant FDA guidance and regulations. Developers should present their argument for a product's regulatory category but must understand that the FDA determines the final regulatory status and obligations. It is critical to avoid providing false or misleading claims or withholding important information, as failure to cooperate or address concerns raised by the FDA can lead to penalties or failure to clear/approve the product for marketing. All communications may be subject to Freedom of Information requests and could become public

Findings
There are various formal and informal engagement pathways available for developers of Digital Health Products and Combination Products to communicate with the FDA to seek advice regarding product classification, regulatory status, and submission strategies. Informal pathways include the Digital Health Inquiry (via the Digital Health Inbox), the DICE Mailbox Inquiry, and the Pre-RFD Process, which provide non-binding feedback. Formal pathways include the 513(g) Program for classification, and the Q-Submission Program (encompassing Pre-Submissions for pre-application feedback and SRD for risk determination).

Recommendations
Manufacturers should use the provided map to determine the appropriate pathway based on their product type (standalone digital health or combination product) and the type of advice they are seeking (informal or formal). The Pre-Submission (Pre-Sub) program is recommended as an opportunity to obtain formal feedback "prior" to submitting an application, particularly if a new product's regulatory pathway is unclear or if planning a study to support a future application. Combination Product manufacturers can use CPAMs to clarify marketing authorization standards or post-market modification requirements.

Regulatory Considerations
The 513(g) Request provides information on a product's classification and applicable regulatory requirements but does not determine substantial equivalence or make final marketing authorization decisions. Programs like the CDRH-Payor Connection and Parallel Review with CMS are voluntary and designed to expedite patient access by aligning clinical evidence for both regulatory clearance/approval and coverage decisions. Participation in these programs, however, does not alter the FDA’s existing, separate standards for regulatory review.

Findings
The FDA has distinct engagement pathways depending on whether the product is a Standalone Digital Health Product or a Combination Product. The pathways are further categorized into Informal and Formal advice.
Informal Pathways include:
Digital Health Inquiry (Digital health inbox, DICE mailbox inquiry).
General Inquiry for combination products.
CDRH List & Learn.
Formal Pathways for digital health and combination products include:
513(g) request (for classification information).
Q-Submission Program (Pre-Submission, Submission Issue Request (SIR), Information meeting).
CDRH-payor connection (Early payor feedback program, Parallel review with CMS).
RFD/Pre-RFD process (Request for Designation).

Recommendations
Developers should use this map to identify the appropriate mechanism for seeking regulatory advice. The initial decision point is whether the engagement is related to the design, development, or deployment of a digital health product. Once the product type is identified, the map directs the user to the appropriate formal or informal path. The various mechanisms are used for different purposes, such as an Information meeting (to share information without expecting feedback) or a Pre-Submission program (for formal feedback on a planned product).

Regulatory Considerations
The pathways involve different Centers and Offices, including the Center for Devices and Radiological Health (CDRH), Centers for Medicare & Medicaid Services (CMS), and the Office of Combination Products (OCP). The FDA's focus is on engagement pathways for digital health products. For information on developing digitally derived endpoints for drugs, developers are directed to the DiMe and CTTI guides. Engagement is related to design, development, or deployment of the product

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.