Industry spotlight

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
Meaningful outcome measures should align with patient priorities and clinical relevance, emphasizing aspects of health that impact daily life.
Digital tools must demonstrate value over traditional methods in capturing outcomes, especially in remote or decentralized contexts.
Questions about therapeutic benefit and endpoint sensitivity must address how these measures reflect patient improvements or disease progression.
Stakeholder collaboration is critical to selecting and validating concepts of interest and corresponding outcome measures.
Challenges include ensuring data privacy, operational feasibility, and addressing potential gaps in endpoint validation.

Recommendations
Engage patients and caregivers to identify meaningful aspects of health and concepts of interest relevant to their daily lives and goals.
Collaborate with clinicians to determine the clinical validity and utility of proposed measures and tools for endpoint development.
Ensure that DHTs selected for measurement add value beyond traditional methods and are feasible for clinical and real-world use.
Incorporate payer perspectives to align outcome measures with cost-benefit evaluations and reimbursement criteria.
Use the question bank as a flexible guide, adapting it to the specific needs and context of individual clinical trials.

Regulatory Considerations
Ensure endpoints and their measures meet regulatory standards for clinical relevance and sensitivity to therapeutic changes.
Align outcome measures with accepted core sets (e.g., COMET database) and validate them through stakeholder engagement.
Address concerns related to data privacy, scalability, and operational feasibility in the use of DHTs for endpoint development.
Plan for regulatory engagement to demonstrate the robustness of digitally-derived endpoints in pivotal clinical trials.
Provide evidence to support the incorporation of novel endpoints into regulatory and payer frameworks for decision-making.

Findings
The FDA’s increasing commitment to patient-focused drug development (PFDD) and patient engagement in translational research presents a significant opportunity to improve the clinical trials enterprise and enhance participation by patient groups . Patient groups can play important roles in improving the entire therapeutic development enterprise, from study endpoint selection that reflects outcomes meaningful to patients, to recruitment and retention in clinical trials, and more effective postmarketing safety . However, there is a lack of clarity about how, when, and by whom patients or patient groups should be engaged during the therapy development process, and which patients or patient groups should be engaged . Metrics by which the value of such engagement, in terms of regulatory and market success, might be measured are also lacking .

Recommendations
PFDD and patient engagement in research should be considered an effort to extend the benefits of incorporating patient insight and experiences, as well as desires and preferences, from bench to bedside and back . The therapeutic development process should meaningfully engage patients throughout, though specific guidance on implementation methods is needed .

Regulatory Considerations
The paper does not provide specific regulatory considerations or recommendations. The focus remains on identifying the opportunity and gaps in current patient engagement approaches rather than detailing regulatory pathways or compliance requirements.

Findings
Digital health technologies (DHTs) enable the creation of novel endpoints that can represent the patient experience more objectively and accurately than traditional measures.
Endpoints derived from DHTs may be more meaningful to patients, healthcare providers, and other stakeholders.
The CTTI pathway for developing novel endpoints is applicable across various chronic conditions, with specific case studies developed for Duchenne Muscular Dystrophy, Diabetes, Parkinson’s Disease, and Heart Failure.

Recommendations
A systematic approach should be used to identify and develop key novel endpoints from digital health technologies.
Development should focus on creating measures that are meaningful to patients.
Stakeholders—including patients, regulators, and investigative site personnel—should be engaged early and often in the planning process.
Biostatisticians and data scientists should be involved in key decisions regarding protocol design, data collection, and analysis.
Novel endpoints should be incorporated as exploratory endpoints in existing clinical trials and observational studies to gather evidence

Regulatory Considerations
Developers are advised to engage with regulators like the FDA early and frequently when planning the development of a novel endpoint.
There are established processes for interacting with the FDA, and resources are available to guide developers through these interactions.
The principles of adaptive trial design are the same for studies using mobile technologies as they are for traditional clinical trials.

Findings
Novel digitally-derived endpoints can provide more reliable data, increase trial efficiency, and enhance patient centricity.
Selecting appropriate outcome measures that are meaningful to patients and clinicians is critical to success.
Developing these endpoints requires a resource-intensive, systematic approach to meet stakeholder needs.
Demonstrating validity and utility of novel endpoints poses unique challenges, especially for new measures without established validation standards.
Sharing lessons learned and promoting transparency can advance the field by enabling collaboration and establishing standards.

Recommendations
Focus on measures that are meaningful to patients and clinically relevant by incorporating both patient and clinician perspectives.
Select technology after identifying the appropriate outcome to ensure alignment between the technology and trial objectives.
Engage with regulators early and often to ensure endpoint acceptance and alignment with regulatory requirements.
Include digitally-derived endpoints in early-phase trials and observational studies to validate their fit-for-purpose status.
Encourage knowledge sharing and collaboration among stakeholders to establish shared standards and accelerate adoption.

Regulatory Considerations
Engage with FDA, EMA, or other regulatory bodies during early stages of endpoint development to gather critical input.
Use established regulatory frameworks, such as Investigational New Drug (IND) or Investigational Device Exemption (IDE), for guidance on endpoint use in pivotal trials.
Validate technologies to meet performance characteristics, ensuring outputs correspond to clinical concepts of interest.
Include digitally-derived endpoints in exploratory studies to build evidence for their regulatory approval.
Reference resources such as the FDA and EMA guides for navigating endpoint-related regulatory interactions.

Findings
Clinical trial protocols designed without patient input often result in a high participant burden and a poor patient experience, leading to challenges in trial enrollment, adherence, and retention.
A lack of early patient engagement can lead to study designs that are not feasible, collect data on outcomes that aren’t meaningful to patients, and require costly protocol amendments later in the process.
Many sponsors and research teams lack a structured, systematic process and standardized tools for effectively planning and executing patient engagement activities.
Meaningful patient partnerships can lead to research of greater quality and relevance, as patients provide unique insights into living with their condition and the practicality of trial procedures.

Recommendations
Adopt a structured toolkit and systematic process to plan patient engagement, define objectives, select appropriate methods, and apply learnings to the protocol.
Engage with patients and caregivers as early as possible in the protocol development lifecycle to ensure their insights can meaningfully influence the study design.
Carefully select diverse patient partners based on criteria like their disease experience, and choose appropriate engagement methods (e.g., advisory boards, focus groups, surveys) to meet defined goals.
Use provided guides, templates, and visual aids to facilitate clear communication, manage expectations, and effectively gather, assess, and implement patient feedback.

Regulatory Considerations
Patient engagement in trial design is strongly encouraged by global regulatory bodies, including the U.S. Food and Drug Administration (FDA).
These activities align with regulatory initiatives like the FDA’s Patient-Focused Drug Development (PFDD) guidance, which emphasizes collecting data that reflects patient experiences, needs, and priorities.
Incorporating patient feedback helps ensure that a clinical trial is designed to capture meaningful endpoints and outcomes, which supports subsequent regulatory and Health Technology Assessment (HTA) review.

Findings
Many researchers, patients, and other stakeholders lack clarity about when and how to engage as partners within the clinical research process . There is a clear need for guidance on creating meaningful stakeholder partnerships in patient-centered clinical comparative effectiveness research . Engaging patients, caregivers, and other health care stakeholders as partners in planning, conducting, and disseminating research is a promising way to improve clinical decision making and outcomes .

Recommendations
The PCORI Engagement Rubric provides a framework for operationalizing engagement to incorporate patients and other stakeholders in all phases of research . The Rubric includes principles of engagement, definitions of stakeholder types, key considerations for planning, conducting, and disseminating engaged research, potential engagement activities, and examples of promising practices from PCORI-funded projects . PCORI encourages applicants, awardees, and others to apply the rubric to shift the research paradigm from one of conducting research on patients as subjects to a pursuit carried out in collaboration with patients and other stakeholders to better reflect the values, preferences, and outcomes that matter to the patient community .

Regulatory Considerations
The paper does not provide specific regulatory considerations. The PCORI Engagement Rubric was designed to illustrate opportunities for engagement to researchers interested in applying for PCORI funding and to patients and other stakeholders interested in greater involvement in research .

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
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.