Developing Digitally Derived Endpoints that Measure what Matters to Patients: The Case for Collaboration
Elektra J. Papadopoulos
Center for Drug Evaluation and Research (CDER)
US Food and Drug Administration
Sonya Eremenco
Critical Path Institute
Michelle Campbell
Center for Drug Evaluation and Research (CDER)
US Food and Drug Administration
I

n recent years, FDA has undertaken multiple efforts to better incorporate the patient’s voice in drug development and evaluation through adoption of clinical outcome assessments (COAs) that measure what matters to patients. Digital health technology (DHT) tools, such as sensor-based assessments of activity or sleep, hold potential to play a pivotal role in modernizing patient-centered outcome measurement by reducing barriers to trial participation and capturing outcomes that matter to patients in daily life. FDA regulations require well-defined and reliable assessment methods, a standard that applies to any outcome assessment intended to support claims of drug effectiveness. A COA is considered fit-for-purpose when the level of validation associated with it is sufficient to support its context of use.

Development of novel, fit-for-purpose digitally derived COA endpoints intended to support regulatory decisions is a complex and potentially lengthy undertaking necessitating a multistakeholder approach, which makes it difficult to achieve within individual sponsors’ drug development programs. We do not know of any regulatory precedent for US FDA labeling claims based on a novel digitally derived endpoint to date.

Precompetitive Collaboration and Public-Private Partnerships in DHT Endpoint Development

Precompetitive collaboration involves multiple stakeholders within the same industry, coming together to address a shared problem outside of a commercial setting. Development of novel digitally derived endpoints is a potentially lengthy commitment that relies on input from a multitude of stakeholders including patients, caregivers, regulators, health technology assessors, technology experts, measurement experts, disease experts, and clinical trialists/medical product developers.

The goals of novel digitally derived COA endpoint development efforts are patient-centric measures that can support regulatory decision making. Challenges include identifying what is both meaningful to patients and related to the condition of interest, defining the specific concept(s) of interest to be measured in clinical trials, determining the best way to measure the concept(s) of interest, defining the endpoint and its interpretation, and ensuring verification of the DHT (e.g., wrist-worn sensor) as well as clinical validation of the DHT-derived endpoint in the context of use. Continuous monitoring through use of digital tools (e.g., wearables) can result in massive datasets without clear interpretation unless carefully considered at the outset. A thoughtful and systematic approach, with early and continued consultation with regulatory authorities, is recommended to ensure that digitally derived COA endpoints are patient-centric and meet regulatory requirements.

Public-private partnerships facilitate communication among stakeholders and regulators, enabling all to learn together. These partnerships also de-risk the evidence-generation process, as it would not be tied to a specific medical product development program that could end if the drug does not progress. DHTs are also rapidly evolving, leading to advantages to endpoint development that is device agnostic. Importantly, Center for Devices and Radiological Health (CDRH) approval of a DHT as a medical device does not imply that the instrument is fit-for-purpose as a drug development tool. At the same time, CDRH approval is not necessarily required to successfully use a DHT in a clinical investigation. Early and continued regulatory input on this and other key endpoint development considerations is key.

Drug Development Tool Qualification and Precompetitive Collaboration

Qualification is a conclusion, based on a formal regulatory process, that within the stated context of use, a medical product development tool can be relied upon to have a specific interpretation and application in medical product development and regulatory review. Drug development tools, once qualified, are made publicly available for use by drug developers. While formal regulatory qualification is not a requirement to support labeling claims in the United States, the qualification process allows FDA to make determinations regarding the fitness for purpose of drug development tools outside of any specific drug development program and lends itself to regulatory review of evidence developed through public-private partnerships. It also facilitates collaborative approaches by including the input of regulators and other stakeholders in key decisions throughout instrument development.

To date, the majority of qualified COAs in the FDA’s COA Drug Development Tool Qualification Program have been developed through precompetitive consortia. The sharing of experience and data, as well as resources and expertise, has led to this success and makes consortia well-poised to tackle the challenges of novel digitally derived, fit-for-purpose COAs for drug development.

Table. Examples of public-private partnerships in the development of novel digitally derived endpoints
Consortium
Project Goal
Critical Path Institute’s Patient-Reported Outcome (PRO) Consortium
To incorporate both patient-reported and activity monitor data into the assessment of clinical benefit in chronic heart failure treatment trials.
Critical Path Institute’s Critical Path for Parkinson’s Consortium: Digital Drug Development Tools (3DT) team
To advance regulatory readiness of digital health technologies in early Parkinson’s disease studies by generating a set of candidate digital measures with optimized performance to complement standard clinical assessments in measuring the progression of Parkinson’s disease and response to treatment in clinical studies targeting early stages following clinical diagnosis.
Innovative Medicines Initiative (IMI) MOBILISE-D
To improve the accurate assessment of mobility in clinical trials through the development of a comprehensive system to analyze people’s gait based on digital technologies, including sensors worn on the body. Includes investigation in multiple disease settings: chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, hip fracture recovery, and congestive heart failure.
Clinical Trials Transformation Initiative
To develop recommendations to help advance the practical use of novel, digitally derived endpoints in clinical trials.
Table. Examples of public-private partnerships in the development of novel digitally derived endpoints
Consortium
Critical Path Institute’s Patient-Reported Outcome (PRO) Consortium
Project Goal
To incorporate both patient-reported and activity monitor data into the assessment of clinical benefit in chronic heart failure treatment trials.
Consortium
Critical Path Institute’s Critical Path for Parkinson’s Consortium: Digital Drug Development Tools (3DT) team
Project Goal
To advance regulatory readiness of digital health technologies in early Parkinson’s disease studies by generating a set of candidate digital measures with optimized performance to complement standard clinical assessments in measuring the progression of Parkinson’s disease and response to treatment in clinical studies targeting early stages following clinical diagnosis.
Consortium
Innovative Medicines Initiative (IMI) MOBILISE-D
Project Goal
To improve the accurate assessment of mobility in clinical trials through the development of a comprehensive system to analyze people’s gait based on digital technologies, including sensors worn on the body. Includes investigation in multiple disease settings: chronic obstructive pulmonary disease, Parkinson’s disease, multiple sclerosis, hip fracture recovery, and congestive heart failure.
Consortium
Clinical Trials Transformation Initiative
Project Goal
To develop recommendations to help advance the practical use of novel, digitally derived endpoints in clinical trials.

Conclusions

A careful, systematic approach to patient-focused outcome assessment is just as critical when developing digitally derived COAs as with all COAs. The diversity of expertise and perspectives needed to surmount the complex development issues associated with digitally derived COAs and their related endpoints lends itself to a precompetitive collaborative effort leveraging time, resources, and expertise. There are multiple examples of ongoing public-private partnerships working to develop novel digitally derived endpoints and/or recommendations to promote the advancement of novel, digitally derived endpoints in drug development. We encourage the medical product development community to become engaged in public-private partnerships to advance our collective goal of measuring what matters to patients.
Disclaimer: This publication reflects the views of the author(s) and should not be construed to represent the views, policies, or guidance of the FDA.

Critical Path Institute is supported by the Food and Drug Administration (FDA) of the US Department of Health and Human Services (HHS) and is 54.2% funded by the FDA/HHS, totaling $13,239,950, and 45.8% funded by nongovernment source(s), totaling $11,196,634. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement by, FDA/HHS or the US Government.

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