Where The FDA And EMA Stand On Digital Endpoints

By Anita Burrell, principal, Anita Burrell Consulting LLC

Digital biomarkers are quickly and quietly becoming a digital revolution in clinical trials. As such, and in the first article of this three-part series, we looked at how companies have integrated digital biomarkers or endpoints into clinical development through case studies. In this article, we review the extent of regulatory acceptance of digital endpoints and how to ensure data produced from digital technologies satisfies regulators.

How Common Are Digital Endpoints In Clinical Development?

More than 130 pharmaceutical and biotech sponsors had used over 1,300 AI-powered digital endpoints in their clinical trials between 2008 and 2022, according to the HumanFirst Institute.¹ The analysis also showed that:

• Sixty percent of the digital endpoints were secondary endpoints, and 25% were primary endpoints.
• Nearly two-thirds of the trials deploying digital endpoints were Phase 2 or Phase 4. This is likely because digital health technology is often introduced in Phase 2 trials, before pivotal Phase 3 studies, and because Phase 4 studies reflect long-term and real-world effects.
• Ten therapeutic areas represented 82% of all trials deploying digital endpoints, with endocrinology, neurology, and cardiology being in the top three. Many used connected sensors, such as glucose monitors and wearable ECG patches.

How Have Regulatory Agencies Responded?

The FDA appears to be all-in on digital endpoints and biomarkers. As part of its Prescription Drug User Fee Act (PDUFA) VII commitments, the FDA published the Framework for the Use of DHTs in Drug and Biological Product Development and established the DHT Steering Committee, which consists of senior staff from CDER, CBER, and the CDRH.²

Additionally, the FDA has created the Digital Health Center of Excellence, based in CDRH, which is intended to provide scientific expertise on DHTs for all of the FDA and connect internal and external stakeholders to the FDA in the DHT space. To further this mission, the FDA created the Digital Health Advisory Committee in October 2023 to advise the commissioner of food and drugs on scientific and technical issues related to DHTs.

What’s more, a December 2023 guidance document, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, provides “recommendations on the use of digital health technologies (DHTs) to acquire data remotely from participants in clinical investigations that evaluate medical products. DHTs for remote data acquisition in clinical investigations can include hardware and/or software to perform one or more functions. Use of DHTs as recommended in this guidance may improve the efficiency of clinical trials for sponsors, investigators, and other stakeholders and may increase the opportunities for individuals to participate in research and make participation more convenient.”³

As noted in the first article, the EMA recently accepted a DHT-derived endpoint (stride velocity 95th centile, or SV95C) as the primary endpoint for ambulatory  Duchenne muscular dystrophy studies,⁴ and this trend is poised to continue with other countries’ health agencies, including Health Canada, Switzerland’s Swissmedic, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), and Australia’s Therapeutic Goods Administration (TGA),⁵ showing interest.  Specific regulatory frameworks for the qualification of drug development tools or novel methodologies in these countries for interactions with sponsors are likely forthcoming.

Practical Steps For Including Digital Endpoints/Biomarkers

The first aspect to consider is whether the digital endpoints will complement accepted endpoints or offer new ways to capture endpoints  that offer additional insight into participant functionality or health that has not been easily measured.

The FDA is clear in the first instance. Where there is digital capture of a clinical characteristic or event that was previously measured in a clinical setting (e.g., blood pressure monitoring or weight measurements at home versus in the clinic), a justification for the endpoint may not be needed since the digital measurement replicated existing measures. However, the digital technology should be “fit-for-purpose,” meaning the DHT’s use and interpretability in the clinical investigation has been validated and the physical parameter of its measures (e.g., acceleration, temperature, pressure) is accurate and precise. Furthermore, regardless of whether the endpoint is novel, if the digital technology is classified as a medical device, it would also have to clear regulatory requirements for devices.³

For novel endpoints, the concept of interest (meaningful and core aspect of the disease) and the context of use (when and how the digital technology will be used) must be proposed in the overall assessment of the clinical trial.⁶ This is in addition to considering the fit-for-purpose aspects, which would include the minimum technical and performance specifications, validation, and verification. Also influencing the evidence requirements for acceptance is whether the measure is a clinical outcome assessment or a biomarker. 

Impact Of Fit-For-Purpose Requirements On Clinical Timelines

The FDA guidance document³ suggests sponsors have a strong rationale for selecting and using a DHT, considering the clinical trial population, technical and performance specifications, design and operation, and the potential for a patient to use their own digital technology. The fit-for-purpose description in a submission is expected to include information on the design and technological characteristics of the digital technology, data provided to the sponsor and investigator, and how the digital technology measures the clinical event or characteristic of interest (e.g., the use of accelerometry to measure steps). Sponsors must also demonstrate verification, i.e., confirmation by examination and provision of objective evidence that the parameter measured by the technology (e.g., acceleration, temperature, pressure) is measured accurately and precisely. Similarly, regulators also expect to see validation through confirmation by examination and provision of objective evidence that the selected technology appropriately assesses the clinical event or characteristic in the proposed participant population (e.g., step count or heart rate). In addition, regulators also appreciate usability evaluations that identify and address any potential use errors or difficulties that trial participants or other intended users may experience when using the technology.

Importantly, studies needed to demonstrate these requirements must be incorporated into the clinical development timeline to ensure successful regulatory acceptance of the digital endpoint or digital biomarker in question. Health authority consultations are highly advised and should begin before clinical studies commence to gain agreement on the concept of interest and the path toward validation and verification of the digital endpoint.

Other Considerations For Digital Endpoints

As digital technologies are faster to innovate, updates in hardware or software or other changes should be anticipated and require a contingency plan to assess the impact of the change on regulatory requirements. This includes documentating the change  in case of an audit and ensuring additional studies for validation or verification purposes can be predicted.

Similarly, sponsors should conduct a privacy assessment to set measures for the transfer of personal data, cybersecurity requirements, and to understand potential risks involved in data collection. On this note, the FDA has a draft guidance addressing electronic records collected through digital technologies during a clinical investigation that provides information on transfer and retention security.⁷ Sponsors should also ensure that site personnel, study participants, and their care providers are adequately trained on the use of the digital technology to ensure the quality and integrity of the data.

So, What Is The Next Step? 

Incorporating digital endpoints into a clinical development program may be met with resistance from clinical trial management due to the investment required and potential impact on overall timelines. The value proposition of including these measures needs to be thoroughly considered and should clearly indicate the advantage that is foreseen. In the next article, we will explain how to provide a compelling business case for digital endpoints.

References:

1. https://www.gohumanfirst.com/posts/digital-endpoints-widely-adopted-in-pharmaceutical-and-biotech-sponsored-clinical-trials
2. https://www.fda.gov/science-research/science-and-research-special-topics/digital-health-technologies-dhts-drug-development
3. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations
4. Servais, L. et al. First regulatory qualification of a digital primary endpoint to measure treatment efficacy in DMD. Nature. Med. 29, 2391–2392 (2023).
5. https://www.transceleratebiopharmainc.com/wp-content/uploads/2023/04/2023-Patient-Technology-Regulatory-Landscape-Tool_4.21.23.pdf
6. Erdemli, G et al Regulatory considerations for successful implementation of digital endpoints in clinical trials for drug development, npj Digital Medicine ( 2025) 8:142 https://doi.org/10.1038/s41746-025-01513-5
7. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/electronic-systems-electronic-records-and-electronic-signatures-clinical-investigations-questions

About The Author:

Anita Burrell has over 23 years of pharmaceutical industry leadership experience in the UK, France, and the U.S. in a variety of roles. She led global pricing and reimbursement for Sanofi, directed the development of Aubagio (an oral MS therapy), and was the head of strategic commercial excellence. As the principal of Anita Burrell Consulting LLC since 2015, Anita helps companies understand market dynamics and payer behavior, design integrated evidence plans and value communication projects, as well as understand the implications of digital health and possibilities to use behavioral economics. Anita served on the Healthcare Businesswomen’s Association Global Board of Directors and is the past chair of the ISPOR Digital Health SIG, which addresses opportunities in the healthcare sector emerging from the increasing use of digital technologies. Anita holds a BA (Hons) in economics from the University of Stirling, an MA in economics from Dalhousie University, and an MBA from Kingston University.