Stakeholders welcome FDA’s framework for DHTs in drug development, cite challenges with adoption

The US Food and Drug Administration’s (FDA) framework on the use of digital health technologies (DHTs) in product development for drugs and biologics has been met with support from stakeholders, although several public comments took the opportunity to inform the agency of their challenges in using DHT.

To meet their commitment under the Prescription Drug User Fee Act (PDUFA VII), FDA’s framework details the creation of an agency-wide steering committee on DHT use in regulatory decision-making for drugs and biologics, and a commitment to hold public meetings or workshops with industry and other stakeholders. It also contains the agency’s plans for efficient evaluation of DHTs through demonstration projects, publishing DHT guidance documents in the areas of traditional and decentralized clinical trials as well as regulatory considerations for software associated with prescription drug use, improving consistency across the agency when engaging with DHTs, and enhancing the agency’s IT capabilities when reviewing data generated by DHTs. (RELATED: FDA outlines plan for digital health technologies for clinical trials, Regulatory Focus 24 March 2023)

In a joint comment, the Pharmaceutical Research and Manufacturers of America (PhRMA) and Biotechnology Innovation Organization (BIO) commended the FDA for publishing the framework and their “commitment to a multifaceted DHT program for drugs.”

“PhRMA and BIO recommend that FDA consider updating the DHT Framework in an iterative process to incorporate the feedback from comments received and lessons learned as the Agency’s experience with DHTs increases, as appropriate, during the PDUFA VII timeframe,” they wrote. “Such updates would improve the Framework and maximize its understandability and utility for stakeholders with the common goal of advancing the use of DHTs to improve drug development and benefit patients.”

The Society for Clinical Research Sites (SCRS) noted it is important for FDA to consider the voice of the clinical site and of the patient, but expressed concern about potential harms of DHT adoption.

“As regulators, it is critical that you understand when these devices are helpful to the research sites and therefore, patients and when they are harmful or burdensome to the clinical trial execution process. We have collected data that reinforces the fact that many of these technologies go against other goals of the agency, including increasing the ability to attract and enroll patients of diverse backgrounds,” they wrote. “We hope to be further engaged, per this documents declaration as an external organization to continue to advise on the viability of subsequent outcomes of this document, along with future related documents that directly affect the clinical research site.”

DHT validation, usability

The Digital Medicine Society (DiMe) called attention to the concepts of analytical validation and clinical validation when applied to DHT technical expertise and training.

“The concept of verification and validation has a lengthy history that precedes the rise of DHTs, particularly in the fields of device and software engineering. When applying these terms to DHTs, we believe it is critical that the concept of validation be parsed out into analytical validation and clinical validation,” DiMe wrote.

Another area of concern is how FDA characterized DHTs in usability studies, DiMe said. While the framework notes that usability studies can be part of validation, DHTs have “specific usability challenges” and “usability relies on specific expertise in user-centered design and human factors engineering,” they explained.

“[I]t is our opinion that DHT usability represents a process that is separate to both analytical validation and clinical validation. It may be appropriate in some cases to address aspects of usability and analytical validation within a single clinical study; however, the objectives and methodological considerations are distinct,” DiMe said.

DHT Steering Committee

A few commenters expressed encouragement at the development of the DHT Steering Committee, with several organizations offering their members up as advisors for the steering committee.

“Indeed, we ask the Agency to consider establishing an external Advisory Group to act as a key resource group for the steering committee,” the Association of Clinical Research Organizations (ACRO) wrote in their comment, recommending the agency also include digital technology developers and digital technology end users in a potential advisory group.

PhRMA and BIO said more information on how sponsors can interact with the steering committee would be welcome in the framework, “especially in relation to the Digital Health Center of Excellence.”

“PhRMA and BIO recommend that FDA provide clarity on the scope of topics that might be appropriate to discuss with each group,” they said.

Harmonization with international regulators

PhRMA and BIO recommended FDA expand on their thinking for how the agency will collaborate on DHT use in drug development with organizations such as the International Coalition of Medicines Regulatory Authorities (ICMRA), the International Medical Device Regulators Forum (IMDRF), and the International Council for Harmonisation (ICH).

It is important for FDA to consider how they will work with other international regulators’ requirements for DHTs in the context of international trials, they noted.

“While we recognize that FDA is actively engaged in international efforts, PhRMA and BIO recommend that the Framework highlight the specific efforts the Agency is involved in to support harmonization and convergence of regulatory approaches to DHTs in clinical trials across regions,” they wrote. “Given the global nature of drug development, it is critical to underscore global harmonization and convergence for regulatory approaches to digital health.”

Artificial intelligence and machine learning

DHT use can overlap with use of artificial intelligence (AI) and machine learning (ML), and a few commenters made note of this in their comments on the DHT framework.

In their comment, the Medicines Development Modernization Initiative (MDMI) said some of the key challenges FDA could help address include inconsistent data quality and standardization issues. They recommended the agency develop a set of “comprehensive, consensus-driven” guidances and standards for AI and ML models.

PhRMA and BIO said the FDA should offer flexibility for sponsors applying AI/ML algorithms to DHTs, citing the recent draft guidance on marketing submission recommendations for AI/ML-enabled device software functions as a reference.

The agency should “allow sponsors to leverage a similar approach described in the guidance for updates/upgrades to DHTs that utilize AI/ML,” they said.

Challenges in DHT use

There can be barriers to adopting DHT use in drug and biologic product development, DiMe noted. For example, a trial that uses a bring-your-own-device (BYOD) model for DHTs will encounter issues when processing data that is "rarely identical or compatible” across DHTs, “meaning that a BYOD trial must deploy multiple algorithms to generate the same outcome measure across study participants.”

“As such, the major challenge for Sponsors is the process of analytical validation rather than verification,” they explained. “DiMe believes that added clarity would be beneficial when the decision to deploy multiple algorithms is intentional (as in the BYOD model) rather than reactive (as a result of hardware, firmware, and/or software updates occurring during the data collection period).”

MIME said that barriers to adoption of DHTs in clinical development include regulatory guidance gaps and challenges, lack of guidance on quality standards and quality assurance processes, and lack of experience among clinical sites and trial participants.

“To address this, MDMI calls for FDA to encourage industry-wide innovation and collaboration through a test-and-learn approach based on regulatory guidance,” they said. “The convenience of DHTs for patients and providers should be a focus, as well as accelerating comfort with DHTs among [principal investigators], patients, and regulators. Comfort with DHTs across stakeholders is critical to realizing the potential of DHTs in clinical development.”

DHT Framework

Stakeholders welcome FDA’s framework for DHTs in drug development, cite challenges with adoption

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