By Maria Bonner and Kalah Auchincloss, Greenleaf Health
Digital health technology (DHT) is increasingly permeating the medical products industry due to its use in general wellness applications, medical devices intended to diagnose, treat, or prevent disease, and as a tool in clinical research. The FDA has issued numerous guidances on topics related to the regulation of such technologies as medical devices.1 However, there is less information available on how FDA intends to manage the use of DHTs in the context of clinical research to support the development of medical products.
Recognizing this gap, in its most recent Prescription Drug User Fee Act (PDUFA VII) commitment letter, FDA agreed to establish “a DHT framework document [to] guide the use of DHT-derived data in regulatory decision-makings for drugs and biological products.”2
Framework For The Use Of Digital Health Technologies In Drug And Biological Product Development
To meet this PDUFA VII commitment, FDA issued its Framework for the Use of Digital Health Technologies in Drug and Biological Product Development in late March 2023.3 While neither a legally binding document nor an agency guidance, the framework represents the agency’s road map for developing an approach to the use of DHTs in regulatory decision-making related to drug and biological product development. Drug developers who are using or intend to use DHTs in their product development activities should pay close attention to this framework and opportunities to engage with FDA as it crafts its regulatory agenda.
The framework, at the outset, defines DHTs as “systems that use computing platforms, connectivity, software, and/or sensors for healthcare and related uses. They include technologies intended for use as a medical product, in a medical product, or as an adjunct to other medical products (devices, drugs, and biologics). DHTs may also be used to develop or study medical products.”4
With respect to their use in clinical research, DHTs may include wearable, implantable, or software applications on mobile devices, among other approaches. DHTs allow for remote data acquisition in a clinical study and enable new study designs, such as decentralized clinical trials. This may confer significant benefits for research by expanding the patient populations that may participate in clinical studies and enabling the collection of data in real time, continuously, and in real-world settings rather than a clinical study site. However, to keep pace with the rapid development and use of DHTs in clinical trials, FDA must also build its capacity to understand and evaluate such technologies.5
The framework details the agency’s plan to effectively identify and address the challenges with the use of DHT in drug and biological product development, encompassing the agency’s internal efforts as well as engagement with external stakeholders.
Internal FDA Efforts
With respect to internal efforts, the framework outlines five workstreams,6 and while all are important, there are a few highlights.
The framework first explains that FDA created a DHT Steering Committee, which drafted and published the framework.7 The Committee includes members from the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), the Digital Health Center of Excellence (DHCoE), the Oncology Center of Excellence (OCE), and the commissioner’s office.8
The framework also includes plans to create consistent regulatory approaches to DHTs across review divisions and centers.9 Specifically, the framework states “review divisions and centers should have consistent approaches to the review and evaluation of submissions that contain DHT-related data. The DHT Steering Committee will help facilitate consistent approaches to the review and evaluation of such submissions.”10 While plans to harmonize guidelines/standards across product centers to facilitate and increase the use of DHTs in product development is a noble goal, implementation could be a challenge. If and how the collaboration across product centers evolves will be critical to operationalizing the framework and to achieving the agency’s DHT goals more generally.
Other internal workstreams include an evaluation of statistical considerations in the analysis of DHT-derived data and improving technical expertise and training. On the latter, there are several sub-workstreams, such as: (i) Verification and Validation; (ii) Use of a Participant’s Own DHT or General-Purpose Computing Platform; (iii) Upgrades and Updates of DHTs in Drug Development; (iv) Artificial Intelligence and Machine Learning; and (v) Technical Consultation of Experts and Staff Training.11
In addition to the above internal workstreams, and consistent with PDUFA VII, FDA has committed to improving its IT capabilities to support the review of DHT-generated data and will coordinate this effort with the agency’s enterprise-wide modernization activities.12 The framework stresses three subpoints with respect to the IT capabilities piece: (i) improving “its internal systems to support the review of DHT-related submissions”; (ii) creating a secure cloud technology to improve its infrastructure and analytics environment … enabl[ing] FDA to effectively receive, aggregate, store, and process large volumes of data from drug trials conducted using DHTs”; and (iii) creating standards to “make DHT data analyzable” (CDER and CBER would collaborate with DHCoE to create those data standards for DHT-generated data sets).13
One significant limitation, or challenge, is that it appears that FDA plans to create its own internal technology systems. Government agencies, including the FDA, have not possessed the technological know-how to stand up internal systems to effectively collect, analyze, and act on data in real time. In some instances, FDA has relied on the private sector for its technology systems, including Big Data analytics, which have been successful. Thus, FDA might want to reconsider its ability to develop in-house IT capabilities in the DHT space specifically, but also more generally for its enterprise-wide modernization efforts.
Overall, while the framework generally envisions a strategically sound internal approach for overseeing DHTs in drug and biological development, the weaknesses or challenges largely lie in the implementation and operationalization. For example, harmonizing standards for DHTs across product centers and review divisions is laudable but may be difficult in practice, and funneling resources to in-house development of IT systems to handle DHT data is risky.
External FDA Efforts And Guidances
In addition to detailing its internal workings, the agency also describes its plans to engage with external stakeholders, including regulated industry, “to better understand the challenges and opportunities associated with using DHTs” in regulatory decision-making for drugs and biological products.14 Such external engagement opportunities include the publication of guidances, public meetings, and demonstration selections,15 among others like sponsor meetings and the drug qualification tool/program.
With respect to guidances, FDA already has published two draft guidances on the use of DHTs in drug development and plans to publish at least two additional draft guidances. The draft guidances currently available include Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, which was published in December 2021,16 and Electronic Systems, Electronic Records, … in Clinical Investigations: Questions and Answers, which was published in March 2023.17 In addition, there are several other guidances not specific to DHTs that are nonetheless relevant to the use of DHTs in clinical investigations.
Digital Health Technologies for Remote Data Acquisition in Clinical Investigations
The draft guidance on use of DHT for remote data acquisition proposed recommendations to facilitate the use of DHTs in clinical investigations, including, for example, “selection of DHTs that are suitable for use in clinical investigations”; “verification and validation of DHTs for use in clinical investigations”; “use of DHTs to collect data for trial endpoints”; “identification of risks associated with the use of DHTs during clinical investigations”; and “management of risks related to the use of DHTs in clinical investigations.”18
Electronic Systems, Electronic Records, … in Clinical Investigations: Questions and Answers
The draft guidance on electronic systems and records discusses commonly asked questions and provides answers related to the applicability of Part 11 to electronic records, electronic signatures, and electronic systems used in clinical investigations, including the use of DHT-derived data.19 Further, the draft guidance makes recommendations for using DHT data and use of DHT in clinical trials.20
On June 6, 2023, FDA issued draft guidance from the International Council for Harmonisation on Good Clinical Practices (GCP) E6(R3) and opened the docket for public comment, with comments due by September 6.21 This FDA draft guidance (embodying the ICH guideline) aims to maintain a flexible GCP framework that ensures the safety of clinical trial participants and data, while also advancing new principles that modernize clinical trials and support more efficient approaches to trial design and conduct.22
One way the FDA guidance envisages modernizing clinical trials is encouraging the use of DHTs, particularly fit-for-purpose innovative DHTs.23 The draft guidance states: “[f]or example, innovative digital health technologies, such as wearables and sensors, may expand the possible approaches to trial conduct.”24 Additionally, the draft guidance stresses the fit-for-purpose nature of DHTs, stressing that “the use of technology in the conduct of clinical trials should be adapted to fit the participant characteristics and the particular trial design. This guideline is intended to be media neutral to enable the use of different technologies for the purposes of documentation.”25
Equally important, the draft guidance acknowledges that, while DHTs can easily be embedded into current healthcare infrastructure, they simultaneously “aid in keeping clinical trial conduct in line with advancing science and technological developments.”26 Indeed, when finalized, the FDA draft guidance would establish harmonized GCP standards for conducting and modernizing clinical trials, which would include, for example, decentralizing some or all elements of these studies, using DHTs and real-world data, and leveraging more complex designs.
Commissioner Califf, in a press release with the issuance of the draft guidance, echoed the guidance themes, emphasizing the importance of creating “a more robust clinical trial ecosystem” and encouraging the use of innovative trial designs and health technologies...to truly advance clinical trials and generate meaningful results.”27 More generally, Commissioner Califf, FDA senior leadership, and other draft guidances and initiatives relevant for DHTs have emphasized how DHTs like patient wearables and sensors may create a robust, efficient, and modernized clinical research system by facilitating patient enrollment in clinical trials, improving patient population diversity,28 and perhaps improving the accuracy of data collected, among other laudable benefits for clinical trial modernization.
And finally, as we discuss in a separate article, two guidances29 issued during the COVID-19 public health emergency that facilitated the use of DHTs in clinical investigations will be revised before Nov. 7, 2023, to either sunset at a later date or to continue indefinitely as traditional guidances. Of particular interest is CDER’s Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (FDA-2020-D-1106-0002).30 FDA’s goal in issuing this guidance was to provide general considerations and recommendations to help sponsors in ensuring the safety of clinical trial participants, maintaining compliance with GCP, and minimizing risks to trial integrity and interruptions for the duration of the COVID-19 PHE.31 One component of this effort encouraged the use of DHTs to allow for remote site monitoring and remote clinical visits for trial participants. FDA released a final version of this guidance at the end of September, with a slightly different title to encompass a broader array of emergency circumstances: Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions to Due to Disasters and Public Health Emergencies.32 The final guidance is similar to the COVID version, and recommends approaches that sponsors of clinical trials of medical products can consider when there is a major disruption to clinical trial operations during a disaster or public health emergency.
Looking forward, the framework stresses the agency’s commitment to publishing two more draft guidances related to DHTs use in drug development this fiscal year: Decentralized Clinical Trials for Drugs, Biological Products, and Devices, a draft of which FDA issued on May 3, 2023, not long after the agency released the framework, and Regulatory Considerations for Prescription Drug Use-Related Software.33 The framework also stresses the agency’s commitment to publishing more guidances, consistent with the PDUFA VII commitment letter that emphasized that draft guidances in identified areas of need informed by stakeholder engagement would be a priority for the agency.34
In addition to the publication of final and draft guidances, the framework discusses the agency’s plans to host five public meetings facilitating dialogue between the agency and patients, academic researchers, and regulated industry including biopharmaceutical companies and digital health companies. Topics will include, for example, understanding priorities for the development of DHTs to support clinical investigations; identifying approaches to DHT verification and validation; understanding DHT data processing and analysis to inform the need for novel analytical techniques; addressing the regulatory acceptance of safety monitoring tools that utilize AI and ML-based algorithms for pharmacovigilance purposes; and understanding emerging issues.35
Relatedly, and consistent with the framework’s themes, including engagement with industry, on October 11, 2023, the FDA announced the establishment of a Digital Health Advisory Committee to help the agency “explore the complex, scientific and technical issues related to digital health technologies.”36 This advisory committee is one forum, or opportunity, for industry to engage on digital health issues. The committee will include nine voting members in addition to several temporary members added to specific panels based on topics. The agency has opened its nomination portal — and will be open for industry/private sector participation until December 11. The committee will help the agency on cross-cutting issues that affect multiple product centers, while digital health product-specific issues will remain in their respective advisory committees and explore issues related to DHTs, such as artificial intelligence/machine learning (AI/ML), augmented reality, virtual reality, digital therapeutics, wearables, remote patient monitoring, and software.37 Indeed, the announcement for the advisory committee is consistent with the agency's recent strategic priorities — namely, advancing "health equity in part through expanding access by bringing prevention, wellness, and healthcare to all people where they live — at home, at work, in big cities, and rural communities. DHTs are critical for achieving this transformation in care delivery."38
Important for regulated industry, including DHT developers, the agency plans to identify and implement at least three demonstration projects “to inform methodologies for efficient DHT evaluation in drug development.”39 The agency, according to the framework and the PDUFA VII Commitment Letter, is particularly interested in the following topics: “validation methods for specific technologies, endpoint development, analytic approaches to missing data, use of multi-channel inputs to characterize an endpoint, evaluation of continuous data versus discrete measurements, use and limitations of DHTs in DCTs, and other related issues.”40
In view of FDA’s emphasis on external engagement, the developers of DHTs, as well as regulated industry writ large, should avail themselves of the multiple and varied opportunities to dialogue with the agency — commenting on draft guidances, engaging at the public meetings, or proposing and implementing demonstration projects or pilots. The agency is explicitly calling on, and relying on, regulated industry and DHT developers in particular to provide feedback in the DHT space and to meet the framework’s objectives. This includes, of course, identifying both challenges and solutions/opportunities in using DHTs in drug and biologics development.
While the framework is a solid baseline from which to work, it is a high-level document that generally reiterates goals the agency has already agreed to in PDUFA VII. Acknowledging an information gap, the document is a road map for the public that signals how FDA intends to approach the process for gathering information to better inform its decision-making around the regulation of DHTs for drug development. The agency commits to numerous internal and external actions as part of that process; thus, it will be critically important for all stakeholders, including patients, DHT manufacturers, and drug and biologics companies, to avail themselves of the numerous opportunities to engage with the FDA and offer substantive input. Now is the time to provide FDA with insight into the benefits and challenges of the use of DHTs in clinical research and to offer regulatory solutions. The biggest challenge for FDA will be in digesting that information and turning it into a cohesive regulatory scheme that is flexible and adaptable to ever-changing technology, but which can also be applied consistently across review divisions and centers.
2. FDA, “Framework for the Use of Digital Health Technologies in Drug and Biological Product Development,” https://www.fda.gov/media/166396/download. See also Comments on the Agency’s Framework can be submitted to the docket (FDA-2022-N-3319) until May 23, 2023.
3. See the Framework. See also Comments on the Agency’s Framework can be submitted to the docket (FDA-2022-N-3319) until May 23, 2023.
5. PDUFA VII Commitment Letter, IV.C. ENHANCING USE OF DIGITAL HEALTH TECHNOLOGIES TO SUPPORT DRUG DEVELOPMENT AND REVIEW (p. 64).
6. Framework at Pages 8-11, “DHT Steering Committee,” “Technical Expertise and Training,” “Consistency of Evaluations Across Review Divisions,” “Statistical Considerations in the Analyses of DHT-Derived Data,” and “IT Capabilities.”
7. Framework at Page 8-9.
8. Framework at Pages 8-9.
10. Framework at Page 11.
11. Framework at Pages 9-11.
12. Framework at Pages 11-12.
13. Framework at Page 12.
14. Framework at Page 12.
15. Framework at Pages 12-26.
29. CDER Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (FDA-2020-D-1106-0002), https://www.fda.gov/media/136238/download and CDRH’s “Enforcement Policy for Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring during the Coronavirus Disease 2019 Public Health Emergency (Revised)” (FDA-2020-D-1138), https://www.fda.gov/media/136290/download.
34. Framework at Page 14. The PDUFA VII Commitment Letter at Page 66.
35. The Framework discusses each of these categories in greater detail, see Framework at Pages 14 and 15.
About The Authors:
Maria Bonner, J.D., is vice president in Greenleaf Health’s regulatory compliance group, where she provides strategic and regulatory advice to clients. She also serves as Greenleaf’s in-house deputy counsel. Prior to joining Greenleaf, Bonner gained policy and legal experience in both the private and public sectors. She formerly served at the White House in several roles: on the Domestic Policy Council as deputy director and special assistant to the President. Bonner also served as the deputy associate counsel in the Office of the Vice President. Former experience includes working at a global law firm in the litigation and international arbitration group. She earned her J.D. from Georgetown University Law Center and her B.A. from Georgetown University.
Kalah Auchincloss, J.D., M.P.H., is executive vice president of regulatory compliance and deputy general counsel for Greenleaf Health. She has more than 15 years of food and drug legal, policy, and regulatory experience at the FDA, on Capitol Hill, and in the private sector. At Greenleaf, Auchincloss advises pharmaceutical and medical device companies on compliance, policy, and other regulatory issues. Before moving to Greenleaf, Auchincloss spent six years at the FDA in the Commissioner’s Office and in CDER’s Office of Compliance and Office of Regulatory Policy. She earned her J.D. from Georgetown University, her M.P.H. from Harvard University, and her B.A. from Williams College.