Clinical Trials - Greenleaf Health

Regulation of Digital Health Technologies After Unwinding of Pandemic Guidances

This article was originally published in Med Device Online.

As a result of COVID-19 pandemic lockdowns and limited in-person healthcare opportunities, FDA (and other regulatory authorities) loosened restrictions on the oversight of digital health technologies (DHTs), and even began to encourage their use in certain settings. The expiration of the public health emergency (PHE) and the related unwinding of certain pandemic guidances that created a more permissible environment for DHTs have significant implications for the DHT landscape.

This article covers three guidances particularly salient to DHTs that may sunset this fall, but which are still critical to understand, as the principles enshrined in at least two of the guidance documents are likely to live on. More specifically, based on recent FDA draft guidances, communications from senior FDA leaders, and other sources, the agency appears to continue to recognize the value of DHTs, particularly in clinical trials and in home-based patient monitoring and healthcare management settings. Industry should take advantage of this opportunity to engage with the FDA as it develops the longer-term framework for regulation of DHTs.

Pandemic Health Emergency’s Expiration and Unwinding of Pandemic Guidances Relevant for DHTs

The COVID-19 PHE declaration and the related authorities it granted expired on May 11, 2023, and as a result, some guidances that FDA issued pursuant to those authorities sunset on that date or will sunset soon.¹ FDA sorted the 72 COVID-19 related guidances that were in effect prior to the PHE expiry into four broad buckets:²

22 guidances that are no longer in effect as of the PHE declaration expiry on May 11, 2023 (“May Terminated Guidances”)
22 guidances that will continue in effect for 180 days after the PHE declaration expiry and then will no longer be in effect as of Nov. 7, 2023 (“November Terminated Guidances”)³
24 guidances that will continue in effect for 180 days after PHE expiry (until Nov. 7, 2023), during which time the agency plans to further revise these guidances and there may be a future sunset date or potentially these will remain in effect indefinitely (“Indefinitely Extended Guidances”)
Four COVID-19 related guidances whose duration is not tied to the COVID-19 PHE and thus will remain in effect.

Several guidances related to digital health technologies are affected by the end of the PHE and fall into the November Terminated or Indefinitely Extended guidance category, which could have critical implications for DHT manufacturers.

Guidance on Mental Health DHTs

There is one guidance with implications for digital health technologies that falls into the second category of guidances terminating on Nov. 7, 2023, namely, CDRH’s Enforcement Policy for Digital Health Devices for Treating Psychiatric Disorders During the COVID-19 PHE (FDA-2020-D-1138).⁴

In brief, the guidance signaled that, for the duration of the PHE, the agency would not object to, or enforce against, the distribution and use of computerized behavioral therapy devices and other digital health therapeutic devices, with some caveats, for psychiatric disorders or for low-risk general wellness and digital health products for some mental health or psychiatric conditions.⁵ These psychiatric disorders included, but were not limited to, obsessive compulsive disorder, generalized anxiety disorder, insomnia disorder, major depressive disorder, substance use disorder, post-traumatic stress disorder, autism, and attention deficit hyperactivity disorder.⁶ The guidance also noted that the psychiatric condition could have been a condition existing prior to the pandemic or may have onset during the public health emergency.⁷ The guidance was issued with the explicit two-fold goals of (i) expanding the availability of DHTs for psychiatric disorders at a time when access to mental healthcare would otherwise have been limited and when mental health disorders were skyrocketing due to the COVID-19 pandemic and lockdowns and (ii) limiting patient and provider contact to minimize the spread of infection but still ensure patients received healthcare.⁸

This guidance will remain in effect until Nov. 7, 2023, unless superseded by a revised final guidance before that date. DHT companies, depending on the technology and stated policy caveats, may need to take action to remove their devices from the market or take steps to comply, such as submitting a marketing application. There are also important implications for patients and providers. Will patients who have come to rely on DHTs for access to mental health care be able to continue using existing options or seek out new treatments? Will they be able to switch seamlessly back to in-person provider-based care or forgo it if their access to DHTs is limited? These are open questions, but ones the agency will consider.

Clinical Trial-Related Guidances

In addition, two guidances particularly salient for the digital health industry fall into the bucket that will be revised before Nov. 7, 2023, to either sunset at a later date or continue indefinitely. One is CDER’s Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency (FDA-2020-D-1106-0002).⁹ 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.¹⁰ The guidance included a lengthy question-and-answer section describing specific scenarios and how FDA would expect sponsors to handle them.¹¹ For example, the guidance discussed when it would be appropriate to conduct remote clinical visits for trial participants; when to remotely monitor clinical sites to ensure both trial participants’ safety but also data integrity; or when and how to ship the studied product to a local healthcare provider to minimize trial participants’ travel and face-to-face contact with others.¹²

In fact, as we anticipated, the 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.¹³ 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.

The other guidance is CDRH’s Enforcement Policy for Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring during the Coronavirus Disease Public Health Emergency (Revised) (FDA-2020-D-1138).¹⁴ This guidance was issued with the express hope of expanding the availability and capability of remote patient monitoring devices.¹⁵ Specifically, with the guidance, FDA signaled its enforcement policy would apply to an enumerated list of legally marketed non-invasive remote monitoring devices that measured or detected common physiological parameters and that are used to support patient monitoring during the PHE.¹⁶ Examples of covered devices would be a non-invasive blood pressure measurement system and a cardiac monitor, among others.¹⁷Further, modified use of these covered devices would improve access to important patient physiological data “without the need for in-clinic visits and facilitate patient management by healthcare providers while reducing the need for in-office or in-hospital services” during the PHE, decreasing COVID-19 infection/contraction risks for patients and providers alike.¹⁸

Just recently, on October 19, the FDA revised the above as updated final guidance on its enforcement policy for remote patient monitoring devices. The new final guidance includes several revisions, or updates, compared against earlier versions. For example, the FDA removed the oximeter and clinical electronic thermometer device types that were listed in table enumerating legally marketed non-invasive remote monitoring devices. The FDA stressed that manufacturers of non-invasive remote monitoring devices the table must submit a premarket notification and receive clearance prior to marketing these devices in the U.S., to the extent the devices are not 510(k)-exempt, as well as comply with post-marketing requirements. The FDA also expressed its intention to allow limited modifications to the indications, functionality, or hardware or software of certain non-invasive remote monitoring devices used to support patient monitoring without prior submission of a premarket notification in certain examples. The examples provided were moving a subject device from the hospital or healthcare setting to the home or making a hardware or software change to improve remote monitoring of patients. Notably, this updated final guidance has no sunset or expiration date.

The Regulatory Landscape for DHTs in a Post-Pandemic World: Forward-Looking Possibilities

Although the expiry of the PHE means the future of the guidances discussed above is uncertain, lessons learned from the pandemic, and general themes embodied in the guidance documents described above, are consistent with FDA’s current vision for the DHT regulatory landscape. DHT developers and manufacturers should pay close attention to how FDA handles these guidances in November.

As such, we suggest that FDA may be inclined to extend these guidances indefinitely, or at least continue to implement the principles included within those guidances if they do sunset. This is particularly likely for the guidance on conduct of clinical trials and the enforcement policy for digital health devices for treating psychiatric disorders. One motivation for extending these guidances indefinitely is that they seem to fit with the agency’s general regulatory stance on increasing the availability, use, and reliance on DHTs in general, but particularly in clinical trial settings and for patients in home healthcare monitoring/home-based healthcare models.

For example, the draft guidance on the conduct of clinical trials complements and is consistent with the March 2023 Framework for Digital Health,¹⁹ several other post-pandemic recent draft guidances, as well as statements from FDA senior leadership associated with the issuance of draft guidances, and other policy/strategy documents that the agency has released, among others.

More specifically, 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^.20 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.²¹

One way the FDA guidance envisages modernizing clinical trials is encouraging the use of DHTs, particularly fit-for-purpose innovative DHTs.²² The draft guidance states: “[f]or example, innovative digital health technologies, such as wearables and sensors, may expand the possible approaches to trial conduct.”²³Additionally, the draft guidance stresses the fit-for-purpose nature of DHTs, stating 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.”²⁴

Equally important to the agency’s emphasis on using DHTs to modernize and decentralize clinical trials, the agency also has stressed the importance of DHTs for patient monitoring/home-based monitoring and care. It is theoretically possible – or maybe even pragmatic – for the agency to extend, revise, or potentially finalize guidance similar to the enforcement policy for digital health devices for treating psychiatric disorders.

Earlier this year, CDRH’s director, Jeff Shuren, gave an interview to Focus, a trade press publication. The interview, published June 16, focused on how the head of CDRH believes that “moving medical technologies from the clinical setting into the home may reduce costs and improve patient care; however, he cautioned that any medical technology used at home must prove that it is fit-for-purpose.”²⁵ Specifically, one of his quoted statements described how the pandemic moved the agency to create “flexible policies to facilitate modifications to devices to have digital remote capabilities to help move care to the home or in some cases even the development of technologies without prior FDA review to be able to facilitate care in the home, some of the adjunctive behavioral therapies, for example.”²⁶

His specific reference to the enforcement policy for digital health devices for treating psychiatric disorders²⁷ guidance demonstrates its significance and that the guidance’s themes are part of, or at least consistent with, the center director’s vision for moving medical technologies into the home and the value of DHTs in doing so. After Director Shuren’s comments, FDA published a list of questions for public comment on what, and how, the agency can do to foster and incentivize the development of at-home DHTs and what factors should be considered when those technologies come to market.²⁸ In particular, the questions include the following:

“How can the FDA support the development of medical technologies, including digital health technologies and diagnostics, for use in non-clinical care settings, such as at home?
What factors should be considered to effectively institute patient care that includes home-based care?
What are ways that digital health technologies can (a) foster the conduct of clinical trials remotely and (b) support local or home-based healthcare models?
How can the FDA facilitate individuals accessing medical technologies in remote locations when they are unable or unwilling to access care in clinical settings?
What processes and medical procedures, including diagnostics, do you believe would be ideal for transitioning from a hospital and/or healthcare setting to non-clinical care settings, for example, home use or school/work use?
- What medical technologies could be ideal to transition to use in non-clinical settings? What aspects of those technologies could potentially benefit from modifications to optimize use in non-clinical settings?
What design attributes and user needs would facilitate the use of medical technologies, including diagnostic and therapeutic devices, for use in a non-clinical setting, for example home use?
For digital health technologies, what design attributes could better facilitate their use by diverse patient populations outside of a clinical setting? What other factors are important to consider which may improve use and acceptance of different digital health technologies by diverse patient populations (for example, older adults, non-English speakers, lower literacy)?
What potential methods and strategies for evidence generation and data analysis could facilitate the regulatory review of medical technologies intended to be used in non-clinical settings, for example home use or school/work use?”²⁹

CDRH’s request for public comment on increasing patient access to at-home use medical technologies, including DHTs, is consistent with CDRH’s broader effort to expand access to home use technologies, including as described, for example, in CDRH’s 2022-2025 Strategic Priority Document focused on advancing health equity.³⁰ Indeed, moving medical technologies including DHTs out of the clinic or traditional healthcare settings into patients’ lives better meets patients where they are.

Conclusion

Expiration of the PHE and the unwinding of COVID-19 related guidances have major implications for FDA-regulated industry and products writ large but also specifically for DHTs. Some guidance documents relevant for DHTs will be in effect until at least November 7 and may be revised to continue indefinitely. However, even if these guidances are not revised or extended indefinitely, it appears FDA has taken “a lessons learned” approach from the pandemic use of DHTs in clinical trials and in at-home patient monitoring/healthcare to inform their vision for the future of the DHT regulatory landscape. As FDA aims to encourage the evolving innovation and technological progress, regulated industry, including DHT developers and manufacturers, should proactively seek opportunities to engage with FDA on DHTs and their use in clinical trials and in patient monitoring/home-based models of care. These technologies hold great promise for modernizing the conduct of clinical trials and for providing patient care.

References/Notes

Fact Sheet, COVID-19 Public Health Emergency Transition Roadmap, https://www.hhs.gov/about/news/2023/02/09/fact-sheet-covid-19-public-health-emergency-transition-roadmap.html. Note that there were 80 COVID-19 related guidances published; however, eight had already been withdrawn because they no longer reflected the agency’s current thinking.
Guidance Documents Related to COVID-19, 88 Fed. Reg. 15417 (Mar. 13, 2023), https://www.federalregister.gov/documents/2023/03/13/2023-05094/guidance-documents-related-to-coronavirus-disease-2019-covid-19.
Note that guidances listed that are subject to the device enforcement policy transition guidance will continue in effect for 180 days after expiration of the PHE declaration unless a different intended duration for the guidance is set forth in the final device transition guidance or the guidance is otherwise superseded by a revised final guidance before that date.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/media/136939/download.
Guidance available here, https://www.fda.gov/media/136238/download.
See id.
See id.
See id.
https://www.fda.gov/media/172258/download
Guidance available here, https://www.fda.gov/media/136290/download.
See id.
See id.
See id.
Id. at 5.
https://www.clinicaltechleader.com/doc/an-overview-of-fda-efforts-to-encourage-dht-use-in-drug-biological-product-development-0001
FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, https://www.fda.gov/media/169090/download. See the FDA Docket, available here, https://www.regulations.gov/docket/FDA-2023-D-1955?utm_source=dailyem,sfmc&utm_medium=email,email&utm_campaign=,Medtech%20Insight%20
Daily%20(Tues%20-%20Fri). Note that the draft guidance tracks with ICH’s recently updated E6(R3) draft guideline, and that guideline was drafted to describe how to deal with technological innovations for clinical trials, among other goals.
FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, https://www.fda.gov/media/169090/download.
Id. at 2.
Id.
Id.
https://www.raps.org/news-and-articles/news-articles/2023/6/shuren-at-home-technologies-must-be-fit-for-purpos?mkt_tok=MjU5LVdMVS04MDkAAAGMZTsbK1r5IMpvnhjfyNGby2h0mjBZwP2wpJ45zqW5JOeu
MFOFTh5GcCY90W3c3KbDVNCWeVLW1JsQ_8a2evANoJRN2mkYXZibZ0bzIuna.
https://www.raps.org/news-and-articles/news-articles/2023/6/shuren-at-home-technologies-must-be-fit-for-purpos?mkt_tok=MjU5LVdMVS04MDkAAAGMZTsbK1r5IMpvnhjfyNGby2h0mjBZwP2wpJ45zqW5JOeu
MFOFTh5GcCY90W3c3KbDVNCWeVLW1JsQ_8a2evANoJRN2mkYXZibZ0bzIuna.
https://www.fda.gov/media/136939/download.
https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/cdrh-seeks-public-comment-increasing-patient-access-home-use-medical-technologies.
https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/cdrh-seeks-public-comment-increasing-patient-access-home-use-medical-technologies.
See https://www.fda.gov/about-fda/cdrh-strategic-priorities-and-updates/cdrh-seeks-public-comment-increasing-patient-access-home-use-medical-technologies. See also CDRH Strategic Priorities, available at https://www.fda.gov/media/155888/download.

An Overview of FDA Efforts to Encourage DHT Use in Drug and Biological Product Development

This article was originally published in Clinical Tech Leader.

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

Other Guidances

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

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.

Conclusion

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.

References/Notes

1. See e.g., Policy for Device Software Functions and Mobile Medical Applications and Software as a Medical Device (SAMD): Clinical Evaluation, among many others included on FDA’s website, which lists guidances with “digital health content”, https://www.fda.gov/medical-devices/digital-health-center-excellence/guidances-digital-health-content.

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.

4. Framework at Page 3.

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.

9. Framework at Page 11.

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.

16. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations)

17. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/electronic-systems-electronic-records-and-electronic-signatures-clinical-investigations-questions)

18. Framework at Page 13; see Guidance Document. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations)

19. Framework at Page 13; see Guidance Document. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/electronic-systems-electronic-records-and-electronic-signatures-clinical-investigations-questions)

20. See the Guidance Document. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/electronic-systems-electronic-records-and-electronic-signatures-clinical-investigations-questions).

21. FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, https://www.fda.gov/media/169090/download. See the FDA Docket, available here, https://www.regulations.gov/docket/FDA-2023-D-1955). Note that the draft guidance tracks with ICH’s recently updated E6(R3) draft guideline, and that guideline was drafted to describe how to deal with technological innovations for clinical trials, among other goals.

22. FDA Draft Guidance on E6(R3) Good Clinical Practice, available here, https://www.fda.gov/media/169090/download.

23. Id. at 2.

24. Id.

25. Id.

26. Id.

27. FDA News Release, June 6, 2023, available here, https://www.fda.gov/news-events/press-announcements/fda-announces-additional-steps-modernize-clinical-trials.

28. Regarding (ii) in particular, improving the diversity of clinical trials has been a particular priority for FDA. See, for example, April 2022 draft guidance describing how sponsors should ensure their trials reach and include more underrepresented racial and ethnic groups, available here, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-plans-improve-enrollment-participants-underrepresented-racial-and-ethnic-populations.

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.

30. Guidance available here, https://www.fda.gov/media/136238/download.

31. See id.

32. https://www.fda.gov/media/172258/download

33. Framework at Page 14. See also CDRH’s List of Proposed Guidances for FY2024, https://www.fda.gov/medical-devices/guidance-documents-medical-devices-and-radiation-emitting-products/cdrh-proposed-guidances-fiscal-year-2024fy2024.

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.

36. https://www.fda.gov/news-events/press-announcements/fda-establishes-new-advisory-committee-digital-health-technologies

37. https://www.fda.gov/news-events/press-announcements/fda-establishes-new-advisory-committee-digital-health-technologies

38. https://www.fda.gov/news-events/press-announcements/fda-establishes-new-advisory-committee-digital-health-technologies

39. Framework at Page 15.

40. Framework at Page 15.

Clinical Trial Diversity, Flexibility Championed by the Food and Drug Omnibus Reform Act

This article was originally published as a guest column in Clinical Leader.

The Food and Drug Omnibus Reform Act (FDORA),¹ signed into law by President Biden on Dec. 29, 2022, which we initially wrote about in February with regard to inspections, also includes numerous provisions intended to modernize clinical trials. These provisions enact and expand upon FDA initiatives over the last decade and could go a long way toward advancing clinical research. The provisions are broadly divided into two categories: (1) encouraging the enrollment of more diverse patient populations in clinical studies; and (2) facilitating novel clinical trial designs and methods for conducting clinical trials, in part by continuing certain flexibilities initiated during the COVID-19 public health emergency.

Clinical Trial Diversity

The diversity (or lack thereof) of patients enrolled in clinical trials has long been a topic of consideration and concern for those in the public health field. There is evidence that minorities, women, the elderly, children, and other demographic subgroups are underrepresented in clinical research, leading to gaps in understanding the safety and efficacy of certain drugs used in those populations.

In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) recognized this gap and required the FDA to report on and create an Action Plan to improve the analysis of demographic subgroup data in clinical trials, expand the inclusion of such data in labeling, and make such data more available and transparent to the public.² In the decade following FDASIA, the FDA took numerous steps to implement this FDASIA provision, including issuing the required report in August 2013, followed by the Action Plan in 2014, and convening a public meeting in between.³

The FDA’s efforts culminated in a draft guidance released in April 2022 (contemplated in the 2014 Action Plan), which encourages the inclusion of diverse patient populations in research conducted to support marketing applications for medical products.⁴ The draft guidance, titled Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, describes when diversity action plans are recommended, the timing for submission of such plans, and the suggested content.

FDORA sections 3601-3604 further promote clinical trial diversity by enacting into law a requirement for diversity action plans as well as requiring additional public communications and information gathering to facilitate diversity in clinical trials, as described below.⁵

§ 3601. Diversity action plans for clinical studies

Amends the FD&C Act to require a “diversity action plan” for all Phase 3 or other pivotal studies (excluding bioequivalence and bioavailability studies) for drugs and biological products and for many medical devices.
The diversity action plan must include the sponsor’s goals for enrollment in the clinical study, the rationale for such goals, and an explanation of how it intends to meet the goals. The plan must be submitted with the clinical study protocol.
The FDA may waive the requirement for a diversity action plan in certain circumstances, including “based on what is known or what can be determined about the prevalence or incidence of the disease or condition for which the new drug is under investigation” or if conducting the study in accordance with a diversity action plan “would otherwise be impracticable” or is against the interests of public health during a public health emergency.
Applies to clinical trials for which enrollment begins 180 days after publication of the final guidance described in § 3602. See § 3602(c).

§ 3602. Guidance on diversity action plans for clinical studies

Requires the FDA to issue or update guidance (e.g., the April 2022 draft guidance) on the requirement for clinical trial diversity action plans, including on their format and content, modifications to such plans, public posting by a sponsor of key information from a diversity action plan that would be useful to patients and providers, criteria the FDA will use when determining whether to grant a waiver for the requirement to follow a diversity action plan, and regular reporting to the FDA on the sponsor’s progress in achieving the goals described in the diversity action plan.
Draft guidance is due 12 months after enactment of FDORA (by Dec. 29, 2023); final guidance must be published within nine months of the close of the comment period of the draft guidance.

§ 3603. Public workshops to enhance clinical study diversity

Requires the FDA, in consultation with drug and medical device sponsors, clinical research organizations, academia, patients, and other stakeholders, to convene one or more public workshops to solicit input from stakeholders on “increasing the enrollment of historically underrepresented populations in clinical studies and encouraging clinical study participation that reflects the prevalence of the disease or condition among demographic subgroups[.]”
The FDA must establish a public docket in association with the meeting and must publish a report on the topics discussed at the meeting(s) within 180 days after the public comment period closes.

§ 3604. Annual summary report on progress to increase diversity in clinical studies

Requires the FDA to publish an annual report beginning two years after enactment of FDORA (Dec. 29, 2024) summarizing, in aggregate, diversity action plans received by the FDA, whether the clinical studies conducted under diversity action plans met the enrollment goals in the action plans, and if not, the reasons provided for why not.

Clinical Trial Flexibilities

Similar to efforts surrounding clinical trial diversity, the FDA and other stakeholders have been considering novel clinical trial designs for at least a decade, including whether the FDA’s regulatory framework must be modified to accommodate the oversight of such trials and allow evidence generated from those studies to satisfy the “substantial evidence” statutory standard.⁶

The FDA held a public hearing to solicit input on a broad effort to “encourag[e] the use of innovative models that may enhance the effectiveness and efficiency of the clinical trial enterprise”⁷ in 2012 and was subsequently granted new authorities related to novel clinical trial design and real-world evidence (RWE)/real-world data (RWD) in the 21^st Century Cures Act of 2016.⁸These efforts continued in PDUFA VI (FY18–FY22) and PDUFA VII (FY23–FY27), both of which include commitments related to RWE/RWD and to advancing the FDA’s capacity to review complex innovative trial designs, including Bayesian and adaptive protocols.⁹ As a result, the FDA has issued several guidance documents reflecting updated thinking on clinical trial design, trial conduct and compliance with good clinical practice (GCP), and the collection and analysis of data.¹⁰

A number of these initiatives were further advanced during the COVID-19 pandemic through flexibilities the FDA exercised to protect the safety of patients and investigators and to ensure adherence to GCP, while also minimizing disruptions to clinical research. The efforts are described in a guidance the FDA issued early in the pandemic that allowed for certain accommodations in the conduct of clinical trials.¹¹ For example, the guidance described when it could be appropriate to conduct remote clinical visits for study participants, remotely monitor clinical sites, and ship investigational product to local providers for administration. The flexibilities outlined in the guidance were intended to address challenges associated with quarantines, travel restrictions, supply chain interruptions, and other disruptions associated with COVID-19.

With the termination of the public health emergency on May 11, 2023, many of the FDA’s guidances issued during the pandemic will sunset.¹² Notably, the FDA has indicated that the guidance on the conduct of clinical trials will remain in effect for 180 days after the end of the PHE as a transitional period.¹³This dovetails with a provision in FDORA that requires the FDA to hold a public meeting to better understand the effectiveness of the clinical trial flexibilities the FDA exercised during the pandemic. Two other sections of FDORA related to decentralized clinical trials, novel clinical trial designs and digital health technology in clinical trials, continue the progress on clinical trial modernization. Below, we describe these three provisions of FDORA in more detail.

§ 3605. Public meeting on clinical study flexibilities initiated in response to COVID-19 pandemic

Within 180 days from the end of the public health emergency (by Nov. 7, 2023), the FDA must hold a public meeting to discuss FDA recommendations during COVID-19 to mitigate disruption of clinical studies, including as described in the guidance.
The FDA must issue a report summarizing the discussion at the public meeting. Topics to be included for discussion at the meeting include, but are not limited to:
- the frequency with which sponsors availed themselves of the flexibilities in the guidance;
- characteristics of the sponsors, studies, and patient populations impacted by such recommendations;
- impact of those flexibilities on patient access to clinical studies, especially underrepresented patient populations; and
- recommendations for incorporating these flexibilities into new guidance to improve clinical study enrollment and diversity.

§ 3606. Decentralized clinical studies

Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance to advance the use of decentralized clinical trials. The guidance must address numerous aspects of decentralized trials, including recommendations related to:
- collecting data remotely, considering the security and privacy of such options (e.g., digital health technology, telehealth, local providers and labs, and patient experience data);
- minimizing or reducing burdens on subject enrollment and participation (e.g., digital health technology, telehealth, local providers/labs, home visits, direct engagement with study participants, direct shipping of investigational drug to the study participants, electronic informed consent, and partnerships with community organizations);
- evaluating the protocol design of decentralized trials and data collected in decentralized trials, including whether evaluations will be different than for non-decentralized trials;
- using decentralized clinical trials to maximize participant diversity;
- validating digital technologies and establishing appropriate clinical endpoints for use in decentralized trials;
- combining centralized and decentralized clinical trial approaches; and
- oversight of decentralized clinical trial sites, including remote oversight.

§ 3607. Modernizing clinical trials

Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance regarding appropriate use of digital health technologies in clinical trials to improve diversity in recruiting and retention of participants and to facilitate novel clinical trial designs; final guidance must be published within 18 months after the close of comment period on the draft guidance.
Within one year after enactment of FDORA (by Dec. 29, 2023), the FDA must issue or update draft guidance on the use of “seamless, concurrent, and other innovative clinical trial designs” to support development and review of new drugs; final guidance must be published 18 months after the close of comment period on the draft guidance.
Directs the FDA to work with foreign regulators to facilitate international harmonization of the regulation and use of decentralized trials, digital health technology, and seamless, concurrent, and other adaptive or innovative clinical trial designs.

The FDA has already begun to implement the FDORA clinical trials provisions with the issuance of the required guidance on decentralized clinical trials in early May, described in more detail in a separate article.¹⁴ Given the short timeframes, we expect the other guidances (diversity action plans, digital health technology, modernizing clinical trials) to be forthcoming shortly and for the FDA to implement the remaining provisions, such as public meetings and reports, in a timely manner. The FDORA guidances are likely to build on the agency’s efforts over the last 10 years, including the already existing guidances discussed in this article. You would be well served to familiarize yourself with the current draft guidances and FDA reports and activities to prepare for the future.

References

Food and Drug Omnibus Reform Act, as included in the Consolidated Appropriations Act of 2023, Pub. Law 117- 328, https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf.
Food and Drug Administration Safety and Innovation Act (FDASIA) § 907, https://www.congress.gov/112/plaws/publ144/PLAW-112publ144.pdf.
Reporting of Inclusion of Demographic Subgroups in Clinical Trials and Data Analysis in Applications for Drugs, Biologics, and Devices, FDA-2013-N-0745, https://www.federalregister.gov/documents/2013/08/22/2013-20352/request-for-comments-on-the-food-and-drug-administration-safety-and-innovation-act-section-907; Notice of Public Meeting, April 1, 2014, https://www.govinfo.gov/content/pkg/FR-2014-03-04/html/2014-04625.htm; FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, August 2014, www.fda.gov/media/89307/download.
Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, Draft Guidance, April 2022, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-plans-improve-enrollment-participants-underrepresented-racial-and-ethnic-populations. FDA also issued a guidance in November 2020 on diversity, titled Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs, https://www.fda.gov/media/127712/download.
FDORA, supra note 1.
The FD&C Act (section 505(d)) requires a sponsor to demonstrate with “substantial evidence” that a drug is safe and effective, and defines substantial evidence as “evidence consisting of adequate and well-controlled investigations, including clinical investigations[.]” FDA has traditionally required two randomized, controlled clinical trials as substantial evidence, but has recently expanded its view of what may meet the statutory standard. See e.g., Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products, Draft Guidance, Dec. 2019, https://www.fda.gov/media/133660/download.
Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice; Public Hearing, March 7, 2012, https://www.govinfo.gov/content/pkg/FR-2012-03-07/pdf/2012-5476.pdf.
21^st Century Cures Act §§ 3021, 3022, Pub. Law 114-255, https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf.
PDUFA VI Commitment Letter, https://www.fda.gov/media/99140/download (see e.g., sections I.6 and J.4); PDUFA VII Commitment Letter, https://www.fda.gov/media/151712/download (see e.g., sections K.6 and L.4).
See, FDA webpage listing clinical trials guidance documents, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trials-guidance-documents.
FDA Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health Emergency, March 2020, updated Aug 2021, https://www.fda.gov/media/136238/download.
Guidance Documents Related to COVID-19, 88 Fed. Reg. 15417 (Mar. 13, 2023), https://www.federalregister.gov/documents/2023/03/13/2023-05094/guidance-documents-related-to-coronavirus-disease-2019-covid-19.
Id.
Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023, https://www.fda.gov/media/167696/download.

FDA Releases Draft Guidance on Decentralized Clinical Trials

This article was originally published as a guest column in Clinical Leader.

In early May, two weeks prior to the expiration of the COVID-19 Public Health Emergency declaration, FDA released the draft guidance Decentralized Clinical Trials for Drugs, Biological Products, and Devices.¹ The timing of this draft guidance is notable as the document builds upon many of the recommendations FDA provided in the March 2020 guidance Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency² (which we covered back in 2020 for Clinical Leader here) which were intended to help sponsors continue their trials throughout the COVID-19 crisis. During the public health emergency, with many trial participants and personnel in isolation, per local COVID-19 control policies, FDA detailed several approaches sponsors could take to maintain continuity of their clinical trials, such as the use of electronic informed consent, use of digital health technologies to conduct assessments, use of local healthcare providers to administer trial procedures, and the direct shipment of investigational products to trial participants, among other measures. Thus, the May 2023 guidance on decentralized trials marks a continuation of FDA’s thinking on the decentralization of clinical trials.

The draft guidance fulfills Section 3606(a) of the Food and Drug Omnibus Reform Act (FDORA)³ requiring the agency to issue guidance on decentralized clinical trials (DCTs) by Dec. 29, 2023. Authored by all three medical product review centers, as well as the Oncology Center of Excellence, the draft guidance recommends a risk-based approach to the conduct and oversight of decentralized clinical trials.

The draft guidance identifies DCTS as trials wherein some or all trial-related activities occur outside of traditional clinical trial sites. More specifically, DCTs incorporate the use of local healthcare facilities, local healthcare providers (HCPs), and local clinical laboratory facilities; visits to trial participants’ homes; and direct distribution of the investigational product to the trial participant. Trials where some activities are conducted at the traditional trial site while other activities, such as follow-up assessments, are conducted remotely are termed “hybrid” clinical trials by the agency.

As noted, FDA recommends a risk-based approach when considering a decentralized trial design – noting that investigational products that are “simple to administer or use, have well-characterized safety profiles, and do not require complex medical assessments”⁴ are the most appropriate and well suited for evaluation in DCTs. The FDA cautions sponsors to be mindful of potential differences in data accuracy and consistency between DCT and conventional trials conducted at a physical site. While these variances may not impact the validity of trial results that seek to establish superiority of one treatment over another, they could impact the accuracy of results in a trial that aims to establish non-inferiority. For example, the effectiveness of a drug tested in a DCT may not be identical to the effectiveness of the same drug tested in a traditional trial that employs an active control, as evaluations performed by local healthcare providers in DCTs may be less precise and more variable than those conducted by dedicated trial personnel at site-based trials.

Beyond defining DCTs and identifying the appropriate situations for their use, the draft guidance provides key recommendations on the innovative approaches sponsors can use to decentralize trials and move trials outside of traditional sites. The draft guidance also includes some important considerations on safety and data security that are likely to arise in remote contexts.

Remote Trial Visits

The draft guidance affirms that telehealth visits can be used instead of in-person trial site visits, especially if no in-person interaction is needed. This was an innovation that FDA introduced in the March 2020 Conduct of Clinical Trials guidance, although it should be noted that the need for alternatives to in-person site visits to facilitate enrollment and conduct of clinical trials was recognized by FDA well before the pandemic. For example, a 2015 Federal Register notice sought comment and recommendations on innovative mechanisms to increase clinical trial enrollment, such as the use of telehealth visits.⁵

In addition to telehealth visits, the draft guidance also provides sponsors with the option to use local HCPs, who are not officially trial personnel. Importantly, the services local HCPs provide should not differ from the services they are qualified to perform in clinical practice. In addition, the activities local HCPs may provide should not require unique or detailed knowledge of the trial protocol or the investigational product.

Should telehealth technologies or local HCPs be used to facilitate decentralized trials, the trial protocol should detail how adverse events will be remotely identified, evaluated, and managed. Additionally, in the interest of trial efficiency and patient experience, sponsors are responsible for training trial personnel on the technology used to conduct a telehealth visit.

Digital Health Technologies

Although digital health technologies (DHTs) are among most common tools used in DCTs, the draft guidance does not focus extensively on this topic as it is well covered in the December 2021 draft guidance Digital Health Technologies for Remote Data Acquisition in Clinical Investigations⁶ [Editor’s note: Covered by Clinical Leader here.] However, the draft guidance does note that sponsors may permit trial participants to use their own DHTs in trials, as long as the sponsor also provides the same DHTs to other participants, so they are not excluded.

Direct Shipment of Investigational Products

The draft guidance confirms that the direct distribution of the investigational product (IP) to trial participants at their homes or other remote location is acceptable. However, should this method distribution be used, sponsors should describe in the protocol how the physical integrity and stability of the IP will be maintained during shipment. Similarly, the protocol should describe how investigators will track and document the receipt of IP by trial participants, as well as how participants should dispose of unused IPs and how this should be documented. IPs that are considered good candidates for direct shipment include those with long shelf lives and good stability profiles.

The draft guidance also notes that sponsors may also use a central distribution service to ship IP directly to trial participants. The investigator, however, must still control the release of the IP by the distributor, as well as monitor receipt and use by trial participants, as specified in the protocol.

Administration of the Investigational Product

As discussed above, sponsors should consider the nature of the IP when determining whether to administer it outside of traditional trial sites. FDA advises that IPs that involve complex administration procedures, have a high-risk safety profile, or are in early stages of development may require in-person supervision by the investigator at a trial site. Similarly, investigators should also consider the safety profile (e.g., risk of hypersensitivity, abuse potential) in determining the type of local care that participants may need to have access to if an adverse event occurs.

Informed Consent and Institutional Review Board Oversight

While discussed extensively in the March 2020 Conduct of Clinical Trials guidance, the DCT draft guidance also addresses the use of remote informed consent, albeit briefly. Specifically, the draft guidance confirms that investigators may obtain electronic informed consent remotely provided that all regulations under 21 CFR Part 50 are met. FDA also recommends that investigators have a central Institutional Review Board (IRB) to facilitate the review of the protocol and the informed consent documents.

Roles and Responsibilities

FDA notes that sponsors’ responsibilities are the same in DCTs as they are in traditional site-based trials. Due to the potential of multiple sources of data collection, sponsors should ensure their data management plan specifies data origin, data flow, and the methods used for data collection and includes a list of vendors involved in data collection, handling, and management. The draft guidance also recommends sponsors detail all operational aspects of a DCT in a trial protocol, while case report forms should identify when and where data is collected.

FDA recognizes that DCTs add complexity to the investigator’s role in overseeing trial conduct, as some decentralized features necessitate additional training and careful coordination of remote activities. FDA reiterates that local HCPs may perform trial-related procedures at a participant’s home or other local healthcare facility. However, local HCPs need not and should not be listed as sub-investigators on Form FDA 1572. The draft guidance also states that some trial protocols may permit the use of clinical laboratory facilities close to the trial participant, although designated clinical laboratory facilities are preferred to minimize variability.

Safety Monitoring

As with site-based trials, safety monitoring plans should describe how participants are expected to respond to and report adverse events, specifically noting where to seek local medical care if needed. In addition, the draft guidance also notes that trial participants should be able to contact trial personnel to report adverse events and arrange for telehealth visits if necessary. Lastly, the safety monitoring report should also describe the information collected by a digital health tool – detailing how the information will be used and monitored and how personnel or participants should respond to electronic alerts.

Software Considerations

The FDA notes that software can be used for multiple purposes in a DCT, including managing electronic informed consent, capturing and storing reports, managing electronic case forms, scheduling trial visits, and tracking IPs shipped directly to participants. Software programs used to produce and process trial records are subject to 21CFR Part 11 and must ensure data reliability, security, privacy, and confidentiality. Real-time video interactions, however, such as telehealth visits, are considered by FDA as live exchanges of information between trial personnel and trial participants and thus are not considered electronic records and subject to 21 CFR Part 11.

The FDA is accepting public comments on the draft guidance until August 1, 2023. All written comments should be identified with the docket number FDA-2022-D-2870.

References

FDA, Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023, https://www.fda.gov/media/167696/download.
FDA, Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency, Guidance, March 2021, https://www.fda.gov/media/136238/download.
H.R. 2617; Food and Drug Omnibus Reform Act (FDORA), https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf.
Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, Lines 63 – 65.
80 FR 66543, October 29, 2015, https://www.federalregister.gov/documents/2015/10/29/2015-27581/using-technologies-and-innovative-methods-to-conduct-food-and-drug-administration-regulated-clinical.
FDA, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Draft Guidance, December 2021, https://www.fda.gov/media/155022/download.

CRO: 3Cs (Competence, Capacity, Compatibility)

Greenleaf expert Maura Norden discusses how to choose the right CRO for your U.S. clinical trial in the new video from KoreaBio.

COVID-19 Pandemic Accelerates Digitalization of Clinical Trials

Greenleaf Regulatory Landscape Series

Recently the Food and Drug Administration (FDA or the Agency), led primarily by the Center for Devices and Radiological Health (CDRH), has been supporting multiple initiatives to promote the development of digital health technologies and to encourage the use of digital health tools (DHTs) in medical product development. In 2017, for example, the FDA published the Digital Health Innovation Action Plan, in which the FDA committed to hiring digital health experts and provided a timeline for issuing new digital health-focused guidances. This was followed by the launch of the Digital Health Center of Excellence (DHCOE) in August 2020. Sitting within CDRH, the DHCOE is intended to serve as a “one-stop shop” for all digital health-related inquires and will coordinate digital health activities both across the Agency and with other regulators internationally.

*Source*: FDA Digital Health Center of Excellence Listening Session #1, 19 Oct 2020,
https://www.fda.gov/media/143078/download.

In the face of the COVID-19 pandemic, as the clinical trial enterprise seeks to maintain continuity while ensuring the safety of trial participants, the FDA’s digital health initiatives seem particularly well-timed. Indeed, during the past few months the use of DHTs have been critical in ensuring the continuity of disrupted trials by supporting remote data collection. During the pandemic, DHTs have been used to facilitate enrollment screening, conduct real-time safety monitoring, evaluate dose effects, and conduct endpoint assessments. In a recent survey of 245 clinical trial investigators, participants reported that 57% of patient interactions during ongoing trials were now conducted remotely.¹ The same survey found that 77% of investigators expected the use of DHTs for remote patient monitoring to increase, while 54% expected an increase in use of DHTs to conduct electronic clinical outcomes assessments (eCOAs) and electronic patient reported outcome assessments (ePROs).² This represents a marked increase over past DHT usage in medical product development, with DHTs only being used in 13% of registrational trials for the time period 2000 to 2018, according to recent research.³

A Regulatory Framework for DHTs

Acknowledging this trend, the FDA has requested funding in the PDUFA VII negotiations to support the development of a DHT framework to strengthen review capabilities of DHT- generated data in submissions, build staff capacity in digital health, and develop IT capacities to store and use DHT data.⁴ The FDA also shared in the summary report on the COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative⁵ that that Agency is currently developing a guidance, which will be released this year, on the use of DHTs to capture study- related data directly from patients.

In the short term, the FDA has addressed the use of DHTs in the guidance “Conduct of Clinical Trials During the COVID-19 Public Health Emergency,”⁶ providing sponsors with recommendations on how to shift from in-person to remote assessments during the pandemic. In the guidance, the FDA provides sponsors with the flexibility to change the method of administration of clinical outcome assessments (COAs), specifically identifying performance outcomes (PerfO) assessments, interview-based clinician-reported outcome (ClinRO) assessments, PRO assessments, and observer-reported outcome (ObsRO) assessments as COAs that can be conducted remotely. In considering this change in administration, the FDA states that the change must be documented, and any additional variables related to the change should be included in the clinical trial data. The Agency also emphasizes the importance of prioritizing trial participant safety and privacy, maintaining data quality and integrity, and ensuring that both trial personnel and participants are appropriately trained on using any new technologies that are introduced.

DHTs in Clinical Trials

The emerging regulatory framework for DHTs in clinical trials is being built upon a regulatory paradigm that is already, in many respects, supportive of the remote collection of data in trials. As early as September 2013, the Agency addressed the use of DHTs to capture trial data in the guidance “Electronic Source Data in Clinical Investigations.”⁷ In the guidance, the FDA encourages electronic data capture, noting that it eliminates unnecessary duplication of data, reduces the possibility for transcription errors, and promotes real-time access for data review.

Although the FDA has not issued guidance specifically addressing the use of DHTs in clinical trials since 2013, the Agency has signaled an openness to the use of DHTs so long as they are fit for purpose, private and secure, and compliant with 21 CFR part 11.⁸ In public meetings and through work with the Clinical Trials Transformation Initiative (CTTI), the FDA has discussed how sponsors could best use digital technology to evaluate clinical benefit in trial participants. For example, prior to selecting a DHT, the FDA states that the concept being measured must be clinically meaningful, measuring what patients would like to see improved through treatment.⁹ Similarly, in selecting a technology, the sponsor should assess the reliability of the DHT through verification in the laboratory and validation in the field. On a practical level, sponsors also need to consider the technical aptitude and willingness to use a DHT among the population they are studying.¹⁰ As DHTs generate large volumes of data, sponsors should pre-specify how the data will be analyzed according to the data characteristics (e.g., intensity, frequency, event, etc.).¹¹ Lastly, as previously noted, DHTs and DHT-generated data must be secure and participants’ privacy must be protected.

1. Xue, et al., “Clinical trial recovery from COVID-19 disruption,” Nature Reviews Drug Discovery, 10 Sept 2020, https://www.nature.com/articles/d41573-020-00150-9.

2. Ibid.

3. Mara, et al., “Quantifying the Use of Connected Digital Products in Clinical Research,” npj Digital Medicine 3, 50 (2020), https://www.nature.com/articles/s41746-020-0259-x.

4. U.S. Food and Drug Administration, “Prescription Drug User Fee Act (PDUFA) Reauthorization: FDA and Industry Digital Health and Informatics,” 30 Sept. 2020, https://www.fda.gov/media/143237/download.

5. FDA, “FDA COVID-19 Pandemic Recovery and Preparedness Plan (PREPP) Initiative: Summary Report,” January 2021, https://www.fda.gov/media/145129/download.

6. FDA, Guidance for Industry, “Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency,” March 2020, https://www.fda.gov/media/136238/download.

7. FDA, Guidance for Industry, “Electronic Source Data in Clinical Investigations,” September 2013, https://www.fda.gov/media/85183/download.

8. 21 CFR part 11 establishes the criteria under which electronic records and electronic signatures are considered by the FDA to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures.

9. FDA, Draft Guidance for Industry, “Patient-Focused Drug Development: Methods to Identify What is Important to Patient,” October 2019, https://www.fda.gov/media/131230/download.

10. John Concato, Comments at FDA/CMS Summit, December 7, 2020.

11. Dashielle-Aje, Ebony, et al., ” Digital Health Technology Tools: Use in Clinical Investigations to Evaluate Clinical Benefit in Patients,” DIA Global Forum, June 2019, https://globalforum.diaglobal.org/ issue/june-2019/regulatory-perspective-digital-health-technology-tools/.

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