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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The FDA’s efforts culminated in a draft guidance released in April 2022 (contemplated in the 2014 Action Plan), which encourages the inclusion of diverse patient populations in research conducted to support marketing applications for medical products.4 The draft guidance, titled Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, describes when diversity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 21st Century Cures Act of 2016.8 These 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.13 This 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

  1. 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.
  2. Food and Drug Administration Safety and Innovation Act (FDASIA) § 907, https://www.congress.gov/112/plaws/publ144/PLAW-112publ144.pdf.
  3. 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.
  4. 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.
  5. FDORA, supra note 1.
  6. 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.
  7. 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.
  8. 21st Century Cures Act §§ 3021, 3022, Pub. Law 114-255, https://www.congress.gov/114/plaws/publ255/PLAW-114publ255.pdf.
  9. 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).
  10. See, FDA webpage listing clinical trials guidance documents, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trials-guidance-documents.
  11. 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.
  12. 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.
  13. Id.
  14. 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

  1. FDA, Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, May 2023, https://www.fda.gov/media/167696/download.
  2. 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.
  3. H.R. 2617; Food and Drug Omnibus Reform Act (FDORA), https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf.
  4. Decentralized Clinical Trials for Drugs, Biological Products, and Devices, Draft Guidance, Lines 63 – 65.
  5. 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.
  6. FDA, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations, Draft Guidance, December 2021, https://www.fda.gov/media/155022/download.

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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