FDA Issues Draft Recommendations for Implementing Decentralized Clinical Trials

On May 2, 2023, the U.S. Food and Drug Administration (FDA) took additional steps to support the use of decentralized clinical trials (DCTs) by releasing a new draft guidance titled “Decentralized Clinical Trials for Drugs, Biological Products, and Devices,” which provides recommendations for sponsors, investigators, and other stakeholders regarding the implementation of DCTs to advance medical product development and research.

As background, in a DCT, some or all of a clinical trial’s activities occur at locations other than a traditional clinical trial site. These alternate locations can include the participant’s home, a local health care facility, or a nearby laboratory. DCTs often incorporate digital health technologies (DHTs), which are devices or systems that capture health care information for clinical trials directly from individuals, and telehealth modalities. The draft guidance builds on agency DCT recommendations and FAQs issued in 2020 in response to the COVID-19 public health emergency and associated disruptions, such as quarantines, site closures, and travel limitations, and it comes as a response to the Food and Drug Omnibus Reform Act of 2022, which requires FDA to publish guidance regarding the modernization of clinical trials through DCTs and DHTs no later than December 29, 2023.[1]

In its press release, FDA indicated that it expects clinical trials with decentralized elements will “play an important role in addressing public health needs,” and by reducing barriers to participation, FDA expects that DCTs will “increase the breadth and diversity of participants in clinical trials and improve accessibility for those with rare diseases or mobility challenges,” which, in return, will “facilitate the development of drugs including in areas of medical need, resulting in more treatment options and improved patient outcomes.”

Public comments and suggestions regarding the draft guidance should be submitted by August 1, 2023, electronically to this website.[2] Written comments should be submitted to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number FDA-2022-D-2870.

The draft guidance reiterates the established understanding that FDA’s regulatory requirements[3] for investigations of medical products are the same for DCTs as traditional site-based clinical trials. The draft guidance also, however, provides FDA’s perspective on specific topics related to the implementation of DCTs, as further summarized below. FDA encourages stakeholders to discuss with FDA, early in the process of developing a DCT, specific issues related to the feasibility, design, implementation, or analysis of a DCT and notes that “appropriate training, oversight, and up-front risk assessment and management will be key to implementing a DCT successfully.”

The draft guidance is helpful in that it sheds light on FDA’s current thinking regarding DCTs and shows FDA’s commitment to working with stakeholders to facilitate this modernized way of conducting trials, which holds promise to increase accrual and retention of a more diverse trial population. That said, certain practical implementation challenges for sponsors and investigators remain and will need to be carefully navigated when considering the feasibility of a DCT model for a particular study.

Summary of Recommendations

DCT Design

With respect to DCT design, FDA recommends the following:

Physical Location for Inspections: Establish aphysical location for inspection purposes where all DCT-related records for participants under the investigator’s care are accessible and where trial personnel can be interviewed. This location should be listed on Form FDA 1572 or, for studies conducted under an investigational device exemption (IDE), must be listed in the IDE application.
Non-Inferiority Trials: Consult with FDA’s review divisions to address any challenges in calculating a non-inferiority margin when planning a non-inferiority trial in a DCT setting. In a non-inferiority trial, when the effect size of an active control drug has only been determined in a traditional site-based clinical trial, it may not be reasonable to assume that the same effect size would be seen for the active control drug in a DCT.

Remote Clinical Trial Visits and Clinical Trial-Related Activities

With respect to remote clinical trial visits and clinical trial-related activities, FDA recommends considering the following:

Telehealth: Telehealth visits with a trial participant can be appropriate when the participant does not need to be seen in person. The protocol should specify which visits may be conducted via telehealth versus in person. During a telehealth visit, the identity of the participant should be confirmed, and appropriate documentation should be completed that includes the date and time of the visit. The responsibility to ensure that trial visits conducted via telehealth comply with laws governing telehealth in the relevant U.S. states or territories and other countries, as applicable, falls on the sponsor and investigator.

Implementation Observations: To the extent the applicable protocol requires the investigator to perform interactions that are considered to be the “practice of medicine,” such as the ordering of investigational drugs or diagnostic tests, there should be processes in place to ensure that clinical trial activities for each subject that constitute the practice of medicine are performed only by a principal investigator or a sub-investigator who is appropriately licensed in the state in which the study subject is located.

In-Person Visits and Trial-Related Activities: Depending on the trial protocol and the type of trial-related activities, in-person visits may be conducted by (i) qualified trial personnel who have been appropriately trained, if the activities are unique to research and/or require detailed knowledge of the protocol or the investigational product (IP), or (ii) health care providers (HCPs) who are located close to a participant’s home but who are not part of the trial personnel if the activities (i) do not require detailed knowledge of the protocol or the IP and (ii) do not differ from those that they are qualified to perform in clinical practice.

Implementation Observations: FDA notes that such HCPs may be used by “sponsors or investigators” to perform certain trial-related activities. Depending on which party opts to use such HCPs, certain contractional, operational, and other considerations should be considered. For example, the party who is responsible for selecting, screening, and contracting with such HCPs will likely bear the responsibility to ensure that the providers are appropriately licensed, certified, and qualified to perform applicable procedures. Also, sponsors and investigators should ensure that the consent forms appropriately inform participants of the HCPs and their role in the study. Finally, although FDA notes that such HCPs for drug trials should not be listed on Form FDA 1572 and for device investigations should not be included in the IDE list of investigators, such HCPs should be included in a task log and, importantly, still fall under the oversight and responsibility of the investigator.

Adverse Events: The protocol should specify how adverse events identified remotely will be evaluated and managed.

Implementation Observations: To ensure participant safety in a DCT where the investigator is geographically distant from study participants, sponsors and investigators must address (i) how data collected continuously from numerous sources will be reviewed for adverse events; (ii) the role of participants and third parties in participant safety and adverse event reporting, including what third parties should do if a participant presents with a potential adverse event or unrelated symptom or condition; (iii) how investigators will remotely facilitate access to medical care, if needed; (iv) how participant privacy will be protected throughout the conduct of the trial and particularly during the reporting of any adverse events; and (v) how investigators can fulfill their regulatory obligations regarding adverse event reporting to sponsors.

Digital Health Technologies

If the use of DHTs is contemplated in a DCT, FDA recommends that sponsors ensure that such DHTs are available and suitable for use by all trial participants to avoid alienating certain groups of participants (e.g., lower socioeconomic groups who cannot afford the DHT). FDA reminded the research community of its DHT-related guidances, including, but not limited to, its 2021 draft guidance titled “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations,” which discusses the selection of DHTs for clinical trials; verification, validation, and usability testing of DHTs; the use of DHTs to collect data for clinical trial endpoints; training on the use of DHTs; and management of risks related to the use of DHTs in clinical trials.

Roles and Responsibilities

The standard roles and responsibilities of sponsors and investigators in connection with clinical trials and clinical investigations still apply to sponsors and investigators of DCTs. In the draft guidance, FDA offers several recommended additional considerations for both stakeholders in carrying out their duties based on the unique nature of DCTs:

Recommendations for Sponsors

From an administrative perspective, FDA recommends the following for sponsors:
- Additional focus on coordination of the various contracted services and vendors involved in the DCT (e.g., mobile services for at-home visits, use of local HCPs, shipping of the IP to participants).
- Added emphasis on promoting diversity and inclusiveness in trial populations. FDA suggests that the use of local health care institutions and HCPs could facilitate the recruitment of diverse participants, both geographically (i.e., recruiting participants from areas that traditionally have had little to no clinical trial sites) and culturally (i.e., reducing cultural and/or linguistic barriers with the use of local HCPs). FDA also mentions that the use of DHTs may help increase access to trials for participants by bringing trial-related activities to participants’ homes.

Implementation Observations: We note that the agency’s guidance for industry on Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials is still in draft form, but it offers additional insights to sponsors as they are addressing diversity considerations in trial design and recruitment.

Practically, FDA makes several recommendations for sponsors related to the following, each of which reflects a common theme that documentation of the methods the sponsor is using to track and organize data in DCTs is crucial to the success of the DCT:
- Documenting the processes in place for data management. The draft guidance describes the development of a data management plan (DMP) to track data origin and flow from all possible sources to the sponsor, suggesting a diagram or flow chart to depict this information, approved methods for remote data acquisition, and a list of approved vendors for data collection, handling, and management. Data integrity has been a focus of the agency for some time now, and this particular recommendation suggests that sponsors should make the development of a thorough and thoughtful DMP a priority for DCTs.
- Describing special operational features of the trial in the protocol. The draft guidance offers examples of some of the DCT-focused details that should be included in the operational descriptions, including a breakdown of scheduled and unscheduled trial visits, as well as remote versus in-person visits; a description of how reports from activities performed at different locations will be transmitted back to the sponsor; how the IP will be delivered and/or administered to trial participants and who is accountable for those products; and safety monitoring and management of adverse events across the different locations for each participant.
- Identifying elements to include in the case report forms, such as when and where data were collected and by whom.
- Structuring an appropriate monitoring program. According to the draft guidance, the trial monitoring plan should be risk-based and should (i) describe how monitoring will assess protocol compliance and data quality and integrity, (ii) specify the frequency of records and source document review, and (iii) identify unique DCT factors.
FDA also highlights the need for sponsors to consider the applicability of local laws in different states, territories, or countries that impact the practice of medicine or IP administration when conducting DCTs.

Implementation Observations: While the draft guidance only references local laws and regulations for these two activities, we note that sponsors should take a more expansive look at local laws and regulations, including, for example, local privacy and data protection requirements.

Recommendations for Investigators

FDA provides recommendations for investigators participating in a DCT in light of the fact that such investigators must oversee several different individuals and/or vendors delegated to perform the various trial-related activities. The draft guidance highlights that a key difference between DCTs and traditional site-based clinical trials is the extent to which the investigator uses telehealth, remote trial workers, local HCPs, and/or DHTs as part of the study. Depending on the structure of the DCT, the study may require additional training, coordination, and adjustment to standard operating procedures to ensure consistent implementation of procedures throughout the DCT. FDA offers some parameters investigators should keep in mind when overseeing the conduct of a DCT, including:
- delegation of trial activities and procedures to local HCPs when permitted by the protocol;
- use of videoconferencing and other modalities to oversee trial personnel when performing trial-related procedures;
- enrollment of only as many participants as can be managed based on the structure of the DCT;
- how to appropriately document investigators, sub-investigators, and other personnel depending on whether it is a drug or device DCT;
- quality control measures to ensure consistent approaches across different practices;
- maintenance of a task log of different HCPs to prepare and maintain adequate case histories;
- use of a designated clinical laboratory facility to run any required tests; and
- receipt of reports of any health emergencies of trial participants from their local health care facilities, as well as other routine health care reports from local primary care providers to the extent relevant to the DCT.

Implementation Observations: We note that, with respect to laboratory testing, the draft guidance does not mention at-home self-collection by participants or the use of an at-home testing kit, processes that are becoming increasingly common in the testing industry. Stakeholders may consider requesting additional guidance from the agency on considerations for incorporating at-home testing or self-collection into a DCT.

Informed Consent and IRB Oversight

FDA acknowledges that the nature of DCTs inherently prompts an increase in the use of remote informed consent processes. In addition to noting that institutional review board (IRB) oversight of the consent process is required, as it is with all clinical trials, FDA provides additional recommendations for obtaining informed consent as part of a DCT, including that:

any electronic modalities used for consent must comply with applicable regulatory requirements, such as 21 CFR Part 50;
participants must be notified of the name of the contact available to answer any questions about the research and whom to notify in the event of a research-related injury;
the consent form should describe who will have access to the participant’s identifiable health information (as is a relatively standard practice already, perhaps suggesting that FDA would like more specific details due to the possibility that a DCT would have a higher number of individuals and vendors with access to identifiable health information than a traditional study); and
DCT sponsors should use a central IRB for review of the protocol, consent documents, and other relevant information.

Implementation Observations: FDA’s comments on informed consent are relatively light compared to some of the other DCT topics addressed in the draft guidance. The agency cites to the existing regulatory requirements for consent, as well as its 2016 guidance Use of Electronic Informed Consent: Questions and Answers. In some respects, this is not surprising given that the ultimate approval of the consent form is the purview of the reviewing IRB, but industry should consider whether additional guidance is needed from FDA regarding the consent process for DCTs specifically. We emphasize that an organized system for maintenance of these consent documents, once obtained, will be important to the integrity of the study and all data collected as part of the study, and may be considered as a part of the sponsor’s DMP.

Investigational Products in a DCT

Drug and Biologic IPs: FDA states that investigators should administer drug and biologic IPs only to study participants under the investigator’s direct supervision or the direct supervision of a sub-investigator. FDA advises that investigators should consider the nature of the IP when determining whether administration outside of a traditional clinical trial site is appropriate for a DCT. Factors to consider when determining whether a DCT is appropriate for a drug or biologic IP include (i) whether the IP can be shipped directly to a participant’s home, (ii) whether the IP’s safety profile allows for remote monitoring, and (iii) whether the IP can be administered remotely.
Medical Device IPs: Unlike drug or biologic IPs, FDA states that some medical device DCTs may be conducted without the investigator’s direct oversight. An example of an appropriate medical device product for a DCT would include a trial that utilizes IPs suitable to home use that would not pose a significant risk to trial participants. The draft guidance further states that certain follow-up visits after using the medical device or surgical implantation may be addressed via telehealth if investigators assess that there are no significant risks from utilizing a remote patient visit and that any adverse events can still be properly assessed and documented.

Packaging and Shipping of Investigational Products

FDA suggests including the packaging and shipping information directly in the study protocol by listing the appropriate packaging materials and shipping methods for the IP, detailing tracking and documentation standards to be used for the IP, and stating the procedures for the return or disposal of any unused IPs. If investigators plan to use a central distribution service for the distribution of IPs to study participants, FDA recommends that the investigator or trial personnel monitor and document all shipments of the IP by the distributor as well as the return of any unused IPs by study participants to the distributor.

Implementation Observations: In addition, state laws regarding the shipment of investigational drugs and devices into the state may need to be addressed. The responsibility for compliance with these state laws will also depend on the nature of the product, the shipper, and the recipient. Such state law requirements may include state board of pharmacy licensure and, if the IP is a controlled substance, state-controlled substance registration.

Safety Monitoring Plans

FDA states that investigators must still create and implement a safety monitoring plan for all DCTs to ensure the safety of trial participants. Investigators must take into account the decentralized nature of their trials when creating a safety monitoring plan for a DCT and should pre-specify when certain telehealth visits are allowed and when in-person visits are required. Trial participants should also be able to utilize telehealth services for unscheduled visits in order to report adverse events or to ask any questions. Finally, when authorized under the study protocol, FDA states that routine monitoring through the use of laboratory testing or imaging may be performed at facilities close to the study participant.

Software Used in Conducting DCTs

FDA advises that software programs may be used to support a number of different operations in a DCT just as they do in traditional clinical trial settings. Any software that is used to produce or process trial records is subject to the standards of 21 CFR part 11, and such programs must adequately ensure data reliability, security, privacy, and confidentiality. However, FDA does not consider live exchanges of information between trial personnel and trial participants using telehealth to be electronic records subject to 21 CFR part 11 (unless such exchange produces documentation that is captured in electronic form). Finally, the draft guidance states that anyone submitting trial data directly into an electronic case report form, including remote trial personnel or local HCPs, should be included in the sponsor’s list of authorized data originators.

****

This Insight was authored by Marylana Saadeh Helou, Lauren Petrin, Megan Robertson, Kate Gallin Heffernan, Andrew P. Rusczek, and Amy K. Dow. For additional information about the issues discussed in this Insight, or if you have any other questions or concerns regarding the draft guidance or decentralized clinical trials, please contact one of the authors or the Epstein Becker Green Health Care and Life Sciences attorney who regularly handles your legal matters.