The Food and Drug Administration (FDA) published final guidance, “Conducting Clinical Trials With Decentralized Elements” on Sept. 18, 2024.1 This final version does not differ substantially from the previously published draft guidance released in May 2023, but it does provide more specific guidance on how to designate decentralized research personnel as either investigators or other personnel based on their role in the research. A decentralized clinical trial (DCT) involves some or all trial activities taking place in locations other than a traditional clinical trial site. This could be a participant’s home, a local health care provider’s office, or a local laboratory. The guidance emphasizes that decentralized trials follow the same regulatory requirements of traditional clinical trials, but it includes a detailed discussion of how to navigate those regulatory requirements in non-traditional protocol designs. What follows is a summary of the guidance with commentary on how the guidance might affect Institutional Review Board (IRB) submission and review.
Design and Conduct of the Research
A decentralized trial can provide much-needed flexibility to participants, but as flexibility in data acquisition increases, variability in the data will also increase.
An example from the guidance includes using self-collected home spirometry measurements vs. in-office spirometry measurements. Participants may interpret instructions in unexpected ways leading them to perform the tests differently whereas a designated, trained healthcare provider could be trained to be more precise in administering the test. The benefit of home testing for recruitment and retention may still outweigh requiring participants to visit a clinic, but the increased variability in the data may require a larger sample size to demonstrate the same effect.
Remote Visits and Related Activities – Who Needs IRB Review?
A variety of alternatives to face-to-face study visits can make clinical trials more accessible to a wider demographic of participants. Telehealth visits are face-to-face visits under FDA regulations, not electronic communications. There may be challenges to overcome in ensuring participants have access to adequate technology and bandwidth for video conferencing. Any electronic visit notes would need to comply with 21 CFR Part 11. Additionally, at-home visits whether telehealth or with visiting health care providers (HCPs) may lead to privacy concerns depending on the participant’s living situation. Investigators should ensure that the participant has adequate privacy for discussions or in-home procedures.
Two of the most frequent questions IRBs get about remote visits and decentralized trial activities are:
- Who is the investigator?
- Which locations are research sites required to have IRB oversight?
According to the FDA guidance, investigators are personnel who contribute directly and significantly to the trial data and who must have detailed knowledge of the protocol, Investigator’s Brochure, or investigational product (IP), and sponsors should list them on the FDA 1572 form. The IRB would also consider these investigators or sub-investigators to be investigators whose activities require IRB review. If decentralized trials include the use of local HCPs to perform certain trial-related activities on a fee-for-service basis, and they are providing services they perform routinely in clinical practice, and do not require special knowledge of the protocol to perform them, then they are not considered investigators.
Because many sites and institutions receive federal funding, the Office for Human Research Protections (OHRP) guidance, “Determining When Institutions are Engaged in Research,” (the Engagement Guidance) may also be applicable for personnel at these locations.2 The Engagement Guidance states that employees or agents who for the purpose of the research obtain the below, are engaged in research and need a Federal Wise Assurance (FWA) and IRB approval of their activities:
- Data about the subjects or the research through intervention or interaction with them.
- Identifiable private information about the subjects of the research.
- The informed consent of human subjects for the research.
Overall, the two guidance documents overlap, but there are a few areas of divergence. Administering an approved drug on label as part of a clinical trial might not require a local health care provider to be an investigator under the FDA guidance and regulations, but administering an approved drug might be engagement in research under the OHRP engagement guidance. For institutions that apply the common rule regulations to all research, these personnel should be investigators, and an IRB should oversee their research activities. Another area of discrepancy is around obtaining identifiable private information or identifiable biospecimens from a research participant. This activity alone might not make personnel an investigator under the FDA guidance, but it would under the OHRP guidance. These cases depend on the specifics of the situation, and investigators should reach out to their IRB office to discuss this to ensure all appropriate personnel have IRB oversight.
While local health care providers may not be investigators, the clinical trial investigators are responsible for ensuring local providers’ activities are in line with the protocol. Maintaining oversight and adequate supervision for providers who are not trial personnel can add additional complexity to managing a clinical trial. Investigators can address concerns about variability of data by communicating any specific protocol instructions for trial-related activities.
Digital Health Technologies
Decentralized trials may involve the use of digital health technologies (DHT) to measure clinical events and characteristics remotely. The FDA guidance references another FDA guidance, “Digital Health Technologies for Remote Acquisition in Clinical Investigations,” for a more detailed discussion around verifying and validating these technologies to be fit-for-purpose for the clinical trial. Additionally, the guidance instructs sponsors to consider whether DHT’s are suitable for use by the population being studied and to consider whether social or other barriers to the use of the technology could affect enrollment and persistence in the trial. Using familiar technology instead of a study-specific device can be a benefit to participants, but sponsors should ensure that participants who lack personal devices can still participate. WCG has additional resources related to digital health technology to support diversity in clinical trials in this Applied Clinical Trials article “Optimizing Technology Implementation to Improve Diversity in Clinical Research” and this WCG Talks Trials podcast episode, “Diversity & Inclusion with Technology in Decentralized Trials.”
Roles and Responsibilities
Sponsor
The DCT guidance confirms that responsibilities for oversight of a decentralized trial are the same as for any other clinical trial, but sponsors may need to oversee complex contracts if they are using local networks of clinics, pharmacies, or laboratories. Sponsors are responsible for maintaining records of these contracts and relationships. Additionally, data management plans should include a description of the data origin and flow from all sources to the sponsor and the methods and technologies used to collect trial data. Sponsors should also maintain a list of service providers for all steps in the data collection, handling, and management as well.
In the protocol, sponsors should describe the details of the DCT including how and where visits will take place, which activities study personnel vs. local HCP’s will perform, how they will manage study data and delivery of investigational products, and safety monitoring. As with any trial, sponsors should use a risk-based approach to monitor the study.
Investigator
Investigators are responsible for conducting the DCT, including overseeing any other personnel who work on the trial. If local HCPs conduct trial activities, then investigators are responsible for ensuring any delegated trial tasks are in adherence with the protocol and for ensuring data resulting from those tasks is complete and accurate. The investigator is also responsible for providing investigational products to participants, whether directly or through local HCPs and pharmacies.
When trial personnel contribute directly to drug trial data, they are investigators or sub-investigators. Local HCPs, who are not investigators, do not need to be listed on the FDA 1572 form, and maintaining a log of local HCPs is not required. Investigators must maintain complete case histories which would include the name of the local HCP and the date of activities. For device trials, HCPs are not investigators and do not need to sign an agreement with the sponsor or to be listed in an Investigational Device Exemption (IDE) application.
DCTs can involve the use of central laboratories and imaging centers for tests specific to the trial, and they can use samples collected remotely and then processed at local facilities if appropriate for the trial. For drug trials under an Investigational New Drug (IND) application, the investigator should list all clinical laboratory facilities on the FDA 1572 form, and for device trials, the investigator should identify clinical labs in the investigational plan.
In the case of an emergency, participants should seek help at their local health care facilities, and investigators should obtain consent to obtain reports regarding any incidents from the local provider.
Informed Consent – Who Can Obtain Informed Consent?
Informed consent is foundational to conducting ethical research, and IRBs review the consent process and consent documents. The guidance notes that consent discussions can take place in remote locations where the participant and investigator are not co-located, and the participant can document their consent electronically or on paper. Investigators can also delegate the informed consent discussion to qualified staff, but these staff must have detailed knowledge of the research, so local HCPs who are not investigators should not obtain informed consent. Participants must also be able to reach someone knowledgeable about the research if they have questions. The consent process should disclose specific details of the decentralized nature of the clinical trial – participants should know whether local HCPs will conduct trial activities and if any activities will take place in their homes.
Summary
The guidance clarifies the roles of local service providers in decentralized trials. While the regulations governing clinical research apply to all trials, decentralized or not, there are novel considerations around how to balance the flexibility of local providers and at-home tasks with the increase in variability of the data this flexibility will introduce. Digital technologies have the potential to expand participation in research, but variability in access and comfort with technology may also lead to the potential exclusion of certain groups. Sponsors, investigators, and IRBs should approach decentralized trials with these complexities in mind.
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