On May 2, 2023, the U.S. Food and Drug Administration (FDA or the Agency) issued a draft guidance entitled Decentralized Clinical Trials for Drugs, Biological Products, and Devices (Draft Guidance).[1] Decentralized clinical trials (DCTs) are clinical trials in which “some or all trial-related activities will occur at locations other than traditional clinical trial sites.”[2] FDA has long recognized the benefits of DCTs, including that they may enhance convenience for clinical trial participants, reduce the burden on caregivers, improve trial efficiencies, facilitate research on rare diseases, and expand access to diverse populations.[3]
The Draft Guidance builds on recommendations the Agency issued during the COVID-19 pandemic to facilitate clinical trial decentralization in light of quarantines, site closures, and travel limitations (2020 Recommendations).[4] At a high level, the Draft Guidance provides direction on designing and implementing DCTs for drugs, biologics, and medical devices. In addition, the Draft Guidance introduces specific recommendations for utilizing digital health technologies (DHTs) in the conduct of DCTs.
Comments on the Draft Guidance must be submitted to FDA by August 1, 2023.
Major Provisions of the Draft Guidance
The Draft Guidance provides recommendations for nine elements of DCT implementation: DCT design, remote clinical trial visits and clinical trial-related activities, DHTs, roles and responsibilities of sponsors and investigators, informed consent and institutional review board (IRB) oversight, investigational products in DCTs, packaging and shipping of investigational products, safety monitoring plans, and software used in conducting DCTs.
DCT Design
According to FDA, given that data obtained in a DCT may differ in terms of variability and precision from data gathered in a traditional clinical trial, the validity of a finding of non-inferiority could be affected. FDA explains that it may be unreasonable to assume that the same effect size determined for an active control drug in a traditional clinical trial would be seen in a DCT, which can present challenges in calculating the non-inferiority margin. In light of these considerations, the Agency recommends that sponsors planning non-inferiority trials in a DCT setting consult FDA. The Agency states that the validity of a superiority finding in a DCT would not be affected, but that the effect size could be reduced.
The Agency also clarifies that even fully remote DCTs should have a physical location where all clinical trial-related records are accessible for inspectional purposes.
Remote Clinical Trial Visits and Clinical Trial-Related Activities
FDA affirms in the Draft Guidance that telehealth visits are appropriate in the context of DCTs, so long as no in-person interaction is needed. The study protocol should state which visits are appropriate for a telehealth visit and which should be in-person. FDA also states that non-trial personnel—such as local HCPs—may perform certain trial-related activities that they are otherwise qualified to perform in clinical practice. But those trial-related activities that are unique to research and/or require detailed knowledge of the study protocol or the investigational product should be performed by trial personnel who are qualified and properly trained.
Digital Health Technologies
DHTs enable sponsors and investigators to acquire data remotely from participants in clinical trials. In addition to complying with the recommendations set forth in FDA’s DHT-specific guidance documents,[5] sponsors and investigators should ensure that DHTs used in DCTs are suitable for use by all trial participants. Sponsor-provided DHTs should be available even if the trial allows participants to use their own DHTs.
Roles and Responsibilities of Sponsors and Investigators
Decentralized clinical trials and traditional site-based trials have identical regulatory requirements.[6] The Agency reinforces this uniformity in the Draft Guidance, noting that DCT sponsors—like their traditional clinical trial counterparts—must ensure proper coordination and oversight of decentralized activities, as well as proper monitoring (see discussion below). In addition, DCT sponsors should describe in the trial protocol how operational aspects of the DCT will be implemented. They also should provide a detailed data management plan to account for multiple sources of data, including data origin, data flow, and the methods used for remote data acquisition. Case report forms should identify when and where data were collected and by whom. FDA explains that sponsors should consider various DCT tools (e.g., the use of DHTs and local HCPs) to strive for diversity and inclusion in trial populations.
Because DCTs can involve telehealth, remote work, local HCPs, and/or DHTs, DCT investigators may need to conduct more training and coordination than investigators of traditional clinical trials. For example, DCT investigators should maintain a task log of local HCPs who perform trial-related activities, which should be available to FDA during an inspection. FDA also notes that the development of standard operating procedures and other quality control measures can help ensure consistent implementation of a DCT, as well as help reduce variability.
Informed Consent and IRB Oversight
Investigators may obtain electronic informed consent from trial participants at their remote locations, provided that all applicable regulatory requirements regarding informed consent are met. The Draft Guidance provides that the informed consent should describe who will have access to trial participants’ personal health information obtained during the DCT.
FDA also recommends the use of a central IRB in DCTs in order for the protocol, informed consent document, and other trial-related information to be reviewed more efficiently.
Investigational Products in DCTs
The Agency recommends considering the nature of the investigational product when determining whether a DCT investigator should administer investigational products outside of a clinical trial site. Investigational products 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. FDA notes that drugs with long shelf lives and good stability profiles are well-suited for direct shipment to a trial participant’s home.
Devices intended for self-administration or over-the-counter use that do not pose a significant risk to subjects may be appropriate for DCTs. The Agency also notes that for other devices administered by qualified trial personnel with investigator oversight, certain follow-up procedures (e.g., follow-up after surgery), may be appropriate for remote telehealth visits, home visits, or in local health care facilities.
Packaging and Shipping of Investigational Products
As a general matter, DCTs may allow for direct distribution of investigational products to trial participants. In the Draft Guidance, FDA recommends that shipping containers include clear instructions for handling and storing the investigational product, as well as for returning unused investigational product. Investigators or delegated trial personnel must monitor the return or disposal of unused product and document such return or disposal accordingly.
Safety Monitoring Plans
DCT sponsors should implement a safety monitoring plan to ensure the safety and welfare of trial participants. This safety monitoring plan should take the decentralized nature of the clinical trial into account and ensure that adverse events are appropriately captured and addressed. If the DCT involves the use of a DHT, FDA recommends that the safety monitoring plan describe the type of information the DHT will collect, how such information will be used, and what action trial participants should take in response to abnormal findings or electronic alerts. If significant safety risks emerge because of the remote administration or use of the investigational product, remote administration or use must be discontinued and, among other things, the sponsor should notify FDA, the IRB, and all investigators.
Software Used In Conducting DCTs
FDA states in the Draft Guidance that training should be provided to all parties—including local HCPs and trial participants, as applicable—using software to support the conduct of a DCT. If a local HCP or remote trial personnel submits trial data directly into the electronic case report form, they should be listed as an authorized data originator. FDA clarifies that real-time video interactions, including telehealth visits, are not considered electronic records and are not subject to 21 CFR Part 11; however, these visits should be documented and if this documentation is captured in electronic form, that documentation is subject to Part 11.
If you have any questions concerning the material discussed in this client alert, please contact the members of our Food, Drugs, and Devices practice.
[1] The issuance of the Draft Guidance fulfills a requirement under Section 3606(a) of the Food and Drug Omnibus Reform Act, which directs FDA to issue or revise draft guidance no later than December 29, 2023 that “includes recommendations to clarify and advance the use of decentralized clinical studies to support the development of drugs and devices.”
[2] Draft Guidance at 16. In fully decentralized DCTs, all activities take place at non-traditional locations, such as trial participants’ homes or local health care facilities. Hybrid DCTs feature a blend of visits to traditional clinical trial sites and non-traditional locations.
[3] Id. at 2. See also FDA, Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs (2020).
[4] FDA, Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards (2020).
[6] See 21 CFR Parts 312 and 812.
Back
