The issuance of this draft guidance is a milestone event that we expect will lead to major changes in how clinical research is conducted in the U.S. In particular, traditional clinical trials were structured on a model where most study-related procedures took place at designated clinical sites – usually research medical centers – and under the immediate supervision of the principal investigator, sub-investigator or other site-based health care professional (HCP). By contrast, the emerging DCT framework embraces a distributed model where study-related activities can take place at the clinical site, a patient’s home, the office of another health care professional, or even a local pharmacy. This paradigm shift offers substantial benefits to study sponsors, but also carries potentially significant regulatory and operational risks.

Below we summarize how the guidance spotlights particular areas of attention for DCT sponsors and investigators, including the need for special planning for adverse event collection, safety monitoring, data management, remote patient interaction, and digital health technology (DHT) use. One specific – and potentially significant – challenge that study sponsors and investigators will face with DCTs is ensuring appropriate oversight of individuals performing remote trial-related activities; to a large degree, the guidance places this oversight responsibility on principal investigators. The guidance also urges compliance with telehealth and health privacy rules in the collection, management, and dissemination of human research subject data.

The timing for this guidance creates greater clarity for clinical trial sponsors who are responding to new technologies and have an appetite for remote communication and assessment coming out of the global pandemic, while simultaneously embracing the learnings and accommodations developed by FDA during that time. FDA seeks comments on the draft guidance through August 1.

Special considerations for DCTs

Earlier this week, FDA released a draft guidance for clinical trial sponsors, investigators, and other stakeholders that supports the use of decentralized clinical trials (DCTs) for drugs, biological products, and medical devices, where some or all of the trial-related activities occur at locations other than traditional clinical trial sites. Section 3606(a) of the recently-enacted Food and Drug Omnibus Reform Act (FDORA) directed FDA to issue a draft guidance on the use of DCTs to support drug and device product development not later than December 29, 2023. We have separately analyzed FDORA’s accelerated approval reforms online here; its impact on FDA inspections online here; and its clinical trial diversity provisions online here.

FDA’s new guidance defines fully decentralized clinical trials as those in which all trial activities take place at a location other than a traditional site, as compared to a “hybrid clinical trial,” for which some activities take place at a traditional trial site while others take place at non-traditional sites. Examples of decentralization in clinical trials include obtaining laboratory tests at a local facility rather than a research medical center, conducting a clinical follow-up visit in the study subject’s home using telemedicine, or using telehealth and digital health technologies (DHTs) to remotely acquire data. DHTs include portable instruments such as activity trackers, smart watches, glucose monitors, blood pressure monitors, or spirometers (devices that measure lung function) that may be used in multiple environments other than traditional clinical study sites, including at patients’ homes. In March, we summarized online here how, during the pandemic, FDA took meaningful steps toward accelerating the adoption of DCT tools such as remote monitoring of study subjects, expanded use of home health visits, direct-to-patient delivery of investigational product, and the use of wearables and other digital health platforms to collect data and perform remote assessments.

Although regulatory requirements for investigations of medical products are the same for both DCTs and site-based trials, FDA lays out in the guidance several special considerations for DCTs:

• Communication with FDA. FDA recommends that sponsors discuss early with the agency specific issues related to the feasibility, design, implementation, and analysis of a DCT.
• Roles and responsibilities: The draft guidance provides detailed recommendations for ensuring that the roles and responsibilities of sponsors and clinical investigators are clearly defined in DCTs. Among other points, FDA emphasizes that sponsors have the primary responsibility of ensuring proper coordination of the decentralized activities. By contrast, investigators are responsible for the conduct of the DCTs and the oversight of individuals delegated to perform trial-related activities, including ensuring that these delegated activities and/or tasks are conducted according to the investigational plan and applicable regulations.
• Safety profile. In determining whether an investigational product (IP) is appropriate for a DCT, the draft guidance cautions that “IPs that involve complex administration procedures; have a high-risk safety profile, especially in the immediate post-administration period; or are in early stages of development such that the safety profile is not well defined may need in-person supervision by the investigator at a trial site.” For medical devices, products “that are not intended for self-use (i.e., devices used in hospital or ambulatory care settings) or that pose significant risks to trial participants should be used or administered by qualified trial personnel with investigator oversight.”
• Local HCP participation. The guidance provides for trial assessments to be performed by local HCPs rather than at trial sites. FDA notes that assessments performed by local health care providers as part of routine clinical practice (e.g., symptom evaluation) may be more variable and less precise than assessments conducted by dedicated trial personnel. Importantly, assumptions built into a DCT trial design that are based on results observed in a traditional site-based clinical trial may prove to be incorrect (e.g., effect size and corresponding sample size calculations). FDA specifically warns that differences between DCTs and traditional trials carry special risks for non-inferiority trials (e.g., there may be challenges in calculating a non-inferiority margin when the effect size has only been determined in a traditional site-based study, and where it may not be reasonable to assume that the same effect size would be seen in a DCT). The guidance generally envisions that local HCPs will be contracted as part of the trial; however, it also recommends “investigators should also attempt to obtain reports from primary providers of routine health care when activities take place that are relevant to the trial.” The guidance acknowledges that coordination of these trial activities with facilities in multiple locations will be a challenge and we note that the administrative burden of managing and securing data generated in multiple sites is likely to present a unique set of challenges.
• Remote participant interaction. The draft guidance recommends that investigators conduct telehealth visits instead of in-person visits with trial participants if no in-person interaction is needed. Thus, DCT protocols should specify when a telehealth visit with a trial participant is appropriate. FDA urges that “both trial personnel and trial participants should be trained on how to conduct or participate in a telehealth visit.”
• Safety monitoring plan. The draft guidance emphasizes the need for sponsors to implement a plan to protect the safety and welfare of trial participants in a DCT. The monitoring plan should prespecify if and when telehealth visits or in person visits will be scheduled with trial personnel or local HCPs to collect safety data.
• Adverse event plan. The DCT protocol should specify how adverse events identified remotely will be evaluated and managed, planning for how care will be provided for adverse events that require urgent or in-person attention.
• Data management plan. Clinical trial sponsors should provide a detailed data management plan (DMP) to account for multiple sources of data in a DCT, including data origin, and flow from all sources to the sponsor and methods used for remote data acquisition.
• Informed consent. The guidance emphasizes that institutional review board (IRB) oversight of the informed consent process remains paramount in a DCT, and suggests the DCT informed consent process:
  • make clear that the study may include remote visits if needed,
  • must notify participants of whom to contact for questions about the research and subjects’ rights and whom to contact in the event of a research-related injury to the subject, recognizing that participants may not routinely visit a clinical site and have access to site-based staff, and
  • describe who will have access to the trial participant’s personal health information obtained during the DCT.
• Shipping IPs. FDA cites specific concerns that sponsors should consider regarding packaging, shipping, and storage of IPs when the product is shipped directly to the home of study subjects. Among other points, the draft guidance recommends that sponsors consider how the physical integrity and stability of the IP will be maintained (e.g., temperature control), documentation concerns, unused IP disposal, and shipment monitoring and tracking.
• Electronic systems used when conducting DCTs. The draft guidance emphasizes that software programs used in DCTs to produce and process trial records required by FDA’s statutes and regulations are subject to 21 CFR part 11. However, the draft guidance also notes that some electronic systems used in DCTs – such as platforms for real-time video interactions – are not considered electronic records and, therefore, are not subject to 21 CFR part 11. We recently analyzed FDA’s new electronic records guidance online here.

DCT inspection concerns

For inspectional purposes, the draft guidance advises that DCTs should maintain a physical location where participants’ records are accessible and where personnel can be interviewed. This location should be listed on Form FDA 1572, or for investigational device exemption (IDE) applications, must be included in the IDE application. The guidance references FDA’s July 2022 draft guidance “Conducting Remote Regulatory Assessments,” which we analyzed online here, and which describes how the agency may use remote assessments of a covered establishment and/or its records to supplement the agency’s onsite inspections. It also builds on agency recommendations issued in 2020 (summarized online here), that provided clarity for investigators to facilitate trial decentralization in response to the COVID-19 public health emergency and associated disruptions such as quarantines, site closures, and travel limitations.

Digital health technology use

The draft guidance references FDA’s December 2021 draft guidance “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” for clarification on how DCTs should use DHTs to collect data. FDA advises that it is the responsibility of the DCT sponsor to ensure that DHTs used are available and suitable for use by all trial participants. In addition, “sponsor provided DHTs should be available as an option to ensure that participants who do not have a protocol-specified DHT are not excluded from the DCT for that reason;” here, the guidance cites concern for lower socioeconomic groups who cannot afford the DHT.

Regarding the use of software in conducting DCTs, the draft guidance advises that training should be provided to all parties (e.g., trial personnel, local HCPs, and trial participants) using the software. In addition, “trial personnel or local HCPs submitting trial data directly into the [electronic case report forms (eCRFs)] should be included in the sponsor’s list of authorized data originators,” the guidance says. FDA warns that real-time video interactions, including telehealth, are a live exchange of information between trial personnel and trial participants, and thus “local laws governing telehealth may apply,” and therefore, the privacy and security of these real-time visits should be ensured, and the visits must be documented.

Promoting diversity through DCTs

The draft guidance directs clinical trial sponsors to prioritize diversity in clinical trial recruitment, recommending community outreach to local health care institutions in areas where there may be limited access to traditional clinical trial sites. The draft guidance encourages use of DCTs and local HCPs as mechanisms for increasing diversity and inclusion in trials, recognizing that “bringing trial-related activities to participants’ homes, including through the use of DHTs, may reduce the need for travel and improve engagement, recruitment and retention amongst potential participants.” This guidance is consistent with FDA’s public statements on the relationship between DCTs and clinical trial diversity. In a press release announcing the guidance, FDA Commissioner Robert Califf hailed the benefits of DCTs and DHTs, saying that “decentralized clinical trials may enhance convenience for trial participants, reduce the burden on caregivers, expand access to more diverse populations, improve trial efficiencies, and facilitate research on rare diseases and diseases affecting populations with limited mobility.”

Similarly, in a “CDER Conversation” blog post published alongside the draft guidance, Leonard Sacks, MD, associate director for clinical methodology in CDER’s Office of Medical Policy, spotlighted the importance of DCTs and DHTs in making clinical trials more inclusive, saying they can help reduce barriers to participation in clinical trials. “Individuals from racial and ethnic minority groups may disproportionately live in areas without clinical research facilities, and DCTs may open access to research for them,” Dr. Sacks noted. We recently analyzed (online here) how the agency is also developing guidance to increase racial and ethnic diversity in clinical trials.

FDA is accepting comments on the draft guidance through August 1, 2023.