FDA Issues Draft Guidance on Decentralized Clinical Trials for Drugs, Biological Products and Devices

As we previously discussed in FDA Offers Guidance on Clinical Trials During Covid-19 Pandemic, FDA issued guidance on March 19, 2020, to provide greater flexibility to adjust clinical protocols and to use telemedicine platforms and virtual clinical sites to address challenges presented by the COVID-19 public health emergency when in-person visits were limited, unsafe or otherwise unavailable for many trial participants.

On May 2, 2023, FDA issued draft guidance, Decentralized Clinical Trials for Drugs, Biological Products, and Devices: Guidance for Industry, Investigators, and Other Stakeholders (Draft Guidance), to assist industry in more broadly adopting DCTs and to meet FDA’s obligations under Section 3606(a) of the Food and Drug Omnibus Reform Act (FDORA), which required FDA to issue or revise draft guidance to advance the use of DCTs to support drug and device development on or before December 29, 2023. The Draft Guidance should be considered along with FDA’s December 2021 draft Digital Health Technologies for Remote Data Acquisition in Clinical Investigations guidance (DHT Draft Guidance), discussed here. FDA’s issuance of these draft guidances represent a broader recognition of the important role that digital health technologies (DHTs) may play in modernizing the conduct of research.

As the Draft Guidance notes, many clinical trials already include decentralized elements. For example, research-related laboratory tests are often conducted by clinical laboratories that are remote from traditional trial sites, and advances in clinical care using telehealth technologies allow for fewer in-person visits to traditional trial sites and have expanded the types of trial-related data that can be obtained remotely from trial participants. FDA recognizes that by enabling remote participation, DCTs may enhance convenience for trial participants, reduce the burden on caregivers, and facilitate research on rare diseases and diseases affecting populations with limited mobility or access to traditional trial sites.

DCTs may not make sense in all cases, however. FDA’s guidance generally notes that fully decentralized trials, where all study activities take place at locations other than traditional trial sites, may be appropriate for investigational products that are simpler to administer or use, have well-characterized safety profiles, and do not require complex medical assessments. Conversely, hybrid decentralized clinical trials, where some trial activities are performed at traditional clinical trial sites and some are performed at other locations, may be appropriate where the administration of an investigational product or a complex medical assessment requires the subject to visit a clinical trial site, but certain follow-up assessments still can be performed remotely through online patient-reported outcome measures, telehealth or in-home visits, or by local healthcare providers (HCPs) not directly involved in the conduct of the clinical trial.

FDA also offers guidance on specific topics for implementing DCTs, specifically:

• DCT design
• Remote clinical trial visits and clinical trial-related activities
• Use of DHTs
• Sponsor and investigator roles and responsibilities
• Informed consent and institutional review board (IRB) oversight
• Investigational products in DCTs
• Packaging and shipping investigational products
• Safety monitoring plans
• Use of software in DCTs.

Sponsors, contract research organizations, investigators, and other stakeholders such as developers of DCT technologies or services should consider the recommendations in the Draft Guidance in connection with the design and implementation of DCTs and DCT-supporting technologies and services, as applicable.

DCT Design

By their nature, DCTs may involve a network of locations where trial personnel and local HCPs perform trial-related services, all under the oversight of the investigator. For inspection purposes, FDA expects a single physical location to be identified on Form FDA-1572 or in the investigational device exemption (IDE) application, as applicable, where all trial-related records for participants under the investigator’s care can be reviewed and all trial personnel can be interviewed.

In addition, FDA encourages sponsors to consult the applicable FDA review division when planning non-inferiority DCTs due to potential challenges in calculating non-inferiority margins presented by the variability and precision of data obtained in a DCT compared against data obtained in a traditional clinical trial. Such challenges may arise particularly in situations where trial participants are responsible for performing their own physiological tests or when local HCPs perform research-related assessments as part of routine clinical practice.

Remote Clinical Trial Visits and Clinical Trial-Related Activities

FDA states that, as a general matter, investigators can consider telehealth visits so long as no in-person interaction is needed, but FDA expects that the protocol specify which visits may be conducted via telehealth and which require the participant to either be seen at a traditional trial site or otherwise be seen in-person by trial personnel who are sent to the participant’s home or other preferred location. Where appropriate, trial personnel and participants should be trained on how to conduct or participate in a telehealth visit.

For telehealth visits, the investigator should confirm the trial participant’s identity, and sponsors and investigators can consider existing digital identity guidelines, such as the National Institution of Standards and Technology (NIST) Special Publication 800-63A: Enrollment and Identity Proofing Requirements, when developing and implementing an identity verification plan. In addition, case report forms and other documentation should be completed and should include the date and time of the visit.

FDA notes that, in certain situations, in-person visits may also be conducted by local HCPs who are not part of the trial personnel but are located close to the participant. In such situations, the HCPs may be used to perform trial-related services on a fee-for-service basis, but the trial-related services should not require a detailed knowledge of the protocol or the investigational product and should not differ from services the HCP is qualified to perform in clinical practice. Conversely, trial-related activities that are unique to the research or require knowledge of the protocol or investigational product should only be performed by properly trained and qualified trial personnel.

FDA also expects the trial protocol to specify how adverse events identified remotely will be evaluated and managed, as well as how care for adverse events that require urgent or in-person attention will be provided.

Digital Health Technologies

Pursuant to its August 2021 Prescription Drug User Fee Act (PDUFA) VII commitment to publish guidance on the use of DHTs in both traditional and decentralized clinical trials, discussed here, FDA also addresses the use of DHTs to allow transmission of data from trial participants, wherever they are located. FDA encourages sponsors, clinical investigators, and others measuring clinical events and characteristics in DCTs to review FDA’s recommendations in its DHT Draft Guidance. In any event, FDA expects sponsors to ensure that DHTs used in DCTs are available and suitable for use by all participants, including by providing DHTs to participants who do not already have protocol-specific DHTs in situations where the protocol permits participants to use their own DHTs.

Roles and Responsibilities

Sponsors

FDA notes that sponsor responsibilities are the same in DCTs and traditional site-based clinical trials, and that sponsors should ensure proper coordination of all decentralized activities. To account for multiple sources of data collection, FDA expects that a data management plan (DMP) will include information regarding:

• Data origin and data flow from all sources to the sponsor, which can take the form of a data flow diagram where appropriate.
• Methods used for remote data acquisition from participants, personnel, and contracted service providers such as clinical laboratories or local HCPs who perform trial-related activities.
• A list of vendors for data collection, handling and management.

In addition, sponsors should ensure that the protocol describes how operational aspects of the DCT will be implemented, including descriptions regarding scheduled and unscheduled visits, transmission of reports on activities performed at other locations, how the investigational product will be delivered to participants and accountability therefor, and safety monitoring and management of adverse events.

FDA also expects sponsors to prepare trial monitoring plans for DCTs that describe how monitoring will be implemented, specify the frequency of reviews and note any unique aspects related to monitoring DCT procedures.

Investigators

FDA encourages investigators to only enroll as many trial participants as they can appropriately manage in a DCT context, and notes that videoconferencing and other technologies may be useful for overseeing trial personnel performing trial-related activities at other locations (e.g., when photographing lesions or fitting wearable devices).

With respect to trial-related activities delegated to local HCPs, FDA generally advises that, for drug investigations, local HCPs who perform trial-related services that are part of routine clinical practice and where detailed knowledge of the investigational product, protocol and other study documentation is not necessary should not be listed on Form FDA-1572 as sub-investigators. For device investigations, the same category of local HCPs should not be included in the IDE list of investigators. In either case, however, FDA expects investigators to maintain a task log of local HCPs who perform trial-related activities and make the task log available to FDA during inspections. The task log should:

• Include the names and affiliations of the local HCPs, a description of their roles and assigned tasks, the dates they are added to the log, and location where activities are conducted.
• Be signed and dated by the investigator when initially created and updated as new local HCPs are added.

For trial protocols that require laboratory services, FDA generally recommends the use of a designated central laboratory, but the agency recognizes that some protocols may permit a variety of clinical laboratories local to the participant to perform laboratory services. FDA notes that while local laboratory facilities may be adequate for routine, well-standardized clinical tests, research specimens could be collected by remote trial personnel, local HCPs or clinical laboratory facilities local to the participant and sent to the designated facility for processing. All clinical laboratory facilities used in a DCT should be listed on Form FDA-1572 (for drug investigations) or the investigational plan for device studies under an IDE.

Informed Consent and IRB Oversight

FDA states that stakeholders may consider obtaining informed consent remotely in DCTs, subject to IRB oversight to ensure the process is adequate and appropriate. FDA recommends the use of a central IRB to promote efficient review and oversight of the DCT. In addition to meeting all applicable regulatory requirements, the informed consent process must include notifying participants of appropriate contacts for answers to questions about the research or research subject rights and research-related injuries. The informed consent should also describe who will have access to the trial participant’s health information.

Investigational Products in DCTs

For drug and biological investigational products, the appropriateness of administration outside of a traditional trial site depends on the complexity and nature of the investigational product itself. For complex administration procedures and high-risk drugs and biologics, in-person supervision by the investigator at a trial site may be required. In addition, drugs and biologics that require special handling, shipping or storage conditions may not be appropriate for shipment outside of the trial site. Alternatively, it may be appropriate for local HCPs or remote trial personnel to administer investigational products that do not involve specialized monitoring after administration and have well-characterized safety profiles. If investigational products will be administered outside of a traditional trial site, sponsors should estimate the urgency and complexity of care that may be needed based on the safety and risk profile of the drug or biologic, and investigators should take steps to ensure that participants have local access to appropriate levels of care.

Similar considerations are present for medical device investigational products. If the device is suitable for self-use (e.g., over-the-counter devices) and does not pose significant safety risks, remote use by trial participants without direct oversight by the investigator may be appropriate. However, if the device is not intended for self-use or poses significant safety risks, administration by qualified trial personnel with direct investigator oversight may be appropriate. FDA notes that certain follow-up procedures related to more complex devices may be performed by local HCPs or trial personnel via telehealth visits (where appropriate) or in-person at the participant’s home or local healthcare facility.

Packaging and Shipping Investigational Products

For DCTs in which investigational products will be distributed directly to participants at their locations, FDA states that sponsors should describe in the protocol how the physical integrity and stability of the investigational product will be maintained during shipment, how investigators will track and document that trial participants receive the investigational product, and the procedures that investigators or participants should use to return or dispose of the investigational product. Further, shipping containers should include clear instructions for handling, storing and returning the investigational products, and DCT personnel should be trained on these procedures and how to appropriately document them.

FDA notes that a central distribution service may be used to ship the investigational product directly to trial participants, and that investigators or delegated trial personnel must control the release of the investigational product by the distributor, monitor receipt and use by the trial participant, and monitor return or disposal of any unused investigational product as directed by the sponsor.

Safety Monitoring Plans

As with traditional clinical trials, FDA expects sponsors to implement safety monitoring plans for DCTs that describe how participants are expected to respond to and report adverse events, including where to seek medical assistance locally and where to receive follow-up care. In addition, the safety monitoring plan should pre-specify if and when telehealth visits or in-person visits will be scheduled with trial personnel or local HCPs to collect safety data and describe the type of information that will be collected by a DHT, how that information will be used and monitored, and the actions trial participants or personnel should take in response to abnormal findings or electronic alerts. Where routine safety monitoring involving laboratory testing and imaging at local clinical laboratory facilities is permitted by the protocol, investigators should ensure that they promptly receive reports of these services and review them in a timely manner.

If significant safety risks emerge related to remote administration or use of the investigational product, FDA states that sponsors must discontinue remote administration or use, notify FDA, the IRB, and all investigators who have participated in the trial, and determine whether the trial should continue.

Software Used in Conducting DCTs

Software can be used to support DCTs in several respects. For example, software can be used to manage electronic informed consent, capture and store reports from remote trial personnel or local HCPs or clinical laboratories, manage electronic case report forms (eCRFs), schedule trial visits and other DCT-related activities, track investigational products shipped directly to participants, sync information collected by DHTs, and facilitate communication between DCT personnel and trial participants. FDA expects that trial personnel, local HCPs and trial participants who use software in connection with a DCT will be appropriately trained on how to use such software.

Where local HCPs perform trial-related activities, FDA states that data from those activities can, among other mechanisms, be submitted for inclusion in trial records directly into the eCRFs or through secure data transfer methods to investigators, who must then enter the trial-related data into the eCRF. Where remote trial personnel or local HCPs submit trial directly into the eCRF, the same individuals should be included in the sponsor’s list of authorized data originators.

Any software program used to produce or process DCT records required by the Federal Food, Drug, and Cosmetic Act and FDA regulations are subject to 21 CFR Part 11 and must ensure data reliability, security, privacy and confidentiality. While FDA notes that real-time video interactions, including telehealth, are not considered electronic records and are not subject to 21 CFR Part 11, FDA nevertheless expects stakeholders to ensure the privacy and security of telehealth visits and to document the visits, including in systems compliant with 21 CFR Part 11 if captured electronically.

Conclusion

DCTs have the potential to enhance convenience for trial participants, reduce the burden on caregivers, and facilitate research on rare diseases and diseases affecting populations with limited mobility or access to traditional trial sites. They may also help improve trial participant engagement, recruitment, enrollment and retention of a meaningfully diverse study population. However, DCTs present special considerations related to coordination of trial activities among individuals and facilities in multiple locations that are not traditional clinical trial sites. The Draft Guidance provides helpful recommendations for sponsors, investigators and other stakeholders regarding implementation of DCTs to advance drug and device development.

Sponsors, investigators and other stakeholders that conduct DCTs should consider submitting comments to the Draft Guidance (Docket No. FDA-2022-D-2870). FDA recommends that the public submit comments by August 1, 2023, to ensure that FDA considers them prior to issuing final guidance.