SACHRP Recommendations on “Decentralized Clinical Trials for Drugs, Biological Products, and Devices - Guidance for Industry, Investigators, and Other Stakeholders”

Approved July 20, 2023

Background

On May 1, 2023, the United States Food and Drug Administration (FDA) released a draft guidance titled "Decentralized Clinical Trials for Drugs, Biological Products, and Devices - Guidance for Industry, Investigators, and Other Stakeholders." The purpose of this guidance is to provide recommendations for implementing decentralized clinical trials (DCTs), including both fully decentralized trials where all activities occur at locations other than traditional sites, as well as hybrid trials that combine in-person visits with activities at non-traditional locations such as a research participant’s home or a local healthcare facility.  Throughout the guidance, it emphasizes that the regulatory requirements for DCTs are generally the same to those for traditional site-based trials and that compliance with other relevant laws, regulations, and local requirements is also a requirement, as these may vary across different regions such as U.S. states, territories, and countries. The guidance also highlights the unique advantages of DCTs as well as the challenges that require careful planning and coordination. Taken as a whole, the guidance demonstrates the FDA's commitment to advancing clinical research and leveraging the potential of DCTs to improve trial efficiencies and expand access to trial participants.  

SACHRP Charge

The charge of the HHS Secretary's Advisory Committee on Human Research Protections (SACHRP) is to “[p]rovide expert advice and recommendations “on issues and topics pertaining to or associated with the protection of human research subjects.” In accordance with this Charge, SACHRP provides the following public comment regarding the FDA’s draft guidance. Heading and page references are to the version of the draft guidance posted on FDA’s website located here: https://www.fda.gov/media/167696/download (Decentralized Clinical Trials for Drugs, Biological Products, and Devices Draft Guidance for Industry, Investigators, and Other Stakeholders (fda.gov).    

SACHRP’s Comments regarding Specific Sections of the Draft Guidance  

1.   Introduction (pg. 1)
The stated purpose of the draft guidance is to “provide… recommendations for sponsors, investigators, and other stakeholders regarding the implementation of decentralized clinical trials (DCTs) for drugs, biological products, and devices.” 

• SACHRP recommends revising this statement to emphasize that effective implementation includes planning and oversight.

In addition, the draft guidance emphasizes that FDA's regulatory requirements for investigations of medical products and adherence to Good Clinical Practice (GCP)¹ are the same for DCTs and traditional site-based clinical trials.

• SACHRP recommends reminding stakeholders that, in addition to the requirements set forth in the FDA regulations, compliance with other relevant laws, regulations, and local requirements is necessary, which may vary across U.S. states, territories, and countries. Although this is already stated throughout the draft guidance, emphasizing this point would be a helpful reminder in this section.   

2.   Background (pg. 2)
The Background section provides and overview of the benefits and challenges of DCTs, and examples of the types of trials that may be appropriate as fully decentralized versus hybrid. As currently written, the potential benefits of DCTs are appropriately emphasized.

• SACHRP recommends including a summary of additional challenges and considerations that generally should be included in a DCT Plan when appropriate for the trial. Although the draft guidance mentions the challenges related to the coordination of trial activities with individuals and facilities in multiple locations, it would be helpful to expand on the challenges and other considerations faced by sponsors, investigators, institutional review boards, and other stakeholders by including additional examples (e.g., trial participant safety; privacy, confidentiality, and security; risks to non-subjects; special considerations related to vulnerable populations; adequate oversight; compliance with relevant laws, regulations, and local requirements (for example, investigational product shipment, prescribing, telemedicine, etc.).

3.   Recommendations for Implementing DCTs (pg. 3)
Section III of the FDA draft guidance includes a number of recommendations for implementing DCTs. These sections collectively provide recommendations and considerations for various aspects of DCT implementation, ensuring the appropriate design, execution, oversight, and safety of DCTs. Specific SACHRP recommendations for each section are below.

a.  DCT Design (pg. 3)
The draft guidance states that for inspectional purposes, “there should be one physical location where all clinical trial-related records for participants under the Investigator's care should be accessible, and where trial personnel can be interviewed.”

• SACHRP recommends clarifying that the one physical location requirement for agency inspections can be satisfied by leveraging electronic platforms to access trial-related records (e.g., use of an eRegulatory binder, etc.) and the possibility of conducting interviews using a virtual communication platform with trial-related personnel who may be located at different physical locations.  For example, it would be highly burdensome to expect Investigators and other trial-related personnel located in different geographic locations to travel to one location for an inspection. They are not expected to do this for traditional trials and therefore should not be expected to do this for a DCT. These clarifications may help provide greater clarity and ensure consistency regarding the one physical location requirement. 

b.  Remote Clinical Trial Visits and Clinical Trial-Related Activities (pg. 4)
This section of the guidance focuses on making trials more convenient and accessible for participants through recommendations regarding remote clinical trial visits and clinical trial-related activities. The following recommendations are provided:

1. Option of telehealth visits: When no in-person interaction is necessary, telehealth visits can be offered as an alternative to in-person visits.
2. Clear definition in the protocol: The protocol should clearly specify when telehealth visits are appropriate and when in-person visits are required.
3. In-person visits in preferred locations: Trial personnel can conduct in-person visits and trial-related activities in a trial participant's home or another preferred location.  
4. Involvement of local healthcare professionals (HCPs): Qualified local HCPs near participants' homes, who are not part of the trial personnel, can perform specific trial-related tasks (e.g., physical examinations, vital sign measurements, etc.) as long as they do not require extensive knowledge of the trial protocol or investigational product.
5. Assignment of protocol-specific tasks: Protocol-specific tasks should be assigned to trained trial personnel who possess the necessary qualifications.
6. Training for telehealth visits: Both trial personnel and participants should receive training on conducting and participating in telehealth visits effectively.
7. Participant identity confirmation: Participant identity should be confirmed during each remote visit.
8. Documentation of telehealth visits: Telehealth visits should be properly documented, including the date and time of the visit.
9. Evaluation and management of remotely identified adverse events: The trial protocol should outline procedures for evaluating and managing adverse events identified remotely.
10. Compliance with telehealth laws: Compliance with relevant telehealth laws in the respective jurisdictions should be ensured.

• While this section addresses many key considerations, the SACHRP recommends including the additional guidance below. 

• Suitability and capacity assessment of DCTs: Develop points to consider and provide additional examples for determining the appropriateness of a DCT for a study or specific trial-related activities, including guidelines for when DCTs or traditional site-based trials are preferred and what aspects of the study should or should not be decentralized, if any. 
• Clarification on decision-making: Clarify who has the authority to decide whether trial activities can occur in the participant's home or another preferred location.
• Participant location preference: Specify whether participants have the option to choose an "other preferred location" if they prefer not to have trial activities take place in their homes.
• Suitability assessment of trial location: Provide guidance on determining the suitability of a participant's home or preferred location for conducting trial-related activities, regardless of the participant's preference (e.g., this could be in the form of minimum standards that should apply regarding where a trial related activity can take place and in what way it can be done.)
• Information for non-trial personnel: Provide basic study information and Investigator/trial personnel contact details to individuals who are not part of the trial personnel but performing certain trial-related activities. The information could be in the form of a Frequently Asked Question (FAQ) document or other format (which is regularly updated when necessary and provided to non-trial personnel) that provides basic information about the study, a list of questions that can be answered, and a list of questions that should be directed to an Investigator or another member of the study team. Furthermore, the information should serve as a reminder to individuals that trial participants are taking part in research and that the rights and welfare of trial participants must be respected. For instance, it should include a reminder that participants have the voluntary right to withdraw from the study or decline a trial-related procedure at any time. The information should address the scope of responsibilities of the non-trial personnel in the research to the participants, including what to do in the event non-trial personnel discover abnormal health findings that fall outside the scope of the research. 
• Consideration of practical challenges and risks: Remind stakeholders to consider practical challenges and potential risks related to safety, privacy, confidentiality, security, and other factors that may affect both participants and non-participants  (e.g., addressing issues such as child abuse, sanitary conditions, neglect, mandatory reporting, proximity to emergency care, etc.) when conducting activities in participants' homes or other locations.

SACHRP believes including these additional considerations and clarifications will bolster the guidance by addressing with more specifics – and through practical examples – important issues that should be taken into account when conducting remote clinical trial visits and activities.

c.  Digital Health Technologies (pg. 5)
This section pertains to the utilization of digital health technologies (DHTs) for remote data acquisition in clinical trials. It is recommended that sponsors ensure DHTs are accessible and suitable for all trial participants. In addition, when participants are allowed to use their personal DHTs, sponsors should offer sponsor provided DHTs as an alternative to avoid exclusion based on affordability, especially for individuals from lower socioeconomic backgrounds. The section also references several FDA guidances published by the FDA related to DHTs.

• SACHRP acknowledges that this section addresses several important considerations regarding DHT accessibility but suggests the addition of a dedicated section that specifically covers issues such as privacy, confidentiality, security, data breaches, third-party use of personal data, terms of service, and potential harm (both physical and non-physical). This new section should provide minimum standards that must be implemented to mitigate these risks which should be noted in the protocol and the proper monitoring of the investigation, the data management plan, and software programs.  It is also recommended to include a reminder that additional language in the consent form might be necessary to inform participants about these risks. Additionally, this section should remind Sponsors, Investigators, and IRBs of their shared responsibility to consider these risks including any specific requirements that should be in place to ensure the protection of participants in addition to the risk considerations referenced in the FDA draft guidance “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” (December 2021).

d.  Roles and Responsibilities (pg. 6)
The draft guidance summarizes the sponsor and investigator responsibilities in DCTs, including ensuring proper planning, implementation, monitoring, compliance, and oversight to maintain the quality and integrity of the trial.  The guidance emphasizes that responsibilities for DCTs are the same as for traditional trials. The guidance highlights the importance of describing in the trial protocol how the DCT’s operational aspects will be implemented and ensuring proper monitoring of the trial and compliance with applicable laws, regulations, and licensing requirements. Responsibilities also include oversight of trial-related activities and proper delegation and oversight. The guidance also distinguishes between trial personnel and local healthcare providers (HCPs) contracted to provide services as part of routine clinical practice and the need for quality control measures to reduce variability in procedures performed by local HCPs, such as regular review of participant data entered by them.

• SACHRP offers the following comments and recommendations regarding this section:

• Clarification of "regular review" in lines 291-299 of the draft guidance: It is recommended to provide clarity regarding the term "regular review" concerning participant data entered by local HCPs in DCTs. This can be achieved by referencing existing guidance or providing further clarification regarding the frequency and specific activities involved. SACHRP emphasizes the importance of regular reviews, even for seemingly simple procedures like glucose monitoring, to ensure high-quality data and facilitate accurate interpretation and comparison of results. These reviews should be conducted frequently enough to detect and rectify errors resulting from staff turnover or variations in practices. Furthermore, comprehensive staff training should be prioritized to maintain consistency throughout the trial process.

• Duty to Ensure Adequate Training: It is important to emphasize the responsibility to ensure that staff are adequately trained to perform delegated tasks for trial-related activities.

• Third-party oversight: Regardless of whether the Sponsor or Investigator employs a third-party for study-related activities, that the Investigator retains responsibility for the conduct of the research.

• Sponsor Duty to Monitor: In the event the Sponsor retains the services of a third-party, that the Sponsor has a duty to appropriately monitor and provide performance metrics in real time to the Investigator.

• Sponsor Contract with Third-Party: The Investigator should have primary or equal access to the key performance terms outlined in the contract between the Sponsor and third-party related to the trial-related activities that will be performed by the third-party.

• Third-party performance: In the event that a third party’s performance of study-related tasks is not adequate and cannot be made satisfactory, the responsibility of the Investigator and Sponsor to document the observed deficiencies and to notify each other.

• Inclusion/exclusion criteria for trial locations: The protocol should include inclusion/exclusion criteria regarding the appropriateness of the home or another preferred location for conducting trial activities. In addition, there may be a need to conduct individualized assessments when screening an individual for eligibility and/or determining the suitability of a participant’s home during the life of the study and/or any reasonable accommodations that may be required to support inclusive participation.

• Research Participant Support: Consider and make reasonable accommodations to support research subjects in their opportunity to participate in DCTs. This includes, but is not limited to, providing resources or additional means of support, to be more inclusive for geographically difficult to reach subjects or those who have less access to clinical trials (including DCTs). For example, if a prospective participant lacks home Internet, but it is needed for participation, make clear that additional support may be provided. The study is not required to provide the same support for everyone, in this case, home Internet.

• Addition of a separate section on Third Party Selection and Oversight: This section should at a minimum address the need for sponsors and investigators to conduct due diligence before selecting a third-party for trial-related tasks. It should also include examples of minimum standards and best practices for assessing and selecting third parties, as well as ongoing management of vendor activities. Furthermore, roles and responsibilities delegated to a third-party should be documented in writing, including expectations, deliverables, and responsibilities both to the trial personnel and participants.  Finally, key performance terms outlined in contracts should be shared by the sponsor and investigator and available to the IRB.

• Separate section on Sponsor-Investigator Responsibilities: This section should serve as a reminder that, as per FDA regulations, an individual who initiates and conducts a clinical investigation assumes the responsibilities of both the Sponsor and Investigator. This acknowledges that Industry sponsors may have more experience with DCTs than Sponsor-Investigators and highlights the need for them to be reminded of the considerations that pertain to both the Sponsor and Investigator when implementing DCTs (e.g., issues related to provider practices across state lines, differences in prescribing laws, and shipping of investigational products, etc.).

By incorporating these recommendations, SACHRP believes the guidance will be enhanced by providing additional clarity regarding roles and responsibilities.

e.  Informed Consent and Institutional Review Board Oversight (pg. 10)  
The section on informed consent and Institutional Review Board (IRB) Oversight provides essential recommendations for DCT trials. These recommendations emphasize the importance of IRB oversight in ensuring the adequacy and appropriateness of the informed consent process. This includes ensuring that research participants are provided with contact information for inquiries related to the research, details about their rights as research subjects, and guidance in case of research-related injuries. Additionally, the section suggests including language in the consent form that specifies who will have access to a participant's personal health information obtained during the trial.

• SACHRP recommends augmenting the guidance related to IRB review and oversight of DCT trials with a statement that the FDA's regulatory requirements concerning IRB approvability for DCT trials, in accordance with 21 CFR 56.111, are the same as those for traditional site-based clinical trials. Alongside the FDA regulations, compliance with other relevant laws, regulations, and local requirements is essential, as these may vary across U.S. states, territories, and countries. In line with these requirements, IRBs should consider various issues pertinent to DCTs, including but not limited to:

• Trial Participant and Non-Subject Safety and other physical safety concerns: This involves considerations for delivering investigational products or interventions remotely, self-administration of products, providing comprehensive safety-related information to participants, offering timely online assistance, ensuring safe collection and storage of specimens by non-specialized personnel, and providing information and support to participants regarding specimen and data collection.

• Privacy, Confidentiality, and Security: IRBs should assess where trial-related procedures will take place and how privacy will be protected, especially in instances where trial activities may occur in a participant's home with others present. The DCT plan should adequately address data security issues associated with digital devices, such as wearables and apps, including measures to handle data breaches or technical failures affecting data security. The plan should also address measures to protect privacy and minimize the intrusiveness of data collection and communication activities.

• Informed Consent: IRBs should consider various aspects related to the electronic consent process, including identity verification of electronic consent when not witnessed by the person obtaining informed consent, ensuring voluntary participation, acceptance of electronic consents and signatures in the trial's jurisdiction, and the comprehensibility and comprehensiveness of the information provided to potential participants through informed consent. Moreover, the consent process should inform participants about where trial procedures will take place, including whether they will take place at their home or another location.

• Participant Support: This involves assessing the level of engagement required from research participants, evaluating direct and indirect costs of participation, and determining whether support will be provided for these costs.  To foster a more inclusive clinical trial, we recommend that IRBs be encouraged to evaluate whether it may be appropriate to allow additional compensation, tools, or financial support to allow individuals to participate in a clinical trial who may otherwise not be able to.

• Trial Monitoring: The DCT plan should include adequate provisions for monitoring the trial, including the monitoring of adverse events and access to medical care in the event of an adverse event.

• Special Populations:  When applicable, the DCT plan should include a specific section that addresses unique considerations for special populations such as children, prisoners, and other populations.  While existing regulatory requirements and agency guidance already exists, it would be a useful reminder to call out some of the special considerations in this guidance for special populations.

• Sponsor-Investigators: These types of trials warrant specific attention from the IRB (and other institutional oversight bodies) due to their tendency to involve higher risks as compared to industry-sponsored/industry-authored trials, where sponsors may possess greater familiarity with DCTs.

This section also recommends the use of a central IRB for efficient evaluation of the protocol, informed consent documents, and other trial-related information in DCTs.

• SACHRP recommends removing this language from the FDA guidance as this is already addressed in FDA regulations and guidance.   

f.  Investigational Products in a DCT (pg. 11)
The FDA's Draft Guidance provides recommendations for the administration of investigational products and devices in DCTs. The guidance emphasizes the importance of considering the nature of the investigational product or device when determining whether administration outside of a clinical trial site is appropriate. Factors such as complex administration procedures, high-risk safety profiles, or early stages of development may require in-person supervision by the investigator. Meanwhile, well-characterized investigational products or devices with established safety profiles and no specialized monitoring may be administered remotely by local healthcare professionals or trial personnel. The urgency, complexity of care, and participant's underlying condition should be taken into account. Drugs with long shelf lives and good stability profiles can be shipped directly to participants' homes, while those requiring specialized handling and storage conditions may not be suitable for shipment. For investigational devices, over-the-counter devices with minimal risks may be used by participants without direct oversight, while devices intended for professional use or posing significant risks should be administered under the supervision of qualified trial personnel.

• SACHRP believes that this section adequately addresses many of the key considerations regarding the administration of investigational products and devices in DCTs but suggests providing specific reminders and references to existing guidance for Sponsor-Investigator DCTs, where appropriate.

g. Packaging and Shipping of Investigational Products (pg. 12)
The draft guidance provides recommendations for the packaging, shipping, and storage of investigational products to trial participants. The guidance indicates that the protocol should outline measures to maintain the physical integrity and stability of the investigational product during shipment, including appropriate packaging materials and methods such as temperature control. DCT personnel should receive training on handling, packaging, shipping, and tracking investigational products. A central distribution service can be utilized, with the investigator or delegated trial personnel responsible for controlling the release of the investigational product, monitoring its receipt and use by participants, and ensuring the return or disposal of any unused product. The protocol should also specify procedures for tracking investigational product distribution, documenting the receipt of investigational products by participants, and outlining the process for returning or disposing of unused investigational products. Finally, this section reminds Sponsors and Investigators to comply with applicable laws, regulations, and other requirements that pertain to shipping investigational products in their respective jurisdictions.

• SACHRP believes that this section adequately addresses many of the key considerations regarding packaging and shipping of Investigational Products, but suggests including specific reminders and references to existing guidance for Sponsor-Investigator DCTs to comply with applicable state, federal, and local laws and to seek the assistance of a service with adequate knowledge of the applicable requirements regarding the packing and shipping of investigational products.

h. Safety Monitoring Plan (pg. 13)
The section regarding safety monitoring emphasizes the importance of implementing a safety monitoring plan to ensure the protection of participants in DCTS. The plan should consider the decentralized nature of the trial and ensure that adverse events are effectively captured and addressed. It should specify the scheduling of telehealth or in-person visits to collect safety data, as well as outline participants' expected response to and reporting of adverse events. Trial participants should have access to trial personnel for reporting adverse events and seeking medical assistance when needed. The plan should also describe the collection and monitoring of data through a DHT (if used in the study), and provide instructions on how to respond to abnormal findings or electronic alerts. In case of significant safety risks associated with remote administration or use of an investigational product, sponsors must discontinue remote procedures, notify relevant parties, and evaluate whether a trial may continue.  Routine safety monitoring involving laboratory testing and imaging may be conducted at local facilities, with investigators promptly reviewing the reports received.

• SACHRP believes that this section adequately addresses many of the key considerations regarding safety monitoring, but recommends adding a specific reminder that the collection of data and study monitoring should occur in real time so that safety risks can be promptly addressed to ensure participant safety.  This is a useful reminder for all stakeholders especially for those conducting Sponsor-Investigator DCTs. SACHRP also recommends placing emphasis in this section that the same standards generally apply to all trials, regardless of whether they are traditional trials or DCTs. For example, in both types of trials, an assessment of the procedures conducted and the environment in which they take place is important for understanding the risks and benefits for participants and determining the feasibility of risk mitigation. This same analysis applies to DCTs as well. In the section (lines 467 – 470 of the draft FDA guidance), SACHRP recommends adding guidance regarding what to do when there are abnormal findings that fall outside the scope of the research while maintaining privacy and confidentiality of participant information.

i. Software Used in Conducting DCTs (pg. 14)
The FDA draft guidance acknowledges the use of various platforms in DCTs and emphasizes training for all stakeholders involved. It focuses on the importance of data reliability, security, and privacy in software programs used for trial records, and distinguishes real-time video interactions as live exchanges, while noting the need for documentation if captured electronically. This section also provides guidance related to the applicability of 21 CFR part 11 and a reminder that local laws governing telehealth may be applicable. 

• SACHRP acknowledges that this section adequately addresses many important considerations regarding using software in DCTs but recommends adding additional guidance and examples regarding when 21 CFR part 11 applies and when it does not. In addition, SACHRP suggests providing clarification on whether there is flexibility or enforcement discretion concerning the use of electronic signatures and compliance with 21 CFR part 11, particularly due to the potential negative impact on inclusion. For instance, there appears to be no practical difference between obtaining a signature witnessed by a study coordinator in person and obtaining consent through an electronic signature witnessed by a study coordinator via video conference. In such cases, a 21 CFR part 11 signature should not be required. In contrast, situations involving an unwitnessed consent process or a subject enrolling and electronically signing asynchronously from the rest of the consent process would necessitate compliance with 21 CFR part 11.

4.   Glossary (pg. 16)

• SACHRP recommends including all important acronyms in the guidance and defining each acronym before using them in the body of the document. For example, please include the definition of “Sponsor-Investigator,” “IND,” and “IDE” in the glossary and ensure that both are defined in the body of the guidance.

5.   SACHRP’s General Comments regarding the Draft Guidance 

• SACHRP recommends the following additions:
• Including some of the flexibilities outlined in previous agency guidance related to the COVID-19 Public Health Emergency for all types of studies including traditional trials (e.g., flexibilities regarding informed consent, the need for amendments and approval by the IRB for certain types of changes, alternative methods for conducting safety assessments, etc.).
• Developing specific guidance for special populations such as children, prisoners, and others in order to address unique considerations when conducting DCTs that may apply for these groups.
• Developing a special guidance or toolkit for Sponsor-Investigators and IRBs related to DCTs.
• Including or developing a checklist as an appendix to the draft guidance of DCT-specific considerations that should be considered as part of a DCT plan and included in a protocol and consent form.
• Working with SACHRP and/or community stakeholders to develop a DCT protocol and consent form template with key DCT considerations included.
• Working with SACHRP and/or community stakeholders to provide further guidance for how to navigate the many different jurisdictional requirements that may apply to DCTs.

Conclusion

SACHRP is pleased that FDA is considering publishing guidance for Industry, Investigators, and other stakeholders related to the planning, implementation, and monitoring of DCTs.  The draft guidance demonstrates the FDA’s commitment to “enabling remote participation, enhance[ing] convenience for research participants, reduc[ing] the burden on caregivers, and facilitate[ing] research on rare diseases and diseases affecting populations with limited mobility or access to traditional trial sites” thus possibly “improv[ing] trial participant engagement, recruitment, enrollment, and retention of a meaningfully diverse clinical population.” If published, the guidance will  further “build[] on agency recommendations issued in 2020, which 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” (https://www.fda.gov/news-events/press-announcements/fda-takes-additional-steps-advance-decentralized-clinical-trials). SACHRP’s recommendations expand upon these guidelines, offering additional clarity regarding specific DCT topics. Thank you for the opportunity to comment.

 

---

Endnotes

¹  Food and Drug Administration, Regulations: Good Clinical Practice and Clinical Trials | FDA. See also, FDA Guidance Document - E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) | FDA (March 2018) and E6(R3) GOOD CLINICAL PRACTICE (GCP) | FDA (June 2023).