Three Of A Kind: FDA Guidance Documents Provide Recommendations On Non-Traditional Clinical Trial Designs

On September 16-17, 2024, FDA issued three guidance documents (one final and two drafts) as part of the Agency's ongoing efforts to modernize its policies for the conduct of clinical trials. These policies address key aspects of the rapidly evolving clinical trial landscape, including the expanding use of decentralized clinical trials ("DCTs"), the growing potential of clinical trials integrated into routine clinical practice to capitalize on the value of real-world data ("RWD"), and design considerations for multiregional clinical trials ("MRCTs") for oncology drugs. The new guidances include:

• A final guidance on "Conducting Clinical Trials With Decentralized Elements" (the "DCT Final Guidance");
• A draft guidance on "Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice" (the "Routine Clinical Practice Trials Draft Guidance"); and
• A draft guidance on "Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs" (the "Oncology MRCT Draft Guidance").

This Alert summarizes key takeaways for clinical trial sponsors, contract research organizations, and the investigators, health care institutions, and providers that perform trial-related activities.

DCT Final Guidance

On September 17, 2024, FDA issued the DCT Final Guidance describing FDA's recommendations for DCTs, which are trials that include at least some decentralized elements where trial-related activities occur at locations other than traditional clinical trial sites. The final guidance is substantially similar to the draft version issued in May 2023, as summarized in a prior Ropes & Gray Alert. Although FDA received more than 90 comments from industry on the draft guidance, FDA incorporated relatively few substantive changes in the final guidance. The most notable changes in the final guidance include:

• No Task Log for "Local HCP" Activities: Under both the draft and final versions of the DCT Guidance, when local HCPs perform activities that (i) do not differ from those they are qualified to perform in clinical practice, and (ii) do not require a detailed knowledge of the protocol, investigator's brochure, or the investigational product, they are not considered trial personnel or sub-investigators for the trial. The draft guidance had recommended that the principal investigator include these local HCPs on a study "task log" that would be available for FDA inspection. FDA has removed this recommendation from the DCT Final Guidance, stating expressly that, "[i]nvestigators do not need to maintain a log of local HCPs performing trial-related activities." Nevertheless, FDA states that investigators should ensure that reports from local HCPs include the name of the local HCP and the date when activities were performed.
• Ensuring Qualifications of Local HCPs: The DCT Final Guidance clarifies that sponsors are responsible for ensuring the qualifications of local HCP networks contracted to perform services in a trial. FDA also recommends that sponsors keep record of these networks and other contracted service providers, including their roles and assigned activities.
• Clarifying Expectations for Investigator Oversight of Local HCPs: Following the issuance of the draft guidance, FDA received numerous comments and questions regarding the Agency's expectations for investigator oversight of activities delegated to local HCPs. In the DCT Final Guidance, FDA states that investigators are responsible for adequately supervising local HCPs and others to whom they have delegated trial-related activities. FDA explains that investigators should review data from local HCPs and follow up on any data that are missing, concerning, or appear to be in error, and should otherwise ensure that activities by local HCPs are conducted in compliance with study documents and applicable FDA regulations.
• Additional Examples of Data Variability Risks and Mitigation Efforts: Both the draft and final versions of the DCT Guidance acknowledge the increased potential for data variability and bias in DCTs as compared to traditional site-based trials. The DCT Final Guidance provides additional examples of potential data variability risks (e.g., acknowledging that allowing participants to choose whether an assessment may take place at a traditional trial site or remotely may result in bias). The DCT Final Guidance also provides recommendations and considerations for ways to minimize such risks, including, for example, by implementing training or video supervision to minimize potential data variability for tests to be performed independently by participants at home (e.g., home spirometry tests), and by specifying in the protocol where each type of visit should take place.
• Clarification on Identification of a Physical Location for Regulatory Inspections: Both the draft and final versions of the DCT Guidance emphasize the need for a physical location where FDA investigators can inspect trial records and perform interviews with trial personnel. The draft guidance had stated that this physical location is generally listed on the Form FDA 1572 for investigational new drug ("IND") applications or on the investigational device exemption ("IDE") application. The DCT Final Guidance provides more flexibility, noting that while this will generally be the case, "other physical locations may be identified for inspection purposes." FDA does not, however, provide clarity as to where or how such locations ought to be identified to FDA.

Routine Clinical Practice Trials Draft Guidance

On September 17, 2024, FDA issued the Routine Clinical Practice Trials Draft Guidance as part of FDA's ongoing efforts to promote the value and use of RWD and real world evidence ("RWE") in drug development to support regulatory decision-making. This guidance is intended to support the conduct of clinical trials with streamlined protocols and procedures that focus on essential data collection, which allows integration into routine clinical practice. These so-called "point of care trials" or "large simple trials" may improve convenience and accessibility for trial participants and allow for enrollment of more representative study populations. Nevertheless, the guidance makes clear that these types of trials remain subject to FDA's informed consent regulations and require institutional review board oversight. Key aspects of the draft guidance include:

• Appropriate Drugs for Trials in Routine Clinical Practice: FDA explains that its recommendations for trials in routine clinical practice can be applied to both studies of FDA-approved drugs (e.g., studies involving new indications, populations, routes of administration, or doses), as well as studies of unapproved drugs when the safety profile is sufficiently characterized and the drug is appropriate to be administered and managed in the setting of routine clinical practice. The draft guidance does not address non-interventional (i.e., observational) studies.
• Sponsor Engagements with Health Care Institutions: While FDA acknowledges that electronic health record ("EHR") systems may facilitate the involvement of health maintenance organizations, clinical networks of local HCPs, and hospital and health systems in clinical trials, sponsors remain responsible for ensuring that such parties are appropriately qualified to participate, and for ensuring ongoing compliance with the study protocol and FDA requirements. FDA recommends that agreements between sponsors and health care institutions document the responsibilities that are assumed by the institutions and their employees and the tasks they will perform. As appropriate, sponsors should also consider obtaining agreements from local HCPs to perform these protocol-related tasks either directly or through the health care institutions in which they work.
• Activities Appropriate for Trial Personnel Versus Local HCPs: Like the DCT Final Guidance, the Routine Clinical Practice Trials Draft Guidance distinguishes between activities that may be undertaken by local HCPs and activities that "contribute directly and significantly to trial data and require study-specific training or detailed knowledge of the protocol" which must be performed by investigators, sub-investigators, or other trial personnel. Examples of trial-specific activities that may be appropriately delegated to local HCPs include referring potential participants to trial personnel for a determination of trial eligibility, collecting routine clinical data for the trial (e.g., vital signs), or performing routine medical procedures at times specified in the protocol. Examples of activities that should be conducted by trial personnel include determining whether a potential participant satisfies enrollment criteria, conducting specialized, trial-specific, non-routine assessments, and assessing whether a trial-related adverse event is attributable to the investigational product.
• Investigator Supervision of Local HCPs: FDA emphasizes that investigators must provide adequate supervision of trial-related activities, including through review of trial-related records provided by local HCPs to ensure accuracy and completeness.
• Use of a Quality by Design ("QbD") Approach: To ensure the quality, integrity, and accuracy of trial data, FDA recommends that sponsors design routine clinical practice trials using QbD principles. A QbD approach is one that focuses during the trial design process on identifying factors that are key to ensuring study quality, prospectively determining the risks that threaten the integrity of those factors, and, as necessary, incorporating design elements to mitigate these risks. The draft guidance discusses various key elements of the QbD approach and how they should be considered in the context of routine clinical practice trials. FDA recommends that sponsors build appropriate flexibility into routine clinical practice trial protocols to accommodate, among other things, variation in the performance of clinical care, as well as the potential need for supplemental data collection. A sponsor's risk-based monitoring of trial activities should address the critical-to-quality factors identified.

Oncology MRCT Draft Guidance

The Oncology MRCT Draft Guidance issued on September 16, 2024 provides detailed recommendations for the planning, design, conduct, and analysis of oncology MRCTs. FDA defines an MRCT as a "trial that is conducted in more than one region under a single protocol," with "region" defined as a geographical region, country, or regulatory region. The draft guidance is FDA's most recent effort to provide insights into how sponsors should approach the design and execution of MRCTs, and follows the Agency's issuance of guidance providing general principles for planning and design of MRCTs.

While FDA has acknowledged the potential value of MRCTs, the Agency has expressed concern about the decreasing proportion of U.S. participants included in oncology MRCTs and the risk that the distribution of demographic or clinical characteristics of those enrolled in these trials may differ significantly from the U.S. population. These issues call into question the generalizability and applicability of oncology MRCT results to the U.S population or U.S. medical practice, and these concerns have featured heavily in FDA's reviews of several recent oncology product applications that relied substantially on clinical trial data generated outside the U.S.

Given these concerns, FDA acknowledges that MRCTs may not be appropriate in all contexts, and recommends that sponsors carefully consider various factors in assessing the suitability of an MRCT, including (i) patient-related factors (e.g., exposure to disease risk factors, genetic ancestral background); (ii) disease-related factors (e.g., prevalence of disease subtypes, the frequency and distribution of certain molecular drivers of oncogenesis in the population); (iii) health care system factors (e.g., access to health care, including specialized oncology care, cancer screening practices) which can impact prior treatments received and available treatments following the investigation; and (iv) socio-cultural factors (e.g., diets, cultural beliefs regarding use of "alternative" therapies to treat cancer). FDA recommends that sponsors designing oncology MRCTs carefully consider:

• U.S. Population Representativeness: To the extent possible, sponsors should enroll a sufficient number of U.S. participants that reflect the diversity of the intended regions in the trial. FDA also recommends that sponsors take a strategic allocation approach that is based on both the prevalence of cancer in the U.S., and in other major geographical regions instead of in singular countries. As a practical matter, this means that, while an equal allocation of subjects in each region may be appropriate for trials for drugs treating cancers common in the U.S., a proportional allocation (i.e., allocating subjects proportionate to the size of the region and level of disease prevalence) may be more appropriate for trials for drugs intended to treat cancers that are less common in the U.S. compared to other regions outside the U.S.
• Standard of Care Considerations: The Oncology MRCT Draft Guidance states that, whenever possible, the control arm should reflect standard of care in the U.S. to ensure that the trial results are applicable to the U.S. population. Even where the standard of care in foreign sites may not align with the U.S., FDA recommends that sponsors consider including a pre-specified physician's choice of treatment that includes the U.S. standard of care in the control arm to ensure that the proportion of participants receiving the U.S standard of care in the control arm is sufficiently large to permit a robust evaluation of safety and efficacy compared to the U.S. standard of care.
• Considerations for Analyses of Data from MRCTs: Sponsors should create an analysis plan that includes an estimation of regional treatment effects and the reasoning behind the estimates, as well as a description and justification of the regional treatment strategies used.
• Early Consultation with FDA and Other Regulatory Authorities: To maximize efficiency, FDA recommends that MRCT sponsors should consult with FDA and other regulatory authorities early in the clinical development process and any time the sponsor identifies imminent changes in the treatment landscape.

Key Takeaways

These three guidance documents reflect continued efforts by FDA to modernize clinical trial policies, including by promoting flexibility in clinical trial design and capitalizing on the technological advances and efficiencies of the modern health care landscape. They also represent a practical step forward in FDA's longstanding effort to increase clinical trial diversity by promoting more accessible, convenient, and efficient studies. (See this prior Ropes & Gray Alert for a detailed discussion of other recent FDA efforts to increase clinical trial diversity.) Finally, the guidance documents evidence FDA's continued commitment to the value of RWE by aiding in the creation of streamlined protocols and procedures that focus on data collection, and ultimately, the integration of research into routine clinical practice.

However, FDA acknowledges that these non-traditional clinical trial designs can present novel challenges for the Agency, sponsors, clinical investigators, and trial personnel as it relates to, among other things, clinical trial compliance, quality, accuracy, and generalizability. Given these potential issues, FDA has cautioned that non-traditional trial designs may not be appropriate for all clinical development programs and has noted that they may create additional burdens that will need to be carefully balanced.

Interested parties may submit comments on the Oncology MRCT Draft Guidance by November 18, 2024 and on the Routine Clinical Practice Trials Draft Guidance by December 17, 2024.

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