In September 2024, the U.S. Food and Drug Administration (FDA) issued three guidance documents to support different clinical trial approaches, including trials that implement decentralized elements, trials that allow integration of research into routine clinical practice, and multiregional oncology clinical trials. These guidances may assist sponsors and investigators design and conduct efficient clinical trials to support medical product development.
The “Conducting Clinical Trials With Decentralized Elements” final guidance provides recommendations for implementing decentralized elements in decentralized clinical trials (DCTs) for drugs, biological products, and devices.1 Decentralized elements allow some or all trial-related activities to occur at locations other than traditional clinical trial sites.2 They include the use of digital health technologies (DHTs) to collect data from participants remotely or conducting follow-up assessments using telehealth or in-home visits with local trial-personnel or local health care providers (HCPs).3
The “Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice” draft guidance provides recommendations on integrating randomized controlled trials into clinical practice settings for data collection.4 The guidance applies to point-of-care trials involving approved drugs or unapproved drugs that have a sufficiently characterized safety profile and can be administered and managed in routine clinical practice settings.5
The “Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs” draft guidance provides recommendations on conducting multiregional clinical trials (MRCTs) in support of marketing applications for drugs and biological products intended to treat cancer.6 The recommendations are intended to help sponsors improve the planning, design, conduct, and analysis of oncology MRCTs to generate data that can be generalized to the U.S. population or medical practice.7
The key considerations discussed in each guidance are briefly summarized below.
I. Conducting Clinical Trials with Decentralized Elements
DCTs, by their decentralized nature, can present unique challenges in feasibility, design, implementation, and analysis.8 Accordingly, the FDA offers general recommendations on implementing decentralized elements in DCTs, including:
Remote clinical trial visits and clinical trial-related activities. Sponsors or investigators should consider: i) the appropriateness of telehealth over in-person visits; ii) protections for participant privacy; iii) the use of trial personnel or local HCPs in conducting in-person visits and trial-related activities; iv) the procedure for evaluating and managing adverse events identified remotely; and v) compliance with relevant state and foreign laws governing telehealth.9
Digital health technologies. Sponsors or investigators should consult relevant agency resources on the considerations and issues regarding the use of DHTs in clinical trials, such as the “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” guidance.10 They should also ensure that DHTs are available and suitable for use by all trial participants.11
Safety monitoring. Sponsors should develop a safety monitoring plan that ensures that adverse events and medication errors are reported and adequately addressed.12
The guidance also includes the FDA’s recommendations on: i) DCT design and conduct;13 ii) roles and responsibilities of sponsors and investigators;14 iii) FDA oversight (inspectors and remote regulatory assessments);15 iv) informed consent and institutional review board oversight;16 v) investigational products in a DCT;17 vi) packaging and shipping of investigational products;18 and vii) electronic systems for managing DCTs.19
II. Integrating Randomized Controlled Trials for Drug and Biological Products into Routine Clinical Practice
Integrated RCTs may leverage local HCPs (either directly or through clinical investigators or health care institutions) to perform trial-related activities during routine clinical practice visits.20 Local HCPs may, for example, conduct a routine physical examination, order a chest radiograph, order a blood test at protocol-specified intervals, or collect protocol-required information (e.g., medical histories or outcomes).21 When moving clinical trials to clinical practice settings, the FDA recommends that sponsors consider:
The role of sponsors, health care institutions, clinical investigators, and local HCPs. Sponsors should, among other things: i) execute agreements that set forth the responsibilities and trial-related tasks performed by the health care institutions and local HCPs; and ii) ensure that the health care institutions and local HCPs are appropriately credentialed and qualified to participate in the research.22
Using a quality by design approach. Sponsors should use quality by design (QbD) principles to help achieve the scientific objectives of the RCTs and ensure adherence to FDA requirements (e.g., good clinical practices).23 Important components of a QbD approach include: i) identifying the trial population; ii) obtaining informed consent; iii) choosing suitable investigational drugs; iv) randomization and blinding; v) comorbidities and concomitant medications; vi) study endpoints; vii) adverse events; viii) data privacy and security; and ix) FDA inspections.24
The FDA notes that some RCTs may not be appropriate for integration into clinical practice settings, such as those that require local HCPs to have trial-specific training or knowledge to perform trial-related tasks and those that may interfere with the delivery or administration of patient care.25 If local HCPs cannot perform all the trial-related activities, the FDA leaves open the possibility for sponsors to adopt a hybrid approach that “combin[es] data contributed by local HCPs with study-specific procedures performed by trial personnel.”26 The FDA is accepting comments to this draft guidance until December 17, 2024.27
III. Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs
When the FDA evaluates oncology MRCTs, it is principally concerned with whether the results are applicable to the intended use population in the U.S. and to the U.S. standard of oncological care.28 The FDA advises sponsors to carefully consider whether a clinical development plan (CDP) using a multiregional approach is appropriate by taking into account, at minimum: i) patient-related factors; ii) disease-related factors (e.g., prevalence of disease subtypes, the frequency and distribution of certain molecular drives of oncogenesis); iii) healthcare system factors that can impact prior treatments received and available treatments following the clinical investigation; and iv) socio-cultural factors.29 If so, then the FDA flags the following issues for sponsors to consider when planning a multiregional CDP:
U.S. population representativeness in the MRCT;30
considerations for U.S. and foreign site selection;31
disease, available treatment, and medical product considerations;32
considerations for analysis of data from MRCTs;33 and
early consultation with the FDA and other regulatory authorities.34
The FDA notes the above list of issues is not exhaustive.35 The FDA is accepting comments to this draft guidance until November 18, 2024.36
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[1] 89 Fed. Reg. 76481, 76481 (Sept. 18, 2024); U.S. Food and Drug Admin., Conducting Clinical Trials With Decentralized Elements: Guidance for Industry, Investigators and Other Interested Parties (Sept. 2024), https://www.fda.gov/media/167696/download (“DCT Guidance”).
[2] DCT Guidance, at 1 and 3.
[3] Id. at 3–4.
[4] 89 Fed. Reg. 76482, 76482 (Sept. 18, 2024); U.S. Food and Drug Admin., Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice: Draft Guidance for Industry (Sept. 2024), https://www.fda.gov/media/181871/download (“Integrating RCT Draft Guidance”). The Integrating RCT Draft Guidance is part of a series of guidance documents under the FDA’s Real-World Evidence Program. See U.S. Food and Drug Admin., Real-World Evidence, https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence (updated Sept. 19, 2024).
[5] Integrating RCT Draft Guidance, at 2–3.
[6] 89 Fed. Reg. 76120, 76120 (Sept. 17, 2024); U.S. Food and Drug Admin., Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs: Draft Guidance for Industry (Sept. 2024), https://www.fda.gov/media/181824/download (“Oncology CDP Draft Guidance”).
[7] Oncology CDP Draft Guidance, at 3.
[8] DCT Guidance, at 1–3.
[9] Id. at 4–5.
[10] Id. at 5–6; see U.S. Food and Drug Admin., Digital Health Technologies for Remote Data Acquisition in Clinical Investigations: Guidance for Industry, Investigators, and Other Stakeholders (Dec. 2023), https://www.fda.gov/media/155022/download; see also U.S. Food and Drug Admin., Guidances with Digital Health Content, https://www.fda.gov/medical-devices/digital-health-center-excellence/guidances-digital-health-content (updated Aug. 21, 2024); U.S. Food and Drug Admin., Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers (Mar. 2023) (revised draft), https://www.fda.gov/media/166215/download.
[11] DCT Guidance, at 6.
[12] Id. at 15–16.
[13] Id. at 3–4.
[14] Id. at 6–11.
[15] Id. at 11–12.
[16] Id. at 12–13.
[17] Id. at 13–14.
[18] Id. at 14–15.
[19] Id. at 16–17.
[20] Integrating RCT Draft Guidance, at 2.
[21] Id.
[22] Id. at 4.
[23] Id. at 3.
[24] Id. at 7–13.
[25] Id. at 2 and 6.
[26] Id. at 7.
[27] 89 Fed. Reg. at 76482.
[28] Oncology CDP Draft Guidance, at 2.
[29] Id. at 3–4.
[30] Id. at 4–6.
[31] Id. at 6–7.
[32] Id. at 7–8.
[33] Id. at 8–9.
[34] Id. at 9.
[35] Id. at 4.
