New FDA clinical trials guidances promote efficient drug development, innovative designs, diversity

Executive summary

• FDA finalized its decentralized clinical trials guidance that embraces a paradigm shift toward conducting study-related activities at locations other than traditional clinical sites, including the patient’s home, the office of another health care provider, or even a local pharmacy.

• FDA emphasizes in new clinical trial guidances the importance of diversity of study participants, including the agency’s plan to soon require “Diversity Action Plans” (DAPs) from sponsors, in order to improve the enrollment of participants from underrepresented populations.

• FDA is encouraging oncology sponsors to conduct multiregional clinical trials to support a new drug or biologic marketing application, but also expressing “paramount” concern that the results of those trials must apply to the intended use population and standard cancer care practices in the U.S.

• In the new guidance, FDA promotes the integration of real-world evidence (RWE) and data from diverse sources to support clinical development. Among other things, the guidance addresses the of electronic health records (EHRs) to flag prohibited medication use, and allocation strategies based on disease occurrence data from registries and databases.

Multiregional clinical trials in oncology

On Monday, FDA’s centers for drugs and biologics issued the draft guidance “Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs”. The guidance provides recommendations to sponsors on improving the evidence obtained from one or more multiregional clinical trials (MRCTs) intended to support a marketing application, for oncology drugs in global clinical development programs. 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.

Citing a “decreasing proportion of US participants” in cancer drug trials, FDA states that its “paramount consideration” for oncology MRCTs is whether the results apply to the intended use population and standard cancer care practices in the U.S. FDA also expressed concern that where the demographic or clinical characteristics of patients enrolled in MRCTs differ significantly from the U.S. population, the generalizability of the data to the U.S. population is limited. Announcing the guidance, FDA encouraged sponsors to pursue MRCTs, while stressing that such trials should be conducted within the “appropriate context.”

Key recommendations in the guidance pertain to the enrollment of a U.S. representative population in the MCRT. The draft guidance explains that an oncology MCRT should utilize a “strategic allocation approach” based on cancer incidence or prevalence in the U.S., “with regions defined by major geographical regions (e.g., across several continents), rather than single countries or regions. For sponsors planning a single oncology MRCT to support approval, FDA recommends sponsors conduct the trial across major geographic regions (e.g., Asia) rather than predominantly in a single country or geographical region. For common types of cancers, FDA recommends “equal allocation of study participants across the selected major geographical regions, including North America.” However, for studies in cancers that occur “much less commonly in the US compared to regions outside the US,” FDA recommends a “proportional allocation approach,” which entails allocation of subjects based on regional size and disease prevalence (emphases added). Sponsors should be mindful of potential drawbacks of this approach, which include regional differences in risk factors that may lead to a narrower indication to more accurately reflect the trial population.

FDA further advises oncology MCRT sponsors to craft a multiregional clinical development program (CDP) that considers specific factors such as:

• patient-related factors, based on exposure to disease risk factors and genetic background;

• disease-related factors, such as disease subtype prevalence and molecular drivers of oncogenesis in a patient population;

• socio-cultural factors, such as diets and cultural beliefs around alternative therapies for cancer; and

• health care system factors, such as the patients’ access to health care facilities, screenings, treatments, and whether such factors are available and affordable to the patient population.

Although this guidance does not come from FDA’s Center for Devices and Radiological Health (CDRH), we anticipate that the agency will look to this Center for further guidance when reviewing devices that treat cancer as well.

Integrating RCTs into routine clinical practice

On Tuesday, FDA’s drugs and biologics centers issued the draft guidance “Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice.” This guidance is part of FDA’s series of guidance documents under its Real-World Evidence (RWE) Program and provides recommendations on “point of care trials,” or “large similar trials,” which are similar to DCTs and aim to bring trial-related activities to more convenient locations for patients. The draft guidance outlines the following responsibilities for each party involved in integrating randomized controlled trials (RCTs) into clinical practice:

• Sponsors: FDA encourages sponsors to engage health care institutions in clinical trials integrated into clinical practice, which can facilitate participant enrollment by improving convenience and accessibility. This approach leverages the operational frameworks of health maintenance organizations (HMOs), hospital systems, clinical networks of HCPs, and national health systems, which have been pivotal in recruiting and engaging trial participants. Sponsors should establish agreements with health care institutions that document the responsibilities of the institutions and their employees, as well as the tasks they will perform in the clinical trial. To support these efforts, FDA suggests sponsors “might consider providing” additional resources to participating health care institutions, such as service providers or contract research organizations. Sponsors must also ensure that the institutions and individual local HCPs are suitably credentialed and qualified to participate in the research.

• Clinical investigators: Clinical investigators, whether affiliated with the institutions or health care systems where trials are conducted or engaged externally by sponsor, are responsible for ensuring that a trial is conducted according to the signed investigator statement, the investigational plan, and applicable regulations, as stipulated under 21 CFR part 312. They must also safeguard the rights, safety, and welfare of participants in the trial. The draft guidance cites how “procedures or processes that contribute directly and significantly to trial data” should be conducted by trial personnel, including:

• Determining whether a trial candidate satisfies the trial’s enrollment criteria.

• Conducting specialized assessments required by the protocol that are not part of routine clinical care and require trial-specific training and expertise (e.g., evaluating tumor responses using RECIST guidelines).

• Assessing whether a trial-related adverse event is attributable to the investigational product.

• Applying protocol-specified criteria for dose modification or discontinuation of investigational products.

• Determining that a trial participant has reached a trial endpoint

• Local health care providers (HCPs): FDA advises that tasks performed by local HCPs during clinical trials should align with their qualifications in routine clinical practice. The guidance offers the following examples of trial-specific activities delegated to local HCPs:

• Referring potential participants for the trial-to-trial personnel for determination of trial eligibility

• Collecting routine clinical data for the trial (e.g., vital signs) in a template provided in an electronic health record (EHR)

• Following prompts in the EHR to document specified clinical events

• Performing routine medical procedures

The RCT integration draft guidance emphasizes the importance of employing a “quality by design” (QbD) approach in the design of point of care and large-scale clinical trials. FDA defines QbD as “incorporating quality into the design of clinical trials by identifying critical-to-quality factors (i.e., those that are likely to have a meaningful impact on participant’s rights, safety and well-being and the reliability of the results), while eliminating procedures and processes that do not contribute to these primary goals.” The QbD approach requires sponsors to build appropriate flexibility into trial protocols to accommodate potential variations in the collection of data in clinical practice or the performance of clinical care. The guidance outlines the following key components of a QbD approach:

• Identifying the trial population: For trials integrated into clinical practice, FDA recommends that “eligibility criteria should be minimal and straightforward,” and avoid compromising the ability to identify the appropriate population for the trial.

• Informed consent: When incorporating RCTs into routine clinical practice, FDA suggests that informed consent documents can be embedded in EHRs for trials, akin to how consent documents are integrated into EHRs for patients undergoing surgery or other procedures.

• Choosing suitable investigational drugs: FDA recommends using an already FDA-approved drug for its intended use in a clinical trial, while acknowledging that “drugs may still need a more robust safety evaluation if there are new concerns raised by their use in a novel combination or use in a new population or indication.” The draft guidance warns that a drug or biologic “might not be suitable for integration into clinical practice” if it has:

  • a narrow therapeutic window,
  • therapeutic dose monitoring,
  • complex dosing or administration regimens,
  • special reconstitution processes, or,

  • specialized storage conditions.

• Randomization & blinding: FDA acknowledges that randomization remains the most effective method for balancing baseline prognostic factors between study groups, thereby minimizing bias and ensuring valid statistical analyses. The agency also highlights the importance of bias in minimizing post-randomization bias. However, when blinding is not feasible, FDA emphasizes identifying potential sources of bias and incorporating measures to mitigate them (e.g., blinded and/or independent central review committees or objective outcome measures).

• Comorbidities and concomitant medications: Clinical trial participants with various comorbidities and who take concomitant medications may be more representative of the intended use population of the drug if it is approved. However, managing concomitant medication use may be more challenging in routine clinical practice settings. FDA recommends using automated EHR messages to flag prohibited medications. Further, if “there is a significant concern about managing concomitant medications, then the study may not be appropriate for integration with routine practice,” FDA advises.

• Endpoints: Outcomes based on significant medical events that typically lead to acute care (e.g., strokes, fractures, and myocardial infarctions) are more readily capture in routine clinical practice records. However, some acute events may lead to hospitalization outside of the patient’s usual health care systems, thereby complicating case histories. The guidance recommends that, in order to maintain adequate and accurate case histories, investigators should access routine clinical practice medical records and maintain consistency in clinical and biomarker measurements. For trials relying on clinical outcome assessments (COAs), simple data entry methods should be utilized, and avoid COA instruments that require more complex patient assessments or extensive data collection.

• Adverse events: FDA advises that for trials relying on routine health care visits with local HCPs, incorporating additional procedures, such as real-time HER monitoring and/or periodic follow-up calls can help identify adverse events. The guidance also recommends using automated notifications to “flag abnormal laboratory results of concern and to describe adverse events that might be anticipated.”

• Data privacy & security: In trials that make use of EHRs, “data privacy and security are reliant on the use of safeguards in these systems,” FDA writes, citing its July 2018 final guidance on the “Use of Electronic Health Record Data in Clinical Investigations.”

• Inspections: The draft guidance spotlights FDA’s bioresearch monitoring program (BiMo), which we describe online here, and which aims to assess practices and procedures that could have a meaningful impact on the reliability of trial results and rights, safety, and well-being of participants. Sponsor must ensure that source records (or certified copies) supporting clinical trial data submitted to FDA are available for review upon request.

Decentralized Clinical Trials final guidance

The third guidance in FDA’s spate of clinical trials-related advice is titled “Conducting Clinical Trials with Decentralized Elements.” Issued by the agency’s centers for drugs, biologics, and devices, the guidance provides finalized recommendations for sponsors, investigators, and other parties on implementing clinical trials with decentralized elements. These elements facilitate trial-related activities to occur remotely at locations convenient for participants.

In May 2023, we hailed the issuance of the draft version of this guidance as a milestone event that could lead to major changes in how clinical research is conducted in the U.S. Traditionally, study-related procedures took place at designated clinical sites – usually research medical centers – under the immediate supervision of the principal investigator, sub-investigator, or other site-based HCP. In contrast, the emerging DCT framework, whereby study-related activities can now take place at the clinical site, a patient’s home, the office of another HCP, or even a local pharmacy, embraces a paradigm shift toward a distributed model. Indeed, the finalized guidance deviates little from the draft version, and should also offer substantial benefits to study sponsors. However, it also presents potentially significant regulatory and operational risks.

Although the draft guidance was titled "Decentralized Clinical Trials for Drugs, Biological Products, and Devices," we suspect it has been renamed to clarify that it applies broadly to clinical trials that may have decentralized elements, even if the entire trial is not decentralized. The draft guidance made a distinction between "fully decentralized clinical trials" and "hybrid decentralized clinical trials." In fully decentralized clinical trials, all activities take place at locations other than traditional trial sites. In contrast, in hybrid decentralized trials, some elements are decentralized while some activities occur at traditional clinical sites. Although the draft guidance applied to both types of trials, there may have been confusion as to whether it only applied to fully decentralized clinical trials. We do not see the name change as affecting the substance of the guidance.

Diversity in clinical trials

Each of FDA’s new guidance documents are consistent with the agency’s ongoing efforts to increase clinical trial diversity. FDA continues to underline the importance of enrolling a participant population representative of the U.S. population, in the context of the disease studied, to help ensure the generalizability of the data to the patient population. For example, although FDA acknowledges that a “thoughtfully designed” MRCT can facilitate enrollment of patients with diverse genetic ancestral backgrounds clinically relevant to the U.S. population, FDA recommends that sponsors plan to enroll a sufficient number of U.S. participants in the trial to help ensure that the generated data is applicable to the U.S. context. FDA also urges sponsors to consider how each clinical trial site may contribute to the overall demographic representativeness of the trial population.

The newly issued guidance documents’ recommendations mirror FDA’s previous statements promoting innovative clinical trial designs as a mechanism to increase clinical trial diversity. For example, FDA’s draft guidance on integrating trials into routine practice emphasizes how point of care trials and use of local HCPs may improve convenience and accessibility for participants and allow for enrollment of more representative populations, resulting in more generalizable trial results.

Indeed, FDA is planning to soon require “Diversity Action Plans” (DAPs) from trial sponsors, in order to improve the enrollment of participants from underrepresented populations in clinical studies, as we explain online here. As is a focus in FDA’s latest guidance documents, the agency had issued draft guidance in June on DAPs, focusing on age group, sex, race, and ethnicity demographic characteristics of clinically relevant study populations. When finalized, that guidance will create binding requirements on study sponsors. The DAP guidance comment period closes on September 26.

Another theme of FDA’s recent guidance has been promoting development of drugs to treat rare diseases, with FDA acknowledging that certain development programs may include a single, small pivotal study, for which participant numbers may be small. We recently summarized online here FDA’s many ongoing efforts to promote rare disease drug development.

Use of Real World Evidence

The integration of RWE and data from diverse sources to support clinical development is another topic highlighted across the recent guidance documents. This includes the use of EHRs to flag prohibited medication use and implementing allocation strategies based on disease occurrence data from registries and databases. FDA encourages sponsors to integrate these data streams into their trial frameworks to address gaps and validate findings more robustly. By doing so, trials can better reflect real-world conditions and patient experiences, ultimately leading to more applicable and generalizable results. This emphasis on data integration not only supports more informed regulatory decisions but also helps in aligning clinical research with current health care practices and patient needs.

Next steps

One key theme we observed in FDA’s latest clinical trials guidance documents is the agency’s acknowledgment that many case-specific factors will affect their evaluations of study conduct. Therefore, early engagement with FDA is recommended during study design. Sponsors should outline their trial design and conduct from the start, including access to relevant datasets, study monitoring, and record maintenance. In addition, if significant changes in the treatment landscape occur during a trial, sponsors can request an FDA meeting to determine how best to adapt the trial accordingly.

FDA has invited comments on the DAP guidance through September 26, the multiregional trials guidance through November 18, and on the trial integration guidance through December 17, 2024. If you may wish to submit a comment to any of the guidance documents, or have any questions on clinical trial diversity, decentralized elements of clinical trials or study design more generally, feel free to contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Robert Church, Melissa Bianchi, Kristin Zielinski Duggan, Heidi Gertner, Stephanie Agu, Deborah Cho, Jason Conaty, Eman Al-Hassan, and Michael Mortillo