Stakeholders want the US Food and Drug Administration (FDA) to consider the logistical and legal challenges when researchers conduct trials across different regulatory jurisdictions in its guidance on multiregional clinical trials (MRCTs) for oncology drugs. They also want more clarification on the statistical methods researchers may use, including Bayesian methods.
Friends of Cancer Research (FoCR) commented on the MRCT draft guidance and addressed several issues related to recruiting sufficient participants. The group requested additional detail on FDA’s definition of population representativeness, especially for trials of rare cancers. It said achieving a diverse and representative sample in such small populations is challenging, and clarification on statistical or qualitative thresholds for representativeness would be useful.
“Further examples of trial population distributions for distinct scenarios—such as early-phase versus late-phase trials, and studies involving common cancers versus rare cancers or rare biomarker-selected subgroups—would be insightful,” FoCR added. “For rare cancers or biomarker-defined populations, achieving US representativeness may be challenging, and additional flexibility in these scenarios would be valuable.”
FoCR also asked for clarity on the FDA’s expectations for early-phase trials across multiple regions, as conducting the trials with a smaller population may be challenging.
“Given the logistical challenges and resource constraints of early-phase trials, we suggest FDA provide scenarios or cancer types where limited geographic representation may be acceptable, particularly where initial data generation may focus on proof-of-concept,” said FoCR. “Additional insights on how to balance the need for diversity with the practical constraints of small early-phase trials would support sponsors in designing trials that facilitate diversity goals.”
Regeneron Pharmaceuticals also commented on the guidance and noted that it understands the need to enroll an adequately representative subgroup of US cancer patients in clinical studies. However, it said requiring trials to meet multiple regional regulatory requirements while enrolling a representative diverse US population may not always be feasible.
The company noted that the guidance defines MRCT as trials conducted in more than one region under a single protocol where the region is defined as a geographical region, country, or regulatory region. It said it would be helpful if FDA clarified that premarket applications based on foreign data can support US regulatory approvals if the data meets certain conditions.
“This will clarify that while the path is available, sponsors need to ensure certain conditions are met and this guidance document helps reinforce recommendations related to MRCT to meet them effectively,” said Regeneron.
The Association of Clinical Research Organizations (ACRO) also raised the need for more clarity when simultaneously submitting premarket applications to multiple regulatory agencies and addressing the different standards of care across regions. The group noted that its members have to submit clinical trial plans across regulatory regions and meet requirements that allow them to make their drugs available quickly to patients across those regions.
“When a certain medicine is included in the clinical trial protocol but is not available in a country, this may exclude the country from inclusion in a study, or require the sponsor to provide the standard of care medicine as part of the trial (which increases complexity of the trial from a number of aspects),” said ACRO. “This may also impact the potential patient population in terms of including patients who are naïve to certain treatment modalities, which may be relevant.”
Several commenters pointed to FDA’s recently published diversity action plan draft guidance and a discussion paper on increasing clinical trial diversity. They said the diversity action plan guidance and the MRCT guidance need to complement each other.
FoCR noted that it would be helpful if the MRCT guidance referred to the documents, and especially the diversity action plan guidance. The group said the documents provide important frameworks that can help sponsors plan cancer trials with diversity in mind and approaches to generate more data in the postmarket setting.
“We recommend FDA consider acknowledging these recent guidance documents to provide additional context on how MRCT recommendations align with broader diversity planning goals,” said FoCR. “Specifically, this could help clarify where flexibility might exist for obtaining supplementary data in the postmarketing phase, especially when initial trial data may have limitations in fully representing US population diversity.”
Regeneron noted that it had submitted comments on the diversity action plan draft guidance and highlighted the difficulty of hitting diversity enrollment goals in the US. It said such challenges could slow drug development, especially when prevalence in a population may be low. It also asked the FDA to consider the MRCT guidance in contrast to the diversity action plan guidance.
“It must also be noted that the primary objective of the study should be to generate evidence that is interpretable in the context of testing the study’s stated scientific hypothesis,” said Regeneron. “Other objectives … must be carefully balanced in light of generating interpretable evidence.”
“Sponsors have worldwide obligations, including both ethical and sometimes legal obligations to make drugs available in the countries in which the clinical studies are conducted,” the company added. “Sponsors are able to expedite the development of potentially lifesaving medicines for US patients by conducting MRCTs; the FDA needs to balance the various needs of patients for timely access to new medicines against overly narrow diversity requirements.”
FoCR also emphasized that FDA’s recommendation in the draft guidance that sponsors consult with multiple regulatory bodies simultaneously may be challenging because regulatory bodies have different timelines and requirements.
“FDA could consider offering a streamlined pre-submission consultation process for MRCTs involving multiple regulatory agencies,” said FoCR. “This approach could support faster, more effective trial planning and global coordination.”
“Considering FDA’s guidance aligns with global [International Council for Harmonization] ICH standards, we encourage FDA to expand upon concurrent regulatory engagement strategies for multinational MRCTs, enhancing both trial efficiency and global patient access to new therapies,” the group added.
FoCR further recommended that the MRCT guidance emphasize the role MRCTs play in enhancing data robustness and integrity and provide more flexibility in cases where disease etiology or treatment standards may differ significantly by region.
Regeneron highlighted that when subgroup size is limited, sponsors should be able to evaluate subgroup effects by pooling patients in the MRCT from countries or regions that share similarities. It said sponsors should be allowed to pre-specify and provide justification for pooling their data or using Bayesian shrinkage methods in their statistical analysis plan.
ACRO asked for more biomarker and statistical considerations for oncology studies. More specifically, it wanted more details on prespecified statistical analysis planning and consideration of Bayesian methodologies, which are increasingly being used.
The group said getting trial participants in the US has become more difficult due to the saturation of cancer trials, which should be addressed in the guidance. It said its members have reported that clinical trial sites are declining the opportunity to participate in cancer trials due to oversaturation.
“This means that sponsors and CROs need to conduct studies across different regions to ensure sufficient patient numbers,” said ACRO. “While sponsors may consider research-naïve sites in the US for oncology trials there are several concerns that make sponsors hesitant to include such sites.”
“Because of concerns about US clinical trial site capacity, ACRO would support activities to enable capacity building in the US in terms of numbers of sites, the capability of sites to conduct trials, and the capability of sites to engage patients from diverse populations,” the group added.
https://www.raps.org/news-and-articles/news-articles/2024/11/stakeholders-seek-changes-to-fda-s-oncology-multir
