FDA drafts guidance on multiregional clinical trials in oncology
In a new draft guidance, the US Food and Drug Administration (FDA) provided recommendations for multiregional clinical trials (MRCTs) in oncology, encouraging sponsors to ensure the results of trials in global oncology clinical development programs that support a marketing application are interpretable to patients in the US.“This guidance expands on principles described in FDA’s existing guidance documents related to this topic, by providing additional recommendations for the planning, design, conduct, and analysis of an oncology MRCT that may facilitate FDA’s assessment of applicability of the data to the US population with the cancer being investigated and to US medical practice,” the agency said.
FDA said there has been a “decreasing proportion” of US participants in oncology MRCTs in recent years, which makes it more difficult to evaluate treatment effect consistency for participants enrolled in the US. For instance, non-US participants in an MRCT may have significantly different demographic or clinical characteristics than US-enrolled participants, and the resulting data obtained from those non-US participants “may not be appropriate to support an FDA regulatory decision.”
The agency said sponsors have also raised questions about demographic representation of US participants in MRCTs. In the draft guidance, FDA noted that the “paramount consideration” when assessing oncology MRCTs is applicability to the US population for the product’s intended use and for standard of care in oncology in the US.
“The FDA encourages sponsors to pursue multiregional clinical trials, but stresses that such trials should be conducted within the appropriate context,” Richard Pazdur, director of FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “It is important that data from multiregional clinical trials are applicable to patients in the United States who may use the drug and our current standards of oncological care. The new draft guidance, when finalized, will not only support the agency’s review of data generated from multiregional clinical trials, but also help sponsors improve the generalizability and applicability of results from these trials to the US population and to US medical practice.”
FDA said that a sponsor’s multiregional clinical development program (CDP) should consider specific patient factors such as disease risk based on exposure and genetic background, disease 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 healthcare system factors such as the patient’s access to health care facilities, screenings, treatments, and whether such factors are available and affordable to the patient population.
“Because the above referenced factors have the potential to impact the clinical outcome of an MRCT, sponsors should carefully evaluate them as part of the feasibility assessment for their CDP,” the agency said.
Concerning US representation in oncology MRCTs, FDA said sponsors need to give “careful consideration” of the trial population. “Given that differences in outcomes within subgroups of individuals enrolled across regions may only become apparent after the trial is complete and fully analyzed, sponsors planning a MRCT intended to support approval of an oncologic drug should plan to enroll a sufficient number of US participants in the trial to help ensure that the evidence generated supports a robust assessment of the safety and effectiveness of the drug in US patients with the disease and in the context of US standard of care practices and treatments,” they wrote.
Early-stage multiregional CDP studies should have a trial population that represents the intended regions of the trial to identify potential signals of differential drug effects, the agency noted, but since these effects may not be identifiable with a small trial population, “the absence of observed differences should not be considered adequate justification to limit the conduct of a trial to a single non-US country or region,” they said.
FDA said adequate regional representation should include the incidence or prevalence of the type of cancer in the US, and the agency recommended using a “strategic allocation approach” that incorporates cancer incidence and prevalence in the US and major geographical regions as opposed to individual countries. For more common cancers in the US, FDA recommended trial participants be enrolled equally among regions; if the cancer is less commonly found in the US, FDA recommended a proportional allocation approach for enrollment based on region size and disease prevalence.
“When discussing the trial design and trial population characteristics with FDA, sponsors should provide justification for the selected geographical regions and the sample size allocation distribution across the geographical region,” they explained. “Information to be included in the briefing documents to aid FDA's assessment of the sponsor's justification should include, but is not limited to, a description of differences and similarities across the proposed geographical regions with respect to patient-, disease-, and healthcare system-related factors.”
When planning site selections for oncology MRCTs, sponsors need to consider regional differences and similarities, including whether the trial sites have a track record of overall good clinical practice and experience in conducting trials for US regulatory submissions. There may also be regional differences in the standard of care for treatment, and in these cases, the agency recommended using the US-based standard of care “whenever possible,” and discuss with FDA the possibility of amending the protocol if the treatment landscape changes.
FDA said they will take specific interest in subpopulations of US-based participants in MRCT results, but the sponsor may also provide a pooling of patients with similar patient demographic, clinical characteristics, medical practice, and available prior treatment in situations where a subgroup is limited in size.
The agency recommended early consultation with FDA officials to discuss the planning of single or multi-MRCTs in oncology. “Early consultation with FDA promotes efficiency in drug development by minimizing the risk that additional studies may be required pre- or -post market, or that the data may be deemed not applicable to the US population or US medical practice, resulting in delays in providing access to innovative cancer therapies,” they said.
Draft guidance, Federal Register notice
