The US Food and Drug Administration (FDA) has released a new draft guidance on multiregional clinical trials (MRCTs) in oncology under a single protocol.
The draft guidance is intended for sponsors with global clinical programmes, including pivotal trials conducted in more than one geographical or regulatory region, for cancer drugs that support a US marketing application.
The FDA emphasised that results from such trials should be interpretable to patients in the US. If the demographic or clinical characteristics of the patients enrolled in MRCTs were statistically different from the US population, then the data “may not be appropriate” to support FDA approval.
The draft guidance addresses the issues raised by the FDA and its Oncologic Drugs Advisory Committee (ODAC) during the regulatory review of Innovent Biologics and Eli Lilly’s cancer therapy Tyvyt (sintilimab). In 2022, the FDA declined to approve Tyvyt in combination with chemotherapy for first-line treatment of advanced non-squamous non-small cell lung cancer (NSCLC), despite the therapy gaining approval in the same indication in China. In a complete response letter, the FDA recommended that an additional MRCT should be conducted to demonstrate Tyvyt’s efficacy in US patients.
Following the high-profile FDA rejection, Lilly gave up on its plans to pursue Tyvyt’s approval in the US and gave up its ex-China rights to the therapy in 2022, as per the company’s Q3 SEC filing.
In the 16 September press release, the FDA said the new draft guidance “will not only support the agency’s review of data generated from multiregional clinical trials but also help sponsors improve the generalisability and applicability of results from these trials to the US population and US medical practice”.
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By GlobalDataThe FDA also notes that a sponsor’s multiregional clinical development programme (CDP) should go beyond general demographic characteristics and consider “specific patient factors”, including disease risk due to environmental factors and genetic predisposition, and molecular drivers of the disease. The agency emphasised that effects from socio-cultural factors such as diets and alternative therapies, and differing healthcare systems should not be minimised.
The agency goes on to explain that sponsors need to give “careful consideration” to the trial population, as some outcome differences, especially those raised in subgroup analysis, only become apparent after trial completion. Thus, the FDA advises the sponsors to “enrol a sufficient number of US participants” to ensure that MRCT data can support 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”.
FDA also provided guidance for early-stage multiregional CDP studies. The agency advised that these trials should include patients that “represent the intended regions of the trial” as these can help sponsors identify potential differential effects of the drug based on demographic characteristics. However, the agency cautioned that the differential effects “may not be identifiable” in a small trial population of the early-stage study. Therefore, the sponsors should not take the “absence of observed difference” as an “adequate justification to limit the conduct of a trial to a single non-US country or region”.
The FDA advised the sponsors to take a “strategic allocation approach” to incorporate patients based on the cancer incidence and prevalence in the US and major geographical regions as opposed to individual countries. The agency added that when discussing the trial design and trial population characteristics with the FDA, sponsors should provide justification for geographical regions and the sample size across those regions.
