FDA Highlights Concerns Over International Cancer Trials

The US Food and Drug Administration (FDA) has issued a draft guidance aimed at ensuring that international trials for oncology drug approvals apply to US patients with cancer.

The agency said in a press release on September 16 that it has been seeing decreasing proportions of US participants in what it calls multiregional clinical trials.

The overall issue, the FDA said, is that there are “known differences in the prevalence, presentation, causes, or severity of cancer” in other countries — differences that can affect the relevance of clinical trial data for US patients and US medical practice.

When companies don’t factor in those differences, the agency said it’s left considering data that “may not be appropriate to support an FDA regulatory decision.” 

“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,” said Richard Pazdur, MD, director of the 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, in the agency press release.

The agency highlighted its concerns over the relevance of trial data to US patients in February 2022 when the FDA’s Oncologic Drugs Advisory Committee (ODAC) rejected approval of the PD-1 inhibitor sintilimab (Eli Lilly and Company and Innovent Biologics) for non–small cell lung cancer.

Among other concerns, the main trial — ORIENT-11 — was conducted entirely in Innovent’s home country of China and the ODAC said the trial did not reflect the broad genetic diversity of patients in the United States. ORIENT’s control arm — chemotherapy instead of another PD-1 blocker — also fell short of the current standard of care in the United States.

ODAC asked for additional studies to prove the value of the agent in a US-based population. But more than 2.5 years later, sintilimab remains unapproved.

The FDA’s concerns also extend to trials for drugs intended to treat cancers that occur much less often in the United States than in other countries. The FDA explained that country-specific disease etiology differences can change how well drugs work in a given population, leaving the agency little clue on how to proceed for US patients.

To counter such problems, the guidance calls for multiregional clinical trials to include US patients or at least accurately reflect them in study populations and to have control arms that are in line with US practice.

The agency also wants companies to consult with the FDA early on global trial designs to make sure that study designs apply to US patients and to ensure that researchers meet US regulatory standards.

The goal is for trials to be “conducted across major geographical regions” instead of in “a single country or in a single geographical region,” the agency wrote in its draft guidance.

“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,” Pazdur said.

The draft guidance is entitled “Considerations for Generating Clinical Evidence from Oncology Multiregional Clinical Development Programs.” Interested parties have 60 days to comment and can do so online.