FDA Nixes Approvals Based Only on Foreign Data

FDA officials and their scientific advisors have come down hard on clinical development programs that rely on study results from a single foreign country, instead of from multi-regional trials following harmonized R&D standards. Even though in the past FDA has approved certain therapies based on limited foreign data, those decisions usually involved new drugs for serious diseases lacking effective treatment. Now regulatory officials seek to clarify that applications are inadequate if they present data from a single foreign study for “me-too” drugs to treat conditions that already have approved therapies.

The issue made headlines recently following a February 10, 2022 meeting of FDA’s Oncologic Drugs Advisory Committee (ODAC) that addressed the degree of generalizability and applicability of data from one country to support approval of a drug for patients in the United States. Here, the debate involved a supplemental application for the PD-1 inhibitor Tyvyt (sintilimab) sponsored by Eli Lilly and Innovent Biologics of China to treat metastatic non-small-cell lung cancer (NSCLC) based on one pivotal trial conducted in China.

FDA officials and its advisors strongly opposed approval of the drug, citing concerns that the drug’s pivotal study in China had limited applicability to the US population. The drug’s broader study design, moreover, raised objections for utilizing an outdated chemotherapy as the control arm, as opposed to the standard of care, Merck’s Keytruda (pembrolizumab).

FDA officials cited a strong preference for multi-regional trials able to support broader drug approval and use, as mapped out by the International Council of Harmonisation (ICH) in its E-5 and E-17 clinical efficacy standards. FDA noted in its briefing document for the ODAC meeting that the more recent E-17 document advances the use of multiregional clinical trials as optimal for global registration of drugs, and that data from a single country trial does not allow for evaluation of treatment effects across geographic regions and subpopulations.

FDA’s main points also are presented by Richard Pazdur, director of FDA’s Oncology Center of Excellence, and Harpreet Singh, director of the Division of Oncology 2 in the Center for Drug Evaluation andResearch (CDER), in The Lancet Oncology journal. Pazdur emphasized at the advisory meeting that while the trial for Tyvyt closely resembles earlier NSCLC trials that had established checkpoint inhibitors as important treatment regimens in the past, the results are less impressive at this time when similar drugs are available to patients.

Objecting to a trend

A broader concern for FDA and the research community is that the Innovent-Lilly study appears to reflect “an increasing number of oncology development programs based solely or predominantly on clinical data from China.” At least 25 such applications are in development, headed for submission or currently under review by FDA, and Pazdur made clear that such drug development programs may similarly meet objections from FDA, particularly for subsequent indications of already-approved treatments.

The sponsors emphasized that the Tyvyt clinical trial, which was originally designed to support approval of the drug in China, followed the guidelines presented in ICH E5 on efforts to expand the acceptability of foreign clinical trial data as a way to reduce duplicative research programs and promote international harmonization. While FDA and other regulatory authorities have accepted foreign trial data for highly novel therapies that treat underserved patients, they regard multiregional clinical trials and bridging studies as important for ensuring ensure that data from one country is applicable to broader populations. In this case, FDA further pointed out that the China-only study failed to reflect the racial diversity of the US population.

FDA also emphasized the need to compare Tyvyt to a checkpoint inhibitor that is approved in the US in order to demonstrate a statistically significant improvement in overall survival—and not just progression-free survival. In light of growing efforts to broaden clinical trials to represent a full range of ethnic and racial patient groups, a drug tested only in China appears to be “a step backward,” Pazdur said at the meeting.

In an unusual strategy, Lilly executives sought to win broader support for Tyvyt approval by pledging to market the drug at a deep discount in the US. That message, however, appeared to further alienate the scientists, as FDA emphasizes that it does not consider price in its review and approval decisions. The ODAC 14-1 vote in support for additional testing for the drug makes it likely that FDA will send Lilly and Innovent back to the drawing boards—and that the agency and others will take a similar stance with additional applications seeking approvals based on single-country trials—many from China.

About the author

Jill Wechsler is Washington editor at BioPharm International.