Drugs

FDA Briefing Slams ‘Single Country’ Drug Data

David McFarland

— 2 min read
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FDA appears poised to be putting its foot down on drug sponsors conducting drug development programs that exclusively rely on foreign clinical trial data conducted in a single country. FDA Oncology Center of Excellence director Richard Pazdur tipped his hand (see story) late last week when he co-authored a comment piece in The Lancet, calling into question the development of dozens of oncology drug development programs that rely almost exclusively on clinical data from China. Pazdur and oncology division director Harpreet Singh said there are at least 25 applications from China in drug development phases, planned to be submitted, or currently under review. And probably more disturbing to the FDA regulators, most of these sponsors seeking FDA approval did not seek regulatory advice under traditional milestone meetings.

Just-released briefing materials on the first of these products going before FDA’s Oncologic Drugs Advisory Committee 2/10 now signal a tough road ahead for the sponsors and their China-based development programs. Panel members are set to discuss ORIENT-11, a clinical trial comparing chemotherapy plus sintilimab, a checkpoint inhibitor, with chemotherapy alone as an initial treatment for metastatic non-small-cell lung cancer (NSCLC). The BLA is sponsored by Innovent Biologics (Suzhou) which is in a global collaboration with Eli Lilly. According to the only draft question before the panel, the agency is asking whether an additional clinical trial “demonstrating applicability to U.S. patients and U.S. medical care be required prior to a final regulatory decision?”

Making matters more dire for the dozens of foreign development programs is FDA’s reading of the Code of Federal Regulations (CFR). The advisory committee briefing document sees the agency citing Section 21 CFR 314.106(b), which outlines three requirements for use of foreign data as the sole basis for marketing approval. If any of these are not met, then FDA can deny approval: 

  • The foreign data are applicable to the U.S. population and U.S. medical practice.
  • The studies have been performed by clinical investigators of recognized competence.
  • FDA is able to validate the data through an onsite inspection or other appropriate means.

Also weighing on FDA’s decision are its interpretations of two International Council of Harmonization (ICH) guidances. Both ICH E5 and more recently ICH E17 directly address the acceptance of foreign data from a single country, and should be used in tandem. Innovent “cites the CFR and ICH E5 as rationale for their approach, however, omits ICH E17, a critical international consensus document which promotes the use of multiregional clinical trials (MRCTs) as the preferred approach to drug development,” the briefing document says.

FDA explains further that ICH E17 “reinforces the MRCT as the optimal method for concurrent global registration based on an emerging consensus that trials requiring international collaboration were preferred over single country trials. ORIENT-11 is not consistent with the principles outlined in ICH E17, thus does not allow for an evaluation of consistency of treatment effects across geographic regions and subpopulations. The data from ORIENT-11 are not applicable to the U.S. population and U.S. medical practice, based on the selected endpoint and control arm.”

Additionally, FDA is snubbing Innovent’s “me too” checkpoint inhibitor because the NSCLC treatment landscape already includes many front-line immunotherapy options “conferring advantages in overall survival (OS) whereas ORIENT-11 was powered for [progression-free survival] PFS. While PFS is an acceptable clinical endpoint, it is less clinically meaningful, and OS remains the preferred endpoint when it can be reasonably assessed.

“Overall survival,” the briefing document continues, “was not formally tested in ORIENT-11, and approval based on a different endpoint than OS risks loss of gains in survival for U.S. patients. Given there are multiple approved agents with OS advantage formally demonstrated with statistical significance, flexibility regarding applicability of results from ORIENT-11 is not indicated or favorable for U.S. patients.”

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