FDA officials, advisors cast doubt on foreign-only clinical strategy

Regulatory NewsRegulatory News | 10 February 2022 |  By 

The US Food and Drug Administration (FDA) raised serious concerns about Eli Lilly and Innovent’s biologics license application (BLA) for the companies’ PD-1 inhibitor sintilimab during an extraordinary meeting of its Oncologic Drugs Advisory Committee (ODAC) on Thursday.
“Today’s ODAC will not follow the traditional paradigm of assessing the benefit-risk profile of a single drug; rather, the concept of generalizability and applicability of single-country foreign data to a US population is the central issue for which we referred this application to the committee,” said Harpreet Singh, director of FDA’s Division of Oncology 2 within the Center for Drug Evaluation and Research.
The agency’s concerns stem from the fact that the pivotal trial in support of the drug was conducted solely in China, prompting questions about the trial’s relevance and applicability to a US population and US medical practice. The trial also relied on an outdated chemotherapy control arm, as other PD-1 inhibitors had not yet been approved in China. In the US, the standard of care would have been Merck’s Keytruda (pembrolizumab), which was approved for the same indication in 2016.
FDA also raised concerns about the growing number of clinical development programs pursuing a similar development strategy, contrary to the current international regulatory consensus favoring the conduct of multiregional clinical trials as outlined in the International Council for Harmonisation (ICH) E17 guideline.
Singh noted that the trial design, enrollment criteria and statistical assumptions underpinning the pivotal ORIENT-11 trail “closely resemble landmark trials which established immune checkpoint inhibitors as part of the initial treatment for non-small cell lung cancer (NSCLC),” and added that the “application reflects an increasing number of oncology development programs based solely on, or predominantly on, clinical data from China.”
“This strategy is in contrast to multi-regional clinical trials which have been promoted by the global regulatory community as the preferred development strategy,” she said.
ODAC members ultimately voted 14-1 in support of the need for additional clinical trials to demonstrate applicability to US patients and US medical care prior to FDA issuing a final regulatory decision.
Part of Eli Lilly and Innovent’s regulatory strategy hinges on the FDA’s flexibility to approve applications based solely on foreign clinical data. However, Singh stressed that FDA’s regulations under 21 CFR 314.106 include several relevant restrictions on its ability to approve such applications, including the applicability of the foreign data to the US population, the recognized competence of the clinical investigators, and FDA’s validation of the data.
Company representatives pushed back on many of FDA’s criticisms, asserting that the trial was initially designed to support regulatory approval in China, where pembrolizumab was approved at the outset of the study, and that that the company followed what it perceived to be a development path supported by ICH’s E5 guideline and US regulation on the acceptability of foreign clinical trial data.
However, FDA officials, including Singh and Richard Pazdur, director of FDA’s Oncology Center of Excellence (OCE), stressed that the bridging strategy described in ICH E5 was appropriate in this instance.
“The current landscape of ‘me too’ drugs was not envisioned in ICH E5 when considering bridging studies as a means of extrapolating foreign data,” Pazdur said. “What is best for drug development is to bring China into the fold as a key player in international multiregional clinical trials.”
“By drawing from diverse geographic areas and ethnic populations, multiregional trials allow for evaluation of regional consistency of treatment effect, avoid duplicative efforts, and the need for bridging studies, and ultimately promote international harmonization of best medical practices,” Singh said, noting that the ORIENT-11 trial was initiated in 2018, after the US granted accelerated approval to Keytruda (pembrolizumab) and after China’s regulatory authority joined ICH.
 “ORIENT-11 could not have been conducted in the United States, as it was no longer applicable to US medical practice,” she stressed. “Investigators would not have enrolled patients to a chemotherapy control arm, given available FDA-approved options conferring substantial survival benefit. Had FDA been consulted regarding ORIENT-11, a formal head-to-head comparison of sintilimab to an FDA-approved checkpoint inhibitor would have been recommended as an initial registration strategy. This type of trial could help address the need for clarity in a crowded field, by comparing regimens directly. Instead, ORIENT-11 only contributes to the lack coordination and redundancy in the checkpoint inhibitor space.”
All other FDA-approved first-line immunotherapy-based regimens for metastatic NSCLC have been based on a statistically significant improvement in overall survival, while the ORIENT-11 trial relied on progression-free survival (PFS) as its primary endpoint, Singh added.
Differences in the enrolled trial population compared to the relevant US patient population raised further questions from FDA. Singh noted that the population enrolled in the study was younger, predominantly male, and had lower rates of smoking than what would be expected in the US. Further, she noted that the agency identified issues with underreporting adverse events and concomitant medicine use when it inspected two of the 48 clinical trial sites that participated in the study. While corrective actions were taken, the presence of those issues underly the agency’s concerns about data integrity in the trial.
Speaking to the benefits of multiregional trials, Pazdur said that they enable regulators to “look at sites in different countries and take a look at differences, so to speak, in adverse event reporting, in efficacy, and compare them and to see if there is any outlier.”
There were several contentious moments during the meeting, with FDA officials strongly rebutting assertions made by Innovent and Eli Lilly. The companies emphasized that they had met with FDA three times prior to submitting their BLA, though all three meetings were held after the ORIENT-11 trial had completed.
Singh said the companies’ portrayal of those meetings was “misleading” and she stressed that “FDA had no knowledge that this trial was ongoing until the primary efficacy results became available.” She added that FDA expressed at the meetings “that there were concerns regarding applicability and generalizability to a US population, and we did discuss the possibility of asking for additional data. We did not elicit exactly what type of data that would look like.”
Julia Beaver, chief of medical oncology at OCE and the acting deputy director of the Office of Oncologic Diseases, added “it’s really well known across industry that in order to receive formal regulatory advice or potential agreement on a drug development plan, discussion with FDA is critical in a formal setting, and this is the way most programs are developed, allowing for that mutual understanding of appropriateness of a trial design and formal discussion regarding FDA’s opinions.”
Beaver pointedly asked the sponsors why they didn’t come to the agency sooner.
At another contentious moment, Singh addressed issues with informed consent documents and processes in the trial. She noted that the trial-level informed consent for ORIENT-11 was never updated to acknowledge that pembrolizumab was approved in China before the trial was completed. “You yourself – the applicant – admitted that the consent form never explicitly addressed this issue, omitted the approval of pembrolizumab, not only in China but worldwide. What is the corporate stance on this, because I feel that this could potentially erode trust in clinical trials, and were you comfortable with a chemotherapy arm that deprived patients of a therapy that prolongs overall survival? And how many times has Eli Lilly conducted trials that have deprived patients of therapies with known survival advantage?” Singh asked
Pazdur emphasized that the “representation of ethnic and racial minority groups is not just a biological reason that we want people on these trials – it is to build confidence in the clinical trial system and also a confidence that after these drugs are approved that they should be used in these groups.”
He also questioned Eli Lilly as to whether any of the investigators or any sites that participated in the trial withdrew voluntarily or were asked by Chinese regulators to withdraw data, citing a report published in The BMJ in 2016 that found that more than 80% of clinical trial data gathered in China was found to be fraudulent or substandard.
Lana Shiu, senior vice president of global regulatory affairs at Innovent, stated that China underwent significant clinical trial reforms in the aftermath of that report and that at least half the trial sites and several of the investigators had participated in other trials that led to FDA approvals.
An Eli Lilly representative said the company would have to follow up with FDA on the matter.
Pazdur also took a moment to address his public comments at the American Association for Cancer Research (AACR) meeting in 2019, which the companies cited as a factor in their regulatory strategy. “Since that time, there has been at least seven approvals for non-small cell lung cancer. All of them are based on overall survival. In addition to that, the survival data on pembrolizumab has been updated, which now shows over a year improvement of overall survival … The world has changed here. Comments that were made at an AACR meeting should not be viewed as regulatory policy.”
He added that “single-country submissions is a step backward in achieving the racial diversity that we need in the United States,” and that FDA “cannot be deaf to this.”
Pazdur also pointed out that FDA must look at the reasons behind a company’s decision to rely solely upon foreign trial data to support approval. “If they’re looking at a regulatory loophole because the drug has not been approved, the comparator drug, the new standard of care has not been approved and they’re doing it in a foreign trial to avoid doing what they would need to do in the United States, that is extremely problematic,” he said.
ODAC meeting


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