Eli Lilly and China-based partner Innovent Biologics will likely need to run an international clinical trial of their lung cancer immunotherapy for the Food and Drug Administration to consider approving the drug in the U.S.
Medical experts convened by the regulator Thursday generally agreed that the drugmakers didn't enroll a diverse enough population in their trial, which took place only at hospitals in China, for results to be applicable to U.S. patients.
The advisers voted 14-1 to recommend the FDA require another, more rigorous study before a final regulatory decision.
At the meeting, FDA officials were particularly critical of Lilly and Innovent's application, which documents released by the agency earlier this week indicate is likely to be rejected. The companies are seeking approval for the drug, called sintilimab, in a common type of lung cancer.
"Single-country trials are a step backward," said Richard Pazdur, the FDA's top cancer drug regulator, who has in recent months raised concerns about approving in the U.S. medicines that were developed exclusively in China.
The FDA's view, and the support it received from its advisers Thursday, could have repercussions for many drugmakers, as the agency expects many more China-developed drugs will be submitted for U.S. approval in the future.
A rejection, should one come by the FDA's decision deadline in March, would also blunt efforts to bring price competition to the market for cancer immunotherapies, many of which have a list price of over $150,000 a year. If Lilly's drug were approved, the drugmaker has said it would set a price roughly 40% below what similar medicines already on the market cost.
The FDA is not supposed to consider price in its approval decisions, a requirement it emphasized to its advisory committee several times on Thursday.
In a statement, Lilly said it was "disappointed" in the advisory committee vote and affirmed that it is committed to ensuring its clinical trials are diverse and ethical. "We had hoped that sintilimab could have played a positive role for patients and the U.S. healthcare system through an aggressive pricing strategy," Lilly said.
Sintilimab is a type of drug known as a checkpoint inhibitor and blocks a protein called PD-1. Seven others like it are approved in the U.S., all costing roughly similar amounts per year based on their wholesale price. The most lucrative, Merck & Co's Keytruda and Bristol Myers Squibb's Opdivo, are widely used and generate many billions of dollars of sales annually.
Lilly and Innovent based their application on a trial of nearly 400 people with lung cancer that Innovent ran in China called ORIENT-11.
The FDA and its advisers took issue with several aspects of the study, particularly the population of patients enrolled. Specifically, the agency didn't believe ORIENT-11 is applicable to U.S. lung cancer patients because too many of the study's participants were non-smokers, men and on average younger than is typical in the U.S. As the study was conducted only at Chinese medical centers, no volunteers were White, Black or Hispanic ethnicity, FDA officials said.
"The key challenge here is it's not generalizable to the US population; from fewer smokers, a younger population, a big difference in terms of gender representation ... and obviously to the ethnic and racial disparity that we see here," said committee member John Deeken, president of the Inova Schar Cancer Institute in Virginia.
Moreover, the trial began after a regimen of Keytruda and chemotherapy became a standard treatment for lung cancer patients. ORIENT-11 tested sintilimab plus chemo against chemo alone, making it very difficult for doctors to judge whether sintilimab was better for patients than Keytruda.
Meanwhile, not all patients in the study were informed by trial investigators when Keytruda was approved in China, a breach of standard clinical practice on so-called informed consent.
"This would be a major setback for the faith and the rigor of the clinical trial process within the U.S.," said committee member Ashley Rosko, a medical professor at Ohio State University.
While committee members recommended an additional trial, many stopped short of proposing a direct head-to-head study that measures whether patients given sintilimab and chemo combo live as long as those taking Keytruda and chemo. Such a trial could require thousands of patients and take several years to complete.
Lilly and Innovent have started a small study that compares sintilimab in Chinese and Western patients to determine if there are any differences in how well the drug shrinks or eliminates their tumors. However, that trial "probably won't answer the question," said committee member Antoinette Wozniak, a University of Pittsburgh medical professor.
As patients already have access to Keytruda, FDA officials along with some committee members said researchers should take the time to answer whether sintilimab is equal to or even better than Merck's drug. "I don't think we should compromise appropriateness for convenience," said Ibiayi Dagogo-Jack, a Harvard University medical professor.
The lone committee member who voted against requiring an additional trials said he believed that there was sufficient evidence for approval, and that the faults observed in trial design weren't reason enough for a delay.
"I'm concerned that if we don't allow these types of trials for me-too drugs, we're going to be limited in our ability to have more drugs for our patients, and that's going to lead to higher costs in general for them," said Jorge J. Nieva, a University of Southern California oncologist.
Along with Lilly and Innovent, several other companies are advancing plans to seek FDA approval of similar China-developed cancer drugs.
For example, EQRx, a startup seeking to compete with established drugmakers on price, is planning to ask for approval of an immunotherapy developed by China's CStone Pharmaceuticals. EQRx and others with similar price plans could adjust course or take longer before seeking approval of their drugs as a result of the FDA's stance on sintilimab, delaying potential price competition.
"The fact that [sintilimab is] clearly headed for rejection means that a real option for substantially lower drug prices is being closed in the U.S.," said Brad Loncar, CEO of Loncar Investments and a biotech investor who closely follows Chinese drugmakers, in an email.
Ned Pagliarulo contributed reporting.