Thumbs down on Lilly, Innovent China trial for lung cancer drug Tyvyt, says FDA AdComm

When is a clinical trial conducted exclusively in a foreign country enough to support FDA approval?

That was the question before the agency's Oncologic Drugs Advisory Committee (ODAC) on Thursday as it weighed whether to recommend Eli Lilly and Innovent Biologics’ application for its PD-1 lung cancer drug Tyvyt (sintilimab).

By a vote of 14-1, the independent panel ruled against the companies, declaring that another clinical trial, demonstrating that that the drug works on U.S. patients, should be required before approval.

The decision might have been different had Tyvyt been destined for a market with no good options for patients—or if the trial had used the gold standard of cancer research, overall survival, as its primary endpoint. But it didn't, and Tyvyt was aiming to treat non-small cell lung cancer, a disease with multiple rival drugs that have proven they can extend patients' lives.

Plus, diversity in clinical trials has become more important than ever.

“Over the past two to three years—especially since the pandemic—this country has experienced significant social change,” the FDA's cancer drugs chief, Richard Pazdur, said during Thursday’s virtual meeting. “And there has been a tremendous outcry for diversity and representation in clinical trials. We as a public agency have to adhere to what patients want in the United States.”

The panel raised a variety of other concerns about the phase 3 trial, dubbed Orient-11, including its endpoint and the companies' lack of communication with the FDA as the trial was underway.

“I was disappointed to hear the lack of engagement between the applicant and the sponsor early on during the trial design,” said committee member Jorge Garcia of Case Western Reserve University. “I would like to believe that if those meetings were held, we probably wouldn’t be having this conversation today.”

The decision came right after Lilly revealed a planned 40% discount on the drug’s list price compared to other PD-1 inhibitors on the market. The most recognizable PD-1 is Merck’s Keytruda, which has an annual sticker price of $150,000.

RELATED: Eli Lilly, Innovent's PD-1 in troubled waters as FDA review, oncology chief's comments portend likely rejection

The regulator made it clear early during Thursday’s meeting that pricing does not factor into its approve-or-not-approve calculus.

“The FDA cannot consider drug pricing in regulatory decision-making and this should not be part of the committee’s consideration or discussion today,” Paz Vellanki, of the FDA, instructed.

"We had hoped that sintilimab could have played a positive role for patients and the U.S. healthcare system through an aggressive pricing strategy," a Lilly spokesman said via email. "We acknowledge that the landscape has changed dramatically on a number of fronts since the ORIENT-11 study was conducted and the sintilimab application was initiated.".

The phase 3 trial pitted Tyvyt and chemotherapy against standard of care in treating newly diagnosed non-squamous non-small cell lung cancer patients.

In addition to lacking an appropriately diverse patient population, other demographics in the study diverged from a typical U.S. patient pool for NSCLC. For example, Orient-11 had a higher percentage of males, fewer smokers and a younger median age.

The FDA also had problems with the study measuring—as its primary endpoint—how well Tyvyt could stall tumor progression or death, known as progression-free survival (PFS). Using PFS as a primary measure does “not meet U.S. regulatory standards or align with U.S. medical practice,” the FDA said.

“(Since 2019) there have been at least seven approvals for non-small cell lung cancer. All of them are based on overall survival,” Pazdur said. “The landscape has significantly changed.”

The FDA doesn't always follow its advisory committees' advice, but typically does—and Pazdur's commentary suggests it will in this case.

The U.S. regulator has cleared drugs based on trials conducted in other countries, but those exceptions were made for novel therapies for underserved patient populations. The FDA didn’t see a reason to extend the same flexibility to Lilly and Innovent, considering similar drugs are on the market that were proven in trials that included more diverse patient populations.

“There’s no need for regulatory flexibility because this application does not address an unmet need,” said committee member David Mitchell, the founder of Patients for Affordable Drugs. “We have treatments that are safe and effective and show an improvement in overall survival.”

RELATED: Eli Lilly promises 40% discount for Innovent’s PD-1 in last-ditch bid to shift FDA review to drug pricing

But disagreeing with that sentiment was Jorge Nieva of the University of Southern California, the lone dissenter on the panel. He said that the availability of more drugs would create downward pressure on prices, to the benefit of all patients.

“This drug works,” Nieva said. “We have no evidence that the data presented is unreliable, synthetic or otherwise fraudulent. We had adequate FDA inspections that were not hampered. If more inspections were needed, it is expected the FDA would have performed them.”

Despite the setback, Jefferies analysts believe the future is bright for drugs developed in China. Thursday's AdComm helps clarify what will be required as companies seek FDA approval.  

"We anticipate more China-developed drugs to enter the U.S. market in the future as more and more companies are adopting thoughtful global drug development strategy from the beginning," wrote Kelly Shi. "Contract research organizations that can help China biotech companies to conduct multi-regional clinical trials should benefit."