The panel debated whether overseas trials could be applied to a more diverse U.S. population. The decision may affect other Chinese drug trials, and spotlights the high cost of immunotherapy.
An advisory committee to the Food and Drug Administration overwhelmingly voted on Thursday against recommending agency approval of a lung cancer drug that was tested only in China and sold there.
The drug, sintilimab, is a checkpoint inhibitor — a type of immunotherapy drug that unleashes the immune system to attack tumors. It was developed and tested in China by Innovent Biologics, which entered into an agreement with Eli Lilly that would have allowed Lilly to market it in the United States, if it were approved. It was to be used in combination with chemotherapy for patients with metastatic non-small-cell lung cancer.
The F.D.A. panel debated a longstanding issue: What standards should be used in approving drugs? Should a drug tested only in China or another country outside the United States be accepted without domestic trials?
The decision is likely to be closely monitored for clues about whether it further exacerbates tensions between the United States and China, especially given the strains between the two countries over research by Chinese scientists in recent years. Immunotherapy drugs are so expensive in the United States that the potential to bring a cheaper therapy to the market also weighed heavily in the background of the discussion on Thursday.
Dr. Richard Pazdur, the powerful director of the F.D.A.’s oncology unit, explained on Thursday why he had backtracked from a far more welcoming attitude in 2019, when he said the agency might consider a checkpoint inhibitor tested solely in China.
“Over the past two or three years, this country has experienced tremendous social change,” he said at the meeting. “We clearly heard from all patient groups that they want faces like theirs.” That, he said, is also important to build confidence in the clinical trials and the drugs being tested.
A drug tested only in China is “a step backward,” he said.
The agency has faced considerable pressure to include diverse patient groups, reflecting various ethnic and racial populations, in clinical trials in the United States as well as to address health disparities.
Lilly released a statement saying that it was disappointed and that it had “hoped that sintilimab could have played a positive role for patients and the U.S. health care system through an aggressive pricing strategy.”
But, the company said that “we acknowledge that the landscape has changed dramatically” and that Lilly “wholeheartedly agrees with the importance of ethics in clinical trial conduct and clinical trial diversity.”
The company said it “will be working with FDA on next steps.”
Another issue surrounded Lilly’s decision to even submit this drug for U.S. approval. An analysis by the F.D.A.’s staff of the trial results in China was scathing on methodological grounds. It cited a failure to provide patients in the control group with an approved therapy that is standard of care; questioned the competence of some of the investigators who had no previous experience with such trials; noted a patient population that was younger, had more men, and had fewer smokers than U.S. lung cancer patients; and criticized use of an endpoint that is considered not always reliable.
Lilly had promoted its application by saying that it wanted to use sintilimab as a wedge to break the stratospheric prices of cancer immunotherapy.
Already on the market are several other checkpoint inhibitors, which make cancers vulnerable by blocking a protein that tumors use as sort of an invisible shield to protect them from an immune system attack. These immunotherapy drugs treat such cancers as colon, breast, liver and lung, and carry list prices that are nearly identical — about $150,000 a year per patient.
Lilly said it would charge 40 percent less if its drug were approved. Sintilimab costs $6,000 a year in China.
The company’s idea of breaking the price lock on such drugs is “a big deal,” Brad Loncar, a biotechnology industry investor, said.
“I’m not aware of any precedent of a company, especially of Lilly’s size and credibility, announcing that a discounted price like this is how they planned to innovate,” Mr. Loncar said.
Now, he added, the near certainty that the drug application would be rejected “means that a real option for substantially lower drug prices is being closed in the U.S.” (The F.D.A. generally follows the recommendations of its advisory committees.)
Others were not persuaded by Lilly’s claim to be a market disrupter.
Dr. Scott Ramsey, a health economist and cancer specialist at Fred Hutchinson Cancer Center in Seattle, was among those who were skeptical of Lilly’s motives. “Yeah, right,” he commented.
“Are they talking about the stranglehold on prices that their current drugs contribute to?” Dr. Ramsey asked. “Maybe they could start by knocking 40 percent off their price” for Cyramza — a stomach cancer drug with a list price of $13,400.32 to $15,075.36 per month — and Verzenio, a breast cancer drug with a similar price.
“I don’t buy it,” Dr. Ramsey said of Lilly’s price disrupter story, and instead chalked it up to a public relations stunt.
It is well known that the F.D.A. is not permitted to consider price in evaluating whether a drug should be approved. That means that any F.D.A. decision must be based solely on whether the drug meets its standards.
For that reason, Dr. Aaron Kesselheim, a professor of medicine at the Harvard T.H. Chan School of Public Health and an expert on the pharmaceutical industry, was puzzled.
“I’m not aware of a company ever before announcing its pricing strategy just before an AdComm meeting, particularly one in which the general perception is that the F.D.A. was going to argue that the data don’t seem to support approval,” he said, referring to the agency’s advisory committee panel. “It does seem like a strategic ploy intended to inject a consideration into the AdComm deliberations that is not supposed to be considered.”
The story of sintilimab dates to 2019 at the annual meeting of the American Association of Cancer Research. Speaking there, Dr. Pazdur said the agency would be open to considering drugs tested solely in other countries.
Lilly, which had said it had not planned to market sintilimab outside China, said at the meeting that it then decided to see if the drug could be approved in the United States. The company met with the agency three times in 2020 and proceeded to apply for marketing approval.
Progress in the field. In recent years, advancements in research have changed the way cancer is treated. Here are some recent updates:
Pancreatic cancer. Scientists are exploring whether the onset of diabetes may be an early warning sign of pancreatic cancer, which is on track to become the second leading cause of cancer-related deaths in the U.S. by 2040.
Chemotherapy. A quiet revolution is underway in the field of cancer treatment: A growing number of patients, especially those with breast and lung cancers, are being spared the dreaded treatment in favor of other options.
Prostate cancer. An experimental treatment that relies on radioactive molecules to seek out tumor cells prolonged life in men with aggressive forms of the disease — the second-leading cause of cancer death among American men.
Leukemia. After receiving a new treatment, called CAR T cell therapy, more than a decade ago, two patients with chronic lymphocytic leukemia saw the blood cancer vanish. Their cases offer hope for those with the disease, and create some new mysteries.
Esophageal cancer. Nivolumab, a drug that unleashes the immune system, was found to extend survival times in patients with the disease who took part in a large clinical trial. Esophageal cancer is the seventh most common cancer in the world.
In the intervening years, however, Dr. Pazdur expressed increasing concern about what seemed to be a rush by companies large and small to bring checkpoint inhibitors to the market.
In December, in The New England Journal of Medicine, Dr. Pazdur noted that more than 2,000 clinical trials testing checkpoint inhibitors were underway, with many trials taking place in China.
Dr. Pazdur added that “the unbridled and rapid growth of checkpoint inhibitors has led to a Wild West of drug development, featuring a stampede of commercial sponsors, clinical trials and redundant development plans.”
“Every major company and even small companies has a checkpoint inhibitor,” said Donald Berry, a statistics professor and cancer clinical trial expert at the M.D. Anderson Cancer Center in Houston. “It’s amazing how easy it is to make these things,” he added.
In an article published on Feb. 4 in Lancet Oncology, Dr. Pazdur wrote that there were “at least 25 applications from China in drug development phases, planned to be submitted or currently under review.”
The agency has long had strict rules about approving drugs that were tested solely overseas, requiring that the data be applicable to patients and medical practice in the United States, that the investigators had “recognized competence” and that the agency be able to validate the data.
In a withering critique of Lilly’s submission on this new trial from China, F.D.A. staff members assigned to conduct an analysis said that on every count the sintilimab application fell short. One issue was how to evaluate the drug. The study asked how long it took before the cancer started growing again or before the patient died. That endpoint, known as progression free survival, Dr. Pazdur said at the meeting, is out of date for such studies. Instead, the appropriate endpoint, he suggested, is what matters to patients most — how long will they live.
“There’s a famous story of Avastin in metastatic breast cancer,” Dr. Berry said. “It showed enormous benefit for progression-free survival, but with additional follow-up it was not beneficial for overall survival.”
A few years ago, progression-free survival might have been more acceptable but, Dr. Pazdur said, it no longer is and it’s another example of how “the landscape has changed.”To get Lilly’s drug approved, the panel voted to recommend requiring another trial that would be applicable to U.S. patients.
But Dr. Jorge Nieva, associate professor of medicine at the University of Southern California, who was the only dissenting panel member, said there was no evidence that the data was unreliable and that it was not the panel’s job to determine how many drugs on the market would be too many.
“Having more drugs competing for those same patients will have, I think, greater impact on equity than the need for diversity in clinical trial enrollment, which I believe is important,” Dr. Nieva said.
But Dr. Pazdur’s views carried the day, alluding to more policy changes, perhaps.
“There is a change in our perception of what we want from international trials,” he said. China has, so far, rarely participated.
“We want to bring China in,” Dr. Pazdur said. “We feel we would all benefit.”
Christina Jewett contributed to this article.