FDA Panel Rejects Sintilimab Clinical Trial Data From China

Kerry Dooley Young

February 11, 2022

The vote of a federal panel could serve as a warning sign for drugmakers seeking to test their medicines solely or largely in China and then seek US approval based on these data, with advisers raising concerns about ethnic and racial diversity of such a single-country trial design.

On February 10, the Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 14-1 to answer yes to a question about whether an additional clinical trial or trials of the drug sintilimab should be required before US approval. The FDA asked the panel to vote on only that question.

The agency considers the views of its advisory committees in deciding on drug approvals, but it is not bound by them.

The FDA's approach to the sintilimab application will be closely watched as a test case of how the agency will handle drug applications based solely or heavily on oncology development programs based in China. There are more than 25 applications in drug development phases, planned to be submitted, or currently under review at the FDA, the agency staff said in its review of sintilimab.

Still, the odds against approval of sintilimab were high even before the meeting took place, given FDA officials' clearly expressed frustrations with the application presented by China's Innovent Biologics and its partner, Eli Lilly & Co.

The companies were seeking US approval of sintilimab for the treatment of people with stage IIIB, IIIC, or stage IV nonsquamous non–small cell lung cancer (NSCLC) with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

Innovent's application rests heavily on a single trial, ORIENT-11, that was conducted entirely in the company's home nation of China. The median time for progression-free survival was 8.9 months for a group of 266 patients for whom sintilimab was added to chemotherapy, vs 5.0 months for a comparison group of 131 patients who received placebo and chemotherapy, according to an FDA review.

Sintilimab is another immunotherapy for cancer using the programmed cell death protein-1 (PD-1) approach. Other PD-1 drugs include pembrolizumab (Keytruda), atezolizumab (Tecentriq), nivolumab (Opdivo)/iIpilimumab (Yervoy), and cemiplimab (Libtayo).

These other immunotherapies have already been approved for use in NSCLC and have been shown to improve overall survival (OS). In contrast, the data on sintilimab presented at the meeting showed only an improvement in progression-free survival, not OS.

Lilly argued that US approval of sintilimab could help drive down the cost of lung cancer treatment, telling media outlets ahead of the ODAC meeting that it planned to offer a discount of about 40% to rival treatments.

But addressing the cost of medicine is outside of the FDA's mandate. The agency is charged with making sure medicines are safe and effective. FDA officials and members of the ODAC panel made it clear that they felt the body of evidence presented to date on sintilimab fell short of its approval standards.

"There's no need for regulatory flexibility, because this application does not address an unmet need," said panelist David Mitchell, who serves as ODAC's consumer representative. Separately from his FDA activities, Mitchell is the president of the nonprofit Patients for Affordable Drugs, which is among the more active groups seeking to lower the costs of medicines in the US.

"We have treatments that are safe and effective and shown an improvement in overall survival rather than this drug, which was tested against a primary endpoint of progression-free survival and not against current standard of care but against chemo and a placebo," Mitchell commented.

Choice of Placebo Arm Questioned

FDA staff questioned repeatedly how well patients in the ORIENT-11 study understood that the study design did not reflect recent advances in cancer care.

The ORIENT-11 trial kicked off in 2018 and compared sintilimab to placebo. That approach would not have been allowed in the US at that time, the FDA staff said. By then, US physicians were looking to use approved checkpoint inhibitors for their patients. While immune checkpoint inhibitors were not approved in China at the time of study initiation, pembrolizumab with chemotherapy gained approval in China some months after the first patient was enrolled in ORIENT-11.

Harpreet Singh, MD, the director of the FDA's Division of Oncology 2 products, asked Lilly officials to explain what consideration was given to patients in designing this trial.

Physicians have a responsibility to offer people who enroll in studies the best available therapies. But the people who enrolled in the placebo arm of the ORIENT-II study were being denied a known therapy to confer survival benefits, Singh said.

"I feel that this could potentially erode trust in clinical trials," she said during discussions with the companies at the ODAC meeting.

At the conclusion of the meeting, several FDA panelists also noted discomfort with this design of the trial.

"While data integrity is of utmost importance in clinical research, moral integrity is of greater importance," said panelist Ravi Madan, MD, of the National Cancer Institute.

"We really need to do a better job and make sure that in all clinical research, but especially in large studies like this, that patients have the appropriate informed consent, updated as needed over time," Madan added.

In a statement issued after the ODAC meeting, Lilly told Medscape Medical News that the company "wholeheartedly agrees with the importance of ethics in clinical trial conduct and clinical trial diversity. We have long-standing initiatives in place to advance diversity and inclusion in Lilly-conducted clinical trials."

Next Steps?

In the statement, Lilly also said it was "disappointed" with the outcome of the ODAC meeting. Still, Lilly said it appreciated the opportunity to publicly discuss the application and broader issues related to single-country clinical trials.

"We had hoped that sintilimab could have played a positive role for patients and the U.S. healthcare system through an aggressive pricing strategy. 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. Along with Innovent, we will continue to work with the FDA as it completes its review of the sintilimab application," the company said.

In this phrasing, Lilly echoed a point that the FDA's top regulator of cancer medicines, Richard Pazdur, MD, had made forcefully during the ODAC meeting.

In making their appeal for US approval of sintilimab, Lilly and Innovent had emphasized comments Pazdur made during a discussion at the 2019 meeting of the American Association of Cancer Research (AACR).

At that AACR meeting, Pazdur spoke about his then recent visit to China. He mentioned in a passing remark during a panel discussion that the FDA would accept "quality" data from a study limited to China. He didn't detail what he meant by "quality" and moved into a broader discussion of the PD-1 class. (Endpoints News reported on this and included this link to the webcast of the AACR session, with the remarks in question at about minute 24.)

At the ODAC meeting, Pazdur said that remarks made at the AACR meeting should not be taken as a full statement of "regulatory policy." He also reflected on the rapid advances with PD-1 drugs since that 2019 AACR meeting, held from March 29 to April 3, 2019. Since then, the FDA has granted approvals for different indications of several PD-1 drugs in NSCLC based on overall survival data.

In addition, FDA staff have grown more concerned in recent years about the need to include people of diverse backgrounds in studies of new medicines, Pazdur said.

Approving drugs based on single-country trials would mark a "step backwards" in the FDA's efforts to try to have drugs tested in people of diverse backgrounds, he said.

"We feel that we would all benefit by having China participate fully in multiregional trials with the US, with Europe, with South America, Central America, and hopefully Africa," Pazdur said. "The world will be a better place, with having all countries participate."

Price Discussion Creeps In

In explaining his dissenting "no" vote, panelist Jorge J. Nieva, MD, of the University of Southern California, agreed that having studies of drugs conducted in several regions of the world is a preferable approach.

But he viewed the Lilly-Innovent application positively. He said that the companies had failed to meet the FDA's standards on process while still delivering solid evidence for sintilimab.

"The FDA should be in the business of evaluating their science and not the process," Nieva said.

Nieva argued that allowing competing drugs into the PD-1 class would allow more patients access to these drugs. "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," he said.

Nieva is a standing member of the ODAC panel. Due to his work with firms competing with Lilly and Innovent, the FDA granted a special waiver for Nieva to participate in the discussion of sintilimab.

This was due in part to Nieva's service on the internal advisory board for Cancer Research, Education, and Engagement (CaRE) Health Equity Center, an NCI-funded partnership of the University of Southern California, Florida A&M University, and the University of Florida. CARE seeks to address cancer disparities in Black and Latinx communities.

In the waiver, the FDA explained that despite the potential conflict due to his research on medicine, Nieva's participation was considered important due to his ability to provide "expert opinion on the development of anti-PD-(L)1 antibodies for the first-line treatment of NSCLC, the current treatment landscape for NSCLC, the inclusion of underrepresented ethnic and racial minorities in clinical trials, and the conduct of multinational clinical trials for patients with cancer."

"Bridge Over So-Called Troubled Waters for Global Drug Development"

The battle over sintilimab spilled into public view days ahead of the ODAC meeting.

FDA officials sought to make clear to the public what they saw as flaws in the application for sintilimab, while Lilly pitched the as-yet unapproved medicine as a potentially cheaper alternative to marketed cancer drugs.

The FDA's Pazdur and Singh took the unusual step of writing a comment that was published on February 4 in The Lancet Oncology. In the comment, they note the work already underway to allow more cooperation among researchers in different nations on what are called multiregional clinical trials (MRCTs). These include the FDA's Project Orbis, meant to allow for concurrent regulatory submissions to multiple nations. They note that there has been significant activity around checkpoint inhibitors in China, with that nation's Center for Drug Evaluation having seen more than 100 investigational new drug applications for this class.

Trials conducted entirely in China likely will not well reflect the ethnic and racial composition of the US population, meaning additional data would be needed to ensure

the generalisability of their results to the US population, Singh and Pazdur write. They call for greater cooperation across nations in testing.

"The true bridge over so-called troubled waters for global drug development and regulatory harmonisation will be MRCTs rather than single country trials," they write.

Before the ODAC meeting, Indianapolis-based Lilly told the news website Endpoints that its US marketing strategy for sintilimab included plans for a steep discount to other drugs in PD-1 class. Lilly confirmed for Medscape Medical News the following statement that it had made: "Our U.S. commercial plan for sintilimab, should it be approved, is to provide a significant and transparent WAC price discount that will be in line with some of the deeper discounts we've seen for biosimilars relative to their branded comparators, an approximate 40% discount. The PD-1 class has been the major cost driver of oncology drug spend over the past few years. There is an unmet need for quality innovation that provides more competition in this market and we believe that our pricing strategy could save the U.S. healthcare system billions of dollars over time. That having been said, the drug is not currently approved in the U.S. and may not get approved."

Comparison to Another PD-1?

The FDA staff review for the ODAC meeting highlighted the lack of early contact with the agency about sintilimab.

The first patient was enrolled to ORIENT-11 on August 23, 2018, while the first interaction between the companies and the FDA was not until April 21, 2020, The ORIENT-11 trial was not conducted under an investigational new drug application (IND), and the FDA was not involved during the planning or implementation of the study, the staff said.

Had the FDA been consulted early in the process, the agency "may have advised that sintilimab be compared to an existing FDA approved anti-PD-L-1 based regimen," the staff wrote. Instead, the trail compared sintilimab added to chemotherapy to a control arm receiving placebo added to chemotherapy.

In commenting on his vote to tell the FDA more study of sintilimab is needed, panelist Jorge A. Garcia, MD, FACP, said he was disappointed to hear about the companies' lack of engagement with the FDA. Companies more normally seek to get the FDA's take on their plans for studying drugs early in the process, seeking to understand what the agency will require for approval, he said.

"I would like to believe that if those meetings were held, we probably wouldn't be here having this conversation today," Garcia said.

Kerry Dooley Young is a freelance journalist based in Miami. She is the core topic leader on patient safety issues for the Association of Health Care Journalists. Young earlier covered health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and the Food and Drug Administration for Bloomberg. Follow her on Twitter at @kdooleyyoung.

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