UPDATED: FDA advisors recommend against approving Eli Lilly’s PD-1, casting shadow over future of China-made cancer drugs
In a lively and sometimes contentious hearing, the FDA’s Oncologic Drugs Advisory Committee (ODAC) nearly unanimously recommended against approving Eli Lilly and Innovent’s anti-PD-1 antibody sintilimab, dealing a blow to “me-too” cancer drugmakers hoping to reach the market based solely on data from China.
But the panel’s concerns were largely overshadowed by FDA officials tearing into Lilly over not making good on its promises to increase trial diversity, submitting the application without consulting regulators before the trial concluded and misrepresenting interactions with the agency during its presentation.
The top two FDA reps at the hearing, oncology chief Richard Pazdur and Director Division of Oncology 2 Harpreet Singh, both said the study did not meet “good clinical practice” standards and suffered data integrity issues. They both asked repeatedly whether there were any instances of fraudulent data reporting, given how a 2016 investigation found about 80% of data from trials conducted in China are counterfeit.
In the wake of the news, Lilly issued a somewhat apologetic statement to Endpoints News, which read in full:
While we are disappointed with the outcome of today’s ODAC as it relates to the investigational product sintilimab, we 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. Lilly 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. Along with Innovent, we will continue to work with the FDA as it completes its review of the sintilimab application.
Lilly remains committed to bringing forward medicines with the potential to meaningfully improve treatment paradigms for patients with cancer.
Earlier Thursday, the panelists were ostensibly supposed to discuss whether or not Lilly’s trial, dubbed ORIENT-11, could be applicable and generalizable to the US population. ORIENT-11 was conducted entirely in China, raising questions at the FDA about if the positive data seen would remain the same in a more heterogeneous setting.
Discussion soon devolved into a public flogging, however, with Pazdur and Singh taking Lilly to task over not just the diversity issues, but the nature of the study itself. Lilly and Innovent used progression-free survival as their primary endpoint, but most of the previous PD-1 drug studies have nabbed approval based on overall survival.
In addition, while Lilly and Innovent were conducting the study, Pazdur and Singh contended that the standard of care for non-small cell lung cancer — the indication in which Lilly is seeking approval — changed to Merck’s Keytruda plus chemotherapy. The regulators pointed to one Keytruda study in particular, KEYNOTE-189, they said was paradigm-shifting in lung cancer. Lilly and Innovent did not update their informed consent guidance to allow patients in the control arm to take Keytruda, with Singh accusing the drugmakers of preventing patients from getting the best available drugs.
Lilly, for its part, noted the ORIENT-11 trial was originally designed to obtain approval in China. Once the company saw the data, it approached the FDA with the study, Lilly VP of gastrointestinal oncology strategy David Ferry told the panel.
This, too, drew the ire of FDA officials. In both its presentation to the committee and while clarifying questions for the panel members, regulators criticized Lilly for not consulting with the FDA at all until the study read out topline data. Competing narratives emerged during the presentations about the timeline of the interactions between the two parties, with Lilly claiming it met three times before submitting its BLA.
After Singh castigated Lilly for misrepresenting its conversations with the FDA, she threatened to release all private correspondences to the public. Singh said that some federal regulations may allow for flexibility on foreign data in certain instances, but only when the FDA can validate the data through inspections and training investigators.
“I find this incredibly misleading,” Singh said to Lilly at one point. “We used much stronger language in invoking the regulations, and would be happy to provide all the info into the public record.”
Company execs apologized multiple times during the hearing, with one saying, “It’s certainly not our intent to mischaracterize our interactions with the agency.”
Panelists voted 14-1 that a new trial should be required for approval. Most of the panelists agreed more so that the data and ORIENT-11 protocol were not good enough to recommend an OK, but split over how to better design an appropriate study. Throughout the meeting, FDA vouched to begin including more Chinese data in multi-regional clinical studies.
A positive recommendation — and potential approval — were likely to be difficult for Lilly. Late last week, FDA oncology chief Richard Pazdur wrote in The Lancet that drug applications seeking approval based on data from a “single foreign country” need to be representative of the US population in order for regulators to be flexible (generally, the FDA requires companies to conduct pivotal studies at least in part in the US).
Pazdur’s article proved to be an about-face from earlier public comments made at a medical conference in 2019 when, while recounting a recent trip to China, he said the FDA would accept applications based solely on Chinese data. In an interview with STAT News on Tuesday, Pazdur defended the flip, declaring, “I have a right to change my mind.”
While discussing the issues with the panelists, Pazdur also took a step further, addressing that former AACR comments “should not be viewed as regulatory policy.” He also described how treatment landscapes have changed in the last three years, both due to improvements in survival data and how the Covid-19 pandemic has changed the public’s desire for diversity in all aspects of life.
“Single country submissions are a step backward in achieving the racial diversity we need in the United States,” Pazdur said, “and we want people to understand this is a major goal not just in oncology submissions but throughout all submissions at the FDA.”
Lilly is unlikely to be the only company affected by this ruling, as several others are attempting to get drugs on the American market through Chinese-only data. Pazdur said in his Lancet article — and the FDA said in its presentation — that there are about 25 such applications either under review, planned to be submitted or currently under development.
Most notably, the biotech EQRx is developing a large suite of drugs in-licensed from Chinese companies with the goal of disrupting pricing models in the US. One of its two lead programs is an anti-PD-L1 antibody, known as sugemalimab, which EQRx has said it could price at a 40% to 50% discount.
Lilly had attempted a similar price disruption strategy, with oncology head Jacob Van Naarden saying Wednesday the company had plans to discount the drug by as much as 40% compared to other PD-1s on the market. So far, each of the seven anti-PD-1 and anti-PD-L1 drugs approved by the FDA has been priced the same at $150,000 per year.
But the FDA does not take pricing into account when reviewing drugs, a point hammered repeatedly in Pazdur’s 2019 comments, his Lancet article and the FDA presentation Thursday. Regulators told panelists that all discussion of pricing would not be allowed.
Even before ODAC made its recommendation and the FDA had thoroughly tongue-lashed Lilly and Innovent, the ramifications of the potential “no” vote were being felt in the industry. During AstraZeneca’s fourth-quarter and FY2021 earnings call earlier Thursday, executive VP of oncology David Fredrickson said he feels more confident now about the company’s Tagrisso franchise, essentially telling Lilly, “I told you so.”
Unlike sintilimab, Tagrisso is an EGFR-TKI inhibitor approved for EGFR-mutated NSCLC in the first-line setting.
“I’ve been fairly consistently wanting to raise the fact that China-only studies that don’t have overall survival, and that compare against an old standard of care, bring with them some regulatory risks,” he said, adding later, “I do think that certainly, the ODAC from today, the briefing documents do give me more confidence that there is regulatory hurdles in front of the competition that’s seeking to come in from some of the competitors that we’ve seen.”
CEO Pascal Soriot piled on, noting, “I’m not sure that declaring a price before an ODAC is a good strategy.”
This article has been updated to include comment from Eli Lilly as well as additional context on the landscape of Chinese-only data, including comments from AstraZeneca executives David Fredrickson and Pascal Soriot.