In a largely expected yet widely debated decision, the FDA declined to approve Eli Lilly and Innovent Biologics’ China-developed immunotherapy sintilimab for certain lung cancer patients. Critics blame the FDA and its oncology chief Richard Pazdur, M.D., for closing the door to meaningful price reductions in the widely used PD-1 drug class, and some suspect that the agency is playing to the growing geopolitical tension between the U.S. and China.
In an interview with Fierce Pharma, Pazdur, director of the FDA’s Oncology Center of Excellence (OCE), defended the rejection.
“I am not against China, that was not the implication here,” Pazdur said in an interview. “It was a future-directing approach to what drug development should be.”
‘It’s in the long-term interests’
The FDA took issue with Lilly and Innovent’s use of a phase 3 clinical trial conducted solely in China as the core data backing sintilimab’s application. As Pazdur and his FDA colleagues have noted in two articles and an internal review document published in the run-up to the eventual rebuff, international multiregional clinical trials are the standard in registrational studies, per guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). China joined ICH as a full regulatory member in 2017.
“It’s in the long-term interests of all countries, including China, really to participate in these global trials,” Pazdur said, because they could solve the problem of trial diversity compared with single-country data.
The FDA oncology czar also warned against using data predominantly from one single country and then adding a small number of patients elsewhere to “give the veneer of an international trial.”
Despite China’s ICH membership and local drug regulators’ crackdown on data integrity in the past few years, the FDA still appears to hold some reservations about clinical data coming out of China. The distrust likely comes from a huge wave of drug application withdrawals in 2015 when Chinese authorities launched a program that threatened penalties against fraudulent clinical data. Although the Chinese biopharma industry viewed that campaign as a push toward more regulatory supervision, the FDA pointed to it as evidence of a data integrity risk in sintilimab’s review document.
“I’m taking a look at our long-term approach of dealing with China on a large basis—in Chinese data,” Pazdur said.
The FDA is still getting familiar with clinical trial sites in China. As Pazdur noted, the FDA has limited inspection capabilities of clinical sites.
When the FDA encounters a trial with data from one country or sites that the agency isn’t familiar with, it usually turns to international data from various sites to gain assurance, Pazdur explained, calling the practice “an experiential type of thing that is developed over years.” But with sintilimab, approved in China under the brand name Tyvyt, that cross-reference wasn’t an option.
China has approved about a dozen PD-1/L1 inhibitors, with several having signed on Western partners in the hope to leverage the low costs of doing drug research there to target the lucrative U.S. market. The FDA expects that at least 25 programs similar to sintilimab’s phase 3 trial will be filed or are currently under review. As SVB Leerink analyst Daina Graybosch said in a February note, the FDA is drawing a line in the sand to discourage this single-country trial approach.
FDA issue with trial's control arm
Also raising concerns at the FDA was the fact that Lilly and Innovent pitted sintilimab against chemotherapy when PD-1 inhibitors have become the standard of care in newly diagnosed non-small cell lung cancer in the U.S. Lilly and Innovent basically had leveraged the lag of drug approvals between the U.S. and China to avoid running a costly head-to-head trial. But to be fair, none of the currently approved PD-1/L1 inhibitors won their go-aheads based on head-to-head clinical trial against an in-class rival.
Further adding to the problem, Lilly and Innovent failed to update the patient consent form to inform patients of the best therapy out there after Merck & Co.’s PD-1 inhibitor Keytruda was approved in China midway through their trial.
Pazdur blasted Lilly and Innovent’s approach. Cancer drug developers should ensure that all patients get the best therapies, he said, and “not exploit nuances in drug regulation that a drug happens not to be approved in a particular country.”
To fill that international drug approval gap, which is already narrowing if not completely gone, Pazdur welcomed his Chinese counterparts to join Project Orbis. The FDA’s OCE initiated the project to provide a framework for concurrent drug submission and review of oncology drugs among international regulatory bodies. However, as Pazdur noted, there are major issues preventing such a collaboration between U.S. and Chinese regulators because of a “confidentiality agreement” between the two countries.
In the meantime, Pazdur invoked a statement from former FDA commissioner Peggy Hamburg: “If you don’t see the light, you soon will see the fire.”
“You really need to see what’s going on here and move forward and work with us, and everyone will be better for that.” Pazdur said.
Pricing and R&D are distinct issues
When the FDA hinted that it would reject sintilimab, many industry watchers lamented the loss of an opportunity to disrupt a stagnant PD-1/L1 drug pricing scene. All seven FDA-approved PD-1/L1 inhibitors currently carry list prices of around $150,000 for a year’s treatment. And as this class of drugs gradually becomes the new standard of care in multiple cancer settings, its burden on the healthcare system is growing.
On the eve of an FDA advisory committee meeting to discuss sintilimab’s application, Lilly pledged that it would offer a biosimilar-like 40% discount for the drug originally developed in China. By shooting down sintilimab, the FDA has denied a low-cost version to potentially save the U.S. billions and increase access, critics of the agency’s stance have argued.
What’s more, sintilimab is cheaper partly thanks to its R&D efforts being conducted in China with clinical trials comparing it to old standard chemotherapy. But as the FDA insists on global head-to-head trials, it will be difficult for sintilimab and other “me-too” drugs to crack the market from the pricing angle.
Still, the FDA can’t take costs into its evaluation, Pazdur said. As he sees it, tackling drug pricing issues through FDA reviews could introduce unintended consequences to drug development.
“I’m concerned about pricing, too, not as a drug regulator but as a U.S. citizen, as somebody that might take one of these drugs eventually,” Pazdur said. “But it isn’t just about PD-1 drugs, it’s about a bigger issue.”
“The pricing issues in drug in America has to be addressed by addressing pricing, not by just duplicative drug development because that introduces a whole cascade of issues.”
Although serious questions remain as to whether Lilly and Innovent’s 40% discount would matter because of how the U.S. reimbursement system is set up, proponents of the move have argued that the FDA should at least allow sintilimab the chance to take a stab at the PD-1/L1 market.
Pazdur said he would question pricing claims made by “established drug companies.”
“There’s an old statement that a charity begins at home,” the OCE chief said. “What about their other drugs that they have on the market that are very high-priced? If they’re so concerned about pricing, why aren’t they addressing those prices too? You can’t have it both ways.”
Lilly, along with other major diabetes med manufacturers, has been embroiled in controversy over rising insulin prices in the U.S. Amid mounting pricing pressure, Lilly first introduced a generic version to its popular Humalog in 2019 at nearly half the original's price. Starting this year, the Indianapolis pharma further cut the price of the generic insulin by 40%.
In a common practice in the pharmaceutical industry, Lilly in January joined a long list of drugmakers in jacking up the list prices of its products by around 3% to 5%, including for popular GLP-1 diabetes med Trulicity and inflammatory disease drug Taltz.