AACR: 'We have to have a level playing field'—FDA oncology chief explains confirmatory trial rejection

Few officials at the FDA have the same influence as Richard Pazdur, M.D. In 2023, the Oncology Center of Excellence (OCE) under his leadership doled out 83 therapeutic approvals, including 14 for new drugs. So when the FDA’s oncology czar speaks, people listen.

At the inaugural American Association for Cancer Research Oncology Industry Partnering Event, Pazdur addressed some key topics at the FDA’s oncology department, including accelerated approval and confirmatory trial requirements, advisory committee meetings, some new regulatory initiatives and even his succession plan.

As always, Pazdur’s statements—sometimes blunt and humorous while other times strategically vague—offer biopharma companies important guidance to the OCE’s practice and priorities.


Two first-of-their-kind complete response letters

The FDA a few days ago issued two surprise complete response letters to Regeneron’s applications for accelerated approvals of its CD20xCD3 bispecific odronextamab in certain blood cancers. The action marked the first time a drug was rejected because of progress on confirmatory trials.

Pazdur said the FDA has been talking about the importance of having timely confirmatory studies for more than a decade. The agency recently gained the authority to require companies to have the confirmatory trial underway at the time of an accelerated approval—and to reject a drug if that prerequisite is not met—thanks to the Food and Drug Omnibus Reform Act of 2022.

Regeneron, for its part, supports the confirmatory trial reforms but told Fierce Biotech last week that industry needs more guidance on what exactly constitutes a confirmatory trial being “well underway.”

The decision for Regeneron was meant to level the playing field among drug developers, Pazdur explained during a fireside chat at the AACR event. Before odronextamab, the FDA has granted accelerated approvals to three other CD20xCD3 bispecifics, namely Roche’s Columvi for diffuse large B-cell lymphoma (DLBCL) and Lunsumio for follicular lymphoma, plus AbbVie and Genmab’s Epkinly in DLBCL.

When considering whether to issue a complete response letter, the OCE takes a patient-centric approach, Pazdur said. And that means possibly different rulings under different circumstances.

“If we really believe that there are no other therapeutic alternatives, then there will be obviously some degree of flexibility,” Pazdur said. “When we do see, however, that there may be accelerated approval with the same class of drugs with the same diseases and with sponsors previously having most of the confirmatory study accrual already completed at the time of accelerated approval, we have to have a level playing field for all of the pharmaceutical companies.”

Regeneron’s proposed confirmatory studies had begun but only for the safety lead-in phase. Because the company is trying to move odronextamab into earlier treatment settings, the confirmatory trials were required to have an extra dose-finding phase before the actual randomized confirmatory efficacy portions begin.

Pazdur made clear that the FDA wants sponsors to “have the studies ongoing.” And that means the actual confirmatory studies are ongoing, not just the dose-finding stage. But in other occasions, including as part of the OCE’s relatively new Project Confirm, Pazdur and the agency “strongly recommend” that the confirmatory trials be “well underway if not fully enrolled” at the time of accelerated approval.

These slightly different descriptions raised the question of the exact level of confirmatory trial progress that the FDA wants to see. The answer? There isn't a straightforward one.

“Really, it’s a case-by-case basis that we’ll be looking at,” Pazdur said. “But the studies have to be enrolling, and we have to have confidence that these studies will meet a pre-specified timeline.”

The FDA these days wants drug companies to have discussions about their “comprehensive development plans,” including the confirmatory trial design, early on with the agency, Pazdur said.

“The exact number of [enrollment] needs to be discussed,” Pazdur added. “We also have to have confidence that the accelerated approval is not going to interfere with the completion of the trial or other accelerated approvals that may be reading out in the same disease, especially with the same class of drugs.”

The FDA has in the past encountered cases where the approval of new drugs rendered patients reluctant to be randomized to older treatments, making enrollment impossible for a confirmatory trial that wasn’t already well underway.

As to some companies’ complaint that they may not have the funding to conduct large, randomized trials without an accelerated approval already under their belt, Pazdur said the argument “falls on deaf ears” because money simply doesn’t play any part in the FDA’s consideration.

New projects

Project Confirm is one of many initiatives that the OCE has launched in recent years. To Pazdur, all of these projects were designed to address specific issues. Project Optimus, for example, asks companies to explore the optimal dose instead of blindly pushing for the highest tolerable dose regardless of potential harm. Project Equity is designed to increase diversity and inclusion in oncology clinical trials.

One program Pazdur would like to see more advancement on is Project Pragmatica, which explores ways to simplify clinical trials in terms of patient eligibility criteria and trial endpoints.

“I just feel over the years, we've made our lives a living hell, so to speak, with more and more complexity to clinical trials,” Pazdur said. “And with greater complexity, I cannot imagine how an investigator could explain this to a patient.”

The FDA previously worked with researchers, Eli Lilly and Merck & Co. on the design of a National Cancer Institute-sponsored phase 3 trial dubbed Pragmatica-Lung. The study evaluates the combination of Cyramza and Keytruda against standard chemotherapy in non-small cell lung cancer following treatment with immunotherapy and chemotherapy. It has one simple efficacy endpoint—overall survival. But since then, the project hasn’t attracted any interest from biopharma companies.

“One of my biggest disappointments is that we have made many overtures to industry, and they have not readily taken these up,” Pazdur said.

The FDA oncology chief said he's had discussions with the European Medicines Agency and regulators in Japan, and both are on board. That means companies don’t have to worry that such a simplified trial won’t be able to support approvals outside the U.S.

Pragmatica-Lung represents just one way to run these as Pazdur emphasized a potential “spectrum of pragmatic trials.” Such a simplified trial could only collect safety data on 20% of the patients and only grade 3 or above toxicities, and it could look at when people start new therapies as an endpoint, Pazdur said.

“So I challenge you to come and meet with us to discuss these statistical designs,” Pazdur said. “And we are interested in pragmatic trials.”

Fixing adcomms

When the FDA has questions about an application, it assembles a team of external experts who form an advisory committee meeting to discuss key issues on the approvability of a drug.

FDA Commissioner Robert Califf, M.D., has said he doesn’t believe that most advisory committee meetings need to have a vote. But to Pazdur, a vote is crucial to the OCE at least when a specific drug application is concerned.

“Many of the people that are arguing for not having this voting question have not been in the review division,” Pazdur said.

“Having sat through 25 years of these meetings, I do not know, before the vote occurs, what is going to happen here,” Pazdur said. “We need that clarity—we have to make a decision.”

Pazdur described companies following the advisory committee meetings as a “fire-breathing dragon.” Because everybody has a different opinion of what attitude the committee experts have expressed, and because millions or billions of dollars in R&D expenses and potential sales are at stake, a vote is necessary to settle the case.

Pazdur was not alone in supporting the vote. Peter Stein, director of the FDA’s Office of New Drugs, recently stated that “the vote is important,” because it allows the experts the explain themselves.

But some changes need to be made to these meetings, Pazdur said.

For one thing, to really have an engaging discussion, Pazdur wants the meetings to go back to in-person attendance. He also wants to put less emphasis on clarifying questions so more time can be allocated to determining the most important issue of benefit-risk.

“Rarely do I say this: I actually feel sorry for the pharmaceutical companies for having to undergo this interrogation with some of these questions that don’t make sense,” Pazdur said. “And I don’t even know why people are asking the questions, because it has nothing to do with the question at hand.”

Pazdur is also concerned about an increasing number of trial investigators who have personal or academic relationships with committee members while standing before the committee defending a drug.

“I think that this has the potential of really providing a lack of confidence in the system if this continues,” Pazdur said.

Building trust

To Pazdur, how he interacts with drug companies is also key in building trust with the public and his oncology review staffers.

“I do not take calls from companies about specific applications,” Pazdur said. “I just feel that that undermines the process here.”

Previously, the FDA’s former neuroscience chief Billy Dunn had a face-to-face meeting with Biogen’s ex-R&D head Al Sandrock in a questionable episode leading up to the FDA’s controversial approval of the Alzheimer’s disease drug Aduhelm. Revelation of the overly intimate relationship between an FDA official and a drug sponsor caused a huge backlash and a congressional inquiry.

Pazdur believes private discussions with a company also leads to distrust within the agency.

“It’s just human nature that you want to have the whole group there if you are going to have a cohesive team,” he said.

Pazdur said he even rarely goes to a company meeting with the FDA group because it would attract all of the attention to him.

“It has to be toward the review division, that they feel that they are really making the decision that they are really in charge of the application. And that's how you build a staff that is interested in staying at the agency, that their viewpoints are really recognized, and they are not being overwritten by somebody,” Pazdur said. “That should be done only in the rarest of circumstances.” 

As one of the three FDA center leaders, Pazdur is viewed as an influential official at the agency alongside the commissioner, the Center for Biologics Evaluation and Research director Peter Marks, M.D., Ph.D., and Namandjé Bumpus, Ph.D., who recently replaced the retired Janet Woodcock, M.D., as the principal deputy commissioner.

When asked who would take on the OCE baton, Pazdur said it isn’t his job to decide who should succeed him. He stressed that it’s important to look at candidates both inside and outside the agency, noting that he came from the academic world.

“It is not my responsibility, nor should it be, to say: This is Richard Pazdur’s philosophy, and it must continue forever,” he added. “It’s a good idea sometimes to shake things up.”