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Pink Sheet – FDA’s Pazdur: Accelerated Approval Is ‘Under Attack,' Supporters Can’t Afford To Remain Silent

Pink Sheet – FDA’s Pazdur: Accelerated Approval Is ‘Under Attack,' Supporters Can’t Afford To Remain Silent

Accelerated approval is “under attack,” by critics who are “one-sided” and not taking a comprehensive look at the program, said Rick Pazdur, the director of the US Food and Drug Administration’s Oncology Center of Excellence.

Pazdur, speaking on 29 July at a Friends of Cancer Research event on the 21 Century Cures Act follow-up legislation Cures 2.0, said that supporters of the program, which speeds drugs to market before they have proven a clinical benefit, need to speak up so that accelerated approval is “not defined by” its critics. Without such champions, he fears a dramatic rollback of the regulatory authority.

“I think that it is extremely important that we have a big picture of what this initiative has provided to us. And those people that are unwilling to voice their support for this program, may one day wake up with a much different regulatory environment, one that may be very ultra-orthodox in its regulatory approaches to the cancer patients and put a p value above the needs of cancer patients,” Pazdur said.

The FDA oncology lead’s comments came in response to a question as to whether expedited approval pathways are working as intended and whether Congress should do anything to improve such programs.

“I think there is room for improvement,” Pazdur said, but he also pointed to the very small fraction of accelerated approvals that have been revoked (about 10 out of more than 155) as a marker of its success. The vast majority – about 85% – of accelerated approvals have been in the oncology field.

What Pazdur neglected to mention, however, is that while few accelerated approvals have been pulled, research points to lingering gaps in the characterization of clinical benefit for many drugs years after their initial clearance by FDA.

For example, a May 2019 paper in JAMA Internal Medicine found that only a fraction (20%) of accelerated approval indications had confirmatory studies that reported an improvement in a clinical benefit of overall survival. In comparison, about 20% had confirmatory trials that used surrogate measures that were the same as those used in the preapproval trials and 21% reported improvement in a different surrogate. A substantial number of accelerated approvals were in limbo due to delayed, or long-pending confirmatory trial results. In at least one case, an accelerated approval was converted to full approval, despite not meeting its clinical endpoint in its confirmatory trial.

Pazdur did indirectly address some of this criticism, pointing to his belief that some drugs, like certain PD-1/L1 inhibitors have failed confirmatory trials not because the drug was a failure, but because of improper trial design. In these cases, similar competitors have succeeded in the same indication. (Also see “FDA’s Pazdur Blames Trial Design Errors For Some PD-1/L1 Failures, Foreshadows Potential Agency Leniency” – Pink Sheet, 30 Jun, 2021.)

Pazdur also acknowledged there could be improvements to the make it easier for FDA to remove accelerated approval drugs from market when they don’t confirm benefit in their post-market studies. The Oncology Center of Excellence has been working with the Friends of Cancer Research to develop potential policy changes for the accelerated approval mechanism that would both make it easier to bring products to the market and withdraw them if warranted. (Also see “Accelerated Approvals Could Be Improved By Focusing On Benefit/Risk, Making Withdrawal Easier” – Pink Sheet, 9 Feb, 2021.)

The Aduhelm Overhang

Those OCE/FOCR efforts were underway before the accelerated approval for Biogen, Inc.’s Alzheimer’s therapy Aduhelm (aducanumab-avwa) thrust the pathway onto center stage. 

Pazdur was consulted on the use of the pathway during Aduhelm’s review, and after Aduhelm was cleared he suggested accelerated approval could transform neurology in the same way it transformed oncology two decades ago. (Also see “Pazdurcanumab: US FDA’s Top Cancer Official Weighs In On That Big Neurology Approval” – Pink Sheet, 9 Jun, 2021.)

The backlash to the Aduhelm might eventually lead to less, not more, frequent use of the mechanism, though, and instead of marking and expansion of  accelerated approval’s use into other therapeutic areas, it could lead to a contraction if opponents hold sway.

Pazdur didn’t mention any of that – or even refer to Aduhelm – when he talked about the need to fight for the pathway. He didn’t have to.

Overall Survival Isn’t The Only Goal

Pazdur also argued that accelerated approval critics are too focused on overall survival as the only endpoint that provides benefit to patients.

“For a person such as me, who has practiced medical oncology for 20 years before I came to the FDA, I recognize that there’s many other endpoints that people recognize that designate benefit to them,” Pazdur said, citing a dramatic reduction in tumor size, and the delay of rapidly progressive disease or progression-free survival as a “benefit into itself.”

“So it’s very important that we just don’t define a very narrow criteria of what defines success,” Pazdur said.

Furthermore, Pazdur said that critics miss that the true benefit of some accelerated approval drugs is getting them out there so they can be used in early stages of disease, in combinations and sequentially.

“People are just focusing on the drug application, this little box here and miss the entire picture of what the drug will mean, once it’s out there and further developed,” he said.

Pazdur’s plea got a boost from the National Cancer Institute Director Ned Sharpless, who served as acting director of the FDA during the middle of the Trump Administration.

While the Aduhelm approval may have stirred up tensions around accelerated approval, in cancer care the program “has really been transformative,” Sharpless said.

“We don’t want to go back to those periods where we have these active agents that we can’t get the cancer patients in a timely manner because of regulatory hurdles. … So I agree that the program should be looked at and perhaps could be improved in some ways. But I don’t think we should lose sight of the fact that these advances are really paying off for cancer,” Sharpless added.