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Endpoints News – FDA leaders Califf and Pazdur dish on accelerated approval reforms, single-country trials and an empty White Oak

Endpoints News – FDA leaders Califf and Pazdur dish on accelerated approval reforms, single-country trials and an empty White Oak

FDA Commissioner Rob Califf sat down for a conversation on Thursday morning with Rick Pazdur, head of the FDA’s Oncology Center of Excellence, with the two agreeing that accelerated approval reforms need to happen, that multi-regional clinical trials are always better than single-country trials, and that returning every last FDAer to the White Oak campus doesn’t make sense.

The conversation, conducted as part of the Friends of Cancer Research’s annual meeting, began with Califf’s questions on the empty space around White Oak as routine staff have mostly moved their operations to the more versatile virtual setting, and as advisory committee and all industry meetings remain virtual.

Pazdur even went so far as to call White Oak “deserted,” noting that “there are more security guards than employees.” But he also made clear that it doesn’t make sense to require everyone to return to an in-person office.

“What is the purpose of going back? To make an administrator happy?” Pazdur asked rhetorically, saying that the clock-punching mentality of years past needs to be rethought given the workload and workforce.

Califf noted that industry has been “loud and clear” about wanting to return to in-person meetings, but a more hybrid environment may be what the FDA settles on moving forward to remain agile.

On the topic of accelerated approval reforms, which Democrats initially sought to include in the user fee legislation but may end up dealing with in this lame duck session, Pazdur reiterated what he wrote in the New England Journal of Medicine in September about cleaning up the confirmatory trial process.

“There’s a period of vulnerability we have to control,” Pazdur told Califf, noting that from accelerated approval announcement to confirmation of clinical benefit, “we should try to reduce that period as much as possible.”

For oncology indications that have been granted AAs, the median time to beginning the withdrawal process “was longer if the confirmatory trial was initiated after the approval,” Pazdur and OCE leaders wrote in the NEJM. “This difference was most striking among withdrawn indications, with a median time to withdrawal of 3.8 years if the confirmatory trial was ongoing at the time of AA, as compared with 7.3 years if such a trial had not been initiated. Delayed withdrawals in this latter scenario represent the greatest risk to patients.”

Pazdur also told the conference and Califf that larger companies are largely adhering to the FDA’s requests when it comes to withdrawing AAs, “but we get into trouble with a company that may not be adequately capitalized,” noting the system needs to be more nimble and suggestions floated in Congress on various ways to expedite the removal of these drugs, or even differential charging for drugs under AA compared to prices for full approvals.

“When I came to the agency in 1999, I realized this was a problem and with your predecessor, I suggested that drugs under accelerated approval not be considered available therapy and my reason for that was that this would make companies want to do these studies as quickly as possible. Unfortunately that didn’t work,” Pazdur said.

While noting that he also highly values the AA pathway, Califf added that “we need more teeth,” particularly on getting those confirmatory trials started prior to the approval. “Once the approval occurs, it’s very hard to hold back marketeers,” Califf added.

On the question of single-country trials, following FDA’s rejection of Eli Lilly’s attempt to bring another PD-1 cancer drug with China-only data to the US market, Pazdur made clear that the FDA favors multi-regional trials.

“We’re not suggesting  that all clinical trials have to be done in the United States or a percentage has to be done in the United States, but we want representation of all of the ICH regions,” including North America, Europe and Asia, Pazdur said.

He also noted that sometimes companies move trials outside the US because of cost issues, which “might be a reasonable issue,” but “one of my problems” is when companies will use single-country trials because they can test the investigational product against an inferior therapy and that trial wouldn’t be ethically run in the US. He added:

I think this is particularly problematic. One of the reason people go on clinical trials is to get the best therapies. There’s no asterisk that says only approved in your country. People are going to lose confidence in the system if they know trials are done with inferior treatments.

“These companies are not Mother Theresa here, they’re using patients here, and we have to always make sure patients aren’t considered commodities,” Pazdur added.

Califf said there is a problem of people leaving the US for treatment and trials, and Pazdur noted that the US clinical trial ecosystem needs to be simplified as patient consent forms can still run 20 pages long.

On that note, OCE is launching “Project Pragmatica” alongside the National Cancer Institute to simplify certain trials with drugs that have known safety profiles, and can answer questions on overall survival more rapidly with a pragmatic trial that preserves randomization.

Both Pazdur and Califf agreed that the key here is randomization. “External controls have limitations and the beauty of randomization really is to take and address factors we don’t know about,” Pazdur said.