Skip to content

Pink Sheet – US FDA Says Confirmatory Trials Should Start Before Accelerated Approval But Is Not ‘Dogmatic’

Pink Sheet – US FDA Says Confirmatory Trials Should Start Before Accelerated Approval But Is Not ‘Dogmatic’

Sponsors should expect increased pressure through the review pathway to ensure products receiving accelerated approval confirm benefits as stakeholders continue working to strengthen the system.

Oncology Center of Excellence Director Richard Pazdur wants to squeeze the US Food and Drug Administration’s so-called “period of vulnerability” between clearance and the determination of a clinical benefit.

“The major thing that we’re really interested in is companies having a comprehensive plan about what their confirmatory study is, what is the evidence that they’re coming in to discuss,” he said during a 17 November Friends of Cancer Research Annual Meeting session.

OCE Associate Director Lola Fashoyin-Aje also said that the “historical practice of kind of seeing if you’re going to get accelerated approval and then initiating that trial isn’t one that’s going to be acceptable moving forward.”

“We think it’s really important to have discussions of those two trials, if it’s two trials, at the same time so as we are considering the accelerated approval application, we have a clear path to verifying clinical benefit,” she said.

Pazdur said in an interview after the meeting that OCE does not want to deny therapy to patients when discussing confirmatory study timing: “We’re not dogmatic about it.”

But he reiterated that running one additional trial to confirm benefit is not a lot to ask.

“If you really believe in a drug you should want to do this,” Pazdur said.

Most sponsors are adhering to the recommendation. But Pazdur said newer or smaller companies sometimes try to avoid it, which could harm patients.

“Where we do get into trouble is with kind of a drug company that may not be adequately capitalized or something like that financially [and] wants to get their foot in the door so to speak with a single arm study in a very limited number of patients,” Pazdur said during the session. “That puts the patient at risk.”

Data from OCE’s Project Confirm already has shown that accelerated approvals convert to full approvals nearly two years earlier if the confirmatory trial is underway when the accelerated approval is granted.  (Also see “Accelerated Approvals Convert Much Faster If Confirmatory Trial Already Underway, FDA Cancer Data Shows” – Pink Sheet, 14 Jul, 2022.)

Outside Of Oncology, A Path Less Followed

FDA guidance recommends that confirmatory trials be underway at the time an accelerated approval is granted. But since guidance does not carry the force of law or regulation, the FDA has limited leverage to ensure the trials are initiated at that time.

Still, FDA’s oncology shop has been fairly effective at convincing sponsors to the adhere to the timetable. Cancer has accounted for the vast majority of the accelerated approvals in the agency’s post-HIV iteration of the pathway, so it makes sense that the division would be the most familiar for the advantages and shortcomings of the process.

And just as they pioneered many uses for accelerated approval, FDA’s oncology regulators are also developing ways to reign it back in, with an emphasis on having confirmatory trials already underway at approval and then pushing to withdraw “dangling” indications when the trials fail or aren’t even completed. (Also see “The Long And Short Of Accelerated Approval Accountability In US” – Pink Sheet, 29 Nov, 2022.)

Outside of oncology, though, some controversial products have received long periods to complete confirmatory studies. Biogen, Inc. was given nine years to enroll and complete the confirmatory trial for its Alzheimer’s treatment Aduhelm (aducanumab-avwa), which roiled critics of the accelerated approval.  (Also see “Aduhelm, One Year Later: US FDA’s Credibility, Accelerated Approval Pathway Feel The Bite From Alzheimer’s Drug Approval” – Pink Sheet, 6 Jun, 2022.)

Sarepta Therapeutics, Inc. also did not have its confirmatory study started when its controversial Duchenne muscular dystrophy drug Exondys 51 (eteplirsen) received an accelerated approval in 2016. The company was given more than four years to complete the study, but it has been delayed multiple times.  (Also see “3,189 Days: Aduhelm Phase IV Timeline Is Long Among Alzheimer’s Drugs And Other Accelerated Approvals” – Pink Sheet, 12 Jul, 2021.)

Congress considered reforms as part of the FDA user fee reauthorization package that would have sped withdrawals and allowed the FDA to mandate confirmatory studies be underway prior to approval.  (Also see “User Fee Bill’s Accelerated Approval Reform Provisions Watered Down, But Could Speed Withdrawals” – Pink Sheet, 4 May, 2022.)

A “clean” bill was passed, but some of the riders left out could find new life during the lame-duck session of Congress.  (Also see “After ‘Clean’ User Fee Renewal, Will Programs Held Hostage Be Enough To Drive A Broader Reform Bill?” – Pink Sheet, 28 Sep, 2022.)

Avastin Withdrawal Still A Nightmare, Pazdur Says

Withdrawing products after confirmatory trials fail remains problematic, especially when the sponsor does not agree that market removal is appropriate. Pazdur said the process needs to be “more nimble.”

If a confirmatory study fails “I think the companies have to step up and take these drugs off the market as rapidly as possible,” he said.

“It’s been 10 years I think since the Avastin hearing and it still is a nightmare for me what we went through as far as the resources, the amount of hours that were spent in preparation both on part of the company, as well as the FDA, for very, very little reward.”

When the FDA moved to remove the breast cancer indication from the label of Genentech, Inc. ’s Avastin (bevacizumab), the process took about a year to complete.  (Also see “Avastin Vs. Makena: A Comparative Timeline Of The Two Accelerated Approval Withdrawal Fights” – Pink Sheet, 19 Jan, 2022.)

The FDA’s effort to remove Covis Pharma’s pre-term birth prevention drug Makena (hydroxyprogesterone caproate) from the market has lasted more than two years, with a decision not expected until 2023.  (Also see “N Of 2: Reflections On The Makena, Avastin Accelerated Approval Withdrawal Hearings” – Pink Sheet, 21 Oct, 2022.)

FDA Commissioner Robert Califf, who interviewed Pazdur during the meeting, also said the withdrawal process needs more teeth, adding that ensuring confirmatory studies are started before the accelerated approval is granted is important.

“Once the approval occurs it’s very hard to hold back the marketeers from the things that they can do,” Califf said.

Indeed, a product can remain on the market while withdrawal proceedings are ongoing, which can lead to months or years of additional sales.  (Also see “One More Message From Makena: Fighting US FDA Can Pay Off” – Pink Sheet, 1 Nov, 2022.)

Accelerated Approval One Of Many Clinical Development Reforms Offered

During the meeting, Pazdur also continued to advocate for improvement and simplification of the clinical development process. He announced the launch of Project Pragmatica, which will encourage simple clinical trials.  (Also see “Project Pragmatica: US FDA’s OCE Initiative Aims To Encourage Simple Clinical Trials” – Pink Sheet, 21 Nov, 2022.)

Pazdur also said the National Cancer Institute should be working more closely with the sponsors and suggested the NCI’s clinical trial network could be used to handle US enrollment of clinical studies for innovative products.  (Also see “US FDA’s Pazdur Suggests NCI Should Help Sponsors Enroll Clinical Trials For Innovative Drugs” – Pink Sheet, 18 Nov, 2022.)

The idea could help improve clinical trial diversity. Stakeholders also have suggested incentives such as exclusivity or tax credits also could help ensure clinical trials better mirror the US population.  (Also see “Clinical Trial Diversity Would Benefit From Regulatory, Financial Incentives, Experts Say” – Pink Sheet, 25 Nov, 2022.)