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Regulatory Focus – This Week at FDA: Califf and Pazdur on return to office, accelerated approval, and more

Regulatory Focus – This Week at FDA: Califf and Pazdur on return to office, accelerated approval, and more

Welcome to another installment of This Week at FDA, your weekly source for updates – big and small – on FDA, drug and medical device regulation, and what we’re reading from around the web. This week, we heard from FDA Commissioner Robert Califf and Oncology Center of Excellence (OCE) Director Richard Pazdur about FDA’s return to office plans, accelerated approvals and a new initiative called Project Pragmatica.

FDA’s Cardiovascular and Renal Drugs Advisory Committee this week recommended the agency approve Ardelyx’s chronic kidney disease drug tenapanor, both on its own and in combination with phosphate binders, Endpoints reports.

The agency also warned seven firms for marketing dietary supplements to treat various cardiovascular diseases. Some of the offending products were listed on Amazon and Walmart, while others were marketed on social media or directly on the companies’ websites. “Given that cardiovascular disease is the leading cause of death in the U.S., it’s important that the FDA protect the public from products and companies that make unlawful claims to treat it,” said Cara Welch, director of the Office of Dietary Supplement Programs within the Center for Food Safety and Applied Nutrition.

Reuters reports that the World Health Organization (WHO) is negotiating rules for handling pandemics in the future. The rules would be legally binding for the international health body’s members, if adopted, and may include provisions to compel drugmakers to release information about drug prices in deals with governments related to products made for future pandemics.

Drugs & biologics

Earlier this week, FDA took an early step toward easing access to the opioid overdose drug naloxone by issuing a notice stating that it believes that low-dose versions of the drug could be safe and effective for over-the-counter use.

On Thursday, FDA issued its latest quarterly batch of product-specific guidances (PSGs) to facilitate the development of various generic drugs. FDA said the batch includes 29 new and 22 revised PSGs, including 28 for complex products, 11 of which that have no generic competition.

The agency also granted several notable approvals this week, including for Provention Bio’s Tzield (teplizumab-mzwv) as the first drug authorized to delay the onset of type 1 diabetes, Immugen’s Elahere (mirvetuximab soravtansine-gynx) to treat platinum-resistant ovarian cancer, and Eli Lilly’s Rezvoglar (insulin glargine-aglr) as the second interchangeable biosimilar insulin product.

FDA recently updated two standard operating policy and procedure documents: SOPP 8403: Issuance, Reissuance, and Voluntary Revocation of Biological Product Licenses and SOPP 8405.1: Procedures for Resubmissions to an Application or Supplement.

Plus, we learned that FDA has finished work on a guidance on homeopathic products. The guidance is currently with the Office of Management and Budget for review and could be released soon.


FDA announced a public workshop on 7 December that will focus on the appropriate use of consensus standards in medical device premarket submissions.

FDA this week handed Roche an emergency use authorization (EUA) for its high-throughput monkeypox test. The cobas MPXV test works with Roche’s cobas 6800/8800 systems.

Califf and Pazdur talk return to office, accelerated approvals and Project Pragmatica

In a candid discussion at the Friends of Cancer Research (FOCR) Annual Meeting in Washington, DC on Thursday, Califf and Pazdur shared their expectations for the agency’s work model after more than two years of operating in a mostly virtual environment.

“One thing I miss now, compared to 2016, is I used to walk around the FDA, and you would just see rooms of people looking at data, trying to figure out what it means,” Califf reflected. “We’re here in person now. If you walk around White Oak right now, there’s a lot of empty space … Now we’re getting to decision time about what we’re going to do about return to office and there are certain members of Congress who have strong views about it.”

“Empty space? The place is deserted,” Pazdur quipped, noting that he foresees the agency maintaining a hybrid work model “with a great degree of flexibility” going forward.

Califf said the agency is finalizing its plans for returning to the office, but “no one I know is arguing that 100% of people should be there like the old days,” and cited job satisfaction and productivity as benefits of remote work. But, Califf said, “the expectations of the industries that we regulate – we’ve heard loud and clear they want in-person meetings, so there will be that component of it.”

On accelerated approvals, Pazdur said the agency is really interested in seeing companies come in with a “comprehensive plan about what their confirmatory study is” when they come to the agency to discuss an earlier approval. While he said that larger companies often adhere to this, he said that “where we do get into trouble is … with a drug company that may not be adequately capitalized [that] wants to get their foot in the door.”

The other issue, Pazdur said, is taking drugs off the market when confirmatory trials fail to verify clinical benefit. “If a study has failed … then I think the companies have to step up and take these drugs off the market as rapidly as possible – and many of the companies have,” he said.

Pazdur referenced the withdrawal of Avastin’s (bevacizumab) breast cancer indication and the agency’s ongoing effort to remove Makena (hydroxyprogesterone caproate injection) from the market as examples where the pathway hasn’t worked as intended. “These represent challenges of how to make the system more nimble because a tremendous amount of resources have gone into these hearings to remove a drug,” Pazdur said.

“It’s been ten years I think since the Avastin hearing and it still is a nightmare for me what we went through,” Pazdur said, noting recent efforts in Congress to reform the accelerated review pathway to make it easier to remove drugs from the market.

“I think we’re in complete agreement [accelerated approval] has been an extremely valuable pathway,” Califf said, noting his own experience with his mother taking a drug that had been granted accelerated approval after exhausting other treatment options. “She got two or three extra years of good life because of that phone call and that accelerated approval.”

Despite his positive experience with the pathway, Califf said the agency needs “more teeth” to withdraw approvals and require drugmakers to begin confirmatory trials before the approval.

Califf then asked Pazdur about his observations on the trend toward “offshoring” of clinical trials in oncology.

“We want multiregional trials that represent the major [International Council for Harmonisation] ICH regions in the world … we want adequate representation of patients from North America, Europe, Asia to be represented. We believe this gives us a spectrum of representation of patients from our own country. We’re not suggesting that all clinical trials have to be done in the United States or there is a percentage that has to be done in the United States, but we want representation from all ICH regions,” Pazdur said.

He also noted the difference between a clinical trial conducted in other countries and one conducted in a single foreign country, referencing the recent Oncologic Drugs Advisory Committee (ODAC) meeting on Innovent’s PD-1 inhibitor sintilimab that largely dealt with the adequacy of the company’s China-only clinical trial strategy. (RELATED: FDA officials, advisors cast doubt on foreign-only clinical strategyRegulatory Focus 10 February 2022)

Pazdur also offered details on a new initiative dubbed Project Pragmatica that aims to simplify the process of conducting pragmatic trials. “This came to me in kind of a lightning bolt when I saw a small trial that was done under Lung-MAP,” Pazdur said. The trial, which looked at ramucirumab plus pembrolizumab versus standard of care in second line lung cancer, had some issues and it “wasn’t meant to be a registration trial.”

“I thought this would really be a great idea of trying to do a pragmatic trial – here again, preserving randomization – but making it as simple as possible. So what we discussed with the NCI is basically having really only one endpoint of the trial and that is overall survival … very minimal eligibility criteria and basically no safety reporting other than for hospitalizations or toxicities that are not described in the safety endpoint.”

“We’ve made these trials way too complicated … when I take a look at informed consents that go on for 20 pages, no patient will read this,” Pazdur said.

However, Pazdur noted that the project would only be appropriate for “the right drug, the right situation,” and when there is a known safety profile.