Scrutiny of Accelerated Approval Continues as FDA Clamps Down

Reprinted with AIS Health permission from the December 2023 issue of Radar on Specialty Pharmacy*

Scrutiny of the FDA’s accelerated approval process has shown no signs of slowing, with an FDA committee holding a recent meeting on the program’s use for oncology indications, as well as on two cancer drugs lacking confirmatory trial data long after their accelerated approvals. And an FDA leader recently asserted his stance on granting the designation only when companies already have started postmarketing trials. Still, these developments should not dampen interest by either manufacturers or payers in drugs hitting the market via the accelerated pathway, says one industry expert.

The FDA established the accelerated approval pathway in 1992 to bring HIV/AIDS medicines onto the market sooner during the ongoing epidemic. Between that time and Dec. 31, 2020, the agency has granted more than 253 accelerated approvals, according to a 2021 report from the Institute for Clinical and Economic Review (ICER) examining the designation. Of those, 125 — 49.4% — later received full approval, with a median time of 3.2 years from accelerated approval to full. Sixteen — 6.3% — of the indications have been withdrawn, and the remaining 112 drugs have been on the market for a median of 1.9 years.

Some studies have examined the accelerated approval program, with many focusing on oncology, revealing some not-so-flattering findings. For instance, a study published in August 2022 on JAMA Health Forum revealed that of the oncology indications given accelerated approval between Jan. 1, 2007, and Dec. 31, 2021, only 36% were rated as having high added therapeutic value compared with 53.3% for noncancer indications. A study published in JAMA Oncology in June 2018 found that of the 93 new accelerated approval hematology and oncology indications from Dec. 11, 1992, to May 31, 2017, only slightly more than half — 55% — had completed confirmatory trials in a median of 3.4 years after approval, while 40% had not completed those trials. Another study published in BMJ in September 2021 showed that even after a negative confirmatory trial, one-third of indications remained on a cancer drug’s label, and half had the second-highest level of recommendation in National Comprehensive Cancer Network (NCCN) guidelines. Over the past few years, various industry experts have called for a variety of overhauls to the pathway.

As part of the Consolidated Appropriations Act, 2023 (H.R. 2617), passed Dec. 29, 2022, the Food and Drug Omnibus Reform Act of 2022 included several modifications to the accelerated approval process, including giving the FDA the ability to require that manufacturers have a postapproval study underway before the agency grants approval. And it looks like the agency may be taking advantage of that change.


Pink Sheet recently reported that Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence (OCE) and acting director of the Office of Oncologic Diseases, told attendees at the Nov. 14 Friends of Cancer Research Annual Meeting that if a company does not have an ongoing confirmatory study for an oncology agent, the drug will not receive accelerated approval. “We may have an application that has demonstrated safety and efficacy, but will we approve the drug if the confirmatory trial is not underway? And the answer to that is no,” he said.

AIS Health and Pink Sheet are part of the same parent company, Norstella.

“We really want to send a clear message that these trials need to be ongoing,” said Pazdur. “We’re writing guidance at the present time on what ongoing means, but let me tell you folks it’s not just one patient on the trial when the trial has been activated at sites.”

An OCE spokesperson declined to tell the publication when the guidance will be available.

Pazdur’s comments were made two days before the FDA’s Oncologic Drugs Advisory Committee (ODAC) Nov. 16 meeting to discuss the accelerated approval program in oncology and Acrotech Biopharma Inc.’s Folotyn (pralatrexate) and Beleodaq (belinostat). The FDA gave accelerated approval to Folotyn on Sept. 24, 2009, and to Beleodaq on July 3, 2014; however, confirmatory trials have been delayed, with completion not expected until 2030.

The meeting came two years after an April 27-28, 2021, ODAC meeting that scrutinized six indications for a handful of checkpoint inhibitors that target programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) and received accelerated approval to determine whether confirmatory trials verified the therapies’ clinical benefits.

According to the ODAC briefing document for the more recent meeting, the median time from accelerated approval to traditional approval is 3.1 years, and it is 4.1 years from accelerated approval to withdrawal. Out of 187 accelerated approvals for unique drug-indication anticancer pairings, confirmatory trial for slightly more than half — 96 — have verified their clinical benefit and resulted in traditional approval. Before 2020, only six oncolytics with the designation had been withdrawn. But since 2020, manufacturers have withdrawn or begun the process for more than 20 cancer indications and/or drugs. Most recently, Bayer said last month that it will work with the FDA to voluntarily withdraw the New Drug Application for its Aliqopa (copanlisib).


Andy Szczotka, Pharm.D., chief pharmacy officer at AscellaHealth, notes that if data from the ICER report were assessed for the period prior to 2016 — giving those older agents time to complete confirmatory trials — more than three-quarters of the drugs were granted traditional approval, 10% were withdrawn, and “13% were reported to be on the market for a median of almost 10 years without confirmatory evidence to warrant traditional approval. From this data, most of the accelerated approvals are confirmed and contributing positively to disease treatment paradigms.

“While a significant number of these accelerated approvals are ultimately receiving traditional approval, one of the main concerns with this process is the time it takes some companies to complete confirmatory studies and what happens when those studies fail or are not completed,” he tells AIS Health.

One of the FDA’s goals is to make sure that approved agents are safe and effective. “When non-traditional endpoints are used to gain approval, this raises the level of scrutiny for the product to ensure that it will be able to ultimately meet the overall objective, traditional endpoint(s),” says Szczotka. “While surrogate markers may be effective in certain situations, sometimes these are not the ultimate measure of a product’s safety and/or efficacy. Continued review of the accelerated approval process should be an essential element to ensure that the program is meeting the goal to expedite access to truly innovative products that provide new treatment options for serious medical conditions and remove products that are not timely completing their confirmatory trials or meeting agreed-upon clinical endpoints.”

When reviewing drugs with accelerated approval, pharmacy and therapeutics (P&T) committees usually follow the same process as that used for products with traditional approval, he says. “Unless there is an urgent medical need, the P&T review process allows for the time to properly gather the available safety and clinical information needed for evaluation. Since the currently available data has the vast majority of these accelerated approval products ultimately gaining traditional approval, it is unlikely that the review timing would be lengthened.”

That could be changing, though, if a small sample of payers is any indication. An MMIT Payer Event Primer conducted over a few days in September with 10 payer stakeholders found that six of them said they distinguish between drugs with traditional FDA approval and those that require postmarket confirmatory trials. Many of them said that they would place more rigorous prior authorization (PA) criteria on fast-tracked drugs than they would on ones with traditional approval.

AIS Health is a division of MMIT.

Still, accelerated approval means that people have access to novel therapies on a speeded-up time frame compared with the traditional approach, and it “has likely helped provide additional therapy options to patients and physicians, hopefully leading to enhanced patient outcomes,” Szczotka says. “One study looking at all malignant hematology and oncology accelerated approvals were available to patients an average of three to four years earlier than a traditional approval would have allowed. Given the additional market time of these accelerated approval products, it is likely that manufacturers will continue to seek accelerated approvals.”

But given all the scrutiny of the pathway, payers likely “will continue to question how the cost of the accelerated approval products correlates with value and/or unmet need given the typically limited clinical data,” says Szczotka. In addition, manufacturers will be pressured “to complete their confirmatory trials in a timelier manner and then take immediate action on their product in case the trials do not demonstrate a clinically meaningful benefit.” When drugs are shown to be ineffective but remain on the market, this “will lead to additional scrutiny and review of these products.”

Asked about the FDA’s requiring drugs to already be in confirmatory trials by the time of accelerated approval, Szczotka observes that such studies “are an essential part of the accelerated approval process and help demonstrate the continued safety and efficacy of the product for its intended use. From a payer’s perspective, the earlier the confirmatory trial is completed, the sooner the product’s place in therapy can be confirmed. By requiring the confirmatory trial to be started at the time of the accelerated approval, this will only assist in completing the trial in a shorter overall time period.” It also will give payers a better sense of when the FDA will make a decision on granting traditional approval.

“Ideally, contracting for products that have not been granted traditional approval should have the manufacturer be responsible for the cost of those ineffective therapies,” he recommends. “Unfortunately, that is not the case for drug use in the U.S. Traditional contracting approaches will likely continue, with potential application of value-based contracting initiatives in targeted, reportable therapeutic areas.”

Contact Szczotka via Caroline Chambers at

By Angela Maas

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