NEW YORK – More and more cancer treatments, and now gene therapies, are receiving accelerated approval from the US Food and Drug Administration as sponsors push to get their novel medicines to patients with few options. But in speeding these drugs to market, sponsors, regulators, and patients accept greater uncertainty about these medicines’ safety and efficacy, especially since results from post-approval studies can take years.
The US Food and Drug Administration’s accelerated approval pathway got its start in the 1990s, spurred by the HIV/AIDS epidemic. “It was really in response to patient advocacy groups who wanted earlier access to treatments that were in the pipeline, essentially, to get them out there faster,” said Joseph Ross, a professor of medicine and public health at Yale School of Medicine. “And one of the ways they hit on to enable the FDA to do this was to allow for regulatory approvals to be based on pivotal trials using surrogate markers as endpoints rather than clinical outcome studies.”
The FDA may grant accelerated approval to a treatment based on a surrogate endpoint that is “reasonably likely” to predict a clinical benefit, such as how much a drug shrinks a tumor, a sign that a treatment is working since tumors typically don’t get smaller on their own. But just because a drug shrinks a tumor for a time doesn’t mean that it won’t eventually become resistant to the treatment and the patient’s health won’t decline. That’s why when a treatment is approved based on a surrogate endpoint like overall response rate, sponsors must conduct confirmatory trials to ensure that it actually benefits patients, ideally, by allowing them to live longer or better.
The accelerated approval pathway and the use of pathway surrogate endpoints has had a particular appeal for cancer therapeutics, said Lola Fashoyin-Aje, senior VP for regulatory strategy for oncology drugs and cell and gene therapies at Parexel, a clinical research organization. This is the case, she said, because there is often an unmet need for new treatments among cancer patients and there are early measures of drug activity, like tumor shrinkage, that can provide a hint as to whether or not the treatment is effective.
Most drugs, 83 percent, approved through this pathway between 2012 and 2021 were for oncology or hematology-oncology indications. Those therapies include a number of cancer therapy heavyweights. Merck’s checkpoint inhibitor Keytruda (pembrolizumab), for instance, has received accelerated approval in a number of biomarker-defined indications, as has Bristol Myers Squibb’s checkpoint inhibitor Opdivo (nivolumab) and Eli Lilly’s RET inhibitor Retevmo (selpercatinib).
Developers of gene therapies are also leveraging the accelerated pathway. For example, Sarepta Therapeutics’ Duchenne muscular dystrophy gene therapy Elevidys (delandistrogene moxeparvovec-rokl) was a recipient of accelerated approval in 2023.
Many drugs granted accelerated approval are eventually converted to full approval. For 129 drugs granted accelerated approval for a cancer indication between 2013 and 2023, about two-thirds were converted to full approval after more than five years of follow-up. Keytruda’s 2015 accelerated approval in metastatic PD-L1-positive NSCLC, for instance, was converted to full approval the following year. The combination of Opdivo and Yervoy (ipilimumab), which won accelerated approval in 2018 for treating unresectable or metastatic microsatellite instability-high or mismatch repair-deficient colorectal cancer, converted to full approval earlier this year. And Retevmo’s 2020 accelerated approval in advanced RET-mutant medullary thyroid cancer became a full approval in 2024. The gene therapy Elevidys, meanwhile, converted to full approval a year after its accelerated approval.
While sponsors of therapies granted accelerated approval are required to conduct additional studies to verify the products’ clinical benefit to get that conversion to full approval, some oncologists and researchers have raised concerns about delays in the completion of those confirmatory trials. According to one analysis of 104 drugs with accelerated approval that had incomplete confirmatory trials as of late 2022, those studies were past their original planned completion dates by an average 20 months. This may leave some drugs with unconfirmed effects on the market.
However, there have been recent changes to the FDA’s authority, allowing it to push sponsors to conduct confirmatory trials more quickly. And the agency has detailed its thinking on managing the accelerated approval process, so more confirmatory trials are completed in a timely fashion, in two recently published guidance documents.
Some 278 drugs were granted accelerated approval between 1992 and the end of 2021. “It’s quite a successful program,” said Jeff Allen, president and CEO of advocacy group Friends of Cancer Research, acknowledging that it brought a number of new drugs to patients with unmet medical needs faster. “That is an important factor to consider.”
Faster, but with more unknowns
While an accelerated approval gets a drug to market quickly, Yale’s Ross noted that it comes with more unknowns because those approvals are largely based on the treatment’s impact on a surrogate outcome or biomarker rather than a gold-standard clinical trial endpoint like overall survival or other irreversible morbidity. “There’s a trade-off with the certainty with which we know whether something works,” he said.
In a 2024 JAMA study, Ross and his colleagues investigated the strength of the data underpinning the associations between 37 markers from the FDA’s Adult Surrogate Endpoint Table that were used as endpoints in clinical trials for either accelerated or full approvals, focusing on non-oncology indications. Most surrogate markers, they found, lacked high-strength evidence from published meta-analyses.
“We were focusing mostly on those that they considered validated and still found very few sources of evidence to confirm that they’re validated,” Ross said.
One surrogate marker they investigated was the reduction in beta-amyloid plaques in Alzheimer’s disease, which was used to support the accelerated approval of Biogen and Eisai’s Leqembi (lecanemab) in 2023. The FDA converted Leqembi to a full approval later that year based on evaluations showing that by lowering beta-amyloid the drug modestly slowed cognitive decline by around 27. However, the three meta-analyses Ross’ group uncovered offered conflicting evidence on the strength of the association between beta-amyloid reduction and how well patients fared on cognitive scales assessing Alzheimer’s disease.
The FDA responded in a letter to JAMA that their decisions to approve Leqembi was based on a range of data sources, including internal analyses. “[T]o evaluate surrogate endpoints, the FDA considers an evidence base that goes well beyond the published meta-analyses considered by [the team],” wrote Peter Stein, then the director of the FDA’s Center for Drug Evaluation and Research’s Office of New Drugs, with two colleagues.
Ross countered that the internal data the FDA used should then be made public. “I would say, ‘Well, then, make that clear, cite it, publish it, let the scientific community understand why you’re making these decisions because it impacts all of us, and it shouldn’t be information that’s sequestered within the agency,'” he said.
Gregory Meyer, VP of regulatory strategy at Premier Research, a clinical research, product development, and consulting firm, believes that the intrinsic uncertainty that comes with surrogate endpoints is necessary to bring innovative drugs to market that otherwise might take years to show clinical benefits, by which time it might be “too late to help people who are desperate for treatment in the meantime.” Eager to try the latest medical advances, patients with deadly cancers or rare diseases without treatment options and their families are often willing to take on the risks of trying a new drug, knowing that there are gaps in our understanding of how well it works or how safe it is.
They’re willing to take the risk “if there’s a chance that this product is going to be a more effective cure for cancer with fewer side effects or can lessen suffering in a rare disease population,” Meyer said. “There’s understandably more risk tolerance among the parents of children who know with certainty that their child will die by the time they get to their late 20s. They want anything that they can get right now.”
“The chance that you’re taking is that most of the time, it is going to be predictive of clinical benefit, but you have to accept that sometimes it will not,” said Fashoyin-Aje, who prior to joining Parexel earlier this year was deputy director of the FDA’s oncology division that regulated drugs for gastrointestinal cancers, superficial cutaneous cancers, melanomas, and sarcomas.
Friends of Cancer Research’s Allen noted that what makes a good surrogate endpoint can depend on the situation and added that “it is worthwhile to examine biomarker qualifications.” Friends of Cancer Research, for example, is looking into validating circulating tumor DNA as a surrogate measure of response.
Some delays
Though post-approval studies are required to verify the clinical benefit of therapies awarded accelerated approval, a 2022 report from the US Department of Health and Human Services Office of Inspector General (HHS OIG) found a number of those trials were incomplete.
Of the 278 drugs granted accelerated approval from the start of this approval pathway through 2021, 104 had incomplete confirmatory trials and 35 of those trials were past their original planned completion dates by more than a year and a half on average. That report came on the heels of the FDA’s controversial accelerated approval in 2021 of Biogen and Eisai’s since-withdrawn Alzheimer’s monoclonal antibody Aduhelm (aducanumab), which prompted the HHS OIG to evaluate the pathway more broadly.
Around this time, the FDA also began cracking down on sponsors who had gotten accelerated approval for certain products, but the confirmatory data hadn’t supported keeping them on the market. This resulted in sponsors pulling a number of precision medicines off the market, such as Genentech’s Tecentriq (atezolizumab) in PD-L1-positive first-line bladder cancer and Merck’s Keytruda in PD-L1-positive third-line gastric cancer. And in 2023, Roche decided to stop selling the RET inhibitor Gavreto (pralsetinib) in RET-mutant advanced medullary thyroid cancer, stating that it wasn’t feasible to conduct the confirmatory trial.
There are a number of reasons why confirmatory trials may be difficult to complete on time. According to Fashoyin-Aje, one reason is that sponsors may not have proactively planned their clinical development program, possibly due to financing constraints, all the way through to post-approval studies. Many new therapies, she said, are being developed by small biotechs that then partner with larger pharma companies when they get to that stage of the process.
Further, once a drug is available on the market, it may be difficult to recruit patients to take part in a confirmatory, randomized trial, in which they must undergo bloodwork, imaging, and other testing, and they might not even receive the novel product if they’re in the comparator arm. “It may be unrealistic to expect patients with a serious disease to enroll in a clinical study to receive a therapy that has been replaced with a better alternative, when that better alternative is available commercially,” Fashoyin-Aje said.
And once a drug is available on the commercial market, sponsors may have little motivation to complete a confirmatory trial quickly, if they are already seeing patient demand and recording revenue.
Ravi Parikh, an associate professor of hematology and medical oncology at Emory University School of Medicine, and his colleagues examined prescribing patterns of oncology drugs after they received accelerated approval and after their subsequent conversion to regular approval. As they reported last month in JAMA Network Open, most of the 29 different oncology indications they analyzed had an average 23 percentage-point rise in prescribing following receipt of an accelerated approval but a much more modest 1 percentage point rise on average in prescriptions following conversion to full approval.
“Once the drug is on the market, it’s on the market,” Parikh said. “Any risk to the drug going on or off the market, there’s no incentive for the pharma companies to be communicating that.”
Getting a move on
There have been in recent years FDA initiatives aimed at encouraging confirmatory trials to begin more quickly.
The Consolidated Appropriations Act of 2023 gave the agency more authority to set requirements for confirmatory studies, including timelines for their start and completion, and directly address some of the delays. Additionally, the agency can now require that a confirmatory trial is underway before it grants a therapy accelerated approval. The agency issued two guidance documents, one in December 2024 and another in January 2025 to provide more details on its expanded authorities. It also created a formal, expedited withdrawal procedure for drugs with accelerated approval, should the confirmatory trial fail to verify its expected clinical benefits.
“The FDA has specified in guidance the criteria they will be using to make a judgment as to whether the trial is underway and describe the factors reviewers will take into account in working with that sponsor to develop a timeline that’s appropriate,” Fashoyin-Aje said, noting that there is flexibility built into the agency’s approach, too.
A 2018 analysis appearing in JAMA Oncology found that for a set of 64 oncology drugs granted accelerated approval in 93 indications, having an ongoing confirmatory trial at the time of accelerated approval was associated with a shorter median time to verification of benefit, 3.1 years versus 5.5 years for the drugs that did not have a trial underway at that time. A separate study appearing in JAMA in 2023 found that, for drugs granted accelerated approval more broadly, trials that started after approval took a median 18.5 months to get off the ground.
“The agency has provided clear guidance, and the key now is to see how this is being implemented and what we can collectively learn as a research ecosystem from the agency’s proposed approach,” Fashoyin-Aje said.
The FDA did not respond to a request for comment on the accelerated approval pathway.
In Ross’s view, the sponsors have a responsibility to get confirmation that their drugs are actually benefiting patients. “We’re asking a lot of patients. They’re paying a lot of money out of pocket for these therapies, and they are often very sick people that could be towards the end of their life with cancer,” he said. “And so the bargain should be that we’re doing everything we can to get recruitment and trials going so that we get the evidence that we need.”
But even if sponsors are pushed to start confirmatory trials faster, they still need to ensure that they generate the necessary data to verify the drug’s clinical benefit. Emory’s Parikh suggested that the FDA could also take a more uniform approach in what it requires from confirmatory studies. In a study appearing in BMJ Oncology in May, he and his colleague found a lot of variability in post-marketing requirements.
Parikh acknowledged that not all post-marketing requirements will be the same, as one sponsor may face, for instance, recruitment challenges due to a small patient population for a drug that another might not. “[But] it didn’t look like a lot of the leniency [from the FDA] was tailored to rareness of a disease or anticipated difficulty recruiting,” he said. It would be OK, in his view, for the FDA to be flexible based on the specific realities of a particular indication, but based on his team’s analysis, “it looked like it was a bit random as to whether the FDA was more stringent or less stringent for a given drug.”
Further, the researchers found post-marketing requirement statements that were less rigorous and allowed studies to use endpoints other than overall or progression-free survival were more likely to be associated with an on-time study submission and conversion to regular approval. That is, Parikh said, there was “a direct correlation between how lenient the FDA was [regarding endpoints] and how quickly the study got done.”
He suggested that post-marketing requirement statements could be better standardized to ensure that the needed outcomes data are collected in confirmatory studies, but with flexibility, for example, for studies of very rare diseases that may need a longer time to accrue participants. “The FDA could ensure that the confirmatory evidence a study actually gives us is the information that we want it to,” he said.
A new voucher
The FDA announced in June another program, dubbed the FDA Commissioner’s National Priority Vouchers, a pilot program, that’s aimed at speeding up the time it takes to review a drug.
In contrast, Fashoyin-Aje explained, the accelerated approval pathway aims to hasten a drug’s development time. “However, both are aligned in that they aim to get the products to patients as quickly as possible,” she said. “The voucher program’s focus is at the tail end of clinical development during the marketing application review, while accelerated approval expedites the development to approval timeline.”
Though there are few details on the program as yet, the agency has said the program will focus on speeding up the review of drugs that tackle a health crisis in the US, deliver an “innovative cure,” address unmet public health needs, or increase domestic drug manufacturing.
To Ross, the voucher program sounded as if it could be akin to the Real-Time Oncology Review Program, in which the FDA review is done in stages. But such an approach could lead to ad hoc reviews, and if that’s the case, he worries that the process would wind up being inefficient, as officials might start reviewing new drug applications whose trials ultimately don’t pan out.
Parikh added that such a program might work best for extremely rare indications or ones that already have amassed strong evidence. “And if that’s the case, I don’t think I have as much of a problem with it,” he said. However, “if it becomes a commonly used mechanism, then it risks exacerbating some of the problems that we and others have been covering.”
Meyer echoed that concern. “Every time you create a new special workaround program, you’re potentially taking resources away from the general activity of the regulatory agency, and you don’t want to be in a situation where you’re robbing Peter to pay Paul,” he said. “There should always be a concern when you create an opportunity for somebody to get to the head of the line.”
As for the accelerated approval pathway, most experts think it is largely achieving its goal of expediting new therapies to patients with unmet needs, but they also see room for improvement. “Personally, as an oncologist, I have seen situations where most of these accelerated approvals are ultimately confirmed, and they’re ultimately confirmed because agents are effective,” Parikh said. “Earlier access has definitely changed many of my patients’ lives for the better.”