Confirmatory study delay after FDA accelerated approval should be ‘cautionary sign’
Key takeaways:
- Cancer drugs that received accelerated approval gained regular approval faster when their confirmatory trials showed high clinical benefit.
- Several other factors also correlated with faster regular approval.
Cancer drugs that received accelerated approval from the FDA gained regular approval significantly faster if their confirmatory trials demonstrated meaningful clinical benefits, according to results of a retrospective study.
The FDA more quickly granted regular approval to drugs that had confirmatory trials underway at the time of accelerated approval, those that did not have boxed warnings, those that had received priority review designation and those supported by pivotal trials achieving intermediate or high clinical benefit.
The time differences could be measured in years.
“These results suggest that the most beneficial accelerated approval drugs tend to complete confirmatory trials soonest, and delayed completions should be a cautionary sign for patients and oncologists considering prescribing these drugs,” Ariadna Tibau Martorell, MD, PhD, associate researcher at Program on Regulation, Therapeutics, and Law (PORTAL) in the division of pharmacoepidemiology and pharmacoeconomics at Harvard Medical School and Brigham and Women’s Hospital, told Healio.
A ‘controversial’ pathway
The FDA’s accelerated approval program has helped drugs reach patients approximately 3 years earlier than they would have with traditional approval, according to study background.
Approximately a third of cancer drugs have been approved through the accelerated approval pathway, including several that demonstrated significant survival benefits.
However, between 15% and 20% of all drugs granted accelerated approval are withdrawn after confirmatory trials do not show clinical benefit, Tibau Martorell said.
“This pathway is particularly controversial due to delays in completing confirmatory studies, which raise concerns about exposing patients to clinical and financial risks—especially when these trials yield negative results and the drug is ultimately withdrawn,” she added. “In addition, the majority of confirmatory trials still depend on surrogate endpoints, many of which are unvalidated, instead of assessing overall survival or quality of life.”
Tibau Martorell and colleagues investigated factors that led cancer drugs given accelerated approval to receive quicker regular approval.
They used the FDA website to gather data on cancer drugs or indications that received accelerated approval and subsequent full approval from the program’s inception in 1992 through 2022.
The analysis included 102 cancer drug indications. Most (81%) had received priority review and about a quarter (26%) had boxed warnings. Two-thirds of indications were for solid tumors and 79% had confirmatory trials initiated before accelerated approval.
Researchers evaluated outcomes and safety of both the pivotal and confirmatory trials.
They used ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) to score both sets of trials, as well.
Time to full approval of each drug served as the primary endpoint.
Results
The median time from accelerated to regular approval reached 3.1 years (range, 1.9-4.8).
For drugs evaluated in pivotal trials, factors associated with significantly shorter time to regular approval included priority review designation (yes vs. no, 2.9 years vs. 5.11 years; P = .002), ongoing confirmatory trial at time of accelerated approval (yes vs. no, 2.78 years vs. 5.59 years; P < .001), boxed warning (no vs. yes, 2.9 years vs. 4.61 years; P < .001), and clinical benefit based on ESMO-MCBS (high or intermediate vs. low, 2.37 years vs. 3.81 years; P = .03).
For drugs evaluated in confirmatory trials, factors associated with shorter time to regular approval included OS benefit (yes vs. no, 2.15 years vs. 3.7 years; P < .001), quality-of-life benefit (yes vs. no, 2.29 years vs. 4.22 years; P = .01) and clinical benefit based on ESMO-MCBS (high vs. other, 2.34 years vs. 3.91 years; P < .001).
“On one hand, the results are reassuring because they confirm substantial time savings and early availability of beneficial drugs for patients,” Tibau Martorell said. " However, prolonged accelerated approvals without timely conversion should be seen as early warning signs of limited clinical benefit." “In addition, a quarter of the drugs that were granted accelerated approval show low clinical benefit with the ESMO-MCBS framework in confirmatory trials. These drugs spend more than 3 years on the market without confirming their clinical benefit.
“The accelerated approval pathway, theoretically, should be given to drugs that offer a meaningful clinical benefit over available therapies,” she added. “We would expect that more drugs offer high clinical benefit.”
Speed matters
In a separate study, Catherine S. Hwang, MD, MSPH, assistant professor of medicine at Oregon Health & Science University, and colleagues previously evaluated four cancer drug indications that initially received accelerated approval but eventually had to be withdrawn.
Their results, published in JAMA Oncology, showed between 12 and 113 months elapsed between accelerated approval and first publicized negative confirmatory trial results.
The time between reporting of results and regulatory withdrawal ranged from 1 to 47 months.
The drugs all had approvals for other indications prior to withdrawal.
Use of one of the drugs, atezolizumab (Tecentriq, Genentech), increased by 16 per 1 million patients for the indication that garnered accelerated approval prior to the negative trial results. That number decreased by 28 per 1 million patients after withdrawal.
These results emphasize the pitfalls of accelerated approval, Tibau Martorell said.
“The confirmation of the benefit or the refutation of the benefit needs to be done as fast as possible,” she added. “The period of uncertainty should be as short as possible.”
Future research should focus on identifying which drugs have a higher likelihood of being withdrawn or have low clinical value.
“We are introducing a new concept, which is the substantial clinical benefit,” Tibau Martorell said. “The number of drugs is increasingly rising. It’s something that should be considered as a way to refine the pathway.”
Kristina Jenei, BSN, MSc, PhD student in the department of health policy at The London School of Economics and Political Science, and colleagues echoed that sentiment in an accompanying editorial in JAMA Network Open.
“The accelerated approval pathway was designed to expedite patient access to promising treatments for serious or life-threatening diseases, allowing approvals based on intermediary surrogate endpoints so long that sponsors verify meaningful clinical benefit through the timely completion of confirmatory studies,” Jenei and colleagues wrote.
“However, work by Tibau [Martorell and colleagues] demonstrate that most drugs are approved on unvalidated surrogate measures that fail to demonstrate meaningful benefit. In this sense, the pathway seems to prioritize speed for clinical benefit, leaving patients with substantial uncertainty and potential harm.”
References:
- Hwang CS, et al. JAMA Oncol. 2025;doi:10.1001/jamaoncol.2025.0359.
- Jenei K, et al. JAMA Netw Open. 2025;doi:10.1001/jamanetworkopen.2025.2040.
- Tibau A, et al. JAMA Netw Open. 2025;doi:10.1001/jamanetworkopen.2025.2026.
For more information:
Ariadna Tibau Martorell, MD, PhD, can be reached at atibaumartorell@bwh.harvard.edu.
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