FDA Questions Single-Arm Studies for Cancer Approvals

Medscape

23-05-2025

The US Food and Drug Administration's (FDA's) approval decision about a new treatment for non–muscle invasive bladder cancer (NMIBC) hinges on whether a single-armed trial can be trusted to adequately demonstrate risks and benefits.
The issue came to a head May 21 when the agency asked its Oncologic Drugs Advisory Committee (ODAC) to weigh in on UGN-102 (UroGen Pharma), an intravesical mitomycin formulation meant to be an alternative to transurethral resection of bladder tumor (TURBT) for recurrent low-grade intermediate-risk NMIBC.
UroGen presented results from its ENVISION trial in 223 patients with recurrent lesions on day 2 of a meeting of the FDA advisory committee. After 6 weekly 75 mg instillations, the complete response rate at the 3-month checkup was 77.6%. Twelve months after a complete response, almost 80% of subjects remained recurrence-free; at 18 months, just over half were still recurrence-free.
UroGen highlighted the convenience of UGN-102, which can be instilled in a urologist's office, over TURBT, which is a surgical procedure usually done under general anesthesia. The company said UGN-102 'can reduce the burden of repeated TURBTs' in elderly, comorbid patients.
However, there was no control arm in ENVISION, so outcomes vs TURBT, the current standard of care, are unclear.
'The lack of a concurrent control in the single-arm ENVISION trial makes interpretation of efficacy challenging,' the FDA said in a meeting document.
Although the complete response rate indicates drug activity, the agency said the durations of response found in the study could simply be due to the fact that some patients with NMBIC recur, while others do not.
The same holds true for safety. Most of the adverse events in the trial were genitourinary and low grade, but it's unclear if there are fewer than with TURBT. For one, patients were at risk for adverse events throughout the entire 6-week treatment window, whereas the duration of side effects with TURBT, as a single procedure, is generally shorter.
'The applicant has not demonstrated that treatment with UGN-102 is safer or more tolerable than TURBT,' the FDA said in the document.
The FDA wanted UroGen to run a head-to-head randomized trial against TURBT. UroGen started one, but there was disagreement with the agency about how it should be conducted, and the trial ended early.
How Committee Members Voted on Benefits vs Risks for UGN-102
On day 2 of the ODAC meeting, the FDA said the preliminary findings can't be used to compare the two approaches due to methodological issues.
Richard Pazdur, MD, head of FDA's Oncology Center of Excellence, said there are also larger issues at play.
If the agency approves UGN-102 for such a condition as common as NMIBC based on a single-arm study, 'guess what? Nobody's going to do a randomized trial. It goes to the lowest denominator for companies,' Pazdur said.
The FDA didn't ask ODAC's opinion on approving UGN-102. Instead, it simply wanted committee members to vote on whether the overall benefit-risk of UGN-102 is favorable for recurrent, low-grade, intermediate-risk NMIBC based on the data.
Five panelists voted 'no,' and four voted 'yes.'
Radiation oncologist Daniel Spratt, MD, a prostate cancer specialist at Case Western Reserve University, Cleveland, was one of the 'no' votes.
Without the randomized trial, he said, 'It's very hard to determine the true benefit of this, and there is toxicity.' Plus, 'this is a $140,000 treatment that might not change how many follow-up TURBTs you need after 3 months.'
Another 'no' vote, Heidi McKean, MD, a community oncologist in Sioux Falls, South Dakota, said that 'in this population, a randomized control trial is feasible and would have really helped us understand the clinical meaningfulness of the intervention.'
Surgical oncologist Mark Ball, MD, a kidney cancer specialist at the National Cancer Institute in Bethesda, Maryland, voted 'yes' in favor of UGN-102.
The complete response rate at 12 months and beyond, 'even though there are differences in the interpretation of the data, is quite encouraging. I don't find the toxicity profile alarming, and therefore,' Ball said, 'the benefit-risk ratio is favorable.'
Isla Garraway, MD, PhD, a urologic surgical oncologist at the University of California, Los Angeles, also voted 'yes,' saying it would be ideal to have a less invasive, in-office alternative to TURBT for the older patients most often affected by NMIBC.
In the end, Pazdur said, 'This a relatively split vote, so we will be meeting with the sponsor to look at future directions.'
ODAC was also asked for its thoughts on whether the FDA should require randomized trials for future low-grade, intermediate-risk NMIBC approval submissions.
Committee members generally agreed, as long as the requirement doesn't delay the approval of promising treatments.