FDA updates bladder cancer drug guidance, expands single-arm study recommendations

The US Food and Drug Administration (FDA) has issued an updated draft guidance on developing treatments for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). It is an update to a final guidance on the topic and expands the agency’s recommendations on the proper use of single-arm studies.

FDA said it received significant feedback from stakeholders after it published the 2018 final guidance on the issue, which it used to propose the updated guidance. The new guidance eliminates several key sections but adds some new recommendations on how to conduct clinical trials to develop the bladder cancer drugs.

One of the most significant changes to the guidance is that the agency has expanded the section on single-arm studies during clinical development.

As in the previous version, FDA notes that single-arm trials to develop these cancer drugs are acceptable where conducting randomized, controlled trials (RCT) would be unethical or infeasible. However, in the new document, the agency notes that patients without active disease should be included in RCTs using a time-to-event primary endpoint, such as recurrence-free survival.

"In contrast, patients with [carcinoma in situ] CIS at trial entry can be studied in either a randomized, controlled trial or a single-arm trial," said FDA. "In the absence of pharmacologic intervention or cystectomy, BCG-unresponsive CIS (a type of NMIBC), with or without resected disease, will persist and progress, making complete response (CR) an interpretable endpoint in the single arm setting.”

"In BCG-unresponsive NMIBC with CIS at trial entry, a single-arm clinical trial with CR rate as the primary endpoint, supported by duration of response, can provide primary evidence of effectiveness to support a marketing application," the agency added. "Sponsors can include patients with completely resected lesions and no evidence of CIS in these single-arm trials but should not include them in the evaluation of the primary efficacy endpoint (e.g., CR rate). However, sponsors should include these patients in the safety analysis."

FDA also lists other factors when a sponsor is considering whether to include a patient in an RCT or a single-arm trial such as what alternative treatments patients may have access to, the number of investigational drugs the patient may be on and the potential for toxicity, and the ability to interpret time-to-event endpoints.

Another major addition to the guidance is taking BCG supply issues into consideration when designing a clinical trial.

"In times of BCG supply issues or when enrollment of sufficient patients who meet the prior BCG criteria in the definition of BCG unresponsive disease is not feasible, sponsors may consider inclusion of patients who received less than adequate prior BCG as defined in Section IIB2, partial doses of BCG, or alternative treatment schedules,” said FDA. “Enrolling these patients will create uncertainty in the interpretation of endpoints such as durable CR as assessed in a single arm trial given that the outcomes in response to subsequent therapies is unknown for these patients.”

The agency recommended that sponsors use a randomized trial design when there is such uncertainty so the results can be better interpreted when the sponsor must enroll a heterogeneous population that has previously received BCG. It also recommended stratifying the patients to control for the differences in how they were exposed to BCG.

In the late-phase drug or biologics development section of the 2018 final guidance, the FDA recommended that sponsors consider whether a person has active NIMBC during trial enrollment, which is key to the trial design and endpoints. The agency said those without active disease should be put in a randomized, controlled trial design using a time-to-event endpoint.

By contrast, the new draft guidance removes that section and instead moves up the dosage selection section. It emphasizes that sponsors should consider non-clinical and clinical data to better understand the investigational drug's dose and exposure-response in the late-phase trial. The agency also noted that the sponsor should provide a strong rationale for their proposed dosage regimens before initiating the trial.

FDA changed its recommendations for determining the trial population and the criteria sponsors should use to enroll patients in their studies. The agency updated that if a patient meets the criteria for BCG-unresponsive disease at any time during their treatment course, the sponsor should take that the patient has BCG-unresponsive NMIBC regardless of whether BCG was the most recent therapy the patient underwent.

"Duration of the disease-free interval following the most recent therapy prior to recurrence should be recorded, as a prolonged versus a short disease-free interval may reflect different underlying biology," the agency added. "Sponsors are responsible for providing evidence to demonstrate that the patient met 'BCG unresponsive' criteria, even if this occurred substantially prior to enrollment."

Draft guidance

FDA updates bladder cancer drug guidance, expands single-arm study recommendations

Related topics

Recommended content

Welcome to the new RAPS Digital Experience