On February 12, 2018, FDA issued final guidance on developing drugs and biologics for treatment of bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC). The guidance provides FDA’s current thinking regarding development of drugs and biologics aimed to treat patients in this population.

For purposes of this Guidance, BCG-unresponsive disease is defined as being at least one of the following: (1) persistent or recurrent carcinoma-in-situ alone or with recurrent Ta/T1 disease within 12 months of completing adequate BCG therapy, (2) recurrent high-grade Ta/T1 disease within 6 months of completing adequate BCG therapy, or (3) T1 high-grade disease at the first evaluation following an induction BCG course. According to FDA, this population of patients have limited current treatment options, with cystectomy (bladder removal) being the current alternative. The goal of therapy in these patients is to avoid cystectomy.

FDA’s guidance covers early product development, late phase development, and additional considerations, such as, risk management and nonclinical safety. During early product development, FDA recommends nonclinical animal studies to assess toxicity, and early nonclinical studies to demonstrate antitumor activity and appropriate dosing regimens. For late phase development, FDA offers a series of recommendations for patients without and with active disease. FDA provides that a key consideration for the recommended trial design and endpoints used to evaluate the effectiveness of an investigational drug treating NMIBC is whether the patient has active disease at the time of enrollment. For those patients without active disease, FDA recommends a randomized, controlled trial design using a time-to-event endpoint such as recurrence-free survival. In contrast, patients with active disease (carcinoma in situ (CIS)) at trial entry can be studied in either a randomized, controlled trial or a single-arm trial. FDA suggests that currently, because no effective therapy is available for BCG-unresponsive NMIBC, single-arm trials with complete response rate and duration of response as the primary endpoint can provide primary evidence of effectiveness to support a marketing application. FDA suggests that if, within three months, a patient does not achieve a complete response, the sponsor should consider whether to continue with the investigational therapy. Regarding risk management, FDA suggests that systemic (as opposed to localized) therapies may require substantially greater efficacy to achieve an overall favorable risk-benefit assessment. It notes that given the potential for increased risks associated with the use of systemic therapies, sponsors should limit early phase trials to patients with few treatment options. Thus, patients with BCG-unresponsive NMIBC are appropriate because their treatment options are limited and the current alternative is cystectomy.