In 2018, the Food and Drug Administration (FDA) formalized the definition of the “bacillus Calmette-Guérin (BCG)–unresponsive” nonmuscle-invasive bladder cancer (NMIBC) disease space for the purpose of stimulating drug development through single-arm registrational trials.^1,2 Since then, we have seen approval of 3 novel therapeutics.^3-5 Several additional therapies await final clinical trial readouts and impending FDA approval. While BCG-unresponsive NMIBC is validated as a poor prognostic indicator,⁶ it was not intended as a clinical definition. By using a strict definition of BCG-unresponsive disease for clinical application, several challenges emerge in this evolving disease space that limit patient access to novel therapies based on label indications.

While the BCG-unresponsive definition was defined precisely for purposes of clinical trial eligibility, it can exclude patients in routine clinical use when considering therapeutic options. BCG-unresponsive NMIBC is defined as (1) persistent or recurrent carcinoma in situ with/without papillary disease (Ta/T1) within 12 months of completing adequate BCG, (2) recurrent high-grade papillary disease within 6 months of completing adequate BCG, or (3) high-grade T1 disease at first evaluation after induction BCG. Adequate BCG is defined as receiving at least 5 of 6 doses of induction plus 2 additional doses as part of maintenance or repeat induction.¹ While up to 40% of patients with high-grade NMIBC will experience BCG failure,⁷ only a fraction of these patients meet the strict definition of BCG-unresponsive NMIBC based on their exposure history and therefore would be eligible for FDA-approved drugs or clinical trials in this disease space. Accordingly, the “BCG-exposed” definition was created to encompass disease states between BCG-naïve and BCG-unresponsive disease. BCG-exposed patients are incorporated into numerous ongoing clinical trials, which will expand access to novel therapies in this heterogeneous patient population.⁸

Additionally, the therapies approved thus far for BCG-unresponsive NMIBC were investigated through single-arm registration trials, which, as recommended by the FDA, included only patients with carcinoma in situ in the evaluable cohorts because of its ability to serve as a marker lesion (the treatment response for patients with papillary-only disease can be confounded by the completeness of endoscopic resection). While these registration trials did include BCG-unresponsive papillary-only cohorts, leading to the inclusion of pembrolizumab and nadofaragene firadenovec as category 2B recommendations in the National Comprehensive Cancer Network guidelines for papillary-only disease,⁹ these drugs are limited to off-label and compassionate use options through insurers. The FDA has made its stance clear with respect to papillary-only BCG-unresponsive NMIBC, advocating for randomized, controlled trials¹ and relegating the data derived from papillary-only cohorts in the single-arm studies as hypothesis generating with early efficacy signals.

Lastly, access to novel drugs and clinical trials in the BCG-unresponsive space is, by definition, predicated on BCG availability. Anticipation of BCG shortages began in 2012 when Merck became the only producer of BCG (TICE) in the United States, and demand has significantly outpaced supply. In 2021, Merck committed $650 million for new facilities to expand production and anticipates the facilities to be operational by late 2026.¹⁰ Accordingly, another year will pass with a shortage, and patients will not have the required exposure to BCG to qualify for agents approved for BCG-unresponsive NMIBC. While initially intended to encourage serial clinical trial enrollment by eliminating a strict time window for inclusion, the “once BCG unresponsive, always BCG unresponsive” concept¹¹ has allowed patients with a remote history of BCG failure to remain trial and drug eligible without the need for BCG rechallenge, which has proven difficult during times of shortages.

During the ongoing BCG shortages, compassionate use of novel therapies may be an essential route for providing care to NMIBC patients with limited treatment options beyond radical cystectomy. Physicians must weigh clinical benefits against access limitations and regulatory burdens. Institutions are encouraged to develop clear triage policies, explore clinical trials, and engage with manufacturers for potential compassionate use and early access pathways. We eagerly anticipate completion of ongoing clinical trials that may make access to novel therapies less predicated on BCG exposure, expanding access into the BCG-exposed and treatment-naïve high-grade disease states.