Despite an increase in the overall utilization of Bacillus Calmette-Guérin (BCG) for non-muscle-invasive bladder cancer (NMIBC) over the last decade, shortages in the supply of the product have stagnated its use, and there was evidence that physicians rationed the product to patients in the highest-risk subgroups during these periods. The study was published in Urology.1non
Researchers from the Glickman Urologic and Kidney Institute at the Cleveland Clinic identified 238,270 patients with NMIBC from 2004 to 2015 from The National Cancer Database. During this period, they sought to determine if a trend existed between BCG supply shortages and the utilization of this medication, with a specific interest in measuring how shortages may impact the incidence of radical cystectomy.
Periods of particular interest were in 2011 and 2012, when there were major supply interruptions. In 2011, the US Food and Drug Administration (FDA) issued a warning letter to Sanofi after finding 58 instances of mold contamination at the plant, leading to a temporary shutdown of the facility.2
And in June 2012, Sanofi Pasteur temporarily suspended production of all BCG products and began renovating its Toronto manufacturing location. But, despite these attempts to conform to the current good manufacturing practice standards, the company issued a release in 2016 stating it was unable to restore production of ImmuCyst/TheraCys BCG live attenuated product, and announced it would stop producing the drug in mid-2017, with supplies potentially only lasting until 2018.3
Many prescribers switched over to Merck’s BCG offering, the TICE strain — which was shown in a 2014 study to be inferior to Sanofi’s Connaught strain4 — but contamination issues with TICE pushed it into a shortage, as well.
The study researchers stated that shortages forced providers “to offer inferior intravesical therapies, use reduced BCG doses split across several patients, deviate from traditional BCG induction and maintenance schedules, forego intravesical therapy altogether, and even offer early radical cystectomy for NMIBC.”
To investigate the reach of these alternative treatments, the investigators categorized patients by tumor grade and clinical stage: Ta-low grade (TaLG), Ta-high grade (TaHG), T1-low grade (T1LG), T1-high grade (T1HG), and carcinoma in situ (CIS). With the shortages in mind, investigators compared utilization of BCG before the shortages and after the supply interruptions (from 2013 to 2015).
Use of BCG grew steadily in the period before the shortages and were stagnant from 2013 to 2015 — but the authors noted a limitation in the calculation of utilization was confounded by the question of whether patients who received rationed doses were still counted as having received BCG. From 2004 to 2012, BCG use increased for all stages of disease except TaLG, but in 2013 to 2015, BCG use declined for the lowest-risk group, TaLG, but increased for the T1HG group, the highest-risk group, suggesting preferential rationing of this treatment to those with worse disease.
Though the study authors originally hypothesized that shortages would increase the instance of radical cystectomy, their analysis did not confirm this suspicion. They wrote that the potential reason for this may be because of “a reluctance among urologists to proceed with life-altering and morbid surgery among NMBIC patients, who would otherwise not be treated with up-front cystectomy.” They added, “If prior BCG supply shortages are any indication, a significant BCG shortage is imminent and can be expected to significantly alter real world clinical practice patterns.”
Because the dataset only included information through 2015, it is possible that Sanofi’s 2017 announcement to stop production of the drug may influence alternative treatment approaches in the future, according to researchers.
The study authors wrote, however, that new treatments in the space should be explored further, including the development of the Moreau BCG strain (which is already being developed in Europe), Tokyo-172 BCG strain, which is already in development by the Southwest Oncology Group (ClinicalTrials.org Identifier: NCT03091660), intravesical gemcitabine, intravesical adenovirus derivatives, and nanotechnology-based options.
- Khanna A, Yerram N, Zhu H, Kim S, and Abouassaly R. Utilization of BCG for non-muscle invasive bladder cancer in an era of BCG supply shortages [published online September 13, 2018]. Urology. doi: 10.1016/j.urology.2018.07.055
- Meeks JJ, Lerner SP, Svatek RS. Bacillus Calmette-Guérin manufacturing and SWOG S1602 Intergroup clinical trial. J Urol. 2017;197(3 Pt 1):538-540.
- Sanofi Pasteur information sur ImmuCyst/TheraCys. https://www.sanofipasteur.com/media/Project/One-Sanofi-Web/sanofipasteur-com/en/media-room/docs/SpecificInformation_ImmuCyst_EN.pdf. Published November 21, 2016. Accessed September 21, 2018.
- Rentsch CA, Birkhäuser FD, Biot C, et al. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol. 2014;66(4):677-688.