No End in Sight, Bladder Cancer Drug Shortage Takes a Toll

Only One Supplier of BCG in US

Nick Mulcahy

March 14, 2019

A bacteria-based immunotherapy product that has been used in the treatment of bladder cancer for the past 40 years is now in short supply, and it appears that the situation will continue for the rest of 2019 at least.

The shortage is now negatively affecting patient care, clinical trials, and clinicians' patience, according to various accounts.

The product is the Tice strain of bacille Calmette-Guérin (BCG), from Merck & Co, which is used intravesically for early stages of bladder cancer.

Specifically, the agent is indicated for the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder and the prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection.

The US Food and Drug Administration added Tice BCG to its official list of drugs in short supply last month, and says that constraints are expected to last throughout 2019.

Merck, which is the sole supplier in the United States and other countries, says the shortages are due to an increasing global demand. Merck has changed its distribution to an allocation model based on historical purchasing patterns. Merck expects this arrangement "will remain in place at least for 2019."

US clinicians have begun to report denials of requests, which are causing delays in treatment. For instance, in early February, Keith Kowalczyk, MD, director of urologic oncology, MedStar Georgetown Cancer Institute, Washington, DC, tweeted (@KeithKow): "Just got first BCG denial. Supposedly two weeks [before availability]. Unbelievable that this happens."

Alexander Kutikov, MD, director of urologic oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, said his center is "keeping its head above water and continues to treat patients" but added that the impact of the shortage is widespread.

"Many private practice providers who refer to our center have had their supplies totally depleted at some point over the last few weeks. In small batches the BCG trickles in; however, to my knowledge, it is sporadic and inconsistent," he told Medscape Medical News.

Temporary treatment guidelines were issued last month by a consortium of organizations in response to the shortage. Among other recommendations, these guidelines suggest substituting chemotherapy when BCG is unavailable.

"This is a major problem," Kutikov said about resorting to chemotherapy.

The shortage is also hampering scientific progress in the field, he added: "Clinical trials that hope to replace BCG with agents such as modern checkpoint inhibitor immunotherapy are being affected, since lack of BCG is impeding trial enrollment."

Kutikov also said the lack of information from Merck about restoring the supply chain is a "major frustration."

The company says, in an online document, that it "increased production by more than 100 percent — which is the full extent of our manufacturing capacity. Despite this increase, with the growing use and need for this product, we still anticipate supply constraints."

Merck also said that the manufacturing process for BCG is lengthy and inherently complex.

Other experts confirm that description. "The fermentation process has not changed in nearly 100 years, since it was first described by Calmette and Guerin in 1921, and is highly unreliable," wrote A. Hugh Mostafid, MD, of the Royal Surrey County Hospital, Guildford, United Kingdom, and colleagues in a 2015 essay that was occasioned by a global shortage at that time.

BCG is an attenuated form of a bacterial pathogen that has been widely used as a vaccine for tuberculosis for close to a century.

However, the precise mechanism of action of BCG in bladder cancer is unknown, says Merck in its package insert.

The American Cancer Society points out that when BCG is infused into the bladder through a catheter, it comes into direct contact with the cancer cells and activates the immune system. BCG must come in contact with the cancer cells to work and therefore is an intravesical therapy.

Clinical Guidelines While Shortages Continue

Last month, the American Urological Association and a group of bladder cancer–related organizations issued an advisory about the BCG shortage.

It outlines strategies to "maximize the care for patients with non-muscle invasive bladder cancer (NMIBC)," as follows:

  1. BCG should not be used for patients with low-risk disease.

  2. Intravesical chemotherapy should be used as the first-line option for patients with intermediate-risk NMIBC. Patients with recurrent/multifocal low-grade Ta lesions who require intravesical therapy should receive intravesical chemotherapy such as mitomycin, gemcitabine, epirubicin, or docetaxel instead of BCG.

  3. If BCG would be administered as second-line therapy for patients with intermediate-risk NMIBC, an alternative intravesical chemotherapy should be used rather than BCG during periods of BCG shortage.

  4. Patients with high-risk NMIBC and patients with high-grade T1 and CIS who are receiving induction therapy should be prioritized for use of full-strength BCG. If not available, these patients and other high-risk patients should be given a reduced 1/2 to 1/3 dose, if feasible.

  5. If supply exists for maintenance therapy for patients with NMIBC, every attempt should be made to use 1/3 dose BCG, and the dose should be limited to 1 year.

  6. In the event of a BCG supply shortage, maintenance therapy should not be given, and BCG-naive patients with high-risk disease should be prioritized for induction BCG.

  7. If BCG is not available, a preferable alternative to BCG is mitomycin (induction and monthly maintenance up to 1 year). Other options, such as gemcitabine, epirubicin, docetaxel, valrubicin, or sequential gemcitabine/docetaxel or gemcitabine/mitomycin, may also be considered with an induction and possible maintenance regimen.

  8. Patients with high-risk features (ie, high-grade T1 with additional risk factors, such as concomitant CIS, lymphovascular invasion, prostatic urethral involvement, or variant histology) who are not willing to take any potential oncologic risks with alternative intravesical agents should be offered initial radical cystectomy, if they are surgical candidates.

However, experts have pointed out that there are problems with some of these recommendations.

The problem with substituting various chemotherapies for BCG is a loss of efficacy, Robert Svatek, MD, University of Texas at San Antonio, told STAT News in a recent story on the shortage.

"There's no question that BCG is more effective," Svatek said. "Multiple trials have compared BCG to chemo, and every time it wins. It beats the chemo."

Fox Chase's Kutikov emphasized that in the absence of the most effective treatment, "critical clinical decision making — such as the need to move forward with bladder removal — can hang in the balance when BCG is not available."

The advice to use reduced doses of BCG for induction and maintenance courses may also cause problems.

The lower doses of BCG are effective, comment the UK's Mostafid and colleagues. This approach is based on a randomized trial by the European Organization for Research and Treatment of Cancer that showed no difference in progression rates between full-dose and 1/3 dose BCG (Eur Urol. 2013;63:462–72).

However, recurrence rates are higher with the reduced dose, they note.

The reduced dose approach also has logistical challenges.

"If 1/2 to 1/3 dose BCG is used, every attempt should be made to treat multiple patients on the same day, while being consistent with product labeling, to avoid drug wastage," states the new advisory.

Reimbursement is also uncertain. "It is unknown at this time whether it is acceptable to bill for more than one patient per vial of BCG," it adds.

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