Sense of urgency surrounds BCG shortage

As urologists maneuver through the third shortage of bacillus Calmette-Guérin (BCG) during the past decade, there is a sense of urgency to find short- and long-term alternative treatments to the only FDA-approved BCG strain as a therapeutic agent for nonmuscle-invasive bladder cancer.

The incidence of bladder cancer is increasing worldwide. In the United States alone, there were 80,000 newly diagnosed cases in 2018, compared with 60,000 newly diagnosed cases 10 to 15 years ago.

Of these, nearly 45% of patients present with high-grade, noninvasive tumors. For these patients, intravesical immunotherapy with BCG remains the best bladder-sparing treatment, says Ashish M. Kamat, MD, MBBS, professor of urologic oncology (surgery) at MD Anderson Cancer Center, Houston.

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The increase in new cases, as well as the recognition by both patients and their doctors that maintenance therapy with BCG is required, has led to an increase in demand-both in the United States and around the world-and the shortage.

Merck is the only manufacturer for the TICE strain of BCG for many countries, including the United States. Earlier this year, the company started to proportionally allocate the medicine across countries where it is the sole or primary supplier, including the United States, based on historical averages.

The company is producing between 600,000 and 870,000 vials annually, which is considered full capacity, but it cannot keep up with the increased demand.

Tyrone Brewer, vice president of global oncology marketing for Merck, told Urology Times the shortage has left the company as equally frustrated as urologists.

“People need to know we’re doing all we can possibly do,” he said. “We’re working with regulatory agencies to understand what options we can pursue.”

Next: Alternative therapiesAlternative therapies

Dr. Kamat said patient care has not been impacted by the shortage because steps were taken ahead of time in the form of alternative therapies.

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One step includes better risk stratification of patients, with more appropriate use of BCG-for example, limiting its use in low-grade patients who have other alternative therapies available. Another step is for patients with high-risk disease but limited tumors to stop BCG after one year of maintenance therapy. Additionally, studies have shown that reduced-dose BCG (one-third dose) has similar efficacy to full-dose BCG.

If BCG is not available, the AUA recommends mitomycin (induction and monthly maintenance up to one year) as an alternative. Gemcitabine, epirubicin, docetaxel, valrubicin, or sequential gemcitabine/docetaxel or gemcitabine/mitomycin may also be considered with an induction and possible maintenance regimen.

Long-term strategies

One long-term hope is to introduce foreign strains of BCG into the United States. While there are BCG strains in Germany, India, and Russia, it is the Tokyo strain that is currently being studied.

In response to the shortage, the SWOG Cancer Research Network is conducting a randomized control trial, S1602, which compares the Tokyo and TICE strains of BCG. The trial is ongoing, meaning it will be some time before results can be forwarded to the FDA for approval. Even if the Tokyo strain is approved for use in the United States, there still needs to be a company that commits to manufacturing and distribution.

“The trial is a good idea, but I’m not sure it will solve any of the problems related to the manufacturing and financial ramifications and the ability to scale BCG,” said Jathin Bandari, MD, a urologist at the University of Pittsburgh.

Bladder cancer options used in Israel and Italy make mitomycin more effective therapy, including electromotive mitomycin-C or the use of a microwave device to heat the drug, says Edward Messing, MD, professor of urology and oncology at the University of Rochester Medical Center, Rochester, NY. In clinical studies, both treatments have looked promising when compared with BCG.

However, the studies are small, they don’t include maintenance treatments, and side effects are greater, Dr. Messing cautions. The treatments are also not being actively pursued in the United States, although Dr. Messing says that could change with another TICE strain shortage and if no new strain is approved.

Michael O’Donnell, MD, professor and director of urologic oncology at the University of Iowa Carver College of Medicine, Iowa City, is studying a combination protocol of sequenced gemcitabine and docetaxel. In his research, Dr. O’Donnell has found excellent responses as an alternative to treat carcinoma in situ (CIS) when BCG cannot be administered.

Gemcitabine and docetaxel are FDA-approved individually but not FDA-approved as a combination. Dr. O’Donnell is close to publishing a multi-institutional retrospective report of the gemcitabine/docetaxel combination’s utility in BCG-naive patients, and he is working through academic circles to develop a prospective clinical trial.

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The Urology Care Foundation recently awarded a grant to evaluate the impact of the BCG shortage and determine whether it has caused any change in mortality or cancer-specific outcomes. The research will also examine alternative treatment strategies, Dr. Bandari says.

Next: Worst-case scenarioWorst-case scenario

There is little hope that the current BCG shortage will be the last because the fundamentals of production are not expected to change. What if Merck comes to the same decision arrived at by Sanofi in 2017-that financial considerations force Merck to permanently halt production of the TICE strain?

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“From our standpoint, that could be catastrophic,” Dr. Bandari commented. “Who would provide the nation with BCG if Merck pulls out? It is an uncomfortable situation to consider.”

Brewer says there are no plans for Merck to halt production.

“As far as the foreseeable future, Merck will continue to produce TICE BCG,” Brewer stressed.

Steven Wahle, MD, a urologist with Physicians Clinic of Iowa in Cedar Rapids, believes future shortages or onerous proposed regulations that obstruct the use of BCG will spur action from every impacted constituent.

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“When patients and doctors realize we can’t offer BCG, I hope and expect changes in the regulations to give a dispensation for BCG in the clinical arena,” he said.

Next:Complexity in production complicates matters

Complexity in production complicates matters

One issue that has led to the shortage of the TICE strain of bacillus Calmette-Guérin (BCG) is the way it is produced.

While it is the first-line therapy for nonmuscle-invasive bladder cancer, BCG is a difficult medicine to produce and there is little financial incentive. BCG is derived from a bacteria that has to be cultured in facilities that cannot be utilized for other drugs in discovery or manufacturing. It takes a minimum of 3 months to obtain a supply from the original culture.

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“That certainly adds to the complexity of production,” said Tyrone Brewer, vice president of global oncology marketing for Merck. “BCG is not something we can produce overnight.”

BCG is priced at between $100 and $200 per dose, far less than the average price per dose of a cancer-fighting drug.

“BCG grows slowly, and it is an expensive proposition,” said Edward Messing, MD, professor of urology and oncology at the University of Rochester Medical Center. “It takes time to culture.”