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The Tice strain of BCG has emerged as a go-to drug for treating primary and recurrent bladder cancer, but in the United States and some other countries, a constellation of marketplace dynamics has reduced manufacturers of this agent to a sole producer that is unable to keep up with demand. Available supplies are being rationed, and sufficient expansion of supply could be years away.
Edward Messing, MD
Over the years, the Tice strain of bacillus Calmette—Guérin (BCG) has emerged as a go-to drug for treating primary and recurrent bladder cancer, but in the United States and some other countries, a constellation of marketplace dynamics has reduced manufacturers of this agent to a sole producer that is unable to keep up with demand. Available supplies are being rationed, and sufficient expansion of supply could be years away.
BCG is indicated for the treatment and prophylaxis of carcinoma in situ of the urinary bladder and for the prevention of primary or recurrent stage Ta or T1 papillary tumors following transurethral resection. Multiple strains of BCG are produced worldwide, but just Merck produces BCG Tice—currently the predominant, if not only, strain available in the US market.
The complexity of developing a viable batch of this product results in tremendous fluctuation in how much Merck can reliably produce each year, which at best falls woefully short of demand. Repeated shortages over the past decade have made rationing and secondbest cancer fighting regimens a necessity in clinics that aren’t allocated sufficient supplies of BCG Tice. This leaves some patients with less-than-desirable outcomes.
“We’ll never know exactly how many patients suffer inferior outcomes because of this shortage, but the numbers are large,” said Edward M. Messing, MD, a professor of urology at the University of Rochester Medical Center. “Bladder cancer is among the most common of all tumor types, and BCG is the most effective treatment we have for early-stage disease. Just recently, we saw 2 patients who would normally have been treated with BCG who will have to have their bladders removed. They will live, but the loss of one’s bladder is a heavy price to pay, and they won’t be the only victims of this shortage. More people are going to have more recurrences because of this. More people are going to progress. More people are going to lose their bladders.”
Studies have not quantified the damage done by prior shortages, so it’s hard to estimate the likely impact of this shortage or the shortages that experts expect to occur periodically during future years. However, each shortage of BCG has common elements (Figure 1).
Sanofi Pasteur, producer of the rival strain BCG Connaught, was forced to suspend production in 2012 owing to mold and other quality maintenance issues in drug manufacturing; the company announced in 2016 that it would not be restoring production. The FDA website currently reports shortages of 124 drugs,1 but the BCG shortage may be affecting an unusually large number of patients. The American Cancer Society estimates that 80,470 Americans will develop bladder cancer this year, and more than three-fourths of them will receive diagnoses early enough to be candidates for treatment with BCG.2 Intravesical BCG is considered the most potent medical treatment for a majority of early bladder cancers.
Sanofi had to shut down its Canadian BCG factory after FDA inspectors found nesting birds in the air ducts, mold in dozens of locations, and many other infractions.3 That single factory had been producing more than 70% of all the BCG used in the United States, and its closure left Merck scrambling to increase production. Fortunately, Merck had enough production capacity to handle more production, but that supply took time to come online. Not only did Merck have to acquire more equipment, lay in supplies, and build up its workforce, it also needed months to produce the extra vaccine, company officials said.
Unlike small-molecule drugs that patients can take orally, BCG contains living organisms that need to be grown. Whereas oral medications may roll off production lines very quickly, a batch of BCG Tice takes about 3 months—if everything goes right. Often it doesn’t. Yields at Merck’s BCG plant in North Carolina vary significantly from 1 batch to the next, the company reports, and any contamination at the plant can ruin an entire batch. Indeed, a few bad batches in 2014 reduced production enough to create another shortage.
“Merck has been making BCG for more than 30 years now, but time doesn’t make the process any simpler. It’s still enormously complex, and there are going to be times when yields are lower than we’d like them to be,” said Tyrone Brewer, Merck’s vice president for global oncology marketing. “The problem right now is that demand exceeds our ability to create supply. We are at the point that we feel comfortable in predicting that we can make 600,000 to 870,000 vials per year, and our yields have actually been on the high end in recent months. Unfortunately, demand is now running around 1 million vials a year,” said Brewer, who added that Merck has doubled its capacity for making BCG since 2012.
Merck does not blame the shortage on regulations that limit what it can charge many payers for BCG. Brewer said the company seeks to profit from its recent innovations rather than exploit its accidental status as the monopoly provider of a treatment that’s nearly 100 years old, and he affirmed Merck’s commitment to ending shortages.
Researchers who have studied the shortage take a different stance. They think significant price hikes might be the best possible thing for patients who need to take BCG. Messing said that the current price of BCG is less than $200 a vial, about a fifth as much as the mitomycin that’s often used to treat bladder cancer when BCG is unavailable. That would appear to give Merck and any other company that started making BCG leeway to raise prices, but BCG makers have limited pricing power. The 2003 Medicare Modernization Act capped annual price hikes for generic drugs to 6% above the Medicare average sale price. Hospital group purchasing organizations, upon notice of price increases, could buy up and hoard available supplies, thereby precipitating shortages and price gouging.3
“I know it’s unusual to suggest that pharmaceutical companies need to be charging more, but in this case, it could be that [the] low price of BCG is contributing to the shortages because there is no other manufacturer in the United States other than Merck,” said Ashish Kamat, MD, a professor of urology at The University of Texas MD Anderson Cancer Center, Houston. “For example, when the Sanofi plant [that used to make BCG] was available for purchase/acquisition, not a single pharmaceutical company took a chance on buying the place. In fact, if someone were to do that now and restart operations, it would reduce the risk of future shortages.”
Origins of BCG
BCG was developed in the early years of the 20th century by the “C” and “G” in its name, French scientists Albert Calmette and Camille Guérin. The pair began researching the mechanisms of tuberculosis (TB) infection in 1905 and eventually hypothesized that a weakened version of the bacteria could produce immunity without first producing infection. Human testing of the vaccine they developed began in 1921.
BCG studies conducted since then have reported wildly different efficacy rates, ranging from 0% to 80%. This is attributed to genetic variability among the many BCG strains produced around the world. A meta-analysis published in 1994 concluded that, on average, the vaccine reduces TB risk by about 50%.4 This mediocre efficacy explains why TB remains a major disease and why, in low-risk countries such as the United States, health authorities only recommend BCG vaccine for small populations with elevated TB risks. BCG studies conducted in the 1950s made the surprising discovery that vaccinated animals contracted cancer less frequently than their unvaccinated counterparts. The first practical application for this finding came in 1976, when Morales et al published a landmark study on BCG in 9 patients with recurrent superficial bladder tumors that found that the vaccine favorably altered recurrence patterns.5 Results of larger trials confirmed the finding, and BCG has been a significant therapy for non-muscle invasive bladder cancer (NMIBC) ever since.
BCG’s complex and multifaceted effects on bladder cancer are not yet fully understood, but research to date demonstrates that the vaccine attacks the tumor both directly and indirectly. BCG attaches itself to tumor cells, and then is internalized within the tumor. This infection increases the expression of antigen-presenting molecules, which leads to the release of several cytokines and stimulates attacks from cytotoxic T lymphocytes, natural killer cells, neutrophils, and macrophages.6
This immune response significantly improves outcomes among patients with NMIBC, as study results began to show shortly after the 1976 paper by Morales et al. A 1980 trial that compared surgery plus BCG to surgery alone reported recurrences in 3 of 18 BCG-treated patients (17%) and 8 of 19 control patients (42%) after 1 year of follow-up.7 A 1985 trial found that BCG also improved outcomes in patients with NIMBC who had experienced recurrence. Researchers randomized 88 patients to the existing standard of care (cystoscopy with fulguration) with or without BCG. Patients treated with BCG, compared with control patients, experienced better outcomes across the board: reduction in the number of recurrent tumors (43 vs 27 patients; P < .001), conversion to negative cytology (11 of 33 vs 3 of 34 patients; P <.05 ), and tumor progression requiring cystectomy (3 vs 15 patients; P <.001 ). Patients with BCG also experienced a longer disease-free interval (P <.001), time with negative cytology (P <.001), and time to progression of disease (P <.003).8
The original BCG treatment used for NMIBC was a single course of 6 weekly intravesical doses of 120 mg, but subsequent trials found that patients get further benefit from maintenance therapy.9 Several maintenance regimes have been tested, but a meta-analysis has yet to definitively prove any particular schedule is the best.10 There is some evidence that 3-year regimens perform better than 1-year regimens, particularly in high-risk patients,11 but guidelines from the European Association of Urology endorse maintenance schedules that range from 1 year to 3 years.12
Other therapies have demonstrated efficacy against NMIBC in the years since BCG emerged as an effective treatment, but none performs as well against the cancer. Most guidelines12,13 for the treatment of bladder cancer recommend the use of intravesical chemotherapy, rather than BCG, for low-risk localized bladder cancers because BCG, although generally very well tolerated, leads to serious adverse effects, including death, in a small percentage of all patients who take it.14 A weakened immune system and co-administration of vaccines are risk factors for mortality.
The evidence for BCG as a superior cancer fighter versus chemotherapy has been a compelling argument for many patients opting for this drug. With BCG in short supply, however, the vaccine isn’t an option for most low-risk patients because medical centers are reserving whatever BCG they can get for highrisk patients. Even with such restrictions in place, medical centers are unable to give highrisk patients as much BCG as they’d like, so they are experimenting with various strategies for further rationing the medication.
At the University of Rochester Medical Center, for example, doctors are giving full induction courses of BCG—both in terms of total bladder instillations and dosage per instillation—but they are not giving patients any maintenance therapy with the vaccine. Patients who see recurrences or progression receive chemotherapy or undergo surgeries to remove part or all of their bladders.
“No one has compared all the strategies for saving BCG and demonstrated the best, so the faculty at each hospital has to review the evidence and decide on a course of action,” Messing said. “Some places have cut induction back from 6 instillations to 5 instillations. Others have reduced the dose per instillation, which we decided against because there’s clear evidence that reduced dosage translates into reduced efficacy.”
Among the cancer centers that have opted to reduce BCG dosage is MD Anderson.
“[Trial results] have shown that reducing BCG dosage does reduce efficacy, but the lower dosage performed nearly as well as the full dose, and we judged that overall outcomes would be better with a greater number of patients receiving a greater number of instillations,” said Kamat. “Dividing each vial into 3 doses rather than using a single vial as a single dose allows us to provide something like a normal number of maintenance instillations. We might end maintenance after 1 year, rather than 3, for a patient who showed no signs of recurrence, but we hope to be able to provide the usual number of maintenance instillations to higher- risk patients—provided the shortage does not get any worse.”
There are several possible developments that would end the need for BCG rationing. The first is a significant increase in production at Merck’s facility in North Carolina. The second is the introduction of a new strain of BCG to the North American market. This could come via a loosening of restrictions at the FDA that prevent strains of BCG manufactured abroad from being distributed in the United States. Alternatively, the development of a new bladder cancer treatment that reduces the need for BCG could make up the shortfall in drug supply.
The Southwest Oncology Group is leading a phase III clinical trial that is comparing the efficacy of the Tokyo-172 strain of BCG against Merck’s BCG Tice in the treatment of patients with bladder cancer (NCT03091660). Researchers hope to enroll nearly 1000 patients in the trial, which could open a new supply of BCG to the US market and greatly reduce the chance of further shortages (Figure 2). Unfortunately, the estimated primary completion date for the study is 3 years away and the estimated final completion is 3 years after that.15
As for the creation of a new treatment that would replace BCG, there are multiple trials underway. Clinicaltrials.gov lists more than 1000 bladder cancer trials, 123 of which are phase III trials. Prior BCG shortages, moreover, have seen greater use of a combination chemotherapy—gemcitabine plus docetaxel [Taxotere]—that has proved itself to be almost as effective as BCG in some high-risk patients.16 That said, none of the sources interviewed for this story expected any treatment to prove superior to BCG for any significant number of patients anytime soon.