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BCG: a real-world example of health care rationing
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Bacillus Calmette-Guérin, or BCG, is highly effective at treating and preventing recurrence of early-stage bladder cancer.
BCG is a strain of Mycobacterium bovis that was originally developed by University of Illinois as a vaccine against tuberculosis. The TICE strain of BCG Live (Organon Teknika, Merck) has been an FDA-approved treatment for bladder cancer since 1998. It is indicated for the treatment and prophylaxis of carcinoma in situ of the urinary bladder and prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors after transurethral resection.
BCG’s use as both a cancer drug and a vaccine against TB is just one reason why, more than 2 decades after its approval, patients with nonmuscle-invasive bladder cancer (NMIBC) are facing current and routine shortages of this relatively cheap and effective treatment.
Its lack of availability has caused the health care community to reactively ration BCG, placing both patients’ health and peace of mind at risk.
HemOnc Today spoke with pharmacists, genitourinary oncologists and other experts about how this shortage came about, the impact it could have on patients’ anxieties and outcomes, and potential solutions.
‘Relatively cheap’ drug
According to Heidi D. Finnes, PharmD, BCOP, senior manager of pharmacy cancer research and assistant professor of pharmacy at Mayo Clinic, BCG Live commands an average wholesale price of about $180 to $190 per 1-mL/50-mg vial in the United States.
“In the scheme of things, it’s a relatively cheap cancer drug,” she told HemOnc Today.
Betty M. Chan, PharmD, BCOP, assistant professor of clinical pharmacy at University of Southern California and clinical oncology pharmacist at USC Norris Comprehensive Cancer Center, agreed. BCG Live is very cheap, especially compared with chemotherapy, targeted therapy and immunotherapy, she told HemOnc Today.
Finnes said the demand for BCG Live has remained steady at Mayo Clinic, but she explained why production has failed to keep up with increasing worldwide demand.
Previously, two companies manufactured BCG Live, but North America and most of the world are now down to one supplier — Organon Teknika, a subsidiary of Merck — because of manufacturing issues at the other supplier.
“BCG is not easy or inexpensive to make or prepare,” Finnes said. “In a setting where a company is now the sole supplier, it has to be hard to keep up with production and make the drug available to all who need it.”
Merck explained in a statement to HemOnc Today that at no point has profitability played a role in decisions on the manufacture and distribution of BCG Live. The company said it “unexpectedly became the sole supplier” of the BCG Live strain when Sanofi Pasteur experienced manufacturing issues in 2012. Sanofi stopped providing BCG at a time when Merck produced only 28% of the world’s supply, according to the company’s statement.
Merck said it has increased production of BCG by more than 100% over the last several years to help meet the demand, and it now produces 600,000 to 870,000 vials of the drug annually.
“Despite our best efforts, increasing demand for this medicine globally and, unfortunately, occasional unanticipated issues within the lengthy and complex manufacturing process have led to the demand for TICE BCG to outpace our maximum supply,” the statement said.
Merck began addressing the shortage in January, when it implemented a proportional allocation system for BCG Live based on historical purchasing patterns in countries where it is the sole or primary provider. Merck allocates the drug to wholesalers and distributors, which then resell amounts to hospitals, pharmacies or private practices.
Proportional allocation will continue throughout 2019 and beyond, Merck said.
The FDA has acknowledged the issue, and its Center for Biologics Evaluation and Research website has listed BCG Live as in shortage since January.
The agency also recognized the difficulty in obtaining BCG Live stems from having only one commercial provider of the product in the U.S., and it recommended physicians contact Merck directly to obtain BCG Live for their patients.
“Merck and the FDA’s Center for Biologics Evaluation and Research are working to mitigate current and future supply constraints,” Megan McSeveney, press officer with the FDA, told HemOnc Today.
“While the FDA has no legal authority to require a manufacturer to begin producing, continue producing or increase their production of drugs, we do work with manufacturers whenever possible to help mitigate shortages,” she added.
When asked what exactly the FDA was doing to help address this shortage, McSeveney told HemOnc Today that efforts are ongoing but that details would be made public if and when a solution is implemented.
‘Nonrandom’ availability
Despite Merck’s practice of allocating the drug based on historical purchasing, patterns of shortages have not emerged. In some cases, large academic centers are experiencing shortages, whereas others have plenty of BCG in stock.
Meanwhile, those who treat patients with bladder cancer have prepared plans to ration BCG when a shortage occurs.
Sam Chang, MD, MBA, chair in urologic surgery at Vanderbilt University Medical Center and spokesman for the American Urological Association, said his practice has felt the squeeze of the BCG shortage in the past, but they currently have an adequate supply.
Source: Vanderbilt University Medical Center.
“I’m unique in this respect because many practices have had issues obtaining BCG,” Chang told HemOnc Today. “One of the issues is that there is no pattern on who has availability vs. who doesn’t.”
When asked if urban academic centers have had an easier time keeping the drug in supply, Chang said that often is the case, but not always.
“Availability has something to do with distribution networks,” he said.
“What those relationships consist of is very opaque,” he added. “Institutions that you would think would have no trouble getting BCG have had trouble, and vice versa. It doesn’t matter — big city, smaller cities — there are no consistencies to availability that I can figure out.”
Chang said this lack of predictability makes the situation even more frustrating.
“There are Centers of Excellence that can’t obtain BCG that should be able to get it,” he said. “It is nonrandom for sure, and what determines availability is unclear.”
Sima P. Porten, MD, MPH, genitourinary oncologist and assistant professor in the department of urology at University of California, San Francisco’s Helen Diller Family Comprehensive Cancer Center, told HemOnc Today that the shortage hit her facility more recently compared with colleagues across the country, who have been dealing with the lack of availability for quite some time.
“Several of our affiliate sites and many of our colleagues across the Bay Area have run out completely,” she said. “Historically, they may not have purchased a lot, so they have not been allocated enough. The ebb and flow of who needs BCG is not always consistent if you are in a smaller practice.”
Porten has seen many cases of patients coming to her urban academic center to obtain BCG Live that was unavailable in their local areas.
“The struggle is determining how to take care of those patients along with the patients diagnosed at our academic medical centers and affiliate practices,” she said. “It has been a difficult issue for all of us, especially at bigger centers that have received a bigger allocation.”
The shortage has prompted a cooperative effort by stakeholders in the health care industry to address the issue while continuing to deliver the highest possible quality of care, Porten noted.
“The good news is that the American Urological Association [AUA] has banded together with many of our professional societies and our largest patient advocacy organization — the Bladder Cancer Advocacy Network [BCAN] — to issue a statement to acknowledge the shortage and identify strategies about how to ration BCG during the shortage,” Porten added.
The AUA and BCAN made key recommendations for health care providers in February (see Table 1). The bottom line of these recommendations is that BCG should be rationed during a shortage among those with highest-risk disease to the detriment of those who could benefit from its use as maintenance therapy to prevent disease recurrence.
“Unfortunately, we had to prioritize certain patients,” said Chang, who helped developed the AUA recommendations. He described the situation as akin to “rationing care.”
“Mostly it was a case of not offering BCG to patients who may benefit from it but did not have active disease,” Chang said. He added that at Vanderbilt, they have done everything possible to obtain BCG but have experienced tight supplies of the drug, which forces conversations with patients about who receives the drug or the alternatives.
“There are no right or wrong answers when faced with a shortage,” Chang said. “Right now, we are fortunate that we have access to BCG, but that doesn’t help lots of patients elsewhere who are deserving and need it.”
Impact on care
Arlene O. Siefker-Radtke, MD, professor in the department of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center, confirmed that her institution has experienced BCG Live shortages in the past. Currently, however, MD Anderson can meet its demand.
“Patients find it extremely frustrating when they can’t access a drug like BCG due to a shortage,” she said. “It creates undue stress in a situation that’s already stressful for them.”
In her experience, patients from rural areas have had trouble obtaining the drug in their communities and have come to MD Anderson as a result.
“Often they drive hours to receive this treatment because it’s unavailable locally,” she said.
MD Anderson has employed some of the same strategies to deal with the BCG Live shortage that are recommended by the AUA. For example, the center has provided available doses to high-risk patients and employed what’s known as a “lower-dose, longer duration strategy.”
“As with other institutions, we have experienced tremendous difficulty in obtaining sufficient BCG to support our patients in need for bladder cancer treatment,” said USC’s Chan. “We continue to communicate inventory shortages within our organization and collaborate with our providers’ teams to identify and prioritize patients in need of BCG treatment.”
Due to the shortage, Chan’s center has been unable to provide BCG Live to patients who otherwise would be indicated for treatment — including as initial and maintenance therapy.
“At our institution, we are prioritizing BCG treatment for patients with high-risk, nonmuscle-invasive bladder cancer, using alternative intravesical chemotherapy for those patients not receiving BCG,” Chan said.
It was around October 2018 when the current BCG Live shortage came to the attention of Seth Lerner, MD, FACS, director of urologic oncology and the Multidisciplinary Bladder Cancer Program at Baylor College of Medicine. Although he has not had issues obtaining BCG Live, he said nearly all other urologists he speaks with have experienced a shortage at one time or another, with some unable to obtain the drug at all.
Lerner advised alternatives that mirror many of the recommendations issued by the AUA and BCAN (see Table 2).
“BCG should be prioritized for patients with high-risk disease,” Lerner told HemOnc Today. “If they don’t have access to BCG, they can use intravesical chemotherapy — there is a combination of drugs we are using with gemcitabine and docetaxel, for example.”
Lerner added that, when a shortage exists, BCG Live should not be given to patients with low-risk disease and that patients with intermediate-risk disease can be treated with intravesical chemotherapy using mitomycin or gemcitabine.
Even with the availability of alternatives, data from Ourfali and colleagues, published in April in European Urology Focus, showed the shortage of BCG can directly impact patient outcomes.
The researchers compared outcomes among 191 patients who underwent resection from November 2011 to September 2013, prior to a shortage, and 211 resected from October 2013 to December 2016, during a shortage.
Significantly fewer patients treated before the shortage experienced recurrence at 24 months (16.2% vs. 46.9%; RR = 0.7; 95% CI, 0.6-0.82). Also, more patients treated during the shortage underwent cystectomy (7.1% vs. 1.5%; RR = 4.52; 95% CI, 1.33-15.39), and they had higher treatment costs, with a financial impact of 783 euros per patient with a new diagnosis of NMIBC during the shortage.
A univariate analysis showed that receiving a full 1-year course of BCG led to a 70% reduction in risk for recurrence (OR = 0.3; 95% CI, 0.17-0.53).
Chang said that although alternatives are available, they often are not as effective.
“One alternative would be earlier radical surgery — so bladder removal, which for some patients might be much more than they actually need,” he said. “It may be the safest in terms of a cancer cure, but it is associated with significant morbidity and possible side effects and complications.”
Porten said she spends approximately 10 to 15 hours per week examining and presenting alternatives to BCG Live for her patients, to reassure them that a backup plan is in place and that they have options other than radical cystectomy.
“Even for the highest-risk patients, we are having to ration the dose and frequency of what we can give to them,” Porten said.
The alternatives offered to patients at her center include intravascular and double-agent chemotherapy. Porten describes these as reasonable alternatives, but untested via clinical trials in the way BCG Live has been tested.
“These alternatives definitely help a lot, but it has been stressful for everybody involved,” Porten added.
A simple solution
Although the reasons behind the BCG Live shortage are multifactorial, the solution to ending the crisis appears to be quite clear.
“It’s a relatively cheap cancer treatment and it’s not hard to see why there are limited supplies,” Siefker-Radtke said. “We operate in a market economy. I’m no economist, but I seem to remember from my undergraduate economics class that there are some market forces at work that dictate prices and availability.”
Lerner echoed this assessment, and said despite efforts to triage against the shortage, market forces will continue to drive it so long as the demand outstrips the supply of the drug.
“The problem is that Merck is the sole supplier of BCG for 70 countries, so the demand is driving this shortage,” he said. “They have increased their manufacturing by 100% over the last year or 2. It appears ... this is a supply-and-demand issue.
“We are all patient advocates, so I would like to see the FDA be proactive in trying to get other strains of BCG approved in this marketplace,” he added.
Having only one manufacturer of BCG Live, and only one FDA-approved strain for bladder cancer treatment, makes it a challenge to provide the drug to all who would benefit from it, Chang said.
“It would certainly be helpful if there are other manufacturers in support of production to better maintain the supply and demand for BCG,” she said.
According to Chang, the AUA is doing “everything possible” to put pressure on Merck and the FDA, and to advocate for patients with bladder cancer.
“The more press that accumulates on this, saying that it’s an untenable and unacceptable situation, the more likely it will be that Merck will start producing more BCG, and we will have alternatives available to us,” he said.
Finnes agreed and said that having another manufacturer of BCG Live would likely ease the shortage in addition to providing a safeguard against future production issues.
“With only a single manufacturer, if something happens in their production process that holds up a batch, that puts everyone at risk for a shortage because there is no one else to pick up the slack in production,” she said.
Even if a center has a solid drug stock, it is wise to prepare for potential shortages, Finnes added.
“What I’ve learned is that it is key to be prepared and make sure that information about drug shortages gets to providers so that they are aware,” she said. “Keep in touch with those who do the ordering at your institution, and make sure you have an alternative plan of action.”
Finnes told HemOnc Today that Mayo Clinic currently has plenty of BCG Live in stock, but her center has a plan in place should a shortage occur.
“We never know when it will happen for us,” she said. “We assume that if it is happening for everyone else, then we need to be prepared as well.” – by Drew Amorosi
Click here to read the 
, “Are there feasible alternatives to BCG for the effective treatment of bladder cancer?”
Reference:
Ourfali S, et al. Eur Urol Focus. 2019;doi:10.1016/j.euf.2019.04.002.
For more information:
Betty M. Chan, PharmD, BCOP, can be reached at bchan@usc.edu.
Sam Chang, MD, MBA, can be reached at sam.chang@vumc.org.
Heidi D. Finnes, PharmD, BCOP, can be reached at finnes.heidi@mayo.edu.
Seth Lerner, MD, FACS, can be reached at slerner@bcm.edu.
Sima P. Porten, MD, MPH, can be reached at sima.porten@ucsf.edu.
Arlene O. Siefker-Radtke, MD, can be reached at asiefker@mdanderson.org.
Disclosures: Porten reports a consultant role with Photocure. Chan, Chang, Finnes, Lerner and Siefker-Radtke report no relevant financial disclosures.