Bob Field was set to kick off his second course of BCG — a potent immunotherapy that treats his fast-growing bladder cancer. Instead, the New York City banking executive got a call from his urologist’s office, canceling that week’s appointment: They were running low on vials of BCG and rationing their dwindling supplies. Field was no longer eligible.
It wasn’t just one doctor’s office. There’s a critical national shortage of BCG, a biologic drug that has been used for decades and that is a remarkably effective medicine. Many smaller clinics have already run out of the lifesaving drug, and larger hospitals — including New York’s Memorial Sloan Kettering Cancer Center, where Field is being treated — have changed their policies on distributing BCG to prioritize newly diagnosed patients with active cancers.
“In a word, I’m horrified. Depressed, annoyed, angry,” said Field, 72, who is now calling hospitals and clinics across New York to see if he can gain access to the drug. “This is a proven, time-tested means of helping people prevent recurrences of bladder cancer — and it’s suddenly unavailable. So there’s some stress.”
Drug shortages are alarmingly common in the U.S., with health care providers often scrambling to make do without sufficient supplies. Those shortages occur for any number of reasons — natural disasters at productions plants or surging demand caused by an outbreak, for instance. But there are also commercial forces at work.
Companies have very little incentive to manufacture a drug like BCG. Although it’s been used to fight cancer since the 1970s, it isn’t easy to produce. And priced at a relatively modest $100-$200 a dose, it’s not a drug that companies are rushing to make, even if it’s no longer patented; right now, Merck is the only manufacturer for the U.S. and European markets.
BCG, in other words, is an example of a medically important drug that gets neglected because it fails to generate a lot of money for its maker.
“This BCG shortage is a huge deal,” said Dr. Robert Abouassaly, a urologist at Cleveland Clinic. “We don’t have any alternatives that are as effective for these patients.”
Merck acknowledges supplies are short and has expressed sympathy for cancer patients in need. At the same time, it says it is already working at capacity to produce more of the drug.
The company has every intention of continuing BCG production for “the foreseeable future,” according to Tyrone Brewer, vice president of global oncology marketing at Merck.
“It’s not our intent that we’ll use this drug to increase our margins,” Brewer said. “This is not about the profits, but a mission to save and improve lives.”
BCG, short for Bacillus Calmette-Guérin, is one of the earliest examples of immunotherapy in medicine. The drug was first used as a tuberculosis vaccine in 1921: It’s a live, but weakened, strain of a tuberculosis-causing bacteria called Mycobacterium bovis.
Researchers began to notice that patients with tuberculosis had lower rates of cancer, prompting early study of BCG as an oncologic tool. In the 1970s, it was found that if the live, attenuated BCG bacteria were fed through a catheter directly into a cancer patient’s bladder, they revved up his immune system — stimulating T cells to attack tumors.
Ever since, BCG has been the standard of care for certain forms of bladder cancer. It beats out both surgery and chemotherapy in keeping bladder tumors at bay. It’s substantially cheaper, too.
There are about 80,000 new cases of bladder cancer in the U.S. each year, making it the nation’s sixth most prevalent cancer. About 20 percent of these cancers — specifically, those with high-grade, non-muscle invasive disease — can be treated with BCG. It doesn’t work for everyone, but the response rate is more than 70 percent.
Standard treatment calls for clinicians to continue checking for cancer every three to six months after initial dosing, and administer follow-on doses of BCG to ensure the cancer remains in remission. Those are the kinds of doses that have remained out of reach for Field.
For him and other patients in similar circumstances, the consequences are as emotional as they are physical.
Donna Hoff, a 71-year-old retired bookkeeper, had her bladder tumors surgically removed, then was put on a regimen of BCG combined with interferon, another drug that boosts immune response. So far, the cancer has not come roaring back. But she’s concerned that if her BCG maintenance treatment is abbreviated, it might.
“You’re never really in remission,” Hoff said. “It’s always sitting on your shoulder, waiting to return.”
Certain chemotherapies, such as gemcitabine or mitomycin, can be used in lieu of BCG. But their efficacy pales in comparison, said Dr. Robert Svatek, chief of urologic oncology at University of Texas San Antonio.
“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.”
Patients can also elect a more extreme route: complete bladder removal surgery, or the construction of a bladder-like pouch made out of intestine. The costs of these complex surgeries are in the tens of thousands of dollars, and require years of follow-up treatment.
As effective as BCG may be, creating a safe strain of a live tuberculosis bacteria is rife with complications. The process, start to finish, takes about three months — beginning with two months of horticulture. BCG is grown on a specific variety of potato, and that alone takes two months to grow. Once harvested, it’s brewed in giant vats over the course of a month. And plenty can go wrong.
Sometimes entire batches of drugs like BCG can get ruined if someone just pushes the wrong switch, or throws one wrong chemical into a big vat of the drug.
“I’ve seen that happen — just a big mistake, somebody puts in the wrong chemical, and several million dollars worth of a drug has to be discarded,” said Dr. Otis Brawley, a physician at Johns Hopkins and until recently the chief medical and scientific officer at the American Cancer Society.
Supplies of BCG have been erratic for several years, beginning in 2011, when the Food and Drug Administration inspected a Toronto vaccine laboratory where Sanofi was manufacturing the drug and found 58 different instances of mold after a flood. The FDA promptly shuttered the lab, triggering the first of a series of BCG shortages.
The shortages continued, on and off, as Sanofi dealt with regulatory blowback. It stopped BCG production in 2016, leaving Merck to supply the drug for most of the world. But right around the same time Merck began experiencing its own manufacturing issues.
When Sanofi attempted to sell off its BCG-making assets at a discount, there were zero takers.
“Companies like Merck don’t make money off of BCG,” said Dr. Benjamin Davies, a professor of urology at University of Pittsburgh. “So there’s very little incentive, outside of altruism, to make this better.”
When shortages of BCH hit, there are ripple effects.
A 2017 New England Journal of Medicine piece authored by Davies found list prices of chemotherapies used in bladder cancers spiked dramatically during a 2014 BCG shortage: The list price for mitomycin jumped by 99 percent from $436 to $869 for the 40-milligram dose. And between 2012 and 2015 — years of BCG drought — annual Medicare Part B spending on mitomycin increased from $4.3 million to $15.8 million.
Companies don’t have their plants producing batches of the same drug year-round — they tend to tool up a plant to manufacture a drug for a finite amount of time, churning out a massive batch. They’ll typically sell that over the course of a year or two.
This is how Merck doles out its BCG — selling it in bulk to hospitals and other large-scale providers, allocating it proportionally around the world, based on need. The company expects to produce anywhere from 600,000 to 870,000 vials of BCG this year, though isn’t providing a timeline on when the drug will ready. It’s also exploring ways to increase BCG output, Brewer said.
At the same time, companies in Japan, Canada, and Europe are developing their own strains of BCG, however — and if they’re ultimately approved by the FDA, they might be able to allay future shortages of the drug.
For now, however, some patients will struggle to get access, just as other patients do with a host of other treatments in the U.S. health care system, said Erin Fox, senior director of drug information services at University of Utah. Common hospital provisions like IV fluids and morphine are constantly in production limbo.
That doesn’t make the shortages any less frustrating. “We pay the highest prices of any country, so these shortage situations shouldn’t happen like this,” she noted.
If there’s a silver lining to the BCG situation, Fox said, it’s that there’s growing evidence that smaller doses show efficacy in battling bladder cancers.
Indeed, to help prolong the supply of BCG, most urologists wind up dividing the dosage into thirds. There are studies, actually, that suggest that these lower doses are similarly effective in treating bladder cancer.
The Bladder Cancer Advocacy Network, a Maryland-based patient advocacy group, along with the American Urological Association and several other physician groups, have come up with treatment guidelines to help navigate the shortage. The suggestions include dividing up doses, and stopping maintenance therapy entirely, as was the case with Fields.
Dr. Karim Chamie, an associate professor of urology at University of California, Los Angeles, said the BCG shortage hasn’t affected his practice just yet. But although the stockpile of BCG at UCLA is still in good shape, Chamie projects that will soon change.
“Urologists in the community have already hit a shortage, and they’re referring their patients to me,” Chamie said. “So my clinic’s clogging up with patients who need BCG — and they may be using some of the BCG I might have given someone else.”
When they get something that works, then you Can’t get it anymore. It isn’t fair to do us that way
A equivalent for intravesical BCG is already 20 years chemohyperthermia with Synergo.(RITE).
Urologia. 2016 Oct 4;83(Suppl 2):7-17.
Radiofrequency-induced thermo-chemotherapy effect (RITE) for non muscle invasive bladder cancer treatment: current role and perspectives.
Colombo R et al
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