- BCG is one of more than a 100 drugs listed by the Food and Drug Administration as in shortage this year.
- The shortages started several years ago when Sanofi-Pasteur and Merck were making the drug.
- But after the FDA cited quality problems at a Sanofi plant in 2012, it left the market in 2016.
Karen Hay felt like she had the cleanest floors in all of Pittsburgh.
It was a miniscule bright side to the nightmare she was going through.
Her cancer diagnosis, two years ago, was hard enough. In her mid-50s, Hay didn't fit the profile of someone typically diagnosed with bladder cancer. But the treatment she got seemed to work: a drug called BCG.
Then another bombshell: there was a shortage of that drug. The medicine she then received instead, a chemotherapy drug called gemcitabine, was so painful she said she couldn't sit down. That's how her floors got so clean.
"One of the things I could do was sweep," Hay said in an interview at her home. "So you walk, you sweep, you walk, you sweep."
BCG is one of more than a 100 drugs listed by the Food and Drug Administration as in shortage this year. It's a persistent issue plaguing the U.S. health system, spanning everything from antibiotics to pain medicines to vaccines and therapies for childhood cancer.
"It's been a longstanding problem," said Erin Fox, senior director of drug information and support services at the University of Utah Health, whose team has been tracking national drug shortages for almost 20 years. "Probably in the last two or three years, it's really gotten significantly worse."
The reason brings a bitter sense of irony: at a time when the drug industry is under siege for its high prices, this problem is caused by prices that are too low.
"In general, these are very, very inexpensive drugs, and so it's not very profitable to make these products," Fox explained. "But it's also difficult to make these products … in many cases, it doesn't make economic sense for a company to make one of these old, cheap drugs when they could make something more expensive."
Such is the case with BCG. Short for Bacillus Calmette-Guerin, BCG is a strain of mycobacterium bovis -- a bacteria commonly found in cows that can cause tuberculosis. Each batch takes three months to make, 30 days of which is just waiting for the bacteria to grow in test tubes with what Merck calls "a very specialized type of potato."
And it's surprisingly effective in treating bladder cancer.
"BCG has been around for decades and it was the first and still most effective immunotherapy for cancer," said Dr. Jodi Maranchie, associate professor of Urology at the University of Pittsburgh and Hay's doctor at UPMC. "With BCG we have about a 70% success rate in obliterating high-grade cells."
It's also very cheap: a list price of $157.07 a vial. Typical dosing is one vial per week for six weeks. For comparison, Merck's blockbuster new cancer drug Keytruda and other similar medicines cost more than $13,000 a month.
And that's part of the problem.
The shortages started several years ago, when at least two companies were supplying the drug: Sanofi-Pasteur, and Merck. But after the FDA cited quality problems at a Sanofi plant in 2012 -- from 58 documentations of mold to nesting birds observed in air-intake grills -- Sanofi decided to leave the market in 2016.
That left Merck as the sole supplier. The company says it's more than doubled production to its maximum capacity, but the shortages persist.
"Merck's manufacturing team continues to work around the clock to get TICE BCG to as many patients as we can," the company said in an e-mailed statement. "Our company remains firmly committed to patients and physicians when other companies have chosen to exit the market and where no others have invested in manufacturing this important treatment."
"When the prices of drugs get too low -- particularly drugs that are generic drugs -- then you don't have a market incentive to put the capital up to build facilities like we need for additional amounts of this BCG drug," Frazier said. "So for Merck, the challenge is: how can we maximize the amount we can make for patients given the fact that the other … companies have now dropped out of the market?"
Doctors and patients say that's incredibly frustrating.
"When we have a drug that's so important to our field and so effective, it's shocking that we don't have more companies that are making this," Maranchie said. "It's unfortunate when you find out that it all comes down to the commercial interest, and if there isn't enough money … then they lose interest in making these drugs."
Sanofi's plant was re-licensed in 2014, but had reduced production capacity as a result of the fixes it had to make, spokeswoman Ashleigh Koss said in an e-mail. The company tried but was unable to find another manufacturer to take over production.
"There was not sufficient interest to overcome the investment and technical risks associated with assuming responsibility for the product," Koss explained. Last year, she said, Sanofi announced it was spending $385 million to transition the former BCG plant to manufacture pediatric and booster vaccines "to meet growing demand."
To Dr. Gary Steinberg, a urologist at NYU Langone Health who called the BCG shortage his biggest headache, Merck is doing more than its fair share.
"Not only have they ramped up [production], but they're producing BCG faster," Steinberg, who consults for Merck, said in a telephone interview. "Merck is not the villain here."
Some, like UPMC urologist Ben Davies, say the company should be doing more. He pointed to Keytruda, which was approved in 2014 and has dramatically changed the way melanoma and other cancers are treated. It drew more than $7 billion in revenue last year for Merck.
"I don't think it'd be too much to ask for them to put a little bit of that money into a new facility," Davies said. "They have a financial responsibility to their investors… but I think you have a moral obligation as well."
It's difficult to quantify the effect of drug shortages on patients' health since the U.S. doesn't have a national tracking system. But "we know that drug shortages certainly affect safety," Utah Health's Fox said. "We know that patients are getting delayed therapies."
In the case of BCG, "the shortage has definitely led to poor outcomes in bladder cancer patients," Davies said. "You just get more recurrences. So that means you have to have more surgeries, you have to come back to the doctor to be screened more… the other outcome is you (could) have to have surgery to have your bladder removed."
And, he noted, "if you had a drug that could stop the movement of the cancer, and we know BCG does this… it's not a question that it's caused deaths."
Work is underway to test new therapies for bladder cancer, including other strains of BCG, as well as next-generation immunotherapies, like Keytruda.
But clinical trials are complicated by the shortage as well, Steinberg said, because in order to prove new therapies work as well or better than BCG, the trials need to have supply of BCG to test against.
And he noted the situation may actually give Merck a "competitive advantage" when it comes to these studies, in the fierce marketplace where the company competes with Bristol-Myers Squibb, Pfizer, Roche, AstraZeneca and others.
"If you have any trial that Merck is running that requires BCG, they're able to supply the BCG for that trial," Steinberg said. In a trial of a Bristol-Myers Squibb drug, he noted, "BMS is not providing BCG for the trial, so the only way you can enroll the patient is that if you have your own supply of BCG for the trial."
Merck said it's "committed to ensure that we can provide supply for clinical trials conducted by Merck and other sponsors to investigate potential medicines for non-muscle invasive bladder cancer, including a number of ongoing trials investigating Keytruda that include patients on BCG therapy."
The company is providing BCG to a cooperative group trial comparing its strain with a Japanese one, called Tokyo BCG, both Steinberg and another urologist, Kelly Stratton from the University of Oklahoma College of Medicine, pointed out.
Stratton is running a trial of a Pfizer immunotherapy, and said he's had to "closely monitor our BCG supply to ensure we maintain adequate supplies of the drug." He said when Merck sponsors a trial, it commits to supplying the medicines, "so providing BCG would just be following through with that commitment."
Doctors universally agree, though, that having an alternative to BCG would be ideal, if supply can't be guaranteed.
Until then, patients like Hay have to deal with rationing, alternatives that haven't been proven to work as well, and the side effects that can come with them.
She described her experience -- first the cancer diagnosis, then the shortage -- with determined reserve, until her husband pointed out how devastated she was.
"I kept looking for BCG elsewhere. I kept asking other people, 'What are my alternatives? What can I do?' But it was very, very hard to get up in the morning. It's hard to keep asking," she said, her eyes wet with tears. "We are perfectly capable of making enough of this, this substance. We just, our system chooses not to."