Sanofi's Halt of BCG Production Worries Bladder Cancer Patients and Urologists

Sanofi Pasteur plans to discontinue production of Bacillus Calmette-Guérin (BCG) for the US market by mid-2017, startling physicians and patients who fear that a shortage of the widely used bladder cancer therapy will develop.

The company announced plans to stop manufacturing the drug, sold under the brand names TheraCys and ImmuCyst, in a statement posted on its website last week¹ after informing urologists about its decision in an email. The product will not be relaunched in the United States.¹

With Sanofi’s exit, that leaves only one other company, Merck, manufacturing BCG for distribution in the United States.

Merck, which produces the vaccine under the brand name Tice, is fully equipped to meet the expanded demand, according to Elaine Perry, MD, FACPM, executive director and chief patient officer at Merck. “As early as 2012, there was a significant increase in demand for BCG. There were challenges initially but, looking at the US, we are already meeting demand with no back orders,” Perry said in an interview with OncLive.

Nevertheless, news of the impending discontinuation is already sending ripples of panic throughout the urologic community.

“There are limited suppliers of BCG live attenuated vaccine indicated for the intravesical instillation for nonmuscle invasive bladder cancer, and now we have one less,” said Andrea B. Apolo, MD, chief of the Bladder Cancer Section of the Genitourinary Malignancies Branch at the National Cancer Institute. “As of yet, it is unclear yet how [the discontinuation] will affect the cost of BCG, but great efforts are ongoing to keep up with demand and find new suppliers.”

She said that more than “70% of patients with bladder cancer present with nonmuscle invasive disease and many require treatment with BCG.”

The email that Sanofi sent to urologists said that the company attempted to find another manufacturer to take over the production of ImmuCyst and TheraCys, but that “ultimately no party would commit to take on this product.”²

Marc A. Dall’Era, MD, associate professor and vice chair of Urology at the UC Davis Cancer Center, said in an interview that “clinicians currently have no adequate treatment alternatives that are proven better or equivalent to BCG.”

Social media, particularly Twitter, is flooded with treating urologists who are concerned about the potential for a BCG shortage. “BCG shortages will lead to rationing and inadequate care of men and women with this disease and will put patients at significant risk,” commented Dall’Era.

Past Supply Shortage

Robert L. Grubb III, MD, an associate professor of Surgery at Washington University School of Medicine in St. Louis, said in an interview, “It’s frustrating for urologists to try to explain to patients why this drug, which has been around for years, is not available to them.”BCG is an intravesical immunotherapy that 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.

Sanofi said the company is discontinuing production because it cannot guarantee the long-term continuity and reliable supply of the product. The decision is not linked to safety issues, and all doses of TheraCys and ImmuCyst which have been released to the market meet all quality, safety, and efficacy guidelines, the company said.¹

There is a feeling among urologists of history repeating itself, since this is not the first time in recent years that the BCG supply has been disrupted. In 2012, Sanofi shut down the Canadian factory where it manufactures BCG after the FDA found numerous sterility and safety infractions, particularly regarding mold. This left the drug at serious risk of contamination.

Among the violations were 58 mold infractions, insufficient environmental monitoring, keys not being stored in a controlled manner in several areas, and nesting birds in the intake grills for the air handling units.³ However, Sanofi shut down the factory in order to correct these problems, and later resumed production.

The FDA noted that TheraCys has not been available in the United States since spring 2012, when Sanofi originally announced that there would be a shortage of the product. At that time, FDA immediately reached out to Organon Teknika Corporation, LLC, a subsidiary of Merck which also manufactures BCG.⁴

During the Sanofi shutdown, Merck ramped up production to meet the burgeoning demand, and the product was placed on allocation as needed by the FDA.⁵ However, there were still problems with supplies. “Many patients had their treatment delayed or discontinued. Providers, in some cases, were forced to ration BCG to their highest-risk patients,” Apolo said.

This stemmed from the fact that BCG is a biologic that takes about 3 months to make, Perry explained. She said that new batches aren’t ready immediately because the live microorganisms need to grow. Then there is quality testing, validation, packaging, and distribution that must be conducted. As a result, the BCG shortage began in 2012 not because Merck could not handle the increase in demand, but because BCG takes a lot of time to produce. “BCG is complex to make, you can’t rush it,” said Perry.

If the recent discontinuation affecting supplies in the future, Grubb said that “although there has been shown to be benefits to patients who receive BCG as maintenance therapy, urologists will have to prioritize patients who require induction course therapy.”

This is reflective of the fear that Merck will be unable to handle an increase in demand, although Perry commented that the company has a “small, but comfortable, supply cushion.” Perry noted that the company is not anticipating a sudden rush of demand, barring a change in current disease burden and practice patterns. She also said that Merck has been able to meet international BCG production needs.

The final concern among urologists is that Tice may not be as effective as TheraCys, still leaving a deficit in the treatment for patients with bladder cancer.⁶ “While there is not definitive proof,” commented Grubb, “there are some randomized trials that report Tice is less effective than Sanofi’s TheraCys.”

There is another option to treat bladder cancer, namely mitomycin C, which is a chemotherapeutic agent. The National Comprehensive Cancer Network recommends BCG as the preferred option over mitomycin C for adjuvant treatment of high-grade lesions, with BCG labeled as a category 1 recommendation and intravesical mitomycin C as a category 2A recommendation.⁷

This is because mitomycin C has been shown to have a lower response rate, in particular for treating Ta and T1 tumors.⁷ Apolo said that there are several chemotherapeutics that can be used to treat nonmuscle invasive bladder cancer, but that they are less efficacious than BCG, as is the case with mitomycin C.

During the BCG shortage from 2012 to 2014, the average wholesale price of mitomycin C rose dramatically, to more than $700 from $350.⁸ This jump in the price is likely a result of the BCG shortage, and there is concern that there will be a similar effect again. Grubb said that it is unclear if a shortage would affect prices for BCG in the same way that the shortage apparently affected prices for mitomycin C.

BCG remains the ideal treatment for patients with bladder cancer and, despite the general feelings of worry among treating urologists and their patients, Merck should be able to take over the sole production of BCG at its plant in North Carolina without the risk of shortages in the future. “At that plant, they are very dedicated,” Perry said. “We recognize the importance of this drug, and we will continue to focus on maintaining supply of the medicine.”

References:

1. Sanofi Pasteur statement on discontinuation of BCG. Sanofi Pasteur US website. https://goo.gl/17gsSp. Published November 21, 2016. Accessed November 28, 2016.
2. Davies B. Sanofi shuts down bladder cancer drug production: inevitable drug shortage to harm patients. Forbes. https://goo.gl/17cquA. Published November 17, 2016. Accessed November 18, 2016.
3. April 2012 inspectional observations (form 483). US Food and Drug Administration. https://goo.gl/3mueUD. Issued April 25, 2012. Updated January 29, 2015. Accessed November 18, 2016.
4. Important information about BCG live (intravesical). US Food and Drug Administration. https://goo.gl/sPtTQt. Updated January 29, 2015. Accessed November 29, 2016.
5. CBER-regulated products: resolved shortages. US Food and Drug Administration. https://goo.gl/FnggRH. Updated November 7, 2016. Accessed November 28, 2016.
6. Rentsch, CA, Birkhäuser FD, Biot C, et al. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol. 2014;66(4):677-688. doi:10.1016/j.eururo.2014.02.061.
7. NCCN Clinical Practice Guidelines in Oncology. Bladder Cancer. Version 2.2016. https://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Published June 23, 2016. Accessed November 18, 2016.
8. Shortages & price increases in drugs used to treat urologic conditions. American Urological Association. https://www.auanet.org/press-media/drugs-for-urologic-conditions.cfm. Updated 2016. Accessed November 28, 2016.