How Sanofi’s discontinuation of BCG affects patients, clinicians

Sanofi Pasteur recently announced that it is discontinuing its BCG products TheraCys and ImmuCyst, prompting fears of a shortage of BCG for bladder cancer patients. In this interview, Dr. Benjamin J. Davies, associate professor of urology at the University of Pittsburgh School of Medicine, discusses the implications of the announcement and what’s next for patients and clinicians.      

Urology Times: What short-term and long-term implications does this announcement have for patients?  

Dr. Davies: I think in the short term, it’s a challenge to predict. We may well see a decrease in supply in the near term, although it’s a bit of a challenge to know if that’s true or not. I think long term, we’ll actually have a little bit easier time predicting that we’re going to have real supply difficulties with BCG. I think it’s fair to say that barring any change or any new announcement, that’s likely to happen. The reason I say that is because we know that Merck has had challenges in the past in increasing supply of the drug, and that was around 2012 into 2013. That’s probably a product of it being a challenging drug to make. You can imagine that this is not the type of drug where it’s chemical XYZ joins chemical ZYX in a pot and it’s spit out into pills. This is a biologic drug that has to grow under very careful medium conditions, and one mistake in temperature, one contamination into the growth medium, and the whole drug can be spoiled. That can mean up to 5,000 to 10,000 doses can go bad day to day. So it’s a challenging drug to make, and we know that it can be a challenge for one manufacturer to really hold the supply of America in good faith.   

And I would say in Merck’s defense, it’s not really good for Merck to be the only supplier in America of a drug that’s very challenging to make. You can imagine from a market perspective that that’s not the way we want to be. We want to have multiple people making challenging drugs, biologics in general, because that way we know the drug will be available. If Merck’s one plant in North Carolina goes down, even for reasons of which it really has no ability to control, what do we do? It’s a real big problem. So I say in summary to that question, short term, we don’t know, we may be okay for the next few months, next 6 months. Long term, I think we have a serious problem.

Next: "I think at this point I would be surprised if we don’t have a severe problem."

How will this change how physicians treat non-muscle invasive bladder cancer?

I don’t think it’s going to do anything for now; nothing will happen for now while the supply is being maintained by Merck. The challenge is that we don’t have assurance, or we have no reason to believe that Merck can always have a productive supply of drugs. In fact, we have the opposite; we know it cannot do it at all times, and potentially through no fault of its own. Look at what happened to Sanofi; it got into trouble making the drug with contamination issues in its Toronto facility. Then, only a few years later Merck had what we think is a similar problem at its facility. So now we have just one maker, Merck, making the drug. So I think the long term is going to be a big problem. Think about all the patients that we tell should be on maintenance therapy for BCG, which is basically the standard of care for high-risk patients with bladder cancer, localized non-muscle invasive bladder cancer. High-risk patients should be offered and explained what maintenance therapy is and that’s usually a year to 2 years of drug. So what I’m telling patients is that it may well be that we can’t give you the drug. And we’ll have to deal with the consequences as they come about.

I should note, my discussions with both of these companies have been sort of tight-lipped. But I have talked to both companies. The discussions with Merck were kind of upbeat and I was happy that they were upbeat. They claim that we’re not going to see a disruption in the network of BCG. They claim that Sanofi really hasn’t been supplying that much drug in the past few years and Merck has been able to do fine. I’ll be happy to be wrong, although I’m quite sure that I won’t be. That’s because we have a track record of them not being able to do that and they haven’t changed the production amount, at least according to them. I’m happy to be disproved, but I think at this point I would be surprised if we don’t have a severe problem.

Do you expect the FDA to take any action on the BCG situation or drug shortages in general? Ideally, what steps should the agency take?

That’s a good question. There’s no agency power for this. We want the government to be proactive when we feel like it, but we have to give them the resources and the legislation to do so. We haven’t, so the FDA has no power to increase BCG supply. There’s no regulatory framework for that. But there is a very arcane regulatory framework for the FDA to intercede on behalf of the American public when they think a drug is being used inappropriately; kind of like an eminent domain issue. The FDA does have that regulatory power. To my knowledge, it has never used it. It would not use it in a situation where there’s no patent protection involved and it’s just simply a matter of money. So the short of it is, there’s no regulatory way that BCG can be, the FDA can do anything about it other than to call and say, “You should be making more, Merck.” The FDA is aware of it. They know what’s going on. They’ve had discussions with Merck and Sanofi. It’s on their website. But there is nothing specific they can do.

Next: What can urologists do?

Do you think Merck will be able to meet demand for BCG after Sanofi exits the market?

I hope so. I have no faith that they will be able to given their track record. Merck claims the past 2 years that basically Sanofi exited the market and basically their announcement was ex post facto; that it was an announcement of fact but the fact had already happened 2 years ago. It’s unclear that’s true because I know that there are VA hospitals which were getting Sanofi’s product, and I don’t feel comfortable saying that Merck will be able to meet the market, to be honest.

Is there anything that urologists can do to help ensure that they’ll have an adequate supply of BCG going forward?

After I wrote an article on this topic for Forbes, people emailed me and called asking if I had any suggestions. I said, look I’m not the national expert on BCG therapy. We have people in our field who are much better positioned to answer that question. And it’s been answered. It’s not like I’m coming up with the answer here by myself. The things we can do are simple. First of all, I wouldn’t do anything for now. We don’t have a shortage as of present. Nothing would change as of today. If and when I suspect that we do get notice that we have supply challenges, I would treat patients the following way. First of all, I would stop maintenance therapy for patients because while maintenance therapy does change recurrence rates in randomized controlled studies, I think it’s more important to give patients the proper induction therapy.

I would consider also halving doses of BCG to sort of get more bang for your buck. There are quite a few studies showing half-dose BCG or even one-third dose BCG is as good as full-dose or close to as good. The third thing I would consider if we really get a shortage is giving patients four doses of BCG or even three doses as induction therapy. I’m not advocating that as an approach, but there are some studies looking at three doses, four doses, or six doses, and while six doses does seem to be the most efficient and the best, it’s not like you don’t get any effect if you give three or four doses. So if we’re stuck in a world where we have two patients who need induction therapy, I’d rather give three and three rather than give one six and the other none. There are strategies that we can use. They’re all kind of horrible strategies, but they will give us something.

Is there anything you would like to add?

I’m hopeful that Merck will be able to increase their capacity. I have no reason to doubt them when they tell me they will be able to meet the demand. What I’m fearful of is in the same way sort of if you think about the food supply, you don’t want to have one producer of lettuce. You know, when you have one producer of lettuce in California and they get an E coli contamination, we all lose lettuce and we all get E coli, right? You don’t want to have a situation in a market where you’re reliant on one agency to provide you an essential drug because all that has to happen is for Merck to have a contamination, which they’ve had before, and we don’t have the drug. That is my cautionary tale here and that’s my worry is that we get a sort of E coli infection of the BCG supply, and there’s nothing else. We have no other choice, we have nothing.

The AUA or the international community has to come up with a good plan here to get other pharmaceuticals interested in developing their BCG drugs. The only way I can think of is from a free market perspective would be to increase the reimbursement to the pharmaceutical biologic agencies to increase prices for BCG. If that’s not going to happen, and it may well not given the current environment, then I think we need to have government control in production for non-patent protected drugs. That’s my sort of socialist Bernie Sanders hat, but if the free market as we have now isn’t going to work for patients, I don’t know what else we do except have the government make it work. People may not like that; they may think it’s anti-American and not market minded, but I would remind those people that right now we have an unacceptable situation where we’re relying on the good graces of Merck, which doesn’t have a great history, and we have no other method of making the drug. None. So we’re in a really scary situation. I’m not trying to be scary, but it is a scary situation. If you’re a patient with bladder cancer, it’s potentially a disaster. We have to make it better.

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