The shortage of platinum-based drugs in the United States is an endemic problem—i.e., Europe is unaffected—caused by the absence of transparency, dearth of early warnings, and a lack of redundancy in the supply chain.
“This particular quality issue is about a surprise audit where documents were found that were shredded, and the plant got shut down,” said Julie R. Gralow, chief medical officer and executive vice president of the American Society of Clinical Oncology. “That plant that made raw materials supplied all of the manufacturers, at least in the U.S.—FDA-approved manufacturers of cisplatin and carboplatin. So, there was no redundancy.”
A key supplier in India, Intas Pharmaceuticals, temporarily suspended manufacturing of essential cancer drugs after FDA found severe quality-control issues, according to a compliance report from December 2022.
“The FDA does not have the authority—which we need to fix—to know for a given manufacturer, where are they getting their raw materials; right?” Gralow said. “So, we had redundancy across manufacturers of these drugs, which in theory should look good.
“My understanding is we had five manufacturers, but they all sourced from the same one place in India that got shut down for quality reasons.”
ASCO is encouraging its members to report drug shortages to the FDA and ask their representatives in Congress to find an enduring fix to this problem in the U.S.
“We need to do everything we can, in the short term, to get the supply back up, get these drugs to patients, and then more importantly, we’ve got to use the political will that I think is coming from these horrible, horrible situations and work with our legislators, work with the regulatory agencies, and help work on the market in the manufacturing end, so that we have permanent solutions in place,” Gralow said.
“We need that early alert system so that we can anticipate problems and be a little more proactive, as opposed to reactive, which is a lot of what happened this time.”
Gralow spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
A video of this interview is posted here.
Paul Goldberg: Well, Julie, thank you so much for agreeing to talk with me about this crazy problem. The thing that’s amazing here is that we’ve been talking about shortages for decades now, and they don’t seem to go away, and this one seems worse than the others. Do you think so? Or am I wrong?
Julie R. Gralow: You’re 100% right. Paul. ASCO has been giving testimony in Congress starting back to 2011, 2012, when we had that cytarabine shortage for leukemias as well as some other drugs. And so, we’ve had roundtables, we’ve had summits on this—and very little has happened. But what makes this platinum—cisplatin and carboplatin—shortage in particular a big problem is just how many cancer types rely on these drugs as a critical part of curative therapy.
Well, you’re a breast cancer doc, so can you imagine having a conversation with a patient in a curative setting, or even not in a curative setting, but let’s say curative at first, and you would be saying, what… We can’t give you the lifesaving therapy. How would you even do that?
JRG: There are big ethical issues and we are hearing from our ASCO members that they need help in how to talk to patients, and they’re having their own mental health issues related to having to have conversations like this.
[We are] supplying our members and their patients with alternative regimens, ways to preserve the limited amount of drug they have, potential for doing things like instead of giving preoperative chemotherapy, switch to postoperative chemo, so that we can give a few more weeks to months to get more supply.
Having that ammunition here are things we are doing and we really are going to do everything we can to get you the critical drugs you need, and if there’s a substitute regimen that’s really equally effective, then let’s let our members know.
Let’s let their patients know so we can preserve these drugs for those situations where there really is truly no alternative.
I’m not a doctor, but I felt that the number of alternatives that would be equivalent is very low. If you are talking about carboplatin, you might switch a large set of patients to cisplatin—and then what? There is no “then what”?
JRG: We’ve got a group we’ve pulled together from our guidelines group who’ve worked with the Society for Gynecologic Oncology on coming up with some potential alternative regimens and drugs. So, we hope to, within the next week or two, by the time of the ASCO annual meeting, to have that on the website. We just don’t have it quite together yet.
You’re right. Usually if you can’t get one platinum agent, a logical substitution is the other one. But there are cases where there are non-platinum regimens that might not be as commonly used, but there are trials that show that they probably have similar efficacy.
It’s just for a variety of reasons, they have not been the number one preferred regimen. So, don’t get me wrong, this is a disaster.
We need to do everything we can, in the short term, to get the supply back up, get these drugs to patients, and then more importantly, we’ve got to use the political will that I think is coming from these horrible, horrible situations and work with our legislators, work with the regulatory agencies, and help work on the market in the manufacturing end, so that we have permanent solutions in place.
I can’t even imagine the talking points in this case. I know they exist already, but good god, how would you even write that?
JRG: Do you mean the talking points to the patients?
Yes.
JRG: Yes. I think that it’s tough, Paul, but we’re oncologists. We’re always weighing risks and benefits and toxicities versus efficacy, and every single conversation is going to be very patient-specific,as it should be. I think knowing that physicians, the hospitals, the cancer centers, the FDA, everybody is working hard to try to fix the situation. So, we’re hoping that by June, we will be in a much, much better place.
I don’t mean to put ASCO on the spot, because you didn’t create this problem. You’re just trying to deal with it, but how did this happen? You’ve looked at it.
JRG: Well, the big picture of drug shortages, whether cancer drugs or others, it’s mostly about manufacturing quality problems.
And it’s been primarily the generic sterile injectables. So, quality issues are number one. This particular quality issue is about a surprise audit where documents were found that were shredded, and the plant got shut down.
That plant that made raw materials supplied all of the manufacturers, at least in the U.S.—FDA-approved manufacturers of cisplatin and carboplatin. So, there was no redundancy.
The FDA does not have the authority—which we need to fix—to know for a given manufacturer, where are they getting their raw materials; right?
So, we had redundancy across manufacturers of these drugs, which in theory should look good. My understanding is we had five manufacturers, but they all sourced from the same one place in India that got shut down for quality reasons.
And the FDA did not have the authority to demand that each manufacturer say where they are getting their raw materials. So, that’s got to be fixed. I think we will fix that. The FDA will have the right to demand that.
We also, I think, need to have some more transparency, Paul, on when a place gets shut down.
When there is a quality issue that’s found and a report is issued, we—you and I, ASCO, our members—don’t have visibility of that report. It just says the plant was shut down and “quality.”
It doesn’t say what the issues were. I think we need more transparency about when quality issues are found. What are they?
If I look at the shortages website, the database, rather, at FDA, I’m not seeing what you’ve just said.
JRG: No details. No details you can find there. And we deserve to have more details, and there needs to be more transparency.
So, the legislative fix might take some time. How soon do you think this can go away? Because people are dying.
JRG: We’ve seen just in the last week—and we’re posting every time more cisplatin or carboplatin gets released in the U.S.—we are saying what company it’s coming from.
And there was just another release of carboplatin yesterday, which we posted on our website. We’re putting it on Twitter. So, we are seeing more release, we are seeing more drug coming out. We are hoping that sometime in June that this will not be so critical.
I think we’ll still need to be careful in June and try to maximize the supply we have. But we’re hoping as we’re watching this day by day, week by week, slow release of more and more drug that we’ve hit the bottom and we’re slowly starting to come out.
So, you think it’s going to be months longer, or you just don’t know?
JRG: Hard to know. We’re going to have to be careful with these drugs for a while, I think. But being able to get them to the critical patients who need them, hopefully will be markedly better within a month. That’s my guess. I don’t know. You don’t know.
I certainly don’t. What about clinical trials? There’s going to be an impact on clinical trials.
JRG: Absolutely. When platinum is in either the control or the experimental arm and you can’t access it, it either pauses your study or you have to scramble and come up with an alternative.
So, there will be trials that are impacted by this, hopefully only for a month or two.
But we’ve learned how to be a bit more flexible. I mean just think about this leading up to this acute issue. We had the pandemic, back in 2020, as the pandemic hit, there was a survey of U.S. oncology pharmacists on oncology drug shortages that led to delays in chemo, changes in treatment, or omission, complications of clinical research, etc.
And there were like five or six cancer-related drugs that just the pandemic and the issue of the pandemic—globally and in the U.S. impacting manufacturing—did that.
So, we were vulnerable from the pandemic.
And fludarabine has been a big recent issue as well. It impacts far less patients than cisplatin and carboplatin, but it’s equally critical in the smaller number of patients where it’s critical.
Currently, we have 15 oncology drug shortages listed on the FDA’s website. The only critical, critical ones right this minute are the platinum agents, but there are others at risk, others in shorter supply. So we’ve gotta fix this.
And I think, based on this drug shortage disaster, we have some political will to really push this through. We’ve been asked to provide testimony to the House to the Senate.
This is being viewed as a national security issue. So, we’ve got bipartisan support to push this through. I think.
Is this an NCI issue? Could somebody suggest that NCI should just administer a stockpile of cisplatin and carboplatin and maybe other drugs as well?
JRG: So, we’ve talked about, should we have a government stockpile? What I hadn’t heard is NCI as a house for it. We’ve talked about doing it through the mechanism of the VA and Medicare.
They have big buying power; right?
So, they are buying the drugs. The NCI is not really buying the drugs. It might make more sense, if we do want to create stockpiles of some critical drugs, that it be done through some government mechanism that’s already buying the drugs.
And another point, when we have such buying power from our government—VA, Medicare, Medicaid—we shouldn’t be getting all of that from one source, either.
We should try to help the market and provide incentives, so that we would encourage, if not mandate, that our government purchase of these drugs be across maybe three different manufacturers for any given drug that helps with stability, long-term contracts, keeps the manufacturers in the market, so that they don’t drop out.
I guess there has to be a way of fixing the economics of the problem, if you can’t fix it in a regulatory fashion.
JRG: I think we’re going to have to agree that for these drugs that are just dirt-cheap—I saw one briefing, they compared the price of these drugs to that of a McDonald’s hamburger.
When these drugs, especially the high-volume ones, go generic, there’s a race to get in to make the generics, and it’s a race to the bottom in terms of price.
And so, you lose a lot of the higher-quality manufacturers. And we’ve got to have incentives to keep high-quality manufacturers in the market.
And it’s going to have to be through some of these long-term contracts, through distributing the contracts and the purchasing across multiple manufacturers, and agreeing, maybe, to pay a little bit more.
And, the FDA created this Quality Management Maturity index, which was supposed to help assess the quality of a manufacturer, and that might help influence where you buy your drug from.
But at this point it’s 100% voluntary. So, there’s no mandate that you need to be part of this index, and that it’s visible.
So, one of our talking points is, it would be important to have some kind of quality reporting index, such as the FDA’s Quality Management Maturity index be mandatory, and be visible, and be used in purchasing, and maybe rewarding hospitals and cancer centers that purchase X percent of their drugs through the high-quality sites, to try to encourage that.
Does ASCO have a model legislation that you’re proposing? I’d love to see that or publish it.
JRG: On our website, we have the testimony that we’ve given to the House Appropriations Committee on Agriculture Rural Development, and FDA.
We’ve also got statements and responses that we’ve given just in the last month, really, to various committees in the House and the Senate.
So, we don’t have the legislation draft per se, but what we are telling our members in contacting lawmakers, there are four major House sponsors of a “Dear-Colleague” letter that is going around.
We’re encouraging our members to write to their representatives to sign on to this “Dear-Colleague” letter that’s asking for additional flexibilities and authorities that are needed to prevent or mitigate future shortages. You can read that letter on our website.
And then, for the Senate, they don’t have such a letter circulating, but we are encouraging you to write to your senators to 1) improve FDA’s visibility into the supply chain that gets to where their raw materials come from, 2) look into importation if existing manufacturers can’t [produce drugs], ramp up importation by manufacturers not currently approved by the FDA, [and 3)] better communication in advance to health systems, so we can help plan for shortages.
We are asking our senators to examine economic incentives that are currently driving generic manufacturers out of the market.
So, we are saying we should encourage long-term contracts, guaranteed prices, and then, lastly, we’re saying, write to your senator and have them talk about how we incentivize the U.S.-based production of critical medications.
How do we do price stabilization and how do we invest in the more advanced and high-quality manufacturing in our country? So, that’s not legislation per se, but it’s things we want various Senate committees and subcommittees and House committees to be working on.
Is there room for an executive order? Is it enough of a problem right now?
JRG: Not sure about that. We have not called for that yet. We’re a little distracted at the present time with our debt ceiling, but it might come to it if we can’t get anything through our current Congress.
This should have been my first question, there’s so much to this—have you seen the numbers of patients who are affected by this? Is there a number somewhere?
JRG: We’ve worked on trying to figure out a number, as have others. So, the FDA approval for these drugs is in ovarian, testicular, and bladder cancer. And so, if you take where there is actually an approved label, and you look at that and you take into account that testicular is only the advanced or metastatic that are getting platinum agents, it’s at least 100,000.
But then you add on top of where there’s a label, you’ve got cervical cancer, non-small cell lung cancer, head-and-neck cancers, for example. There are estimates that up to 500,000 patients possibly could have a stage and a diagnosis that would rely on a platinum agent.
Although I think that 500,000 hasn’t [been] adjusted for stages where we wouldn’t use it. So, Paul, it’s somewhere between 100,000 and 500,000 of Americans each year would be diagnosed or have a cancer that this would be relevant to. That’s a lot of patients.
Astounding. As a percentage of the total, what would be the overall number of people with cancer? Patients per year? Do you have that?
JRG: I think we have about 1.8 million new cases reported annually, somewhere around there.
So, it’s close to a third, a little under a third at that moment.
JRG: And this is why this particular shortage has risen to headlines in all the papers and stressed on the part of patients, physicians, healthcare systems everywhere. It’s just the absolute number of patients impacted.
This really should have been my first question, but is there anything I forgot to ask? Anything we forgot to talk about?
JRG: Once the acute shortage is over, we cannot forget about this. We’ve got to keep pushing, pushing.
We’ve got to all be partners in helping with an early alert system. In addition to writing to members of Congress, we are asking our members—on our ASCO drug shortage website—we show where you can report to the FDA any drug shortage, [reporting when] your particular clinic is having trouble getting certain drugs.
We need that early alert system so that we can anticipate problems and be a little more proactive, as opposed to reactive, which is a lot of what happened this time.
Thank you very much.
