Unraveling the Complexity of Drug Shortages: Grim Reality Is a Bitter Pill to Swallow

Michael P. Link, MD

The last thing an oncologist wants to hear is that a medication he or she has prescribed is unavailable. But the reality is that drug shortages, while not new, have reached a crisis level. The medications in short supply run across multiple specialties, but the impact is most prevalent—and devastating—in oncology.

The American Cancer Society reports that patients with lung, breast, ovarian, and rarer forms of cancer face the biggest health risks when medications like paclitaxel, fluorouracil, doxorubicin, and bleomycin are scarce. An alternate drug may not work as well, and there may be increased side effects.

A recent statistic points to the magnitude of the problem: an IMS Institute for Healthcare Informatics analysis found that 550,000 cancer patients were impacted by the drug shortage as of June 30, 2011.

One of the more prominent leaders working toward a solution is Michael P. Link, MD, president of the American Society of Clinical Oncology (ASCO). This past summer, Link addressed the drug shortage problem at a Capitol Hill briefing. ASCO’s influence also was evident when, on November 30, 2011, the US House of Representatives Oversight and Government Reform Subcommittee on Health Care, District of Columbia, Census and the National Archives held a hearing on drug shortages.

Testimony ranged from declaring the situation a “massive national emergency” to calling on the FDA to accelerate regulatory processes that help resolve drug shortages.

In addition to his role as ASCO president, Link also serves as the Lydia J. Lee Professor of Pediatric Hematology/Oncology at Stanford University School of Medicine and director of the Bass Center for Cancer and Blood Diseases at the Lucile Salter Packard Children’s Hospital at Stanford. Link recently spoke with our oncology editors to discuss the impact of drug shortages.

How common are drug shortages? Dr Link: Let me start by saying that this is an issue that is not only related to oncologic drugs. It relates mostly to generics, but includes antibiotics and anesthetic drugs, as well as oncologic drugs and many others. I think it is now getting more attention because there has been a crescendo effect, almost a tripling of the number of drugs being followed that are in short supply over the last five years. There are hundreds of drugs in short supply, versus 20 or 30 in years past.

The reason? That’s a bit more difficult. The companies don’t have to announce the reason for a shortage, so we really don’t know the reason in more than half the cases. Sometimes it’s a manufacturing problem, meaning they’re having difficulty producing a sterile injectible, because that’s what most of the drugs in short supply are. There can be issues the drug precipitates, or a problem with the line. I understand one manufacturing plant was closed down by the FDA because they had a number of problems, and that creates a shortage because there are very few manufacturers making a given drug. If there’s two and one goes out of business for a while, that creates a shortage.

It sounds like the bigger issue is having some sort of advance notice that you know this is going to happen, so you can make alternative treatment plans.

Well, now you’re on to the solution, but I want to make sure that another problem is highlighted. That is that there is not much profit to be made on these drugs, certainly the oncologics. If a company is having problems making the drug that would require retooling and expense to solve, and they’re not making much money on the drug, there’s not much incentive to fix the problem. Also, because of the limited profits, these companies may have a different drug they can make, with a better business plan, and so there’s nothing to stop them from just ceasing to make the drug, as a business decision. Given that, the solutions are variable depending on what the real problems are, but economics has to be considered a key factor. Regarding advance notification, companies are not required to notify the FDA they’re going to stop making a drug if it is not listed as a medically necessary drug. Admittedly, if the FDA has advance notice, they can do something preemptively to prevent a shortage. They can explore alternatives like importing a drug from a source outside the United States where the manufacturing is FDA approved, try to induce somebody else to make the drug, etc. The longer the lead time, the more clout the FDA might have. The penalties for not notifying the FDA, even if it’s a medically necessary drug, are not terrible, so there’s not much incentive for the companies to let people know. One issue that has been raised is that advance notification actually could exacerbate the problem, because if it’s known a shortage is going to happen, distributors might buy up supplies, and there would be hoarding of drugs both by the hospitals and larger users, as well as distributors.

Can you talk a little more about the Preserving Access to Life-Saving Medications Act? Is that going to help solve this problem so it becomes less of an economic situation for the manufacturers?

I don’t know if that’s going to solve the problem. One of the key things about this proposal is, number one, to focus attention on the issue. It would certainly do that. Early notification is not going to solve the problem. But, I think this is a good first step. It’s important because at least it’s focusing attention on the issue where we can hope to get to the bottom of the true nature of the drug shortage, and be more intelligent in how we address it.

What kind of impact have you seen when all of a sudden a medication that you need to prescribe to a cancer patient isn’t available? What are the implications there?

I have faced this situation a couple of times, and it’s devastating. I first became aware of this problem when a drug we used in the treatment of lymphoma became unavailable. I prescribed it, ordered it, and our pharmacy said, “We don’t have any.” That’s when I realized it wasn’t just that drug in short supply, but a number of others, which is how ASCO got into this. In that case, there was already an effective and well-known work-around, an alternative medication that was also available and cheap; it was not on patent, and we could be pretty sure the outcome for the patient would not be affected. The second area where we thought we would run into trouble was in the shortage of cytarabine and daunomycin, which are both necessary to treat leukemia. For these drugs there is no work-around, and not just for pediatricians, but for medical oncologists as well—if you don’t have cytarabine and daunomycin, you just can’t treat the most common form of adult leukemia. And we need them for treatment of childhood leukemia as well. So, this is where there would be a real impact on patient care. The FDA did step in and provide a supply of cytarabine. Our pharmacist got a supply, with the unfortunate consequence that it was obtained at a substantial markup. So, that’s one possible solution. Sometimes the drug is in short supply and there is no work-around, and then one has to consider the unpleasant option of changing a patient’s therapy. That could involve telling a patient we don’t have the drug now, but we could have the drug available, let’s say, next week. That creates additional anxiety.

I think all oncologists know that delaying therapies and increasing the time between therapies is not a good thing. For some patients, even if they have delays they’ll be cured, and for some it may not make a difference, but in the aggregate, we know that having delays in therapy is going to be harmful, that the cure rates of curable cancers will be lowered. An alternative would be to use a substitute. With cisplatin, which is the mainstay drug in the curative therapy for testicular cancer, there’s another platinum analogue available, carboplatin, but it’s less effective. So, we can give a regimen which we know is suboptimal, if you will, but we don’t know the effect it will have on an individual patient. We know that the cure rate for, let’s say, 1000 patients will be less than for cisplatin, but it’s not as if we can’t cure any patient without cisplatin. So, we could do that—with a great deal of anxiety and trepidation.

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For these drugs there is no work-around, and not just for pediatricians, but for medical oncologists as well—if you don’t have cytarabine and daunomycin, you just can’t treat the most common form of adult leukemia. ”

—Michael P. Link, MD

If you had to use a secondary drug, would you have to use more of it for a greater length of time to have the same impact as your drug of choice?

I don’t know that we have that information in that kind of detail, but we’d have to use a higher dose. We try to use regimens where we have some track record so we know what to do. In pediatric oncology, for example, we’ve done many studies where we take a standard regimen and add a new drug, and we prove that it adds to the cure rate. It may add 5, 10, 15 percent. We know we can cure some children without that drug if it’s now in short supply; we just know we would be curing fewer of them. But, I don’t know if we know that we could make up the difference by giving the other drugs more intensively, or at a higher dose, or longer. I don’t think we’ve ever done those kinds of studies. We try to prove that a drug adds to the recipe, and then we assume we will have that drug available. One of the horrible things is, we’ve spent a lot of time proving that these drugs work, and now that they’re unavailable, saying to a family, we do know what should be given, but we can’t because the drug is unavailable, is a conversation that is very uncomfortable.

Is there a cost impact?

Society will bear the cost, but it’s not clear how it will break down. Let’s start with the example I gave you where our institution was able to get a drug that is necessary, but paid more for it. It’s not clear the patients will get reimbursed for the difference, and it’s not clear that we will bill the difference. The hospital will have to eat that cost because that’s the cost of obtaining the drug which we bear. There are times when a patient will be offered a drug that is a more expensive version. And, of course, that will add cost to the healthcare system. But, that’s what you have to do when a drug is in short supply. Costs that are being added are, first, using a more expensive drug that maybe we think is effective, but which is not on the drug label in terms of its indication for use. The insurance companies may not reimburse the patient for use of the drug. The other costs are, of course, pharmacies and practices spending money, time, and resources rounding up supplies of the drug. And then we know that when you start using drugs that you’re not used to using, you’re going to have to take more time to figure out dosing. It’s not second nature. You have to think about it more, and it also increases the opportunity for errors. If you made a medication error it would certainly add costs and potentially serious problems, and there has been documentation that such things have occurred. Those are additional costs to the system if not to an individual patient.

In talking about other areas that are affected as far as therapeutic areas, are there certain ones prevalent besides oncology, or is it just really across the board?

I think most areas are affected. Anesthetic drugs and antibiotics are among the leading agents, but cardiovascular drugs are affected as well. The reason the cancer drug issue is so compelling is that there are so few work-arounds. We don’t have that many oncologic drugs, and for most of the indications, there are not good, verified substitutes. Whereas one can argue that for most antibiotics there’s an alternative, if you forget about the cost and other details. In anesthesia the argument I would make is, you can still put people to sleep without Propofol, which is one of the drugs in short supply. It’s very convenient, it’s got a good toxicity profile, but there are other drugs we can use, maybe not as conveniently.

In cancer, though, especially in pediatric oncology, without these drugs we really can’t operate. About 80 percent of children with cancer can now be cured almost entirely with these generic drugs that are off patent, and yet many of them are in short supply. It is a crisis because without those drugs we’re back to where we were in the 1960s and 1970s. One disease for example, osteosarcoma, is a tumor where we now cure probably about 70 percent. And yet of the three drugs used for the treatment of osteosarcoma, doxorubicin is in short supply, cisplatin is in short supply, methotrexate with leucovorin is in short supply, and the leucovorin rescue, which is necessary to give the methotrexate, is in short supply. So, if you’re a physician who takes care of osteosarcoma, or a patient, that’s a pretty formidable obstacle.

From our point of view it’s unconscionable when we have a curative therapy that we know about, but we’re unable to deliver it because of the unavailability of a drug that has been around for 20 to 30 years. This is what we’re up against and what is so frustrating for us as oncologists and for our patients.

As ASCO president, do you have more influence?

Yes, I have influence with ASCO. Since we’ve identified this problem, ASCO has been extremely active in advocating for our patients, the people we serve. We were involved in the Drug Shortages Summit in November. In fact, that bill [Preserving Access to Life-Saving Medications Act] really came directly out of the summit. If you look at the legislation and recommendations from this summit, it was almost a cut and paste. So we’re happy to see we had some influence, though we’re not convinced it will solve all the problems related to the shortage. Our government relations staff has been very active on the Hill looking for individual legislators who will take an interest in this. When we were up on the Hill in May to brief individual congressmen and senators, I was disconcerted to find how few of them really were aware of this shortage. By the time we had this Hill briefing in July it was standing room only. So very clearly this has gained some momentum.

I think it’s important not to create a panic among patients who are already very anxious about their prospects, you know, cancer patients undergoing treatment, because many of them may not be affected by this at all. Their therapies have nothing to do with the drugs that are in short supply, or where they are getting treated the drug supply is not an issue. And for some patients, as in my own example that I gave, there is a very effective and well-known work-around, so their therapy will not particularly be affected. I think we do want to encourage people on an individual basis to talk to their physicians about the shortage and what the impact will be on their care.

That’s a huge thing for our audience—cost-effectiveness and still being able to increase quality of care.

Managed care managers should be aware that there are costs to the system that will have an impact on them. Using a substitute may cost more. The procurement charges may be higher because of supply and demand and because hospitals, and practices particularly are forced to spend more of their resources trying to find sources of drugs. Those all impact the cost of care. Obviously, our major concern is the effect this is having on cancer care in our country. It’s not just confined to the United States, it’s a problem elsewhere also, so we’re hoping we can come to some sort of creative solution. It will be a combination of entrepreneurial things, legislative things, it’s going to be more than one solution to this problem, but we hope it can be solved before it becomes a larger crisis.