I’d mentioned several weeks ago about wanting to dig into the reported shortage of drugs for cancer and other diseases, but have been putting it off because I had nothing more to offer beyond pre-digested news stories which you could just as easily read yourself. But when news came a few days ago that the FDA is expecting the shortages to worsen, and that no one knows exactly why they’re happening, it seemed like a good time to do a little research. At the same time, the good people at The Why Files alerted me to their new report about the drug shortage, which has plenty of useful, if disconcerting, information.
What’s Going On?
Drug shortages are not new, but they are increasing. Though not confined to cancer, this disease is being hit most severely because many chemotherapy drugs don’t have equivalent substitutes. If you’re short of a drug for blood pressure, you can select another one, but this is often not the case for cancer (though sometimes it is). And, 132 of 178 shortages in 2010 were for sterile injectables, many of which were for cancer.
The increase in the number of drugs of which there are shortages is alarming. In 2006, there were 56 reported scarcities. This year, the total has already reached more than 200 — and that is not counting the ones that the FDA has reportedly saved from shortage at the last minute.
It’s important to keep in mind that we are talking about shortages, not extinction. The drugs are being made, but, for various reasons (we’ll get to that), they are coming in dribs and drabs, not at the pace at which they’re needed to treat patients. Sometimes, an order arrives from a company without an expected medication, forcing doctors and nurses to formulate a new treatment plan with no advance notice.
Patients have died from drug shortages. This past March, nine patients died from contaminated IV fluid from a replacement supply because the usual supply was unavailable.
There have also been shortages in injectable nutrients, like calcium and potassium. These nutrients are often a key component of a bigger treatment plan, because they need to be kept in balance while other rigorous drugs are poured into the body. Newborn infants with intestinal damage also need a reliable supply of calcium and phosphates. The Why Files report notes that vaccines for hepatitis A, rabies, and MMR are all on the shortage list. You can read the full list of shortages on the FDA’s website.
Example 1: Doxil for Breast Cancer
Doxil (doxorubicin), a chemotherapy agent used to treat breast cancer, is one example. This drug is not curative; women who are given this medication have incurable cancer. But it’s effective for treating and controlling the disease. That is, when it’s around. A recent shortage of Doxil left many patients without this treatment option.
For patients who had not yet been started on Doxil, an alternate chemo drug could be used. “There are other drugs we can substitute for the time being while we wait for the shortage to resolve,” Craig Bunnell, Associate Chief Medical Officer and breast medical oncologist at Dana-Farber Cancer Institute, told me. “It was more of an issue for patients who were [already] receiving and responding to the drug.” Bunnell was treating patients who were two or three cycles into treatment with Doxil when a shortage occurred, and switching these women to a different drug was an option, but a complicated one. “It’s certainly difficult to tell a patient responding to the drug that we have to stop treating her with it,” says Bunnell.
The problem was exacerbated by the fact that no one knew for how long the shortage would last. “We were assured that the manufacturer would get to a point where they could produce it,” says Bunnell. “We thought it was going to be a shorter amount of time.”
Eventually, the issue was resolved — sort of. Now, Bunnell and his fellow doctors need to apply to the manufacturer for doses of Doxil on a per-patient basis. There is no guarantee that any patient will get the drug because the company decides which patients will get it, based on the applications it receives. At that point, the company guarantees that the patients it has chosen will get as much of the drug as they need, but the doses arrive separately for each treatment cycle, adding administrative complications.
Bunnell emphasizes that the issue, though difficult, has been manageable, particularly because Doxil was not a life-saving drug. But there are situations where the missing drug has been one used to cure people.
Example 2: Daunorubicin for Leukemia
The first drug shortage issue that Elihu Estey, who treats leukemia patients at the Seattle Cancer Center Alliance (and formerly of M. D. Anderson Cancer Center), faced was with cytarabine, also known as ara-C. That issue was resolved, but another came close on its heels: a shortage of daunorubicin, a chemotherapy drug for acute myeloid leukemia (AML). A subset of patients — under 65 years of age, with normal karyotype AML — can be cured by daunorubicin. That is, if it’s available.
When Estey and his colleagues found out that there was a shortage of daunorubicin, they knew they could substitute idarubicin, a similar agent. But it’s not an exact replacement. Idarubicin is associated with more cardiac toxicity, for one thing. And, a study had shown that the optimal dose of daunorubicin for AML was 90 mg/m^2. The equivalent dose of idarubicin would be 18 mg/m^2. But Estey himself had co-authored a paper showing that it’s difficult to give patients even 15 mg of idarubicin. It was unsafe to assume that idarubicin could replace daunorubicin at the dose that had been proven optimal for curing patients of their disease. “You can’t just take one fifth of daunorubicin and convert it to idarubicin,” Estey explains.
Patients being treated during the shortage could take a chance with a potentially dangerously toxic amount of idarubicin, or be treated in a suboptimal way. During the daunorubicin shortage, many patients were given the idarubicin equivalent of 60 mg of the drug. Estey recalls people pointing out that maybe giving the equivalent of 60 mg of daunorubicin wasn’t bad; after all, the original dose of daunorubicin, when the drug was first approved for AML, was 45 mg. “How do you know that 90 mg is better than 60 mg?” says Estey. “That’s a silly question because 90 mg is well tolerated. If 90 mg is well tolerated, why do I want 60 mg?” But giving patients the equivalent of 90 mg of daunorubicin wasn’t an option. “It makes you wonder who’s controlling the situation,” says Estey. “It’s not fair to the patient.”
According to the headlines, the authorities are “perplexed.” Apparently, no one knows exactly why drug shortages are spiking, with no sign of slowing down.
I’m not so sure about that. After all, we are talking about something that is trackable, that is find-out-able. We are not looking into the outer reaches of outer space here; we are talking about generic drug makers. And yet, says Peter Lurie, of the FDA, in a Reuters article, “Anybody who is sure they know the answer to this question is probably kidding themselves.” Well, life is nothing without a little humor, right?
That being said, the problem is multi-fold. My advice would be to not assume that the shortages are all due to generic drug makers refusing to produce medications that don’t earn them enough money to be worthwhile. The Reuters report does note that 11 of the shortages in 2010 were due to companies ceasing to make a drug, “usually for business reasons.” But there are other issues at play.
One problem is contamination. The FDA says that half of the 2010 shortages were due to poor product quality and manufacturing problems. Metal shavings were found in vials. Drugs that need to be kept sterile were found to have fungal contamination. Knock those out of the pharmaceutical supply chain, and boom, you have a shortage.
When that happens, you can’t just pop another company that makes the same drug into the spot formerly occupied by the company with the messed-up shipment. As has been noted here before, in super fancy rhymes, the pharmaceutical supply chain is complex. Plus, you have raw materials coming from one place, the plastic vials coming from another place, and on and on, all of which results in bedside delays.
Aging facilities are another, related problem. Several companies that make generic sterile injectables have had manufacturing issues as the squeaky wheels of old plants grow tired and need replacement.
Consolidation of drug companies can also lead to a shortage. When generic drug makers merge into a single business, there’s no longer a spare company to pick up the slack when one falls short on inventory.
Well, you may be thinking, when there’s a shortage in the U.S., why can’t we just get drugs from overseas? Many generic manufacturers in the U.S. ship drugs abroad. Can’t those be reimported? Are there facilities outside the U.S. where scarce drugs can be produced in a hurry? Both of these are possible, but again you run into safety concerns. The FDA needs to inspect any facility from which are coming drugs sold in the U.S. And, exported generics can’t just be flown back across the ocean willy nilly. There are guard dogs preventing that in the name of patient safety, because we don’t know where those drugs have been. For example, certain drugs have specific storage requirements. How do you know if they were stored properly in their overseas home? You don’t, and you can’t.
Drug shortages are happening globally, a fact that curbed my initial urge to point the finger at decreasing reimbursement rates as a disincentive for drug makers to continue making these products. After all, we still, in general, pay more for pharmaceuticals in the U.S. than people do elsewhere in the world. And yet, for companies that stopped making a drug for “business reasons,” reimbursement rates may be a factor.
Impact on Medical Research
Drug shortages are also slowing down investigations of new drugs. Clinical trials depend on having a control arm, in which well-known treatments are given to a group of patients for the purpose of comparison. If those standard treatments are not reaching the clinic, then these studies get delayed, slowing down the already years-long process of bring effective new drugs to market.
The Gray Coats Are Coming
And now, the moment you’ve been waiting for: when the drug shortage problem goes from difficult to disturbing. The term “gray market” refers to sources that operate outside of the pharmaceutical supply chain, renegade free radicals that show up in your e-mail inbox to sell you drugs that you’ve been unable to get through normal channels. As you have probably already guessed, those gray market sellers price the otherwise scarce drugs at a huge mark-up. Cisplatin, the platinum-based chemotherapy drug that is fundamental to cancer care, has a wholesale acquisition cost of $17.23. The gray market price: $120.00. Paclitaxel, normally priced at $52.78, can cost as much as $695 on the gray market.
A 2011 survey from the Institute for Safe Medication Practices has all the stomach-churning numbers. Among 549 hospitals surveyed, 56% said they were receiving daily solicitations from up to 10 different gray “marketeers.” Only 23% of these purchases could be verified in terms of their source, their purity, and their dosage.
As one individual responded to the ISMP during the survey: “You are hesitant to tell gray market vendors what you need because they will buy it all up if they find it, and then harass you [to buy it] for months afterwards.”
And another: “Once, the gray market vendor increased the price of a 25-count box of electrolytes from $200 to $325 in a period of 4 hours because he informed me, ‘That’s what the market will bear.’ My contract price for the same electrolytes is $17.”
Read the whole survey or press release, if you can. Guaranteed to get your dander up!
How do these companies know when a shortage is about to happen? And how do they end up with such quantities of drugs that are otherwise unavailable? As Allen Vaida, executive vice president of ISMP, told The Why Files, “There is speculation going on. Some secondary wholesalers may try to buy up some available drugs and sell them for higher prices … Some are playing it almost like Wall Street, anticipating what may go on shortage — if two manufacturers have just consolidated, and there’s a generic product that is only going to be made by one of them.” Those speculations don’t answer the question, but they do stir the stew.
Not much has happened to solve the problem yet. A bill has been introduced to force drug companies to alert the FDA about impending shortages. Such notifications have already enabled the drug agency to curtail more than 90 potential problems. But this measure has no bearing on preventing shortages at their root(s).
Creating an incentive to continue production of slim-margin generics won’t really work. Such incentives, usually tax-based, can be an effective way of getting companies to make new drugs (eg, medications for rare diseases that will ultimately be purchased by very few people). But creating a similar path for endangered generics could just lead those companies to slow down production, so that they’ll get the tax breaks or what-have-you for making more of the drug.
But while government is left to sort out the issue on a large scale, hospitals and medical practices are left to cope with it locally. That means creating fair systems for rationing drugs when rationing is needed. That need isn’t so bad when easy substitutions can be made, but if the drug is a life-saving, unique product, the situation could become sticky.
As it turns out, that experience has been okay so far, at least for Bunnell, in Boston, where moments of scarcity have created a new kind of community. “We haven’t had a situation where people are hoarding drugs,” says Bunnell. “Hospitals in our area have been very cooperative with each other. That’s been a very positive thing.”
Then again, Bunnell has not encountered the problem of a unique, life-saving treatment going missing.