The chemotherapy medication cytarabine was first approved by the Food and Drug Administration in 1969. For four decades, it has been the backbone of AML treatment.With cytarabine combination chemotherapy, the cure rate in AML is 40 percent to 50 percent. Without cytarabine, there is no cure.
In December, it was added to the FDA’s drug shortage list. There is no therapeutic equivalent to cytarabine, and optimal treatment starting on Day One is critical to the cure. Simply put: No cytarabine, no cure. Never in my 30 years of treating patients with leukemia has such a drug shortage occurred, resulting in inadequate therapeutic options for patients.
Take, for example, the 43-year-old Kentucky father who got a substandard dose of cytarabine because his doctor used all the doses he could find but still didn’t have enough. “I don’t know what I’ll do next,” the doctor told me.
Or the 45-year-old retired Air Force lieutenant colonel from Colorado, father of an incoming Air Force Academy cadet, whose leukemia came back after six months. His doctor looked all over the state for cytarabine with no luck and so was forced to give his patient second-line therapy.
Or the 15-year-old boy from Florida who is in remission but can’t get the therapy that will cure him.
Recently I sent out a plea on this national crisis to 8,000 oncologists who subscribe to a monthly e-mail newsletter published by the leukemia department at the MD Anderson Cancer Center. Within 12 hours, my in-box was jammed with replies from doctors in more than 25 states, each with his or her own horror story.
One works for a large California provider that cares for several million members. “As of this morning, the entire inventory of cytarabine in our system was 30 grams,” he wrote. “We are prioritizing the little remaining drug to go first to pediatric patients requiring cytarabine. . . . Patients will inevitably die as a result of this tragedy.”
A colleague from Wisconsin wrote, “We have been forced to form a panel of physicians, pharmacists and nurse practitioners to make difficult decisions regarding . . . this drug (i.e. who can receive it and who can’t).”
A doctor at a large center in Nebraska wrote, “We are completely out after the end of the week and no cytarabine in sight. It is like we live in a Third World country!”
Cytarabine used in the United States is manufactured by three companies: Bedford Laboratories, Hospira and APP Pharmaceuticals.
“We are currently facing manufacturing capacity constraints that are resulting in back orders of some products and we are working diligently to prioritize and expedite manufacturing for all current orders,” wrote Bedford spokesman Jason Kurtz in an e-mail in which he blamed Bedford’s shortage largely on increased demand as supplies from others were squeezed. He said Bedford expects to release more cytarabine in late May or early June. Hospira notified the FDA last week that it had begun releasing new supplies of the drug. And APP will begin releasing newly manufactured cytarabine this week, according to a company spokeswoman.
Along with cytarabine, dozens of other drugs are on the list, including such cancer-fighting workhorses as doxorubicin, cisplatin, etoposide and bleomycin. Shortages are not limited to cancer drugs; they also encompass categories such as antibiotics, heart medications and painkillers. Brand-name drugs rarely appear on the list.
All of these shortages can be critical for individual patients; none is more critical than the shortage of cytarabine.
Several of the concerned calls I received were from colleagues in Houston’s Texas Medical Center, the largest medical center in the world with 49 institutions that occupy an area the size of downtown Chicago. If these colleagues cannot get cytarabine, imagine how difficult it is for a solo practitioner in small-town America.
The drug-shortage problem has grown rapidly in this country in the past decade. The FDA reported a record 211 shortages in 2010, up from 58 six years ago, according to the American Society of Health-System Pharmacists. Eighty shortages were reported in the first quarter of 2011 alone. At this rate, the year-end total will be more than double the number last year.
“This problem is not just a blip,” said ASHP spokeswoman Cynthia Reilly. “It is getting worse, not better.”
What is behind these shortages, and what can be done to prevent them?
The FDA has no authority to compel manufacturers to continue producing a drug, nor does it have the power to force companies to inform it about issues that might result in drug shortages. Sen. Amy Klobuchar (D-Minn.) and Sen. Robert Casey (D-Pa.) are attempting to address this issue with legislation that would compel manufacturers to notify the FDA when there are supply problems or when they plan to discontinue a product. This is a start.
Valerie Jensen, associate director of the FDA’s drug shortages program, says it’s not clear why the shortages are getting worse. “We really don’t know the reason, but it is a concerning trend,” she said. Asked whether financial considerations play a role in the shortages, Jensen said, “The older drugs are often not cost-effective for companies to make. Often we see products like [cytarabine] get discontinued. . . . We cannot require a company to manufacture a product.”
Jensen said that the FDA is working with the companies to make cytarabine widely available again. She said the FDA is examining the possibility of allowing temporary importation of the drug from foreign sources.
Why are these shortages almost unique to the United States? We pride ourselves on being the No. 1 nation in medical care, but today a patient with AML in an emerging nation, such as my native Lebanon, may be treated with more-effective therapy than a patient in the United States. No shortages of cytarabine have been reported in other countries. We urgently need to examine and address the reasons behind the increasing occurrence of shortages of generic drugs in the United States.
The most common explanations given for drugs’ presence on the FDA list are “manufacturer delays,” “increased demand” and shutdown of plants for manufacturing issues. Some generic drugs called “sterile injectables,” including cytarabine, are on the list because of their cost and complexity of manufacturing.
There is little financial incentive for any company to produce labor-intensive medications that are heavily regulated but offer a slim profit margin. The fewer companies that manufacture a drug, the more vulnerable the supply, though in the case of cytarabine three companies produce it, which Jensen said “is actually good for one of the older drugs.” The drug is very inexpensive. At my hospital, a two-gram vial costs $16.
Cytarabine is used to treat a leukemia affecting patients numbering in the thousands rather than the millions. Shortages of other drugs affect much larger groups. Why not offer tax incentives to companies willing to fill this need, or perhaps subsidies similar to those offered in the agricultural sector?
In a country as rich as ours, patients should not have the misfortune of contracting a fatal disease for which an unprofitable treatment is withdrawn or not available.
Shortages of sneakers, the latest electronic gizmos and toys around the holidays routinely make headlines with a notable public outcry and demand for more. Surely the shortages of lifesaving medicines demand more attention and more action.
“Sorry, we’re out of stock” is simply not acceptable.
Kantarjian is chairman of the department of leukemia at the University of Texas’s MD Anderson Cancer Center.