Drug shortages force rationing of treatments

CLEVELAND — In the operating room at the Cleveland Clinic, Dr. Brian Fitzsimons has long relied on a decades-old drug to prevent hemorrhages in patients undergoing open-heart surgery. The drug, aminocaproic acid, is widely used, cheap and safe. "It never hurt," he said. "It only helps."

Then manufacturing issues caused a national shortage. "We essentially did military-style triage," said Fitzsimons, an anesthesiologist, restricting the limited supply to patients at the highest risk of bleeding complications. Those who do not get the once-standard treatment at the clinic, the nation's largest cardiac center, are not told. "The patient is asleep," he said. "The family never knows about it."

In recent years, shortages of all sorts of drugs — anesthetics, painkillers, antibiotics, cancer treatments — have become the new normal in U.S. medicine. The American Society of Health-System Pharmacists currently lists inadequate supplies of more than 150 drugs and therapeutics, for reasons ranging from manufacturing problems to federal safety crackdowns to drugmakers abandoning low-profit products. But while such shortages have periodically drawn attention, the rationing that results from them has been largely hidden from patients and the public.

At medical institutions across the country, choices about who gets drugs have often been made in ad hoc ways that have resulted in contradictory conclusions, murky ethical reasoning and medically questionable practices, according to interviews with dozens of doctors, hospital officials and government regulators.

Some institutions have formal committees that include ethicists and patient representatives; in other places, individual physicians, pharmacists and even drug company executives decide which patients receive a needed drug — and which do not.

An international group of pediatric cancer specialists was so troubled about the profession's unsystematic approach to distributing scarce medicine that it developed rationing guidelines that are being released Friday in The Journal of the National Cancer Institute.

"It was painful," said Dr. Yoram Unguru, an oncologist at the Children's Hospital at Sinai in Baltimore and a faculty member at the Berman Institute of Bioethics at Johns Hopkins University. "We kept coming back to wow, we've got that tragic choice: two kids in front of you, you only have enough for one. How do you choose?"


At the Cleveland Clinic, which has been unusually proactive in dealing with shortages and allowed a reporter access to personnel making decisions about them, one scarce leukemia drug, daunorubicin, was saved for patients in clinical trials, to avoid making the results invalid by substituting another drug. But when a different drug, methotrexate, was in short supply, pediatricians stopped giving it to all patients who required high doses, including those in research trials. "We didn't want to say just because you're on a clinical trial you get an advantage," Dr. Rabi Hanna said.

Patients' weight can be taken into account. Obese patients, who researchers found needed up to three times the amount of an antibiotic before surgery than average-size patients, were given only the standard dose at the Cleveland hospital until a shortage subsided.

Some institutions prioritize based on age; others do not. Marc Earl, a Cleveland Clinic pharmacist, said children were not favored over adults during chemotherapy shortages. But at other hospitals, they have been, because of their potentially longer life span or because they sometimes require smaller doses of a drug.

"We do play the pediatric card for sure," said Alix Dabb, a pharmacy specialist in pediatric oncology at Johns Hopkins Hospital. Dr. Kenneth Cohen, director of pediatric neuro-oncology there, and his colleagues were close to being forced into making "very, very hard decisions," he said. "The discussions became, 'Why are two kids more important than one adult?'"

Ning-Tsu Kuo, a pharmacist at the Cleveland hospital's home infusion pharmacy, said children came first during shortages of nutritional products such as intravenous vitamins and fats for patients who cannot absorb them from food. The logic was that adults have more reserve. But after one man pleaded not to have his dose cut, Kuo agreed. When reprimanded by colleagues, she recalled saying: "Patients are not equally the same. You need to look case by case."

‘Downright Scary’

Such decisions have real consequences. For some shortages, doctors can soon see the effects of rationing, such as increased pain or nausea when drugs typically used to control symptoms are withheld, or patients who have to undergo invasive surgery to control cancer when anti-tumor medications are delayed.

Studies have associated alternative treatments during drug shortages with higher rates of medication errors, side effects, disease progression and deaths. For example, children with Hodgkin's lymphoma who received a substitute to the preferred drug had a higher rate of relapse, researchers found, and adults with a genetic disorder called Fabry disease had decreased kidney function when their medication was cut by two-thirds. One alternative guideline adopted during a shortage of intravenous nitroglycerin "was downright scary from a clinical perspective," according to Dr. Nicole Lurie, a senior federal health official.

Physicians say that many of the changes they are compelled to make appear to do no harm. But, they acknowledge, typically no one is tracking outcomes in patients who get a drug and others who get a substitute or delayed treatment.

Doctors and hospitals often do not tell patients about shortages and the resulting rationing because they do not want them to worry, especially when alternative drugs are available, or because they feel it would stir up too much anger.

Dr. Ivan Hsia, an anesthesiologist in Ontario, Canada, said many physicians in his field adopt what he called "the paternalistic model — like I'll inform them when I think it's unsafe enough to inform them."

When he and his colleagues surveyed hundreds of patients at the Mayo Clinics in Arizona and Florida and others in Canada about their preferences, the results surprised him. Most wanted to know about a drug shortage that might affect their care during elective surgery, even if there was only a minor difference in potential side effects, and many said they would delay surgery.

When the study was published last year in the journal Anesthesia and Analgesia, an accompanying editorial urged health professionals to disclose shortages and their implications. "Patients want to know and they should know," the editorial said. "There is no ethical ambiguity."

Dr. Eric Kodish, a children's cancer doctor who heads the Cleveland Clinic's center for ethics, humanities and spiritual care, said patients

should be told. "It's their bodies and their lives that are on the line."

Indeed, Beverly Smith, a Cleveland patient who has Crohn's disease, said she had no idea that an important ingredient had been removed from the daily intravenous nutritional treatments she depends on until she developed side effects from the deficiency. "Why didn't anybody tell me?" she asked.

Who Gets Preference?

In a basement storeroom filled with plastic crates and cardboard boxes, Chris Snyder, a Cleveland Clinic pharmacist and the point man for drug shortages, spends part of each workday poring over the hospital's drug orders.

He tracks a list of shortages that included more than 75 drugs the first week of January. Snyder moves stocks among the hospital's campuses, identifies alternatives, and — in the most dire situations — helps devise and enforce restrictions on which drugs can be ordered for which types of patients.


Many drugs are made by only one manufacturer, so production or safety problems at a single plant can have big effects. For another company to begin making the products and getting them approved by regulators requires the right combination of manufacturing capabilities and economic incentives.

The chances of getting a drug also depend in part on where a patient happens to live, how adept the local hospital is at finding — and hoarding — scarce drugs, or a patient's access to a major medical center.

The Cleveland Clinic, for example, has an advanced compounding room where workers swaddled in disposable gowns, bouffant caps and blue gloves mix up remedies from raw ingredients. During a shortage of papaverine, a drug used for surgery on blood vessels, the clinic produced its own version. When other hospitals began asking about it, Snyder said he had to tell them, "It's a franchised recipe we can't give out."

At Cleveland, decisions about conserving, substituting and allocating scarce drugs typically are made by small groups of doctors and pharmacists; Kodish's ethics committee is not involved. But such decisions are not always made by doctors or hospitals. One company, Janssen, chose to ration its ovarian cancer and multiple myeloma drug Doxil on a first-come-first-served basis during a prolonged shortage.

Another company, Jazz Pharmaceuticals, recently consulted a small group of oncologists to recommend how to allocate its cancer drug, Erwinase, if it ever became necessary. "Who deserves the drug more than anyone else?" said Dr. Wendy Stock, a leukemia specialist at the University of Chicago Medicine, who participated in the discussion. "We gave them some guidelines on that."

In a survey of cancer doctors conducted in 2012 and 2013, 83 percent of respondents who regularly prescribed cancer drugs reported having been unable to provide the preferred chemotherapy agent at least once during the previous six months. More than a third of them said they had to delay treatment "and make difficult choices about which patients to exclude," according to a letter published in The New England Journal of Medicine.

The threat of future shortages in children's treatments is serious enough that Dr. Peter Adamson, who leads the Children's Oncology Group, the largest international group of children's cancer researchers, assigned his organization to set priorities. "We've been forced into what we think is a highly unethical corner," he said in an interview.

The effort, led by Unguru, the Baltimore oncologist, recommended that the drugs be rationed based on the ability to save lives or years of life, including curability of a child's cancer and the importance of the drug in improving the chances. It also recommended that children participating in clinical research should not get priority over those who are not, because of concerns about coercing families into trials. The group also advised that allocation decisions be public.


A recent shortage of a therapy for bladder cancer, BCG, demonstrates how the lack of national guidance can lead to very different decisions. One Cleveland Clinic urologist, Dr. Andrew Stephenson, said he came up with BCG rationing guidelines that were used with dozens of patients after being shared with colleagues. "We tried to reserve the BCG for those patients who needed it the most," he said.

Merck, the manufacturer, said it filled requests a waiting list in the order received, and left rationing decisions to doctors. Some cancer centers reduced the length of BCG treatment from three years to one, because the benefit may be smaller after the first year. Others restricted BCG to patients whose tumors were mostly likely to spread or recur. And still others decided to reduce the typical dose so that each vial could be used for three patients instead of one, which some experts say raises questions about efficacy.

In interviews and comments on a support website, Inspire, patients seemed confused about why they were or were not getting BCG. "I found out people were getting it in different parts of the country," said Don Keating, whose bladder cancer was diagnosed in 2014. He was told by his doctor in Boston that he needed BCG but that it was not available.

Keating had to wait about six months before obtaining the drug, during which time his cancer recurred. "I believe if I had gotten it when it was first prescribed, I wouldn't have had to go through those operations," he said.

Many urologists said they saw similar recurrences because of the shortage, and that some patients underwent high-risk bladder removal surgery that probably would have been avoided if BCG had been fully available.

Kamal Pohar, a urologist at Ohio State University's cancer hospital, said he remembered driving home, wondering if he was making the right calls for his patients. "I can still feel the stress," he said. "I've never been faced with this."

The vagaries in distribution and inconsistencies in rationing have led to calls for change. Doctors and others have suggested the creation of a clearinghouse of scarce drugs and voluntary sharing to promote equitable access for patients. Others argue that there should be a registry of patients given nonstandard treatments so the results can be tracked.

Lurie, the federal health official in charge of emergency preparedness and response, said that the government was working to encourage hospitals to conserve and substitute drugs to avoid a crisis and trying to fill gaps in manufacturing. Steps taken by the Food and Drug Administration have also helped reduce the number of shortages, she said.

Still, she argued that tools developed for disaster response, including ethical and procedural guidelines, should be applied. "Different places around the country are each doing their best to patch together their own guidelines," she said, adding, "if they're doing anything at all."