Drug Shortages Forcing Hard Decisions on Rationing Treatments
Such shortages are the new normal in American medicine. But the rationing that results has been largely hidden from patients and the public.
By SHERI FINK

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 Dr. 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 American 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 food. The logic was that adults have more reserve. But after one man pleaded not to have his dose cut, Dr. 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. Dr. 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, Dr. 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; Dr. 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 Dr. 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 from 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. Some outpatient clinics just ran out.

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.

Mr. 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 possibly due to the shortage, and that some patients underwent high-risk bladder removal surgery that probably would have been avoided if BCG had been fully available.

Dr. 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.” Supplies of BCG are again adequate, Merck and doctors report.

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.

Dr. 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.”

美國缺藥危機…「備胎藥」流竄 誰當白老鼠

在美國克里夫蘭醫學中心的手術房裡，麻醉師費茲西蒙長期給接受心內直視手術（Open Heart Surgery）後的病人一種避免出血的藥，這種藥叫氨基已酸，便宜、安全且廣為使用。但由於藥品製造過程發生問題，全美陷入供應不足的窘境，院方只能把有限的藥供應給出血併發症最嚴重的病人，其他病人無法再取得這種原本是標準選項的藥品，卻沒人知道實情。

類似的缺藥危機在美國日復一日上演，從麻醉藥、止痛藥、抗生素、癌症治療甚至生理食鹽水都供不應求。追蹤藥品供給的猶他大學藥品資訊服務部統計，美國藥物短缺數量有265種，比五年前增74%。

世界衛生組織（WHO）在1月底一份報告中談到全球藥品短缺指出，包括美國在內，多國都有藥物或治療方式匱乏的情況，以老藥、專利過期的藥、或難以規劃的治療方法，最容易有這方面的問題。這些國家藥品匱乏的原因不一而足。

首先，藥品可能在製造過程發生問題（如藥廠產能不足、設備沒有定期維修保養、老舊工廠在生產過程中可能遭到汙染）。藥商也可能基於商業經營考量，放棄低利潤的產品。此外，新科技影響、市場破碎、藥價太高也是數國研究指出的共同問題。在美國還由於美國食品暨藥物管理局（FDA）取締品質不佳藥物，意外讓缺藥危機惡化。

WHO表示：「藥品需求的數據難以取得、品質參差不齊，供應鏈和採購之間的管理實作不合宜、大型投標合約過於強調最低價格、某些藥品的利潤過低，都是導致藥品短缺的因素。」

藥品匱乏已經導致「治療分配」的扭曲現象，卻是美國一般病人和社會大眾所不知情的。紐約時報調查全美醫師、醫院主管和政府官員的結果顯示，目前全美醫療院所能分配稀少藥物的方法其實無規則可尋，經常產生道德模糊地帶和令人質疑的醫療行為。

某些醫院有病人代表參與的正式委員會來發配，某些則由醫師、藥師甚至藥廠代表，來決定哪些病人拿到亟需的藥品，剩下的多改用替代藥物，但不是所有替代藥品的治療成效都和標準藥品一樣好。德州大學醫學院傳染病部門主任莫瑞就表示，藥品短缺迫使醫生必須轉向效果不佳的替代藥物。

這個讓醫病雙方都痛苦的現況，促使美國不少醫師和醫療團體提出建言，希望針對短缺藥品成立「結算所」，並鼓勵自願分享機制，讓藥物分配更公平。另外還有人主張應該登記哪些病人接受非傳統或替代藥品，來追蹤後續治療成效。

藥價狂飆 大選熱門議題

美國圖靈藥廠（Turing）執行長史克雷利（Martin Shkreli）因買下愛滋病老牌藥的專利權，再把藥價哄抬50倍，被媒體評為「美國公敵」，他漲價漲得離譜固然令人不齒，但藥價上漲是業界普遍情況。

美國藥價狂飆已經成為總統大選的熱門議題。美國民主黨總統參選人希拉蕊1月底在推特上抨擊藥廠「坑錢」；約莫同一時間，史克雷利和加拿大藥廠Valeant都被要求前往美國國會作證，談的是節節高升的藥價。

許多藥品的價格以折合年率超過10%的速度在上漲，無論是威而鋼、心臟科藥品、基本耗材，還是專利早就過期的藥。雖然生產特殊藥的藥廠漲價漲最兇，但大藥廠如輝瑞（Pfizer）、葛蘭素史克（GSK）等也實施相對較溫和的漲價。

雖然許多藥廠主管說，老藥價格飆升是幾顆老鼠屎搞的鬼，但藥價持續上漲卻是不爭的事實。

據彭博新聞調查，過去八年來，3,700種醫院用學名藥中，超過400種的價格至少翻漲一倍，裡頭甚至有50種至少漲了九倍。所有老藥中，約25%的漲幅比同期間的物價漲幅還要大，意味著藥價漲幅超越通膨率。

明尼蘇達大學經濟學家兼藥學家夏德梅爾表示：「這是個破碎的市場。藥廠知道這種任他們開支票的時代總有一天會結束，所以現在先拚命開支票。」

即便是供應充足的常規藥品，價格走勢也可能違背正常經濟學規律。例如，格隆溴銨（glycopyrrolate）是一種減少術前唾液分泌的基本藥品。2012年，第一三共旗下藥廠Luitpold為了解決品質管理問題，暫時關閉一條產線，此藥僅存的藥廠Hikma隔年就將價格調漲逾八倍。如今兩家公司都開始生產這種藥物，雖然供應充足，Hikma的產品價格仍是2013年初時的八倍多，Luitpold也樂得跟著漲價。

格隆溴銨的例子並非單一事件，從治療心律不整的藥物、到生理食鹽水這類基本耗材，所有的醫院用藥品都呈現日益短缺的趨勢，這背後的原因眾多：既有工廠老舊、品質控制的問題，也有因併購導致供應商減少的因素。但最終的結果卻驚人地相似：即使供應已不再吃緊，藥價依然居高不下。

身兼遊說組織「美國藥學研究和製造商」主席的美國默克藥廠（Merck）執行長佛萊茲（Kenneth Frazier）說，製藥業必須更努力處理藥價居高不下的問題；不過他也不忘強調，高藥價是推動企業勇於進行高風險研發計畫的必要動機。

默克的糖尿病藥片佳糖維（Januvia）自2006年問世以來，價格翻漲超過一倍，近來也成為被抨擊的目標。

原文參照：
http://www.nytimes.com/2016/01/29/us/drug-shortages-forcing-hard-decisions-on-rationing-treatments.html

2016-03-12．經濟日報．S04．本周精選．編譯余曉惠