SODIUM THIOPENTAL WAS ONCE THE MOST COMMONLY USED INJECTABLE ANESTHETIC. In recent years, anesthesiologists came to rely on other medications, such as propofol, but sodium thiopental (also called thiopental injection, and sold under the trade name Pentothal) was still preferred for some types of surgery—including emergency cesarean sections, because it was less likely than propofol to sedate the infant.

But beginning in 2009, hospital pharmacists frequently found sodium thiopental to be in short supply. Hospira, its only manufacturer, cited unspecified problems at its factories. Then, in early 2011, sodium thiopental was gone for good. Hospira had tried to move production of the drug to a plant in Italy, which company officials say was better equipped to make it. But Italian authorities demanded assurances that sodium thiopental made at the facility would not be used for one specific nonmedical procedure: lethal injections. Although Hospira had never condoned that application, sodium thiopental had long been part of a three-drug cocktail used to execute condemned prisoners in the United States. Unable to make that guarantee, Hospira decided to stop producing the drug altogether.

Though the reasons for sodium thiopental’s disappearance may seem unique, its demise points to increasingly serious disruptions in the supply chain for prescription drugs in the United States. In 2010, for example, 211 different drugs—triple the number in 2005—were in short supply or completely unavailable for all or part of the year, according to the University of Utah Drug Information Service, which provides shortage data for the American Society of Health-System Pharmacists (ASHP). What’s more, shortages are lasting longer. “This is as bad as it has been in three decades,” says Michael Link, a pediatric oncologist at Stanford University School of Medicine and president-elect of the American Society of Clinical Oncology (ASCO).

For hospital pharmacists, the shortfalls have meant a constant battle to keep medications in stock. “For the past two years, we’ve had persistent shortages of ‘workhorse’ drugs,” says Meg Clapp, chief of pharmacy at Massachusetts General Hospital. “I don’t see any relief in sight.” And when medications are unavailable, patients feel the effects. In an anonymous  survey last year by the Institute for Safe Medication Practices (ISMP), in which 1,800 health practitioners (about two-thirds of them hospital pharmacists) were asked about the impact of drug shortages at their institutions, respondents noted more than 1,000 cases in which people had been harmed or endangered or had had care delayed. At least two people died, in both cases because caregivers mistakenly thought they were giving the patient morphine; because that drug wasn’t available, it had been replaced by hydromorphone, which is 7 to 10 times more potent. (Morphine shortages have led to a run on hydromorphone, which now can also be difficult to keep on hand.) And there have been reports of patients who may have died because chemotherapy drugs weren’t available and treatment was postponed or not received at all.

Some hospitals have resorted to using expired drugs—a risky proposition, given uncertainty about the safety and effectiveness of medicine past its “use by” date. Pharmacists have begun comparing the situation to that of a medicine-starved developing nation—a stunning development in a country that spends more than $65 billion a year creating pharmaceutical products. While medicine shortfalls have been seen before, some on the front lines now think shortages are becoming more common because manufacturers are putting economic interests ahead of the needs of patients and insist that fundamental changes are needed in the way medicine is made and distributed in the United States. Otherwise, they fear, more doctors will soon hear that the drug a patient needs—a treatment that a doctor has prescribed for years, the one he or she knows will work—is no longer available.

IN THE SIMPLEST SENSE, DRUGS ARE COMMODITIES AND, like gold or pork bellies, are subject to the laws of supply and demand. If a manufacturer can’t obtain the raw materials needed to make a medication, production may drop. A disease outbreak or a change in treatment recommendations, meanwhile, could increase demand. Actions by the Food and Drug Administration—such as identifying code violations at manufacturing plants or enacting new regulations—may require a pharmaceutical company to shut down production while it retools operations. Any of these situations could result in a shortage.

But that has all been true for years. For a clue to why drug shortages are an increasing problem, consider that more than three-quarters of the medications that were difficult or impossible to obtain last year were injectable drugs that have been off patent for many years. These include a number of widely used oncology drugs, specifically cisplatin, cytarabine, doxorubicin, etoposide and leucovorin. But many other types of injected drugs have also been in short supply during the past year, including amikacin (an antibiotic), prefilled epinephrine syringes (for cardiac arrest), potassium phosphate (for phosphorus deficiency) and succinylcholine (a muscle relaxant).

Although they’re a diverse bunch, older injectables have a few things in common. For one, the number of manufacturers that produce them is rapidly diminishing. “A few years ago, we might have had seven or eight firms making each of these drugs,” says Valerie Jensen, head of an FDA unit that deals with drug shortages. “Now, most are made by only two or three. That’s really a problem.”

As Jensen and Bob Rappaport wrote in The New England Journal of Medicine last August, pharmaceutical companies are increasingly abandoning production of older injectable drugs because, unlike drugs still under patent protection, they don’t generate big profits. And with several manufacturers in competition, prices tend to fall and margins contract. Jensen believes that many companies have stopped making older injectable drugs so that they can devote their resources to newer, more lucrative medications.

Because drug companies have finite manufacturing capacity and often use the same production line to make several medicines, they have to choose which drugs to focus on, says Toon van Beeck, a senior analyst at IBISWorld, an independent industry research firm, and the decision really comes down to the bottom line. “Profitability is just one cause of shortages, but I believe it’s a major one,” he says. “If product A is a little more profitable than product B, then manufacturers are liable to emphasize product A.”

At the same time, the few companies that still make older injectable drugs produce only as many doses as they think they can sell and don’t maintain large inventories, according to van Beeck. So when one company has a production problem, others are unlikely to have extra supplies of a drug on hand, resulting in at least a short-term shortage. If no other company is willing or able to step up production of the drug, the shortage could last much longer.

That scenario played out during the past few years with propofol, the drug that has largely supplanted sodium thiopental in anesthesiology. Until recently, three companies made this fast-acting sedative and hypnotic the anesthetic of choice for many surgical procedures. But in fall 2009, one firm, Teva Pharmaceutical Industries, had to recall several lots when tests showed they were contaminated with bacteria. Then a second manufacturer, Hospira, recalled much of its propofol, because of contamination with stainless steel particles. That left a third company, APP Pharmaceuticals, as the drug’s sole source.

APP wasn’t able to produce enough propofol to take up the slack, so the FDA took the unusual step of allowing an unapproved drug to be sold in the United States. The agency granted APP permission to market Propoven 1%, a version of propofol that is made in Europe by APP’s parent company, Fresenius Kabi. (Whereas Hospira put propofol back on the market in October 2010, Teva has decided to exit the market.) Propoven contains the same amount of propofol as the FDA-approved drugs, but its inactive ingredients are different.

Though bringing in the European version has eased the shortage of propofol, supply problems for many other drugs persist, often for mysterious reasons. “The companies never tell you why there’s an issue,” says pharmacist Erin Fox, who heads a team at University of Utah Hospital that has been tracking drug shortages, in a partnership with ASHP, since 2001. If a manufacturer does say anything about why it can’t provide a therapy, it will typically cite manufacturing delays or other similarly vague reasons. But many doctors, pharmacists and patients who have had to deal with drug shortages are skeptical of those explanations. Oncologist Joe Merchant of McFarland Clinic in Ames, Iowa, says that he recently struggled to obtain cancer therapies, including cytarabine and leucovorin. Last January, when a colleague needed cytarabine for a patient but the clinic had run out and the usual distributors had none to offer, McFarland tried unsuccessfully to borrow some from other hospitals. Meanwhile, the clinic’s pharmacy was scrambling to find more leucovorin, the supply of which had also been exhausted. “These drugs cure people,” Merchant says. “And we can’t get them. It’s like somebody invented penicillin, then took it away.” He notes that he routinely treats patients with newer chemotherapy drugs still under patent protection that cost up to $12,000 a month: “Those don’t go on shortage.”

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FROM A BUSINESS STANDPOINT, IT MAY MAKE SENSE for drug companies to focus on producing the most profitable medications, to be close-mouthed about manufacturing problems and to maintain minimal inventories of marginal drugs. But where do ethical considerations enter in? “The pharmaceutical industry has responsibilities to the common good,” says James DuBois, director of the Bander Center for Medical Business Ethics at Saint Louis University in St. Louis, who notes that government-supported research is often crucial in drug development and that the United States spends more than $50 billion a year on prescription drugs through Medicare. Given the direct and indirect support that the pharmaceutical industry receives, DuBois calls the recent rise in drug shortages “unacceptable.”

But manufacturers insist they’re not abandoning drugs with low profit margins. “Although some of these products do have small margins, Teva is committed to providing safe, affordable medications to the public,” a company spokesperson says. The largest U.S. maker of generic drugs, Teva had more than a dozen products on the FDA’s drug shortage list earlier this year. All of them were made at a plant in Irvine, Calif., that was shut down for a year due to quality-control problems. Some production resumed in May, with the rest of the facility scheduled to come back online later this year.

Another major manufacturer of generic injectable drugs, Bedford Laboratories, had a similar number of drugs on the FDA’s shortage list in early 2011. “Bedford is currently facing manufacturing capacity constraints that are resulting in back orders of some products,” wrote company spokesman Jason Kurtz in an e-mail, adding that the company is “working diligently” to fulfill existing orders.

REGARDLESS OF WHY DRUG SHORTAGES ARE BECOMING MORE COMMON, there’s little doubt that patients are feeling the effects. Many hospitals and clinics have had to postpone or cancel elective surgeries because they lacked sodium thiopental, propofol or another anesthetic drug, etomidate, says Arnold Berry, vice president for scientific affairs at the American Society of Anesthesiologists and a professor of anesthesiology at Emory University School of Medicine in Atlanta. In May an ASA survey of more than 1,300 anesthesiologists found that many had been forced to substitute medications when preferred anesthetics weren’t available and that in roughly half of those cases, patients experienced an increased risk for postsurgical nausea and longer recovery times. A lack of anesthetics has led to even graver circumstances. Consider the impact of a shortage of succinylcholine, a muscle relaxant that may be used to reverse laryngospasm (contraction of the larynx), a rare complication that obstructs breathing in patients undergoing procedures using general anesthesia and could lead to death.

Patients are also coping with the shortfall in cancer drugs. After Bob Dierker, a 64-year-old with colon cancer, received his eighth round of chemotherapy at a clinic in northern Virginia last October, his doctor told him he would have to be taken off leucovorin, because the clinic couldn’t buy enough of the drug. Leucovorin improves the activity of fluorouracil, a standard treatment for colon cancer, and protects healthy cells. Dierker had experienced virtually no side effects throughout his initial rounds of chemotherapy, but without leucovorin, subsequent rounds left him severely nauseated, fatigued and sore in his extremities.

With many oncology drugs in short supply, doctors increasingly find themselves delaying treatment or considering alternative regimens that may be less effective, says ASCO’s Michael Link. For instance, cisplatin, the drug of choice for testicular cancer, is currently hard to get, and while a similar drug, carboplatin, has also been used to treat the disease, its cure rate is 10% to 15% lower than cisplatin’s. Deciding to treat a patient with carboplatin if it’s all that’s available is “an unfortunate decision we think some physicians are having to make,” Link says. Worse, for some other chemotherapy drugs in short supply, such as doxorubicin—a mainstay for treating metastatic breast cancer, lymphomas and sarcomas—“there really isn’t a suitable alternative.”

To cope with this situation, some hospitals have had to add personnel, including buyers whose only role is to obtain hard-to-find medications. When a substitute drug must be used, doctors and nurses have to be notified and the drug physically added to supplies throughout the hospital. It can take a full day, with several employees on the task, for a pharmacy to switch to an alternative medication when a drug goes off the market. Larger hospitals may be able to head off shortages by buying in bulk, and more than half the respondents in the ISMP survey admitted to hoarding drugs; if word surfaces that a manufacturer has stopped making a vital medication, pharmacy buyers may grab as many doses of the drug from distributors as they can stockpile in their storage room. Meanwhile, institutions with extra supplies often must decide whether they can afford to share a drug with other institutions.

Sometimes hospitals turn to expired drugs. Last summer, ASHP heard anecdotal reports that expired stock was used when hospitals couldn’t obtain naloxone (also sold under the brand name Narcan), to treat patients who experience slow breathing after receiving opiates such as morphine and oxycodone and to reverse respiratory failure in people who have overdosed on heroin or other street drugs. Having stocks of expired Narcan presented a dilemma for pharmacists, who are legally responsible for dispensing good-quality medicine. Expiration dates mark the end of a period when a manufacturer guarantees a drug will remain stable, and though it may remain potent for some time after that, how potent and for how long is largely unknown. “Some hospitals made the decision to use expired Narcan, based on their pharmacist’s recommendation,” says Bona Benjamin, director of medication-use quality improvement at ASHP. “It’s a tough call. But ethically, what else can you do when patients need the drug? In this case, having the drug to treat patients for a life-threatening emergency took priority over the important but lesser issue of expiration date.”

In other cases, new hospital protocols have helped address medication shortages. Last fall, after some of Sutter Health’s 27 hospitals in Northern California had difficulty obtaining succinylcholine, Sutter began asking pharmacists throughout the system to report to one another every Wednesday: Who had succinylcholine and who didn’t? Hospitals that had the drug in stock shared with others that needed it, and physicians agreed to ration succinylcholine, using it only when no alternative was available. “This is a new paradigm for us,” says Toni Brayer, chief medical officer for Sutter’s West Bay Region. “We were able to get through that shortage.”

LAST NOVEMBER, A GROUP OF PHYSICIANS, PHARMACISTS AND REPRESENTATIVES from health organizations and the drug industry convened in Bethesda to discuss ways to solve the growing problem of drug shortages. Most participants seemed to agree that one important step would be for manufacturers to notify the FDA when, for any reason, they planned to stop making a drug. “It’s the best way to prevent a shortage,” says the FDA’s Jensen. “But such communication rarely happens.” With advance warning, she says, the agency can take steps such as asking other companies to increase production.

But the FDA can’t force a company to continue making a drug, and companies are required to notify the agency only if its decision to stop making a drug falls under a specified circumstance. If, for example, a manufacturer is the sole supplier of a drug deemed medically necessary, it’s supposed to provide six months’ notice before ceasing production. But in practice, it’s left to the company to decide whether a drug is medically necessary. And there’s no punishment for failing to notify the FDA before a shortage occurs.

“The FDA needs more authority,” says Allen Vaida, executive vice president of ISMP, who attended the meeting. Legislation recently proposed in the U.S. Senate would require drug manufacturers to notify the FDA whenever a shortage might occur. Vaida would go further, predicating FDA approval of a drug that will be the only one in its class on a pledge by the maker to ensure an uninterrupted supply.

Vaida, Link and others who were at the meeting say they came away believing that most drug manufacturers are sincere about taking steps to prevent shortages. Yet evidence that the situation is improving remains elusive. In fact, at the end of July, 180 drugs were in short supply in the United States, a pace of about one per day, which would far exceed 2010’s total. Physicians and pharmacists alike say they know it will take cooperation and creativity to cope with missing medications in the years ahead. “We have to come up with solutions in the short term and the long term,” says Berry, who worries that the growing problem imperils patient safety. “It’s the patients we all need to think about.”