Drug Shortages: A Growing Crisis in Oncology

Drug shortages continue to plague the United States, compromising patient safety and placing additional strain on healthcare resources. The shortages encompass common drugs used to treat a range of conditions, from everyday infections to heart attacks.

The problem has escalated in recent years, with the number of drugs deemed unavailable or scarce jumping from 74 in 2005 to more than 240 in 2010, according to the Drug Information Service (DIS) at the University of Utah Hospitals & Clinics. DIS, which started tracking drug shortages in January 2001, is among the first groups to recognize the problem. Erin Fox, PharmD, manages DIS and said in an interview, “I believe the current state of shortages is a crisis for the United States.”

The shortages have hit oncology hard. “In so many cases there are no good alternative agents, particularly for chemotherapy agents. We have seen over 20 different chemotherapy drugs in short supply during 2010 and continuing into 2011,” Fox explained. The nonprofit Institute for Safe Medication Practices (ISMP) warns “there is little relief in sight.”

Providers See the Effects of Drug Shortages
Local news reports from Alaska, California, Maryland, Pennsylvania, Texas, Tennessee, Virginia, and elsewhere show that hospitals in virtually every state are struggling to manage the growing list of hard-to-get drugs. A hospital administrator in Tennessee told her local paper that drug shortages were “the new norm.” Small hospitals feel the burden more than large hospitals, which can use their purchasing power to stockpile drugs on the shortage list. Many hospitals in networks manage shortages by shifting supplies to whichever sister facility needs them.

In 2010, ISMP surveyed 1800 pharmacists, physicians, nurses, and healthcare administrators at hospitals and long-term care facilities and found that nearly all had been affected by drug shortages. More than 80% complained that they were never warned of a looming drug shortage nor told how long it might last, and 82% said it required considerable resources to come up with a management plan. Shortages have also affected providers on a personal level, with 55% of physicians surveyed saying they felt anger toward other staff or the hospital when a drug was not available.

Three-quarters of respondents told ISMP that drug shortages had cost their facility money. This corresponds with results of a survey by Premier, Inc, an alliance of 200 hospitals and health systems in the United States. From July to December 2010, Premier questioned 311 pharmacy experts about the effect of drug shortages on their practice. At least 98% acknowledged substituting a more expensive drug 1 or more times, and 40% said they had done so more than 21 times.

Premier estimates oncology providers shelled out an additional $10.5 million in 2010 for the generic equivalents of drugs on the shortage list. Not every drug in short supply has a generic equivalent, and Premier says using the best therapeutic alternative increases treatment costs an average of 11%. Across all areas of care, hospitals paid an extra $200 million in 2010 for therapeutic substitutions.

More than Dollars and Cents
The highest costs of drug shortages have been borne by patients. Healthcare providers have only a few options when they are unable to give the patient the drug he or she needs: they can substitute an equivalent or nearequivalent agent, give nothing, or delay treatment until the drug becomes available. All these options could lead to worse outcomes.

Respondents to the ISMP survey reported “more than 1000 near misses, errors, and adverse outcomes” attributable to drug shortages. Some errors led to a patient’s death. At one facility, hydromorphone was substituted for morphine, which was not available due to shortages. The provider administered the hydromorphone at the dose originally indicated for the morphine prescription, leading to the deaths of 2 patients and nonfatal overdose in another. Whenever a drug has been substituted for another, it is essential to ensure that the new drug is correctly dosed or that the correct infusion rate is used.

Other dosing errors occur when the only way the hospital can get the drug is by ordering a different concentration. For example, when preloaded syringes of epinephrine were difficult to get, some hospitals ordered the drug in vials. Because epinephrine is typically used in emergencies, the nurse is pressured to draw the dose from the vial quickly, increasing the risk of delivering an underdose or overdose.

Institutions might try to conserve supplies of a hard-to-get drug by using smaller doses. ISMP said attempts to conserve propofol by cutting the dose at some hospitals led to inadequate sedation or anesthesia awareness. Some hospitals are shortening the duration of therapy when prescribing medications in short supply. For patients with cancer, both approaches could lead to worse outcomes.

Substituting one drug for another compromises outcomes if the replacement drug proves to be less effective or less tolerable. Not every drug has a suitable replacement, such as amikacin and acyclovir. As Beth Faiman, RN, MSN, APRN, BC, AOCN, a nurse practitioner at the Cleveland Clinic Taussig Cancer Institute in Ohio and editor-in-chief of The Oncology Nurse- APN/PA, explained, “Last year, acyclovir was virtually unavailable for a few months, which put our patients at risk to develop viral infections.”

In addition to the detrimental physical effects of drug shortages on patients with cancer, Catherine Bishop, DNP, NP, AOCNP, doctor of nursing practice and an oncology nurse practitioner at Virginia Cancer Care, Inc, pointed out that there are also psychological considerations. “Some of the issues patients face are the likelihood or need to discontinue a certain medication, such as leucovorin or etoposide. For patients in the metasta tic setting, this can produce a great deal of anxiety,” she said. Talking to patients about drug shortages is also tough on the practitioner. “For any provider to tell a patient that the drug that may benefit them the most is not currently available is difficult and almost impossible to explain,” she said.

Why Are So Many Drugs in Short Supply?
The drug shortage crisis has emerged from a confluence of factors. “Our country depends on just a few generic manufacturers to make the majority of the critical drugs we need in our hospitals and operating rooms each day,” said Fox. A problem at one facility or a decision by one manufacturer to reduce production is ultimately felt at the clinic.

The Pharmaceutical Research and Manufacturers of America (PhRMA) released a statement on drug shortages in March, noting that “according to the FDA [US Food and Drug Administration] and other experts, drug shortages can occur for any number of reasons.” PhRMA cited “natural disasters; shifts in clinical practices; wholesaler and pharmacy inventory practices; raw material shortages; changes in hospital and pharmacy contractual relationships with suppliers and wholesalers that can cause fluctuations in the availability of certain products; adherence to FDAmandated distribution protocols, which can impact patients’ timely access to medicines; individual company decisions to discontinue specific medicines; and manufacturing challenges” as some of the causes of the country’s drug shortage problem.

In 2010, the FDA reported that 40% of drug shortages were caused by manufacturing issues, which includes difficulty obtaining the drug’s raw materials or containers and quality control issues. Another 20% of shortages occurred when the manufacturer decided to stop making the drug, often because it was no longer profitable, and 20% resulted from production delays. Premier notes that foreign companies provide nearly 80% of the raw materials for drug manufacture in the United States. In 2010, concerns over the integrity of ingredients from China led some drug companies to look for a new supplier, disrupting production for some drugs and landing them on the shortage list.

At the Drug Shortages Summit convened in November 2010 by the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists, the American Society of Clinical Oncology, and the ISMP, participants recognized that regulatory issues can cause shortages. As part of the 2006 Unapproved Drugs Initiative, the FDA is requiring manufacturers of drugs approved prior to the adoption of stricter drug regulations in 1938 to conduct trials and file a New Drug Application for their generic product. Some drug companies balked at the expense of complying with the initiative and instead elected to stop making the drug. A drugmaker must also file an application with the FDA when it wants to change suppliers for active ingredients, and several have complained that the agency is slow to approve these applications. Complex packaging re quirements and demands for risk evaluation and mitigation strategies for certain drugs have also contributed to delays.

Premier outlines other potential causes for drug shortages. When the economy was in recession, many companies in the drug production chain scaled down the quantity of supplies kept on hand. Any disruption in one company’s ability to restock supplies has a ripple effect on the manufacturer’s ability to get the drug to market.

Some pharmacists complain that “gray market distributors” are causing artificial drug shortages by buying large quantities of important, inexpensive drugs and reselling them at greatly inflated prices once the drugs are difficult to obtain. This is a bit like when a ticket outlet purchases all the premium tickets for a major rock concert or popular Broadway show and offers them at a high markup once the show has sold out. Providers who stockpile drugs for fear that they might become hard to get also contribute to artificial shortages. Temporary shortages occur when one drug is discontinued, everyone switches to the same alternative, and the manufacturer cannot keep up with supply.

Is Anything Being Done?
Fox expressed optimism about a few recent developments reguarding the drug shortage. “I am hopeful the problem may subside in part because 2 of the largest generic companies with multiple shortages seem to be resolving their manufacturing problems,” she said. If this happens, Fox said the number of shortages might fall to 2009 levels, which she notes were still too high.

Congressional legislators have introduced US Senate Bill 296, the Preserving Access to Life-Savings Medications Act. The bill requires drugmakers to notify the FDA at least 6 months before stopping or delaying production for a drug. Many in the medical community support the bill. “There is widespread belief by many in the medical community that there needs to be oversight and regulations, which should be strictly enforced, so manufacturers cannot just decide to stop the manufacturing of a drug without significant notice,” said Bishop. Bill 296 also requires the FDA to identify drugs vulnerable to shortages and take steps to ensure that the supply is not interrupted.

“The bill won’t solve all shortage problems, but it is a great start,” said Fox. She encouraged clinicians to contact their congressional officials and urge them to support the bill.

Some patients are not waiting for legislation to resolve the problem and have decided to head to court. Genzyme, which has been plagued with problems at its manufacturing facilities, has been named in a civil lawsuit by a group of patients with Fabry disease. Genzyme manufactures Fabrazyme, the primary drug used to treat the genetic disorder. In the past year, the company started rationing access to the drug and cutting dosages; the lawsuit claims at least 3 patients have died from this approach. Genzyme had similar manufacturing problems with Cerezyme, its drug for Gaucher disease, but believes it will soon have the situation corrected.

As the Drug Shortages Summit participants pointed out, the FDA cannot require a drug manufacturer to keep making a product. They said Congress can and should, however, offer incentives to companies that manufacture life-saving generic medications, such as tax breaks and extended exclusivity rights.

Taking Steps to Protect Patients
Fox listed a few steps hospitals can take to minimize the effects of drug shortages on their patients. “Pharmacists can discuss shortages with clinicians as far ahead as possible.” She noted that sometimes this is not possible, but “as much advance notice as possible can help when decisions about therapy are being made, particularly if another treatment choice is available and will work well for the patient.”

She recommended that clinicians consider centralizing their supply of medications and tracking what they need based on their patient roster. “This strategy is particularly helpful with chemotherapy shortages,” Fox said. “Track out the needs of the patients and then, if insufficient drug is available, the physicians can decide the best action.” In some cases that might be not accepting a new patient, delaying treatment, or altering the treatment plan.

ISMP recommends “establishing a shortage network” with other healthcare providers. The organization also suggests adopting strategies to prevent errors when using substitutes and consulting the ethics committee about any decisions to prioritize or place limits on medications in short supply.

Several online resources are available to identify ongoing and potential shortages and ways to manage a drug shortage. Fox recommended visiting www.ashp.org/shortage, which maintains a list of current shortages, resolved shortages, and drugs no longer available. The site also contains several resources on managing drug shortages and encourages clinicians to report possible shortages to ASHP.

Because the vast majority of drugs in short supply or no longer available are injectables, nurses often have the final opportunity to ensure that the substitute drug provided is being used at the correct dose. The ASHP Website offers help with this, by highlighting the possibility of confusion or dosing errors with some substitute medications. For example, ASHP warns providers of the “potential for dosing errors when interchanging leucovorin and levoleucovorin (Fusilev),” noting that the levoleucovorin dose should be one-half the racemic leucovorin injection dose.

Etoposide for injection is another drug in short supply, and many hospitals are substituting oral etoposide. The oral version has only half the bioavailability of the injectable. This means that the oral dose needs to be double that of the intravenous dose.

As the ISMP study indicates, problems have also occurred with epinephrine dosing. Miscalculations have been made when switching be tween the 1-mg/mL strength of epinephrine and the 0.1-mg/mL dose. In addition, some hospitals are using the 1-mg/mL syringe that has an intracardiac needle permanently affixed. The ISMP warns providers not to attempt to remove this needle.

To prevent errors due to confusion about differences in dosing, activity, adverse effects, etc, between the intended drug and its substitution, ASHP recommends updating automated systems and order-entry systems. Pharmacy staff should also communicate with nursing staff about alternative therapies and any special considerations.

Talking to patients or caregivers about why you have to delay their surgery, interrupt their treatment, or cannot give them the most effective drug for their disease is probably one of the greatest difficulties providers face in dealing with the shortages. It is also one problem for which the organizations advising hospitals on how to manage drug shortages have few suggestions.