Investigators have published the first clinical evidence that a persistent drug shortage has the potential for compromising patient care. They documented a 13% drop in two-year event-free survival rates when pediatric patients with Hodgkin’s lymphoma were given cyclophosphamide in place of mechlorethamine when the latter chemotherapy agent was in extended short supply.

The study, published in The New England Journal of Medicine (2012;367:2461-2463), “is eye-opening, given the changes in response rates and potentially even overall survival that resulted from the mechlorethamine shortage,” said Jeff Kaiser, PharmD, BCOP, a specialist in hematologic malignancies at the University of Colorado Hospital in Denver, who was not involved in the research.

The opportunity to evaluate the effects of the drug shortage emerged during the middle of an existing study of a 12-week chemotherapy regimen of mechlorethamine, vinblastine, doxorubicin, vincristine, bleomycin, etoposide and prednisone. Known as the Stanford V regimen, the strategy was believed to be as effective as, and safer than, existing treatments for pediatric Hodgkin’s lymphoma, according to lead author Monika Metzger, MD, an associate member in the Oncology Department at St. Jude Children’s Research Hospital in Memphis, Tenn. But the study hit a snag when a worldwide shortage of mechlorethamine occurred in 2010. Dr. Metzger and her colleagues had already treated 181 patients with the regimen by the time the mechlorethamine shortage occurred. In an effort to find a substitute, they searched the literature and identified cyclophosphamide as a potential equivalent. That drug had been widely used in adults and children with Hodgkin’s lymphoma as part of the COPP (cyclophosphamide, vincristine, procarbazine and prednisone) regimen; COPP was thought to be as effective as the almost identical mechlorethamine-based MOPP (mechlorethamine with the same three drugs) regimen. By 2012, when mechlorethamine again became available after two years, they had treated 40 patients with the cyclophosphamide-based Stanford V regimen, accumulating enough data to retrospectively compare outcomes using the two treatment arms.

Their analysis showed that two-year event-free survival rates dropped from 88% when mechlorethamine was used to 75% with cyclophosphamide (P=0.01). Statistical analyses controlling for possible confounding variables confirmed that the disparity in outcomes was indeed due to the regimen changes. Although overall survival rates did not differ between the groups, Dr. Metzger noted that the median follow-up in the cyclophosphamide group was only 1.5 years compared with 4.7 years in the mechlorethamine group.

For Dr. Metzger and her colleagues, the lesson learned was clear: “What might appear to be a suitable alternative may result in an inferior outcome,” she told Pharmacy Practice News. “In case a shortage like this were to happen again, I would look for an alternate regimen with a track record and for which all drugs are available rather than try to go for a substitution. I would only use a substitution as the very last resort.”

Oncology Pharmacist’s Take

The study “begs the question of whether we have enough data on comparative clinical efficacy” to effectively managed shortage-driven therapeutic substitutions, said Ali McBride, PharmD, a stem cell transplant specialty practice pharmacist in the Department of Pharmacy at Ohio State University’s Arthur G. James Cancer Hospital in Columbus. “When there are shortages, there may be suggestions for other therapies, but head-to-head data are rarely available,” said Dr. McBride. “As this study demonstrates, we don’t always know what the outcome will be.”

Although Dr. McBride was not involved in the NEJM trial, he and his colleagues have conducted their own research on the effects of oncology drug shortages. The study has been accepted for publication and should be released in the coming months, Dr. McBride noted. He said the survey-based findings are expected to provide further evidence that drug shortages have negatively affected outcomes in certain cancer patients.

William Greene, PharmD, who is chief pharmaceutical officer at St. Jude, said his hospital has faced more than a decade of drug scarcities, but the mechlorethamine shortage was different. “We’ve been forced many times to make decisions on alternative therapies, but for the most part, those decisions are made based on evidence and, for the most part, we’re very comfortable that the alternatives are equally effective as the original drug we would choose,” he said. In the case of mechlorethamine, he said, there was a lack of data on proven alternatives.

Dr. Greene said St. Jude follows a “disciplined process” for coping with drug shortages when they hit. “If it gets to the point of a severe shortage, managing it can be intense, but fortunately it’s rare that such a severe shortage occurs,” he said. “When a severe situation does occur, we pull in the relevant group of physicians, engaging them in a discussion, informing them of the critical nature of the shortage and what we believe will happen with the drug supply, how long we expect the shortage to persist, and then we make recommendations for a discussion on alternative therapies.”

In some cases, Dr. Greene added, “we ask the physicians for guidance about other ways to extend the drug supply, such as prioritizing use for patients who really are going to benefit the most, and we also look at operational ways to minimize use of a drug such as dose rounding, scheduling multiple patients on the same day or other procedures that minimize waste.”

Although the challenge of managing prolonged shortages can seem insurmountable, there are measures pharmacists can implement to preserve diminishing stock, said the University of Colorado’s Dr. Kaiser. “When we don’t expect any more of a drug in shortage to be available for weeks or months, decisions become complex,” he said. “We have seen this in the past year with drugs such as thiotepa and foscarnet sodium, which most pharmacies could only purchase from manufacturers outside of the United States. When a worldwide shortage occurs, substitutions with potentially less data may need to be considered.”

Erin Fox, PharmD, the director of the drug information service at the University of Utah Hospitals & Clinics in Salt Lake City, whose service provides shortage data for the American Society of Health-System Pharmacists (ASHP), echoed Dr. Kaiser’s sentiments. “Pharmacists can do a great deal when there are shortages, in terms of seeking out product from alternate sources and prioritizing use of limited stock, but once it gets past that point to where there is no drug, there’s not much you can do,” she told Pharmacy Practice News. (For tips that do work when coping with chemotherapy drug shortages, see sidebar.)

Hard Evidence Lacking

The St. Jude data are invaluable in terms of documenting the safety and efficacy of potential drug alternatives and in demonstrating the toll extended drug shortages can take on patients. However, Dr. Greene does not expect that similar opportunities to examine the effects of drug shortages on patient outcomes will arise. “Most shortages are short-term, often do not affect large groups of patients and do not cause us to exhaust our stocks,” he said. “Mechlorethamine was certainly the most significant and persistent chemotherapy shortage that affected a large number of our patients.”

Nevertheless, collecting data on a piecemeal basis also can be important, Dr. Fox said. And pharmacists can play a significant role in doing so. “If they’re using substitutes, pharmacists can put together a retrospective review to evaluate outcomes or differences in rates of adverse effects or medication errors during the time of substitution,” she said. “That’s really important information to have and it doesn’t have to be only physicians who do this data collection.”

Dr. Fox added some mixed news regarding the number of shortages that have been occurring. “We’ve seen evidence that the rate of new shortages has decreased, which is great,” she said. “Unfortunately, the shortages we’re following are taking a long time to resolve.”

More Resources

For more information on current and anticipated drug shortages and suggestions on how to manage them, visit the websites of the ASHP (www.ashp.org/​menu/​drugshortages/​resources) and the FDA (www.fda.gov/​drugs/​drugsafety/​drugshortages/​default.htm). Additionally, the February issue of Clinical Pharmacology & Therapeutics (www.nature.com/​clpt/​index.html) includes several articles, including a commentary by Dr. Fox, that delve into the underlying causes of drug shortages. In one of the articles, the authors point to a lack of incentives for quality manufacturing that, if addressed, could mitigate the drug-shortage crisis.



Drs. Metzger, Greene, Kaiser and Fox reported no relevant financial conflicts of interest.

Seven Ways To Manage a Chemo Drug Shortage

  1. Rather than stockpiling a drug, order only what is needed for current patients. This may be especially helpful in cases of drugs with short expiration dates as a way of ensuring they are not wasted.
  2. Look to a different wholesaler other than the one your pharmacy is contracted with. They might have a larger stock or supply of drug that is produced by a different manufacturer.
  3. Try to place an order directly with the manufacturer. During a shortage, many manufacturers allocate product to direct customers. The company may also have an emergency supply for completing a patient cycle.
  4. Consider using drugs manufactured outside of the United States as long as good manufacturing practices are followed and the FDA and your state’s board of pharmacy have approved it.
  5. Look to drug manufacturers, literature searches and tertiary references for ways to extend drug stability and help prevent wastage of any drug in short supply.
  6. Consider rounding doses and scheduling patients on the same day when possible to avoid waste.
  7. Ensure that in extreme shortages curable cancers are given priority, especially when no other alternatives exist.

Sources: Drs. Kaiser and Fox