November 19, 2010 — Across the United States, shortages of many critical drugs, including several cancer drugs, are placing patients at risk.
"The oncology community is experiencing severe and worsening shortages of many critical therapies, including but not limited to doxorubicin, leucovorin, etoposide, nitrogen mustard, vincristine, propofol, and morphine," the American Society of Clinical Oncology (ASCO) announced this week.
"The lives and well-being of cancer patients — including children — are at risk," said Michael Link, MD, president-elect of ASCO and pediatric oncologist at Lucile Packard Children's Hospital at Stanford University, California.
"Shortages of critical cancer drugs are causing delays in treatment, which can impact survival," Dr. Link said in a statement. "Additionally, administration of alternative therapies, if they are available, can lead to less optimal treatment, as well as increased costs, for patients and increased administrative burdens for oncology practices."
"There is no single reason or solution for the shortages," Dr. Link added.
The current drug shortages listed on the Web site of the US Food and Drug Administration (FDA) indicate that most are due to "manufacturing delays" and "increased demand."
"We have seen a record number of shortages this year," an FDA spokesperson told Medscape Medical News in a written statement. "Most of these shortages involve parenteral products, including the oncology drugs cisplatin, doxorubicin, and leucovorin."
"Factors we see contributing to these shortages, especially of older parenteral products, include limited production capacity at the firms making these products," said Captain Valerie Jensen, RPh, associate director of the Center for Drug Evaluation and Research (CDER) Drug Shortage Program at the FDA in the written statement. "We also see fewer firms making these products each year since they are often discontinued in favor of newer, more profitable products."
"Finally, the complex manufacturing process for these products involves a long lead time relative to other dosage forms, making it difficult for firms to suddenly ramp up production. When one firm has a manufacturing problem or suddenly discontinues, unfortunately a shortage almost always develops," Capt. Jensen explained.
"As posted on our Web site, for cisplatin, 2 firms have experienced manufacturing delays and the third has been working to keep up with demand. For doxorubicin, 1 firm has had manufacturing delays and the other 2 have been trying to meet demand. For leucovorin, both manufacturers have experienced delays. One of those firms has now been releasing and is working to increase supplies," she reported.
Affecting Patient Care and Clinical Trials
The shortages have affected patient care and clinical trials, said Kathy Miller, MD, associate professor of medicine, Indiana University School of Medicine, Indianapolis. "It has been miserable," she told Medscape Medical News.
"In September, we could not get any etoposide," she said. "Several patients were converted from outpatient [bleomycin, etoposide, cisplatinum] regimens to inpatient [vinblastine, ifosfamide, cisplatin] regimens. In this case, there is no efficacy difference, but there is a major difference in toxicity and convenience," she said.
"We are currently struggling with . . . word that the doxorubicin supply problem is now creating an epirubicin supply issue," Dr. Miller reported.
"This has become a major issue for breast cancer clinical trials, which typically specify an anthracycline," she said. "While there are very good data to support substituting epirubicin (at 1.5× the dose) for doxorubicin with equivalent efficacy and toxicity, doing so is a major protocol violation." There is concern about how these trials will now be viewed, for example, by regulatory authorities, she added. There is also concern about how these trials are going to be continued — she had just received contact from a site reporting an epirubicin shortage.
Shortages Are Reaching Crisis Point
Although there have been drug shortages in the past, the shortages that are currently being experienced are "the worst that we have ever seen," said Bona Benjamin, BS Pharm, from the American Society of Health System Pharmacists (ASHP). Ms. Benjamin is director of medication-use quality improvement at the Practice Development Division, and runs the ASHP Drugs Shortages Web Resources Center.
For hospital pharmacists, the shortage of injectable products — many of which have no therapeutic alternatives — is approaching a national crisis, she told Medscape Medical News.
There seem to be various reasons for the shortages, she said, including manufacturing problems, quality-control problems (which halt production while the issue is addressed), shortages of raw materials, and shortages of container materials.
Cancer drugs in short supply listed on the ASHP Web site include carboplatin, cisplatin, doxorubicin, etoposide, and leucovorin.
Action to Combat the Shortages
The ASHP has opened up a dialogue with pharmaceutical manufacturers, the FDA, and other organizations to examine the reasons for the shortages and to develop action plans to resolve the shortages, Ms. Benjamin said. "We are going to be moving forward with this and responding to the urgency of the situation."
"When these shortages occur, the FDA has a process in place, and we are doing everything we can within our regulatory authority to help increase supplies," the agency spokesperson explained to Medscape Medical News.
"If there is a specific quality problem causing the shortage, we are working with the affected firm to address the issue while encouraging the remaining firms to increase production. If a new manufacturing site or supplier is needed, we can expedite review to help address a shortage. In rare cases, we have allowed temporary importation to address a shortage. This is currently being done with [foscarnet sodium] injection, as posted on our Web site," Capt. Jensen from the FDA explained. "We are working with all of the firms involved with the leucovorin, cisplatin, and doxorubicin shortages."
However, she pointed out that the "FDA does not have the authority to require a firm to increase production, nor can we stop a firm from discontinuing a product. Firms are not required to report shortages or discontinuations to the FDA, except in certain circumstances involving sole-source products, and there is no penalty if a firm does not report this information to us."
Lack of Financial Incentive?
Most of the cancer drugs that are in short supply are generic products and are manufactured by a few companies. For example, cisplatin and doxorubicin are manufactured by Teva, Bedford, and APP.
The fact that they are generic products and not trademark-protected drugs from large pharmaceutical companies is part of the problem, according to Carlea Bauman, president of the patient advocate group Colorectal Cancer Coalition. There is no financial incentive to manufacture cheaper generic drugs, she said: "In a free market, there is nothing to compel manufacturers to make drugs that don't make them money; there is no hammer."
The Colorectal Cancer Coalition has been highlighting shortages of leucovorin (manufactured by Teva and Bedford). This is used with 5-fluorouracil (5-FU) to increase its effectiveness, Ms. Bauman explained, but patients have been reporting that shortages of leucovorin have meant they have received treatment with 5-FU alone, the consequences of which are unclear, she said.
In addition, some patients have been switched over to levoleucovorin (Fusilev, Spectrum Pharmaceuticals), which is 60 times more expensive. The group cautions patients to be aware of its cost and the possibility that insurance might not cover its administration for colorectal cancer. Also, there could be dosing problems because the drugs cannot be substituted on a 1:1 basis.
"Alarming" Impact on Hospitals and Patients
The drug shortages are having an "alarming impact on hospitals and patients throughout the country," according to the Institute for Safe Medication Practices (ISMP) president Michael Cohen, RPh, MS, ScD, FASHP.
A recent survey of 1800 health professionals conducted by the ISMP found that 20% of practitioners reported that their hospital has experienced medication errors due to drug shortages, and that 19% of these errors resulted in adverse patient outcomes. In some cases, patients have died.
Some details of the survey responses have been reported by Pharmacy Practice News.
Two patients died from an overdose after shortages of morphine led to the administration of intravenous hydromorphone, but without dosing readjustments (the dose differs by a factor of 10). In other cases, overdosing required critical care and administration of the opioid antagonist naloxone.
Shortages of leucovorin have led to substitution with capecitabine (Xeloda), resulting in serious gastrointestinal toxicity in many patients, according to some of the survey respondents. One reported that "chemotherapy treatments were delayed in a patient with high potential for remission amid attempts to find a source of the needed drug."
In addition to cancer drugs, the shortages are affecting antibiotics, anesthetic agents (such as propofol and neuromuscular blockers), and epinephrine, heparin, and fosphenytoin, according to the ISMP survey.
The drugs in short supply "are used so commonly that virtually every patient coming into hospital is affected," said Tom Van Hassel, RPh, MPA, director of pharmacy at the Yuma Regional Medical Center in Arizona. "We've always had drug shortages come and go, but it is now an everyday occurrence," he told Pharmacy Practice News. "It has a huge impact on patient safety because we're forcing doctors to use drugs that they are not used to."
This is a healthcare crisis, but "because it is primarily a hospital pharmacy issue and not a drugstore problem, it is not on the public radar screen," Michael Rubino, RPh, FASHP, director of pharmacy at Hartford Hospital in Connecticut, said in the same report.
Recent Summit Meeting
The drug shortages were discussed at an invitation-only meeting held November 5 in Bethesda, Maryland. This Drug Shortages Summit was convened by several groups — ASCO, the American Society of Anesthesiologists, ASHP, and ISMP. Also invited were representatives from pharmaceutical manufacturers, supply chain companies, and the FDA.
"Significant drug shortages have occurred in every class of medications, including some critical life-saving drugs," ASHP executive vice president Henri Manasee Jr., PhD, ScD, noted after the meeting. "We have a social responsibility to solve this serious threat to our ability to safely and effectively care for our patients."