Drug Shortages Adversely Affect Treatment Decisions

Andrew D. Seidman, MD

Shortages of cancer drugs caused many oncologists and hematologists to choose suboptimal treatment plans for their patients last year, and government efforts have done little to boost the availability of the hard-to-find medications, according to results of three surveys presented June 3 during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO).

In a survey conducted by investigators at the University of Pennsylvania,¹ 94% of 214 oncologists and hematologists said their patients’ treatment had been affected by drug shortages between March and September of 2012. Of those doctors reporting shortages, 83% said they had been unable to provide standard chemotherapy at some point during that time period, and 13% reported that patient enrollment or continuing participation in clinical trials had been compromised due to drug unavailability.

Two-thirds of the respondents work in community oncology settings.

A separate pair of surveys conducted by ASCO reported that members of the organization noticed only a slight easing of drug shortages between October 2012 and April 2013 but during the same period became increasingly concerned about the limited availability of treatments critical to supportive cancer care, such as antiemetics, pain medications, and basic IV fluids and electrolytes.

“Quality cancer care also means providing patients with the right treatments at the right times, and we’re learning today that cancer drug shortages are still interfering with that mission,” said ASCO spokesperson Andrew D. Seidman, MD, an oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “This ongoing crisis must not be forgotten—it demands urgent solutions from regulators, policymakers, and manufacturers today.”

According to ASCO, generic drugs, especially common chemotherapies, have been most affected by shortages. In oncology, there are often no replacements for the standard agents that have been shown to improve survival, the organization reported, and when there are substitutes available, they are sometimes brand-name drugs, which can be several hundred-fold more expensive. This cost burden is shared by patients and institutions, as brand-name drugs typically have higher copayments and out-of-pocket costs, ASCO stated.

In many cases, ASCO said, there is also a lack of clinical trial evidence to determine the appropriate dose for the substitute drug. In addition, according to a survey taken by the Institute for Safe Medication Practices,² mistakes are sometimes made in the formulations or strengths of drugs given as alternatives for medications in short supply.

Drug shortages have also spawned borrowing and hoarding among medical institutions, the sale of counterfeit drugs, and a gray market for medications in limited supply, experts have said.

In the University of Pennsylvania survey, respondents said that the drugs most commonly in shortage were leucovorin, liposomal doxorubicin, 5-fluorouracil, bleomycin, and cytarabine. These drugs are commonly used in the treatment of various forms of cancer, including gastrointestinal, blood, breast, ovarian, and testicular cancers. Cytarabine is particularly critical for curing certain forms of acute leukemia, ASCO stated.

Researchers noted that doctors adapted to such shortages in different ways, including switching treatment regimens (78% of doctors), substituting alternate drugs partway through therapy (77%), delaying treatment (43%), choosing among patients to determine which one should receive the available supply of the chemotherapeutic agent (37%), omitting doses (29%), reducing doses (20%), and referring patients to another practice where drugs in shortage were available (17%). Most providers (70%) said they had no institutional guideline or committee to help make the difficult treatment modification decisions.

Keerthi Gogineni, MD, MSHP

“We were surprised by the large number of cancer doctors that had to make changes in the way they care for patients due to drug shortages,” said study coauthor Keerthi Gogineni, MD, MSHP, a medical oncologist in the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “Unfortunately, cancer drug shortages will likely be a persistent issue. Doctors are adapting to this new reality as best as they can, but more uniform guidance is needed to ensure that modifications are made in the most educated and ethical way.”

The research was supported, in part, by a Pfizer Medical and Academic Partnership Research Fellowship in Bioethics.

Need for Drug Substitutions Persists

ASCO’s 2012 and 2013 surveys of its members asked whether, in the previous six months, legislative and regulatory efforts to address drug shortages had been effective. A total of 390 and 462 doctors, respectively, responded.

Although the results from the second survey suggested that chemotherapy drug shortages may have eased very slightly, the changes were small, and practices were still faced with the need for drug substitutions. Moreover, respondents expressed growing concern over the shortage of supportive care drugs.

In the more recent survey, 59% of responding physicians were aware of ongoing drug shortages in their own or colleagues’ practices, versus 70% in the earlier survey.

Also in the 2013 survey, more than 40% of doctors said that drug shortages had not been resolved. Seventeen percent said the shortages were worse than in the fall of 2012, 16% responded that they were the same, and 9% that some shortages had improved while others had worsened.

“ASCO believes that there are likely numerous causes of drug shortages and will continue to call on Congress to convene a blue ribbon panel that includes providers, manufacturers, suppliers, FDA, and patients to develop comprehensive legislation to resolve these critical shortages,” said ASCO Chief Medical Officer Richard L. Schilsky, MD. “The Government Accountability Office is also conducting a comprehensive investigation of the causes of the shortages, and we will be eager to learn its assessment when the report is published early next year.”

Schilsky added that ASCO’s Ethics Committee has drafted a white paper aimed at providing guidance to physicians faced with the need to substitute other medications for cancer drugs in shortage. The paper is currently under review.

Meanwhile, more study of the issue is warranted, Gogineni said. One issue that deserves a look, she said, is patient outcomes in the face of the drug shortages.

Many Factors Behind Shortages

At last year’s annual meeting of ASCO, Rear Admiral Sandra Kweder, MD, deputy director of the FDA’s Office of New Drugs, blamed the shortages on manufacturing and quality problems and the plant closures that often result. Most shortages have involved sterile injectable drugs, she said, and as of last June, more than half of those were “due to product quality issues such as particulates, microbial contamination, impurities, and stability changes resulting in crystallization.”

Shortages may also occur due to industry consolidation, increases in demand, and a lack of access to pharmaceutical ingredients, she said.

Meanwhile, Hagop Kantarjian, MD, a professor and chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, has blamed the shortages on the extremely low price of generics, which he said can’t be raised to meet demand due to a Medicare physician reimbursement formula.

Under the recent government sequestration that slashed the budgets of many federal agencies, including the FDA, that formula became even more likely to hold down the prices of generic drugs, a dynamic that could further contribute to drug shortages, Schilsky said at the June 3rd press briefing.

The administration of President Barack Obama has been trying to help avert drug shortages, in particular through the Food and Drug Administration Safety and Innovation Act (FDASIA) that became effective in October 2012, which requires drug manufacturers to alert the FDA 6 months in advance about anticipated market withdrawals or drug-supply interruptions. The aim is to give the FDA time to step in with tactics such as helping to arrange for other companies to pick up the slack.

In the 6 months that followed the passage of the FDASIA, there was a six-fold increase in early notifications from manufacturers, Commissioner Margaret Hamburg, MD, wrote on the FDA’s website. In that6 months, the FDA prevented 128 drug shortages and saw fewer occur—42 reported between January and May 2012, as compared with 90 new shortages reported during that period in 2011, she stated.

“This data is a testament to how FDA exercises flexibility and discretion in much of our work on drug shortages and the importance of strong collaboration and constant communication with industry, health professionals, and patients,” Hamburg wrote.

Schilsky added that he is hopeful about another tenet of the FDASIA, which requires generic drug makers to contribute money intended to bolster the FDA’s resources, so it can review generic drug applications more quickly and conduct swifter inspections of generic drug manufacturing facilities when questions about safety come up.

Based on anecdotal evidence, Schilsky said, he believes that similar shortages are ongoing in many European countries.

1. Emanuel Z, Shuman K, Chinn D, Gogineni K. Impact of oncology drug shortages. Presented at: 49th Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, Illinois. Abstract CRA6510.
2. Institute for Safe Medication Practices. A shortage of everything except errors: Harm associated with drug shortages. Institute for Safe Medication Practices. http://www.ismp.org/newsletters/acutecare/showarticle.asp?id=20. Published April 19, 2012. Accessed June 3, 2013.

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