Director, Oncology Pharmaceutical Affairs Oncology Analytics, Inc, Plantation, FL
Chief Oncology Nurse Oncology Analytics, Inc, Plantation, FL
Chief Executive Officer and Chief Medical Officer, Oncology Analytics, Inc, Plantation, FL
Senior Executive Medical Director and Chief Scientific Officer, Oncology Analytics, Inc, Plantation, FL
Research Program Manager Oncology Analytics, Inc, Plantation, FL
Associate Medical Director Oncology Analytics, Inc, Plantation, FL
After being in short supply since 2008, leucovorin, an analog of folic acid, is now more readily available, and the economics of US cancer care are about to have a bit of a reprieve. Leucovorin is used in part to increase the efficacy of chemotherapy with 5-fluorouracil (FU) for the treatment of colorectal cancer (CRC). While the supply dwindled, the demand rose as chemotherapy regimens containing leucovorin gained popularity. For reasons that are unclear, the 2 main manufacturers of leucovorin (Teva Pharmaceuticals and Bedford Laboratories) were unable to keep up with the demand.
Drug shortages are not new in oncology. Almost all chemotherapy drugs in short supply have been generic, because of their lower price and lower profits. With little incentive for manufacturers to invest in low-margin drugs, and with more incentive to produce lucrative patent-protected agents, it is no surprise that shortages develop. Although “production problems” resulting from contamination, regulatory issues, and shortages of raw materials are often cited as causes, it is estimated that these account for only 10% of drug shortage sources; nearly 90% of the issues are economic.1
Amid this evolving chaos, in March 2008, the US Food and Drug Administration (FDA) approved levoleucovorin (Fusilev; Spectrum Pharmaceuticals), a different version of leucovorin. These drugs are 2 isomers—namely, 2 chemicals with the same chemical formula, but with different molecular configurations. Racemic leucovorin is a 1:1 mix of d-(dextro) and l-(levo) isomers, which are molecular mirror images of each other. The l-isomer is the active ingredient, whereas the d-isomer lacks biologic activity. Levoleucovorin is a pure form of the l-isomer, a purification of leucovorin that yields only the active ingredient. Spectrum Pharmaceuticals announced that it had developed a product free of “contamination” by the harmless d-isomer.
It is more costly to manufacture the pure form of levoleucovorin, which allows the use of a dose of only half that of generic leucovorin. However, this purified form exhibits similar efficacy and tolerability (Table) to racemic leucovorin,2 and clinical trials data indicated no true need for such purification.3-6
In the testing leading to the 2011 FDA approval of levoleucovorin for CRC, levoleucovorin proved to be “noninferior” to generic leucovorin. In a March 7, 2008, press release, Richard A. Bender, MD, FACP, Spectrum Pharmaceutical’s former Chief Medical Officer, said, “With this drug, patients undergoing cytotoxic chemotherapy are spared the administration of the pharmacologically inactive dextro-isomer.”7 The Medicare allowable monthly price of a standard treatment of levoleucovorin is $2475 compared with the cost of $139 for generic leucovorin.8 The value of being spared the administration of a harmless inactive isomer is regarded by many clinicians and pharmacists as nonexistent.
Many in the oncology community were dumbfounded at the price of levoleucovorin. Leonard Saltz, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering, noted, “It’s not clear to me why somebody decided to make levoleucovorin, but they did, and they experimented to see if it was any better, and gosh-golly-gee-wiz, it’s not.”9
Faced with a shortage of leucovorin, oncologists using 5-FU–based therapy had difficult choices: to not use leucovorin and to increase the planned 5-FU dose by 10%, to purchase leucovorin from “gray market” scalpers at inflated prices, to self-ration leucovorin by administering lower-than-standard doses, to substitute an expensive oral variant of 5-FU (capecitabine), or to use levoleucovorin.
Many thought the choice of substituting levoleucovorin interfered the least with patient care. Insurers had no choice but to provide coverage for the drug, which was heavily marketed. However, UnitedHealthcare Group’s Senior Vice President, Lee N. Newcomer, MD, MHA, issued a warning. “What we won’t do is cover levo[leucovorin] as a long-term substitute,” he said. “As soon as this shortage is over, this drug is going to lose coverage, because there is no reason for it.”9
Over the past few years, many oncology practices have become accustomed to using levoleucovorin, and, for them, the economics have been very favorable. In situations where Medicare allows a 6% markup in the sale of chemotherapy drugs in the oncology office, it makes more economic sense to earn $148.50 monthly on levoleucovorin than $8.34 on leucovorin.
What constitutes a financial advantage to some can often be in conflict with the larger societal economics involving third-party payers, Medicare, and all who ultimately pay for the costs of care. In the example of levoleucovorin, some oncologists continue to insist on using the more expensive drug instead of returning to the less expensive leucovorin. Often the argument is made that patients are doing well on levoleucovorin and there should be no requirement to change drugs mid-treatment. Based on our discussions with providers and payers, some oncologists persist in asserting that generic leucovorin cannot be obtained, and others say they want to avoid confusion in the chemotherapy room where dosages are different from one drug to the other. At times, patients are put in the middle, being told to petition their payers for coverage of a drug essential to their care.
To date, no patients are known to have been harmed by levoleucovorin, which had the advantage of becoming available when a reasonably priced generic agent was in short supply. An expensive alternative is better than no drug. However, with the current steady supply of generic leucovorin, clinicians and payers should consider returning to a cost-effective standard of care. The challenge is to strike a balance that respects the economics of free market innovations and ensures the free flow of important medications for patients with cancer.
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