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Off-Label Drug Use Accounts for 18% of Spending

TOP - October 2013 VOL 6, NO 4

Mean Number of Unapproved Claims Averaged 11 per Patient

An examination of the Sur-veillance, Epidemiology and End Results (SEER)-Medicare database from 1998 through 2008 revealed that a significant number of patients with cancer received unapproved drugs—anticancer agents that are neither approved by the US Food and Drug Administration (FDA) nor endorsed by the compendia of the National Comprehensive Cancer Network (NCCN)—and that off-label drug use accounted for 18% of drug costs.

“We found a lot of off-label use,” said Dawn Hershman, MD, of Columbia University Medical Center, New York, at the 2013 American Society of Clinical Oncology Annual Meeting. The extent of off-label use is a policy concern because the clinical benefits of such use to patients may not outweigh costs or adverse health outcomes, she said.

The study identified 42,634 patients with metastatic breast, ovarian, uterine, lung, colon, and prostate cancer, or multiple myeloma. It documented the proportion of drug claims in a given year that were FDA approved, NCCN compendia approved, or unapproved. FDA drug approvals and their dates were identified; if the drug claim was within 1 year prior to FDA approval, it was categorized as compendia supported. If it followed the approval date, it was categorized as FDA approved. The researchers also determined which of the drugs were ever approved.

The Medicare reimbursement rate was determined, calculated for the most common regimen and dosing, and was not adjusted for inflation.
The investigators considered all anticancer agents used for the 7 common tumor types and found the following number of unapproved drugs (ie, neither FDA approved nor compendia endorsed): 33 in prostate cancer, 28 in ovarian cancer, 20 in breast cancer, 18 in multiple myeloma, 13 in uterine cancer, and 8 each in colon and lung cancer, Hershman reported.

The percentage of patients receiving only an approved drug was 55%, meaning that 45% of patients received a drug that was neither FDA approved nor compendia supported. There was strong variability by tumor type, with patients with multiple myeloma the most likely to receive an unapproved drug (~80%) and patients with colon cancer the least likely (~10%). The pattern was consistent across the 10-year time period.

Then the investigators evaluated which of the unapproved drugs were compendia approved and found that 70% were endorsed and 30% were not. The mean number of unapproved claims averaged 11 per patient overall, while the mean number of unapproved drugs averaged 1.5 per patient.

“The bulk of unapproved drugs are, however, compendia approved, and this is reassuring because we think the compendia are appropriate,” Hershman acknowledged. About half the compendia-supported drugs were eventually approved by the FDA for that indication, but those that did not become FDA approved were not deleted from the compendia, she added.

Cost of Off-Label Use: $150 Million
A breakdown of the cost according to appropriate use revealed that nearly $150 million in reimbursements was paid for drugs that were neither FDA approved nor compendia supported (Table).1 Most of the cost for off-label drug use was for the treatment of patients with multiple myeloma and prostate cancer.


“Of $850 million spent on drugs in this cohort, $150 million was for drugs only supported by compendia and $150 million was for unapproved indications,” she concluded, adding that drug costs have increased substantially in the past 5 years and therefore the costs today may be much greater.

Hershman cited data from another recent study that detailed which patent-protected chemotherapy agents were the most likely to be used inappropriately.2 Conti and colleagues showed that off-label use (neither FDA approved nor NCCN endorsed) was greatest for rituximab and gemcitabine (~40%) and bevacizumab (~25%). The least inappropriate use was for trastuzumab, for which essentially no inappropriate use was documented, and for pemetrexed (<10%).

The estimated national spending on these common, patent-protected drugs amounted to $12 billion, of which $2.5 billion was for off-label and NCCN-unsupported use, the Conti study reported.

While acknowledging limitations to her group’s study that pertain to the use of billing codes, estimates of cost, and other factors, Hershman commented, “We didn’t think we would find any unapproved use of drugs. We thought regulations were in place to stop that.”

1. Hershman DL, Neugut AI, Buono D, et al. Off-label and compendia use of chemotherapy in patients with metastatic cancer. J Clin Oncol. 2013;31(suppl):Abstract 6509. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.
2. Conti RM, Bernstein AC, Villaflor VM, et al. Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. J Clin Oncol. 2013;31(9):1134-1139.

The Good, the Bad, and the Ugly

Monika K. Krzyzanowska, MD, MPH, of the Princess Margaret Cancer Centre, Toronto, Canada, discussed the study by Hershman and colleagues and noted that some off-label use is not completely “inappropriate” but may exist in terms of a different administration schedule, or a different context for the same disease. In some cases, of course, the drug is used in the treatment of a disease for which it has not been well studied. Bevacizumab is a good example of this, she said.

According to Krzyzanowska, this matters because there can be “bad” consequences, such as a negative impact on trial accrual and undue financial costs, or “ugly” consequences, such as harm to the patient. Of course, she noted, some consequences are “good,” such as drug access for patients with rare diseases and the promotion of innovation.

She said the study by Hershman and colleagues confirms previous research showing that off-label prescribing is common in oncology and varies by disease, though a substantial proportion of off-label use is supported by NCCN compendia. Several questions remain to be answered:

  • Is compendium-compliant use of drugs appropriate?
  • What is the impact of off-label prescribing on patients (ie, benefit and toxicity)?
  • What is the motivation for off-label prescribing?
  • How can the cost of off-label therapy be best estimated?
  • What is the incidence of off-label use in oral chemotherapy?
  • How would molecular profiling affect off-label prescribing?

Clearly, Krzyzanowska said, oncologists are not “choosing wisely” in all circumstances. She concluded that greater scrutiny of off-label use is needed, “especially for diseases or drugs with a high prevalence of this, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial.”

Krzyzanowska MK. The good, the bad, and the ugly of off-label prescribing in oncology. Presented at: 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.

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