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Study: Off-Label Anticancer Drug Use Less than Had Been Thought

Butcher, Lola

doi: 10.1097/01.COT.0000430973.48852.c3


Off-label chemotherapy use, frequently pointed to as a big factor in America's high cancer treatment costs, accounts for an estimated 30 percent of the total U.S. sales of the most common patent-protected therapies, according to the first-ever analysis of nationwide chemotherapy data.

The study, published in the March 20 issue of the Journal of Clinical Oncology (2013;31:1134-1139) and led by University of Chicago health economist Rena Conti, PhD, found that nearly half of all off-label use is supported by the National Comprehensive Cancer Network (NCCN) compendium recommendations that many insurers use to determine their coverage policy.

The study is noteworthy because it creates a benchmark that will prove useful as physicians, payers, and policymakers evaluate what constitutes appropriate treatments and use of health care dollars. This is the first time that cancer indication, stage, and line of therapy have been used to classify chemotherapy use, on and off label.

“Given that there has been so much in the news about the value of medical care, and in cancer care specifically, I think this is one of the pieces of the puzzle that's very important,” said Monika Krzyzanowska, MD, MPH, an oncologist at Princess Margaret Cancer Centre in Toronto, who wrote an accompanying editorial (JCO 2013;31:1125-1127).

Before this, she said, the only national estimate of off-label drug prescribing considered all uses, not just cancer treatment, and estimated the nationwide prevalence to be about 20 percent.

In light of the unique aspects of cancer treatment, the 30 percent off-label level was not surprising to Krzyzanowksa, who studies the quality of cancer care at the Institute for Clinical Evaluative Sciences at the University of Toronto “It was probably less than what people would have thought,” she said.

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Study Details

Conti and her colleagues (Arielle Bernstein, Victoria Villaflor, Richard Schilsky, Meredith Rosenthal, and Peter Bach) conducted the study, they said, to help understand the level of off-label infused chemotherapy use, which is frequently cited as a potential source of low-value care: “The extent of inappropriate chemotherapy use is a public policy concern because of the cost and potential harms to patients from the use of toxic agents with little likelihood of clinical benefit.”

Of the 30 most commonly used chemotherapies, 20 drugs were excluded from the study because their patents died before the first quarter of 2010 or because the treatment is taken orally.

The researchers analyzed prescribing data from IntrinsiQ Intellidose data systems, which maintains a database of prescriptions from oncology practices across the country. Included for the study were data on 135,000 chemotherapy administrations by 122 medical oncology practices during calendar year 2010.



A chemotherapy administration was classified as on-label when the use was consistent with a Food and Drug Administration-approved cancer diagnosis, stage of diagnosis, and line of therapy. Off-label use was bucketed into two categories:

  • An NCCN-supported off-label indication;
  • Associated with an FDA-approved cancer site but not supported by NCCN as to cancer stage and/or line of therapy.
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What It Means for Costs

The study found that, of the $12 billion spent on the 10 agents during 2010, $7.3 billion was for on-label uses. Another $2 billion was spent on off-label uses that are supported by NCCN recommendations, and $2.5 billion went for off-label uses that are not recommended by the NCCN.

Conti said some observers have worried that the findings may prompt insurers to limit reimbursement for some agents, but she said that is not warranted: “We do not believe that the off-label estimates reported in this study constitute adequate supportive data to justify the pursuit of policies including restrictions in use, cuts in spending, or targeted financial incentives limiting prescribing of these chemotherapies to the on-label setting,” she said.

Lowell Schnipper, MD, who chairs the American Society of Clinical Oncology's Cost of Cancer Task Force and is Chief of the Hematology/Oncology Division at Beth Israel Deaconess Medical Center, said off-label use that does not conform to NCCN compendium recommendations may be inappropriately running up cancer care costs: “I think it's a small part of the problem—at least that's what the data seem to suggest—but it certainly is a problem. A small percentage of inappropriate use of very expensive agents represents a reasonable target to look at with respect to the kind of value proposition that society wants and that most patients and physicians would like to think they are delivering.”





In her editorial, Krzyzanowska suggested that, in the short term, reimbursement policies represent the greatest opportunity for curtailing inappropriate off-label use: “On the part of payers there should be greater scrutiny of reimbursement for drugs that are potentially toxic and expensive and are associated with a high proportion of off-label prescribing,” she wrote.

“In my view, any of the agents for which greater than 50 percent of use is off label meet those criteria.” Three drugs—bevacizumab, gemcitabine and rituximab—fall in that category.



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In an interview, she explained that she was not advocating increased use of prior authorization for off-label use, but rather that payers and providers work together to identify clinical pathways for patients with specific disease states.

“We need to have that conversation to make decisions, taking into account the evidence about efficacy, the evidence about toxicity, and the likelihood of benefit in a given patient scenario, together with the cost, and come up with system-level solutions that improve patient care.”

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Bevacizumab Quickly Loses Luster

Physicians are sometimes criticized for being slow to respond to emerging evidence—but that was not the case with the use of bevacizumab for breast cancer patients.

Another study of nationwide oncology prescribing practices led by Rena Conti, PhD, found a 65 percent decline in the use of bevacizumab for breast cancer starting when the Food and Drug Administration first voiced skepticism about the drug's efficacy. In the study, now available online ahead of print in the journal Medical Care (doi: 10.1097/MLR.0b013e318290216f), the researchers reviewed IntrinsiQ Intellidose prescribing data from 122 medical oncology practices in 35 states, starting in February 2008.

That is when the FDA granted bevacizumab (Avastin), the first antiangiogenic drug on the market, accelerated provisional approval to be used as first-line therapy for metastatic HER2-negative breast cancer. The FDA decision was based on the early results of a clinical trial that suggested that the drug increased progression-free survival.

In July 2010, though, the FDA's Oncologic Drugs Advisory Committee voted to remove the drug's label of its indication for breast cancer, citing longer term follow-up results that showed bevacizumab failed to improve overall survival. Conti and her colleagues found that use of the drug for breast cancer patients fell by 37 percent immediately (See box).

In December 2010, the FDA announced its plan to rescind bevacizumab's approval for breast cancer. The following July, ODAC reiterated its vote to withdraw approval; and in November 2011, the FDA revoked the indication. Throughout that period, oncologists slowed their prescribing of bevacizumab for their breast cancer patients. By the final segment of the study—November 2011 to April 2012—use of bevacizumab had fallen by 65 percent from the first time period.

“Almost a year before the FDA withdraws approval for Avastin's use in metastatic breast cancer, with no change in compendia guidelines or alterations in coverage by major insurers, doctors shifted their practice and stopped prescribing Avastin for breast cancer,” Conti said. “That tells you that doctors in this context are actually very responsive to the evidence.”

© 2013 Lippincott Williams & Wilkins, Inc.
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