August 25, 2016

A group of University of North Carolina Lineberger Comprehensive Cancer Center researchers is calling for an overhaul of the process that determines which cancer drugs used off-label – or beyond their approved use — are reimbursed by federally-funded health insurance in the United States.

In a “Viewpoint” article published online Aug. 25 in the Journal of the American Medical Association, the physician-researchers raised concerns that there are inconsistencies between the five reference guides, or compendia, used by the Centers for Medicare and Medicaid Services to determine which drugs it will reimburse for off-label uses in cancer care. They also cited the “weak quality” of evidence used in some cases to green-light some off-label uses in oncology, which they argue could be leading to poor quality of patient care and high costs.

Dr. Ethan Basch, headshot

Dr. Ethan Basch

Ethan Basch, MD, professor of health policy and management at the UNC Gillings School of Global Public Health and of hematology/oncology in the UNC School of Medicine, is a co-author of the study. Basch also is director of UNC Lineberger’s Cancer Outcomes Research Program.

“The quality and consistency of these very important compendia resources is not what it should be, given the level of scrutiny that’s appropriate for highly toxic and expensive cancer drugs,” Basch said. “We could be causing substantial suffering for cancer patients because of the sometimes cavalier use of off-label drugs. A new, more rigorous approach is warranted in order to protect our patients.”

The researchers report that off-label use of drugs is widely practiced in oncology care. A 2013 study found that off-label uses accounted for $5 billion in cancer drug costs in 2010.

“Off-label drugs are used in many different scenarios in cancer care,” said William A. Wood, MD, MPH, a UNC Lineberger member, an associate professor in the UNC School of Medicine Division of Hematology/Oncology and study co-author. “They can be used if treatment options are limited in a certain situation, or if a clinician wants to try something unconventional, which could be a high-quality decision or a poor-quality decision. The concern is that people could be getting treatments that are inappropriate and that the risks may be greater than the benefits of these treatments.”

Federal law specifies that the Centers for Medicare and Medicaid Services should pay for a drug not used in accordance with the U.S. Food and Drug Administration’s label when one of the five reference guides states the drug’s off-label use is medically appropriate. The researchers also report that private insurers often use the compendia recommendations to inform coverage decisions.

However, previous research has found that the quality of evidence in the reference guides used is sometimes less rigorous than standards for FDA-approved drug uses, the authors said. In their own analysis of off-label uses for cancer drugs, Basch and his colleagues found limitations in the level, quantity, consistency and timeliness of evidence cited.

The researchers offer four steps for improving the review process – develop methodological standards for evaluating evidence used to back off-label drug recommendations; combine the findings into one “single, rigorously developed resource” rather than five inconsistent reference guides; assess whether those reviewing and determining off-label drug use policies have potential financial conflicts of interest; and make the compendia listings, which currently are only available by subscription, free to the public.

They also recommended that the U.S. Food and Drug Administration (FDA) or a public-private partnership should oversee the decision-making process.

“The FDA has the ability to review evidence using strict standards, and the purview of the FDA over oncology is increasing with the development of the FDA Oncology Center of Excellence,” Basch said. “We are advocating for an approach that would be different from regular drug approval, but improving on the current system.”

Angela K. Green, MD, MSc, formerly of the UNC Lineberger’s Cancer Outcomes Research Program and the UNC School of Medicine who is now at the Memorial Sloan Kettering Cancer Center, was also a co-author of the JAMA viewpoint.

This news originally was published by UNC Lineberger Comprehensive Cancer Center.

Gillings School of Global Public Health contact: David Pesci, director of communications, (919) 962-2600 or

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