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Robust Evidence Supports Off-label Recommendations in the NCCN Guidelines

An in-depth re-analysis of recommendations beyond the FDA-approved indications
12 Aug 2019
Anticancer agents & Biologic therapy

A group of authors from multiple US institutions wrote on 2 August 2019 in the Annals of Oncology that off-label drug use is a frequent component of cancer care. They performed an in-depth re-analysis of the off-label recommendations listed in the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology and found that the strength of the evidence supporting recommendations beyond the Food and Drug Administration (FDA)-approved indications is robust, with a significant subset of these drugs later becoming FDA approved or supported by randomised clinical trial (RCT). Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

Off-label use of therapies is estimated to be around 30% in the US. The reasons behind the prevalence of off-label use are multifaceted, stemming from the relatively narrow indications often specified on the FDA label, a lack of FDA-approved drugs available for a certain disease or setting, and the desire to provide a promising new drug to a patient who might not have access through an FDA approval or a clinical trial. In addition, even when there are positive trials supporting the use of an FDA-approved drug in new settings, the pharmaceutical company may not pursue FDA approval for these expanded indications due to the cost. Insurance coverage of off-label drug prescriptions is guided through the use of compendia.

The current study was conducted in response to a retrospective observational study published in the March 2018 issue of BMJ. Based on an analysis of off-label oncology drug indications recommended in the NCCN Guidelines, the authors of that article concluded: “The NCCN frequently recommends beyond the FDA approved indications even for newer, branded drugs. The strength of the evidence cited by the NCCN supporting such recommendations is weak.”

In particular, the previous analysis of 113 NCCN recommendations reported 44 off-label recommendations for which the evidence was characterised as weak. It prompted the study team led by Dr. Razelle Kurzrock of the University of California San Diego, Moores Cancer Center in San Diego and colleagues to determine the evidence supporting the recommended off-label indications and the rationale behind these recommendations listed in the NCCN Guidelines.

Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by data from RCT. In addition, 8 recommendations were either very minor extrapolations from the FDA label and 5 were actually on-label. Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options with a median response rate 43%, 7 were based on non-RCT data showing significant efficacy with >50% response rates, and 2 were later removed from the NCCN guidelines because newer therapies with better activity and/or safety became available.

The authors concluded that their findings are in agreement with previous research that the NCCN recommendations for systemic agents are based upon scientific evidence in settings frequently beyond the FDA-approved indications. In most cases, the strength of the evidence supporting off-label recommendations in NCCN guidelines is robust. The NCCN asserts that when effective drugs are available, patients should have access to these therapies, even if they do not have an FDA-approved indication for that specific clinical context.


Kurzrock R, Gurski LA, Carlson RW, et al. Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals. Annals of Oncology; Published online 2 August 2019. pii: mdz232. doi: 10.1093/annonc/mdz232.

Last update: 12 Aug 2019

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