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Off-Label Drug Coverage in Oncology

Compendia listings for the tyrosine kinase inhibitor erlotinib
26 Oct 2016
Bioethical Principles and GCP;  Cytotoxic Therapy

Off-label use of drugs is widely practiced in oncology care. Examples include bevacizumab in metastatic esophageal cancer or cetuximab in metastatic prostate cancer. In an article published in JAMA, a group of authors wrote their viewpoint about current compendia-based approach for coverage decisions in oncology and illustrate it by findings from examination of the current compendia listings for erlotinib.

The Centers for Medicare & Medicaid Services (CMS) uses federally designated third-party drug compendia, which are privately owned pharmaceutical reference guides, to inform coverage decisions for off-label cancer drug use in the United States. The CMS is directed by the 1993 Omnibus Budget Reconciliation Act to provide coverage when the indication for an off-label cancer drug is supported by at least 1 of these compendia.

There are currently 5 designated compendia: American Hospital Formulary Service (AHFS), National Comprehensive Cancer Network (NCCN) Drugs and Biologics, Clinical Pharmacology, Micromedex DrugDex, and Wolters Kluwer Clinical Drug Information Lexi-Drugs.

A systematic review published in 2009 found that the quality of evidence cited in compendia for off-label cancer drug usage is less rigorous than the standards supporting FDA-approved drugs. This analysis of 14 off-label indications of cancer drugs found substantial limitations in the level, quantity, consistency, and timeliness of evidence among commonly used compendia. Evidence cited by the compendia was often not up-to-date and differed from evidence retrieved through an independent search by the authors. This raises concern that payers may be compelled to cover inadequately proven treatments for which the risks outweigh benefits. Despite the findings of this systematic review, this issue has not been addressed since then.

Therefore, the authors of paper published in the JAMA examined the current compendia listings for the tyrosine kinase inhibitor erlotinib, which is currently FDA-approved for treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer. They compared the off-label indications for erlotinib listed within recent versions of the compendia and evaluated the evidence cited for each indication.

Persistent inconsistencies were noted in recommendations between the compendia and methodological weaknesses in the analyses of the evidence. For example, erlotinib has no off-label indications in AHFS, 1 off-label indication for head and neck cancer in Clinical Pharmacology, 8 off-label indications for colorectal cancer, newly diagnosed glioblastoma, recurrent glioblastoma, recurrent or metastatic head and neck cancer, renal cancer, NSCLC, ovarian cancer, and prostate cancer in DrugDex, and 3 off-label indications for chordoma, leptomeningeal metastases, and renal cancer in NCCN.

Moreover, the evidence cited to support the off-label indications for erlotinib is of weak quality in several instances, such as single case reports, small case series, and a phase I trial. In cases in which compendia disagree, generally a use is covered if at least 1 reference includes that indication.

Development of the compendia-based model for coverage decisions originated in an era when fewer drugs were available for patients, the cost of oncology drugs was lower, there was less appreciation of the potential long-term side effects of treatments, and views on evidentiary standards differed from today. Given changes in the landscape of cancer treatment and costs, this model should be reassessed.

The authors also wrote that there is limited transparency about how compendia are assembled or about conflicts of interest on the part of their contributors, and there are substantial inconsistencies both between and within these resources. They concluded that the current compendia-based approach for coverage decisions in oncology has lacked oversight and is not suitable for making safe recommendations or coverage decisions for cancer drugs. Given the clear limitations of this outdated system, a different model is warranted.


Green AK, Wood WA, Basch EM, et al. Time to Reassess the Cancer Compendia for Off-label Drug Coverage in Oncology. JAMA. 2016;316(15):1541-1542. doi:10.1001/jama.2016.12770 

Last update: 26 Oct 2016

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