Existing Evidentiary Gaps

A study by the Friends of Cancer Research, published in 2018, compared the labels for 43 cancer drugs approved between 1999 and 2011 to the NCCN compendia’s recommendations. Overall, the 43 drug labels included 99 approved treatment indications versus 451 recommended through the NCCN compendium. Of the 43 drugs, 79.1% had at least 1 well-accepted off-label use and 34.8% had at least 5 such uses, according to that analysis, published in Therapeutic Innovation & Regulatory Science.5

The potential stakes involved with off-label prescribing was underscored earlier this month when FDA officials posted a safety notice, alerting physicians that the 10 mg, twice-daily dosing regimen for tofacitinib that’s been approved for ulcerative colitis, has not been so approved for rheumatoid arthritis. At the time that FDA officials approved tofacitinib, they required a study in rheumatoid arthritis patients to look at the risk of cancer, heart-related effects, and infections. The most recent analysis of that trial’s data found a higher rate of blood clots in the lungs and death at the 10 mg, twice-daily regimen compared with patients on the 5 mg, twice-daily dosage or a TNF inhibitor.

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Moreover, there have been critiques about the extent of the evidence and biases that can underpin some compendia recommendations. For instance, a look in 2016 at the off-label recommendations in 5 compendia for erlotinib — initially approved to treat pancreatic and non-small cell lung malignancies — found that they ranged from 0 suggested off-label uses in 1 compendia to as high as 8 in another. NCCN cited 3 off-label indications for the medication, according to the 2016 viewpoint piece in JAMA.6

If the compendia used consistent processes, there shouldn’t be such variations in the results, said oncologist Ethan Basch, MD, one of the JAMA study coauthors and a professor of medicine at the University of North Carolina at Chapel Hill.

“It has huge implications for patients, for clinicians, and for society,” Dr Basch told Cancer Therapy Advisor. “Because if low-value treatments are being recommended, that means that higher-value treatments maybe aren’t, or that a lot of resources are being burned up on treatments that are low value, may be of little benefit, or may be very toxic.”

Dr Basch credited the NCCN guidelines process with incorporating some commendable components, such as gathering groups with expertise in a particular malignancy to look at research data and develop consensus recommendations. But there are also potential risks in relying too much upon expert opinion rather than research studies, he said.

One such risk is that treatments can be promoted too preliminarily, without sufficient evidence, Dr Basch said. “Too often we think things work, and then they turnout not to work,” he said.

Another potential risk involves underlying financial conflicts, said Dr Basch, who coauthored an analysis published in JAMA Oncology highlighting such conflicts among NCCN guideline authors. Of the 125 guideline authors in 2014, 108 reported at least 1 financial conflict of interest.8