Taking stock of the evidence for ‘off-label’ use of cancer drugs

Doctors often expand the use of cancer drugs to situations beyond those explicitly approved by the Food and Drug Administration. And health plans will pay for those uses as long as they are supported by professional guidelines known as compendiums.

Figure: Breakdown of the evidence cited by a compendium for off-label use of cancer drugs (OHSU/Joe Rojas-Burke)But new research raises questions about the reliability of compendium recommendations. They sometimes endorse costly cancer drugs with serious toxicities for uses in which there appears to be limited evidence of effectiveness.

“The cited evidence to support these recommendations is generally poor, with heavy reliance on uncontrolled studies, case reports, expert opinion, or no offered evidence,” the researchers conclude in a report this week in the British Medical Journal. Medical students Jeffrey Wagner, John Marquart, and Julia Ruby at the OHSU School of Medicine, and hematology oncology fellow Austin Lammers are the primary authors. The senior author is Vinay Prasad, M.D., M.P.H., Knight Cancer Institute physician and assistant professor in the OHSU School of Medicine.

The researchers chose to focus on guidelines issued by the National Comprehensive Cancer Network, one of five compendiums used for coverage decisions by health insurance companies and the federal Centers for Medicare and Medicaid Services.

Off-label prescribing is especially prominent in oncology because effective treatment options are often limited for people facing a life-threatening cancer, and because it’s not practical for researchers and drug companies to submit FDA applications for every combination of agent and tumor type.

Compendiums such as NCCN’s thus play an important role in cancer care, for instance, by guiding treatment decisions for rare cancers with patient populations too small for trial recruitment, or for individual patients who don’t meet the strictly defined criteria for inclusion in the randomized clinical trials that inform FDA decisions. Practicing oncologists have to make treatment decisions for patients who find themselves in situations where the evidence is incomplete, flawed, or absent. Compendiums are meant to help guide decision-making based on whatever level of evidence exists, sometimes expert opinion alone.

The new study took stock of the recommendations made by the NCCN for all 47 of the adult cancer drugs approved by the FDA between 2011 and 2015. For each drug, the researchers compared the FDA approved indications with NCCN recommended uses as of March 25, 2016. They appraised the level of supporting evidence for each added indication, and whether the recommended use later gained FDA approval.

NCCN recommended the drugs for 113 indications, 44 more than approved by the FDA. Treatment of a different type of tumor accounted for 32 percent of the expanded uses, while 29 percent removed the requirement of prior treatment, 16 percent removed the requirement of concurrent treatment, 18 percent removed other inclusion criteria, and 4 percent permitted a novel combination of drugs.

Sixteen of the 44 expanded uses cited no evidence to support the recommendation.


Evidence from randomized, controlled trials was cited to support ten of the 44 expanded uses. Seven of the expanded uses cited evidence from phase 3 studies. Sixteen of the 44 expanded uses cited no evidence to support the recommendation.

That’s not to say that any of the guidelines go against evidence, first author Jeffery Wagner said. In fact, the FDA later granted approval for six of the additional recommendations, or 14 percent, during the study’s 21 months of follow-up. But Wagner said the findings by his group make clear that compendium authors need to be more transparent about the evidence base for their recommendations.

In a written response to the study, NCCN Chief Executive Officer Robert W. Carlson, M.D., said the organization’s guidelines “are continuously updated based on the strongest scientific evidence available” in a process “designed to make sure the most effective, life-saving therapies are accessible and available to the patients who need them.” Carlson said NCCN’s 1,355 panel members come from 27 academic cancer centers. “Their expertise allows them to evaluate complex circumstances based on all available data, in order to come to a consensus about what constitutes optimal care.”

For drug manufacturers, gaining an off-label indication by means of a compendium recommendation has the potential to yield millions of dollars in additional sales beyond the on-label indications.

The new study found that many of the 44 expanded uses endorsed by NCCN involved a targeted therapy, a class of cancer drugs that typically cost in excess of $100,000 per year of treatment. Prasad, the senior author, said he’s concerned that compendium recommendations that broaden cancer drug uses will decrease the incentive for pharmaceutical companies to sponsor the rigorous clinical trials needed to establish the effectiveness of anti-cancer agents.

Ethan Basch, M.D., a medical oncologist at UNC Lineberger Comprehensive Cancer Center, who was not involved in the new study, said that the aim of compendium recommendations is noble and practical: to provide expert guidance for real clinical decisions. “Unfortunately,” he said, “the processes for developing recommendations have not been sufficiently rigorous.” 

Basch and colleagues have published a number of papers examining the quality of compendium recommendations and the financial conflicts of interest among compendium authors. He said the new study by Prasad and co-authors furthers the case for revamping the process for developing guidelines for off-label use of cancer drugs to a more public, accountable method, for example under the FDA’s new Oncology Center of Excellence. “Because these resources are the basis for clinical, reimbursement, and policy decisions, they have a responsibility to be rigorous and impartial.”  

Further reading:

Frequency and level of evidence used in recommendations by the National Comprehensive Cancer Network guidelines beyond approvals of the US Food and Drug Administration: retrospective observational study by Jeffrey Wagner, John Marquart, Julia Ruby, Austin Lammers, Sham Mailankody, Victoria Kaestner, and Vinay Prasad. British Medical Journal (March 2018)

Financial Relationships With Industry Among National Comprehensive Cancer Network Guideline Authors by Aaron P. Mitchell, Ethan M. Basch, and Stacie B. Dusetzina. JAMA Oncology (December 2016)October 18, 2016

Time to Reassess the Cancer Compendia for Off-label Drug Coverage in Oncology by Angela K. Green, William A. Wood, and Ethan M. Basch. JAMA (October 18, 2016)