As medical care rapidly evolves, there’s really no debate over the potential for drug labels to become outdated, particularly in the high stakes world of cancer treatment. The question is how best to ameliorate the problem, while still protecting the process from financial and other conflicts.

Off-label prescribing of cancer drugs is common, occurring 30% of the time, according to a frequently cited 2013 study in the Journal of Clinical Oncology, which looked at 10 chemotherapy drugs. Some drugs, such as gemcitabine and rituximab, were used off-label two-thirds of the time, while pemetrexed and trastuzumab were prescribed off-label less than 10% of the time.1

While cancer physicians can reference various compendia, most notably from the National Comprehensive Cancer Network (NCCN), that’s a lot of drug information for busy doctors treating patients with numerous malignancies to stay on top of, said Jeff Allen, PhD, chief executive officer at Friends of Cancer Research. “What we’ve found is that the discrepancies between the label and the recommended uses may ultimately cause confusion,” Dr Allen told Cancer Therapy Advisor.

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The nonprofit organization last year backed S. 3519 to provide Food and Drug Administration (FDA)officials the authority to update generic drug labels with newer treatment insights.2 Dr Allen said that the Washington, DC-based organization is hopeful that the bipartisan legislation will be reintroduced this session with a new cosponsor, following the retirement of Sen. Orrin Hatch (R-UT).

But S. 3519 is not the only sign that federal leaders are looking at ways to better align what’s on the label with the most recent science. In senate committee testimony in the Spring of 2018, FDA Commissioner Scott Gottlieb, MD, pointed out that when the brand-drug sponsor voluntarily withdraws its marketing application, there’s no sponsor responsible for making such updates to the generic version. “The result is that these drug labels get frozen in time,” Dr Gottlieb said.3

While more frequent updating of labels is a laudable goal, the challenge will be how to structure the process so that drug manufacturers, patient advocacy groups, or others with a vested interest don’t wield a disproportionate influence, said Tewodros Eguale, MD, PhD, an associate professor in the pharmaceutical economics and policy department at Massachusetts College of Pharmacy and Health Sciences,Boston. Dr Eguale coauthored a study in 2016 looking at off-label prescribing,which found that 80.9% of off-label prescribing wasn’t backed up by strong scientific evidence.4

“It’s always the dilemma,”Dr Eguale said. “Are you going to go with the science or are you going to go with the testimony by the clinician or the patient?”

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.

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

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Strengthening Protections

Both Drs Basch and Eguale support more frequent label updates, as long as sufficient protections are incorporated. Dr Eguale noted that his 2016 study, along with finding insufficient evidence for 80.9% of off-label prescribing, also identified a higher rate of adverse drug events with off-label use compared with on-label.4

 But that also means that nearly 20% of off-label prescribing does have strong scientific backing, and thus should be widely known clinically, Dr Eguale said. If updating labels is “done really quite well, this is something [that] is really important,” he said.

But Dr Eguale raised some concerns about the language in the previously introduced senate bill, such as making decisions regarding updating in part based on “whether there is a relevant accepted use in clinical practice.”2 That wording is“really very vague,” he said.

It’s unclear whether an off-label use recommended in a compendia would meet that standard, Dr Eguale said, or whether a more rigorous bar would be required, such as randomized clinical trial data. Also, he questioned who would be in charge of initiating the updating process — would that be led by FDA officials or could it be driven by other interested parties? “I am concerned, for example, if pharmaceutical companies start to suggest a group of drugs to be reevaluated for treatment indications,” he said.

Any improvements to the updating process should include a set of criteria for how FDA officials ultimately decide whether it would be prudent to revisit a drug’s label, Dr Eguale said.After reading through S. 3519, Dr Basch shared these concerns. “I think what this [legislation] misses is a lot of the texture of how this is going to be done and by whom.”

Some possible improvements would include setting a schedule to review drug labels, Dr Basch noted. There also needs to be a mechanism to fact-check any data submitted by manufacturers and others, he said.

FOCR’s Dr Allen said the legislation’s intent is clear that, while evidence might be submitted by manufacturers and other groups, any decisions on updates would be led by FDA officials as “the independent arbitrator of information.” While FOCR’s study focused on off-label treatment indications, any updating could also address edits to recommended dosing or could reflect other changes that have the potential to reduce adverse drug effects for patients, Dr Allen said.

“One of our hopes of having this more flexibility in the labeling for older drugs,” he said, “is to allow the label to more accurately reflect their current demonstrated uses as accurately as possible.”


  1. ContiRM, Bernstein AC, Villaflor VM, Schilsky RL, Rosenthal MB, Bach PB. Prevalence of off-label use and spending in 2010 amongpatent-protected chemotherapies in a population-based cohort of medicaloncologistsJ Clin Oncol. 2013;31(9):1134-1139.
  2. S. 3681, 115thCong. 2018.   Introduced September 27, 2018. AccessedFebruary 25, 2019.
  3. US Food and Drug Administration. Remarksfrom FDA Commissioner Scott Gottlieb, MD, as prepared for testimony before a USSenate Committee on Appropriations on FDA’s Fiscal Year 2019 budget. April 24, 2018. Accessed February25, 2019.
  4. Eguale T, Buckeridge DL, Verma A, et al. Association of off-label drug useand adverse drug events in an adult population. JAMA Intern Med. 2016;176(1):55-63.
  5. Shea MB, Stewart M, Van Dyke H, Ostermann L, Allen J, SigalE. Outdated prescriptiondrug labeling: how FDA-approved prescribing information lags behind real-world clinicalpractice.Ther Innov Regul Science. 2018;52(6):771-777.
  6. Green AK, WoodWA, Basch EM. Time to reassessthe cancer compendia for off-label drug coverage in oncology. JAMA. 2016;316(15):1541-1542.
  7. US Food and Drug Administration. Xeljanz,Xeljanz XR (tofacitinib): safety communication – safety trial finds increasedrisk of blood clots in the lungs and death with higher dose in rheumatoidarthritis patients. Published February 25, 2019. Accessed February 26,2019.
  8. Mitchell AP, Basch EM, DusetzinaSB.Financial relationships with industryamong National Comprehensive Cancer Network Guideline authors. JAMA Oncol. 2016; 2(12):1628-1631.

This article originally appeared on Cancer Therapy Advisor