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.

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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.