Keeping Doctors in the Dark May Heighten Risks of Off-Label Drug Use

OncologyLive, Vol. 17/No. 5, Volume 17, Issue 5

The appropriateness of off-label drug use in the management of patients with cancer in the United States is one of the most contentious issues confronting individual oncologists, patients, insurers, and governmental policy makers.

Maurie Markman, MD

The appropriateness of off-label drug use in the management of patients with cancer in the United States is one of the most contentious issues confronting individual oncologists, patients, insurers, and governmental policy makers. On the one hand, it is recognized by essentially all cancer physicians and most third-party payers that there are highly legitimate uses of antineoplastic drugs outside the narrow confines of the FDA-approved drug label. However, there is also appropriate concern that, in the absence of clinically relevant data demonstrating the relative risks (specific side-effect profile) versus the potential benefits of these agents in particular settings such as elderly populations and patients with serious comorbidities, there is the potential that serious harm may be caused.

Consider, for example, the theoretical potential of excessive cardiac toxicity associated with the use of the antiangiogenic agent bevacizumab in the presence of preexisting cardiac dysfunction. There is a paucity of data regarding the safety of such therapy as a result of the fact that patients with these and other highly clinically relevant comorbidities were excluded—either intentionally or as a result of physician concern—from clinical trials leading to regulatory approval of the drug. In fact, one most interesting report evaluating the SEER-Medicare database found that 35.5% of patients >65 years of age treated with this agent in the management of cancers of the lung, breast, or colon from 2004 until 2009 had a contraindication to its use.1

But the issue here is the question of whether the data actually indicate possible inappropriate or unsafe care or, conversely, the distressing lack of existing data to assist oncologists in safely utilizing this important drug in the elderly population, which comprises the large majority of patients in the Unites States with malignant disease.

Added to this ongoing and quite heated debate is a provocative new paper from Canadian investigators reporting on the risk of adverse events associated with the use of prescription pharmaceutical agents (not specifically anticancer agents) for on-label versus off-label indications.2

The investigators report that off-label delivery of such drugs is associated with an adverse event rate that is greater than that observed with on-label use in this large population-based study. Of interest, the authors also note that there is no statistically significant increase in adverse events for off-label administration in the approximately 20% of indications where there is “strong evidence” (a term defined in the article) for use of the drug. Finally, the investigators conclude that “caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence.”2

In an accompanying commentary, the authors rather remarkably use this paper as a justification to challenge efforts by many to modify or formally remove commercial speech restrictions established by the FDA on pharmaceutical manufacturers, whose representatives are currently only able to discuss with physicians what is explicitly stated on the label regarding the drug.3

This restriction has apparently been interpreted to prevent discussions of other off-label uses regardless of the level of evidence and published data on alternative doses, administration schedules, experience suggesting relative contraindications to drug delivery, and methods to reduce treatment-related side effects.

The authors note that the Canadian analysis has “provided compelling evidence that off-label prescribing is frequently inappropriate and that prescribing in these circumstances increases the risk for an adverse event substantially.”3 Finally, they conclude that “the FDA and the courts must carefully consider these findings as they contemplate guidance that would relax regulations to permit promotion of drugs beyond their labeled indications.”3

However, there is a far more rational and clinically meaningful interpretation of the Canadian study results which leads to a strikingly different approach to reducing avoidable risk of adverse events in the off-label setting.

The argument is best illustrated in a previously reported case study of potentially serious patient risk in the oncology arena resulting from the inability of a pharmaceutical company manufacturer to discuss specific off-label dose modifications.4 Efforts by multiple academic oncology groups to reduce the potentially serious skin and mucous membrane toxicity associated with the delivery of pegylated liposomal doxorubicin (PLD) at the FDA-approved (“on-label”) dose of 50 mg/m2 every 4 weeks in the noncurative management of previously treated epithelial ovarian cancer resulted in a number of peer-reviewed publications that revealed the substantially improved safety profile and similar efficacy of a 40 mg/m2 every 4 week regimen.4

However, in view of the fact that this was an unapproved off-label dose that did not satisfy the regulatory agency’s requirements for being included “on-label,” widespread dissemination of these data and marketing of this far safer alternative dosing program by the drug manufacturer would not have been a strategy consistent with existing physician-communication rules.

As a result, how many patients during the past many years might have experienced an avoidable serious adverse event due to the use of PLD based on its more toxic on-label dosing strategy?

Similarly, how many patients might have suffered a serious adverse event due to off-label delivery of an antineoplastic agent whose use oncologists felt was in the best interest of their patients, simply because the pharmaceutical manufacturer had not been permitted to provide information available to them regarding how the drug might be most safely administered in these circumstances?

Such situations might include the delivery of a drug in a relatively contraindicated (“black box warning”) setting or in patients suffering from a nonapproved cancer setting where particular comorbidities are present and use of a far safer alternative (off-label) treatment regimen might be more medically appropriate.

In conclusion, the legitimate concern with the finding of a higher risk of adverse events in patients receiving drugs off label should result in more open communication between pharmaceutical manufacturers and practicing oncologists, rather than less discussion. These companies are likely to be in the best possible position to provide advice regarding alternative strategies in unique situations to optimize the chances for the safest delivery of their own product.

Maurie Markman, MD, editor-in-chief, is president of Medicine & Science at Cancer Treatment Centers of America, and clinical professor of Medicine, Drexel University College of Medicine.


  1. Hershman DL, Wright JD, Lim E, et al. Contraindicated use of bevacizumab and toxicity in elderly patients with cancer. J Clin Oncol. 2013;31(28):3592-3599.
  2. Eguale T, Buckeridge DL, Verma A, et al. Association of off-label drug use and adverse drug events in an adult population. JAMA Intern Med. 2016;176(1):55-63.
  3. Good CB, Gellad WF. Off-label drug use and adverse drug events: turning up the heat on off-label prescribing. JAMA Intern Med. 2016;176(1):63-64.
  4. Markman M. Serious ethical dilemma of single-agent pegylated liposomal doxorubicin employed as a control arm in ovarian cancer chemotherapy trials. J Clin Oncol. 2010; 28(19):e319-e320.