Off-label treatments were not consistently better or worse than approved drug treatments in randomized trials

Off-label treatments were not consistently better or worse than approved drug treatments in randomized trials. Aviv Ladanie et al. Journal of Clinical Epidemiology, https://doi.org/10.1016/j.jclinepi.2017.11.006

Highlights

---What is already known
⁃    Off-label drug use is highly prevalent in clinical practice, but its use is controversial and often discouraged
⁃    Lack of regulatory approval nourishes the assumption that off-label drug treatment effects are systematically less favourable compared to approved drug treatments
⁃    However, this assumption has never been empirically assessed using clinical trial evidence

---What this study adds
⁃    Medical effects associated with off-label drug use are highly heterogeneous and do not appear to be systematically inferior when compared to approved drug treatments
⁃    Relying on the approval status of drugs should not replace thorough assessment of benefits and harms on a case by case basis to ensure that patients receive the best available care

Abstract

Background: Off-label drug use is highly prevalent, but controversial and often discouraged assuming generally inferior medical effects associated with off-label use.

Methods: We searched Medline, PubMed Health and the Cochrane Library up to May 2015 for systematic reviews including meta-analyses of randomized clinical trials (RCTs) comparing off-label and approved drugs head-to-head in any population and on any medical outcome. We combined the comparative effects in meta-analyses providing summary odds ratios (sOR) for each treatment comparison and outcome, and then calculated an overall summary of the sOR across all comparisons (ssOR).

Results: We included 25 treatment comparisons with 153 RCTs and 24 592 patients. In six of 25 comparisons (24%), off-label drugs were significantly superior (five of 25) or inferior (one of 25) to approved treatments. There was substantial statistical heterogeneity across comparisons (I2=43%). Overall, off-label drugs were more favorable than approved treatments (ssOR 0.72; 95% CI=0.54-0.95). Analyses of patient-relevant outcomes were similar (statistical significant differences in 24% (six of 25); ssOR 0.74; 95% CI=0.56-0.98; I2=60%). Analyses of primary outcomes of the systematic reviews (n=22 comparisons) indicated less heterogeneity and no statistically significant difference overall (ssOR 0.85; 95% CI=0.67-1.06; I2=0%).

Conclusions: Approval status does not reliably indicate which drugs are more favorable in situations with clinical trial evidence comparing off-label with approved use. Drug effectiveness assessments without considering off-label use may provide incomplete information. To ensure that patients receive the best available care, funding, policy, reimbursement, and treatment decisions should be evidence based considering the entire spectrum of available therapeutic choices.