Aviv Ladanie1, John P A Ioannidis2, Randall S Stafford3, Hannah Ewald1, Heiner C Bucher4, Lars G Hemkens5. 1. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Spitalstrasse 12, 4031 Basel, Switzerland; Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland. 2. Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, 1265 Welch Rd, MSOB X306, Stanford, CA 94305, USA; Meta-Research Innovation Center at Stanford (METRICS), Stanford University, 1265 Welch Rd, MSOB X306, Stanford, CA 94305, USA; Department of Health Research and Policy, Stanford University School of Medicine, 1265 Welch Rd, MSOB X306, Stanford, CA 94305, USA; Department of Statistics, Stanford University School of Humanities and Sciences, 1265 Welch Rd, MSOB X306, Stanford, CA 94305, USA. 3. Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, 1265 Welch Rd, MSOB X306, Stanford, CA 94305, USA; Department of Health Research and Policy, Stanford University School of Medicine, 1265 Welch Rd, MSOB X306, Stanford, CA 94305, USA. 4. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Spitalstrasse 12, 4031 Basel, Switzerland. 5. Basel Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, University Hospital Basel, University of Basel, Spitalstrasse 12, 4031 Basel, Switzerland. Electronic address: lars.hemkens@usb.ch.
Abstract
OBJECTIVES: Off-label drug use is highly prevalent but controversial and often discouraged assuming generally inferior medical effects associated with off-label use. STUDY DESIGN AND SETTING: We searched PubMed, 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%). CONCLUSION: 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.
OBJECTIVES: Off-label drug use is highly prevalent but controversial and often discouraged assuming generally inferior medical effects associated with off-label use. STUDY DESIGN AND SETTING: We searched PubMed, 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%). CONCLUSION: 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.
Keywords:
Drug label; Drug regulation; Evidence-based health care; Meta-analysis; Meta-epidemiology; Off-label; Systematic review; U.S. Food and Drug Administration
Authors: Sadia Shakeel; Wajiha Iffat; Ambreen Qamar; Shagufta Nesar; Fareeha Butt; Sobia Naseem Siddiqui; Hina Rehman; Anees Ur Rehman Journal: Front Public Health Date: 2022-03-24