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Original Investigation
October 2017

Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011

Author Affiliations
  • 1University of Maryland School of Pharmacy, Pharmaceutical Health Services Research Department, Baltimore
  • 2University of Queensland School of Public Health, Brisbane, Queensland, Australia
  • 3Centre for Evidence Based Medicine, University of Oxford, Oxford, England
  • 4University of Maryland School of Medicine, VA Maryland Healthcare System, Baltimore
  • 5Center for Disease Dynamics, Economics and Policy, Washington, DC
  • 6North Carolina State University, College of Veterinary Medicine, Raleigh
  • 7now with Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill
  • 8George Washington University School of Medicine, Washington, DC
JAMA Intern Med. 2017;177(10):1452-1459. doi:10.1001/jamainternmed.2017.3820
Key Points

Question  How often is the study purpose explained to potential participants in randomized clinical trials of antibiotics?

Findings  In this cross-sectional analysis of trial documents submitted to regulators, no informed consent forms consistently conveyed the primary hypothesis of the study.

Meaning  Patients enrolling in antibiotic clinical trials are not accurately informed of study purpose, raising fundamental questions of the ethics of consent in antibiotic drug trials.


Importance  Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use “noninferiority” hypotheses allowing a degree of inferior efficacy deemed “clinically acceptable” compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials.

Objective  To determine the degree to which the study purpose is explained to potential participants in randomized clinical trials of antibiotics and the degree to which study protocols justify their selection of noninferiority hypotheses and amount of “clinically acceptable” inferiority.

Design and Setting  Cross-sectional analysis of study protocols, statistical analysis plans (SAPs), and informed consent forms (ICFs) from clinical study reports submitted to the European Medicines Agency. The ICFs were read by both methodologists and patient investigators.

Main Outcomes and Measures  Protocols and SAPs were used as the reference standard to determine prespecified primary hypothesis and record rationale for selection of noninferiority hypotheses and noninferiority margins. This information was cross-referenced against ICFs to determine whether ICFs explained the study purpose.

Results  We obtained trial documents from 78 randomized trials with prespecified efficacy hypotheses (6 superiority, 72 noninferiority) for 17 antibiotics conducted between 1991 and 2011 that enrolled 39 407 patients. Fifty were included in the ICF analysis. All ICFs contained sections describing study purpose; however, none consistently conveyed study hypothesis to both methodologists and patient investigators. Methodologists found that 1 of 50 conveyed a study purpose. Patient investigators found that 11 of 50 conveyed a study purpose, 7 accurately and 4 inaccurately compared with the reference standard. Seventy-one of 72 noninferiority trial protocols or SAPs provided no rationale for selection of noninferiority hypothesis. None provided a clinical rationale for the chosen amount of decreased efficacy.

Conclusions and Relevance  Patients were not accurately informed of study purpose, which raises questions regarding the ethics of informed consent in antibiotic trials. Noninferiority and superiority trials entail different benefit-harm trade-offs that must be conveyed for ethical informed consent.