A team of researchers led by Peter Doshi, PhD, assistant professor in the Department of Pharmaceutical Health Services Research (PHSR) at the University of Maryland School of Pharmacy, has found that randomized clinical trials for antibiotics often fail to accurately inform patients about the purpose of those trials. Published in JAMA Internal Medicine, the study raises concerns about the ethics of informed consent, specifically in antibiotic trials.
“Obtaining informed consent from potential research participants is paramount to conducting ethical research involving humans,” Doshi says. “The foundational ethical texts, like the Declaration of Helsinki and Belmont Report, are clear that the purpose of a trial must be clearly explained to participants. Our study aimed to examine how often the trial’s purpose was explained to potential participants in clinical trials for antibiotics.”
‘Superiority’ vs. ‘non-inferiority’
Clinical trials that compare an experimental therapy against an existing therapy can evaluate the “superiority” or “non-inferiority” of the potential new treatment. While superiority trials are designed to determine whether the new treatment is more effective than an older treatment, non-inferiority trials accept that a new treatment can be less effective than an older treatment if it offers an added benefit to the patient, such as fewer side effects. For the study, Doshi and his colleagues examined six superiority trials and 72 non-inferiority trials (78 trials total) from the European Medicines Agency conducted between 1991 and 2011.
“Because of the very different trade-offs between efficacy and harm, informed consent should differ between superiority and non-inferiority trials,” Doshi says. “However, to our knowledge, there has never been a systematic evaluation of the information provided to potential research participants to determine whether the information provided is sufficient to distinguish the differing study purposes of superiority and non-inferiority trials.
“If patients assume that the hypothesis of the study in which they are enrolled is a superiority trial that is actually a non-inferiority trial, or vice versa, they may incorrectly assess the balance of benefits and harms to which they may be exposed based on the study’s intended purpose.”
The issue of informed consent
Three patient investigators and two methodologists on Doshi’s research team reviewed the informed consent forms (ICFs) from 50 trials to assess whether those forms clearly communicated the intended purpose of the study to patients. The patient investigators were asked to determine if the purpose of the study was to evaluate whether a new drug was more effective than an older drug or just not substantially worse than the older drug, while the methodologists were asked to determine if the forms clearly indicated whether the trial was a superiority or non-inferiority trial.
The methodologists found that only one of the 50 trials clearly conveyed the study’s purpose, while the patient investigators identified 11 trials that conveyed the study’s purpose. From the 11 trials identified by the patient investigators, seven were found to accurately explain the purpose of the study, with four inaccurately stating the purpose when compared with the reference standard.
None of the ICFs consistently conveyed the study’s intended purpose to both the methodologists and patient investigators.
“Although all of the ICFs examined in our research included a section that described the study’s purpose, neither our patient investigators nor our experienced methodologists could determine what that purpose was for the majority of the trials,” Doshi says. “These results make it clear that investigators need further guidance on how to ensure that ICFs clearly communicate the intended purpose of a study to patients – and our paper offers some example language.”
A look at the big picture
Doshi and his colleagues also examined whether the researchers who conducted the non-inferiority trials provided justification for what benefit was hypothesized as possibly more favorable to patients than increased effectiveness. The team reviewed the protocols or statistical analysis plans (SAPs) for all of the non-inferiority trials included in their study, identifying only one trial that provided a rationale for its selection of non-inferiority criteria.
The team also assessed that the explanation study documents provided for the degree of decreased efficacy deemed “clinically acceptable” based on the study’s hypothesis; however, they found that none offered a clinical rationale for the chosen amount of decreased effectiveness, and in no case was there any mention that patient input was sought.
“Based on our results, it appears that patients enrolling in clinical trials for antibiotics are not accurately informed of their study’s intended purpose,” Doshi concludes. “In fact, because non-inferiority trials do not aim to demonstrate the superior effectiveness of new treatments and entail trade-offs of hypothesized lesser efficacy for other benefits, our study raises fundamental questions of the ethics of consent in antibiotic trials and the ethical rationale for non-inferiority hypotheses in life-threatening infections for which effective current standard-of-care therapy exists.”