A study published in JAMA Internal Medicine this week finds that patients participating in noninferiority trials for antibiotics are not always accurately informed of the purpose of the study, based on an analysis of informed consent forms.
Unlike superiority trials, which test whether a new drug has greater efficacy than an existing therapy, noninferiority studies test that the new treatment does not fall outside a predetermined range of "clinically acceptable" inferior efficacy.
"If potential research participants assume that they are enrolled in superiority trials that are actually noninferiority trials 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 authors write.
To figure out how well a study's purpose was explained to participants, the authors looked at documents from 78 clinical trials from 1991 to 2011 obtained through an access to documents request made to the European Medicines Agency (EMA).
Of those, EMA provided informed consent forms for 52 trials, though two were excluded from the analysis as they were used by the authors to develop rating methods for the study.
The informed consent forms were then reviewed by a team of raters—two methodologists with clinical trial design experience and three patient investigators with no clinical experience—and assessed to determine whether the studies were meant to test for superiority or noninferiority based on language in the informed consent forms.
After reaching a consensus, the two methodologists said they could not tell the study purpose based on information in the informed consent forms in 49 of the 50 studies.
And, the one study the methodologists were able to determine the purpose of was inaccurately identified as a superiority study, though language in the informed consent form may have led them in the wrong direction ("the purpose of this study is to find out if taking PAR-101 is better than taking vancomycin").
Similarly, the patient investigators said they could not whether the purpose of a study was to test for superiority or noninferiority in 38 of the 50 studies. The patient investigators were able to accurately determine the purpose for 7 of the 50 studies, but inaccurately judged four noninferiority studies as superiority studies.
"These results raise questions about the ethics of antibiotic development. Clarity on study purpose is central to the ethical principles of respect for persons, as well as minimizing risk," the authors write.
As such, the authors propose that noninferiority studies include language in their informed consent forms that specifically inform patients that the study is being done to test that the new drug "is no more than X% less effective than the standard treatment."
But, in a commentary on the study, Jerry Menikoff, director of the Office for Human Research Protections at the Department of Health and Human Services, says that the main issue is not whether trial participants fully understand the purpose of a study, but that they are given an appropriate explanation of the study's risks.
Citing a paper by the Antimicrobial Availability Task Force of the Infectious Disease Society of America, Menikoff also points out that superiority testing is difficult for new antibiotics, as patients that are most likely to benefit—those with drug resistant infections—are typically excluded from clinical trials.
Because of this, noninferiority studies have become the standard for testing new antibiotics, as such studies can demonstrate that the new agent at least does not work less than the comparator, while giving new treatments a more feasible path to market.
"Regardless of whether one fully agrees with the existing rules allowing the conduct of such trials (such as whether using a noninferiority analysis is the right way to correct for study bias), it does not seem reasonable to ask a participant to try to understand the complicated debate in the research community about whether these trials should even be allowed," Menikoff writes.