Fig 1.

Effect of non-adherence on biocreep. Panels show four scenarios if consecutive non-inferiority trials (comparing standard-of-care versus treatment A; treatment A versus treatment B; treatment B versus treatment C; treatment C versus treatment D) were to be carried out at 100%, 90%, 80% and 70% adherence. X axis represents consecutive non-inferiority trials; y axis represents decrease in true efficacies of treatments A, B, C, and D compared with the initial standard-of-care treatment. Treatments A, B, C, and D are 10%, 20%, 30%, and 40% less effective than the standard of care, respectively. Dot sizes are probabilities (represented by percentages next to dots) for the new and inferior experimental treatment to be accepted as non-inferior at the end of each trial. For example, if 100% adherence is maintained in the trials (first panel), the probability of treatment A being accepted as the new standard of care is 2%. By contrast, when the consecutive trials are conducted with 70% adherence (last panel), treatment D has a 7% chance that it will be accepted as the new standard of care, when its true efficacy is 40% less than the current standard of care. This pattern of non-adherence is crossover (that is, in the 70% adherence scenario, 30% of participants from each arm cross over to the opposite arm)¹²