A Systematic Evaluation of Effect of Adherence Patterns on the Sample Size and Power of a Clinical Study

Abstract

The objective of our study was to evaluate the effect of adherence patterns on the sample size and power of a clinical trial. Simulations from a population pharmacokinetic/pharmacodynamic (PK/PD) model linked to an adherence model were used. Four types of drug characteristics, such as long (~35 hours) and short (~12 hours) half‐life in combination with earlier or delayed time to reach steady‐state PD end points were studied. Adherence patterns were simulated using Markov chains. Our results clearly demonstrate the significant impact of varying levels and patterns of nonadherence on the sample size and power of a study. For drugs with short half‐lives the evidence to support efficacy could be diluted by various patterns of nonadherence that would make its efficacy indistinguishable from the response to placebo. Prospectively utilizing clinical trial simulations with thorough incorporation of various adherence patterns would provide valuable information when designing a trial.

Digitally Enabled, Patient‐Centric Clinical Trials: Shifting the Drug Development Paradigm

“…In the event of an IND failing to demonstrate efficacy in a clinical trial, this technology can help mitigate questions as to whether this was due to lack of efficacy at the selected dose(s) or a result of medication nonadherence within the trial population. Finally, adherence has a substantial impact on study power; 33,34 therefore, a truer signal of adherence may lead to reduction in clinical study size. 35 At Merck & Co., Inc. (Kenilworth, NJ), we have performed clinical pilot testing with several smart dosing technologies of interest 36,37 and are proceeding with use of some of these technologies in IND trials, including trials in neuroscience, infectious disease, and cardiovascular disease therapeutic areas.…”

“…In the event of an IND failing to demonstrate efficacy in a clinical trial, this technology can help mitigate questions as to whether this was due to lack of efficacy at the selected dose(s) or a result of medication nonadherence within the trial population. Finally, adherence has a substantial impact on study power; 33,34 therefore, a truer signal of adherence may lead to reduction in clinical study size 35 …”

Medication adherence reporting in pivotal clinical trials: overview of oral oncological drugs

“…In clinical trials, intensive resources are dedicated to maximising medication adherence where adherence levels need to be high 22. However, certain factors may lead to non-optimal rates causing an increase in the variance of the sample, a weakening of the power of the study and a reduction in the potency of the effects of the treatment,23 24 resulting in negative regulatory and public health consequences 25…”

Recruitment characteristics and non-adherence associated factors of fibromyalgia patients in a randomized clinical trial: A retrospective survival analysis

“…Moreover, the adherence rates in RCTs and their associated factors are an understudied topic. It has been reported that low adherence negatively affects the trials' generalizability and validity, complicates the statistical analysis, and confounds the researcher's ability to confer scientific conclusions [ 19 ] by affecting the statistical power and increasing the Type –II error [ 20 , 21 ] Click or tap here to enter text. Despite the considerable rate of non-adherence in RCTs [ 22 ], few studies report it or discuss it [ 23 ] .…”