David Sackett defined compliance bias in his 1979 paper on Biases in Analytic Research “In experiments requiring patient adherence to therapy, issues of efficacy become confounded with those of compliance, e.g. it is the high-risk coronary patients who quit exercise programs.”
Participants, therefore, who are compliant with an intervention may differ from those who are non-compliant, and in ways that might affect the risk of the outcome being measured. This means that compliance is a confounding factor in assessing the effect of the intervention. Compliance can also be termed adherence.
Medication compliance may be a surrogate for factors that improve health outcomes such as fractures. Little is known about the size of this potential “healthy adherer” effect. One study evaluated the hypothesis that compliance with placebo (defined as they took 80% or more of dispensed study medication) is associated inversely with bone loss and fractures among women participating in the Fracture Intervention Trial (FIT) using daily medication diaries.
Among 3,169 women randomised to placebo, 82% had high compliance. Bone loss at the total hip was lower in the compliant placebo-treated women (p = 0.04), and in women, with high placebo compliance compared to those with low compliance a nonsignificant reduced risk for hip fracture was observed (adjusted hazard ratio = 0.67, 95% confidence interval 0.30-1.45).
Research has shown that adherence to prescribed treatment reduces adverse outcomes (van Boven et al. 2014; Higgins et al. 2009).
It is therefore important to know about and account for compliance when investigating the effect of interventions. In 1980, the Coronary Drug Project Research Group explored the influence of adherence on mortality in the long-term treatment of coronary heart disease. Good adherers to clofibrate (defined as patients who took 80% or more of the protocol prescription during the five-year follow-up period) had substantially lower five-year mortality than poor adherers (15.0 vs 24.6%). However, the authors found results in the placebo group, (15.1 per cent mortality for good adherers vs 28.3% for poor adherers.
Clinical trials should attempt to collect data on compliance and while analyses should include the intention to treat analysis, where possible, exploratory secondary analyses investigating the impact of non-compliance would help inform the levels of compliance that affect the outcome of interest.