Statement of the problem and pharmacological and clinical requirements for the ideal marker

Patients' nonadherence or low adherence to prescribed medication regimes threatens the satisfactory conduct of controlled clinical trials for the efficacy of drug treatment. Suboptimal adherence is costly since an increased sample size must be used to achieve and maintain study power. Accurate measurements of patients' adherence to test medications are not generally available. Current, popular, indirect methods provide uncertain estimates of adherence. As a result, behavioral strategies for management of adherence during trials have been handicapped, and analyses of trial results utilizing adherence levels are poorly developed. These problems could be solved by the ingestion, concomitant with the test medication, of a metabolically and pharmacologically inert compound (adherence marker) whose measurement in body fluids or secretions would indicate the extent of ingestion of the prescribed dose of the test medication. An adherence marker with proven wide applicability has not yet been developed or identified. The detailed requirements for an adherence marker include that it be pharmacologically and chemically inert, nontoxic, unaffected by the physical and chemical properties of body tissues and fluids, not accumulated in the body, and undetectable by the patient. The pharmacodynamics and tissue distribution of the marker should be appropriate for the medication being evaluated. The interindividual and intraindividual variances of marker metabolism should be small enough to permit precise and accurate estimates of adherence. For each trial, the choice of using an adherence marker in lieu of direct analysis of the test medication must be evaluated considering the circumstances of the trial and the pharmacokinetics of the test medication.