Both indirect and direct methods have been widely employed for measuring medication compliance. Indirect methods include therapeutic or preventive outcome, assessment by the physician, interview with the patient, whether or not the prescription was filled, and a count of remaining pills. In many situation,, direct methods may be feasible, including measurement of blood or serum levels or testing urine for excretion of the medication itself, a metabolic by-product, or a marker or tracer that has been added to the medication for detection purposes. For example, detection of penicillin or of salicylates can be used in measuring compliance, while in other circumstances, it may be necessary to add a detectable label to the medication. Ideally, such a marker should be nontoxic and pharmacologically and chemically inert [Porter AM: Br Med J 1:218-222, 1969]. The marker should be unaffected by physical and chemical properties of the urine, such as pH and temperature, quickly and freely excreted, and noncumulative. A simple, sensitive, and specific detection method should be available, and the marker should be such that the patient is unaware that it has been added. In direct measures of compliance, it is necessary to consider pharmacokinetic variations among individuals in absorption, distribution, metabolism, and excretion of drugs. In addition, temporal aspects of the sampling scheme assume great importance. Finally, the definition of compliance and noncompliance for a given study in relation to the specific question being tested in the investigation, as well as in regard to use of the marker itself, is an important issue for consideration. Since indirect methods are often insufficient for measuring compliance, direct measures of compliance are usually preferable in clinical trials.
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