Contending paradigms for the interpretation of data on patient compliance with therapeutic drug regimens

Abstract

Electronic and chemical marker methods provide the first reliable measurements of drug exposure in ambulatory trials. These data contradict the usual claim in published drug trials of > 90% of patients having been satisfactorily compliant with the protocol-specified dosing regimen. Such exaggerated claims are based, usually, on count of returned dosing forms, which afford patients easy ability to manipulate by discarding or hoarding untaken doses. Electronic monitoring provides, for the first time, data on intervals between doses, revealing the 'drug holiday'--3 or more consecutive days without dosing--as a basis not only for lapsed therapeutic action, but as a pharmacodynamic trigger for hazardous rebound effects on recurrent first dose effects. Another new findings is the evident non-specificity of poor or partial compliance, the range and distributions of which appear to be hardly affected by drug, disease, prognosis, or symptoms. This finding contradicts often repeated but unsupported claims that noncompliance is a specific response to drug action, disease, prognosis or other treatment-related factors. New statistical methods are needed for trial design and analysis, to use drug exposure data as covariate information, to incorporate into drug labelling estimates of dose-related efficacy, holiday-related hazard, the limits of safe variation in dose-timing, and what one should best do when those limits are exceeded. Oral contraceptive labelling in the U.K. and U.S. is exemplar for this next step toward full-disclosure labelling.

The Impact of Monitoring on Adherence and Persistence with Antiresorptive Treatment for Postmenopausal Osteoporosis: A Randomized Controlled Trial

“…It is important to demonstrate a biological response to increased adherence (28), because there are potential adverse consequences of interventions that modify behavior, including loss of privacy, loss of autonomy, increased adverse events, and potentially wasted resources (1,26,28). This study suggests that implementing monitoring as a tool to improve long-term adherence may result in an improved outcome for patients with postmenopausal osteoporosis.…”

“…There is, however, no consensus on how to analyze the more complex patterns of adherence observed using electronic monitoring devices (38). Drug holidays represent a pattern of nonadherence that may result in a period of nontherapeutic coverage and therefore reduced drug efficacy (28,39). In this study adherence only accounted for 9% of the observed change in BMD and 13% of the observed change in bone markers.…”

An adherence self-report questionnaire facilitated the differentiation between nonadherence and nonresponse to antihypertensive treatment

“…Not informing patients that adherence is measured can alleviate this problem, but is problematic ethically. A broad consensus supports the view that patients should be informed that their drug intake is being measured [36]. We have no conclusive information if or by how much the monitoring process, or indeed just taking part in the study, may have affected the taking patterns of the study participants.…”

Comparing Measures of Medication Taking in a Pharmacotherapy Trial for Cocaine Dependence

“…Most studies have offered only passing reference to this issue without evaluating medication adherence as a test of trial integrity or as a source of variance in treatment outcomes. 2,3 In order for medication adherence to be usefully applied in clinical trials, the amount of medication consumed must be accurately measured.…”