Medication adherence assessment in a clinical trial with centralized follow-up and direct-to-patient drug shipments

Abstract

Background: Assessment of adherence to study medications is a common challenge in clinical research. Counting unused study medication is the predominant method by which adherence is assessed in outpatient clinical trials but it has limitations that include questionable validity and burdens on research personnel.

Purpose: To compare capsule counts, patient questionnaire responses, and plasma drug levels as methods of determining adherence in a clinical trial that had 2056 participants and used centralized drug distribution and patient follow-up.

Methods: Capsule counts from study medication bottles returned by participants and responses to questions regarding adherence during quarterly telephone interviews were averaged and compared. Both measures were compared to plasma drug levels obtained at the 3-month study visit of patients in the treatment group. Counts and questionnaire responses were converted to adherence rates (doses taken divided by days elapsed) and were categorized by stringent (≥85.7%) and liberal (≥71.4%) definitions. We calculated the prevalence-adjusted bias-adjusted kappa to assess agreement between the two measures.

Results: Using a pre-paid mailer, participants returned 76.0% of study medication bottles to the central pharmacy. Both capsule counts and questionnaire responses were available for 65.8% of participants and were used to assess adherence. Capsule counts identified more patients who were under-adherent (18.8% by the stringent definition and 7.5% by the liberal definition) than self-reports did (10.4% by the stringent definition and 2.1% by the liberal definition). The prevalence-adjusted bias-adjusted kappa was 0.58 (stringent) and 0.83 (liberal), indicating fair and very good agreement, respectively. Both measures were also in agreement with plasma drug levels determined at the 3-month visit (capsule counts: p = 0.005 for the stringent and p = 0.003 for the liberal definition; questionnaire: p = 0.002 for both adherence definitions).

Limitations: Inconsistent bottle returns and incomplete notations of medication start and stop dates resulted in missing data but exploratory missing data analyses showed no reason to believe that the missing data resulted in systematic bias.

Conclusions: Depending upon the definition of adherence, there was fair to very good agreement between questionnaire results and capsule counts among returned study bottles, confirmed by plasma drug levels. We conclude that a self-report of medication adherence is potentially comparable to capsule counts as a method of assessing adherence in a clinical trial, if a relatively low adherence threshold is acceptable, but adherence should be confirmed by other measures if a high adherence threshold is required.

Figure 1.

Plasma folate (ng/mL) of participants in the treatment group at 3 months (ordinate) compared to capsule counts in bottles returned at the 3-month visit and to questionnaire responses at the 3-month visit. The results are divided into ‘under-adherent’ (<85.7% of doses taken), and ‘adherent’ (≥85.7% of doses taken) by the stringent definition. The median folate value for the under-adherent (n = 64) and adherent (n = 192) groups according to capsule count were 1888 and 2452, respectively (p = 0.005). The median folate value for the under-adherent (n = 27) and adherent (n = 397) groups according to questionnaires were 1255 and 2424, respectively (p = 0.002). Notes: The central line in the box indicates the 50th percentile (median) value; the + indicates the mean; the box represents the interquartile range (IQR) (25th and 75th percentiles), the ends of the whiskers represent the maximum value within 1.5 times the IQR, and the small boxes represent outlier values greater than 1.5 times the IQR.

Figure 2.

Plasma folate (ng/mL) of participants in the treatment group at 3 months (ordinate) compared to capsule counts in bottles returned at the 3-month visit and to questionnaire responses at the 3-month visit. The results are divided into ‘under-adherent’ (<71.4% of doses taken), and ‘adherent’ (≥71.4% of doses taken), by the liberal definition. The median folate value for the under-adherent (n = 34) and adherent (n = 222) groups according to capsule count were 1063 and 2365, respectively (p = 0.003). The median folate value for the under-adherent (n = 10) and adherent (n = 414) groups according to questionnaires were 133 and 2359, respectively (p = 0.002). Notes: As given in Figure 1