VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center, 2401 Centre Ave. SE, Albuquerque, NM 87106, USA.
Clin Trials. 2013;10(3):441-8. doi: 10.1177/1740774511410331. Epub 2011 Aug 3.
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.
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.
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.
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).
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.
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.
评估研究药物的依从性是临床研究中的常见挑战。在门诊临床试验中，评估依从性的主要方法是计算未使用的研究药物，但这种方法存在一些局限性，包括有效性值得怀疑，并且给研究人员带来负担。
比较胶囊计数、患者问卷调查回答和血浆药物水平作为评估 2056 名参与者的临床试验中依从性的方法，该试验采用集中药物分发和患者随访。
参与者归还的研究药物瓶中的胶囊计数和每季度电话访谈中关于依从性的问题回答被平均，并进行比较。这两种方法均与治疗组患者在 3 个月研究访问时获得的血浆药物水平进行比较。计数和问卷回答被转换为依从率（服用的剂量除以经过的天数），并根据严格（≥85.7%）和宽松（≥71.4%）的定义进行分类。我们计算了调整后流行率偏倚的校正 kapp 值，以评估两种方法之间的一致性。
通过预付费邮件，参与者将 76.0%的研究药物瓶返回给中央药房。胶囊计数和问卷调查回答均可供 65.8%的参与者使用，用于评估依从性。胶囊计数比自我报告识别出更多的依从性差的患者（严格定义为 18.8%，宽松定义为 7.5%）。调整后流行率偏倚的校正 kapp 值为 0.58（严格）和 0.83（宽松），分别表示适度和非常好的一致性。两种方法均与 3 个月时的血浆药物水平一致（胶囊计数：严格定义的 p 值为 0.005，宽松定义的 p 值为 0.003；问卷：严格和宽松定义的 p 值均为 0.002）。
由于瓶的归还不一致以及药物开始和停止日期的不完全记录，导致数据缺失，但探索性缺失数据分析表明，没有理由认为缺失数据导致了系统偏差。
根据依从性的定义，在返回的研究瓶中，问卷结果和胶囊计数之间存在适度到非常好的一致性，这一点通过血浆药物水平得到了证实。我们的结论是，如果接受相对较低的依从性阈值，则自我报告的药物依从性可能与胶囊计数一样，是评估临床试验中依从性的一种方法，但如果需要较高的依从性阈值，则应通过其他方法确认依从性。
