Research and References

Adherence to Medications: Insights Arising from Studies on the Unreliable Link Between Prescribed and Actual Drug Dosing Histories

This paper is probably the most important paper written to date that clearly shows the benefits of electronically measuring adherence in drug development. It also articulates the downside of missing key insights when only relying on data collected from pill counts and electronic diary methods. The discussion on discerning whether a patient is truly a non-responder or simply non-adherent is worth the read.

Advancing the Science and Practice of Medication Adherence

Provides and overview on how new technologies to measure adherence can be used by clinicians to advance patient intervention techniques to improve adherence

Methods for Measuring, Enhancing, and Accounting for Medication Adherence in Clinical Trials

Discusses the consequences of not fully realizing when variable underdosing occurs in clinical trials due to the use of unreliable adherence measurement techniques. Makes the case that the adoption of electronic adherence measurement techniques will lead to more efficient trials, fewer failures, stronger claims for efficacy, increased statistical power and fewer trial participants. Importantly, a richer and more reliable measure of adherence can provide more accurate data on dose-dependent efficacy and safety.

Patient Adherence: Clinical Pharmacology’s Embarrassing Relative

Pharmacologist author takes the position that many clinicians believe adherence is only a significant issue with approved drugs and not a factor in clinical trials, then uses three quantitative examples to support the view that patient adherence in clinical trials can be abysmal.

Important quote: “Ironically, there exists a covariate which may be quantifiably measured and interpreted, is capable of decreasing the residual variability in population pharmacokinetic studies by upwards of 50%, is positively correlated with efficacy, but is almost never measured in clinical trials. That covariate, of course, is patient adherence. By simply quantifying when and if a given patient takes his medicine [editor note: date and time of the medication event], we remove an enormous amount of noise from both the pharmacokinetic and pharmacodynamic signals of the drug under investigation.” Also: “We collect body weight, race, age, genomics, and renal function data routinely in all trials, but seldom, if ever, collect [unbiased] data on whether our patients actually take the medicine we work so hard to develop.”

Identification and Assessment of Adherence-Enhancing Interventions in Studies Assessing Medication Adherence Through Electronically Compiled Drug Dosing Histories: A Systematic Literature Review and Meta-Analysis

This study was a meta-analysis of 79 randomized clinical trials that all used electronically measured patient drug dosing histories to assess improvements in adherence from 8 different intervention tactics. The study was somewhat limited by the heterogeneity of the pooled data and the different definitions of medication adherence the researchers used. Results showed the tactic of providing feedback to the patient on their own passively measured drug dosing histories had the most significant impact.

How the EMERGE guideline on medication adherence can improve the quality of clinical trials

The authors describe patient adherence in clinical trials as “sub-optimal”– leading to an overestimation of patient exposure to study drug. To compensate for this trial protocol designers overpower the study with unduly large sample sizes (time, cost) and test the highest effective dose (risk of additional side effects), but still do not reliably measure adherence – tactics that made sense last century when scaleable, low cost electronic adherence measurement techniques did not exist.

The authors recommend using the International Society for Patient Adherence’s new EMERGE Guidelines (linked below) to consistently measure, analyze and report patient adherence from clinical trials. The paper recommends several intervention techniques to bolster adherence during the trials. Importantly, it recommends various adherence analysis strategies to gain additional insight on study results. Lastly, the authors call on global pharmaceutical regulators to officially endorse the EMERGE Guidelines to ensure that adherence to investigational products and trial protocols are adequately reported.

ESPACOMP Medication Adherence Reporting Guideline (EMERGE)

These are the International Society of Patient Adherence’s Guidelines for defining, measuring, analyzing, and reporting results from research on medication adherence. Up until the publication of this important research, there was little standardization on the terms used to define research results, discussions and conclusions making it nearly impossible to compare research results. The Guidelines highlight the need to acknowledge and specify the three different phases of medication adherence (Initiation, Implementation and Persistence) as distinct parts of the medication taking process and that each part “requires specific considerations regarding conceptualization, definition, measurement and analysis.”

FDA’s Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products

Recommendations for the use of electronic adherence measurement to support patient adherence to trial protocol and maximize patient exposure to study drug during a trial can be found on Page 4.

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