It is human nature for people to trust the things that are known to them ahead of the things that are not. Familiarity, after all, brings with it a sense of comfort and reassurance.
It is perhaps understandable, therefore, that traditional approaches are typically favoured when it comes to assessing medication adherence in drug trials. In these situations, more familiar methods can benefit from conforming with expectations and precipitating expected outcomes.
But given the critical role that medication adherence assessments play within the overall process of a trial, there is a risk that adhering to familiar approaches – such as pill count or patient self-report – also brings familiar risks and limitations. Indeed, there is no guarantee that such ‘known’ methods of assessment will reveal the genuinely unknown, raw insights that are necessary for informed decision-making in drug development.
In reality, it is only by gaining a truthful, objective understanding of drug exposure and medication adherence among trial participants that the effectiveness and safety of investigational medications can be fully evaluated. Without such a comprehensive understanding of adherence to the prescribed treatment regimen, the integrity and dependability of trial results can be compromised.
It is this fundamental, contradictory premise that underlines the need for clinical trials to adopt measures that can accurately and reliably assess behaviours related to the taking of medication. Using electronic monitoring, for example, ensures sponsors can truly differentiate between any minor errors or significant deviations in dosing that may impact judgements regarding a drug’s efficacy and safety. Such methods arm researchers with robust data and hard evidence of drug exposure, empowering them to make more informed decisions, identify potential confounding factors, and appropriately interpret study outcomes. This, ultimately, ensures the trial’s validity and enhances the value of the findings.
Distilled down to a simple model, trials are essentially an investigation to analyse the output caused by a particular input. Here, the input is the drug under investigation and the outputs are the resulting estimates of efficacy and safety. In order to uphold the integrity of these outcomes, trial participants are carefully chosen to represent specific characteristics of the target population and close attention is also paid to assessment of the findings. Comparatively little attention is devoted, however, to guaranteeing the quality and precision of the input data, a situation that presents clear potential for output integrity to be compromised – summarised succinctly by the adage “garbage in, garbage out”.
At the core of this compromise is the assumption that participants religiously follow the dosing regimen set out in the study protocol. However, it is crucial to acknowledge that in ambulatory care settings, adherence often deviates from expectations. In 2012, Blaschke et al. conducted an analysis of a database containing electronically compiled dosing history data from 95 clinical studies, revealing that half of the 16,907 study participants exhibited substantial deviations from the dosing regimen outlined in the study protocol.[1]
A common example is for only a small fraction of study participants to adhere strictly to a 24-hour dosing schedule for trials involving once-daily medications. Most will display variability in the timing of their medication intake, typically within a few hours’ interval. Besides variability in dose timing, it is not uncommon for participants also to unwittingly miss doses on occasion or to take extra doses. This is highlighted in a study analyzing drug trials for once-daily prescribed anti-hypertensive medications, which emphasized that approximately half of patients experienced a monthly rate of missing a single day’s dose. [2]
Perhaps surprisingly, this suboptimal adherence behaviour is often considered acceptable in drug trials and sometimes even desired. In theory, by accepting the diverse factors that can influence adherence, such as individual routines, lifestyle demands and occasional forgetfulness or mistakes, the results are deemed to be more representative of actual clinical practice and real-world patient activity.
But concern regarding adherence in trials is not just limited to minor variations in timing and dose levels. Research has shown that more severe issues, such as interruptions in dosing or even complete discontinuation of medication, are also frequently observed within trials.1 Drug holidays, characterized by two or more consecutive days without medication dosing, are a particular cause for concern. And, conversely, overdosing can also be a more serious problem in trials. When characterized by the consistent intake of additional doses or intervals between doses being too brief, the likelihood of participants encountering side effects can increase.
The prevalence of these more extreme behaviors and more significant errors underlines the complex nature of medication adherence within drug trials and the potentially harmful consequences that can arise, both in regard to the participants’ health and also in terms of the compromise to outcome integrity. This not only emphasizes the importance of understanding the full spectrum of adherence behavior and its potential impact on treatment outcomes, but also highlights the value of employing precise and reliable methods to measure medication adherence.
Today, we live in an era of evidence-based medicine and yet the clinical trials that lay the foundation for drug efficacy and safety do not follow an evidence-based approach to adherence. There is a need for this situation to be challenged and for the existence of non-adherent trial participants to be acknowledged, explored and resolved.
Approaches such as electronic monitoring might be less well-known to organisers, but they are known for delivering scientific rigor and insightful analysis of drug exposure within clinical trials, helping to speed up the development process and accelerate the delivery of significant clinical benefits for patients.
[1] Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol. 2012;52:275-301. Doi: 10.1146/annurev-pharmtox-011711-113247. Epub 2011 Sep 19. PMID: 21942628.
[2] Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008 May 17;336(7653):1114-7. doi: 10.1136/bmj.39553.670231.25. Epub 2008 May 14. PMID: 18480115; PMCID: PMC2386633.
