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Understanding the Practice-Protocol Paradox in Medication Adherence
As humans, the unconscious act of making assumptions is inherent in our DNA. These mental shortcuts are deeply wired into our brains as a way of quickly making sense of the world around us.
And yet, throughout history, great thinkers have warned us about the risks that come from relying on assumed information and jumping to automatic judgments. It’s a sentiment neatly summarized by a quote attributed to Irish playwright George Bernard Shaw: “Beware of false knowledge; it is more dangerous than ignorance.”
Perhaps it is surprising, then, that it has taken such a long time for the notion of medication adherence (or non-adherence) to attract the attention it deserves. For many years, it was assumed that a physician’s instructions to follow a course of treatment were sufficient to guarantee compliance on behalf of the patient.
These assumptions around a patient’s behavior were underpinned by a complex range of factors, such as the trust in the healthcare professional’s expertise and their motivation to act on guidance designed to improve their health.
The Hidden Problem of Medication Non-Adherence in Clinical Trials
As time goes on, we are learning more and more about how wrong those assumptions can be. Studies continue to show significant variation between levels of adherence required for drug regimens to achieve therapeutic efficacy and observed levels of adherence among patients in the real world.
In the case of chronic medication, where persistent adherence is a prerequisite, the 50% compliance rate established by the World Health Organization (WHO) decades ago remains an accepted marker of a problem that potentially has a more direct impact on patient outcomes than the treatment itself.[1]
But while assumptions around good adherence in medical practice continue to be challenged, the same is not necessarily true for clinical trial environments. Here, the fundamental problem of non-adherence persists, fueled by the misconception that this issue is managed within the closely controlled environment of a trial.
There are understandable reasons why this view persists. A clinical trial presents a different context for patients compared with their everyday lives. And with the underlying risk of adverse events far higher for pre-approval drugs compared with those that have already received marketing authorization, it is understandable that there are high expectations around adherence monitoring to support participant safety while also gauging therapy efficacy.
But contrary to the idea that clinical trials set the scene for pro-compliant behavior, there are many ways that trials actually serve to hinder medication adherence.
Factors That Undermine Patient Adherence in Trials
A major factor within this dynamic is the placebo effect. Placebos are fundamental in assessing the efficacy of a drug against a zero baseline, and, by definition, candidates and coordinators in a randomized double-blind trial will not be aware of whether they are taking the active drug or a placebo alternative.
But because they must review and consent to the protocol pre-trial, candidates will be aware of the possibility that they are in the placebo group. For some, that knowledge could be enough to make them think that their actions might be pointless, negatively impacting their motivation to adhere to the trial protocol.
A little knowledge of the randomization process can also be bad for adherence if candidates—who are cognizant of the fact they are taking an unauthorized drug at an unproven dose—suspect they are either being under or overmedicated.
On occasion, this kind of information has been known to have been shared among participants on social media, fueling speculation and suspicion. This situation has the potential to set the conditions for non-compliance, as questions arise in individuals’ minds about the efficacy (or inefficacy) of the medication under trial, eroding their commitment to the process and their resolve to stay adherent.
More simply, candidates might just fail to follow through on their promise to act as instructed, contrary to their own best intentions. This phenomenon—known as the Intention-Behavior Gap—can be driven by any number of factors, from competing priorities and distractions to poor organization and planning.
Compliant behavior can also slip over time if participants begin to tire of the effort involved. This is particularly the case for more demanding protocols that include elements such as regular clinic visits, blood tests, and the completion of lengthy questionnaires.
Things can be further complicated by complex dosing regimens designed to satisfy blinding requirements or combination drug products, where candidates might be burdened with self-injecting using a pre-filled syringe.
Negative thoughts and behaviors can even be triggered by the unfamiliar, bulky medication packaging prevalent in trials. For some, this acts as a reminder that the drug—or placebo—they are taking is as yet unproven, introducing doubts over the trial’s likely success and possibly even despondency among those who initially had high hopes for an effective treatment or cure.
The Impact of Non-Adherence on Clinical Trial Integrity
In many cases, these barriers to adherence in clinical trials are not necessarily logical or rational. They are, however, reflective of the biases and inconsistencies that characterize human behavior, as seen in the poor levels of adherence accepted within real-world medical practice.
As such, it must also be acknowledged and accepted that such non-adherent behaviors present very real risks in the context of a clinical trial, where adherence is a critical factor in understanding the relationship between drug exposure and efficacy.
Failing to address the issue has the potential to compromise the effectiveness and integrity of the trial itself. This underlines the vital importance of employing robust, advanced methods of adherence monitoring in trials, which currently over-rely on flawed legacy methods, such as pill count and patient self-report.
Moving Beyond Legacy Adherence Monitoring Methods
Overall, it is encouraging that the problem of adherence in medical practice continues to be better understood and addressed. However, more must be done to translate this thinking into clinical trials, where patient behaviors play a critical role in progressing promising new treatments.
It might seem counterintuitive or paradoxical, but the belief that trials are a haven for good compliance is a dangerous assumption.
Harnessing Advanced Medication Adherence Technology for Reliable Clinical Trial Data
Establishing hard evidence for your trial starts with accurate, objective adherence data.
AARDEX applies a best-practice methodology, independent of any device package or software platform. Utilizing our expertise and experience in medication adherence and patient compliance, we acquire, monitor, analyze, guide, and interpret data to deliver absolute clarity and bring confidence to sponsors, trialists, and ultimately, patients.
As the only mature, robust, and proven adherence solution on the market, AARDEX delivers the insight and reliability needed to maximize rewards, mitigate risks, and strengthen the integrity of your clinical trial. All delivered with the clarity, integrity, and certainty you need to proceed with complete confidence in the exposure-response.
Bibliography
[1] https://www.uspharmacist.com/article/medication-adherence-the-elephant-in-the-room
