Dr. Job van Boven, Associate Professor at the University Medical Center Groningen, shares his invaluable insights on the evolution of medication adherence monitoring solutions.
According to Dr. Job van Boven, Associate Professor at the University Medical Center Groningen, Founding Director of the Medication Adherence Expertise Center of the northern Netherlands (MAECON), and Chair of the European Network to Advance Best Practices and Technology on Medication Adherence (ENABLE) COST Action, in the realm of routine practice and clinical trials, the persistent issue of poor medication adherence has proved to be quite a stubborn challenge. However, the tides are turning as cutting-edge digital medication adherence monitoring solutions emerge, promising to revolutionize how we approach this longstanding problem.
Dr. van Boven has spent his career studying the causes, effects, and solutions to poor medicine-taking behavior. Here, he shares his invaluable insights on the evolution of medication adherence solutions.
What First Triggered your Interest in Medication Adherence?
Job van Boven: “My interest in medication adherence started back when I was training to become a pharmacist. During my first internship at a community pharmacy, I was surprised by the number of prescriptions that were prepared but not dispensed. At the time, I asked the pharmacist why these medicines, some of which could be life-saving drugs, were not being picked up, but they had no idea.
I was intrigued enough to start researching the reasons behind non-adherence and how it could be improved, and I did my Ph.D. on adherence to medicines used in patients with chronic obstructive pulmonary disease (COPD). The more I looked into the topic, the more I realized that there were far more questions than there were answers, so I am still working in adherence research all these years later.”
Can you Summarize your Key Findings from the Adherence-Focussed Evidence Base?
Job van Boven: “There are many papers on the causes, effects, and solutions of poor medication adherence during drug development but also in daily practice. Regarding the trials, Poor medication adherence in clinical trials: Consequences and solutions, by Breckenridge et al., published in 2017, for example, concludes that poor adherence in clinical trials reduces their value by altering estimates of benefits and harms, wasting time and money and negatively affecting patient experience.1 A 2019 study by Mokoka et al., Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy: Results from a systematic literature review and modeling study, found that few trials of add-on therapy monitored adherence and that this resulted in greater variance in trial outcomes and inadequate power for determining efficacy.2 Such findings are reflected across therapeutic areas.
Triggered by some of these papers in specific areas, I have worked with colleagues to structurally look at adherence in clinical trials. We recently published an extensive review of more than 100 medicines approved by the European Medicines Agency (EMA) between 2010 and 2020. To our knowledge, the study was the first systematic analysis of how adherence is measured and defined in pivotal clinical trials, and we found considerable variations in approaches. Almost all stated that they measured medicine-taking behavior, but the vast majority used subjective, non-granular methods like pill count or self-report, despite them being sub-optimal.3
It has been widely confirmed that medication adherence is also sub-optimal across chronic diseases in the real world. Our work to date has shown that adherence can be improved, but only with a personalized approach – there is no one size fits all solution. We have also demonstrated that improving adherence is generally cost-effective, as the costs of measurement and interventions are often offset by things like reductions in hospital admissions or avoiding the need to escalate to more expensive drugs.”
How do Digital Medication Adherence Monitoring Solutions Compare to Traditional Approaches, Such as Pill Count and Self-Report?
Job van Boven: “Our review found that most trials measured adherence using pill count or self-report. In the paper, we explained these methods were inaccurate and only provided an average proxy measure for intake between trial visits. Bioanalytical assays were also used, but these cannot determine if a patient has taken the medicine just before the trial visit, a phenomenon known as ‘white coat adherence,’ or continuously throughout the study.3
Around 3% of studies we reviewed used medication adherence packaging, such as smart pill bottles, which generate a date stamp every time they are opened and closed.3 These can create accurate, granular dosing histories that show the variability of intake over time and have many advantages.
Such digital approaches operate in near real-time, meaning they enable the delivery of direct, personalized support. This is important because we know there is no one size fits all solution to poor adherence. Healthcare professionals can monitor the data for signs of poor adherence among trial participants and take targeted action when necessary.
They are also non-invasive, unlike bioanalytical methods, which require dense sampling schedules and can be burdensome for patients and laboratories alike.”
Do you Think Regulators Should do More to Guide Sponsors on Medication Adherence Monitoring?
Job van Boven: “Currently, neither the FDA nor the EMA mandate objective (digital) adherence monitoring in clinical trials. The recently updated International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH-E9 document recommends sponsors measure adherence, but it does NOT say how. Nor does it clearly define important factors such as the adherence phases of initiation, implementation discontinuation, or how to handle these constructs.4
The digital age is new to everyone, and regulators need some time to adjust. I think we need to build awareness of the solutions that are available and share best-practice case studies that show their value for regulatory assessment.”
Regulators Rely on ITT Analyses to Approve New Drugs. Do you See the Value of Adherence Adjusted- Analysis to Complement ITT?
Job van Boven: “We must remember that a clinical trial population is different from the end-user population. An adherence-adjusted ITT analysis will more closely mimic drug effect for individual patients with different extents of adherence in the real world than an overall population ITT analysis alone. An adherence-adjusted ITT analysis enables researchers and regulators to understand the difference between assumed clinical trial and routine practice adherence and, therefore, the drug effect in a real-world setting.
It will also help teams to better understand individual variability in drug response. As part of the shift to personalized medicine, we are always talking about things like biomarkers and genetics. Still, we ignore the elephant in the room – that people do not always take the medicine as prescribed. I think if we want to talk about personalized medicine, we should adequately measure and monitor and support medication adherence and use that data to complement ITT analyses.”
What are your Top Tips for Sponsors Embarking on an Adherence Journey?
Job van Boven: “Firstly, I would recommend they find a non-invasive, granular, objective and preferably digital solution that fits their drug’s administration route and has a solid evidence base. Next, they should engage with patients, the trial sites, and regulators to ensure everyone understands how to interpret, analyze, and work with this kind of adherence data.
It is also worth noting that adequately measuring adherence during a clinical trial can reduce the sample size. Calculating the potential per-study cost savings can help support the business case for adherence monitoring investment.”
References
- Breckenridge, A., Aronson, J. K., Blaschke, T. F., Hartman, D., Peck, C. C., & Vrijens, B. (2017). Poor medication adherence in clinical trials: consequences and solutions. Nature reviews Drug discovery, 16(3), 149-150.
- Mokoka, M. C., McDonnell, M. J., MacHale, E., Cushen, B., Boland, F., Cormican, S., … & Greene, G. (2019). Inadequate assessment of adherence to maintenance medication leads to loss of power and increased costs in trials of severe asthma therapy: results from a systematic literature review and modeling study. European Respiratory Journal, 53(5).
- Mantila, K. M., Pasmooij, A. M., Hallgreen, C. E., Mol, P. G., & van Boven, J. F. (2022). Medication Adherence Measurement Methods in Registration Trials Supporting the Approval of New Medicines: A Cross‐Sectional Analysis of Centralized Procedures in the European Union 2010–2020. Clinical Pharmacology & Therapeutics, 112(5), 1051-1060.
- (2017). ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical 6 principles for clinical trials. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-trials-guideline-statistical_en.pdfLast accessed: 15 February 2023.
