Digital Medication Adherence in Clinical Trials

Drug developers work tirelessly progressing their compounds from the laboratory to the clinical phases, and rigorously assessing the medication use in Phase II and Phase III clinical trials is crucial to the future success of the treatment. Significant investment of time, resources and capital is employed in these developments – yet they are still, to a great degree, vulnerable to the risks associated with medication non-adherence.

There’s no one single reason for poor adherence during studies. Poor investigator / patient communication can leave participants unsure on how to use the drug, or on the protocol itself. Today’s increasingly complex clinical trials have complex, hardto-follow dosing regimens; some people stop taking the medication if they feel no benefit; and some people just forget. The fear of side-effects and protocol burdens can also play a part.

In order to address this pervasive problem of striking magnitude in clinical trials, solutions are needed that seamlessly measure and analyse patient medication adherence in clinical trials, research settings, and professional healthcare systems to support successful management of patient adherence to medication. To manage medication adherence in clinical trials, some sponsors use biased and imprecise measurement methods such as pill counting, blood sampling and patients’ self-reporting, while others have chosen digital medication adherence monitoring.

Electronic compilation of dosing history data, enabled by smart packages, has been proven to be the most effective way to monitor, identify, manage, and document the risks associated with poor patient adherence to medications in clinical trials. Overlooking medication nonadherence in planned clinical trials can lead to significant issues. However, they can be easily diminished by implementing a mitigation plan based on proven digital medication adherence monitoring systems. Key Risks Associated with Patient Nonadherence to Study Medications Poor medication adherence is a threat to drug development. Half of clinical trial participants do not adhere to the dosing regimen specified in the protocol. Studies have shown that 40% have stopped taking their medication as per the protocol by month 12. Additionally, a further 15% do not implement the study dosing regimen. Such protocol deviations go undetected by traditional measures of adherence, such as pill counts, blood sampling and subjects’ self-report.

It’s hard to overestimate the impact of medication non-adherence across the healthcare ecosystem.

In terms of clinical trials, it can skew drug efficacy calculations and risk-benefit profiles. Sponsors often need to increase sample sizes to compensate for the adherence-related drain on study power, an expensive, time-consuming process that can significantly delay regulatory approvals.

For patients, risks include severe health complications, premature deaths, and lower quality of life. All of this can create increased healthcare services demand in addition to wasted medications. To that end, only 30% of approved drugs on the market are commercially successful.1 The variability in patient outcomes from medication nonadherence is a significant contributor to this low success rate. The Perils of Unreliable Methods to Assess Medication Adherence The financial and practical implications of medication non-adherence are wideranging, but they are not new. Sponsors have grappled with these issues for decades.

Traditionally, they have employed methods such as directly observing the patient taking their medication or measuring drug titre levels in blood or urine. Other traditional methods include pill counts, patient diaries and questionnaires, or measuring prescription refill rates, clinical responses, and physiologic markers.

However, these methods do not compare to the accuracy and precision of digital medication adherence monitoring. In fact, electronic monitoring is the most objective, precise way to understand medication adherence during a clinical trial.

It typically involves an electronic microcircuit being placed within the medication packaging, which automatically generates a timestamp each time the patient takes their medication.2 The timestamps are then stored within the packaging’s ‘memory’ and then wirelessly transferred to a central, cloud-based software system where it’s downloaded and analysed.

Advanced digital medication adherence monitoring provides complete oversight of the adherence metrics and risk indicators that matter the most. According to studies, smart electronic packaging/device monitoring is 97% accurate, ahead of drug levels and markers (70%), pill counts (60%), healthcare professional ratings (50%) and patient self-reporting and electronic patient diaries (27%).3

Such digital solutions not only provide more reliable data, but also more detailed data about actual patient adherence behaviours, such as dose frequency, dose interval and medication dose timing – details that traditional methods do not capture. Electronic monitoring shows that medication non-adherence, especially dosage omission or changing intervals, is more prevalent than previously recognised. Furthermore, this data is captured passively, as it does not require the patient to take any additional action. Solutions that do require an additional action, such as a digital diary on an app, will often be ignored by poorly adherent patients.

These digital monitoring systems enable sponsors to improve drug efficacy by managing patient adherence to the study medications. For typically less than 1% of the overall clinical study cost, pharmaceutical companies can safeguard their clinical trials and build a stronger argument about the efficacy of their medication from the development stage to commercialisation.

Crucial Benefits in Using Digital Medication Adherence Monitoring The electronic compilation of dosing history data is enabled by smart packages, and is a highly effective way to passively monitor, identify, manage and document the risks associated with poor patient adherence to medications in clinical trials.

As well as improving adherence, data quality and integrity, medication adherence technology, including smart packaging, gives investigators all the information they need to intervene and change behaviour before the problem impacts on the quality of the study.

Adherence-informed clinical trials enable sponsors to optimise drug development by deploying proactive evidence-based risk mitigation strategies, which in turn boosts compliance with FDA and ICH guidance.

Crucially, the role of electronic adherence monitoring does not stop at study end. The collected data gives sponsors a window into how the product is used in the real world, and this key patient behavioural data can prove invaluable when developing a successful marketing strategy.

Digital medication adherence monitoring is straightforward and easy to implement in a clinical study without delays in the supply chain, and is applicable to all study participants without additional burden for the patients. Patients are empowered as the solution is usable without any necessary configuration by patients. Such innovations are non-intrusive and completely frictionfree for patients. There is no need to combine an app and a phone, nor to recharge/change the battery.

The captured data is used to provide a proxy for drug intakes. In turn, this enables the patient’s actual medication adherence to be mapped and graphs and charts and other forms of tangible analysis to be produced that illustrate a patient’s medication intake over a given period of time. Conclusions According to the World Health Organisation,4 up to half of patients with long-term conditions do not take their medications as prescribed, and numerous studies have shown that this problem extends to clinical trials.5 The impact is huge. It can lead to the underestimation of drug efficacy, delay market approval, and drain study power. In short, it is an expensive problem.6

Traditional measures, such as pill count, blood sampling and self-reporting, have done nothing to alleviate this problem. Manual methods can be biased or just not sensitive enough to detect issues.

Experts acknowledge that digital medication adherence monitoring enables the most objective and precise medication adherence monitoring. Evidence-based digital medication adherence monitoring systems can help improve clinical results and conclusions, maximising the chances of success in clinical trials. Sponsors can improve drug efficacy by managing patient adherence to the study medications. For clinical trials, the integration of this kind of tool will improve the speed and accuracy of medication adherence assessment and intervention efficacy. It will also potentially decrease the rate of unnecessary interventions. It very well can be the critical factor in a trial that fails or succeeds. REFERENCES

1. www.syneoshealth.com/2019-health-trends 2. https://www.oecd-ilibrary.org/social-issuesmigration-health/investing-in-medicationadherence-improves-health-outcomes-andhealth-system-efficiency_8178962c-en 3. 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 4. https://www.who.int/chp/knowledge/ publications/adherence_report/en/ 5. https://www.oecd-ilibrary.org/social-issuesmigration-health/investing-in-medicationadherence-improves-health-outcomes-andhealth-system-efficiency_8178962c-en 6. Breckenridge A, Aronson JK, Blaschke TF, Hartman D, Peck CC, Vrijens B. Poor medication adherence in clinical trials: consequences and solutions. Nat Rev Drug Discov. 2017 Mar;16(3):149-150. doi: 10.1038/nrd.2017.1. Epub 2017 Feb 3. PMID: 28154411.

Bernard Vrijens

Dr. Vrijens holds a PhD from the Department of Applied Mathematics and Informatics at Ghent University, Belgium. He currently leads a research program investigating (a) the most common errors in dosing using a simple but robust taxonomy, (b) particular dosing errors that can jeopardize the efficacy of a drug, and (c) the optimal measurement-guided medication management program that can enhance adherence to medications and maintain long-term persistence. Dr. Vrijens is also the co-author of seven book chapters, over 100 peer-reviewed scientific papers, and named as inventor on 6 patents. He is a founding member of the International Society for Medication Adherence (ESPACOMP), and an active member of several EU- and US-funded collaborative projects around the theme of adherence to medications.