Non-adherence to medication in general medical practice is a long-standing problem, and its impact on health outcomes has been well documented.
What is less readily explored, however, is its effect on clinical trials. Across all studies, therapy areas and stages of development, around 50% of participants admit they do not adhere to the dosing regime set out in the protocol and around 30% of subjects in Phase III studies are non-adherent by day 100.
The impact of this lack of adherence can be huge. From underestimated drug efficacy and delays in the approval of investigational products, to increases in development costs and lost revenues, non-adherence is an issue that costs sponsors money and reduces patient access.
Fortunately, the technology and the expertise needed to take control of medication compliance not only exists but is relatively easy to implement.
Getting to the Root of the Problem
Barriers to adherence are both multiple and complex. People may have swallowing difficulties, and find it psychically challenging to take as many tablets as a protocol calls for. Others may be concerned about side effects, or simply forget to take their medicine at the right time.
It’s a problem that extends across delivery routes and therapy areas, but some spaces are more affected than others.
In trials of self-injectable molecules delivered by pre-filled syringes (PFS), for example, patients face unique challenges. They may find it hard to handle the device, or they may experience needle phobia.
While autoinjectors have been introduced to overcome many common usability issues in day-to-day care, this has not yet been extended to clinical development – despite the huge increase in PFSdelivered drugs currently in development.
The PFS market, fuelled by the growing popularity of biological agents for the treatment of long-term diseases, is expected to be worth $9.7B by 2025. But while they are highly efficacious, and, in many cases lifechanging for the people who take them, biological drugs, which are made from living organisms, are also extremely expensive to develop.
Tackling the costly consequences of non-adherence, it could be argued, has never been so important.
Study Power Drain
We all know the importance of study power during clinical trial design. The higher the study power, the higher the probability of detecting a drug’s true effect. A higher statistical power increases the chances of success, enables more informed go/no go decisions, and shortens the time to market.
It’s a complex equation that depends on three factors: the effect size of the drug itself, the variability in drug response, and the sample size. In short, the sample size must be large enough to show the maximum effect size with the lowest variability.
But when subjects do not take their medication as directed, it decreases effect size and increases variability. This, in turn, drains study power. The exponential relationship between non-adherence and sample size means that any decrease in adherence must be met with an expensive, labor-intensive increase in study participants if power is to be maintained.
Non-adherence, then, has a direct effect on the cost and duration of clinical trials, and can slash return on investment (ROI).
Overcoming this challenge calls for a modern solution that is adapted to the specifics of the field.
Digital Transformation
Digital adherence monitoring gives trial leaders an invaluable insight into adherence levels. It allows them to identify and correct problems before they can drain study power and interfere with study results.
Non-digital methods, such as pill counting or patient self-report diaries, are biased and not sensitive enough to detect non-adherence. Data-driven digital solutions are different.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from Pharmaceutical Outsourcing – all delivered right to your inbox! Sign up now!
Studies have shown that smart package monitoring, for example, is 97% accurate, compared to 60% for pill count, 50% for healthcare professional rating, and just 27% for self-report.
What’s more, advanced digital monitoring provides a complete understanding of the patient adherence behaviors and the risk indicators that matter most for the success of a study.
What is Digital Adherence Monitoring?
Digital adherence monitoring consists of smart drug packaging that uses microcircuitry to record dose administration and transmit that information to the study team’s software for analysis. In essence, the packaging monitors, and the study team uses the resulting data to manage adherence.
Connected PFS devices can, for example, collect essential information such as if the injection has been completed, time and date, type of drug, batch number, and expiration date. This information is sent to a cloud-based platform that provides sophisticated analysis of medication-taking behaviors and creates powerful visualization and focused feedback for both study teams and participants.
Adherence Strategies
This information can also be integrated into third-party applications, such as patient-facing apps designed to build engagement and encourage adherence.
Systems feature onboarding screens to ensure participants have all the information they need about the clinical trial, such as dosing regimens, instructions, and adherence information, as well as advice on developing strong medication intake behavior.
Throughout the trial, people can access their scheduled appointments, reminders, and medication history, transfer their data to the central system, and send additional adherence-related information by answering simple questions.
This advanced approach is a feasible, non-invasive, reliable, and easily implemented method of quantifying medication adherence.
How Does This Work in Practice?
Connected drug delivery devices company, BioCorp, and clinical trial digital adherence management solution provider, AARDEX, have joined forces in a bid to overcome the adherence problem and demonstrate the value of placing adherence-improving strategies front and centre in clinical trials.
Their collaboration places BioCorp's Injay, a connected PFS which records and shares dosing data, into AARDEX’s Medication Event Monitoring System Adherence Software (MEMS AS®) ecosystem, creating a single comprehensive adherence solution.
MEMS AS is a secure, cloud-based platform that provides sophisticated analysis of medication-taking behaviors for visualization and feedback.
Using 70 proprietary and validated algorithms, it processes patient data from various compatible smart packages/devices, such as the Injay PFS. It can then present a comprehensive picture of patient adherence based on electronically compiled dosing history data. It can also be integrated with Electronic Data Capture (EDC) system, Interactive Response Technology (IRT) system, and third-party applications.
Cost Effective
As suggested by the recent FDA guidance on trials enrichment strategies and the ICH 9 (R1) addendum on estimands and sensitivity analysis in clinical trials, adherence-informed trials lead to optimized drug development.
The benefits include improved medication intake accuracy to planned study medications, improved data quality and statistical power, reduction in patient population size, and a reduced time to market.
Incorporating digital monitoring measures and using them to encourage adherence can radically increase the chances of a clinical trial’s success, but it also helps teams to avoid errors in the interpretation of patient risk and benefits.
It is the most cost-effective approach to compensating for the drop in study power that results from non-adherence and, ultimately, shorten the whole development process.
Towards a Healthier Future
Despite the long-standing nature of the adherence problem in clinical research, it has never truly been overcome. Trials often rely on the traditional, manual methods of compliance monitoring that have been shown to be largely ineffective in the clinical trial setting.
But, if we are to build transformative, affordable medications, nonadherence during trials cannot be ignored. Sponsors, especially those working with expensive, PFS-delivered products, must take every opportunity they can to reduce costs and expedite the drug development pathway.
Digital adherence solutions are one such opportunity that developers cannot afford to miss.
Author Biography
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.