DCT Risk/Benefit Profile: A Focus on Adherence

Decentralized clinical trials (DCTs) are here to stay, as demonstrated by international regulators’ recent commitments to the model. But while the approach offers a multitude of benefits, from expanding access to increasing cohort diversity, it can also serve to magnify existing challenges, such as managing medication adherence.

The benefits of DCTs have been well documented in recent years. The FDA’s Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance for Industry, Investigators, and Other Stakeholders, for example, says that technological advances have “revolutionized the ability to remotely obtain and analyze clinically relevant information”.¹

The guidance, published in January, said that using digital health technologies (DHT) for direct, frequent data collection in the home environment provides a broader picture of people’s daily lives and behaviors. In addition, technological solutions can capture information from those who might otherwise be unable to report their experiences, such as infants or people living with cognitive impairment, it said.

In Europe, the Accelerating Clinical Trials in the EU (ACT EU) initiative, part of the updated EU Clinical Trial Regulation, has also placed the spotlight on this new way of working.² Launched by the European Commission, the Heads of Medicines Agencies, and the European Medicines Agency in January, the program lists enabling innovative trial methods and supporting the modernization of good clinical practice as being among its 10 “priority actions” for 2022.

Documents such as these are installing confidence in remote monitoring and giving the industry the framework it needs to embrace the potential of DCTs or at least a hybrid trial.

DCTs and adherence

As we move into this new world, however, we must be cognizant of the pitfalls as well as the benefits of DCTs. Adherence to medication, long an issue in clinical trials, is one potential casualty.³

Sponsors and CROs know that patients not taking their medication as prescribed can drain study power, even to the point of study failure, and lead to underestimations of drug efficacy. But they also need to be aware that DCTs can magnify the problem. The removal of at least some of the face-to-face contact between site and participant can impact on the person’s engagement with the trial protocol­­—a well-documented factor in poor medicine-taking behavior.^4,5

In addition, because DCTs facilitate a more diversified population, the potential for non-adherent patients may be increased. Currently, study teams can have a selection bias toward those patients they know to be disciplined in their medication-taking behavior. By facilitating broader inclusion, however, DCTs can serve to remove this site filter, and compound issues surrounding poor adherence to medication.

In recent years, a variety of DHTs that purport to solve the problem of adherence have emerged. Solutions that ask people to record every medication intake in an e-diary or submit videos of themselves taking their medicine, could be considered counterintuitive. They can place additional burden on the patient—the very thing remote data monitoring is attempting to avoid.^6,7

Other solutions, that combine the power of connected packaging and data analytics/visualizations, for instance, can provide a frictionless experience
for patients. Connected blister packs, smart bottles, or pre-filled syringes, for example, can collect the time and date of dose, and transmit it to a cloud-based platform. Algorithms conduct a sophisticated analysis of medication-taking behaviors and present the site staff with those visualizations. This enables them to spot patterns that might indicate “at-risk” participants, allowing for risk stratification and informing individualized interventions.

The approach can even be integrated into third-party applications, such as patient-facing mobile phone apps, which are designed to continually encourage adherence, and reinforce protocol engagement.

Digital adherence monitoring, then, gives site teams the ability to get to know participants, even when not meeting in person, thereby maintaining the human connection of face-to-face trials.

How does it work: Case studies

AARDEX has been working with sponsors and CROs to embed its evidence-based adherence tools into clinical trials for some time, and have concluded that there is no one-size-fits-all solution.

The right service or combination of services will depend on a variety of factors. It means that the best adherence management partner is one that can offer an ecosystem of solutions that can be matched to the needs of the trial and its cohort.

In February, for example, AARDEX started working with Trials@Home, a center for excellence for remote DCTs, on a Phase III study. It will include participants with type 2 diabetes across more than 60 sites in several countries. Of those, some will be site-based and hybrid, and others will be in the remote arm.

A monitoring tool will collect dosing data from Sanofi’s insulin pens, and send it via Bluetooth, to AARDEX’s MEMS® Adherence Software for analysis.

The study, due to end in August 2024, aims to provide an optimal understanding of patient behaviors. The insights could help improve medication adherence in a patient cohort where non-adherence has a direct causal association to hospitalization and mortality.

In Australia, the University of Sydney and the University of New South Wales took a different approach when they used AARDEX’s digital solutions to verify adherence during a clinical research project.

The study, to determine whether the self-monitoring of serum uric acid concentrations improved adherence to the urate-lowering drug allopurinol among people with gout, enrolled participants for one year follow up.

They chose AARDEX’s MEMS® Cap, a customizable smart package, and the MEMS® Mobile for Research app, which participants downloaded to their own phones in a bring your own device (BYOD) model that kept costs to a minimum.

Participants used the app to access their time-stamped dosing events from the smart package and transmit the data to the MEMS AS® software. This allowed the team to collect and review dosing information in real time so as to spot erratic dosing patterns and provide additional support when needed.

Patients were also able to send comments to the study team via the app, which staff said had helped to increase engagement

DCTs are fast becoming the new normal, as they offer huge benefits for more streamlined, patient-centered trials. But if we are to fully embrace the advantages, we must be aware of the pitfalls as well. Remote data monitoring can magnify the issue of poor medication adherence as it risks eroding the relationships that can keep people engaged in the protocol.

However, when tailored to the needs of the trial and the cohort, digital adherence monitoring wraps its arms around participants. And in doing so it provides a frictionless solution that informs targeted interventions and re-establishes the all-important connection between site and patient.

Bernard Vrijens, CEO & Scientific Lead, AARDEX Group

References

1. Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. 2022. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations
2. Accelerating Clinical Trials in the EU (ACT EU) Delivering an EU clinical trials transformation initiative. 2022. Available at: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/accelerating-clinical-trials-eu-act-eu-delivering-eu-clinical-trials-transformation-initiative_en.pdf
3. Vrijens B, Urquhart J. Methods for measuring, enhancing, and accounting for medication adherence in clinical trials. Clin Pharmacol Ther. 2014 Jun;95(6):617-26. doi: 10.1038/clpt.2014.59. Epub 2014 Mar 12. PMID: 24739446.
4. Balkrishnan R, Kulkarni AS, Cayce K, Feldman SR. Predictors of healthcare outcomes and costs related to medication use in patients with acne in the United States. Cutis. 2006 Apr;77(4):251-5. PMID: 16706243.
5. Muddasani S, Heron CE, Fleischer AB Jr, Feldman SR. Time Intervals Until the First Return Office Visit After New Medications. J Drugs Dermatol. 2020 Dec 1;19(12):1226-1230. doi: 10.36849/JDD.2020.5542. PMID: 33346517.
6. Example of AIcure: Larsen KG, Areberg J, Åström DO. Are self-reported and self-monitored adherence good proxies for reaching relevant plasma concentrations?: Experiences from a study of anti-depressants in healthy volunteers. Clin Trials. 2021 Aug;18(4):505-510. doi: 10.1177/17407745211012683. Epub 2021 May 2. PMID: 33938259.
7. Thomas, B. E., Kumar, J. V., Chiranjeevi, M., Shah, D., Khandewale, A., Thiruvengadam, K., ... & Subbaraman, R. (2020). Evaluation of the accuracy of 99DOTS, a novel cellphone-based strategy for monitoring adherence to tuberculosis medications: comparison of DigitalAdherence data with urine isoniazid testing. Clinical Infectious Diseases, 71(9), e513-e516.