Bernard Vrijens

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”.

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.

 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.

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.

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.

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.

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.

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.

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

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

Vrijens B, Urquhart J. Methods for measuring, enhancing, and accounting for medication adherence in clinical trials. 

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Articles

Assessing the benefits of digital adherence monitoring for sites and patients.

DCT Risk/Benefit Profile: A Focus on Adherence

Drug development is inherently risky, with some analysis showing that just 13.8% of products that enter industry-sponsored Phase I trials go on to obtain FDA approval.

 Of course, the exact figure varies across therapy areas and development stages, but it is an expensive problem no matter how you slice the data.

So, what can sponsors and contract research organizations (CROs) do to increase their chances of success? We take a look at some of the leading causes of study failure and explain how improving medication adherence could be the key to risk mitigation.

Clinical trials are incredibly complex, containing multiple opportunities for study failure. Common reasons include a shortage of funding for completion, failure to maintain good manufacturing protocols or to follow FDA guidance, and problems related to patient recruitment, enrolment, and retention.

However, the primary source of trial failure has been and remains an inability to demonstrate efficacy, according to a 2018 review of data from the previous 30 years.

 which assessed 640 Phase III trials of novel therapeutics. It found that 54% had failed in clinical development, and that 57% of these failures were attributed to inadequate efficacy.

Yet failure to demonstrate efficacy during a clinical trial does not always translate to mean the drug does not work. Such a finding could be the result of uncertainties related to dose selection or the study being underpowered, for example.

Safety is another leading reason for study collapse, with Hwang 

 finding it to be the root cause of failure in 17% of the Phase III trials examined.

Again, a study failing due to safety concerns does not necessarily mean the drug is unsafe. Incorrect dosing, for instance, can result in adverse events that do not accurately reflect the effect of the product.

Ultimately, the reasons for study failure are as varied and complex as the trials themselves. Yet there is a common thread that runs through the most common factors (i.e. efficacy, safety, dose selection), and that is poor medication adherence.

Poor medication adherence may be a key confounder of the root causes of study failure, but it is not a new problem. It is a well-documented issue, and one the industry has been grappling with for some time.

Studies have shown that each Phase III trial participant is responsible for an average of $42,000 in costs

 Across all clinical trial phases, 50% of participants admit to not following the dosing regimen set out in the protocol.

And when study participants do not take their medication as directed, it can lead to underestimation of drug efficacy, overestimated dosing requirements, and raise concerns about safety—the key reasons for delay and denial of regulatory approval.

By decreasing effect size and increasing variability, poor medication adherence drains study power. The exponential relationship between nonadherence and sample size means that any decrease in adherence must be met with a risky increase in dose and/or expensive increase in study participants to maintain power and avoid study failure.

Poor adherence to medication can thus have a concerning impact on patient safety. It generates poor data, leading to improper calculations of the correct therapeutic dose, and resulting in avoidable adverse events. Participant-driven sporadic dosing patterns, such as taking medication holidays, for example, can also lead to problems such as unnecessary withdrawal symptoms or side effects.

In essence, poor medication adherence gives in distorted picture of how a drug works in each patient population, compounding the very issues that can lead to study failure.

The factors that lead to poor medication adherence are multifaceted and individual to each participant. And while they fit broadly into two categories, intentional and unintentional, in truth there is a degree of crossover between the two.

Intentional non-adherence is deliberate, and largely associated with patient motivation, whereas unintentional non-adherence is largely driven by a lack of capacity or resources to take medications.

“However, it is important to acknowledge that the reasons underlying intentional and unintentional non-adherence are not entirely independent in those certain types of unintentional non-adherence e.g. forgetting, are logically more likely when motivation for medication is low.”

Traditional tools for the measurement of adherence, such as pill counting, self-reporting, and biomarkers, are simply not sensitive enough to identify non-adherence in this rich tapestry of factors drivers.

Counting returned tablets is the most commonly used adherence measure in clinical trials. However, it is easily censored by participants and only provides a summary of medication taking behavior between visits.

The self-reporting approach, whereby participants record their doses in a patient diary, is, in theory, a sound medication adherence assessment method. The reliability of such diaries, however, can be poor, as they are intrinsically vulnerable to inaccuracies and bias.

Even those with advanced digital applications, such as mobile app, reminders, or even the ability to film the medication being taken, can be troublesome. They require increased patient involvement and are intrusive. This can lead to lower patient acceptability and has been associated with missing data and poor reliability.

Likewise, monitoring drug or drug metabolites in blood, urine, or hair only provides a snapshot of behaviors. So-called “white coat adherence”, where participants only take the investigational product the day before the visit, is a particular vulnerability. In addition, the approach is invasive, places additional burden on participants and staff, and is largely restricted to use in the active arms of a trial.

 highlighted the inadequacies of traditional methods in a 2017 paper on the consequences and solutions of poor medication adherence in clinical research.

They conclude: “Methods for measuring and encouraging adherence are essential components of clinical trials and every effort should be made to incorporate adherence measures in phase II and phase III trials in order to avoid important errors in interpreting benefits and harms.”

Traditional methods are imperfect at best. But digital adherence monitoring, which utilizes connected packaging and powerful data analytics, is different, write Breckenridge 

. It is objective, qualitative, and able to guide informed decisions and interventions.

Connected pre-filled syringes, for example, can collect essential information, such as whether the injection has been completed, time and date of dose, type of drug, batch number, and expiration date.

These data analytics are then transmitted to a cloud-based platform for sophisticated analysis of medication-taking behaviors. Visualizations enable study teams to spot patterns that might indicate “at-risk” participants, allowing risk stratification and guiding individualized interventions.

The approach can even be integrated into third-party applications, such as patient-facing apps designed to continually encourage adherence and engagement with the protocol.

This is no longer an emerging technology. In fact, studies have shown that smart package monitoring is 97% accurate, compared to 60% for pill counting, 50% for healthcare professional rating, and just 27% for self-report.

Crucially, it provides a complete understanding of the patient adherence behaviors and the risk indicators that matter most for study success.

Drug development is costly and the stakes, both for industry and for the patients waiting for life-changing medications, are high. Organizations, then, must do everything they can to maximize their chances of success.

While we know that poor medication adherence can contribute to two of the biggest reasons for study failure—a lack of drug efficacy and safety concerns—addressing the problem has proved challenging.

Yet, with the emergence of digital adherence solutions sponsors and CROs now have the tools they need to improve medication taking behaviors, thus mitigating the risk of study failure and increasing return on investment.

is the CEO and Scientific Lead, AARDEX Group

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Breckenridge, A., Aronson, J., et al. Poor medication adherence in clinical trials: consequences and solutions. (2017). https://www.nature.com/articles/nrd.2017.1?WT.ec_id=NRD-201703&spMailingID=53536275&spUserID=ODkwMTM2NjI2OQS2&spJobID=1120295377&spReportId=MTEyMDI5NTM3NwS2

Alili, M., Vrijens, B., et al. A scoping review of studies comparing the medication event monitoring system (MEMS) with alternative methods for measuring medication adherence. (2016). https://pubmed.ncbi.nlm.nih.gov/27005306/

Vrijens, B., Urquhart, J. Methods for measuring, enhancing, and accounting for medication adherence in clinical trials. (2014). https://pubmed.ncbi.nlm.nih.gov/24739446/

A look at some of the leading causes of study failure and explain how improving medication adherence could be the key to risk mitigation.

Bernard Vrijens

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