When clinical trial participants do not follow the dosing protocol, it can result in an underestimation of a drug’s therapeutic effect. With inability to demonstrate efficacy being the leading cause of study failure worldwide1, it’s an issue sponsors cannot afford to ignore – and with digitally enabled medication adherence packaging, they no longer have to.
Poor adherence to the investigational product is a significant problem in clinical trials. Studies have shown that by day 100, 20% of participants have stopped following the dosing protocol, and a further 12% have sub-optimal adherence.2
This matters because it negatively impacts data quality, data integrity, and research outputs.
Modern clinical trials are complex and contain multiple opportunities for failure. Chief among them is an inability to demonstrate efficacy,1 but this doesn’t necessarily mean the drug does not work. It could be result of uncertainties related to dose selection or the study being underpowered, for example, both of which can be influenced by poor adherence.
In a world where just 13.8% of products entering industry-sponsored Phase I trials ever go on to obtain FDA approval,3 sponsors need to ensure they are giving their candidate the very best chance of success.
Direct Correlation
Evidence from the HIV pre-exposure prophylaxis (PrEP) arena shows exactly how adherence can sometimes have a direct and highly impactful effect on drug efficacy calculations during clinical trials.
A prime example is a study of oral FTC/TDC for women (FEM-PrEP) which returned a statistically insignificant efficacy rate of just 6%. When researchers saw that adherence measured by self-report was recorded at 83%, compared to just 30% when measured by blood concentrations, they asked if this, rather than drug formulation, was the problem.4
They had a solid grounding for the hypothesis as a review of trials in similar products, with varying degrees and methods of adherence support, appeared to show a correlation between improving adherence rates and higher drug efficacy (see figure 1).5
Partners PrEP study, of prophylaxis product Truvada, for example, used a tried and testing method of adherence management that combines connected packaging and data analytics for holistic, real-time medication taking behavior management. The researchers recorded an adherence rate of 96%, and an efficacy rate of 100%.6
Protocol Deviations
The reasons people do not take their medicines are set out in the protocol are as varied as they are complex. While they broadly fit into the two categories of intentional and unintentional, the truth is there is often a large degree of interplay between the two.
Intentional non-adherence is deliberate and is largely associated with patient motivation and concerns, whereas unintentional non-adherence tends to be driven by a lack of capacity or resources to take medications. However, certain types of unintentional non-adherence, such as forgetting to take a dose, tend to be more likely when the person’s motivation to take the medication is low and those who unintentionally cannot access their medicine intentionally do not take it.
Other common reasons include poor communication between healthcare providers and patients, the patient having limited knowledge of the drug and how to use it, and a fear of
adverse or side effects. The complicated dosing regimens often associated with clinical trial protocols can also prove a to be a barrier, as can a patient’s perception that they are deriving no benefit from the investigational product.
In short, there is no one reason for protocol deviations, meaning there is no one size fits all intervention sponsors can deploy to make sure people stay adherent to study requirements.
Holistic, Frictionless, Actionable
Traditional methods of adherence management have proved ineffective.
Pill count, and self-report, for example, are open to bias and provide but a snapshot of medicine taking behaviour at a particular time and place. Measuring drug concentrations and metabolites in blood, urine, or hair, while being no more holistic, is also invasive and places an additional burden on patients and study sites alike.
More advanced, digital methods have emerged in recent years, but it is important to remember that not all technological approaches offer improvement opportunities.
Asking patients to fill in an e-medication diary in real-time, or record and submit a video of themselves administrating the medication, for example, only serve to create more barriers to optimal adherence.
Any approach that necessitates patients’ active involvement is self-selecting. Only those who are engaged in the protocol and with the technology will use it, but robust drug development, and maximum study power, relies on collecting data from all participants.
Those who are less engaged will feel the pressure of the additional requirement, whether it is recording a video or ticking a box, and this makes poor adherence more, not less, likely.
To support people to take their medication on schedule, we need to be removing barriers, not putting them up. The key is passive data collection that works automatically in the background, without the patient even noticing.
The Future of Packaging
Connected drug packaging, combined with powerful data analytics, allows sponsors to manage medicine taking behaviour without asking one more thing of patients.
Connected pre-filled syringes or blister packs, for example, can detect when the injection was administered or the tablet removed from the package, and transmit that information to a cloud-based platform. Algorithms then work to spot missed doses or erratic dosing patterns, such as medication holidays or overdosing, and present the results as data visualizations.
It allows teams to risk stratify participants, and prepare and deliver individualised interventions, based on that person’s reasons for poor adherence before the issue even has a chance to impact on data quality or study power.
These platforms can even be integrated with third-party applications, like patient-facing engagement-building apps which can further encourage long-term adherence.
Crucially, they are evidence backed: studies have shown that connected package monitoring is 97% accurate. That’s compared to 60% accurate for pill count, 50% for healthcare professional rating, and just 27% for self-report.6
Regulatory Backing
In 2019, the FDA published a 42-page document aimed at improving the efficiency of drug development, in which it recognised the role of adherence in decreasing variability within clinical trials. It said reliable patient adherence data provided valuable safety and efficacy information, and that more attention should be paid to this information during regulatory review.7
Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products outlined two approaches that could help in this quest. The first was identifying and selecting patients with good adherence patterns, via a run-in phase before the trial starts, for example, though this is rarely used in the industry.
The second was to encourage medication adherence throughout the study by ensuring patients are aware of the conditions and demands of the trial, and avoiding overly rapid titrations that could cause early adverse reactions. It also recommended the use of adherence prompts and alert systems, and tools such as smart bottles, or connected packaging.
When it comes to digital health technologies (DHT), the FDA has also advocated a frictionless approach, as demonstrated in its 2021 publication, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance for Industry, Investigators, and Other Stakeholders.8
The guideline places a strong emphasis on the usability of technologies, explaining that design and ease of use will influence whether trial participants will engage with the solution for the duration of the trial, and in the manner described in the protocol.
To date, industry has focused on the scientific validity of technologies, but, as these guidelines explain, user experience is just as crucial part of the puzzle. Participant engagement must be top of the DHT wish list if sponsors and CROs are to collect meaningful, actionable adherence data.
Measure to Manage
As in any other arm of science and drug development, adherence has to be measured if it is to be managed.
Empowering patients to follow the dosing regimen, through frictionless digital adherence monitoring and individualised support, improves medicine taking behaviour, giving trials a better chance to succeed, and setting the stage for better outcomes.
References
- Fogel, D. B. (2018). Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: a review. Contemporary clinical trials communications, 11, 156-164.
- Eliasson, L., Clifford, S., Mulick, A., Jackson, C., & Vrijens, B. (2020). How the EMERGE guideline on medication adherence can improve the quality of clinical trials. British Journal of Clinical Pharmacology, 86(4), 687-697.
- Wong, C. H., Siah, K. W., & Lo, A. W. (2019). Estimation of clinical trial success rates and related parameters. Biostatistics, 20(2), 273-286.
- Karim, S. S. A., & Karim, Q. A. (2011). Antiretroviral prophylaxis: a defining moment in HIV control. The Lancet, 378(9809), e23-e25.
- Baeten, J. M., Donnell, D., Ndase, P., Mugo, N. R., Campbell, J. D., Wangisi, J., … & Celum, C. (2012). Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. New England Journal of Medicine, 367(5), 399-410.
- El Alili, M., Vrijens, B., Demonceau, J., Evers, S. M., & Hiligsmann, M. (2016). A scoping review of studies comparing the medication event monitoring system (MEMS) with alternative methods for measuring medication adherence. British journal of clinical pharmacology, 82(1), 268-279.
- US Food and Drug Administration. (2019). Enrichment strategies for clinical trials to support determination of effectiveness of human drugs and biological products guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enrichment-strategies-clinical-trials-support-approval-human-drugs-and-biological-products Last accessed: 3 August 2022.
- US Food and Drug Administration. (2021). Digital Health Technologies for Remote Data Acquisition in Clinical Investigations Guidance for Industry, Investigators, and Other Stakeholders. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations Last accessed: 3 August 2022.
