By Deborah Borfitz 

December 20, 2023 | Medication adherence in phase 2 and phase 3 clinical trials is far less perfect than the 98% often cited in peer-reviewed published papers on those studies, according to Bernard Vrijens, Ph.D., CEO and scientific lead at the AARDEX Group, who has spent a lot of time in recent years exposing the crisis. While solutions to address it exist in the form of smart packaging, the will to adopt such technologies has been tepid, leading to widespread overdosing of trial participants—most notably those who take the drug as instructed—and, ultimately, directions for use on drug labels and unnecessary side effects once the drug hits the market. 

The problem “goes completely undiagnosed because no one wants to see it,” he says. This is because of the shortcomings of the two main methods used to measure adherence—pill counting and self-reporting by patients; the pressure from regulators, sponsors, and investigators to get good outcomes; and pressure on participants to be good, compliant patients. 

Among sponsor companies, the tendency is to select higher-than-needed doses for studies to “build forgiveness in the drug” to compensate for the major deviations from the protocol-prescribed treatment regimen, says Vrijens. Cases have been documented where 50% or more of trial participants have either stopped taking the experimental drug, skipped a few doses, or secretly took a drug holiday.   

The upshot of all this? Possibly one in five drugs on the market are prescribed at a dose that is at least 50% higher than necessary, based on findings of a study by pharmaceutical medicine specialists in Japan published in PLOS One ( DOI: /10.1371/journal.pone.0218534). “It is clearly clustered in oncology, but it affects all therapeutic areas,” Vrijens says. 

Up until 2018, the AARDEX Group worked exclusively in the business of smart packaging for pharmaceuticals, best known for its Medication Event Monitoring System (MEMS) Cap that transforms regular pill bottles into smart pill bottles, he shares. But some of those former competitors became clients once the company pivoted to managing medication adherence data on a secure cloud platform, MEMS AS, which is open to all smart packages and connected devices on the market. 

A dozen validated partners are now part of that ecosystem, says Vrijens. These include smart packaging manufacturers AdhereTech, Mevia, Pill Connect, Schreiner MediPharm, Westrock, and Wisepill, and connected device makers Aptar, Beckton Dickinson, Biocorp, Haselmeier, and SHL as well as contract manufacturing organizations like Thermo Fisher Scientific, Almac, and Catalent. Pharma customers pick and choose their favorites from that list and the data they generate will all be processed on the MEMS AS platform in the same way. 

As far as Vrijens is concerned, the AARDEX Group’s top competitor is manual pill counting. The other major players in the field primarily rely on apps that might require patients to videorecord themselves swallowing a pill. While these solutions intend to demonstrate the advantage of proving ingestion, he says, they put the burden on patients and thereby have limited utility. 

Some study participants won’t videorecord themselves. Others will but are out of focus. Or they have trouble getting the technology to work. In the end, app-based technologies are useful for about half of the individuals they are targeting, says Vrijens. That level of engagement may look like a “huge success” in medical practice but a major failure in a clinical study where almost 100% reliability is required for effectiveness—again highlighting the value of smart packaging.  

Software Support 

MEMS AS processes data in real time, thereby providing feedback to improve medication adherence during clinical trials, says Vrijens. This can be done by building risk stratification and prevention modules targeting either the investigator or patients, including sending out reminders and feedback to participants to take their medications.  

The U.S. Food and Drug Administration (FDA) has in fact issued guidance on clinical trials enhancement strategies that recommends such data-driven adherence feedback to assure fidelity to the research protocol, he points out. Big pharma foresees an enlarging role for digital adherence monitoring, prompting most of the top 15 companies to integrate with the MEMS AS platform and start pilot studies. “They want to be ready to scale up in the future when it [may] be a requirement,” says Vrijens.   

The software is additionally providing data that can be used as inputs for pharmacokinetics and pharmacodynamics modeling and to estimate the efficacy of treatments when patients are adhering to the treatment regimen, he adds. This has already been done on several occasions to rescue a medication that failed in clinical trials predicated on the intent-to-treat (ITT) principle, which assumes adherence levels among participants are good. 

Gilead’s HIV pre-exposure prophylaxis drug TRUVADA (emtricitabine-tenofovir disoproxil fumarate), FDA-approved in 2012, was the first to be so rescued. It marked the beginning of the AARDEX Group’s expansion into phase 2 and phase 3 drug development studies where medication adherence was a concern at the protocol development stage—either because it involved a complex dosing regimen, had a lengthy follow-up period, or the drug had a narrow therapeutic window. 

To date, the therapeutic areas benefitting from the MEMS AS platform have included infectious diseases, (e.g., HIV and hepatitis C), cardiovascular, inflammation and immunology diseases, central nervous system (e.g., depression), and, more recently, Alzheimer’s disease and oncology, reports Vrijens. 

Underutilized Tools  

For phase 2 and phase 3 trials, participants are ideally representative of real-world patients who don’t robotically take their medications at the same precise minute every 24 hours, Vrijens says. So, there needs to be some leeway—perhaps a few percentage points of nonadherence—but not the major discrepancies that have come to plague the industry. 

If the input, or level of drug exposure, is unknown, it is impossible to draw a sound inference on the output, or clinical outcome in terms of safety and efficacy, he stresses. “Do we have a perfect measure for the input? No... [but] what we know is that self-reporting and pill counting are extremely biased towards perfect adherence, especially the way they’re applied in drug development trials.” 

Smart pharmaceutical packages have shown to be “the most reliable [solution] in terms of broad applicability,” and passively capture medication adherence information in roughly 97%-98% of study populations, says Vrijens. Though available for many years now, they have been woefully underutilized in randomized clinical trials. 

The products come in various forms—different types of pill bottles, blister packs, reusable topical treatment caps, tubes, inhalers, and injectable therapy containers—but all record dosing events via a discreet microprocessor chip to monitor exactly when patients take their medications.  

Concern about potential issues with medication adherence began with pharmaceutical companies of every size who, having read some of the dozens of papers Vrijens had co-authored on the topic (e.g., Clinical Pharmacology and Therapeutics, DOI: 10.1038/clpt.2014.59 and Nature Reviews Drug Discovery, DOI: 10.1038/nrd.2017.1), reached out about extending the value of smart packaging from research settings to clinical trials. Interest in the MEMS AS platform among big-pharma companies has been particularly high over the past few years in direct response to publication of the final FDA guidance focused on enrichment strategies for improving the ability of a study to detect a drug’s effectiveness. 

During the early days of the Covid-19 pandemic when decentralized clinical trials (DCTs) and remote monitoring were practically the only ways to keep study programs running, smart packaging was more often viewed as a necessity. But phase 2 and phase 3 trials remain “very traditional” in that they require frequent in-person study visits by participants, says Vrijens, noting that as of earlier this year not a single drug was approved in Europe based on a DCT. 

Hybrid trials, involving a mix of decentralized and traditional study elements, is where the industry is heading for all phases of clinical development. That means fewer study visits and greater opportunities for nonadherence, he says. “The regulators have to acknowledge that adherence is imperfect in trials, and it is not a problem... because if you measure it, you can address it.”  

Some study sponsors, for their part, remain content with the status quo, Vrijens adds. “Unless they see or are afraid of the issue for a specific drug, they don’t jump on [smart packaging], and they keep overdosing the population.” 

Evidence Build 

There is now ample evidence of an overdosing problem in both clinical trials and clinical practice, according to Vrijens. Given two dose choices at the end of a phase 2 trial, drug developers will always opt for the higher one, he cites as an example. This tendency is so strong in oncology that the FDA launched Project Optimus to reform the dose optimization and selection paradigm. 

In addition to the paper by researchers in Japan, two others published a decade ago underscored the need to improve pre-marketing optimization of dosage and indicated population—including one whose lead author worked in the Division of Metabolic and Endocrine Drug Products in the FDA’s Center for Drug Evaluation and Research (Pharmacoepidemiology & Drug Safety, DOI: 10.1002/pds.744). Similar findings were reported by European researchers published head-to-head in the same journal issue (Changes in prescribed drug doses after market introduction - Heerdink - 2002 - Pharmacoepidemiology and Drug Safety - Wiley Online Library). 

In addition to the paper by researchers in Japan, two others published a decade ago underscored the need to improve pre-marketing optimization of dosage and indicated population—including one whose lead author worked in the Division of Metabolic and Endocrine Drug Products in the FDA’s Center for Drug Evaluation and Research (Pharmacoepidemiology & Drug Safety, DOI: 10.1002/pds.744). Similar findings were reported by European researchers in the same journal issue (DOI: 10.1002/pds.745).   

A recent intriguing example showcasing the tendency to select a higher dose than needed for adherent patients can be seen because of the disappointing outcomes of the MOUNTAIN phase III study, which investigated zuranolone (30mg, 20mg, placebo) in major depressive disorder. The main study, based on a traditional ITT analysis, did not meet its primary endpoint, improvement against placebo, but reported 98.3% medication adherence (Journal of Clinical Psychiatry, DOI: 10.4088/JCP.22m14445). “However, this adherence figure, based on manual pill count, is highly improbable in a population known to struggle with adherence issues,” Vrijens says. 

In the modified population used for the posthoc analysis, 9% of the samples showed no detectable plasma zuranolone concentration, he notes. Removing those samples from the analysis produced a significant improvement of the 30mg against placebo at all time points, “a clear signal” of poor adherence and its impact on clinical outcome.  

“Interestingly, after this trial failure, rather than addressing the medication adherence issue, further developments were made at an increased dosage of 50 mg, where zuranolone met its primary endpoint in phase 3 trials for the treatment of postpartum depression,” says Vrijens. It was recently approved by the FDA for that indication. 

“One can imagine the potential change in fortunes for the pharma sponsor and the respective patients if the study participants’ adherence to the IP [investigational product] was appropriately measured and managed in the MOUNTAIN phase III study,” he says. 

‘Informed Decisions’ 

Thermo Fisher Scientific keeps its “finger on the technology pulse” through a formal prequalification process whereby adherence measurement solutions that make the cut can be seamlessly integrated into the clinical trial supply chain, according to Sarah Englert, senior director of innovation and program management. It then partners with research sponsors to make “informed decisions,” on a case-by-case basis, about which technologies to potentially deploy in studies. 

“We are agnostic because, honestly, we can be,” Englert says. “We are constantly looking... [for the] latest and greatest technologies to help us to innovate for the clinical trials of tomorrow.” 

Many of the solutions tested in-house don’t meet the quality or regulatory bars to be added to the portfolio, says Englert. The collection currently reflects the popularity of smart caps, which passively capture a pill bottle being opened, and blister packages, for pill-by-pill tracking, which is where the shift to smart packaging began.  

But the portfolio will be expanding with the addition of other solution types—e.g., smart injectable therapy containers with a sensor-triggering plunger, smart metered-dose inhalers equipped with built-in sensors for tracking consumption patterns and daily use, and smart sharps containers that track injection adherence. There are even tabletop pill-dispensing devices with programmable alerts and reporting capabilities that will also remind individuals to take their blood pressure and have the reading sent to study teams via Bluetooth technology. 

A vast number of data platforms and patient information management systems exist on the market capable of receiving the signals sent from these various smart technologies, providing analytics that could potentially help study teams monitor and manage medication adherence, Englert says. Those will oftentimes be linked with a smartphone app that films the dosing event, or the interactive response technology system that manages patient randomization. 

The biggest issue in using any digital platform in the context of a clinical trial is to ensure it is “super secure,” says Englert, meaning it can meet all data security and privacy regulations in the jurisdictions where it is to be used. And those types of regulations are always changing and specific to a country and even the trial type. “You have to look at the use case.” 

Game-Changing Insights 

Englert likens advancements in the field to digital innovation across industries, like the evolution in how a pizza gets ordered and delivered. A decade ago, “I didn’t know it got to my house until it got to my house,” she says, “and now I can literally see that dot on my cell phone... [and] manage my expectations.” 

But instead of harvesting insights to improve the customer experience with pizza delivery, technology can be repositioned to produce real-time insights about adherence with an investigational product, so study teams know “when and where to proactively intervene,” says Englert. “Those types of insights are going to change the game for clinical trials... and optimize them to be able to touch more people globally. 

“It really is a race against time here, and... a tremendous opportunity to transform clinical trials for tomorrow based on some of this meaningful innovation,” Englert continues. “It is all about making things customer-centric, or patient-centric... [as has been seen] in every other industry.” Smart packaging has the potential to “improve flexibility and agility... improve quality and reduce waste,” she adds, pointing to its ability to help companies reach their sustainability goals.  

Adoption of smart packaging is driven by both study design and objectives, she says. They are often a great fit for direct-to-patient trials, where participants are administering a therapy on their own at home, but also in cases where a dosing schedule is particularly complex to “mitigate the extra variables” that impinge on adherence. “Traditionally the way that clinical trial protocols would mitigate for this is either over-enroll or by focusing on education.”