Total costs of conducting randomized clinical trials in the biopharmaceutical industry continue to increase. Improving efficacy prospects, subject retention, enrolling subjects timely and data quality are major areas of focus for study teams. Nevertheless, the biopharmaceutical industry often neglects to address patient non-adherence to protocol, which impacts study costs and efficacy prospects.
Gossec et al in 2007 assessed that merely 33% of randomized clinical trials that published in high-impact journals reported adherence1. Non-adherence can lead to toxicity and suboptimal therapy efficacy as a function of the drug’s PK/PD characteristics and subject medication utilization patterns in between site visits. It can jeopardize subject’s health and leads to larger samples to achieve adequate statistical power. Non-adherence can lengthen study duration and approval prospects as data variability demands a higher number of required participants making trials costlier than they could be. Table 1 exhibits the average estimated cost to enroll patients at different trial phases, and Table 2 outlines the estimated impact of non-adherence and the opportunity cost of adherence improvement.
Per Table 2, on average in all therapeutic indications, a Phase III trial, for example, needs to enroll an additional 460 patients (totaling 828 patients (Table 1) to maintain equivalent statistical power, assuming a constant 40% study drug non-adherence rate. The operational cost to enroll 460 patients is estimated at $12 Million.
Adherence Measurements Currently Available
Legacy tools to measure adherence in randomized clinical trials were not good enough. Patient diaries, for example, are limited by recall bias and vulnerable to social desirability that led to measurable overstatements of adherence. Pill counts, on the other hand, don’t explain utilization patterns in between site visits, are subject to “pill dumping” before counts, and consume site staff resources that could be deployed to other value-added activities.
In their paper “Accuracy of Self-Report and Pill-Count Measures of Adherence in PrEP Clinical Trial”2 Agot et al reported in 2014 that self-reports and pill counts that were intended to capture consistent pill use over 4 week periods had the lowest predictive values (less than 30% on average). They elaborated that the large discrepancy found between adherence assessed through self-report or pill-count and adherence assessed through drug concentrations or other biomarkers was not unique to their study, for example, in an HSV-2 suppression therapy trial3, acyclovir was detected in 55% of participants’ urine, yet adherence by pill count was 90%. Adherence measured by pill count and self-report in the iPrEx trial4 was 93%, yet a sub-study of drug concentrations showed that only 50% of participants were swallowing their pills.
Pill counts upon site visits and self-reports are not accurate enough adherence measures and are retrospective ones that leave no room for proper screening and timely enrichment interventions.
New approaches have surfaced in recent years. For example, biomarkers in the study drug which once ingested and absorbed are transported via blood to the lungs coupled with an accompanying device that takes a post-ingestion breath sample. The methodology provides a proof of the study medicine being ingested, but it doesn’t provide dosing history and results can be affected by nutraceutical interactions and formulation changes. Other novel approaches include facial recognition technologies for visual confirmation of drug intake. This methodology, while intriguing from a technology point of view, disrupts patient’s lifestyles and compromises subject retention and satisfaction. These approaches can be thought of as novel Direct Observation (DoT) solutions which provide “proof of ingestion” but are not scalable into clinical settings nor provide information about natural patient behaviors. They have their place in trying to dissect intentional non-adherence from “professional subjects” not interested in participating in the study but for the economic incentives to do so. However, the use of these solutions may disrupt the majority of the subjects due to few professional ones and no system is infallible. Thankfully, other, less invasive approaches can help screen “professional subjects” before randomization.
Another methodology which has received significant press and venture capital investment includes ingestible sensors coupled with a companion wearable devices attached to the body or skin. Upon ingestion, the microchip generates a signal that the wearable captures. Acceptability to ingesting an over-encapsulated pill with a microchip is low, deployment in randomized clinical trials is costly, and “professional subjects” that don’t want to take the study medicine can circumvent the system— the microchip doesn’t authenticate that the right subject or even if a pet ingested the microchip; pills can be placed in settings that parallels contact with the digestive system.
Collecting adherence information is paramount and DoT and microchips provide higher reliability of study medicine ingestion than diaries and pill counts. However, the selected approach should not conflict with subject enrollment, satisfaction and retention.
A Better Non-Invasive Approach
Compliance Meds Technologies (CMT) offers a novel approach to medication tracking during randomized clinical trials with its patented CleverCap devices that track and record real-time dispensation of oral solid medication events in the outpatient setting. The technology captures detailed dosing logs of how patients are dosing, enables timely screening and empowers enrichment interventions by sites. CMT’s platform presents data in ways that allow sponsors and CROs to benchmark sites and shed light to investigators regarding correlations between dispensation dosing patterns and efficacy.
CMT devices can be used in silent mode to simply track or coupled with different cues (visual, sound, SMS, phone) to encourage better adherence habits throughout the study. The platform not only tracks patient behaviors in real-time, but it allows the team conducting the study to take immediate action and engage with patients to resume proper protocol adherence. CMT’s platform offers the perfect balance of tradeoffs between scalability, ease of use, intuitiveness, granularity, costs, ease of implementation and timely data capture. It is easy to implement within clinical operations daily practice: it doesn’t add extra burden to how clinical trials are run; no change to the current system for labeling material; no special labeling nor transfer of medications (neither by the clinical supplies team, site nor the patient); no changes in formulation/over encapsulation, nor lifestyle intrusive asks from the subject that may compromise turnover and enrollments (e.g. patches, microchips, staring at a screen, exhaling into a device, frequent site or lab visits for PK samples, blood-level monitoring and frequent bioassays/markers, etc.). CMT’s CleverCap devices enjoy compact form factors, are mobile, and provide real-time information globally.
CMT’s technology is applicable across different phases in research and development. Phase II-IIIb studies where the participant is not taking the medicine in the presence of someone. PK sampling studies not dosing in clinic – where evidence of the exact time that a subject took a dose prior to PK sampling is helpful. Protocols that call for multi-doses, irregular, complex and/or infrequent dosing schedules; studies that require titration or adaptive studies. Studies in high toxicity therapy classes and narrow PK profiles (e.g. Cancer, Hepatitis C, Transplant Immunosuppressant, CNS – MS, ALS, Parkinson’s). Therapy classes with concerns of overdosing or in which the study medicine is prone to diversion (e.g. Opioids, high cost biologics).
Innovative approaches like CMT’s are becoming fundamental components in the biopharmaceutical research and development toolkit to track and improve adherence during randomized clinical trials. Receptiveness to modernizing clinical trial processes will render long-term benefits to biopharmaceutical research and development efforts.
1Gossec L et al. Reporting of adherence to medication in recent randomized controlled trials of 6 chronic diseases: A systematic review. Am J Med Sci 2007;334(4):248-254
2Kawango Agot, Douglas Taylor, Amy L. Corneli, Meng Wang, Julie Ambia, Angela D. M. Kashuba, Caleb Parker, Ansley Lemons, Mookho Malahleha, Johan Lombaard and Lut Van Damme. Accuracy of Self-Report and Pill-Count Measures of Adherence in the FEM-PrEP Clinical Trial: Implications for Future HIV-Prevention TrialsAIDS Behav (2015) 19:743–751 DOI 10.1007/s10461-014-0859-z
3Watson-Jones D, Baisley K, Rusizoka M, et al. Measurement and predictors of adherence in a trial of HSV suppressive therapy in Tanzania. Contemp Clin Trials. 2009;30(6):504–12.
4Amico KR, McMahan V, Anderson PL, et al. Adherence indicators and PrEP drug levels in the iPrEx study. 18th Conference on Retroviruses and Opportunistic Infections. Boston; 2011 [abstract 95LB]