Patient-Centric Methods for Tackling Clinical Trial IP Nonadherence

The topic of investigational product (IP) nonadherence in clinical trials has recently garnered a lot of interest from the industry, and technology enterprises are now offering clinical trial solutions to better IP tracking and adherence. While there are many approaches towards tackling the issue of IP nonadherence, Nadir Benouali, Founder & President of MEDICODOSE Systems, will elaborate on his perspectives regarding the causes and issues of IP nonadherence, what the pharmaceutical industry is doing to tackle IP nonadherence, patient-centric and site friendly solutions to addressing IP nonadherence.

MA: What are the issues of investigational product (IP) nonadherence in clinical trials?

Nadir Benouali

NB: There are a lot of scientific papers that have been published on the issue of IP nonadherence, so this issue is not entirely new, as it has gained a lot of momentum in the US and Europe in the last few decades. While the issue of IP nonadherence is a direct consequence of the deviation of enrolled patients’ behavior from the study requirements, the majority of clinical trials still use a combination of pill counts and self-reported data to measure IP adherence. Research has also shown that IP adherence declines constantly as a study progresses; 100 days into a study’s execution, IP adherence declines from 100% to a range of 70%-80%, and by day 300, adherence drops to a range of 60%-70%¹. What’s worse is that IP nonadherence decline has an exponential impact on pharmacological and safety data variabilities in response to the IP. Reasons for nonadherence include patients’ volitional acts; some patients may doubt in the IP and disengage from following study procedures and decide to either double the dose thinking they are “catching up” on missed ones, or skipping doses, whereas and most have busy lives and simply forget, and as we all know forgetfulness is the major factor, if not, the main culprit of patient non-adherence.

MA: What is the biopharmaceutical industry currently doing to mitigate IP nonadherence?NB: Pharmaceutical companies around the world are adopting innovative measures to address and measure IP nonadherence. Since the advent of electronic era, many scientific papers have shown the value of shifting from conventional IP testing only to introducing smart packaging to support patients’ adherence as well. There are intelligent bottle caps that record the opening and closing events, assuming the patient took the right dose from the bottle. Then there are calendarized adherence prompting blister packaging and smart blister packaging that monitor IP adherence, which are becoming a trend in the pharmaceutical industry at the moment. In most cases, the data collected include only the days of the week, numbers of pills, and time of the day. However, some smart packages do need extra devices, such as readers to download dosing histories, which can increase the workload burden on the site. Other technologies use smartphone cameras to visually confirm that the IP is swallowed. This can be effective, as we have the confirmation that the patient ingested the IP, but that approach does not take into account the patient’s willingness to participate in studies using such technologies as they may be averse to it.

MA: Are there other approaches to managing IP nonadherence?NB: The approach we have developed to managing IP nonadherence consists of a combination of two technologies: a smart blister that monitors and reports patients’ medication intake adherence along with adherence platform, which enables sites and investigators to track IP and PRO adherence rates to evaluate nonadherence-related risks in real-time. Using either IVR or IWR systems, the adherence platform remotely captures IP adherence, ePRO adherence and e-diaries reported data. The smart blister packaging is a stand-alone packaging that doesn’t require a reader to download dosing histories (date, time stamps and pill position), nor a connection to WiFi, and neither NFC nor Bluetooth. The packaging looks the same as any conventional medicine blister packaging, thus staying with what the patient is familiar with, except for a tiny LCD screen display on the packaging. What is unique about this approach is that it allows cross-validating IP adherence with PRO adherence data versus the predefined protocol time windows and the specific order of the patient’s execution.

MA: So, how does this approach and technology work?NB: The adherence platform is compatible with existing EDC-based technologies. The platform was designed by considering the views and expectations of patients, sites and study teams. For example, the platform includes an IP reminder feature if the patients wish to be reminded, and remote monitoring capabilities for patients who wish to have less study visits. The platform is also patient-friendly for non-tech savvy patients, as training involvement is minimal, and processes do not change patients’ regular habits. The platform automatically flags and alerts investigators in real-time to any nonadherence. In a nutshell, the platform allows sponsors, CROs and investigators to have direct access to dynamic dashboards that accounts for IP adherence rates and PRO data simultaneously, thus allowing systematic protocol deviation detection.

MA: What impact does this solution have on improving data quality?NB: Without tracking IP adherence, neither the investigator, nor the sponsor know whether the patient is taking their IP or not, which can impact data variability, patient safety, and study outcomes. The adherence platform allows site staff to intervene with and address noncompliance-related safety and efficacy outcomes in clinical trials.


References:

1. Source: Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Blaschke TF¹, Osterberg L, Vrijens B, Urquhart J., Annu Rev Pharmacol Toxicol. 2012
2. Smith, Dorothy PharmD, Patient Nonadherence in Clinical Trials: Could There Be a Link to Post Marketing Patient Safety?, Consumer Health Information Corporation, October 2011