Poor adherence to the investigational product can bring even the most carefully planned clinical trial to its knees. It is time to accept that traditional approaches such as pill count do not work. We need to upset the status quo by embracing the potential of modern medication adherence management.
Suboptimal medicine-taking behavior, which affects around 30% of all trial participants by day 90,1 reduces effect size and increases variability, draining painstakingly calculated study power and resulting in non-significant findings.
A 2012 review of six HIV pre-exposure prophylaxis (PrEP) product trials demonstrated this perfectly, by showing a direct correlation between medicine-taking behavior and recorded drug efficacy. An oral FTC/TDC for women (FEM-PrEP) with an adherence rate of less than 30% reported efficacy of just 6%, whereas another, of Truvada, achieved an adherence rate of 96% and an efficacy rate of 100%. This was despite the products being similar in mode of action.2
Sponsors who neglect to manage this important source of variation leave themselves open to wholly avoidable study failure. When we consider the expense of modern clinical trials, and that just 13.8% of products entering industry-sponsored Phase I trials ever go on to obtain FDA approval,3 it is clear why pharma is starting to acknowledge the impact of poor medication adherence in clinical trials. They need to give their candidates every chance of success. Last month, drug giant Pfizer said study participants not adhering to their investigational product regimen was “corrosive to the integrity of the trial itself”. It increases the number of patients required to complete a study, prolongs study length, and drives up costs, as well as masks important safety signals and greatly complicates trial execution, said the organization’s chief medical officer, Dr. Freda Lewis-Hall.4 It is a similar story at Novartis, which has highlighted the role of poor medication adherence in the fight against the current cardiovascular disease (CVD) epidemic. Speaking as part of a company-sponsored video series, Dr. Steven Nissen, researcher, patient advocate, and chairman of cardiovascular medicine at the Cleveland Clinic, explained that CVDs are the leading cause of mortality the world over, accounting for 32% of all deaths.5 This is despite the emergence of highly effective, evidence-backed drugs for primary and secondary prevention, such as statins and angiotensin-converting enzyme (ACE) inhibitors, he said, adding: “We have powerful drugs, but they don’t work if you don’t take them…the problem is adherence.”6
Regulators are also placing an additional emphasis on adherence rates. The FDA’s 2019 Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products, for instance, said that reliable patient adherence data “provided valuable safety and efficacy information”. As such, more attention should be paid to this information during regulatory review, it went on.7
Tackling a problem like medication adherence requires the right tools for the job but, until relatively recently, they have been in short supply. Pill count has been a mainstay of dose tracking for decades. Its accuracy, however, has been in question for more than 30 years. Back in 1989, researchers compared adherence as recorded by pill count to that as measured by plasma phenobarbital concentration in 216 patients from three separate studies. They found that 161 appeared to have between 90% to 109% compliance by return tablet count, yet, of these, 51 (32%) had plasma phenobarbital concentrations less than 90% of the lowest value previously found in normal volunteers. The authors concluded that the return tablet count “grossly overestimates compliance”, and this finding has been reproduced multiple times in the intervening years.8
Self-report, which relies on the study participant’s memory making it vulnerable to recall bias, is equally problematic. The trial included in the HIV PrEP review returned a statistically insignificant efficacy rate of just 6%, for example, recorded self-reported adherence at 83%, but this figure stood at 30% when measured by blood concentrations.2