The impacts of undetected nonadherence in phase II, III and post-marketing clinical trials: An overview.

Aims: This research aims to provide an overview of the consequences of undiagnosed nonadherence (noninitiation, suboptimal implementation, nonpersistence) in randomized clinical trials (RCTs).

Methods: This research was conducted by combining a literature review and qualitative semistructured interviews with key opinion leaders. Based on this groundwork, the consequences of undiagnosed nonadherence in RCTs were summarized and reported in a figure. This study focused on phases II, III and post-marketing in ambulatory settings across a variety of therapeutic areas and indications.

Results: Various consequences of nonadherence in RCTs were investigated. In phase II, drug efficacy may be underestimated, variability in the outcomes may be high and a distorted picture of side effects could be reported, resulting in an uncertain impression of the investigational product's profile and complicating decision-making. The sponsor may need to increase the sample size of the upcoming phase III study to improve its power, representing additional costs, or even terminate the study. In phase III, similar phenomena may be observed, making demonstration of efficacy to the regulatory bodies more difficult. Lastly, after commercialization, a distortion in pharmacometrics may occur: the drug may underperform, prescriptions may be refilled less often than expected or extra expenses may be incurred by the payers. This can result in post-marketing dose reduction, new competitors coming into the market and, eventually, product withdrawal.

Conclusions: This research highlighted the many potential adverse consequences of undiagnosed nonadherence in RCTs, including additional costs. Collecting accurate data appeared to be crucial for decision-making throughout the drug development process.