Letter to the editor concerning the article: ‘The impacts of undetected nonadherence in phase II, III and post-marketing clinical trials: An overview’

Abstract

We read with great interest the article by Le Flohic et al., ‘The impacts of undetected nonadherence in phase II, III and post-marketing clinical trials: An overview’,¹ which highlights the critical challenges posed by undiagnosed medication nonadherence in randomized controlled trials (RCTs). The authors present a valuable synthesis of the potential consequences of suboptimal adherence in RCTs, emphasizing how undetected medication nonadherence can lead to biased results, compromised trial outcomes and increased costs. In this context, we aim to contribute to this important discussion by providing additional insights into current regulatory and consensus-based research guidelines for defining, measuring and reporting medication adherence in RCTs.

Current regulatory guidelines emphasize the importance of addressing medication adherence in RCTs to ensure accurate and reliable results.^{2, 3} In its guideline on the clinical investigation of medicines for chronic heart failure, the European Medicines Agency (EMA) emphasizes maintaining stable background therapy throughout the study and continuing outcome assessments in all participants, regardless of adherence status.² Meanwhile, to mitigate the risks associated with medication nonadherence, the US Food and Drug Administration (FDA) recommends implementing strategies such as adherence monitoring and alert systems, educating patients on the conditions and demands of the trial and avoiding overly rapid titration of drugs to minimize early adverse reactions.³ Advances in digital health technologies can potentially enhance these efforts by enabling the remote collection of adherence-related data.^{4, 5} Furthermore, patient-reported outcome measures (PROMs) can provide valuable insights on medication adherence from the patient's perspective.^{6, 7} While digital health technologies often provide more accurate and reliable data on adherence compared to PROMs, self-reported adherence questionnaires remain essential for understanding the underlying determinants and reasons for medication nonadherence. Nevertheless, despite the critical importance of adherence in RCTs, no regulatory body currently provides dedicated, specific guidelines for defining, measuring or reporting medication adherence in clinical research, resulting in inconsistent methodologies, limited data availability and suboptimal adherence reporting in RCTs.

Recent consensus-based research guidelines for defining, measuring and reporting medication adherence can help address the lack of regulatory guidance in this area. The ABC Taxonomy for Medication Adherence provides a structured framework by categorizing adherence into three phases: initiation (‘occurs when the patient takes the first dose of a prescribed medication’), implementation (‘is the extent to which a patient's actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose’) and discontinuation (‘occurs when the patient stops taking the prescribed medication, for whatever reason(s)’), ensuring consistent definitions and interpretations in clinical trials.⁸ Building on this, the Timelines-Events-Objectives-Sources (TEOS) framework offers a practical tool for operationalizing adherence measurement by integrating four pillars: mapping treatment timelines, identifying key events, aligning study objectives with measurement needs and selecting appropriate data sources (e.g., electronic monitoring, self-report).⁹ Additionally, transparent and accurate reporting of adherence data can be facilitated by the Medication Adherence Reporting Guideline (EMERGE), which offers comprehensive recommendations for adherence reporting.¹⁰

Adopting these consensus-based research guidelines (i.e., ABC Taxonomy, TEOS and EMERGE) can effectively address methodological challenges in adherence measurement and reporting in RCTs, enabling the generation of more robust insights for regulatory and reimbursement decisions for novel medications. In parallel, dynamically monitoring medication adherence as the trial progresses can play a crucial role in uncovering barriers to adherence. By identifying early patterns of medication nonadherence, timely interventions—such as exploring potential safety issues, patient education or reminders—can be implemented to support appropriate treatment management within the trial. Integrating these adherence-focused approaches across all phases of clinical research will not only enhance trial validity but also optimize resource utilization and improve patient outcomes.

T.A., L.E. and B.B, contributed to the conception and design, revisions of critically important intellectual content and the final review and approval of the letter.

T.A. is the Chair of ESPACOMP (the International Society for Medication Adherence). B.B. is the Chair, T.A. is the Past Chair, and L.E. is the Member Engagement Co-Chair of the ISPOR (International Society for Pharmacoeconomics and Outcomes Research) Medication Adherence and Persistence Special Interest Group.