Protecing quality in clinical trials

To use an engineering analogy, clinical trials are sophisticated machines where their many moving parts must synchronise in harmony for the study to run according to plan and for it to achieve its stated aims.

However, as sponsors and clinical teams are all too aware, the theory of synchronicity can be derailed by any number of practical issues. In a previous article in this series we have considered, for example, how poor patient retention has the potential to introduce a metaphorical spanner into even well-oiled operations, particularly in the case of rare diseases.

And in a subsequent piece, we explored how the spotlight on such challenges has intensified since 2025, following a shift in the regulatory landscape introduced by the International Council for Harmonisation (ICH) and the updated E6 guideline on Good Clinical Practice, referred to as ICH E6(R3).

In this chapter, we look at where these developments leave the clinical trials sector today, with stakeholders both cognizant of the need to manage sources of risk while also looking to comply with updated regulatory expectations. What are the critical operational realities that must be managed in order to balance these two objectives? How can the potentially fragile dynamic of trials for rare disease drugs be made more robust and deliver on the updated guidance?

Predictably, there are no silver bullet solutions here, but it can be helpful to zoom in to areas where avoidable complications can arise. Take adherence, for example. Despite being crucial to acore understanding of the relationship between a patient’s exposure to a drug and its resulting efficacy and safety, adherence is often overlooked in the planning stages and taken for grantedwhen the trial has built momentum.

However, participants’ failure to comply with the dosing regimen specified by the protocol can be a clear indicator of their poor engagement with the trial itself. Poor engagement, in turn, can be a precursor to drop-out, a particularly acute issue in rare disease trials, which ultimately leads to a weakening of study power and, potentially, trial failure.

This situation underlines the valuable importance of establishing adherence as a key metric from the outset and then ensuring adherence monitoring as trials are in progress. So, why are adherence signals sometimes missed?

• CRO complexity. Trials are inherently network driven, integrating layers of stakeholders across multiple vendors. This can lead to fragmentation of oversight mechanisms, meaning signals of poor adherencedissipate before they are heard or anyone responds.
• Distance from patients. If decision makers are sufficiently removed from the actual patient experience, early warning signs can become abstract metrics rather than true evidence of human activity; they become absorbed into dashboards and reports rather than being surfaced as real and actionable concerns.
• No ‘single source of truth’. Even if patient data is effectively captured and integrated into trial systems, there might not be a mechanism for connecting behavioral patterns before they eventually manifest themselves in the form of dropouts. Being able to rely on a clear ‘single source of truth’ when it comes to adherence provides a clear, valuable marker of engagement, or indeed risk.
• Lagging indicators. Without real-time insight into adherence, trial coordinators can be falsely confident of patient compliance with the protocol. This has the potential to temporarily mask disengagement until it surfaces, at which point the problem has morphed into something more significant and often, irretrievable.

To raise these challenges is certainly not a witch hunt in demonstrating failings among clinical teams. Rather, it serves to highlight the various ways that patient retention and study viability can be endangered within the complex structure of modern clinical trials. And in the context of rare diseases, where recruitment can be incredibly challenging and undeniably costly, this becomes even more poignant.

There is therefore a convergence of problems: maximising patient engagement and retention; minimising dropouts and trial failures; and aligning to the new quality outcomes driven landscape shaped by ICH E6(R3). The impetus then clearly shifts to the need to find a practical solution to plugging adherence gaps. Or, to put it in simple terms, having answered questions of ‘what?’ and ‘why?’ retention difficulties arise in trials for rare diseases, teams must uncover a pragmatic and robust answer to the question of ‘how’ if they are to improve quality, reduce risk and enhance compliance.

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