In the early stages of drug development, as the promise surrounding a new therapy builds, there is a palpable sense of the stakes being raised. And when encouraging findings lead to progress on the clinical trial pathway, those stakes are ratcheted higher at every phase.
In the context of such intense scrutiny, it is absolutely crucial that randomized trials are underpinned by the most robust of protocols. There is simply no room for errors, flaws or weak points in the design and conduct of trials that are expected to deliver a watertight environment for evaluating the safety and efficacy of the treatment in question. From pre-trial early planning to in-trial execution and post-trial evaluation of findings, protocols provide a backbone to the process, designed to support the prerequisites of consistency, quality and rigour.
SPIRIT 2025: what’s new and what’s missing
For these reasons, the recent updating of the SPIRIT Statement by pre-eminent academics and experts in the field is a move to be welcomed. SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) was first published over a decade ago in 2013 with the intention of providing guidance to improve the completeness of trial protocols. The 2025 incarnation is the result of a systematic update to incorporate “the latest evidence and best practices”, providing a checklist of minimum items to be addressed by co-ordinators.
Updates include the addition of two new protocol items, the revision of five items and the integration of items from other guidelines. In total, 34 protocol areas are covered, many of them bringing important value by reflecting advances in trial approaches over the past decade or more.
For example, the new item (29) on ‘Trial monitoring’ requires co-ordinators to specify the frequency and procedures for monitoring trial conduct. If no monitoring is implemented, the guidance dictates that an explanation should be given. While broad in scope and open to interpretation, the emphasis on the area of trial monitoring is to be applauded, underlining the importance of applying close controls throughout the entire process to ensure the protocol is faithfully followed and standards upheld throughout.
However, the same praise cannot necessarily be attributed to the updated item on ‘Intervention and comparator’ within the new SPIRIT guidelines (15). Arguably, the new guidance represents a weakening in this area compared with the previous SPIRIT Statement from 2013. Item (11c) of this earlier version referenced “Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (e.g., drug tablet return, laboratory tests)”.
While drug tablet return is widely recognized as an upward biased measure that can be relatively easily manipulated, obscuring true adherence levels, the mention of laboratory tests pointed to a need for co-ordinators to employ more robust methods when seeking a reliable assessment of the presence of the drug in the body. Although, it is important to note that this would only be the case for the measurement of active chemical compounds and not for placebo or other behavioural interventions, for example.
Disappointingly, the new guidance of 2025 references “Strategies to improve adherence to intervention/comparator protocols, if applicable, and any procedures for monitoring adherence (for example, drug tablet return, sessions attended)”. Here, the attendance of sessions is aligned to behavioural interventions, leaving drug tablet return as the only measure of medication adherence given the omitted reference to laboratory tests.
The removal of this more robust measure of medication adherence from the SPIRIT guidance is difficult to understand. And in light of the significant advances in adherence measurement technologies since 2013, it smacks of a missed opportunity that does not sit comfortably with the authors’ ambitions “to reflect the evolving trials environment and methodological advancements”.
Why Accurate Adherence Monitoring Can’t Be Optional
For trials to deliver robust analysis of the relationship between medication exposure and physiological impact, co-ordinators must not only encourage good adherence but also establish a reliably accurate measure of true adherence levels. This provides the essential foundation for analysis.
Digital methods of medication monitoring, including the advanced AARDEX technologies successfully deployed by our pharmaceutical partners, are representative of more robust adherence approaches that are being adopted in forward-thinking trial environments. For example, the use of smart bottle caps, which electronically transmit data on human-initiated medication activity, has been shown not only to be well-accepted by patients, but to support active adherence monitoring and avoidance of medication errors.[1],[2]
Among trial co-ordinators, the SPIRIT Statement is trusted in the design stages to provide a checklist of crucial items to consider. And its underlying principle of collective industry agreement is highly valuable for encouraging consensus on best practice approaches and working towards universally consistent quality standards. Updating the guidance to reflect industry advances is undoubtedly a worthy and important undertaking, but questions should be raised by the perceived ‘softening’ of trial monitoring measures and the absence of any reference to digital adherence measurement.
A potential counter argument here is that the guidance is only designed to be “a minimum standard”. If this is the case, then there is arguably an onus on all stakeholders within the clinical trial ecosystem not just to comply with these benchmarks, but also to work beyond them, advocating for continued improvement and employing more advanced, robust and accurate approaches that are now well within reach. In this way, the SPIRIT Statement becomes less of a set of standards to aspire to and more of a platform to be built upon in the spirit of enhancing study power.
[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC11214196/
[2] https://www.sciencedirect.com/science/article/pii/S2414644721000920
