WHO cares. It’s now time you did
The old adage tells us not to fix things the things that aren’t broken. Logic suggests, therefore, that wherever we do see a fix being applied, we can safely assume things aren’t working as they should.
And this is certainly the case when it comes to clinical trials. Late in 2024, the World Health Organization’s launch of best-practice guidance speaks volumes about the need to re-evaluate global and national approaches to an area of the pharmaceutical industry that is fundamental to the advancement of new treatments and better healthcare.
WHO’s guidance stems from Resolution 75.8, which was adopted by the World Health Assembly in May 2022 and stresses the urgent need for “strengthening clinical trials to provide high-quality evidence on health interventions and to improve research quality and co-ordination”.[1] Within a 76-page document, it sets out a clear picture of the importance of clinical trials, and randomized clinical trials (RCT) in particular. At the same time, it highlights the range of current challenges that can hinder best practice and compromise the quality of trial outcomes, pointing to the need “to enhance clinical research efficiency, minimize research waste and provide guidance on sustained clinical trials that are always functional and active for endemic conditions and can pivot in time of emergency or pandemics”.
Achieving those multiple objectives will no doubt require concerted implementation of the document’s various recommendations by many different stakeholders across all aspects of the design, co-ordination, implementation, analysis and reporting of clinical trials. In these terms, it appears to reflect a challenging and highly complex task.
And yet, underlying all this complexity, there is a very simple message that sits at the heart of the guidance: better trial practices are needed if we are to elicit better answers to key questions around efficacy and safety. Indeed, WHO spells this out clearly in its own language in section 2.1, where it states that “Good clinical trials are designed to produce scientifically sound answers to relevant questions”.
Going further, WHO adds that adherence plays a pivotal role in uncovering these answers, given its importance to accurately determining and quantifying the impact of the allocated trial intervention. In essence, it is saying that we can only develop a reliably complete understanding of the clinical response to a drug under trial if we have absolute certainty over the level of exposure. However, if there are weaknesses relating to medication adherence, then it is well documented that the findings will be skewed, the quality of the data will be diminished, and the critical questions of efficacy and safety will go unanswered.
Reference to medication adherence within the guidelines reinforces how it is central to the principle of RCTs based on ITT (intention to treat) analysis. But despite its importance, many clinical trials conducted today do not acknowledge, identify and address the potentially harmful weaknesses in this area. Analysis has found marked disparities in the measurement methods and definitions across trials, leading to wide variability in how adherence rates are presented across trials and therapeutic areas.[2] In addition, the common use of self-reported adherence-tracking methods such as pill count present opportunities to introduce human error as well as the different forms of psychological bias that can foreshadow more deliberate false reporting.[3]
In these situations, medication intake behaviours are not accurately tracked, leading to poor assessment of true exposure levels and flawed interpretation of study data. In turn, co-ordinators cannot be assured of the validity and reliability of clinical trial results.[4]
Implementing more reliable methods for measuring medication adherence can, therefore, be seen as critical to enhancing the integrity of trial evidence and analysis. For co-ordinators, being equipped with a genuine record of dosing history throughout the study provides the means to manage adherence more effectively and more efficiently, while also illuminating the true relationship between exposure and effect. This point is underlined by WHO in its guidance, which states that “Efforts should be made to facilitate and encourage adherence to the allocated intervention(s)”.
Complementing this point, the organization also advocates the use of digitally enabled automatic data-collection processes to enhance data relevance, reliability and completeness without burdening trial participants and staff. While this message applies across the board, in the context of adherence this approach is symbolised by the replacement of self-reporting methods with smart packaging and drug delivery devices which directly facilitate the seamless gathering of reliable data on medication exposure.
The transition to such technologies perhaps represents a departure from the status quo, but they are in line with the vision of an enhanced clinical trial landscape set out by WHO within the guidance. In publishing the document, the organization has provided both tacit admission that the current system is flawed as well as a blueprint for its improvement. Undoubtedly, it is a significant step, but whether it proves to be a pivotal moment will depend on whether stakeholders embrace the underlying sentiment, accept that change is needed, and deliver a fix to adherence that ensures trials can fulfil their invaluable promise of delivering scientifically sound answers to the crucial questions of efficacy and safety.
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[1] https://apps.who.int/gb/ebwha/pdf_files/WHA75/A75_R8-en.pdf
[2] https://pubmed.ncbi.nlm.nih.gov/35816103/
[3] https://aardexgroup.com/pill-count-compliance-its-time-to-burst-the-drug-trial-bubble/