Clinical Trial Registration: Past, Present, and Future

This blog post, for International Clinical Trials Day, examined clinical trial registration detailing its origins, current strengths and weaknesses, and a call to re-engage with the vital practice moving forward.
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Well-conducted clinical trials are essential to the generation of medical evidence. This International Clinical Trials Day, it’s worth reflecting on a key tool used to ensure transparency and accountability in clinical trial research: clinical trial registries.

The value proposition of a clinical trial registry is simple. By having a public record of clinical trials that are planned, ongoing, and completed, various communities are better served. Patients can more easily discover clinical trials to join, researchers learn about studies to inform their research and evidence synthesis, and anyone with an interest in evaluating research is provided with an opportunity to check information about a registered trial.

How Did The Global Registration System Come to Be?

The movement for a global system of clinical trial registration began in the 1980s. Researchers like Robert John Simes and Kay Dickersin demonstrated the impact of reporting biases on the evaluation of clinical interventions. Trial registries were seen as one way to combat these biases. Alongside this academic interest, patient communities, especially those in the HIV/AIDS and cancer communities began to lobby for the establishment of comprehensive registers of ongoing studies to aid matchmaking of patients to trials of new emerging therapies.

Throughout the 1990s, the evidence-based medicine movement continued to champion the potential utility of clinical trial registries, and tried to develop solutions, but these efforts were usually disparate and entirely voluntary. One initiative was the launch of Current Controlled Trials which would eventually become the ISRCTN registry, the UK’s primary registry. However, this would change in the early 2000s prompted largely by the Paroxetine scandal in which evidence of harms for this antidepressant drug in young people was misreported and suppressed. This was a highly public case that eventually resulted in a large settlement with the US Government and provided the impetus needed to give real momentum to the trial registration movement.

ClinicalTrials.gov, the US government trial registry since the late 1990s, would become a leading piece of global research infrastructure and a core feature of US clinical trial regulations (i.e., the FDA Amendments Act 2007). Today ClinicalTrials.gov houses nearly half a million registrations. Other countries, and the EU, would follow suit and begin to launch their own registries throughout the early 2000s. The WHO began to coordinate these efforts and, under the auspices of the International Clinical Trials Registry Platform, would set standards registries had to meet, and specify a minimum dataset that all registries would collect and feed to the ICTRP. Currently the ICTRP recognises 17 primary registries and ClinicalTrials.gov as contributors to their database. By 2005, the members of the International Committee of Medical Journal Editors would require prospective trial registration in order to publish new clinical trial research leading to massive growth in new registrations.

The Current Registration Landscape

Registration has become an important part of the regulation and administration of clinical trials. It is mandated for many trials in the US, UK, and EU and is often a practical necessity for publication, funding, and institutional guidelines. Most importantly, it is seen as an ethical imperative under the Declaration of Helsinki and by the WHO. Many journals will indeed turn down clinical trial reports for publication if they are un- or retrospectively registered. The Cochrane Handbook considers registry searches a key part of standard systematic review methodology. Comprehensive action in the UK has led to high levels of registration of clinical research. Recent evidence suggests the footprint of publication bias in clinical medicine is substantially less than in other fields which may be owed, at least partially, to the comprehensive global registration infrastructure in place.

However, this does not mean clinical trial registration has fully solved all the problems it set out to address. Registration is still often retrospective; systematic reviewers often fail to search registries; peer reviewers may rarely be using registries as tools for accountability; dissemination of results on registries is rare, unless required by law; information on registries is often unreliable and out of date; and phenomena like outcome reporting bias persist while journals are skeptical of the potential utility of registries to address these issues. Even the regulators in charge of ensuring compliance with regulatory registration are unwilling to concede the utility of registries as tools for effective dissemination of trial information with the FDA recently stating that “It is generally not possible to draw conclusions about the safety or efficacy of FDA-regulated medical products based solely on the limited amount of public information on ClinicalTrials.gov for any specific trial, nor is this the intent of the data bank.” 

My own work has often highlighted where additional attention is required. From gaps in the enforcement and implementation of regulations in the US and EU (see 1, 2, 3, 4), to questions about the dissemination of COVID clinical trial results. Even irregularities in individual studies have caught my eye and prompted letters to the editor, but with no satisfactory resolution.

All this underlies the fundamental need for stakeholders throughout clinical science to re-engage with why we have clinical trial registration, the purpose we want it to serve, and how we can ensure it works to those ends. We need to, as a community, reflect on how and why the impressive clinical trial registration infrastructure came to be, and how we want to move it forward. We cannot allow the massive effort in establishing, and maintaining, this system to fall into little more than a bureaucratic check-box activity. Organizations that have contributed to the past success of the global registration system need to re-engage with why they made those commitments to begin with. 

I hope this piece allows you a moment, on this International Clinical Trials Day, to reflect on how clinical trial registration impacts your work and how you can potentially work to ensure more meaningful engagement with the practice within your community.

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  • ISRCTN registry ISRCTN registry

    A primary clinical trial registry recognised by WHO and ICMJE that accepts studies involving human subjects or populations with outcome measures assessing effects on human health and well-being, including studies in healthcare, social care, education, workplace safety and economic development.