Does draft RCT guide set the scene for future trials?

A common set of standards for randomised clinical trials (RCTs) aims to help researchers develop the drugs and interventions of the future – no matter what they do or where they are based.

The Good Clinical Trials Collaborative (GCTC) has published a draft guidance document, and is asking for the life sciences sector to make its views known.

The publication, which is out for public consultation until 15 September, said RCTs played a central role in generating the evidence needed to inform the development and implementation of health interventions.

“However, useful evidence from good RCTs is often lacking. This can be because the RCTs were never done, because those that were done failed to produce scientifically robust and clinically relevant answers, or because the results were never published.

“This can result in failure to identify and use effective interventions or the continuing use of ineffective or hazardous interventions,” they said, adding that these issues waste resources, cause unnecessary harm or suffering, and reduce trust in the system.

“Many guidelines focus narrowly on clinical trials that are intended to generate data for regulatory submission to support a new drug license. There is an unmet need for guidance to promote the unique benefits of RCTs across all contexts and which focuses on the unique strengths of randomisation.”

Collective action

A range of clinical trial guidelines do exist, but these “largely fail to provide guidance on the underpinning principles of RCTs” in a way that helps to safely and ethically generate reliable results, regardless of context.

“Many guidelines focus narrowly on clinical trials (including non-randomized studies) that are intended to generate data for regulatory submission to support a new drug license.

“There is an unmet need for guidance to promote the unique benefits of RCTs across all contexts and which focuses on the unique strengths of randomisation.”

The GCTC has brought representatives from across the spectrum of clinical research together to develop and promote the adoption of new guidance. Members include those who fund, regulate, design, and deliver RCTs, as well as provide quality assurance, audit or inspection functions, research organisations, ethicists, clinicians, participants, and lay health advocates.

Crucially, the guidance is intended to support all those involved in the planning, conduct, analysis, oversight, interpretation, funding, and oversight of RCTs – no matter the study design, the health intervention, or the study setting.

“The objective of this guidance is to establish the key principles of RCTs: what makes an RCT good in its design and analysis, as well as ethical and social value… (It) aims to enable those involved in RCTs to work out for themselves how to design and deliver their particular RCT in their particular setting,” it said.

Underpinning principles

The guidance sets out a range of underpinning principles which, when taken together, “capture the qualities of a well-planned, well-run, and clinically relevant trial”. While the methods and approaches necessary to achieve these qualities will differ from trial to trial, their validity, said the document, is universal.

These include ensuring an appropriate trial population, with inclusive eligibility criteria that increases the relevance of the findings, setting outcomes that are “sensitive to the anticipated effects of the intervention, appropriate to the study question, and applicable… and meaningful to the relevant population”, and utilising robust intervention allocation for proper randomisation.

The guidance also talks about the importance of the proportionate, efficient, and reliable capture of data, warning against excessive data collection.

“The choice of data collection approach may be influenced by considerations such as availability, suitability, and usability, as well as the extent to which such information is sufficiently comprehensive, detailed, and timely,” it said. “Disproportionate data collection wastes time and resource and detracts from the objective of the RCT.”

In terms of trial size, the guidance makes it clear that studies need to be large and statistically powered enough to robustly assess the research question, though it recognises this may not always be possible.

“The only way to guarantee the avoidance of moderate random errors is to study sufficiently large numbers… However, there are scenarios for which it is inappropriate or challenging to randomise large numbers of participants, such as trials assessing interventions in rare diseases,” it said.

When this is the case, it may be helpful to select a relevant outcome for which the effect size is expected to be larger, for example a physiological or imaging biomarker, or it may be possible to reduce random errors through statistical analyses.

“For example, a continuous outcome adjusted for baseline values of that outcome would typically increase statistical power compared with an analysis of either mean follow-up levels or an analysis of mean changes in levels,” it said.

Respecting participants

A good RCT, the authors said, respects the rights and the well-being of its participants.

“All those involved in RCTs share responsibility for building and sustaining the trust of collaborating partner organisations and clinical communities, participants, and the wider public.

“Trust is undermined when RCTs are not sufficiently relevant, fair, transparent, and respectful of the rights, interests, concerns, and values of all involved, especially those people who participate in them or whose care will be influenced by the results.”

It is important, then, to work in partnership with people and communities, provide timely access to relevant, accessible information, and ensure that consent is informed, voluntary and competently given.

Transparency is key to the whole process, as it can help generate knowledge while also building and maintaining trust.

“Communication of trial results regardless of what those findings are, is vital to guide future research and reduce unnecessary duplication of effort, which wastes resources,” said the paper.

Building a gold standard evidence base

RCTs are the gold standard when it comes to evidence for healthcare interventions. But the space is evolving. Drug products and study designs are becoming ever more complex, and emerging clinical trial technologies are changing the way we collect and measure data.

These new guidelines aim to provide a blueprint for future trials, so the life sciences community can continue to develop the life changing, lifesaving medicines of the 21^st century.