INTRODUCTION

Guidance overview

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The role of randomized controlled trials in improving health

Randomized controlled trials (RCTs) play a central role in generating the evidence needed to inform the development and implementation of health interventions.

Most interventions have modest effects on health and disease, even if they have a large effect on intermediate features (e.g. physiological or laboratory tests). However, even modest improvements in health can be important provided any benefits are not substantially offset by detrimental effects. To establish reliably whether a health intervention has any effect requires that any biases or random errors inherent in the study design are both small with respect to the expected treatment effect. 

Unfortunately, useful evidence from good RCTs is often lacking. This can be because RCTs were never done, or those that were done failed to produce scientifically robust and clinically relevant answers, or 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. Such problems waste resources, cause unnecessary harm or suffering, and reduce trust in those who develop or use health interventions. It must be made easier to do good RCTs to inform the development of better interventions and the delivery of future care.

Guidance development

There is a clear need for guidance to promote the unique benefits of RCTs across all contexts and which focuses on the unique strengths of randomization while setting out the underpinning principles of RCTs necessary to generate reliable results safely and ethically, regardless of context. 

The Good Clinical Trials Collaborative was established to develop and promote the adoption of new guidance to address this issue. The Collaborative has brought together a wide range of individuals and organizations with an interest and role to play in the design, delivery, analysis and reporting of RCTs, and in implementing the results. This includes those who fund, regulate, design, deliver, or are responsible for RCTs, those who provide quality assurance, audit or inspection functions, research organizations, ethicists, clinicians, participants, and lay health advocates. It also includes those from a wide variety of sectors (industry, academia, government, charitable, non-governmental organizations, participant and public groups) and settings (including higher and lower income countries around the world).

Objective

The objective of this guidance is to establish the key principles of RCTs: what makes a RCT good in its design and analysis, as well as ethical and social value; and why this is so. This guidance aims to enable those involved in RCTs (in any capacity) to work out for themselves how a RCT should be designed and delivered in a particular setting.

This new guidance has been developed to be:

  • Based on key scientific and ethical principles and focused on issues that materially matter to the well-being of trial participants and the reliability of RCT results; 
  • Clear, concise, consistent and proportionate to the context and setting in which RCTs are conducted, recognizing that there are risks associated with both usual clinical practice and a lack of reliable evidence on the effects of an intervention; 
  • Forward looking, fostering innovation in health interventions and trial methods, including the appropriate use of routine healthcare data, technologies, and designs; and 
  • Flexible, widely applicable, utilizable and durable across disease areas, intervention types, development phases, trial designs, geographies and time. 

Scope

This guidance is intended to support all individuals and organizations involved in the planning, conduct, analysis, interpretation, funding, and oversight of all trials in which randomization is used to assess the effects of any health intervention for any purpose in any setting. The remit includes, for example: 

  • Any design: including comparisons of two or more interventions (one of which may be to provide no additional active intervention beyond usual practice); blinded or not; parallel, cluster, crossover or other design. 
  • Any health intervention: including pharmaceutical and biological therapies; medical devices; surgical procedures; vaccines; nutritional measures; cognitive, behavioural and psychological interventions; digital and public health approaches.  
  • Any purpose: intended to support reliable evaluation of the safety and efficacy of new and existing interventions; regulatory submissions; health technology assessments; and public health strategies. 
  • Any setting: including any geographic, economic or societal context; and any context including RCTs based in hospital, primary care or community settings; or delivered direct to participant.
  • Any role: including researchers and clinicians; patient and public groups (including trial participants); regulators and other government bodies; ethics committees and institutional review boards; funders; trial sponsors (e.g. academic or commercial); the health intervention industry and those who regulate or provide audit and quality assurance functions. 

How to use this guidance

This guidance provides the underpinning principles of good RCTs. In the guidance, ‘good’ should be taken to mean reliably informative, ethical and efficient. The following principles, taken together, capture the necessary qualities of a well-planned, well-run and clinically relevant trial. The methods and approaches needed to achieve these qualities will differ in small or large ways from trial to trial but their validity is universal.

The word ‘should’ implies that something is generally the right approach or a good idea but absolutes are rare. The details of how the principles are applied to any particular trial will vary and the guidelines are not intended to be applied rigidly or uncritically.