Explanation

The ethical and scientific justification for a trial depends on the uncertainty of the benefit or harm of the intervention to be tested. This uncertainty depends in turn on what is known on the topic before the trial commences. The background section of a protocol should summarise the relevance of the research question, justify the need for the trial in the context of available evidence, and present any available preliminary data regarding the potential effects of the interventions (benefits and harms), thus reporting a rationale for the trial.

This information is particularly important to the trial participants, as it provides motivation for contributing to the trial.(140) It is also relevant to funders, research ethics committees/institutional review boards, and other groups who evaluate the scientific and ethical basis for trial approval. The background should also present a plausible explanation for how the intervention might work. Understanding the rationale or theory underpinning an intervention helps readers to understand which aspects or components are likely to be essential to its efficacy or harm, and which are likely to be incidental.(24)

Reviews of two samples of 108 and 292 trial protocols from 2016 found that 44% and 26% justified the research question, respectively.(9, 10)

The World Medical Association’s Declaration of Helsinki states that biomedical research involving people should be based on a thorough knowledge of the scientific literature, as it is unethical to expose humans unnecessarily to the risks of research.(2) To place the trial in the context of available evidence, it is strongly recommended that an up-to-date, systematic review of relevant trials be summarised and cited in the protocol, or in the absence of a published review, that the protocol authors systematically identify and summarise previous trials.(141, 142) This evidence can also help researchers to optimise the usefulness of the new trial by informing design aspects such as outcome definition and sample size.(143-145)

Several funders request this background information in grant applications.(146, 147) Failure to review the cumulative evidence can lead to unnecessary and wasteful duplication of research(148) or to trial participants being deprived of effective interventions, or exposed to harmful interventions.(144, 149-151) Prior reviews of trial protocols have found that many do not cite the systematic reviews or trials that exist on the same topic.(152-154)

Summary of key elements to address

● Importance of the research question

● Why a new trial is needed in the context of available evidence

o Explanation of how the intervention might work

o Pretrial evidence of the benefits and harms of the interventions

o Reference to systematic review(s) of relevant trials; if none is available, a summary of relevant trials based on a systematic search