Provide justification

The overall aim of the protocol, which is a helpful concept to check along the way, is ‘is the protocol answering the question that is set’? Omitting important information on study design can hinder external review. It is important to justify how the proposed study methodology is appropriate for the question posed. Why it is the best approach?

This article is based on HRA guidance entitled ‘Specific questions that need answering when considering the design of clinical trials’. The guidance lays out questions that researchers, sponsors, peer reviewers and ethics committees should ask when planning or reviewing clinical studies.

Will the proposed design answer the research question?

'The research protocol should explain how the proposed study methodology is appropriate for the question posed, demonstrate that the design is likely to answer the research question, and why it is the best approach. The design should be underpinned by a systematic review of the existing evidence, which should be reported in the protocol [8, 9]. Absence of a systematic review raises the question: what is the design based on?

Unfortunately, our and other research has found that study protocols often lack important information on study design, which hinders external review [2, 3, 7, 12]. The HRA guidance therefore encourages researchers to explain:

  • how the proposed research method is appropriate for the question posed
  • the reasoning behind the choice of any treatment difference sought, as well as the other parameters used in the determination of the sample size
  • how the relevant successes and failures of previous studies have been taken into account in the design of the planned trial
  • the reason for the choice of comparators
  • the randomisation and blinding methods
  • the suitability of the statistical tests
  • how the sample to be studied is representative and thus, generalisable to the wider group of patients'

Five questions that need answering when considering the design of clinical trials

Trial design

There are many ways to design a clinical trial and using the most efficient and appropriate design approach is important. Applying the right design will give you the best chance of answering the question that you set. The most appropriate design will allow you to use the minimum number of subjects to answer the question.

Consider an adaptive trial design. Flexible, agile trial designs are more efficient and allow for various options to be built in to the design of the trial. Adaptive design is particularly useful when there is minimal information available on which to base the sample size calculation. Therefore, having an adaptive design allows the protocol to be adjusted within the same study as more data is gained. This is ethical and efficient and allows for growing evidence to guide the study.

Click here for a paper on adaptive trial design.

Systematic review

Item number 6a in the SPIRIT Statement Checklist requires: 'Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention.'  To place the trial in the context of available evidence, the explanation and elaboration document strongly recommends an up-to-date systematic review of relevant studies be summarised and cited in the protocol.

Click here to access the Cochrane group interactive learning modules on conducting systematic reviews.

Sample size calculation

It is important to get sample size calculation right, if the sample size is too small it will not be able to answer the question posed, and would be a waste of time and money (and unethical).  All study protocols should provide information on sample size with solid reasoning behind the calculations and how they have been determined. The justification should be a concise summary of how the assumptions used in the calculation were chosen and why they are considered plausible for the planned study. Assumptions should take into account data from previous studies and any systematic review of existing relevant evidence [Noclor Research Support Statistical Considerations]. 

Statisticians should be involved, if possible and if you need them, at an early stage of development. They provide input on the study design, outcomes measures, sample size, randomisation and analysis and these factors will influence all your subsequent steps.

Click here for the ICH Topic E 9 Statistical Principles for Clinical Trials

Click here for the CREDO statistics training module which provides a background of statistical principles relevant to clinical research and trial design