The following information on Protocols is taken from the Cochrane Handbook. Though it is specific in referencing Cochrane Reviews, anyone conducting a systematic review, whether for Cochrane or not, should develop a Protocol as one of the formative steps in conducting a systematic review. Example protocol.
Chandler J, Cumpston M, Thomas J, Higgins JPT, Deeks JJ, Clarke MJ. Chapter I: Introduction. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.
1.5 Protocol Development
All Cochrane Reviews must have a written protocol, specifying in advance the scope and methods to be used by the review, to assist in planning and reduce the risk of bias in the review process. Preparing a systematic review is complex and involves many judgements. To minimize the potential for bias in the review process, these judgements should be made as far as possible in ways that do not depend on the findings of the studies included in the review. Review authors’ prior knowledge of the evidence may, for example, influence the definition of a systematic review question, the choice of criteria for study eligibility, or the pre-specification of intervention comparisons and outcomes to analyse. It is important that the methods to be used should be established and documented in advance.
Publication of a protocol for a review that is written without knowledge of the available studies reduces the impact of review authors’ biases, promotes transparency of methods and processes, reduces the potential for duplication, allows peer review of the planned methods before they have been completed, and offers an opportunity for the review team to plan resources and logistics for undertaking the review itself.
The review question should determine the methods used in the review, and not vice versa.
The protocol sets out the context in which the review is being conducted. It presents an opportunity to develop ideas that are foundational for the review. This concerns, most explicitly, definition of the eligibility criteria such as the study participants and the choice of comparators and outcomes. See MECIR Box 1.5.a, MECIR Box 1.5.b and MECIR Box 1.5.c.
MECIR Box 1.5.a (Planning the Search):
Plan in advance the methods to be used for identifying studies. Design searches to capture as many studies as possible that meet the eligibility criteria, ensuring that relevant time periods and sources are covered and not restricted by language or publication status.
Searches should be motivated directly by the eligibility criteria for the review, and it is important that all types of eligible studies are considered when planning the search. If searches are restricted by publication status or by language of publication, there is a possibility of publication bias, or language bias (whereby the language of publication is selected in a way that depends on the findings of the study), or both. Removing language restrictions in English language databases is not a good substitute for searching non-English language journals and databases.
A key purpose of the protocol is to make plans to minimize bias in the eventual findings of the review. Reliable synthesis of available evidence requires a planned, systematic approach. Threats to the validity of systematic reviews can come from the studies they include or the process by which reviews are conducted. Biases within the studies can arise from the method by which participants are allocated to the intervention groups, awareness of intervention group assignment, and the collection, analysis and reporting of data. Methods for examining these issues should be specified in the protocol. Review processes can generate bias through a failure to identify an unbiased (and preferably complete) set of studies, and poor quality assurance throughout the review. The availability of research may be influenced by the nature of the results (i.e. reporting bias). To reduce the impact of this form of bias, searching may need to include unpublished sources of evidence (Dwan et al 2013)
MECIR Box 1.5.b (Planning the Assessment of Risk of Bias in included studies):
Plan in advance the methods to be used for assessing risk of bias in included studies, including the tool(s) to be used, how the tool(s) will be implemented, and the criteria used to assign studies, for example, to judgements of low risk, high risk, and unclear risk of bias. Predefining the methods and criteria for assessing risk of bias is important since analysis or interpretation of the review findings may be affected by the judgements made during this process.
Developing a protocol for a systematic review has benefits beyond reducing bias. Investing effort in designing a systematic review will make the process more manageable and help to inform key priorities for the review. Defining the question, referring to it throughout, and using appropriate methods to address the question, focuses the analysis and reporting, ensuring the review is most likely to inform treatment decisions for funders, policy makers, healthcare professionals and consumers. Details of the planned analyses, including investigations of variability across studies, should be specified in the protocol, along with methods for interpreting the results through the systematic consideration of factors that affect confidence in estimates of intervention effect.
MECIR Box 1.5.c (Planning the Synthesis of Results):
Plan in advance the methods to be used to synthesize the results of the included studies, including whether a quantitative synthesis is planned, how heterogeneity will be assessed, choice of effect measure (e.g. odds ratio, risk ratio, risk difference or other for dichotomous outcomes), and methods for meta-analysis (e.g. inverse variance or Mantel Haenszel, fixed-effect or random-effects model).
Predefining the synthesis methods, particularly the statistical methods, is important, since analysis or interpretation of the review findings may be affected by the judgements made during this process. C23: Plan in advance the methods to be used for assessing the certainty of the body of evidence, and summarizing the findings of the review.
Methods for assessing the certainty of evidence for the most important outcomes in the review need to be pre-specified. In ‘Summary of findings’ tables the most important feature is to predefine the choice of outcomes in order to guard against selective presentation of results in the review. The table should include the essential outcomes for decision making (typically up to seven), which generally should not include surrogate or interim outcomes. The choice of outcomes should not be based on any anticipated or observed magnitude of effect, or because they are likely to have been addressed in the studies to be reviewed.
While the intention should be that a review will adhere to the published protocol, changes in a review protocol are sometimes necessary. This is also the case for a protocol for a randomized trial, which must sometimes be changed to adapt to unanticipated circumstances such as problems with participant recruitment, data collection or event rates. While every effort should be made to adhere to a predetermined protocol, this is not always possible or appropriate. It is important, however, that changes in the protocol should not be made based on how they affect the outcome of the research study, whether it is a randomized trial or a systematic review. Post hoc decisions made when the impact on the results of the research is known, such as excluding selected studies from a systematic review, or changing the statistical analysis, are highly susceptible to bias and should therefore be avoided unless there are reasonable grounds for doing this.
Systematic reviews should be replicable, and retaining a record of the inclusion decisions, data collection, transformations or adjustment of data will help to establish a secure and retrievable audit trail. Systematic reviews can be operationally complex projects, often involving large research teams operating in different sites across the world. Good data management processes are essential to ensure that data are not inadvertently lost, facilitating the identification and correction of errors and supporting future efforts to update and maintain the review. Transparent reporting of review decisions enables readers to assess the reliability of the review for themselves.
Review management software, such as Covidence ($) and EPPI-Reviewer ($) or Rayyan, can be used to assist data management and maintain consistent and standardized records of decisions made throughout the review. These tools offer a central repository for review data that can be accessed remotely throughout the world by members of the review team. They record independent assessment of studies for inclusion, risk of bias and extraction of data, enabling checks to be made later in the process if needed. Research has shown that even experienced reviewers make mistakes and disagree with one another on risk-of-bias assessments, so it is particularly important to maintain quality assurance here, despite its cost in terms of author time. As more sophisticated information technology tools begin to be deployed in reviews it is increasingly apparent that all review data – including the initial decisions about study eligibility – have value beyond the scope of the individual review. For example, review updates can be made more efficient through (semi-) automation when data from the original review are available for machine learning. For more information, please see the following article on Software Tools for Literature Screening by Van der Mierden, et al.
Formal Registration of Protocols: https://www.crd.york.ac.uk/prospero/