The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) statement guides the reporting of this protocol and is included as Additional file 1 . The PROSPERO International Prospective Register of Systematic Reviews, registration number is CRD42016032452.
Multiple crossover studies with a repeat challenge-withdrawal design (treatments are switched sequentially such as A-B-A-B or A-B-C-A-B-C) will be included. Trials with the sequence A-A-B-B or A-A-B-B-C-C will only be included if there is an assessed washout period in between periods that administer the same treatment. The order of allocation need not be randomised, but at least one of the treatments under investigation will be a drug, and studies should aim to determine the effect of a treatment for individual study participants. In the context of this review, a drug will be defined as any chemical substance or combination of this substance which may be used, for administration to a person, for the purpose of altering, correcting, or restoring physiological functions by exercising a metabolic, immunological, or pharmacological action .
All studies in human participants using the N of 1 trial design as defined above will be included in the review.
Included trials should at least have one of the following comparators tested for within patients: placebo, or standard care, or alternative treatment or specific dose(s) of the same treatment. The washout period will be considered as a control period if an assessment is undertaken.
The outcomes referred to below relate to the results of our study objectives, that is, the properties of the individual trials. The outcomes were chosen based on the Cochrane Consumers and Communication Review Group’s taxonomy , outcomes of relevance to end-users with regards to effective medicine use , reviews on enhancement of medication adherence , and individualised care planning .
Outcomes will include:
In terms of aim 1, the identification of different study types and their categorisation.
For aim 2, the identification of the clinical challenges addressed and their categorisation.
The identification of the clinical conditions for which N of 1 trials have been conducted and their categorisation.
Measures of clinical usefulness for aim (4) will include the following: trial enabled participants to find the most acceptable treatment or allowed trial objectives to be met based on the patient, clinician or researcher’s judgement. Other measures of usefulness will include identification of treatment responders and non-responders, improvement in patients’ health care utilisation, knowledge and understanding about their condition, treatment satisfaction, post-trial preference, self-management practices, self-efficacy, and ability to access support and/or information, confidence, and competence.
For aim (5), typical practices in N of 1 trials that could allow patients to participate actively in the research process and decision-making—that is elements of shared decision-making or pre-trial dose finding. These may include patients selecting their outcomes, use of subjective health and wellbeing measures, and use of objective health and wellbeing measures. Data on dropout rates will also be included.
For aim (6), outcomes will include participants’ experiences, views, and perceptions about N of 1 trials.
We will exclude studies without a multiple crossover design or without a repeat challenge-withdrawal design (such as A-B, or A-B-C or A-B-A, or A-B-A-C-A-D) and trials with a crossover design involving simultaneous treatment on both sides of the body. Molecular/genetic studies, study protocols, methodological papers, reviews, and studies which aim to prevent or determine causation of a disease or in which a drug was not among the treatments will also be excluded.
The following biomedical electronic databases will be searched for relevant articles: MEDLINE, EMBASE, PsycINFO (all via Ovid), AMED, CINAHAL (via EBSCO), The Cochrane Library (including CENTRAL, NHS EED, and DARE), and Web of Science (Thomson Reuters). A draft search strategy developed in MEDLINE has identified approximately 2000 abstracts (see Additional file 2). This will be adapted for use in the other databases and grey literature resources. The search strategy, developed with the help of an information specialist (SB) includes terms for N of 1 combined using AND with terms for randomised controlled trial and individualised care, with no limitation in dates.
The authors are aware that some N of 1 studies are present in the grey literature; therefore, the following sources will be searched: Controlled Clinical Trials, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), and Epitemonikos (a systematic review database). Organisational websites will also be searched: World Health Organization, UK Department of Health, U.S. Department of Health and Human Services, American College of Clinical Pharmacology, American Society for Clinical Pharmacology and Therapeutics, British Pharmacological Society, Australian Department of Health and Ageing and Health Canada. Additional papers will be identified by citation tracking, reference list checking and contacting authors of relevant articles. All searches will be conducted by one reviewer (WD).
Study selection process
Results of all searches will be exported into Endnote X7 where duplicates identified automatically will be moved to a separate folder and reported in the final flow diagram. WD will also hand search for additional duplicates not previously identified by the software. Inter-rater agreement will be tested prior to the commencement of the screening process. All titles and abstracts identified from the search will be screened independently by two reviewers based on the eligibility criteria. All full text articles of potentially relevant papers will be retrieved and screened independently by two reviewers based on the same criteria. Discrepancies during the screening process will be resolved through discussion and where consensus cannot be achieved, a third reviewer will be consulted.
Assessment of study quality of all included papers will be undertaken by WD and checked for accuracy by another reviewer. Currently, there are no quality assessment tools for the appraisal of N of 1 trials in clinical medicine. A modified version of the CONSORT extension for reporting N of 1 Trials (CENT)  will be used to appraise the quantitative papers. This will be in a yes/no format to determine if the studies reported items in the checklist. Consolidated criteria for reporting qualitative research (COREQ)  and CENT will be modified and incorporated for the assessment of qualitative papers. Any discrepancies will be discussed and a third reviewer involved when necessary.
A data extraction form will be developed using a modified version of the Consumers and Communication Review Group’s Data Extraction Template . Data will be extracted independently by WD and checked for accuracy by another reviewer. The completed forms will be compared and disagreements discussed with reference to the original paper. A third reviewer will be consulted if a consensus cannot be reached. Authors of included N of 1 studies will be contacted and asked to provide missing data or clarify any ambiguities. If authors are unable to provide relevant information on any areas of uncertainty (due to missing data or missing details) in the trial reports, this will be noted.
Data will be extracted on the following: Study methods- aims and purpose of the study, N of 1 study design subtype, funding source, competing interests, and trial coordinator; participant information- country, setting, number of participants, characteristics of participants, and nature of the condition; intervention details- type of intervention, selection of intervention, procedure, intervention provider, frequency of intervention, comparator, presence or absence of washout, and fidelity; outcomes- all outcomes regarding clinical usefulness and typical practices as stated above, selection of outcome (by whom), method of assessment, timing of measurement, and dropout rates; themes- relating to participant views, satisfaction, perception, and attitude towards N of 1 trials will be extracted; patients’ preferences, experiences of being in an N of 1 trial, professional opinion about its relevance, factors guiding patient’s choice of an outcome, other qualitative data identified in the studies and relevant to the review question will also be extracted.
Depending on the nature of the data extracted, quantitative data will be analysed descriptively. The first, second, and third aims of the review, i.e. typology of N of 1 trials based on the design sequences, particular challenges that they address and conditions in which they have been useful will be identified from the studies. They will be grouped and presented descriptively using numbers and percentages for categorical variables and means and standard deviations or medians and interquartile ranges for continuous data. It might further be presented in a graphical form to enable mapping of the typology to conditions in which they have been useful. The fourth aim, which is the clinical usefulness of N of 1 trials as stated above, will also be identified and reported. The fifth aim, typical practices in N of 1 trials as judged by the inclusion of elements of shared decision-making or pre-trial dose finding will be summarised descriptively. Trials with the stated practices will be compared to trials without them to ascertain if there are any differences in the clinical usefulness and results will be presented using percentages.
For the qualitative data, about participants’ experiences of N of 1 trials, the primary method of synthesis might be meta-ethnography if appropriate . Meta-ethnography will be judged as appropriate if there are sufficient papers containing conceptually rich and detailed qualitative data to enable translation of studies into one another . A summary of each paper will be constructed and diagramming or mapping may also help to organise and interpret data in the initial phases. This involves presenting information in a graphical form in order to show the relationship between the data . The key themes and concepts identified in these studies will form the basis for the synthesis. Variability in accounts due to any of the following elements will be investigated: study design, participant’s condition, and methodology. Our analysis will be led by the study findings themselves, but we also anticipate that analysis will be informed by the findings in the quantitative synthesis to assess similarities, links, and differences between the two bodies of literature.
If it is not possible to summarise the data in the manner stated above, a narrative approach will potentially be used to summarise the quantitative and qualitative data into a coherent whole .