Individual Participant Data Meta-Analysis. Группа авторов

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deviations from intended intervention balanced between groups? 2.6 Was an appropriate analysis used to estimate the effect of assignment to intervention? 2.7 If N/PN/NI to 2.6: Was there potential for a substantial impact (on the result) of the failure to analyse participants in the group to which they were randomised? Having IPD means that participants can be analysed by their allocated intervention, irrespective of how they were analysed in the original trial (Section 4.6.2). Then, provided that patients, those delivering treatments or outcome assessors are not aware of the treatments being given, and the outcomes are objective, this would mean there is no risk of bias in this domain. If the IPD do not enable analysis by the allocated intervention, there may be sufficient detail in the trial dataset to check whether participants who deviated from intended intervention did so for pre‐specified or otherwise rational reasons. Domain 3: Missing outcome data 3.1 Were data for this outcome available for all, or nearly all, participants randomised? 3.2 If N/PN/NI to 3.1: Is there evidence that the result was not biased by missing outcome data? 3.3 If N/PN to 3.2: Could missingness in the outcome depend on its true value? 3.4 If Y/PY/NI to 3.3: Is it likely that missingness in the outcome depended on its true value? Access to IPD provides opportunity to request data for participants completely excluded from the IPD dataset, and for any outcomes missing for particular individuals (Section 4.6.3). Also, the IPD obtained can be examined to check for any potential undisclosed exclusions (Section 4.6.3). Where all the relevant IPD are provided, any data that were not analysed in the trial can be reinstated in the meta‐analysis, as appropriate. Also, methods for dealing with missing outcome data (e.g. mixed models) can be implemented, even if not undertaken by trial investigators in the original analysis. Domain 4: Measurement of the outcome 4.1 Was the method of measuring the outcome inappropriate? 4.2 Could measurement or ascertainment of the outcome have differed between intervention groups? 4.3 If N/PN/NI to 4.1 and 4.2: Were outcome assessors aware of the intervention received by study participants? 4.4 If Y/PY/NI to 4.3: Could assessment of the outcome have been influenced by knowledge of intervention received? 4.5 If Y/PY/NI to 4.4: Is it likely that assessment of the outcome was influenced by knowledge of intervention received? Access to IPD offers some opportunities to redress situations where inappropriate measurement may have been used. For example, component participant‐level data can be used to construct a new composite outcome (Section 4.6.4) and this may also reduce heterogeneity across trials. Even if a range of instruments have been used in trials, a more appropriate one may be obtained via the IPD. Domain 5: Selection of the reported result 5.1 Were the data that produced this result analysed in accordance with a pre‐specified analysis plan that was finalized before unblinded outcome data were available for analysis? As new analyses are carried out according to the IPD meta‐analysis project protocol and SAP, this domain is not applicable.

      Y: yes, PY: probably yes, N: no, PY: probably no, NI: no information. Note that in RoB 2, Domain 2 has an additional/alternative series of signalling questions for risk of bias arising from deviations from interventions in terms of adhering to interventions. The additional information that may be available from the IPD is similar to those given for the effect of assignment to the intervention in the table. Domain 5 has a sub‐list of questions that are not listed, because they are not relevant to IPD meta‐analysis projects.

      Details of ways to evaluate the IPD in relation to the relevant RoB 2 domains are provided in the following sections. Findings of risk of bias and data checking can usefully be presented using a modified version of the ‘traffic light’ table used for standard risk of bias assessments (Section 4.7).

      4.6.1 The Randomisation Process

      For randomised trials, it is important to check that the methods of sequence generation and allocation concealment appear robust. This will help guard against the inclusion of non‐randomised trials, or non‐randomised participants, in the IPD meta‐analysis project. While a description of the methods can be gleaned from trial documentation and/or trial personnel, interrogating the IPD directly can highlight any unusual allocation patterns that may need further investigation.^7,9,43

A simple method of checking the pattern of allocation is to look at the cumulative number of participants randomised into each treatment group over time. For example, Figure 4.7 shows the pattern for a trial included in an IPD meta‐analysis evaluating the effects of chemoradiation for cervical cancer.⁹³ There are a similar number of participants allocated to each group throughout, and the curves cross frequently, which is what we would expect in a trial with robust randomisation procedures. It should be noted that for smaller trials, greater separation of curves and less crossing over might be expected, even if they are properly randomised, particularly if a simple method of randomisation was used. Also, where the allocation ratio is not 1:1, the curves would not be expected to cross, but rather would be expected to track one another.

Figure 4.7 The cumulative number of participants randomised to the intervention and control groups in a trial included in an IPD meta‐analysis of chemoradiation for cervical cancer.⁹³

      Source: Based on Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2008;26(35):5802–12.

A similar pattern is seen in the early stages of a trial included in an IPD meta‐analysis of chemotherapy versus radiotherapy for multiple myeloma, but for a short time period all the participants were allocated to the chemotherapy group (Figure 4.8).⁷ The trial investigator explained that this was when the radiotherapy machine had broken down, and all participants were given chemotherapy. As this particular cohort of participants were not randomly allocated to treatment, they were excluded from the IPD, thereby still allowing the trial to be included in the IPD meta‐analysis.

Figure 4.9 shows another example of how treatment allocation can be plotted, and was used to examine the pattern of assignment in a trial from another IPD meta‐analysis project. In this case, all participants except one were allocated to one intervention (arm 1) in the first months of the trial, and participants were allocated to the other intervention (arm 0) mostly in the final months. The trial investigator was unable to explain the pattern, agreed that it was not consistent with randomisation, and that the trial should be excluded from the meta‐analysis. As this was a single‐centre trial, where treatments were supplied in independently

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