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Included: Randomised controlled parallel group trials

Excluded: Quasi randomised trials, cluster randomised trials, cross‐over trials

Source: Lesley Stewart.

If many small trials are unavailable, this may have little impact on an IPD meta‐analysis project, because they will usually add little information to the analyses (Section 2.6.3). Conversely, if IPD are not available for several large trials, this may raise serious questions about feasibility.

If the available trials are in keeping with current practice, and the unavailable trials are old and less relevant, it may not be necessary to include the older trials, and it may even be better to exclude them (although it is preferable to identify and address this through tighter eligibility criteria when developing the project scope). If unavailable trials are deemed at high risk of bias, their omission could in fact lead to more robust results. There may even be an element of self‐selection, if those responsible for low‐quality trials, or in extremis, fraudulent trials may decline to participate because their data would not stand up to scrutiny.

Determining whether available data will be sufficient for credible analysis requires ascertaining what trials are likely to make data available. This may include gauging whether trial investigators would, in principle, be willing to share their IPD and/or establishing what data are available in repositories, and on what terms.

Before contacting trial investigators to request in principle agreement to partner in the IPD meta‐analysis, the team should ascertain whether any clarification about their trial’s eligibility is needed, for example, whether the trial population matches the IPD project’s inclusion criteria. These enquiries may be particularly important in clarifying trial design factors, such as details of randomisation and allocation concealment, which are often not well reported in trial publications. This information might then be used as part of an initial informal risk of bias assessment for each trial, if, for example, only those trials at low risk of bias are to be included in the IPD meta‐analysis. Whilst undertaking full risk of bias assessment (based on trial publications) can be done, it is not generally essential at this stage. It can however be helpful to explore key domains. Section 4.6 discusses risk of bias assessment and its relationship with data retrieval and checking. Initial communications with trial investigators should therefore be clear that their trial is potentially eligible for inclusion in the IPD project and request any additional information required to determine eligibility. Subsequently, any trials found to be inappropriate (e.g. due to inclusion criteria, design, or high risk of bias), should be excluded as early as possible and with little inconvenience for trial investigators.

When seeking in principle agreements and trying to establish feasibility, it should be borne in mind that trial investigators may not pledge support until it is certain that the IPD meta‐analysis project will go ahead, or until they know that certain other trial investigators are participating. This can make it challenging to provide an early assessment of feasibility, for example, within a funding application. Building collaboration is time consuming and an iterative process such that the decision to go ahead with an IPD meta‐analysis project almost always involves a leap of faith, and a judgement that even though not all data are yet pledged, there is a reasonable chance that, with persistence (Section 4.3), additional trials can be brought on board as the project progresses.

If planning to use IPD from a repository, it is important to map out which repository holds data from each trial, and to investigate current repository data release processes and timescales. This should include finding out the duration for which IPD will be made available in the repository, as access may be granted only within a specified time period, which could cause logistical problems if using IPD from different repositories or sources, and any charges involved. It is particularly important to find out whether data can be provided for use outside the confines of the repository, or whether analyses must be done within the repository platform.

Many repositories do not allow IPD to be exported, and so require analyses to be done within a secure space on their site, yet not all trials required for an IPD meta‐analysis project will be included within the same, or indeed any, repository. This precludes the central IPD meta‐analysis research team from creating a harmonised ‘master database’ that contains IPD from all trials and housing it locally. Importing IPD from other trials into the repository (to create a master database to be used to perform the IPD meta‐analysis within the repository space) may not be acceptable to other trial investigators. A similar issue occurs when a trial agrees to share IPD, but only allows the IPD meta‐analysis team to access it via a secure server at the trial’s host institution.

If IPD have to be accessed at more than one location, this forces a two‐stage meta‐analysis (Chapter 5) whereby IPD for each trial are firstly analysed separately within the confines of their host repository or database to generate aggregate data, and then these aggregate data are exported and combined in a meta‐analysis in the second stage. Whilst this is often entirely appropriate, there are circumstances where a one‐stage approach (Chapter 6), which analyses IPD from all studies simultaneously, is preferable, especially when outcomes are rare (Chapter 8) or when developing risk prediction models (Chapter 17). In future, sharing data across repositories or distributed syntheses (where a central data processor communicates with several data hubs, passing statistical information back and forth, without exposing the raw data at each site) may help get round such problems.⁷⁷ But for now, a one‐stage approach is rarely feasible if trials’ IPD are stored in different databases and locations. Therefore, at the outset, careful consideration must be given as to whether the trial IPD stored in repositories and the conditions of use will support the planned IPD synthesis. If restricted access would preclude or weaken the planned synthesis, repositories can be approached to see whether an exception can be made (with a careful explanation of why analysing within the repository space is not adequate).