Protocol meta-analysis

Ludwig M, Katalinic A, Diedrich K. Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis. Arch Gynecol Obstet 2001 265(4) 175-82. 

It is recognised that the studies usually being combined in a meta-analysis will not all be identical and will not all have the same protocol. The dosages may be different, the endpoints may be different, treatment duration may differ, the nature of both the treatment and the comparator may be different and so on. Clearly, the more specific the question being addressed by the meta-analysis the more closely the studies must match, but the breadth of the studies that are combined will depend on the breadth of the question being asked. 

The CPMP (2001) Points to Consider on Application with 1. Meta-Analysis 2. One Pivotal Study indicates that it is good practice to write a protocol for the meta-analysis ... 

Writing a protocol in this way is important for a meta-analysis that is prespecified within a development plan, but, in order to ensure its integrity, it is maybe... 

It is still important even in this retrospective setting to write a protocol so that the meta-analysis can be performed as objectively as possible. The CPMP Points to Consider paper lists the prerequisites that are needed for such a retrospective analysis. 

It is certainly possible to pool the data from several identical toxicological studies. One approach to this is meta-analysis, considered in detail later in this chapter. For example, if an acute inhalation study was performed where only three treatment group animals survived to the point at which a critical measure (such as analysis of blood samples) was taken, there would not be enough data to perform a meaningful statistical analysis. In such a case, the protocol could be repeated with new control and treatment group animals from the same source. At the end, after assurances that the two sets of data are comparable, the data from survivors of the second study could be combined (pooled) with those from the first. 

A criticism of meta-analysis is that apples are mixed with pears. Studies with different protocols and different populations have different messages. It may well be that the studies were too small to deliver these messages clearly, but this does not mean that the result of pooling them will be meaningful. 

An important aspect that contributes substantially to the quality and strength of evidence is the availability of patient-level data and individual study protocols for each study in the meta-analysis. Such availability allows evaluation of each study s quality and eligibility for inclusion in the meta-analysis. It allows for more precise outcome definition and ascertainment. The patient-level data permit time-to-event and subgroups analyses, including dose-response analyses. These issues are discussed further in the following section below (see Section 13.6). 

Shorf of prospectively collecting fhe safety outcome, the outcome can be retrospectively obtained and adjudicated with a well-defined procedure. This approach was faken in fhe antidepressant meta-analysis example in this chapter. This approach requires detailed extensive patient-level data. It is also helpful to have fhe individual sfudy protocol to understand the information collected in fhe frials. Wifh fhis version of a retrospective outcome ascertainment, attention should be given to potential differential outcome ascertainment between the treatment arms. If the outcome was not actively solicited, there may be differences in reporting between the arms because of unrelated side effecfs of fhe freafmenf. For example, if a drug has more side effecfs, fhe patienf may be more likely to have encounters with the study investigators and report the safety outcome. 

Completeness and transparency are key principles in the reporting of a meta-analysis for the evaluation of safety in the regulatory framework. The protocol and the statistical analysis plan should be completed and finalized prior to the conduct of the meta-analysis. Any deviations or additional investigations after the finalization of the protocol should be clearly identified as such. 

The protocol should discuss what information was available prior to designing the meta-analysis and what information motivated the research objectives of the meta-analysis. The reporting should clearly state which trials were conducted and which trial results were known by study investigators prior to the design of the meta-analysis. The protocol should state the trial and patient inclusion, including discussion on any possible publication bias. The protocol should state the sources of the trial and patient data. 

Systematic errors affect the accuracy but not the precision of the result. They are usually errors in calibration or observation where the same incorrect protocol is applied to all measurements. They displace all measurements from the true value by the same amount so they cannot be detected by a statistical analysis of only one data set. However, systematic error can be detected and reduced by comparing data sets from several different sources using meta-analysis and systematic review (Rimstidt et ah, 2012). 

The described protocol for IMS allows the mapping of molecular distributions directly in tissue sections and on cell surfaces. The different approaches to SIMS are able to deliver images of distributions of small organic compounds like lipids and steroids. Since ME-SIMS and especially MetA-SIMS are capable of imaging biological surfaces with very high spatial resolution, these techniques could be very well suited for direct analysis of lipid distributions on single-cell surfaces. 

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