Statistical Analysis Plans

In order to reduce unnecessary data queries, the statistics group should be consulted early in the clinical database development process to identify variables critical for data analysis. Optimally, the statistical analysis plan would already be written by the time of database development so that the queries could be designed based on the critical variables indicated in the analysis plan. However, at the database development stage, usually only the clinical protocol exists to guide the statistics and clinical data management departments in developing the query or data management plan. 

Ideally, rules for combining centres should be detailed in the Statistical Analysis Plan. 

We will discuss the decision-making process with regard to the Statistical Analysis Plan and the Blind Review in Section 16.3. 

Covariates to be included in the analysis must be pre-specified in the protocol or in the statistical analysis plan. ... 

If new knowledge becomes available regarding important covariates after completion of the statistical analysis plan then modify the plan at the blind review stage. 

A key aspect of the definition of analysis sets and the way that missing data is to be handled is pre-specification. Usually these points will be covered in the protocol, if not, in the statistical analysis plan. If methods are not pre-specified then there will be problems as the way that these issues are dealt with could then be data driven, or at least there may be suspicion of that. This is, of course, not unique to analysis sets and missing data, but is true more generally in relation to the main methods of statistical analysis. 

It is good practice to pre-specify in the protocol, or certainly in the statistical analysis plan, the statistical method to be used for analysis for each of the endpoints within the confirmatory part of the trial. This avoids the potential for bias at the analysis stage, which could arise if a method were chosen, for example, which maximised the treatment difference. As a consequence changing the method of analysis following unblinding of the study in an unplanned way, even if there seem sound statistical reasons for doing so, is problematic. Such a switch could only be supported if there was a clear algorithm contained within the statistical analysis plan which specified the rules for the switch. An example of this would be as follows ... 

The statistical analysis plan (SAP) is a more detailed elaboration of the statistical methods of analysis contained in the protocol. The SAP is written as the trial... 

The aim of the book is not to turn non-statisticians into statisticians. I do not want you to go away from this book and do statistics. It is the job of the statistician to provide statistical input to the development plan, to individual protocols, to write the statistical analysis plan, to analyse the data and to work with medical writing in producing the clinical report also to support the company in its interactions with regulators on statistical issues. 

Biostatistics and medical writing Statistical analysis plan Review and approval of analysis plan... 

Statistical analysis plan—while it is not essential for QA to have any extensive knowledge of statistical evaluation, it is important for CQA to ensure that the analysts follow the statistical plan and do not perform analysis at inappropriate time intervals, such as an interim statistical evaluation. An interim statistical analysis may serve to invalidate and confound the data, causing the study to be out of compliance and statistically invalid. 

Identifying the statistical techniques that will be used to describe and analyze the data in an associated statistical analysis plan, which should be written in conjunction with the study protocol. 

Several summary tables are commonly presented to report safety data. Two examples of typical formats are provided here. Table 10.3 shows the format for the overall summary of adverse events falling within several adverse event categories. Such table shells are typically prepared by medical writers in advance of the study results being available and are based on the clinical study protocol and/or the statistical analysis plan written before the study started. Preparation in advance of the availability of the data saves time during the preparation of the clinical study report once the data are available. 

In the fixed sample clinical trial approach, one analysis is performed once all of the data have been collected. The chosen nominal significance level (the Type I error rate) will have been stated in the study protocol and/or the statistical analysis plan. This value is likely to be 0.05 As we have seen, declaring a finding statistically significant is typically done at the 5% p-level. In a group sequential clinical trial, the plan is to conduct at least one interim analysis and possibly several of them. This procedure will also be discussed in the trial s study protocol and/or the statistical analysis plan. For example, suppose the plan is to perform a maximum of five analyses (the fifth would have been the only analysis conducted had the trial adopted a fixed sample approach), and it is planned to enroll 1,000 subjects in the trial. The first interim analysis would be conducted after data had been collected for the first fifth of the total sample size, i.e., after 200 subjects. If this analysis provided compelling evidence to terminate the trial, it would be terminated at that point. If compelling evidence to terminate the trial was not obtained, the trial would proceed to the point where two-fifths of the total sample size had been recruited, at which point the second interim analysis would be conducted. All of the accumulated data collected to this point, i.e., the data from all 400 subjects, would be used in this analysis. 

From a statistical point of view, compelling evidence of unexpected adverse events is the hardest to address satisfactorily. When unanticipated safety concerns arise, the fact that they are unanticipated means by definition that they would not have been addressed in the study protocol or statistical analysis plan and that no prespecified analytical strategy is in place. Additionally, file vast range of possible adverse events that might be anticipated means that controlling adequately for multiplicity problems is difficult (Ellenberg et al., 2003). 

Draw up a statistical analysis plan as part of the experimental design. 

Draw up a statistical analysis plan as part of the experimental design - it is not a last minute add-on... 

Apart from compliance with SOPs for biostatistics and report writing, the statistical analysis plan, the trial protocol, regulatory requirements and guidelines (ICH E3, 1995 ICH E9, 1998 ISO 9000 2005, 2005), QA auditors check the internal consistency of the trial report and appendices and between data in tables, figures and graphs and numbers cited in the text. All numbers and percentages must be substantiated by attached tables and listings. In summary, the trial report should be an accurate representation of the clinical data. Allocation of trial... 

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