Statistics, clinical trial guidelines

Draft Guideline on Statistical Principles for Clinical Trials Notice of Availability... 

Statistical thinking and practice is very much determined by the regulatory guidelines that are in place. Primarily it is ICH E9 Statistical Principles for Clinical Trials , published in 1998, which sets down the broad framework within which we operate. In 2001 we saw the publication of ICH ElO Choice of Control Group which contained advice on the appropriate choice of concurrent control group and in particular first introduced the concept of assay sensitivity (see Section 12.5) in active control, non-inferiority trials. 

Statistical Principles for Clinical Trials ICH Harmonized Tripartite Guideline (E9), 1998. 

Guidelines on statistical analysis of clinical trials (Notification No. 20 in 1992)... 

An applicant may provide an overall summary of data from controlled trials. This section is optional and many firms do not include it because the results of the trials are presented in the integrated summaries of efficacy and safety, which will be discussed later in this chapter. The Guidelines for the Clinical and Statistical Sections of a New Drug Application also address the format and content of an integrated clinical/statistical report for a clinical trial this too will be discussed later. 

Given the level of research activity devoted to identification of influential observations, considerably less effort has been devoted to what to do about them. Under guidelines (E9 Statistical Principles for Clinical Trials) developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (1997), more commonly called ICH, several principles for dealing with outliers or influential observations are presented. First, data analysis should be defined prior to analyzing the data, preferable before data collection even begins. The data analysis plan should specify in detail how outliers or influential observations will be handled. Second, in the absence of a plan for handling outliers or influential observations, the analyst should do two analyses, one with and the other without the points in question, and the differences between the results should be presented in the discussion of the results. Lastly, identification of outliers should be based on statistical, as well as scientific rationale, and that the context of the data point should dictate how to deal with it. 

All chapters have been brought up to date in the new edition and in particular, there is extensive reference to various guidelines of the International Conference of Harmonization that have been issued since the first edition, in particular ICH E9, Statistical Principles for Clinical Trials. A new chapter on pharmaco-genetics has been added. For the reader in possession of a first edition who wishes to know whether to splash out on a second, Figure P.l may be helpful. (This is partly so that I can underline the fact that nothing in life, not even an author s preface, should be exempt from statistics ) This compares the two editions chapter by chapter in terms of their length in thousands of words. 

ICH E9 (1998) Statistical principles for clinical trials. Available at http //www.ich.org/fileadmin/ PubUc Web Site/ICH Products/Guidelines/Efficacy/E9/Step4/E9 Guideline.pdf. Accessed 23 Nov 2015... 

Section 1 of the guidelines establishes the context of the submission. It asks for a description of the drug, its use on the PBS and the therapies that wiU be co-administered or substituted. Section 2 asks for the best available evidence on the clinical performance of the drug, including the scientific and statistical rigour of randomised trials, and a preliminary economic evaluation based on evidence from the randomised trials. Section 3 describes when extrapolation beyond the preliminary economic evaluation maybe made and how adjustments can be made in a modelled economic evaluation. Section 4 requests a financial analysis from the perspective of the PBS and government health budgets. 

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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