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A Henry Stewart Briefing on
NEW ICH Statistical “Points to Consider” when
 Analysing and Presenting Clinical Trial Data
in European Licensing Applications

Thursday, 20 & Friday, 21 February 2003
Radisson SAS Portman Hotel, London W1

Background to this Briefing

The ICH Guidelines concerned with statistics do not, and cannot, address all the statistical topics encountered in licensing applications in sufficient depth. Difficulties continue to arise in practice and a need for additional guidance has been identified. To address this need, the EMEA’s Committee for Proprietary Medicinal Products (CPMP) has released Points to Consider (PtC) documents on methodological topics. They are targeted at statistical topics found to be a regular source of problems during the assessment of licensing applications, chiefly those concerned with the design and analysis of clinical trials.

Missing Data : Problems highlighted with the “Points to Consider” document on Missing Data
The CPMP “Points to Consider” on missing data was adopted in November 2001, but it may be revised. Missing values lead to bias, but judging and correcting for this bias is fraught with problems. The interpretation for an equivalence/non-inferiority study is different from that in a study designed to show a difference. This PtC document is especially useful as it is the first substantial regulatory guidance in this area and it is designed to be readable by both statisticians and non-statisticians. This presentation will highlight the important points of the document and raise some serious questions concerning its overall applicability.

  • Should ‘last observation carried forward’ be the standard approach or have its limitations been overlooked?
  • Is ‘worst case imputation’ too conservative to be useful?
  • Will newer statistical methodology, such as multiple imputation, provide better results and be acceptable to regulatory authorities?
  • What about ‘missing at random’ ?
  • Is there any real value in recording data from patients who withdraw?

Adjustment for Baseline Covariates
The CPMP “Points to Consider” on adjustment for baseline covariates was issued as a draft in December 2001 but has not yet been adopted. The document is very thorough and it expands on ICH E9 recommendations by clarifying which baseline covariate should be included in the protocol and how results should be reported. This presentation will highlight the important points in the document and also challenge some of the contents.

  • How strong should an expected correlation be to justify including it in the primary analysis model?
  • Is there a need for unadjusted analyses when use of a covariate is standard for that indication?
  • Can a covariate be used if it was not specified in the protocol?
  • Is there now a standard approach for adjusting for differences between centres?
  • Do the assumptions of linearity and parallelism need to be checked?
  • Is it sensible to categorize if the covariate is non-linear?