European Medicines Agency September 1998 CPMP/ICH/363/96 ICH Topic E 9 Statistical Principles for Clinical Trials Step 5 NOTE FOR GUIDANCE ON STATISTICAL PRINCIPLES FOR CLINICAL TRIALS (CPMP/ICH/363/96) TRANSMISSION TO CPMP February 1997 RELEASE FOR CONSULTATION February 1997 COMMENTS REQUESTED BEFORE June 1997 FINAL APPROVAL BY CPMP March 1998 DATE FOR COMING INTO OPERATION September 1998 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 85 75 Fax (44-20) 75 23 70 40 E-mail: [email protected] http://www.emea.eu.int EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged STATISTICAL PRINCIPLES FOR CLINICAL TRIALS ICH Harmonised Tripartite Guideline Table of Contents I INTRODUCTION..................................................................................................................... 4 1.1 Background and Purpose ................................................................................................ 4 1.2 Scope and Direction........................................................................................................ 5 II CONSIDERATIONS FOR OVERALL CLINICAL DEVELOPMENT ............................. 6 2.1 Trial Context ................................................................................................................... 6 2.1.1 Development Plan................................................................................................. 6 2.1.2 Confirmatory Trial ................................................................................................ 6 2.1.3 Exploratory Trial................................................................................................... 7 2.2 Scope of Trials................................................................................................................ 7 2.2.1 Population ............................................................................................................. 7 2.2.2 Primary and Secondary Variables......................................................................... 7 2.2.3 Composite Variables ............................................................................................. 8 2.2.4 Global Assessment Variables................................................................................ 9 2.2.5 Multiple Primary Variables................................................................................... 9 2.2.6 Surrogate Variables............................................................................................. 10 2.2.7 Categorised Variables ......................................................................................... 10 2.3 Design Techniques to Avoid Bias................................................................................. 10 2.3.1 Blinding............................................................................................................... 11 2.3.2 Randomisation .................................................................................................... 12 III TRIAL DESIGN CONSIDERATIONS................................................................................. 13 3.1 Design Configuration.................................................................................................... 13 3.1.1 Parallel Group Design......................................................................................... 13 3.1.2 Crossover Design ................................................................................................ 13 3.1.3 Factorial Designs................................................................................................. 14 3.2 Multicentre Trials..........................................................................................................15 3.3 Type of Comparison...................................................................................................... 17 3.3.1 Trials to Show Superiority .................................................................................. 17 3.3.2 Trials to Show Equivalence or Non-inferiority................................................... 17 3.3.3 Trials to Show Dose-response Relationship ....................................................... 18 3.4 Group Sequential Designs............................................................................................. 19 3.5 Sample Size................................................................................................................... 19 3.6 Data Capture and Processing ........................................................................................ 20 IV TRIAL CONDUCT CONSIDERATIONS............................................................................ 20 4.1 Trial Monitoring and Interim Analysis ......................................................................... 20 © EMEA 2006 2 4.2 Changes in Inclusion and Exclusion Criteria ................................................................ 21 4.3 Accrual Rates ................................................................................................................ 21 4.4 Sample Size Adjustment ............................................................................................... 21 4.5 Interim Analysis and Early Stopping ............................................................................ 22 V DATA ANALYSIS CONSIDERATIONS ............................................................................. 23 5.1 Prespecification of the Analysis.................................................................................... 23 5.2 Analysis Sets................................................................................................................. 24 5.2.1 Full Analysis Set ................................................................................................. 24 5.2.2 Per Protocol Set................................................................................................... 26 5.2.3 Roles of the Different Analysis Sets ................................................................... 26 5.3 Missing Values and Outliers ......................................................................................... 26 5.4 Data Transformation ..................................................................................................... 27 5.5 Estimation, Confidence Intervals and Hypothesis Testing ........................................... 27 5.6 Adjustment of Significance and Confidence Levels..................................................... 28 5.7 Subgroups, Interactions and Covariates........................................................................ 28 5.8 Integrity of Data and Computer Software Validity....................................................... 29 VI EVALUATION OF SAFETY AND TOLERABILITY ....................................................... 29 6.1 Scope of Evaluation ...................................................................................................... 29 6.2 Choice of Variables and Data Collection...................................................................... 29 6.3 Set of Subjects to be Evaluated and Presentation of Data............................................. 30 6.4 Statistical Evaluation..................................................................................................... 31 6.5 Integrated Summary...................................................................................................... 31 VII REPORTING........................................................................................................................... 31 7.1 Evaluation and Reporting.............................................................................................. 32 7.2 Summarising the Clinical Database .............................................................................. 33 7.2.1 Efficacy Data....................................................................................................... 33 7.2.2 Safety Data.......................................................................................................... 34 GLOSSARY ......................................................................................................................................... 35 © EMEA 2006 3 I INTRODUCTION 1.1 Background and Purpose The efficacy and safety of medicinal products should be demonstrated by clinical trials which follow the guidance in 'Good Clinical Practice: Consolidated Guideline' (ICH E6) adopted by the ICH, 1 May 1996. The role of statistics in clinical trial design and analysis is acknowledged as essential in that ICH guideline. The proliferation of statistical research in the area of clinical trials coupled with the critical role of clinical research in the drug approval process and health care in general necessitate a succinct document on statistical issues related to clinical trials. This guidance is written primarily to attempt to harmonise the principles of statistical methodology applied to clinical trials for marketing applications submitted in Europe, Japan and the United States. As a starting point, this guideline utilised the CPMP (Committee for Proprietary Medicinal Products) Note for Guidance entitled 'Biostatistical Methodology in Clinical Trials in Applications for Marketing Authorisations for Medicinal Products' (December, 1994). It was also influenced by 'Guidelines on the Statistical Analysis of Clinical Studies' (March, 1992) from the Japanese Ministry