Adaptive Designs and Multiple Testing in Clinical Trials
Course tittle: Adaptive Designs and Multiple Testing in Clinical Trials
Faculty: Franz König and Martin Posch. Center for Medical Statistics, Informatics und Intelligent Systems. Medical University Vienna. Spitalgasse 23, 1090 Vienna, Austria. www.meduniwien.ac.at/medstat.
Franz König is currently Associate Professor at the Section of Medical Statistics at the Medical University of Vienna, Austria. From 2008 till 2010 he was seconded to the European Medicines Agency (London, UK) as statistical expert in the Unit Human Medicines Development and Evaluation. At the EMA he held the Scientific Secretariat of the then newly founded Biostatistics Working Party (BSWP). He was involved in the development of guidelines and assessment of statistical methods and clinical trial protocols. His main research interests are multiple testing, adaptive/flexible designs, interim analyses and data safety monitoring boards (DSMB). Franz König has served as Guest Editor for Special Issues in Biometrical Journal and Statistics in Medicine.
Since September 2012 Martin Posch is professor of Medical Statistics at the Medical University of Vienna and head of the Section of Medical Statistics. Lastly, he worked as statistical expert at the European Medicines Agency (London, UK) in the Human Medicines Development and Evaluation sector, where he contributed to guideline development and the assessment of study designs. He has a PhD in Mathematics from the University of Vienna and was scientific assistant and associate professor at the Medical University of Vienna. His research interests are group sequential trials, adaptive designs and multiple testing, focusing on applications in clinical trials and Bioinformatics. Martin Posch serves as Associate Editor of Biometrics and Biometrical Journal.
Course language: English.
Course schedule: July 8 - 11, 2014. July 8-10 from 3p.m. to 7p.m; July 11 from 3p.m. to 6p.m.
Place: rooms PC3 (July 8) and PC2 (July 9-11) at FME (Facultat de Matemàtiques i Estadística, UPC)
Type of activity and class load: 15 hours classroom course.
Description: This short course will focus on two important issues for confirmatory clinical trials:
- multiplicity,
- design modifications after an interim analysis.
The first part of the short course starts with a general introduction to the problem of multiple testing. Explanations of some basic concepts are given (experimentwise and familywise error rate, strong and weak type I error control, etc.), as well as an overview of some common methods for dealing with multiple comparisons. Different sources of multiplicity such as testing multiple endpoints, multiple treatment groups and/or at multiple time points are discussed. At the end of this session, the audience should be able to identify when it is necessary to adjust for multiple comparisons, and select an appropriate adjustment. Subsequently we introduce iterative graphical approaches to construct and extend powerful multiple testing procedures, including fixed sequence tests, gatekeeping and fallback procedures. The graphical approach is illustrated with several examples from real clinical trials.
The second part is on adaptive clinical trial designs. First we introduce the key principles and statistical methodologies of adaptive designs for clinical trials. Adaptive (flexible) designs allow for mid-course design adaptations based on interim data without compromising the overall type I error rate. Examples of design adaptations are the adjustment of sample sizes or the number and timing of interim analyses. These design parameters may be adapted depending on interim estimates of the variance, the treatment effect and safety parameters. An important field of application of the adaptive design methodology are clinical trials with several treatment arms, where promising treatments can be selected at an interim analysis. Using adaptive multiple test procedures the type I error rate can be controlled even if the selection rule, the number of selected treatments or the final sample sizes are not prefixed. Adaptive multiple testing procedures can also be used in adaptive designs with the option of population enrichment. In such designs a sub population may be selected in an interim analysis and further recruitment of patients is restricted to the selected subgroup.
Adaptive designs offer a great potential for clinical trials in small populations, e.g., when developing orphan drugs for rare diseases or in personalized medicines. They make most efficient use of the information collected as because the incorporate learning & confirming paradigms into a single confirmatory trial. E.g., in the course of an adaptive dose finding trial interim information can be used to drop inefficient doses and randomize patients to the more promising doses.
The course provides an overview of methods from the published literature including the most recent developments. Special emphasis is put on sample size adjustment and multiple hypotheses testing with adaptive designs.
Finally, regulatory guidance documents relevant for multiple testing and adaptive designs will be addressed.
Evaluation:
Each day will end with a session called “Recap present day” (~30 minutes) and each day will start with a session like “Quiz on previous day” (30~minutes). These quizzes will be one part of the evaluation. Additionally, the students would have to work out exercises after the course.
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