Key Multiplicity Issues in Clinical Trials (Part I)

An 8-part online training course on traditional multiplicity problems in clinical trials:

  • Introduction.
  • Module A. Clinical trial examples (Phase III trials with multiple primary and co-primary endpoints, multiple dose-control comparisons, multiple patient populations).
  • Module B. Key concepts: Inferential goals (at-least-one, all-or-none and global procedures), Error rate definitions, Classification of multiple testing procedures (single-step and stepwise procedures, nonparametric, semiparametric and parametric procedures).
  • Module C. Nonparametric and semiparametric multiple testing procedures I: Data-driven hypothesis ordering (Bonferroni, Holm, Hochberg and Hommel procedures).
  • Module D. Nonparametric multiple testing procedures II: Pre-specified hypothesis ordering (fixed-sequence, fallback and chain/graphical procedures).
  • Module E. Parametric multiple testing procedures (regular Dunnett and step-down Dunnett procedures).
  • Module F. Simultaneous confidence intervals for commonly used multiple testing procedures (single-step and stepwise procedures).
  • Module G. Power calculations in clinical trials with multiple objectives.

Clinical trial simulation software

The R package (Mediana) is used in this training course to implement the multiple testing procedures and perform power calculations for Phase II and Phase III trials. For more information on this package, see the online manual. The latest stable version of this package can be downloaded from CRAN.

The R and SAS code used in the training course can be downloaded from GitHub.

References

Key papers and books used in the training course:

  • Alosh, M., Bretz, F., Huque, M. (2014). Advanced multiplicity adjustment methods in clinical trials. Statistics in Medicine. 33, 693-713.
  • Dmitrienko, A., Tamhane, A.C., Bretz, F. (editors) (2009). Multiple Testing Problems in Pharmaceutical Statistics. Chapman and Hall/CRC Press, New York.
  • Dmitrienko, A., D’Agostino, R.B., Huque, M.F. (2013). Key multiplicity issues in clinical drug development. Statistics in Medicine. 32, 1079-1111.
  • Dmitrienko, A., D’Agostino, R.B. (2013). Tutorial in Biostatistics: Traditional multiplicity adjustment methods in clinical trials. Statistics in Medicine. 32, 5172-5218.
  • Huque, M.F., Dmitrienko, A., D’Agostino, R.B. (2013). Multiplicity issues in clinical trials with multiple objectives. Statistics in Biopharmaceutical Research. 5, 321-337.