Adaptive designs and clinical trial simulation

A 10-part online training course on adaptive designs and clinical trial simulation:

  • Part 1: Introduction to adaptive designs in Phase II trials.
  • Part 2: Introduction to adaptive designs in Phase III trials.
  • Part 3: Response-adaptive designs in Phase II trials.
  • Part 4: Response-adaptive designs in Phase II trials (Case study and software).
  • Part 5: Adaptive designs with sample size re-estimation in Phase III trials (Methodology and examples).
  • Part 6: Adaptive designs with sample size re-estimation in Phase III trials (Case study and software).
  • Part 7: Adaptive designs with treatment selection in Phase III trials (Methodology and examples).
  • Part 8: Adaptive designs with treatment selection in Phase III trials (Case study and software).
  • Part 9: Adaptive designs with population selection in Phase III trials (Methodology and examples).
  • Part 10: Adaptive designs with population selection in Phase III trials (Case study and software).

Clinical trial simulation software

The R package (MedianaDesigner) is used throughout this training course to illustrate the process of designing adaptive Phase II and Phase III trials.

For more information on this package, visit Mediana’s web site and review the online manual.

The latest stable version of the package can be downloaded from CRAN.

References

Papers, book chapters and books used in the training course:

  • Barnes, P.J., et al. (2010). Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulmonary Pharmacology and Therapeutics. 23, 165-171.
  • Bauer, P., Kohne, K. (1994). Evaluation of experiments with adaptive interim analyses. Biometrics. 50, 1029-1041.
  • Berry, D. (2015). The Brave New World of clinical cancer research: Adaptive biomarker‐driven trials integrating clinical practice with clinical research. Molecular Oncology. 9, 951-959.
  • Bretz, F., Pinheiro, J.C., Branson, M. (2005). Combining multiple comparisons and modeling techniques in dose response studies. Biometrics. 61, 738-748.
  • Bretz, F. et al. (2006). Confirmatory seamless Phase II/III clinical trials with hypotheses selection at interim: General concepts. Biometrical Journal. 48, 623-634.
  • Bretz, F. et al. (2009). Tutorial in biostatistics: Adaptive designs for confirmatory clinical trials. Statistics in Medicine. 28, 1181-1217.
  • Brugger et al. (2011). Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced nonsmall-cell lung cancer. Journal of Clinical Oncology. 29, 4113-4120.
  • Cappuzzo, F. et al. (2010). Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled Phase 3 study. Lancet Oncology. 11, 521-529.
  • Dmitrienko, A., Tamhane, A.C., Bretz, F. (2009). Multiple testing problems in pharmaceutical statistics (editors). Chapman and Hall/CRC Press: Boca Raton, FL.
  • Dmitrienko, A., Paux, G. (2017). Subgroup analysis in clinical trials. Clinical Trial Optimization Using R. Dmitrienko, A., Pulkstenis, E. (editors). Chapman and Hall/CRC Press: Boca Raton, FL.
  • Dmitrienko, A., D’Agostino, R.B. (2018). Multiplicity considerations in clinical trials. New England Journal of Medicine. 378, 2115-2122.
  • Elsäßer, A. et al. (2014). Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency. Trials. 15, 383.
  • Grieve, A.P., Krams, M. (2005). ASTIN: A Bayesian adaptive dose-response trial in acute stroke. Clinical Trials. 4, 340-351.
  • Grignolo, A., Pretorius, S. (2016). Phase III trial failures: Costly but preventable. Applied Clinical Trials. 25.
  • Halperin, M., Lan, K., Ware, J.H., Johnson, N.J., DeMets, D.L. (1982). An aid to data monitoring in long-term clinical trials. Controlled Clinical Trials. 3, 311-323.
  • Hegi et al. (2005). MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma. New England Journal of Medicine. 352, 997-1003.
  • Hu, F., Rosenberger, W.F. (2008). The Theory of Response-Adaptive Randomization in Clinical Trials. New York: Wiley.
  • Jennison, C., Turnbull, B.W. (2000). Group Sequential Methods with Applications to Clinical Trials. Chapman and Hall/CRC Press: Boca Raton, FL.
  • Lawrence, J., Hung, H.M.J. (2003). Estimation and confidence intervals after adjusting the maximum information. Biometrical Journal. 45, 143-152.
  • Léauté-Labrèze C et al. (2015). A randomized, controlled trial of oral propranolol in infantile hemangioma. New England Journal of Medicine. 372:735-746.
  • Lee, J.J., Gu, X., Liu, S. (2010). Bayesian adaptive randomization designs for targeted agent development. Clinical Trials. 5, 584-596.
  • Lin, M. et al. (2015). CBER’s experience with adaptive design clinical trials. Therapeutic Innovation & Regulatory Science. 50, 195-203.
  • Marcus, R., Peritz, E., Gabriel, K.R. (1976). On closed testing procedures with special reference to ordered analysis of variance. Biometrika. 63, 655-660.
  • Millen, B., Dmitrienko, A., Ruberg, S., Shen, L. (2012). A statistical framework for decision making in confirmatory multi-population tailoring clinical trials. Drug Information Journal. 46, 647-656.
  • Proschan, M., Hunsberger, S.A. (1995). Designed extension of studies based on conditional power. Biometrics. 51, 1315-1324.
  • Proschan, M.A., Lan, K.K.G., Wittes, J.T. (2006). Statistical Monitoring of Clinical Trials: A Unified Approach. Springer: New York.
  • Ravandi, F., et al. (2015). Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): A randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncology. 16, P1025-1036.
  • Rubin, E.H. et al. (2011). The BATTLE trial: a bold step toward improving the efficiency of biomarker-based drug development. Cancer Discovery. 1, 17-20.
  • Schmidli, H. et al. (2006). Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: Applications and practical considerations. Biometrical Journal. 48, 635-643.
  • Wassmer, G., Brannath, W. (2016). Group Sequential and Confirmatory Adaptive Designs in Clinical Trials. New York: Springer.