Potential of adaptive clinical trial designs in pharmacogenetic research.

Adaptive trial designs can be beneficial in pharmacogenetic research when prior uncertainty exists regarding the exact role and clinical relevance of genetic variability in drug response. This type of design enables us to learn about the effect of the genetic variability on drug response and to immediately use this information for the remainder of the study. For different types of adaptive trial designs, we discuss when and how the designs are suitable for pharmacogenetic research: adaptation of randomization, adaptation of patient enrollment and adaptive enrichment. To illustrate the potential benefits of an adaptive design over a fixed design, we simulated an adaptive trial based on the results of the IPASS trial. With a simple model we show that for this example an adaptive enrichment design would have led to a smaller trial, with less EGF receptor mutation-negative patients unnecessarily exposed to the drug, without compromising the α level or reducing power.

[1]  I. Tweel,et al.  Early stopping in clinical trials and epidemiologic studies for "futility": conditional power versus sequential analysis. , 2003 .

[2]  J Licinio,et al.  Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response , 2004, Molecular Psychiatry.

[3]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Abdulkadir Hussein,et al.  Statistical Monitoring of Clinical Trials , 2008, Technometrics.

[5]  F. Hirsch,et al.  Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Robert T O'Neill,et al.  A Regulatory View on Adaptive/Flexible Clinical Trial Design , 2006, Biometrical journal. Biometrische Zeitschrift.

[7]  D L DeMets,et al.  An aid to data monitoring in long-term clinical trials. , 1982, Controlled clinical trials.

[8]  Sue-Jane Wang,et al.  Adaptive patient enrichment designs in therapeutic trials , 2009, Biometrical journal. Biometrische Zeitschrift.

[9]  D. Berry,et al.  Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  Edward S. Kim,et al.  Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  M. Krams,et al.  Adaptive Designs in Clinical Drug Development—An Executive Summary of the PhRMA Working Group , 2006, Journal of biopharmaceutical statistics.

[12]  M. J. van der Laan,et al.  Optimizing randomized trial designs to distinguish which subpopulations benefit from treatment. , 2011, Biometrika.

[13]  Y. Lecrubier,et al.  Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. , 2002, The American journal of psychiatry.

[14]  Blair T. Johnson,et al.  Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration , 2008, PLoS medicine.

[15]  C Furtek,et al.  Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine , 2008, Neurology.

[16]  T. Mok,et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. , 2009, The New England journal of medicine.

[17]  D. Haber,et al.  Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. , 2005, Cold Spring Harbor symposia on quantitative biology.

[18]  P. Bauer,et al.  Evaluation of experiments with adaptive interim analyses. , 1994, Biometrics.

[19]  J. Lachin.  A review of methods for futility stopping based on conditional power , 2005, Statistics in medicine.

[20]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[21]  A. Egberts,et al.  Pharmacogenetics in randomized controlled trials: considerations for trial design. , 2011, Pharmacogenomics.

[22]  G. Guyatt,et al.  Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. , 2010, JAMA.