Adaptive designs: The Swiss Army knife among clinical trial designs?

There has been considerable progress in the development and implementation of adaptive designs over the past 30 years. A major driver for this class of novel designs is the possibility to increase the information value of clinical trial data to enable better decisions, leading to more efficient drug development processes and improved late-stage success rates. In the first part of this article, we review the development of adaptive designs from different perspectives. We trace back key historical papers, report on landmark adaptive design clinical trials, review major cross-industry collaborations, and highlight key regulatory guidance documents. In the second, more technical part of this article, we address the question of whether it is possible to define factors which guide the choice between a fixed or an adaptive design for a given trial. We show that in non-linear regression models with a moderate variance of the responses, the first-stage sample size of an adaptive design should be chosen sufficiently large in order to address variability in the interim parameter estimate. In conclusion, the choice between an adaptive and a fixed design depends in a sensitive manner on the specific statistical problem under investigation.

[1]  J. Ware Investigating Therapies of Potentially Great Benefit: ECMO , 1989 .

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

[3]  M A Proschan,et al.  Designed extension of studies based on conditional power. , 1995, Biometrics.

[4]  D. Berry,et al.  I‐SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy , 2009, Clinical pharmacology and therapeutics.

[5]  S. Day,et al.  Internal pilot studies for estimating sample size. , 1994, Statistics in medicine.

[6]  H. F. Dodge,et al.  A method of sampling inspection , 1929 .

[7]  Robert A. Beckman,et al.  On Group Sequential Enrichment Design for Basket Trial , 2016 .

[8]  P. Armitage,et al.  Repeated Significance Tests on Accumulating Data , 1969 .

[9]  T. W. Anderson,et al.  Staircase Methods of Sensitivity Testing , 1946 .

[10]  Frank Bretz,et al.  Adaptive and Model-Based Dose-Ranging Trials: Quantitative Evaluation and Recommendations. White Paper of the PhRMA Working Group on Adaptive Dose-Ranging Studies , 2010 .

[11]  R. Khan,et al.  Sequential Tests of Statistical Hypotheses. , 1972 .

[12]  Frank Bretz,et al.  Twenty‐five years of confirmatory adaptive designs: opportunities and pitfalls , 2015, Statistics in medicine.

[13]  José Pinheiro,et al.  Practical Considerations for Adaptive Trial Design and Implementation , 2014 .

[14]  C. Stein A Two-Sample Test for a Linear Hypothesis Whose Power is Independent of the Variance , 1945 .

[15]  I. Bross,et al.  Sequential Medical Plans. , 1952 .

[16]  J. Wittes,et al.  The role of internal pilot studies in increasing the efficiency of clinical trials. , 1990, Statistics in medicine.

[17]  R. G. Cornell,et al.  Extracorporeal circulation in neonatal respiratory failure: a prospective randomized study. , 1985, Pediatrics.

[18]  Lili Zhao,et al.  Modern Adaptive Randomized Clinical Trials: Statistical and Practical Aspects , 2016 .

[19]  H. Robbins Some aspects of the sequential design of experiments , 1952 .

[20]  G. Watkinson,et al.  Treatment of Ulcerative Colitis with Topical Hydrocortisone Hemisuccinate Sodium , 1958, British medical journal.

[21]  Andrew P. Robinson Adaptive design theory and implementation using SAS and R , 2009 .

[22]  O. Keene,et al.  Adaptive designs for pivotal trials: discussion points from the PSI Adaptive Design Expert Group , 2006, Pharmaceutical statistics.

[23]  H. Dette,et al.  On the efficiency of two‐stage response‐adaptive designs , 2013, Statistics in medicine.

[24]  Peter Armitage,et al.  The evolution of ways of deciding when clinical trials should stop recruiting , 2014, Journal of the Royal Society of Medicine.

[25]  Frank Bretz,et al.  INHANCE: An Adaptive Confirmatory Study with Dose Selection at Interim , 2014 .

[26]  Bradley P. Carlin,et al.  Bayesian Adaptive Methods for Clinical Trials , 2010 .

[27]  Mark Chang,et al.  Innovative Approaches in Drug Development , 2007, Journal of biopharmaceutical statistics.

[28]  L. J. Wei,et al.  The Randomized Play-the-Winner Rule in Medical Trials , 1978 .

[29]  Robert A. Beckman,et al.  Statistical Design and Considerations of a Phase 3 Basket Trial for Simultaneous Investigation of Multiple Tumor Types in One Study , 2016 .

[30]  P. Armitage,et al.  N-Acetyl-para-aminophenol as an Analgesic , 1956 .

[31]  S. Pocock,et al.  Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. , 1975, Biometrics.

[32]  N. L. Johnson,et al.  Breakthroughs in Statistics , 1992 .

[33]  M. Krams,et al.  Innovative Approaches for Designing and Analyzing Adaptive Dose-Ranging Trials , 2007, Journal of biopharmaceutical statistics.

[34]  S. Chow,et al.  Handbook of Adaptive Designs in Pharmaceutical and Clinical Development , 2010 .

[35]  S. Pocock Group sequential methods in the design and analysis of clinical trials , 1977 .

[36]  A. Atkinson,et al.  Randomised Response-Adaptive Designs in Clinical Trials , 2013 .

[37]  Andrew P Grieve,et al.  Acute Stroke Therapy by Inhibition of Neutrophils (ASTIN): An Adaptive Dose-Response Study of UK-279,276 in Acute Ischemic Stroke , 2003, Stroke.

[38]  Oleksandr Sverdlov,et al.  Modern adaptive randomized clinical trials : statistical and practical aspects , 2015 .

[39]  Michael D. Smith,et al.  Adaptive Bayesian Designs for Dose-Ranging Drug Trials , 2002 .

[40]  H. Magnussen,et al.  Integrating Indacaterol Dose Selection in a Clinical Study in COPD Using an Adaptive Seamless Design. , 2009, ATS 2009.

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

[42]  Peter Armitage,et al.  Sequential Medical Trials , 1961, Biomedicine / [publiee pour l'A.A.I.C.I.G.].

[43]  H Merabet,et al.  The design and analysis of sequential clinical trials , 2013 .

[44]  Herman Chernoff,et al.  Forcing a Sequential Experiment to be Balanced , 2008 .

[45]  P ARMITAGE,et al.  Comparison of two hypotensive agents; report of a clinical trial. , 1959, Anaesthesia.

[46]  Gernot Wassmer,et al.  Group Sequential and Confirmatory Adaptive Designs in Clinical Trials , 2016 .

[47]  J. Matthews,et al.  Randomization in Clinical Trials: Theory and Practice; , 2003 .

[48]  W. R. Thompson ON THE LIKELIHOOD THAT ONE UNKNOWN PROBABILITY EXCEEDS ANOTHER IN VIEW OF THE EVIDENCE OF TWO SAMPLES , 1933 .

[49]  A L Gould,et al.  Interim analyses for monitoring clinical trials that do not materially affect the type I error rate. , 1992, Statistics in medicine.

[50]  P. Armitage,et al.  Clinical comparison of diamorphine and pholcodine as cough suppressants by a new method of sequential analysis. , 1957, Lancet.

[51]  J. Bolognese,et al.  A Monte Carlo comparison of three up-and-down designs for dose ranging. , 1983, Controlled clinical trials.

[52]  Alexander M. Mood,et al.  A Method for Obtaining and Analyzing Sensitivity Data , 1948 .

[53]  B. Turnbull,et al.  Group Sequential Methods with Applications to Clinical Trials , 1999 .

[54]  M. Zelen,et al.  Play the Winner Rule and the Controlled Clinical Trial , 1969 .

[55]  P. Armitage,et al.  Sequential tests in prophylactic and therapeutic trials. , 1954, The Quarterly journal of medicine.