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A Commentary on the U.S. FDA Adaptive Design Draft Guidance and EMA Reflection Paper from a Regulatory Perspective and Regulatory Experiences

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Practical Considerations for Adaptive Trial Design and Implementation

Part of the book series: Statistics for Biology and Health ((SBH))

Abstract

Fixed design confirmatory trials rely on emerging and reliable prior data and knowledge to provide necessary assumptions about the key design parameters including nuisance parameters. Traditionally, a fixed design has been the gold standard for its simplicity, validity, and ability to provide an unbiased estimate of the treatment effect. To allow for pre-specified flexibility in an ongoing trial, a simple two-arm controlled trial with a single primary efficacy endpoint, the repeated significance testing involving multiplicity adjustment becomes more complex than a fixed design approach. The repeated significance testing recognized in group sequential design and analysis was proposed as early as the randomization ratio adaptation in late 1960s (Zelen 1969), e.g., Armitage et al. (1969).

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References

  • Armitage P, McPherson K, Rowe BC (1969) Repeated significance tests on accumulating data. J Roy Stat Soc A 132:235–244

    Article  MathSciNet  Google Scholar 

  • Bauer P (1989) Multistage testing with adaptive designs (with discussion). Biometrie und Informatik in Medizin and Biologie 20:130–148

    Google Scholar 

  • Bauer P (2006) Discussion: methodological developments vs. regulatory requirements. Biom J 48:609–612

    Article  MathSciNet  Google Scholar 

  • Bauer P, Kieser M (1999) Combining different phases in the development of medical treatments within a single trial. Stat Med 18(14):1833–1848

    Article  Google Scholar 

  • Bauer P, Kohne K (1994) Evaluation of experiments with adaptive interim analysis. Biometrics 50:1029–1041

    Article  MATH  Google Scholar 

  • Bauer P, Brannath W, Posch M (2001) Flexible two-stage designs: an overview. Methods Inf Med 40(2):117–121

    Google Scholar 

  • Bauer P, Koenig F, Brannath W, Posch M (2010) Selection and bias—two hostile brothers. Stat Med 29(1):1–13

    MathSciNet  Google Scholar 

  • Benda N, Branson M, Maurer W, Friede T (2009) A framework for the evaluation of competing development strategies. Drug Dev 4:84–88

    Google Scholar 

  • Benda N, Brannath W, Bretz F, Burger HU, Friede T, Mauer W, Wang SJ (2010) Perspectives on the use of adaptive designs in clinical trials. Part II. Panel discussion. J Biopharm Stat 20:1098–1112

    Article  Google Scholar 

  • Bowden J, Glimm E (2008) Unbiased estimation of selected treatment means in two-stage trials. Biom J 50(4):515–527

    Article  MathSciNet  Google Scholar 

  • Brannath W, Posch M, Bauer P (2002) Recursive combination tests. J Am Stat Assoc 97:236–244

    Article  MathSciNet  MATH  Google Scholar 

  • Brannath W, Koenig F, Bauer P (2006) Estimation in flexible two stage designs. Stat Med 15:3366–3381

    Article  Google Scholar 

  • Bretz F, Wang SJ (2010) From adaptive design to modern protocol design for drug development: part II. Success probabilities and effect estimates for phase III development programs. Drug Inform J 44(3):333–342

    Google Scholar 

  • Bretz F, König F, Brannath W, Glimm E, Posch M (2009) Adaptive designs for confirmatory clinical trials. Stat Med 28(8):1181–1217

    Article  MathSciNet  Google Scholar 

  • Ellenberg SS, Geller N, Simon R, Yusuf S (eds) (1993) Proceedings of ‘practical issues in data monitoring of clinical trials’, Bethesda, Maryland, USA, January 27–28, 1992. Stat Med 12: 415–646

    Google Scholar 

  • (2007) Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design. European Medicines Agency EMA CHMP/EWP/2459/02 October 2007. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003616.pdf

  • Food and Drug Administration Moderation Act of 1997. http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDAMA/FullTextofFDAMAlaw/default.htm

  • (1998) FDA guidance for industry on providing clinical evidence of effectiveness for human drug and biological products. http://www.fda.gov/downloads/Drugs/…/Guidances/ucm078749.pdf

  • FDA (2002) Food and Drug Administration, Health Human Services, Code of Federal Regulation, 21CFR314.126. http://edocket.access.gpo.gov/cfr_2002/aprqtr/21cfr314.126.htm

  • FDA (2002) Food and Drug Administration, Health Human Services, Code of Federal Regulation, 21CFR312.23(a). http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.23

  • (2006) Guidance for clinical trial sponsors: on the establishment and operation of clinical trial data monitoring committees. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126578.pdf

  • U.S. Food and Drug Administration (2010) Draft guidance for industry on adaptive design clinical trials for drugs and biologics. Released on February 25, 2010 for public comments. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf

  • Friede T, Herderson R (2009) Exploring changes in treatment effects across design stages in adaptive trials. Pharmaceut Stat 8:62–72

    Article  Google Scholar 

  • Friede T, Parsons N, Stallard N, Todd S, Valdés-Márquez E, Chataway J, Nicholas R (2011) Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis. Stat Med 30:1528–1540

    MathSciNet  Google Scholar 

  • Gao P, Ware JH, Mehta C (2008) Sample size re-estimation for adaptive sequential design in clinical trials. J Biopharm Stat 18:1184–1196

    Article  MathSciNet  Google Scholar 

  • Hung HMJ, O’Neill RT, Wang SJ, Lawrence J (2006) A regulatory view on adaptive/flexible clinical trial design. Biom J 48:565–573

    Article  MathSciNet  Google Scholar 

  • Hung HMJ, Wang SJ, O’Neill RT (2010) Flexible design clinical trial methodology in regulatory applications. Stat Med. doi: 10.1002/sim.4021. www.interscience.wiley.com

    Google Scholar 

  • ICH (1998) ICH topic E9: statistical principles for clinical trials. www.ich.org/LOB/media/MEDIA485.pdf

  • Koch A (2006) Confirmatory clinical trials with an adaptive design. Biom J 48:574–585

    Article  MathSciNet  Google Scholar 

  • Lawrence J, Hung HMJ (2003) Estimation and confidence intervals after adjusting the maximum information. Biom J 45(2):143–152

    Article  MathSciNet  Google Scholar 

  • Müller HH, Schäfer H (2004) A general statistical principle for changing a design any time during the course of a trial. Stat Med 23:2497–2508

    Article  Google Scholar 

  • Point to consider on multiplicity issues in clinical trials. European Medicines Agency EMA CHMP/EWP/908/99 September 2002. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003640.pdf

  • Posch M, Koenig F, Branson M, Brannath W, Dunger-Baldauf C, Bauer P (2005) Testing and estimation in flexible group sequential designs with adaptive treatment selection. Stat Med 24:3697–3714

    Article  MathSciNet  Google Scholar 

  • Posch M, Maurer W, Bretz F (2011) Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim. Pharmaceut Stat 10(2):96–104

    Article  Google Scholar 

  • Proschan MA, Hunsberger SA (1995) Designed extension of studies based on conditional power. Biometrics 51:1315–1324

    Article  MATH  Google Scholar 

  • Schäfer H, Müller HH (2001) Adaptive group sequential designs for clinical trials: combining the advantages of adaptive and of classical group sequential approaches. Biometrics 57:886–891

    Article  MathSciNet  MATH  Google Scholar 

  • Schmidli H, Bretz F, Racine A, Maurer W (2006) Confirmatory seamless phase II/III clinical trials with hypotheses selection at interim: applications and practical considerations. Biom J 48(4):635–643

    Article  MathSciNet  Google Scholar 

  • Wang SJ (2006) Regulatory update on pharmacogenomics: an FDA perspective. Special report in the first multi-track DIA workshop on DIA congress on the development and utilization of pharmaceuticals moving towards e-regulation/risk management—safety and efficacy/biostatistics in Japan. pp 16–20

    Google Scholar 

  • Wang SJ (2007) Genomic biomarker derived therapeutic effect in pharmacogenomics clinical trials: a biostatistics view of personalized medicine. Taiwan Clin Trials 4:57–66

    Google Scholar 

  • Wang SJ (2009) Discussant: adaptive dose-finding studies. Proceedings of the American Statistical Association, biopharmaceutical section [CD-ROM]. American Statistical Association, Alexandria, VA

    Google Scholar 

  • Wang SJ (2010a) Perspectives on the use of adaptive designs in clinical trials: part I. Statistical considerations and issues. J Biopharm Stat 20(6):1090–1097

    Article  Google Scholar 

  • Wang SJ (2010b) Editorial: adaptive designs: appealing in development of therapeutics, and where do controversies lie? J Biopharm Stat 20(6):1083–1087

    Article  Google Scholar 

  • Wang SJ, Bretz F (2010) From adaptive design to modern protocol design for drug development: part I. Editorial and summary of adaptive designs session at the third FDA/DIA (Drug Information Association) statistics forum. Drug Inform J 44(3):325–331

    Google Scholar 

  • Wang SJ, Hung HMJ (2005) Adaptive covariate adjustment in trial design. J Biopharm Stat 15:605–611

    Article  MathSciNet  Google Scholar 

  • Wang SJ, Hung HMJ (2013a) Adaptive enrichment with subpopulation selection at interim: general concepts, applications and practical considerations. Contemp Clin Trials 36:673–681

    Article  Google Scholar 

  • Wang SJ, Hung HMJ (2013b) A conditional adaptive weighted test method for confirmatory trials. Ther Innov Reg Sci. doi:10.1177/2168479013513891

    Google Scholar 

  • Wang SJ, Nevius SE (2005) On the commonly used design and statistical considerations in double blind, potentially unblind, and open-label clinical trials. Clin Res Regul Aff 21(4):213–229

    Google Scholar 

  • Wang SJ, Hung HMJ, O’Neill RT (2005) Uncertainty of effect size and clinical (genomic) trial design flexibility/adaptivity. The Proceedings of American Statistical Association, biopharmaceutical section [CD-ROM]. American Statistical Association, Alexandria, VA

    Google Scholar 

  • Wang SJ, O’Neill RT, Hung HMJ (2007) Approaches to evaluation of treatment effect in randomized clinical trials with genomic subset. Pharmaceut Stat 6:227–244

    Article  Google Scholar 

  • Wang SJ, Hung HMJ, O’Neill RT (2009) Adaptive patient enrichment designs in therapeutic trials. Biom J 51(2):358–374

    Article  MathSciNet  Google Scholar 

  • Wang SJ, Hung HMJ, O’Neill RT (2010) Impacts of type I error rate with inappropriate use of learn for confirm in adaptive designs. Biom J 52(6):798–810. doi:10.1002/bimj.200900207

    Article  MathSciNet  MATH  Google Scholar 

  • Wang SJ, Hung HMJ, O’Neill RT (2011a) Regulatory perspectives on multiplicity in adaptive design clinical trials throughout a drug development program. J Biopharm Stat 21:846–859

    Article  MathSciNet  Google Scholar 

  • Wang SJ, Hung HMJ, O’Neill RT (2011b) Adaptive design clinical trials and logistics models in CNS drug development. Eur Neuropsychopharmacol J 21:159–166

    Article  MathSciNet  Google Scholar 

  • Wang SJ, Hung HMJ, O’Neill RT (2012) Paradigms for adaptive statistical information designs: practical experiences and strategies. Stat Med 31:3011–3023

    Article  MathSciNet  Google Scholar 

  • Wang SJ, Brannath W, Bruckner M, Hung HMJ, Koch A (2013) Unblinded adaptive statistical information design based on clinical endpoint or biomarker. Stat Biopharm Res 5(4):293–310. doi:10.1080/19466315.2013.791639, In honor of Dr. Robert T. O’Neill special issue

    Article  Google Scholar 

  • Zelen M (1969) Play the winner rule and the controlled clinical trials. J Am Stat Assoc 64:131–146

    Article  MathSciNet  Google Scholar 

Download references

Acknowledgments

The book chapter materials are based on the presentation “Adequate and well-controlled confirmatory clinical trials with adaptive design: reflections about similarities and options in two regulatory guidance documents” given at the 22nd Annual DIA Euro Meeting held in France on March 10, 2010, the webinar “U.S. FDA draft guidance adaptive design clinical trials for drugs and biologics: statistical/contents/documentation/trial integrity/interaction/reporting” given at DIA Webinar—FDA Discusses the draft guidance on May 05, 2010 and the collaborative regulatory science research conducted by the author and her collaborators. The author wishes to thank Professor Dr. sc. hum. Armin Koch, Director, Institute of Biometry, Hannover Medicine School, Hannover, Germany, the former Head of Biostatistics, Federal Institute for Drugs and Medical Devices (BfArM), one of the primary authors of the EMA reflection paper, for his extensive contribution to regulatory science. Thanks are due to Dr. Robert O’Neill’s visionary leadership and Dr. H.M. James Hung’s diligent input on the simulated Type I error rate and other aspects of adaptive design trials, and colleagues from Office of New Drugs, CDER, US FDA for their coordinated efforts with Office of Biostatistics on adaptive design regulatory submissions. The author would also like to thank the three book Editors for their kind invitation to contribute.

Disclaimer This article reflects the views of the authors and should not be construed to represent the views or policies of the U.S. Food and Drug Administration.

Author information

Authors and Affiliations

  1. Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Building 21, Room 3526, HFD-700, Silver Spring, MD, 20993-0002, USA

    Sue-Jane Wang Ph.D.

Authors
  1. Sue-Jane Wang Ph.D.
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Corresponding author

Correspondence to Sue-Jane Wang Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Clinical Biostatistics, Merck & Co., Inc., Rahway, New Jersey, USA

    Weili He

  2. Johnson & Johnson, Raritan, New Jersey, USA

    José Pinheiro

  3. Department of Clinical Biostatistics, Merck & Co., Inc., Rahway, New Jersey, USA

    Olga M. Kuznetsova

Appendices

Appendix 1: Table of Contents of the EMA Reflection Paper on Adaptive Design

Executive summary

  1. 1.

    Introduction

  2. 2.

    Scope

  3. 3.

    Legal basis

  4. 4.

    Main reflection paper text

    1. 4.1.

      Interim analyses—general considerations

      1. 4.1.1.

        The importance of confidentiality of interim results

      2. 4.1.2.

        Considerations about stopping trials early for efficacy

      3. 4.1.3.

        Overrunning

    2. 4.2.

      Interim analyses with design modifications

      1. 4.2.1.

        Adaptation of design specifications: minimal requirements

      2. 4.2.2.

        Sample size reassessment

      3. 4.2.3.

        Change or modification of the primary end-point

      4. 4.2.4.

        Discontinuing treatment arms

      5. 4.2.5.

        Switching between superiority and noninferiority

      6. 4.2.6.

        Randomization ratio

      7. 4.2.7.

        Phase II/phase III combinations, applications with one pivotal trial and the independent replication of findings

      8. 4.2.8.

        Substantial changes of trial design

      9. 4.2.9.

        Futility stopping in late phase II or phase III clinical trials

    Definitions

    References

Appendix 2: Table of Contents of the FDA Adaptive Design Draft Guidance

  1. I.

    INTRODUCTION

  2. II.

    BACKGROUND

  3. III.

    DESCRIPTION OF AND MOTIVATION FOR ADAPTIVE DESIGNS

    1. A.

      Definition and Concept of an Adaptive Design Clinical Trial

    2. B.

      Other Concepts and Terminology

    3. C.

      Motivation for Using Adaptive Design in Drug Development

  4. IV.

    GENERAL CONCERNS ASSOCIATED WITH USING ADAPTIVE DESIGN IN DRUG DEVELOPMENT

    1. A.

      Potential to Increase the Chance of Erroneous Positive Conclusions and of Positive Study Results That Are Difficult to Interpret

    2. B.

      Potential for Counterproductive Impacts of Adaptive Design

    3. C.

      Complex Adaptive Designs—Potential for Increased Planning and More Advanced Time Frame for Planning

    4. D.

      Adaptive Design in Exploratory Studies

    5. E.

      Study Design Changes That Are Not Considered Adaptive Design

  5. V.

    GENERALLY WELL-UNDERSTOOD ADAPTIVE DESIGNS WITH VALID APPROACHES TO IMPLEMENTATION

    1. A.

      Adaptation of Study Eligibility Criteria Based on Analyses of Pretreatment (Baseline) Data

    2. B.

      Adaptations to Maintain Study Power Based on Blinded Interim Analyses of Aggregate Data

    3. C.

      Adaptations Based on Interim Results of an Outcome Unrelated to Efficacy

    4. D.

      Adaptations Using Group Sequential Methods and Unblinded Analyses for Early Study Termination Because of Either Lack of Benefit or Demonstrated Efficacy

    5. E.

      Adaptations in the Data Analysis Plan Not Dependent on Within Study, Between-Group Outcome Differences

  6. VI.

    ADAPTIVE STUDY DESIGNS WHOSE PROPERTIES ARE LESS WELL UNDERSTOOD

    1. A.

      Adaptations for Dose Selection Studies

    2. B.

      Adaptive Randomization Based on Relative Treatment Group Responses

    3. C.

      Adaptation of Sample Size Based on Interim-Effect Size Estimates

    4. D.

      Adaptation of Patient Population Based on Treatment-Effect Estimates

    5. E.

      Adaptation for Endpoint Selection Based on Interim Estimate of Treatment Effect

    6. F.

      Adaptation of Multiple-Study Design Features in a Single Study

    7. G.

      Adaptations in Noninferiority Studies

  7. VII.

    STATISTICAL CONSIDERATIONS FOR LESS-WELL UNDERSTOOD ADAPTIVE DESIGN METHODS

    1. A.

      Controlling Study-Wide Type I error Rate

    2. B.

      Statistical Bias in Estimates of Treatment Effect Associated with Study Design Adaptations

    3. C.

      Potential for Increased Type II Error Rate

    4. D.

      Role of Clinical Trial Simulation in Adaptive Design Planning and Evaluation

    5. E.

      Role of the Prospective Statistical Analysis Plan in Adaptive Design Studies

  8. VIII.

    SAFETY CONSIDERATIONS IN ADAPTIVE DESIGN TRIALS

    1. A.

      Safety of Patients in Adaptive Design Dose Escalation Studies Early in Drug Development

    2. B.

      Earlier Design and Conduct of Adequate and Well-Controlled Studies with Major Expansion in the Number of Treatment-Exposed Subjects

  9. IX.

    CONTENT OF AN ADAPTIVE DESIGN PROTOCOL

    1. A.

      A&WC Adaptive Design Studies

    2. B.

      Adequate Documentation in a Protocol for an Adaptive Design Study

  10. X.

    INTERACTIONS WITH FDA WHEN PLANNING AND CONDUCTING AN ADAPTIVE DESIGN

    1. A.

      Early and Middle Period of Drug Development

    2. B.

      Late Stages of Drug Development

    3. C.

      Special Protocol Assessments

  11. XI.

    DOCUMENTATION AND PRACTICES TO PROTECT STUDY BLINDING AND INFORMATION SHARING FOR ADAPTIVE DESIGNS

  12. XII.

    EVALUATING AND REPORTING A COMPLETED STUDY

    GENERAL REFERENCES

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Wang, SJ. (2014). A Commentary on the U.S. FDA Adaptive Design Draft Guidance and EMA Reflection Paper from a Regulatory Perspective and Regulatory Experiences. In: He, W., Pinheiro, J., Kuznetsova, O. (eds) Practical Considerations for Adaptive Trial Design and Implementation. Statistics for Biology and Health. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1100-4_3

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