The Role of Adaptive Designs in Clinical Development Program*

Transcription

1 The Role of Adaptive Designs in Clinical Development Program* Sue-Jane Wang, Ph.D. Associate Director, Adaptive Design and Pharmacogenomics Office of Biostatistics, Office of Translational Sciences Center for Drug Evaluation and Research, U.S. FDA Presented at 2010 Rutgers Biostatistics Day Rutgers University, NJ, April 16, 2010 * FDA current thinking, with some professional views

2 Adaptive Design Prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study Analysis of the accumulating study data are performed at prospectively planned time-points within the study Analyses can be performed in a fully blinded manner or in an unblinded manner, and can occur with or without formal statistical hypothesis testing

3 Design Elements for Adaptation Total sample size of the study Treatment regimens Study objectives Study eligibility criteria (patient population) Randomization procedure Baseline Covariate Planned schedule of patient evaluations for data collection Primary endpoint Selection and/or order of secondary endpoints Analytic methods to evaluate endpoints, multiplicity, type I error control Combinations of design elements.

4 Learning vs. Confirming A Unique Paradigm of Adaptive Design in Drug Development

5 Learning using adaptive designs in exploratory trials has different context than that in confirmatory trials in therapeutic drug development

6 Common Theme Flexibility prospectively specified

7 In adaptive exploratory trials, adaptation tries to deal better with learning e.g., adaptive dose-ranging study: explore several doses to study Dose-Response for POC/POA while identify minimum number of potentially effective/safe doses based on, e.g., predictive probability Learn Dose, Population, Endpoint, Effect Size, etc. Careful estimation of effect size seem more important*

8 Planning an adaptive confirmatory trial requires a lot of informative prior data, as such there are some, but, limited pre-specified flexibility for handling the remaining uncertainty Need to be adequate and well-controlled

9 Study Design Learning Stage I (2 weeks) Dose 1, n=100 Dose 2, n=100 Dose 3, n=100 Confirming? Stage II (24 weeks) Dose S1, n=400 ( ) Dose S2, n=400 ( ) Dose 4, n=100 Dose 5, n=100 Placebo, n=100 Placebo, n=400 ( ) Active Drug, n=100 Active Drug, n=400 ( )

10 Adaptive Design Proposals Stage 1 / Stage 2 Phase IIB / Phase III Phase IIA / Phase IIB Early Aspect / Later Aspect Part 1 / Part 2 Purpose: combining data into one-trial Nature of Study: Exploratory vs A&WC

11 Adequate & Well-Controlled (A&WC) 21CFR Not exploratory adaptive design clinical trial In addition to experimentwise type I error rate control Should possess the following characteristics clear statement of the objectives, proposed and actual methods of analysis in protocol, SAP, and reports design that permits a valid comparative evidence of T-effectT methods of adequate assurance of patient selection patient assignments that minimize bias, group comparability minimize bias b on all parties: pts, investigator, data analyst endpoints well-defined that address clinical primary hypo. analysis results interpretability of the effects of drug

12 One A&WC Trial One Study-wise Type I Error Rate Accumulating data* Accumulating data* Adaptive Decision or Inference More accumulating information* Accumulating data* * Plan to use accumulating data in stage I or early stage data for adaptive decision or inference; also plan to use data from all stages for final analysis

13 Maintain Validity/Integrity of Trial Result Principle Independence and objectivity Sponsor-Only Model: Sponsor only ISAC Model: ISAC (blinded / unblinded) Sponsor DMC-Only Model: DMC Sponsor Combination Model: ISAC DMC Sponsor Sponsor Relevance to MRCTs (size, practice, genomic) Legal consequence of confidentiality agreement Need more m experiences and some proposals

14 Are safety data sufficient for the particular drug s entire development program?

15 Upfront more careful planning more upfront planning time may be facilitated by M&S Logistics for adaptive monitoring Complex design & implementation Worth the efforts for short-term term vs. long-term clinical endpoint?

16 Statistical Controversies for A&WC Trials Biometrical Journal, Adaptive Designs in Clinical Trials, Vol 48, (2006), 4, Pharmaceutical Statistics, Adaptive Designs Special Issue 5 (2006) Burman & Sonesson: : Are Flexible Designs Sound? Biometrics 62, , 2006; with discussion: Effect Size Moving Target in A&WC?

17 Remarks Flexibility in planning provides opportunity for increasing chance of successful A&WC trials Complex adaptive designs often require extensive simulation studies to access power performance; still, study-wise type I error rate control needed for evidence in A&WC trial Confirming Trial Integrity: SOPs, adaptive monitoring to ensure firewalls vital for interpretability of trial results

18 U.S. FDA Draft Guidance on Adaptive Design Clinical Trials for Drugs and Biologics rmation/guidances/ucm pdf Sue-Jane Wang, Ph.D. Associate Director for Adaptive Design and Pharmacogenomics Office of Biostatistics, OTS/CDER/US FDA Presented at Adaptive Design for Clinical Trials: FDA Draft Guidance Symposium, Silver Spring, Maryland, U.S.A., March 26, 2010

19 Concepts & Terminology Design: Conventional vs. Adaptive Adaptation: Prospective Plan vs Reactive Changes Adaptations: Unblinded vs Blinded non-comparative Interim Analysis: beyond ICH E9 Bias: Statistical vs Operational Study: Exploratory vs A&WC (can have expl element) Ph I, II, III, confirmatory, seamless ph 2/3 not used Group Sequential Trial & Beyond: Firewalls Adaptive Monitoring Process/Procedure/Documentation

20 Draft Guidance Overview (1)* Description and motivation for adaptive designs General concerns associated with using adaptive designs in drug development (AD in exploratory) Generally well understood adaptive designs with valid approaches to implementation Adaptive study designs whose properties are less well understood Statistical considerations for less well-understood adaptive design methods * Statistical Focus * More Inclusive

21 Draft Guidance Overview (2)* Safety considerations in adaptive design trials Content of an adaptive design protocol Interaction with FDA when planning and conducting an adaptive design Documentation and practices to protect study blinding and information sharing for adaptive designs Evaluating and reporting of a completed study * Statistical Focus * Trial Integrity

22 Comments, Clarification, Critiques?

23 Docket Process on the Draft Guidance Comment Periods: : 90 days of the publication announcement (February 25, 2010) Submit comments to: : Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, RM# 1061, Rockville, MD 20852, U.S.A. Docket number FDA D

24 DOCKET # FDA D Or you can access via and click on the link for Dockets Management 24

25 Acknowledgments Robert T. O Neill Robert Temple H.M. James Hung Marc Walton CDER Members CBER Members Members of the statistical review teams and clinical review teams within Center for Drug Evaluation and Research that work with Office of Biostatistics on adaptive design PIND/IND/NDA/BLA submissions Regulatory Science Research Awards on Adaptive Designs resulted in technical publications, Discussant, Commentary between 1999 to 2010

26 Selected References Bauer (1989, Biometrie and Informatik in Medizin und Biologie) Cohen, Sackrowitz (1989) Bauer, Köhne (1994, Biometrics) Bauer, Röhmel (1995, Stat. In Med.) Proschan, Hunsberger (1995, Biometrics) Lan, Trost (1997, ASA Proceedings) Fisher (1998, Stat. In Med.) Shen, Fisher (1999, Biometrics) Cui, Hung, Wang (1999, Biometrics) Bauer, Kieser (1999, Statistics in Medicine) Posch, Bauer (1999, Biometrical J.) Kieser, Bauer, Lehmacher (1999, Biometrical J.) Lehmacher, Wassmer (1999, Biometrics) Sill (2000) Müller & Schäfer (2001, Biometrics)

27 Hellmich (2001, Biometrics) Liu & Chi (2001, Biometrics) Wang, Hung, Tsong, Cui (2001, Stat in Med) Bauer, Brannath, Posch (2002, Method Inform Med) Brannath, Posch, Bauer (2002, JASA) Cui (2002, Encyclopedia of Biopharmaceutical Statistics) Li, Shih, Xie, Lu (2002, Biostatistics) Lawrence (2002, J. of Biopharmaceutical Statistics) Lawrence (2002, J. of Pharmaceutical Statistics) Lawrence & Hung (2002, Biometrical J.) Posch, Bauer & Brannath (2003, Stat in Med) Jennison & Turnbull (2003, Stat in Med) Tsiatis & Mehta (2003, Biometrika) Liu, Proschan, Pledger (2002, JASA) Proschan, Liu, Hunsberger (2003, Stat in Med) Chen, DeMets, Lan (2003, Controlled Clinical Trials) Brannath, Bauer, Maurer, Posch (2003, Biometrics) Chen, DeMets, Lan (2004, Stat in Med)

28 Wang, Hung, O Neill (2004, ASA Proceedings) Hung, Wang, O Neill (2004, ASA Proceedings) Koyama, Sampson and Gleser (JASA 2004) Lan, Soo, Siu, Wang (2005, J. of Biopharmaceutical Statistics) Hung, Cui, Wang, Lawrence (2005, J. of Biopharm. Statistics) Posch, Koenig, Branson, Brannath, et al. (2005, Stat in Med) Maitournam, Simon (2005, Stat in Med) Freidlin, Simon (2005, Clinical Cancer Research) Simon, Wang (2006, The Pharmaceutical J.) Wang, Hung, O Neill (2006, Pharmaceutical Statistics) Hung, Wang, O Neill (2006, Pharmaceutical Statistics) O Neill (2006, Biometrical J.) Wassmer G. (2006, Biometrical J.) Hung, O Neill, Wang, Lawrence (2006, Biometrical Journal + rejoinder) Gallo, Maurer (2006, Biometrical Journal) Wittes, Lachenbruch (2006, Biometrical Journal) Hung, Wang, O Neill (2006, JSM Proceedings) Chow and Chen (2006, book)

29 Bauer, Koenig (2006, Stat in Med) Ellenberg. Golub, Mehta (2006, Stat in Med, FDA-MIT workshop) Bretz, Schmidli, Konig, Racine, Maurer (2006, Biometrical J. with rejoinder) Schmidli, Bretz, Racine, Mauer (2006, Biometrical J.) Shih WJ (2006, Biometrical J., discussion) Gould L (2006, Biometrical J., discussion) Jennison & Turnbull (2006, Biometrical J., discussion) EMEA CHMP reflection paper (2006) on methodological issues in confirmatory clinical trials with flexible design and analysis plan Koch A (2006, Biometrical J. with rejoinder) Wittes, Lachenbruch (2006, Biometrical J.) Wang J (2006, Biometrical J.) Hartung, Knapp (2006, Biometrical J. with rejoinder) Mehrotra, Fan (2006, Biometrical J.) Bauer (2006, Biometrical J.) Brannath, Konig, Bauer (2006, Stat. in Med.) Ellenberg. Golub, Mehta (2006, Stat in Med, FDA-MIT workshop)....

30 . Wang (PhRMA/FDA Adaptive Design Workshop, Nov , 2006) O Neill (PhRMA/FDA Adaptive Design Workshop, Nov , 2006) Wang, Hung (2006, DIA Stat Meeting) Wang (2006, JSM Discussants: early adaptive, confirmatory adaptive) Wang (2007, JBS Discussant PhRMA Adaptive Dose Ranging) Wang (2007, EMEA/EFPIA 1 st adaptive design in confirmatory trials) Wang, O Neill, Hung (2007, Pharmaceutical Statistics) Wang (2008, 2009, DIA, JSM, FDA/Industry workshops) Wang, Hung, O Neill (2009, Biometrical J.) Wang (2009, EMEA/EFPIA 2 nd adaptive design in confirmatory trials) Wang (2009, Statistics in Biopharmaceutical Research, Commentary) U.S.FDA Draft Guidance for Industry Adaptive Design Clinical Trials for Drugs and Biologics (2010) Wang (2010, 1-day symposium on FDA adaptive design draft guidance) O Neil (2010, 1-day symposium on FDA adaptive design draft guidance) Temple (2010, 1-day symposium on FDA adaptive design draft guidance) Wang et al. (2010s).