The Role of Adaptive Designs in Clinical Development Program * Sue- - - PowerPoint PPT Presentation

Sue Sue-

• Jane Wang, Ph.D.

Jane Wang, Ph.D.

Associate Director, Adaptive Design and Pharmacogenomics Associate Director, Adaptive Design and Pharmacogenomics Office of Biostatistics, Office of Translational Sciences Office of Biostatistics, Office of Translational Sciences Center for Drug Evaluation and Research, U.S. FDA Center for Drug Evaluation and Research, U.S. FDA Presented at Presented at “ “2010 Rutgers Biostatistics Day 2010 Rutgers Biostatistics Day” ” Rutgers University, NJ, April 16, 2010 Rutgers University, NJ, April 16, 2010 * FDA current thinking, with some professional views * FDA current thinking, with some professional views

The Role of Adaptive Designs in Clinical Development Program*

Adaptive Design

• Prospectively planned opportunity for modification
• f 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
• r in an unblinded manner, and can occur with or

without formal statistical hypothesis testing

Design Elements for Adaptation 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
• …

… … … … … … .

Learning vs. Confirming Learning vs. Confirming

A Unique Paradigm A Unique Paradigm

• f
• f

Adaptive Design in Drug Adaptive Design in Drug Development Development

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

prospectively prospectively specified specified Flexibility Common Theme Common Theme

In adaptive exploratory trials, In adaptive exploratory trials, adaptation tries to adaptation tries to deal better with learning deal better with learning e.g., adaptive dose e.g., adaptive dose-

• ranging study: explore

ranging study: explore several doses to study Dose several doses to study Dose-

• Response for

Response for POC/POA while identify minimum number of POC/POA while identify minimum number of “ “potentially effective/safe potentially effective/safe” ” doses based on, doses based on, e.g., predictive probability e.g., predictive probability Careful estimation of effect size seem more Careful estimation of effect size seem more important* important*

Learn Dose, Population, Endpoint, Effect Size, etc.

Need to be adequate and well-controlled

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

Study Design Study Design

Dose 1, n=100 Dose 2, n=100 Dose 3, n=100 Dose 5, n=100 Placebo, n=100 Active Drug, n=100 Dose S1, n=400 (100 + 300) Dose S2, n=400 (100 + 300) Placebo, n=400 (100 + 300) Active Drug, n=400 (100 + 300)

Stage I (2 weeks) Stage II (24 weeks)

Learning Confirming?

Dose 4, n=100

Adaptive Design Proposals Adaptive Design Proposals

Stage 1 / Stage 2 Stage 1 / Stage 2 Phase IIB / Phase III Phase IIB / Phase III Phase IIA / Phase IIB Phase IIA / Phase IIB Early Aspect / Later Aspect Early Aspect / Later Aspect Part 1 / Part 2 Part 1 / Part 2 Purpose: combining data into Purpose: combining data into one

• ne-
• trial

trial Nature of Study: Exploratory Nature of Study: Exploratory vs vs A&WC A&WC

Adequate & Well Adequate & Well-

• Controlled

Controlled (A&WC) 21CFR314.126 (A&WC) 21CFR314.126

• Not exploratory adaptive design clinical trial

Not exploratory adaptive design clinical trial

• In addition to experimentwise type I error rate control

In addition to experimentwise type I error rate control

• Should possess the following characteristics

Should possess the following characteristics

♦ ♦ clear statement of the objectives, proposed and actual clear statement of the objectives, proposed and actual methods of analysis in protocol, SAP, and reports methods of analysis in protocol, SAP, and reports ♦ ♦ design that permits a valid comparative evidence of T design that permits a valid comparative evidence of T-

• effect

effect ♦ ♦ methods of adequate assurance of patient selection methods of adequate assurance of patient selection ♦ ♦ patient assignments that minimize bias, group comparability patient assignments that minimize bias, group comparability ♦ ♦ minimize b minimize bias on all parties: pts, investigator, data analyst ias on all parties: pts, investigator, data analyst ♦ ♦ endpoints well endpoints well-

• defined that address clinical primary hypo.

defined that address clinical primary hypo. ♦ ♦ analysis results analysis results – – interpretability of the effects of drug interpretability of the effects of drug

* 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

Adaptive Decision or Inference More accumulating information*

One A&WC Trial

One Study-wise Type I Error Rate

Accumulating data* Accumulating data* Accumulating data*

Principle Principle – – Independence and objectivity Independence and objectivity

• Sponsor

Sponsor-

• Only Model: Sponsor only

Only Model: Sponsor only

• ISAC Model: ISAC (blinded / unblinded)

ISAC Model: ISAC (blinded / unblinded)

• Sponsor

Sponsor

• DMC

DMC-

• Only Model: DMC

Only Model: DMC Sponsor Sponsor

• Combination Model: ISAC

Combination Model: ISAC

• Relevance to

Relevance to MRCTs MRCTs (size, practice, genomic) (size, practice, genomic)

• Legal consequence of confidentiality agreement

Legal consequence of confidentiality agreement

• Need m

Need more experiences and some proposals

• re experiences and some proposals

Maintain Validity/Integrity of Trial Result

DMC Sponsor Sponsor

Are safety data Are safety data sufficient sufficient

for for the particular drug the particular drug’ ’s s entire development program? entire development program?

Upfront more careful planning Upfront more careful planning

♦ ♦ more upfront planning time more upfront planning time ♦ ♦ may be may be facilitated by M&S facilitated by M&S Logistics for adaptive monitoring Logistics for adaptive monitoring Complex design & implementation Complex design & implementation Worth the efforts for short Worth the efforts for short-

• term

term

• vs. long
• vs. long-
• term clinical endpoint ?

term clinical endpoint ?

Statistical Controversies for A&WC Trials

• Biometrical Journal, Adaptive Designs in

Biometrical Journal, Adaptive Designs in Clinical Trials, Clinical Trials, Vol Vol 48, (2006), 4, 485 48, (2006), 4, 485-

• 740

740

• Pharmaceutical Statistics, Adaptive

Pharmaceutical Statistics, Adaptive Designs Special Issue 5 (2006) Designs Special Issue 5 (2006)

• ……

……

• Burman

Burman & & Sonesson Sonesson: Are Flexible Designs : Are Flexible Designs Sound ? Biometrics 62, 664 Sound ? Biometrics 62, 664-

• 683 , 2006;

683 , 2006; with discussion: with discussion: Effect Size Moving Effect Size Moving Target in A&WC ? Target in A&WC ?

Remarks 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

U.S. FDA Draft Guidance

• n Adaptive Design Clinical

Trials for Drugs and Biologics

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM201790.pdf

Sue Sue-

• Jane W ang, Ph.D.

Jane W ang, Ph.D.

Associate Director for Adaptive Design and Pharmacogenomics Associate Director for Adaptive Design and Pharmacogenomics Office of Biostatistics, OTS/CDER/US FDA Office of Biostatistics, OTS/CDER/US FDA

Presented at Adaptive Design for Clinical Trials: FDA Draft Guid Presented at Adaptive Design for Clinical Trials: FDA Draft Guidance Symposium, ance Symposium, Silver Spring, Maryland, U.S.A., March 26, 2010 Silver Spring, Maryland, U.S.A., March 26, 2010

Concepts & Term inology

• 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

Draft Guidance Overview ( 1 ) * 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

Draft Guidance Overview ( 2 ) * 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

Comments, Clarification, Critiques ?

23 23

Docket Process on the Draft Docket Process on the Draft Guidance Guidance

• Comment Periods

Comment Periods: 90 days of the publication : 90 days of the publication announcement (February 25, 2010) announcement (February 25, 2010)

• Submit comments to

Submit comments to: Division of Dockets : Division of Dockets Management (HFA Management (HFA-

• 305), Food and Drug

305), Food and Drug Administration, 5630 Fishers Lane, RM# 1061, Administration, 5630 Fishers Lane, RM# 1061, Rockville, MD 20852, U.S.A. Rockville, MD 20852, U.S.A. – – Docket number Docket number FDA FDA-

• 2010

2010-

• D

D-

• 0090

0090

24

WWW.REGULATIONS.GOV WWW.REGULATIONS.GOV DOCKET # FDA DOCKET # FDA-

• 2010

2010-

• D

D-

• 0090

0090 Or you can access via Or you can access via www.fda.gov www.fda.gov and click on the link for and click on the link for Dockets Management Dockets Management

Acknowledgments 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 Regulatory Science Research Awards on Adaptive Designs resulted in technical publications, Discussant, Designs resulted in technical publications, Discussant, Commentary between 1999 to 2010 Commentary between 1999 to 2010

Selected References 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)

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)

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)

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)

………..…..

……. Wang (PhRMA/FDA Adaptive Design Workshop, Nov. 13-14, 2006) O’Neill (PhRMA/FDA Adaptive Design Workshop, Nov. 13-14, 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 1st 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 2nd 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)

…………………….