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

The Role of Adaptive Designs in Clinical Development Program * Sue- -Jane Wang, Ph.D. Jane Wang, Ph.D. Sue 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 “ “2010 Rutgers Biostatistics Day 2010 Rutgers Biostatistics Day” ” Presented at 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

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

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 of of 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

Common Theme Common Theme Flexibility prospectively prospectively specified specified

In adaptive exploratory trials, In adaptive exploratory trials, adaptation tries to deal better with learning deal better with learning adaptation tries to e.g., adaptive dose- -ranging study: explore ranging study: explore e.g., adaptive dose several doses to study Dose- -Response for Response for several doses to study Dose 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 Learn Dose, Population, Endpoint, Effect Size, etc. Careful estimation of effect size seem more Careful estimation of effect size seem more important* important*

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

Study Design Study Design Learning Confirming? Stage I (2 weeks) Stage II (24 weeks) Dose 1, n=100 Dose S1, n=400 (100 + 300) Dose 2, n=100 Dose 3, n=100 Dose S2, n=400 (100 + 300) Dose 4, n=100 Dose 5, n=100 Placebo, n=100 Placebo, n=400 (100 + 300) Active Drug, n=100 Active Drug, n=400 (100 + 300)

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 one one- -trial trial Purpose: combining data into Nature of Study: Exploratory vs vs A&WC A&WC Nature of Study: Exploratory

Adequate & Well- -Controlled Controlled Adequate & Well (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 ♦

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

Maintain Validity/Integrity of Trial Result Principle – – Independence and objectivity Independence and objectivity Principle � 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 � DMC � � Sponsor � Combination Model: ISAC Combination Model: ISAC � Sponsor � 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 ore experiences and some proposals

Are safety data Are safety data sufficient sufficient for for the particular drug’ ’s s the particular drug 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- -term term Worth the efforts for short vs. long- -term clinical endpoint ? term clinical endpoint ? vs. long

Statistical Controversies for A&WC Trials � Biometrical Journal, Adaptive Designs in Biometrical Journal, Adaptive Designs in � Clinical Trials, Vol Vol 48, (2006), 4, 485 48, (2006), 4, 485- -740 740 Clinical Trials, � 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- -683 , 2006; 683 , 2006; Sound ? Biometrics 62, 664 with discussion: Effect Size Moving Effect Size Moving with discussion: 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 on Adaptive Design Clinical Trials for Drugs and Biologics http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfo rmation/Guidances/UCM201790.pdf Sue- - Jane W ang, Ph.D. Jane W ang, Ph.D. Sue 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 Guidance Symposium, Presented at Adaptive Design for Clinical Trials: FDA Draft Guid 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