data monitoring models and adaptive designs: some regulatory experiences sue-jane wang, ph.d....

Data Monitoring Models and Adaptive Designs: Some Regulatory Experiences

Sue-Jane Wang, Ph.D.

Associate Director for Adaptive Design and Pharmacogenomics, Office of BiostatisticsOffice of Translational Sciences, CDER,U.S. Food and Drug Administration

Presented at DIA China in Data Monitoring and Adaptive Designs: Is China Ready? May 17, 2011 | Beijin, China

Wang SJ, May 17, 2011, DIAChina 2

The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.

These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission only. All rights reserved. The professional views presented here are those of the author and not necessarily those of the U.S. Food and Drug Administration. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.

Disclaimers


OUTLINE

3

• Adaptive Design Consideration

• Monitoring trial conduct / trial integrity

• Monitoring adaptive process

• Concluding Remarks


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


Adaptive Designed Clinical Trials

5

• Early Stages

• Early tolerability

• Early drug activity

• Early safety/tolerability signal



6

• Mid to Later Stages

• Dose response

• Short term trial

• Long term trial


Over-arching principles“The well-being of trial participants takes precedence over societal interests” – The World Medical Association Declaration of Helsinki



8

• How to maintain

• Validity of the trial results

• Integrity of the trial being implemented

• Applicable to both fixed design trial and adaptive design trial

• More complex with adaptive design trial


Adaptive Design – Validity

– Pre-specification of possible modification of design elements

– Statistical methods that yield a valid false positive error control for regulatory consideration (ICH E9)

– A valid point estimate and CI that is consistent with the proposed test method in assessment of treatment effect

Some principles


In addition to overall false positive-error control, forscientifically interpretable AD results, potential sourcesof bias need to be minimized by maintaining trialintegrity on – Trial conduct– Trial logistics– Trial operation

* May consider sub-structure of DMC for AD* Plan double-blinded study whenever possible

Adaptive Design – Integrity


Data Monitoring Committee (DMC) Current Practice: A Formal Committee in GSD

Safety monitoring required by a formal committee WHEN Safety concerns are unusually high In general, study is large, of long duration, multi-center

Is DMC review practical in small trials, short term trials ? Will a DMC help assure the scientific validity of trial ?

Who are unblinded parties Who makes changes in an ongoing trial if there is a need Will changes impair the credibility of study results?


External changes may prompt an interest in modifying some aspects of the trial as it progresses

Sometimes accumulating data from within the trial may suggest the need for modification

Recommendations to change the inclusion criteria, the trial endpoints, or the size of the trial are best made by those w/o knowledge of the accumulating data

Even aggregate data on safety and efficacy may be informative, these data may be needed for some trial management functions

The DMC Has Been a GSD Framework

“Possibility of Adaptations” by Blinded Party


Setup firewalls to ensure those proposing interim protocol changes based on external data are insulated from knowledge of interim comparative results

Regulatory staff generally remain blinded to interim unblined results

Unblinded interim dataInterim Protocol Changes


Adaptive Design of Wider Interests Study hypotheses may be a moving target May use biomarker for adaptive selection Interim analysis may be blinded or unblinded Adapt mainly from internal accumulating study

data that are pre-specified Often safety at DMC’s discretion May drop for partial futility or terminate for full

futility Seamless between stages


ObjectivityIndependence

Wang et al. (2011, European Neuropsychopharmacology Journal)


Key components for a successful Adaptive Design Trial


Challenges with Adaptive Monitoring Balancing Adaptive Rules Against Safety Monitoring Adaptive Rules

Allocation, sampling, stopping, decision Pre-specified with limited flexibility in confirmatory

trials Chosen rules may not be ‘medically or scientifically

sound’ This is of less concern in exploratory trials

Safety Monitoring Control of objectivity with adapting multiple (global)

nulls to just a few or single nulls for final analysis When DMC overrules

Concluding Remarks Prospective adaptive scenario planning to mimic the

possible adaptive monitoring scenarios An established infrastructure for adaptive monitoring

and/or adaptive decision making Documentation on “How adaptive designs were

implemented in real time including the resulting trial conduct, interim analyses, changes, etc.” could help address the issues on biases due to adaptation

Legal consequence of confidentiality agreement ? More research and experiences are needed


data monitoring models and adaptive designs: some regulatory experiences sue-jane wang, ph.d....

Documents

diachinawang sj

adaptive design trialwang

disclaimerswang sj

adaptive designs

adaptive designprospectively

fixed design trial

study design

trial resultsintegrity