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Adaptive and Flexible Clinical Trials

By Richard Chin

CRC Press – 2011 – 198 pages

Purchasing Options:

  • Add to CartHardback: $98.95
    978-1-43-983832-7
    August 25th 2011

Description

Adaptive clinical trial designs, unlike traditional fixed clinical trial designs, enable modification of studies in response to the data generated in the course of the trial. This often results in studies that are substantially faster, more efficient, and more powerful. Recent developments in web-based real-time data entry and advances in statistical methods have made adaptive clinical trials much more popular because they have become both more practical and attractive. However, there is paucity of resources that explain the mathematical framework and the practical considerations for adaptive designs without the use of highly technical statistical jargon.

Suitable for readers in academia, industry, and government involved in drug development, Adaptive and Flexible Clinical Trials is the first book that comprehensively explains all essential aspects of adaptive clinical trials. Written in an easy-to-understand style aimed at clinicians and other non-statisticians, this book focuses not on the statistical details, but rather on the application of statistical concepts for adaptive clinical trials. Utilizing concrete examples, the book thoroughly explains the design, conduct, and analysis of adaptive and flexible clinical trials, allowing readers to select and design the appropriate trial designs from a conceptual perspective. From basic theory to real-life practical issues, it covers all aspects of adaptive and flexible clinical trials, including regulatory issues, interim analysis, adaptive dosing, and sequential designs.

Reviews

"For the past few decades, adaptive clinical trials (ACT) have been enjoying increasing popularity and attention in biomedical research and industry … what was lacking was a ‘real’ book that would summarize these techniques to a wider audience. Dr. Richard Chin fills this void with his commendable book … The book is nicely written and lucid, with a proper sequencing of concepts."

Journal of the American Statistical Association, December 2013

"… later chapters in the book … are most useful. They describe the various types of adaptations that can be used. … This book is helpful for a starter in adaptive designs, to get an idea of the visions behind applying such designs."

—Philip Hougaard and Corine Baayen, ISCB Newsletter, June 2013

Contents

Background

Introduction

Definition and History of Traditional Clinical Trials

Definition of Adaptive Clinical Trial

Precursors to Modern Adaptive Clinical Trials

New Enabling Technologies and Other Requirements for Adaptive Trials

Rationale for Adaptive Clinical Trials

Learn and Confirm

Classification and Terminology of Adaptive Clinical Studies

Non-Adaptive Study Designs

Limitations of Adaptive Clinical Trials

Performance Criteria for Well Designed Clinical Trials

Evolving Regulatory Environment for Adaptive Clinical Trials

Regulatory Guidance from the FDA

References

Background: Conventional Statistics

Basic Statistics

Statistical Schools

Frequentist Method

Bayesian Method

Likelihood Method

Other Schools

Descriptive Statistics

Inferential Statistics

Comparative Statistics

Hypothesis Testing

Null Hypothesis and Standard of Proof in Clinical Trials

Example of Inference and Hypothesis Testing

Statistical Tests and Choice of Statistical Test

Examples of Statistical Tests

Fundamental Statistical Assumptions

Statistics Used in Adaptive Clinical Trials

Introduction

Preserving the Alpha

What Is Alpha?

Misconception about p Values

Splitting the Alpha

Methodologies for Allocating Alpha

Evolution of Adaptive Analytic Methods: Interim Analysis

Adaptive Methods

Limitations of Adaptive Statistical Techniques

Bayesian Approach

Simulations and Modeling

The FDA’s Stance on Adaptive Techniques

References

Specific Requirements for Adaptive Trials

Requirements for Endpoints in Adaptive Studies

Surrogates and Biomarkers

Practical Requirements

Adaptive Randomization and Allocation

Traditional Fixed Allocation

Simple Randomization

Restricted and Blocked Randomization

Stratified, Nested, and Similar Randomization

Balancing (Covariate) Adaptive Randomization

Response (Outcome) Adaptive Randomization

Combination and Multimodal Randomization

Bayesian Randomization

Adaptation of Inclusion and Exclusion Criteria Based on Blinded Data

Patient Enrichment Adaptations

Sample Size Reestimation

Background

Sample Size Reestimation Based on Blinded Data

Sample Size Reestimation Based on Unblinded Data

Adjustment in Follow‑Up Time

Internal Pilot Studies

Additional Rules

References

Traditional Dosing

Introduction

Definitions and Objectives of Dose Selection

Issues

Pharmacokinetics

Factors Affecting Pharmacokinetics

Dose–Response Curves

Types of Dosing

Traditional Dose‑Escalation and Dose‑Ranging Studies

Adaptive Dosing

Adaptive Dose Finding

Phase I Studies

3 + 3 and Related Designs

Continual Reassessment Method

Dose Escalation with Overdose Control

Stochastic Approximation Methods

Summary of Single‑Parameter Models

Additional Models and Methods

Dose Adaptation in a Pivotal Study

Changes in Concomitant Medications and Procedures

References

Interim Analysis and Adaptive Termination of Study and Study Arms

Overview

Data and Safety Monitoring Boards

Stopping Rules

Individual Sequential Designs

Group Sequential Designs

References

Adaptive Changes in Study Design and Decision Rules

Overview

Changes to Follow‑Up Period

Flexible Designs

Changing the Endpoints and Hypothesis

Changes to Test Statistic or Analysis

References

Seamless Designs and Adaptive Clinical Trial Conduct

Seamless Designs

Challenges in Adaptive Trials

Maintaining the Blind

Infrastructure and Operations

Adaptive Trial Protocols

Analysis and Interpretation of Results

General Issues in Interpretation of Clinical Trial Results

Interpretation of Adaptive Trial Results

Documentation of Trial Integrity

Statistics of Adaptive Trial Analysis

Summary

References

Index

Author Bio

Richard Chin, M.D. is the Chief Executive Officer of OneWorld Health, a nonprofit pharmaceutical company largely funded by the Bill and Melinda Gates Foundation, developing drugs for impoverished patients in the developing world. Previously, Dr. Chin held multiple senior positions in several biotechnology companies and has extensive expertise in drug development including 10 new drug registrations filings/launches and over 45 Investigational New Drug (IND) Applications. Some of the drugs he has overseen include Rituxan, Lucentis, Tysabri, TNKase, Raptiva, Xolair, Cathflo, Prialt, Protropin, Nutropin, Pulmo- zyme, Azactam, Maxipime, and Bapineuzumab, among others. Dr. Chin was named by Businessweek in 2006 as one of the youngest 99 public company CEOs in the United States. Dr. Chin earned his M.D. from Harvard and the equivalent of a J.D. from Oxford, where he studied as a Rhodes Scholar. Dr. Chin serves as Associate Professor at UCSF School of Medicine and was previously on the adjunct faculty at Stanford University School of Medicine.

Name: Adaptive and Flexible Clinical Trials (Hardback)CRC Press 
Description: By Richard Chin. Adaptive clinical trial designs, unlike traditional fixed clinical trial designs, enable modification of studies in response to the data generated in the course of the trial. This often results in studies that are substantially faster, more efficient,...
Categories: Medical Statistics & Computing, Clinical Trials - Pharmaceutical Science