Clinical Trial Methodology: 1st Edition (Hardback) book cover

Clinical Trial Methodology

1st Edition

By Karl E. Peace, Ding-Geng (Din) Chen

Chapman and Hall/CRC

420 pages | 34 B/W Illus.

Purchasing Options:$ = USD
Hardback: 9781584889175
pub: 2010-07-20
eBook (VitalSource) : 9780429142079
pub: 2010-07-20
from $62.50

FREE Standard Shipping!


Now viewed as its own scientific discipline, clinical trial methodology encompasses the methods required for the protection of participants in a clinical trial and the methods necessary to provide a valid inference about the objective of the trial. Drawing from the authors’ courses on the subject as well as the first author’s more than 30 years working in the pharmaceutical industry, Clinical Trial Methodology emphasizes the importance of statistical thinking in clinical research and presents the methodology as a key component of clinical research.

From ethical issues and sample size considerations to adaptive design procedures and statistical analysis, the book first covers the methodology that spans every clinical trial regardless of the area of application. Crucial to the generic drug industry, bioequivalence clinical trials are then discussed. The authors describe a parallel bioequivalence clinical trial of six formulations incorporating group sequential procedures that permit sample size re-estimation. The final chapters incorporate real-world case studies of clinical trials from the authors’ own experiences. These examples include a landmark Phase III clinical trial involving the treatment of duodenal ulcers and Phase III clinical trials that contributed to the first drug approved for the treatment of Alzheimer’s disease.

Aided by the U.S. FDA, the U.S. National Institutes of Health, the pharmaceutical industry, and academia, the area of clinical trial methodology has evolved over the last six decades into a scientific discipline. This guide explores the processes essential for developing and conducting a quality clinical trial protocol and providing quality data collection, biostatistical analyses, and a clinical study report, all while maintaining the highest standards of ethics and excellence.


This comprehensive text introduces the key areas of clinical trial methodology from the perspective of the biostatistician in the pharmaceutical industry. … Throughout, the text benefits from a highly structured and logical flow … the arguments made in the book are grounded in many years of practical experience in drug development and at the very least will act as a prompt for in-depth discussion or critical review of one’s own perceptions. … Clinical Trial Methodology will be of substantial value to early career pharmaceutical industry statisticians.

—Christopher J. Weir, Pharmaceutical Statistics, 2012

… informative discussions of mechanisms such as IND and NDA … are unique strengths of this book, distinguishing it from the many other clinical trial texts available. … Case studies … are presented carefully … The authors’ writing style is disciplined, careful, and informative. … this is a helpful and informative book, a nice reference to have for most biostatisticians working on clinical trials.

—Mithat Gönen, Journal of Biopharmaceutical Statistics, 21, 2011

The book is an excellent overview predicated on the first author’s seasoned experiences in designing, analyzing, and communicating the results of clinical trials across a broad number of medical disciplines. … A nice introductory feature is the history of drug law and regulation, which helps to frame the subsequent statistical discussion nicely. … The real-world examples that dominate the last few chapters are fantastic. … There is nothing like a series of examples from an experienced clinical trialist to whet the appetite of those involved in the noble enterprise of medical (and more specifically pharmaceutical) research with the goal of improving the public’s health. This book does an admirable job in giving the regulatory and statistical foundations for clinical trials, coupled with real-world examples of how statistical methodology has guided the development of important medicines. …

—Gregory Enas

Table of Contents

Overview of Clinical Trial Methodology

Clinical Trials

Clinical Trial Methodology

Summary of Clinical Trial Methodology

Overview of the Drug Development Process and Regulation of Clinical Trials


The Drug Development Process

History of Drug Regulation

Principles of Adequate and Controlled Investigations

Content and Format of the IND

Content and Format of the NDA

Organizational Structure of the FDA

The FDA Review Process

Labeling and the Package Insert

Pharmaceutical Company Organization and Role of the Biostatistician

Ethical Considerations in the Design and Conduct of Clinical Trials


History and Evolution of Ethical Considerations in Clinical Trials: Key Milestones

Independent Review Boards

Clinical Trial Ethics: Who Should Practice?

Informed Consent, Sample Size, and Power

Common Ethical Principles of Various Codes and Regulations

Sample Size Considerations in Clinical Trials Pre-Market Approval


Phases of Clinical Trials and Objectives

The Clinical Development Plan: Pre-Market Approval

Sample Size Requirements


Philosophical Issues

Sequential, Group Sequential, Stochastic Curtailment, and Adaptive Design Procedures in Clinical Trials


Sequential Procedures

Group Sequential Procedures

Stochastic Curtailment

Adaptively Designed Clinical Trials

Biostatistical Aspects of the Protocol

The Background or Rationale


Plan of Study

Statistical Analysis Section


Protocol References Section

The Statistical Analysis Plan


Protocol Objective

Efficacy Data Collected and Protocol Schema

Primary and Secondary Efficacy Endpoints

Objectives, Translated as Statistical Hypotheses

Protocol Design Features

Statistical Analyses

Pooling of Data from Multicenter Clinical Trials


Multicenter Clinical Trial Experimental Setting

Pre-Study Planning

Multicenter Clinical Trial Conduct

Biostatistical Analysis

Validity of Statistical Inference


Planning the Investigation

Conducting the Investigation

Statistical Analyses, Interpretation, and Inference

Reporting Results of Investigations

Bioequivalence Clinical Trials


Absorption, Distribution, Metabolism, and Excretion (ADME)


Factors That Affect Bioavailability

Blood Level Clinical Trials


Design of Bioequivalence Trials

Analysis of Bioequivalence Trials

Analysis of Ratios

Pharmacokinetic Models

Support of Bioequivalence Trials in the Pharmaceutical Industry


Dose and Frequency Determination from Phase II Clinical Trials in Stress Test-Induced Angina


Overview of Response Surface Methodology

Full Quadratic Response Surface Model

Phase II Clinical Trial Program in Stress Test-Induced Angina

Confirmation of Clinically Optimal Dosing in the Treatment of Duodenal Ulcers: A Phase III Dose Comparison Trial




Designing and Planning the Investigation

Conducting the Investigation

Statistical Analyses

Other Considerations

Innovative Aspects of the Clinical Trial Program

Pivotal Proof-of-Efficacy Clinical Trials in the Prevention of NANSAID-Induced Gastric Ulceration



The Protocols

Monitoring and Data Management

FDA Meeting

Clinical Trials in the Treatment of Alzheimer’s Disease Based upon Enrichment Designs


Enrichment Design Clinical Trials


Primary Efficacy Endpoints

Sample Size Determination

Statistical Methods


A Clinical Trial to Establish Reduction of CHD Risk



Designing and Planning the Investigation

Conducting the Investigation

Data Management

Statistical Analyses



Pivotal Proof-of-Efficacy Clinical Trials in the Treatment of Panic Disorder


Design of Pivotal Proof-of-Efficacy Trials

Traditional Statistical Analysis Methods

Overview of Efficacy Results of the Two Trials

Alternative Design and Analysis Strategies

Combination Clinical Trials


Two-by-Two Factorial Design

Effectiveness of the Combination

Contribution of Components to the Effectiveness of the Combination

Factorial Designs in Other Clinical Development Areas

Example 1: Actifed in the Treatment of SAR Following DESI Review

Example 2: Crossover Trial of Actifed in the Treatment of SAR

Example 3: Parallel Trial of Actifed in the Treatment of the Common Cold

Monitoring Clinical Trials for Adverse Events


Designing for Safety: Antibiotic Rash Example

Designing for Safety: Hypokalemia Example

Designing for Safety: Hypertensive Rebound Example

Premarket Approval Trials: Designed for Efficacy

Premarket Approval Trials: Quality of Adverse Event Information

Monitoring for Safety

Statistical Methodology: Individual Trial


Statistical Methodology: Across Trials


References appear at the end of each chapter.

About the Authors

Karl E. Peace is the Georgia Cancer Coalition Distinguished Cancer Scholar, founding director of the Center for Biostatistics, and professor of biostatistics in the Jiann-Ping Hsu College of Public Health at Georgia Southern University.

Din Chen is the Karl E. Peace Endowed Eminent Scholar Chair in Biostatistics and professor of biostatistics in the Jiann-Ping Hsu College of Public Health at Georgia Southern University.

About the Series

Chapman & Hall/CRC Biostatistics Series

Learn more…

Subject Categories

BISAC Subject Codes/Headings:
MATHEMATICS / Probability & Statistics / General
MEDICAL / Pharmacology
MEDICAL / Pharmacy