Clinical Trial Methodology

Clinical Trial Methodology

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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.
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Product details

  • Hardback | 420 pages
  • 160.02 x 233.68 x 25.4mm | 703.06g
  • Chapman & Hall/CRC
  • Boca Raton, FL, United States
  • English
  • 263 - PPI 496; 83 Tables, black and white; 34 Illustrations, black and white
  • 1584889179
  • 9781584889175
  • 1,675,098

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.
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Review quote

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 Goenen, 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
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About Karl E. Peace

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.
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