Principles of Translational Science in Medicine: From Bench to Bedside

by Martin Wehling (Editor)

Overview

Despite advancements in the cloning of the total human genome, biomedical innovations at the patient level are becoming rare events. However, translational medicine is a burgeoning science that shows the potential to reverse the trend.

This textbook comprises a state-of-the-art survey of translational medicine, with emphasis on its emerging scientific backbone, its strengths, and its weaknesses. It explores all aspects of preclinical and clinical issues that are relevant to the success of translational pharmaceutical or medical device or diagnostic innovations, including target risk assessment, biomarker evaluation, and predictivity grading for both efficacy and toxicity; early human trial designs that are adequate to guide go-or-no-go decisions on the grounds of biomarker panels; and biostatistical methods for analyzing multiple readout situations and quantifying risk projections. The book provides guidance for designing smart profiling strategies for new approaches aimed at cutting timelines and concentrating on the comparison of quality issues of early developmental processes for pharmaceutical and biotechnology research.

By furthering the substantiation of translational medicine, creating awareness about its potential to promote innovations in clinical practice, and examining the terminology surrounding current biotechnologies, this book hopes to create a dialogue about translational science and what it will mean for patient care in the near future.

Product Details

ISBN-13:	9780128007211
Publisher:	Elsevier Science
Publication date:	04/02/2015
Sold by:	Barnes & Noble
Format:	eBook
Pages:	364
File size:	14 MB
Note:	This product may take a few minutes to download.

About the Author

Martin Wehling is the Managing Director at the Institute of Experimental and Clinical Pharmacology and Toxicology. Martin Wehling is Director in Clinical Pharmacology at Mannheim Medical Faculty, Mannheim University of Heidelberg, Mannheim, Germany.

Table of Contents

List of Contributors xi

Foreword Francesco M. Marincola xvii

Preface xxi

1 Introduction and Definitions M. Wehling 1

1.1 What Is Translational Medicine? 1

1.1.1 Primary Translation versus Secondary Translation 3

1.1.2 The Scope of Translational Medicine, Its Remits, and Why We Need It 4

1.1.3 What Translational Medicine Can and Cannot Do 8

1.1.4 The Present Status of Translational Medicine (Initiatives and Deficiencies) 11

1.1.5 Translational Science in Medicine: The Current Challenge 15

1.2 References 17

2 Target Identification and Validation 18

2.1 Tools 18

2.1.1 "Omics" Translation: A Challenge for Laboratory Medicine M. Plebani (corresponding) M. Zaninotto G. Lippi 18

2.1.2 "Omics" Technologies: Promises and Benefits for Molecular Medicine E. Marrer F. Dieterle J. Vonderscher 35

2.1.3 How to Assess Cellular Products? Potency Analysis of Cellular Therapies: The Role of Molecular Assays D. Stroncek P. Jin E. Wang J. Ren F. M. Marincola 59

2.1.4 Translational Pharmacogenetics to Support Pharmacogenetically Driven Clinical Decision Making J. Kirchheiner 78

2.1.5 Tissue Biobanks W. Peeters W. J. M. Derksen D. P. V. de Kleijn G. Pasterkamp 101

2.1.6 Experimental Surgery and Medical Engineering Groups M. Grasso 111

2.1.7 Localization Technologies and Immunoassays: Promises and Benefits for Molecular Medicine E. Marrer F. Dieterle J. Vonderscher 136

2.1.8 Biomarkers in the Context of Health Authorities and Consortia J. Vonderscher E. Marrer F. Dieterle 151

2.1.9 Human Studies as a Source of Target Information M. Wehling 156

2.2 Target Profiling in Terms of Translatability and Early Translation Planning M. Wehling166

2.2.1 Essential Dimensions of Early Translational Assessment 167

2.2.2 References 173

3 Biomarkers 175

3.1 Defining Biomarkers as the Most Important Contributors to Translational Science M. Wehling 175

3.1.1 References 179

3.2 Classes of Biomarkers M. Wehling 180

3.2.1 References 190

3.3 Development of Biomarkers M. Wehling 190

3.3.1 References 197

3.4 Predictivity Classification of Biomarkers and Scores M. Wehling 197

3.4.1 References 206

Biomarker Panels and Multiple Readouts D. Bernardi M. Plebani 206

3.5.1 Introduction 206

3.5.2 Computational Methods in Clinical Proteomics 207

3.5.3 Multiparameter Approach: Single Results, Score, or Index? 208

3.5.4 Diagnostic Panels and Algorithms 215

3.5.5 Conclusions 217

3.5.6 References 218

3.6 Typical Examples of Translational Biomarkers 220

3.6.1 Cardiovascular Biomarkers: Translational Aspects of Hypertension, Atherosclerosis, and Heart Failure in Drug Development L. Lind 220

3.6.2 Biomarkers in Oncology F. Azam R. Midgley D. J. Kerr 235

3.6.3 Translational Imaging Research L. Johansson 240

3.6.4 Translational Medicine in Psychiatry: Challenges and Imaging Biomarkers A. Meyer-Lindenberg H. Tost 251

4 Early Clinical Trial Design 277

4.1 Methodological Studies F. Azam R. Midgley D. J. Kerr 277

4.1.1 Conventional Phase I Trial Methodology 277

4.1.2 Measuring Endpoints 283

4.1.3 Mechanism-Oriented Trial Design 284

4.1.4 Can We Make Go-or-No-Go Decisions at the End of Phase I? 286

4.1.5 Phase II Trials 286

4.1.6 Personalized Medicine 287

4.1.7 References 288

4.2 Microdosing and Experimental Investigational New Drug Studies C. Karlsson 289

4.2.1 Introduction 289

4.2.2 Traditional Drug Development 290

4.2.3 Investigational New Drug Applications 290

4.2.4 Exploratory Investigational New Drug Studies 291

4.2.5 Repeated Dosing 295

4.2.6 Should Exploratory Investigational New Drug Studies Be Performed in All Projects? 296

4.2.7 Practical Applications 296

4.2.8 Conclusions 297

4.2.9 References 298

5 Pharmaceutical Toxicology S. Ernst S. Boyer S. Platz 299

5.1 Introduction 299

5.2 Basic Principles of Toxicology 300

5.2.1 Elements of Toxicity 300

5.2.2 Viewpoints of Toxicity 307

5.2.3 Risk Assessment 308

5.3 Regulatory Toxicology 309

5.3.1 Introduction 309

5.3.2 Regulatory Toxicity Studies 310

5.3.3 The Importance of Good Laboratory Practice 313

5.3.4 Animal Models 314

5.3.5 New Approaches in Regulatory Toxicology: The Exploratory Investigational New Drug Approach 315

5.4 Biomarkers 316

5.5 Links 317

5.5.1 Regulatory Agencies and Testing Guidelines: Pharmaceuticals 317

5.5.2 Societies 317

5.5.3 Related Sites 317

5.6 The Practice of Discovery Safety Assessment 318

5.6.1 Target-Based Safety Assessment 319

5.6.2 Safety-Directed Drug Design 322

5.7 Summary 324

5.8 Preclinical Safety from a Translational Perspective 325

5.9 References 326

6 Translational Science Biostatistics G. Ferber E. Glimm 327

6.1 Statistical Problems in Translational Science 327

6.2 Statistical Models and Statistical Inference 329

6.3 Design and Interpretation of an Experiment 332

6.4 Multiplicity 337

6.5 Biomarkers 339

6.6 Biological Modeling 342

6.6.1 Example 1: Pharmacodynamics 342

6.6.2 Example 2: Pharmacokinetics 342

6.7 Statistical Models 347

6.8 References 348

7 Learning By Experience: Examples Of Translational Processes in The Cardiovascular Field M. Wehling 350

7.1 Example of a Smart, Successful Translational Process 350

7.2 Example of a Failed Translational Process 352

7.3 References 357

Index 359

What People are Saying About This

From the Publisher

The principles, tools, and algorithms of translational science in medicine, plus an update on major achievements in translating research into medically relevant therapies

Editorial Reviews

"This is an easy to read resource for biomedical scientists interested in the current and evolving approach to integrating various scientific approaches to answer questions important for the diagnosis and treatment of human disease. Score: 86 - 3 Stars" —Doody's

From the Publisher

Reviewer: Ryan Sol Funk, PharmD, MS, PhD (University of Kansas Medical Center)
Description: This book evaluates the current and evolving field of translational science in medicine with a focus on issues relevant to the translation of preclinical scientific discoveries to the development of pharmaceuticals, medical devices, and diagnostic innovations. Although the translation of basic science discoveries to clinical practice is by no means a novel phenomenon, this book seeks to define translational science based on the methodologies used in the field and the process by which information is generated and translated between the preclinical and clinical sciences. A major bonus is that the text highlights these issues through real world examples of success and failure in the translational sciences.
Purpose: The purpose is to educate scientists on the current state of translational science in medicine as a freestanding scientific discipline focused on moving preclinical and early clinical findings through the development process to generate scientifically sound tools for clinical use. After successfully highlighting the fact that translating scientific discoveries to clinical care is not a novel idea, as evidenced by the long history of therapies used to treat human disease, the book highlights the importance of standardizing the methodologies and strategies involved in the translational process to define this new science.
Audience: The targeted audience is biomedical investigators involved in the late preclinical and early clinical development phase for pharmaceuticals, medical devices, and diagnostics. The book provides a good overview of topics and innovations in these areas without getting overly detailed. The authors are biomedical scientists that represent viewpoints of industry, academia, and the government.
Features: The book begins with an introduction to translational science in medicine and a discussion of the recent efforts of government and private industry to spur innovation in this area. It highlights the infancy of this science and the need for its clear definition and distinction. Focusing on major methodologies represented in this area, the authors describe the process through which these findings move from discovery to clinical practice. Major focus areas in this text include: "omics" technologies, biomarker development, innovative clinical trial design, early safety assessment, biostatistical methodologies, intellectual property, geriatrics, the pharmaceutical industry, and integration of scientific investigation into clinically relevant decision-making. Overall, the title maintains a consistent focus on methods and processes involved in translation of scientific findings through preclinical and clinical investigation.
Assessment: This is an easy to read resource for biomedical scientists interested in the current and evolving approach to integrating various scientific approaches to answer questions important for the diagnosis and treatment of human disease. The book is well developed and written by experts in the field. The figures are of good quality and thoroughly explained. Some of the later chapters are not as cohesive as the early chapters and, in some instances, interrupt the logical flow. Although the book is not intended to be comprehensive, some of the chapters and examples seem rather narrowly focused in specific clinical subdisciplines. Overall, however, the book does an excellent job of presenting and defining the science of translational medicine.

Doody's Review Service