TRANSLATIONAL MEDICINE: TOOLS AND TECHNIQUES Edited by A S Amir hAhzAd President, European Society for Translational Medicine (EUSTM), Vienna, Austria; School of Medicine University of Colorado, Aurora, CO, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-12-803460-6 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For information on all Academic Press publications visit our website at http://store.elsevier.com/ Typeset by TNQ Books and Journals www.tnq.co.in Printed and bound in the United States of America List of Contributors Adriana Amaro Molecular Pathology, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Giovanna Angelini Molecular Pathology, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Laurent Audoly Pierre Fabre Pharmaceuticals, Toulouse, France Pierre Ferré Pierre Fabre Pharmaceuticals, Toulouse, France Parviz Ghahramani Chief Executive Officer, Inncelerex, Jersey City, NJ, USA; Affiliate Professor, School of Pharmacy, University of Maryland, Baltimore, USA, [email protected] Dimitris Kalaitzopoulos Oracle UK, Health Sciences Global Business Unit, Reading, UK Ross D. LeClaire The Translational Bridge, LLC, Albuquerque, NM, USA Elizabeth K. Leffel Leffel Consulting Group, LLC, Berryville, VA, USA Alexandre Passioukov Head of Translational Medicine, Pierre Fabre Pharma- ceuticals, Toulouse, France Ketan Patel Oracle UK, Health Sciences Global Business Unit, Reading, UK Andrea Petretto Core Facility, Istituto G. Gaslini, Genova, Italy Ulrich Pfeffer Molecular Pathology, IRCCS AOU San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Benedikte Serruys Department of Pharmacodynamics & Translational Medicine, Ablynx, Ghent-Zwijnaarde, Belgium Thomas Stöhr A2M Pharma, Monheim, Germany Hans Ulrichts Department of Pharmacodynamics & Translational Medicine, Ablynx, Ghent-Zwijnaarde, Belgium Maarten Van Roy Department of Pharmacodynamics & Translational Medicine, Ablynx, Ghent-Zwijnaarde, Belgium Katrien Vanheusden Department of Pharmacodynamics & Translational Medicine, Ablynx, Ghent-Zwijnaarde, Belgium Gabriel Vargas Neuroscience Early Development, Amgen Inc., Thousand Oaks, CA, USA Stephen Wood Neuroscience Discovery Research, Amgen Inc., Thousand Oaks, CA, USA Erfan Younesi Fraunhofer Institute for Algorithms and Scientific Computing, Bioinformatics Department, Schloss Birlinghoven, Sankt Augustin, Germany ix About the Editor Dr Shahzad is currently serving as the president for the European Society for Translational Medicine. Moreover, he is the chairman, Steering Committee for the Global Translational Medicine Consortium. Dr Shahzad is a management committee member of the European Commission’s COST action to Focus and Accelerate Cell-based Tolerance-inducing Therapies (A FACTT) and also for the European Commission’s COST action on the Development of a European-based Collaborative Network to Acceler- ate Technological, Clinical and Commercialization Progress in the Area of Medical Microwave Imaging. Dr Shahzad is affiliated with the School of Medicine, University of Colorado, USA. He is visiting professor at the Basic Medical School, Harbin Medical University, and also holds visiting professorship at the First Affiliated Hospital, Harbin Medical University. Dr Shahzad is serving as an editor-in-chief for the “New Horizons in Translational Medicine” (NHTM) and “Translational Medicine Case Reports” (TMCR) journals, published by the Elsevier. Dr Shahzad has advised and participated in establishing translational medicine infra- structure for several organizations. Dr Shahzad has organized several international conferences and is invited chair for numerous international life sciences conferences. xi Preface In recent years, Translational Medicine (TM) has emerged as a powerful interdisciplinary field. To help clarify the many facets of TM the European Society for Translational Medicine (EUSTM) defined TM as an interdisci- plinary branch of the biomedical field supported by three main pillars: benchside, bedside, and community. The goal of TM is to combine disciplines, resources, expertise, and techniques within these pillars to promote enhancements in prevention, diagnosis, and therapies. Thus, the primary objective of TM is to combine available resources within the individual pillars in order to improve the global health care system. Translational Medicine: Tools and Techniques is a further initiative of the EUSTM to provide the scientific community with concise knowledge about TM tools and techniques. The initiative was undertaken to reduce confusion about techniques, tools, and applications. This book is intended to help professionals both in academia and industry as well as students and young investigators perusing careers in TM field. The book is divided into seven chapters and written by the internation- ally respected authors from both academia and industry. New approaches for biomarkers discovery, development, and validations are discussed in the Chapter 1. Chapter 2 presents advancements in data mining and management tools. Chapter 3 discusses the modeling and simulation applications in drug development process. Advancements in omics sciences are described in Chapter 4. Chapter 5 provides an overview of the regulatory process in United States of America, Europe, China, and Japan. A pearl of this book is the inclusion of case reports and studies, which will help the reader better understand TM applications. Chapters 6 and 7 include translational medicine case studies and reports. I am thankful to all the authors for their valuable time and contri- butions for this timely book. Moreover, I am very grateful to Ms Mica Haley and Ms Lisa Eppich from Elsevier for their continuous support and kindness during all stages of book production; without their help the pub- lication in such a short duration of time would not have been possible. Aamir Shahzad October 2015 xiii Acknowledgments Prof. Randall J. Cohrs Prof. Got t fried K(cid:31)hler USA Austria This book is dedicated to Prof. Randall J. Cohrs and Prof. Gottfried Köhler. Randall’s application of basic molecular virology findings to clini- cal problems demonstrates the many facets within translational medicine. Gottfried’s scientific journey from biophysics to molecular diagnostics is an inspiration to all endeavoring to succeed in translational medicine. Together, their excellent contributions and achievements in their fields, continuous encouragement, and support are always a source of inspira- tion. Special thanks to Ms Sandra Oberhuber for her wonderful support. The Acknowledgments section would remain incomplete without men- tioning my family: Mahrose Aamir and Sarah Shahzad as they sacrifice their time for completing the book. xv C H A P T E R 1 New Developments in the Use of Biomarkers in Translational Medicine Benedikte Serruys1, Thomas Stöhr2, Hans Ulrichts1, Katrien Vanheusden1, Maarten Van Roy1 1Department of Pharmacodynamics & Translational Medicine, Ablynx, Ghent-Zwijnaarde, Belgium; 2A2M Pharma, Monheim, Germany O U T L I N E Introduction 2 Biomarkers as Part of a Translational Strategy 4 New Types of Biomarkers 6 From Blood- to Tissue-Specific Biomarkers 6 From Static to Functional Biomarker Assays 9 From Static Ex Vivo Monitoring to In Vivo Continuous Imaging 10 From Single Protein Molecules to Nonbiochemical Biomarkers 13 New Ways of Analyzing Biomarker Data 15 From Single Biomarkers to Biomarker Patterns 15 From Describing the Status Quo to Predicting/Modeling the (yet) Unknown 19 Biomarker Documentation 22 From Isolated Reporting to Meaningful Representation of Results that Allows Replication and Confirmation 22 1 Translational Medicine: Tools and Techniques http://dx.doi.org/10.1016/B978-0-12-803460-6.00001-5 © 2016 Elsevier Inc. All rights reserved. 2 1. NEW DEVELOPMENTS IN THE USE OF BIOMARKERS Promising Applications 25 From the Discovery of Pathomechanisms to the Definition of Patient (Sub)populations 25 Conclusions 28 References 29 INTRODUCTION A biomarker can be defined as a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic inter- vention [1]. The first publication associated in PubMed with the search term “biomarker” dates back almost 70 years [2]. Since then there has been an explosion of published research on biomarkers yet with limited trans- lation into clinical practice and back to bench. Classically, biomarker experiments involved the assessment of one or several proteins in the blood of a group of patients or experimental ani- mals versus a control group. In recent years there have, moreover, been many developments in biomarker research that makes biomarkers an extremely valuable tool in translational medicine. This chapter is not intended to provide a general review on the use of biomarkers in translational medicine. For this the reader is referred to a number of recent review articles or books [96–98]. The goal of this chapter is to highlight a number of recent developments that advanced the field and may help to value the sophisticated use of biomarkers in biomedical research. The selection of biomarkers should normally be part of a transla- tional strategy (Section Biomarkers as Part of a Translational Strategy). Rather than measuring proteins in blood, biomarker assessment can be done locally in the target tissue or even intracellularly (Section From Blood- to Tissue-Specific Biomarkers). Biomarker measurements can include functional assays (Section From Static to Functional Biomarker Assays), in vivo imaging (Section From Static Ex Vivo Monitoring to In Vivo Continuous Imaging), or even abstract measures such as a qual- ity of life score (Section From Peptide Molecules to Nonbiochemical Biomarkers). Moreover, the analysis of biomarker results can be done using algorithms (Section From Single Biomarkers to Biomarker Patterns) or with modeling (Section From Describing the Status Quo to Predicting/ INTRODUCTION 3 Modeling the (yet) Unknown). To be of real value, biomarker results need to be sufficiently documented to enable further clinical develop- ment (Section From Isolated Reporting to Meaningful Representation of Results that Allows Replication and Confirmation). The usefulness of biomarkers has been clearly demonstrated in the area of patient stratifi- cation, especially in the field of oncology, and this is slowly progressing to get established in more heterogeneous autoimmune diseases as well (Section From the Discovery of Pathomechanisms to the Definition of Patient (Sub)populations). In the next sections (overview see Table 1), we will highlight these developments and give particular emphasis to recent examples from the literature. TABLE 1 Chapter Overview Area of recent biomarker developments Section Biomarker selection Embedding in a Biomarkers as Part of a translational strategy Translational Strategy New types of biomarkers Target tissue and From Blood- to Tissue-Specific intracellular biomarkers Biomarkers Functional biomarker assays From Static to Functional Biomarker Assays In vivo imaging From Static Ex Vivo Monitoring to In Vivo Continuous Imaging From peptide molecules to From Peptide Molecules to nonbiochemical biomarkers Nonbiochemical Biomarkers New ways of analyzing Biomarker patterns From Single Biomarkers to biomarker data Biomarker Patterns Biomarker modeling From Describing the Status Quo to Predicting/Modeling the (yet) Unknown Biomarker documentation Reporting standards From Isolated Reporting to Meaningful Representation of Results that Allows Replication and Confirmation Promising applications Patient stratification From the Discovery of Pathomechanisms to the Definition of Patient (Sub) populations 4 1. NEW DEVELOPMENTS IN THE USE OF BIOMARKERS BIOMARKERS AS PART OF A TRANSLATIONAL STRATEGY Biomarkers are valuable tools when used fit for purpose to answer spe- cific questions during the course of clinical drug development. For instance, a particular biomarker may be suitable to answer one specific question (e.g., Does the drug candidate show direct target engagement in a certain study?) but may not be useful to answer another question (e.g., Does the drug candidate show efficacy in that same or in another study?). An answer to specific questions during translational research is often generated via an isolated approach, i.e., by focusing on one single experiment and question- ing which biomarker is the best candidate for this specific experiment. A higher translational value would be obtained by embedding the biomarker question into a more long-term translational strategy, by investigating the question in multiple studies, going from in vitro experiments over ex vivo studies to in vivo preclinical studies to finally clinical trials. The ultimate goal of this integrated approach is to increase (pre)clinical development effi- ciency and to decrease the failure risk in the process of bringing products to the market. The main prerequisites for a successful translational strategy are (1) a high translational value of the in vitro/ex vivo/in vivo models and (2) a high translational value of the specific biomarkers. However, translational challenges in biomarker measurements make it difficult to bridge results from the preclinical to clinical setting (and back). For example, efficacy (of intervention) biomarkers are generally more difficult to translate between ex vivo/in vivo models and the human situation as these correlate with a favorable outcome by drug treatment in the specific species and the model (i.e., efficacy) and are therefore often less closely linked to the direct action of the drug in man. To illustrate, imaging techniques in osteoarthritis (OA) focus on in-life assessment in the clinic, in contrast to terminal assessment via histopathology in animals. Also, pain assessment is difficult to trans- late, as pain is mainly monitored by self-reporting questionnaires in clinical research, but these cannot be readily mirrored in animal studies. In contrast, pharmacodynamic (PD) biomarkers are often more translational, as they reflect direct target engagement. Overall, the ideal biomarker strategy starts with considering the tar- get product profile of the compound and translating this backward. If, for instance, a superior efficacy is the ultimate goal, then the transla- tional strategy should determine how this efficacy can be best measured with the help of biomarkers and in which particular step of the develop- ment. This way of thinking with the long-term goal in mind may help to select more relevant biomarkers and to enhance their translational value. To answer a specific question by biomarkers without a lot of up front information on which biomarkers are appropriate for this objective, it is recommended to start preclinical development with a range of candidate biomarkers, which are being investigated in parallel in pilot in vitro/