Clinical Trials Handbook

Edited by

Shayne Cox Gad, Ph.D., D.A.B.T.Gad Consulting Services

Cary, North Carolina

A John Wiley & Sons, Inc., Publication

InnodataFile Attachment9780470466353.jpg

Clinical Trials Handbook

Clinical Trials Handbook

Edited by

Shayne Cox Gad, Ph.D., D.A.B.T.Gad Consulting Services

Cary, North Carolina

A John Wiley & Sons, Inc., Publication

Copyright © 2009 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifi cally disclaim any implied warranties of merchantability or fi tness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profi t or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.

Library of Congress Cataloging-in-Publication Data:

Clinical trials handbook / [edited by] Shayne Cox Gad. p. ; cm. Includes bibliographical references and index. ISBN 978-0-471-21388-8 (cloth) 1. Drugs–Testing–Handbooks, manuals, etc. 2. Clinical trials–Handbooks, manuals, etc. I. Gad, Shayne Cox, 1948- [DNLM: 1. Clinical Trials as Topic–Handbooks. QV 39 C64175 2009] RM301.27.C578 2009 615'.1—dc22

2009005648

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

http://www.copyright.comhttp://www.wiley.com/go/permissionhttp://www.wiley.com/go/permissionhttp://www.wiley.com

To my mother and father (Norma and Leonard Gad), now both gone but always remembered for all they gave me.

Contents

Preface xi

Contributors xiii

1 Introduction to Clinical Trials 1John Goffi n

2 Regulatory Requirements for Investigational New Drug 23Venkat Rao

3 Preclinical Assessment of Safety in Human Subjects 71Nancy Wintering and Andrew B. Newberg

4 Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies 87Jean-Pierre Valentin, Marianne Keisu, and Tim G. Hammond

5.1 History of Clinical Trial Development and the Pharmaceutical Industry 115Jeffrey Peppercorn, Thomas G. Roberts, Jr., and Tim G. Hammond

5.2 Adaptive Research 135Michael Rosenberg

6 Organization and Planning 161Sheila Sprague and Mohit Bhandari

7 Process of Data Management 185Nina Trocky and Cynthia Brandt

vii

viii CONTENTS

8 Clinical Trials Data Management 203Eugenio Santoro and Angelo Tinazzi

9.1 Clinical Trials and the Food and Drug Administration 227Tarek M. Mahfouz and Janelle S. Crossgrove

9.2 Phase I Clinical Trials 245Elizabeth Norfl eet and Shayne Cox Gad

9.3 Phase II Clinical Trials 255Say-Beng Tan and David Machin

9.4 Designing and Conducting Phase III Studies 279Nabil Saba, John Kauh, and Dong M. Shin

9.5 Phase IV: Postmarketing Trials 303Karl Wegscheider

9.6 Phase IV and Postmarketing Clinical Trials 325Ali Miraj Khan

9.7 Regulatory Approval 349Fred Henry and Weichung J. Shih

9.8 New Paradigm for Analyzing Adverse Drug Events 373Ana Szarfman, Jonathan G. Levine, and Joseph M. Tonning

10.1 Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug-Eluting Stent 397J. Doostzadeh, S. Bezenek, W.-F. Cheong, P. Sood, L. Schwartz, and K. Sudhir

10.2 Clinical Trials Involving Oral Diseases 435Bruce L. Pihlstrom, Bryan Michalowicz, Jane Atkinson, and Albert Kingman

10.3 Dermatology Clinical Trials 461Maryanne Kazanis, Alicia Van Cott, and Alexa Boer Kimball

10.4 Emergency Clinical Trials 477Joaquin Borrás-Blasco, Andrés Navarro-Ruiz, and Consuelo Borrás

10.5 Gastroenterology 501Lise Lotte Gluud and Jørgen Rask-Madsen

10.6 Gynecology Randomized Control Trials 519Khalid S. Khan, Tara Selman, and Jane Daniels

CONTENTS ix

10.7 Special Population Studies (Healthy Patient Studies) 531Doris K. Weilert

10.8 Musculoskeletal Disorders 563Masami Akai

10.9 Oncology 587Matjaz Zwitter

10.10 Pharmacological Treatment Options for Nonexudative and Exudative Age-Related Macular Degeneration 607Alejandro Oliver, Thomas A. Ciulla, and Alon Harris

10.11 Paediatrics 627Anne Cusick, Natasha Lannin, and Iona Novak

10.12 Clinical Trials in Dementia 661Encarnita Raya-Ampil and Jeffrey L. Cummings

10.13 Clinical Trials in Urology 695Geoffrey R. Wignall, Carol Wernecke, Linda Nott, and Hassan Razvi

10.14 Clinical Trials on Cognitive Drugs 705Elisabetta Farina and Francesca Baglio

10.15 Bridging Studies in Pharmaceutical Safety Assessment 733Jon Ruckle

10.16 Brief History of Clinical Trials on Viral Vaccines 769Megan J. Brooks, Joseph J. Sasadeusz, and Gregory A. Tannock

11 Methods of Randomization 779Gladys McPherson and Marion Campbell

12 Randomized Controlled Trials 807Giuseppe Garcea and David P. Berry

13 Cross-Over Designs 823Raphaël Porcher and Sylvie Chevret

14.1 Biomarkers 851Michael R. Bleavins, Claudio Carini, Malle Jurima-Romet, and Ramin Rahbari

14.2 Biomarkers in Clinical Drug Development: Parallel Analysis of Alzheimer Disease and Multiple Sclerosis 869Christine Betard, Filippo Martinelli Boneschi, and Paulo Caramelli

x CONTENTS

15 Review Boards 895Maureen Hood, Jason F. Kaar, and Vincent B. Ho

16 Size of Clinical Trials 913Jitendra Ganju

17 Blinding and Placebo 933Artur Bauhofer

18 Pharmacology 949Thierry Buclin

19 Modeling and Simulation in Clinical Drug Development 989Jerry Nedelman, Frank Bretz, Roland Fisch, Anna Georgieva, Chyi-Hung Hsu, Joseph Kahn, Ryosei Kawai, Phil Lowe, Jeff Maca, José Pinheiro, Anthony Rossini, Heinz Schmidli, Jean-Louis Steimer, and Jing Yu

20 Monitoring 1019Nigel Stallard and Susan Todd

21 Inference Following Sequential Clinical Trials 1043Aiyi Liu and Kai F. Yu

22 Statistical Methods for Analysis of Clinical Trials 1053Duolao Wang, Ameet Bakhai, and Nicola Maffulli

23 Explanatory and Pragmatic Clinical Trials 1081Rob Herbert

24.1 Ethics of Clinical Research in Durg Trials 1099Roy G. Beran

24.2 Ethical Issues in Clinical Research 1111Kelton Tremellen and David Belford

25 Regulations 1153Ramzi Dagher, Rajeshwari Sridhara, Nallaperumal Chidambaram, and Brian P. Booth

26 Future Challenges in Design and Ethics of Clinical Trials 1173Carl-Fredrik Burman and Axel Carlberg

27 Proof-of-Principle/Proof-of-Concept Trials in Drug Development 1201Ayman Al-Shurbaji

Index 1219

xi

Preface

The Clinical Trials Handbook represents a collective attempt to present the entire range of approaches to the clinical development process for potential new thera-peutic moieties, assembled in the context of this Wiley series on the entire process of pharmaceutical discovery and development. This volume, in fact, is the seventh in this series, which is intended to be comprehensive in its coverage.

The volume is unique in that it seeks to cover the entire range of general topics in the fi eld of clinical trials while also presenting chapters that focus on a specifi c therapeutic usage over a wide range of disease claims. The 52 chapters cover intro-ductory, regulatory and logistical issues, data management, general study design issues, types of clinical trials, and ethical and oversight issues.

This book would not have occurred without the dedicated efforts of Wiley ’ s managing editors, Zabrina Mok and Gladys Mok. Their persistence in the recruit-ment of contributors and ensuring follow through was essential.

While like all textbooks this one presents the state of the practice and fi eld at a specifi c period in time, I hope that it will become a frequently consulted friend.

S hayne Cox G ad

xiii

Contributors

M asami A kai , Director, Rehabilitation Hospital, National Rehabilitation Center Japan, Saitama, Japan, Musculoskeletal Disorders

A yman A l - S hurbaji , Experimental Medicine, International PharmaScience Center, Ferring Pharmaceuticals A/S, Copenhagen S, Denmark, Proof - of - Principle/Proof - of - Concept Trials in Drug Development

J ane A tkinson , National Institutes of Health/NIDCR, Bethesda, Maryland, Clini-cal Trials Involving Oral Diseases

F rancesca B aglio , Neurorehabilitation Unit, Don Carlo Gnocchi Foundation, Scientifi c Institute and University, IRCCS, Milan, Italy, Clinical Trials on Cogni-tive Drugs

A meet B akhai , Barnet General & Royal Free Hospitals, London, United Kingdom, Statistical Methods for Analysis of Clinical Trials

A rtur B auhofer , Institute of Theoretical Surgery, Philipps - University Marburg, Marburg, Germany; current address: CSL - Behring GmbH, Marburg, Germany, Blinding and Placebo

D avid B elford , GroPep Limited, Adelaide, South Australia, Ethical Issues in Clinical Research

R oy G. B eran , Strategic Health Evaluators, Chatswood NSW 2067, Australia, Ethics of Clinical Research in Drug Trials

D avid P. B erry , Department of Hepatobiliary and Pancreatic Surgery, The Leicester General Hospital, United Kingdom, Randomized Controlled Trials

C hristine B etard , Global Strategic Drug Development Unit, Quintiles, Levallois - Perret, Cedex, France, Biomarkers in Clinical Drug Development: Parallel Analy-sis of Alzheimer Disease and Multiple Sclerosis

S. B ezenek , Clinical Science Department, Abbott Vascular Inc., Santa Clara, California, Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug - Eluting Stent

M ohit B handari , Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, Ontario, Organization and Planning

xiv CONTRIBUTORS

M ichael R. B leavins , Michigan Technology and Research Institute, Ann Arbor, Michigan, Biomarkers

B rian P. B ooth , Offi ce of Translational Science, Offi ce of Clinical Pharmacology, Division of Clinical Pharmacology, Food and Drug Administration, Rockville, Maryland, Regulations

C onsuelo B orr á s , Department of Physiology, University of Valencia, Valencia, Spain, Emergency Clinical Trials

J oaqu í n B orr á s - B lasco , Pharmacy Service, Hospital de Sagunto, Sagunto, Spain, Emergency Clinical Trials

C ynthia B randt , Center for Medical Informatics, Yale University School of Medi-cine, New Haven, Connecticut, Process of Data Management

F rank B retz , Clinical Information Sciences, Novartis Pharmaceuticals Corp., East Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

M egan J. B rooks , Victorian Infectious Diseases Service, Centre for Clinical Research Excellence in Infectious Diseases, The Royal Melbourne Hospital, Parkville, Victoria, Australia, Brief History of Clinical Trials on Vaccines

T hierry B uclin , Division of Clinical Pharmacology and Toxicology, University Hospital of Lausanne, Lausanne, Switzerland, Pharmacology

C arl - F redrik B urman , Technical & Scientifi c Development, AstraZeneca, M ö lndal, Sweden, Future Challenges in Design and Ethics of Clinical Trials

M arion C ampbell , Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, Methods of Randomization

P aulo C aramelli , Cognitive Neurology Unit, Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil, Biomarkers in Clinical Drug Development: Parallel Analysis of Alzheimer Disease and Multiple Sclerosis

C laudio C arini , Fresnius Biotech of North America, Waltham, Massachusetts, Biomarkers

A xel C arlberg , Department of Cardiothoracic Surgery, Lund University Hospital, Lund, Sweden, Future Challenges in Design and Ethics of Clinical Trials

W - F. C heong , Clinical Science Department, Abbott Vascular Inc., Santa Clara, California, Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug - Eluting Stent

S ylvie C hevret , D é partement de Biostatistique et Informatique M é dicale, H ô pital Saint - Louis, France, Cross - Over Designs

N allaperumal C hidambaram , Offi ce of New Drug Quality Assessment, Division of Post-Marketing Evaluation, Food and Drug Administration, Rockville, Mary-land, Regulations

T homas A. C iulla , Department of Ophthalmology, Indiana University, India-napolis, Indiana, Pharmacological Treatment Options for Nonexudative and Exudative Age - Related Macular Degeneration

J anelle S. C rossgrove , Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio, Clinical Trials and the Food and Drug Administration

J effrey L. C ummings , Departments of Neurology and Psychiatry and Biobehav-ioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, Clinical Trials in Dementia

CONTRIBUTORS xv

A nne C usick , School of Biomedical and Health Sciences, University of Western Sydney, Sydney, Australia, Paediatrics

R amzi D agher , Pfi zer, Inc., New London, Connecticut, Regulations J ane D aniels , Clinical Trials Unit and Academic Department of Obstetrics

and Gynaecology, University of Birmingham, Birmingham, United Kingdom, Gynecology Randomized Control Trials

J. D oostzadeh , Clinical Science Department, Abbott Vascular Inc., Santa Clara, California, Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug - Eluting Stent

E lisabetta F arina , Neurorehabilitation Unit, Don Carlo Gnocchi Foundation, Scientifi c Institute and University, IRCCS, Milan, Italy, Clinical Trials on Cognitive Drugs

R oland F isch , Modeling and Simulation, Novartis Pharma AG, Basel, Switzer-land, Modeling and Simulation in Clinical Drug Development

S hayne C ox G ad , Gad Consulting Services, Cary, North Carolina, Phase I Clinical Trials

J itendra G anju , Amgen, Inc., South San Francisco, California, Size of Clinical Trials

G iuseppe G arcea , Cancer Studies and Molecular Medicine, The Leicester Royal Infi rmary, United Kingdom, Randomized Controlled Trials

A nna G eorgieva , Modeling and Simulation, Novartis Pharmaceuticals Corp., East Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

L ise L otte G luud , Copenhagen Trial Unit, Cochrane Hepato - Biliary Group, Copenhagen, Denmark, Gastroenterology

J ohn G offi n , Department of Oncology, Juravinski Cancer Center, McMaster University Hamilton, Ontario, Canada, Introduction to Clinical Trials

T im G. H ammond , Safety Assessment, AstraZeneca, Macclesfi eld, Cheshire, United Kingdom, Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies

A lon H arris , Department of Ophthalmology, Indiana University, Indianapolis, Indiana, Pharmacological Treatment Options for Nonexudative and Exudative Age - Related Macular Degeneration

F red H enry , Drug Development and Regulatory Affairs, Taisho Pharmaceuticals R & D Inc., Morristown, New Jersey, Regulatory Approval

R ob H erbert , The George Institute for International Health, Sydney, Australia, Explanatory and Pragmatic Clinical Trials

V incent B. H o , Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, Bethesda, Maryland, Review Boards

M aureen N. H ood , Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, Bethesda, Maryland, Review Boards

C hyi - H ung H su , Clinical Information Sciences, Novartis Pharmaceuticals Corp., East Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

M alle J urima - R omet , MDS Pharma Services, Montreal, Quebec, Biomarkers J ason F. K aar , Offi ce of General Counsel, Uniformed Services University of

Health Sciences, Bethesda, Maryland, Review Boards J oseph K ahn , Modeling and Simulation, Novartis Pharmaceuticals Corp., East

Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

xvi CONTRIBUTORS

J ohn K auh , Emory University School of Medicine, Winship Cancer Institute, Department of Hematology and Oncology, Atlanta, Georgia, Designing and Conducting Phase III Studies

R yosei K awai , Modeling and Simulation, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, Modeling and Simulation in Clinical Drug Development

M aryanne K azanis , Department of Dermatology, Massachusetts General Hospi-tal, Boston, Massachusetts, Dermatology Clinical Trials

M arianne K eisu , Patient Safety, AstraZeneca, S ö dert ä lje, Sweden, PredictingHuman Adverse Drug Reactions from Nonclinical Safety Studies

A li M iraj K han , Phase IV and Postmarketing Clinical Trials K halid S. K han , Birmingham Women ’ s Hospital, Birmingham, United Kingdom,

Gynecology Randomized Control Trials A lexa B oer K imball , Department of Dermatology, Massachusetts General

Hospital, Boston, Massachusetts, Dermatology Clinical Trials A lbert K ingman , National Institutes of Health/NIDCR, Bethesda, Maryland,

Clinical Trials Involving Oral Diseases N atasha L annin , Rehabilitation Research Studies Unit, Faculty of Medicine,

University of Sydney, Sydney, Australia, Paediatrics J onathan G. L evine , Food and Drug Administration, CDER, Silver Spring,

Maryland, New Paradigm for Analyzing Adverse Drug Events A iyi L iu , Biostatistics and Bioinformatics Branch, Eunice Kennedy Shriver

National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, Inference Following Sequential Clinical Trials

P hil L owe , Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland, Modeling and Simulation in Clinical Drug Development

J eff M aca , Clinical Information Sciences, Novartis Pharmaceuticals Corp., East Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

D avid M achin , Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore, Phase II Clinical Trials

N icola M affulli , Department of Trauma and Orthpaedic Surgery, Keele Univer-sity School of Medicine, Keele, Staffordshire, United Kingdom, Statistical Methods for Analysis of Clinical Trials

T arek M. M ahfouz , Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio, Clinical Trials and the Food and Drug Administration

F ilippo M artinelli B oneschi , Neuro - Rehabilitation Unit, Department of Neurology, San Raffaele Scientifi c Milano, Italy, Biomarkers in Clinical Drug Development: Parallel Analysis of Alzheimer Disease and Multiple Sclerosis

G ladys M c P herson , Health Services Research Unit, University of Aberdeen, Aberdeen, Scotland, Methods of Randomization

B ryan M ichalowicz , School of Dentistry, University of Minnesota, Minneapolis, Minnesota, Clinical Trials Involving Oral Diseases

A ndr é s N avarro - R uiz , Pharmacy Service, Hospital General Universitario de Elche, Elche, Spain, Emergency Clinical Trials

J erry N edelman , Modeling and Simulation, Novartis Pharmaceuticals Corp., East Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

A ndrew B. N ewberg , Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, Preclinical Assessment of Safety in Human Subjects

CONTRIBUTORS xvii

E lizabeth N orfl eet , Gad Consulting Services, Cary, North Carolina, Phase I Clinical Trials

L inda N ott , Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, Clinical Trials in Urology

I ona N ovak , Cerebral Palsy Institute, Sydney, Australia, Paediatrics A lejandro O liver , Department of Ophthalmology, Indiana University, Indianapolis,

Indiana, Pharmacological Treatment Options for Nonexudative and Exudative Age - Related Macular Degeneration

J effrey P eppercorn , Division of Medical Oncology, Duke University, Durham, North Carolina, History of Clinical Trial Development and the Pharmaceutical Industry

B ruce L. P ihlstrom , School of Dentistry, University of Minnesota, Minneapolis, Minnesota, Clinical Trials Involving Oral Diseases

J os é P inheiro , Clinical Information Sciences, Novartis Pharmaceuticals Corp., East Hanover, New Jersey, Modeling and Simulation in Clinical Drug Development

R apha ë l P orcher , D é partment de Biostatistique et Informatique M é dicale, H ô pital Saint - Louis, France, Cross - Over Designs

R amin R ahbari , Innovative Scientifi c Management, New York, New York, Biomarkers

V enkat R ao , National and Defense Programs, Defense Division, Alexandria, Virginia, Regulatory Requirements for Investigational New Drug

J ø rgen R ask - M adsen , Department of Medical Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark, Gastroenterology

E ncarnita R aya - A mpil , Department of Neurology and Psychiatry, University of Santo Tomas, Manila, Philippines, Clinical Trials in Dementia

H assan R azvi , Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, Clinical Trials in Urology

T homas G. R oberts , Jr., Noonday Asset Management, L.P., Charlotte, North Carolina, History of Clinical Trial Development and the Pharmaceutical Industry

M ichael R osenberg , Health Decisions, Inc., Durham, North Carolina, AdaptiveResearch

A nthony R ossini , Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland, Modeling and Simulation in Clinical Drug Development

J on R uckle , Covance Clinical Research Unit, Honolulu, Hawaii, Bridging Studies in Pharmaceutical Safety Assessment

N abil S aba , Emory University School of Medicine, Winship Cancer Institute, Department of Hematology and Oncology, Atlanta, Georgia, Designing and Conducting Phase III Studies

E ugenio S antoro , Laboratory of Medical Informatics, Department of Epidemiol-ogy, “ Mario Negri ” Institute for Pharmacological Research, Milan, Italy, ClinicalTrials Data Management

J oseph J. S asadeusz , Victorian Infectious Diseases Service, Centre for Clinical Research Excellence in Infectious Diseases, The Royal Melbourne Hospital, Parkville, Victoria, Australia, Brief History of Clinical Trials on Vaccines

H einz S chmidli , Clinical Information Sciences, Novartis Pharma AG, Basel, Switzerland, Modeling and Simulation in Clinical Drug Development

L. S chwartz , Clinical Science Department, Abbott Vascular Inc., Santa Clara, California, Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug - Eluting Stent

xviii CONTRIBUTORS

T ara S elman , Birmingham Women’s Hospital, Birmingham, United Kingdom, Gynecology Randomized Control Trials

W eichung J. S hih , Department of Biostatistics, School of Public Health, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, Regulatory Approval

D ong M. S hin , Emory University School of Medicine, Winship Cancer Institute, Department of Hematology and Oncology, Atlanta, Georgia, Designing and Conducting Phase III Studies

P. S ood , Clinical Science Department, Abbott Vascular Inc., Santa Clara, California, Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug - Eluting Stent

S helia S prague , Department of Clinical Epidemiology & Biostatistics, Depart-ment of Surgery, McMaster University, Hamilton, Ontario, Organization and Planning

R ajeshwari S ridhara , Offi ce of Translational Science, Offi ce of Biostatistics, Division of Biometrics, Food and Drug Administration, Rockville, Maryland, Regulations

N igel S tallard , Warwick Medical School, University of Warwick, Warwick, United Kingdom, Monitoring

J ean - L ouis S teimer , Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland, Modeling and Simulation in Clinical Drug Development

K. S udhir , Clinical Science Department, Abbott Vascular Inc., Santa Clara, California, Clinical Trials in Interventional Cardiology: Focus on XIENCE Drug - Eluting Stent

A na S zarfman , Food and Drug Administration, CDER, Silver Spring, Maryland, New Paradigm for Analyzing Adverse Drug Events

S ay - B eng T an , Singapore Clinical Research Institute, Singapore, Phase II Clinical Trials

G regory A. T annock , Department of Biotechnology and Environmental Biology, RMIT University, Bundoora, Victoria, Australia, Brief History of Clinical Trials on Vaccines

A ngelo T inazzi , Merck Serono, Global Biostatistics, Geneva, Switzerland, Clini-cal Trials Data Management

S usan T odd , Applied Statistics, University of Reading, Reading, United Kingdom, Monitoring

J oseph M. T onning , Food and Drug Administration, CDER, Silver Spring, Mary-land, New Paradigm for Analyzing Adverse Drug Events

K elton T remllen , Repromed, Dulwich, South Australia, Ethical Issues in ClinicalResearch

N ina T rocky , The University of Maryland Baltimore School of Nursing, Processand Data Management

J ean - P ierre V alentin , Safety Assessment, AstraZeneca, Macclesfi eld, Cheshire, United Kingdom, Predicting Human Adverse Drug Reactions from Nonclinical Safety Studies

A licia V an C ott , Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts, Dermatology Clinical Trials

D uolao W ang , Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom, Statistical Methods for Analysis of Clinical Trials

CONTRIBUTORS xix

K arl W egscheider , Department of Medical Biometry and Epidemiology, Univer-sity Hospital Eppendorf, Hamburg, Germany, Phase IV: Postmarketing Trials

D oris K. W eilert , Clinical Pharmacology, Quintiles, Inc., Kansas City, Missouri, Special Population Studies (Healthy Patient Studies)

C arol W ernecke , Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, Clinical Trials in Urology

G eoffrey R. W ignall , Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, Clinical Trials in Urology

N ancy W intering , Department of Radiology, University of Pennsylvania, Phila-delphia, Pennsylvania, Preclinical Assessment of Safety in Human Subjects

J ing Y u , Modeling and Simulation, Novartis Institutes for BioMedical Research, Inc., Cambridge, Massachusetts, Modeling and Simulation in Clinical Drug Development

K ai F. Y u , Biostatistics and Bioinformatics Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Heath, Rockville, Maryland, Inference Following Sequential Clinical Trials

M atjaz Z witter , Institute of Oncology, Ljubljana, Slovenia, and Department of Medical Ethics, Medical School, University of Maribor, Slovenia, Oncology

1

1

Clinical Trials Handbook, Edited by Shayne Cox GadCopyright © 2009 John Wiley & Sons, Inc.

Introduction to Clinical Trials

John Goffi n Department of Oncology, Juravinski Cancer Center, McMaster University Hamilton,

Ontario, Canada

Contents

1.1 Goals of Chapter 1 1.2 Goals of Clinical Trials and What Is at Stake 2 1.3 Introduction to Phase I – IV Clinical Trials 2

1.3.1 Introduction to Phase I Trials 2 1.3.2 Introduction to Phase II Trials 4 1.3.3 Introduction to Phase III Trials 5 1.3.4 Introduction to Phase IV Trials 6

1.4 Principles of Trials Development 7 1.4.1 Big Picture, Small Picture 7 1.4.2 Human Element 8 1.4.3 Multidisciplinary Nature of Clinical Trials 10 1.4.4 Know Your Audience, Know Your Market 12

1.5 Example in Drug Development 14 References 16

1.1 GOALS OF CHAPTER

The purpose of this chapter is to consider the overall goals and requirements of conducting clinical trials. It is an opportunity to avoid pitfalls by viewing the larger picture. This chapter seeks to provoke consideration of key issues without duplicat-ing the more detailed work of later chapters.

2 INTRODUCTION TO CLINICAL TRIALS

1.2 GOALS OF CLINICAL TRIALS AND WHAT IS AT STAKE

The ultimate goal of drug development is the creation of new, safe, and effective compounds for treating human disease. Clinical trials comprise the portion of this endeavor involving human subjects. While the basic tenants of scientifi c inquiry do not differ from preclinical research, the stakes are higher and the regulations more stringent.

The cost of conducting clinical trials can be measured in two ways: the human cost and the resource cost. The human cost is the cost from the patient ’ s perspective. The patient suffers from a condition dire enough that experimental therapy is a consideration. He or she holds out hope for this therapy and trusts to the scientifi c skill and integrity of those conducting the trial. The patients expose themselves to an incompletely understood therapy and usually suffer some degree of toxicity in order to gain uncertain benefi t. Prior to a drug being declared useful or not, hun-dreds or thousands of patients may be involved in trials related to the drug.

On another balance sheet, there is the impressive economic burden of drug development. The cost of successfully bringing a new drug to market is now in the range of $ 800 million [1] . The interval between the start of clinical testing and the submission of an application for regulatory approval of a new drug is estimated at 6 years [1] . Even so, fi elds such as oncology are seeing an increase in drugs under study [2] . Yet there are limits to the number of clinical centers able to conduct trials. More importantly, there is a limit to the number of patients that are eligible to par-ticipate in a given trial, either by reason of demographic factors, comorbidity, incom-patible disease parameters, or willingness. These limitations suggest that investigators must be selective about which drugs they study in clinical trials.

While drug discovery still involves an element of happenstance, contemporary drug development is ever more focused on mechanisms specifi c to a given disease. Frequently, therefore, a disease population will have been targeted during preclini-cal development. It is up to the clinical trials process to assess whether the new agent is both safe and effective in this or other populations. Generally, the fi rst concern is assessing drug toxicity and the related dosing and pharmacokinetics. Fol-lowing this, some evidence of effi cacy is sought. If it is found, effi cacy must be con-fi rmed in larger, randomized trials. Finally, postmarketing surveillance studies may be performed. These successive clinical trials are usually categorized by phase, and these phases will be introduced below.

1.3 INTRODUCTION TO PHASE I–IV CLINICAL TRIALS

1.3.1 Introduction to Phase I Trials

Purpose New drugs are fi rst introduced into human subjects in phase I trials. The primary goal of these fi rst studies is to assess the safety of the agent and to determine an acceptable dose for further study. Related goals include the assessment of phar-macokinetics as well as pharmacodynamics. To study pharmacokinetics is to study how the body affects the drug: How is the drug absorbed? How is the drug distrib-uted between body compartments? How is the drug metabolized and excreted? Pharmacodynamics is the relationship between drug exposure and drug effect. Here

we ask what normal physiological or disease processes are altered when a drug is administered at varying doses.

Methods The method used is to some extent dictated by the drug and disease under consideration. In fi elds other than oncology, phase I trials are typically under-taken in healthy volunteers. Typically, increasing doses of a drug are employed in small successive cohorts of patients. Each cohort is assessed, and subsequent dose levels are only used if excessive toxicity (often termed dose - limiting toxicity) is not encountered. At each dose level, blood or other body fl uid is taken for pharmaco-kinetic studies.

In oncology studies, the fi rst and lowest dose level may be based upon animal toxicities (e.g., 10% of the dose that is lethal in 10% of mice (LD 10 )) and dose incre-ments are often based upon a modifi ed Fibonacci sequence (1, 2, 3, 5, 8, 13, … ), a scheme that decreases the dose increment with each subsequent level. The notion is to limit patient exposure to dose - limiting toxicity through more cautious later stage dose increases. Alternative dosing schemes employ one patient per dose level or a continuously modifi ed dosing increment based upon observed toxicities; the goal of such alternative methods is to increase phase I effi ciency and limit the number of patients who receive too little or too much drug [3] . At some point, toxic-ity is deemed to be excessive, and the appropriate dose level is then established, typically at the dose just below this point of excessive toxicity.

Pharmacokinetics is the study of the drug absorption, transport, distribution, metabolism, and elimination; the goal is to improve drug delivery and effi cacy. An understanding of the molecular target may have implications for drug exposure. For example, antimetabolites used against cancer are considered to be most effective in the DNA (deoxyribonucleic acid) synthesis phase (S - phase) of the cell cycle. To best inhibit tumor growth, it is considered optimal to maintain a constant or prolonged exposure of the cancer to drug such that most cells are caught as they transit through S - phase. Pharmacokinetic analysis can tell the investigator if such an exposure is occurring and may prompt alternative dose schedules in subsequent studies.

Pharmacodynamic assays — assays that assess the effect of the drug on normal physiology or disease — may be useful in assessing whether a drug is likely to have a clinical effect. In cardiology, for example, the effects of a new agent on subjects ’ blood pressure or electrocardiogram may be relevant [4] . In studies of new antibod-ies or other targeted therapies, a therapeutic effect may be seen without the dose - dependent toxicities expected with other agents (e.g., the antimetabolite methotrexate used in rheumatoid arthritis or cancer). Conducting assays that demonstrate molec-ular changes in the relevant target could serve as a proof of concept for the agent; this, in turn, could prevent the need for higher dose levels, levels that could induce toxicity and would increase the duration of the study.

Results At the end of a phase I study, acute toxicities should be understood. Toxicities related to more long - term exposure may not be apparent until future studies are undertaken. In conjunction with the pharmacokinetic assays and any pharmacodynamic work, an assessment must be made as to whether further studies should be conducted, and, if so, at what dose. Pharmacokinetic analysis may suggest that changes in dose or dosing frequency are required. In instances where toxicity may be excessive at doses not expected or observed to have a useful biological

INTRODUCTION TO PHASE I–IV CLINICAL TRIALS 3

4 INTRODUCTION TO CLINICAL TRIALS

effect, further phase I studies may be designed to circumvent the toxicity. While preliminary activity against disease may be observed in phase I studies, the initial assessment of positive clinical outcomes is primarily the arena of phase II studies.

1.3.2 Introduction to Phase II Trials

Purpose Phase II studies are conducted to assess the initial activity of an agent against disease. Further information is gathered about an agent ’ s adverse effects, and additional pharmacokinetic or pharmacodynamic studies may be conducted.

Methods Unlike phase I studies, which may employ many different doses of an agent, phase II trials typically employ one or occasionally a few dose levels. Larger cohorts of patients are exposed to the drug in order to observe one or more clinical endpoints. The measured endpoints will vary depending upon the drug and fi eld of study. In trials of heart failure, for example, physiological parameters (e.g., ventricu-lar remodeling) may be assessed in addition to clinical measures such as exercise tolerance [5, 6] . Vaccine studies typically assess safety and immune responses and may involve both treatment and control groups [7] . In oncology, tumor response (shrinkage) rates have traditionally been used as a measure of response, but newer targeted drugs have led to greater reliance upon endpoints such as stable disease rates. Prior to conducting the study, investigators should specify what minimal level of drug activity will be accepted as evidence to warrant subsequent investigation. Phase II studies should be designed as precursors to phase III studies.

Phase II studies may be single - arm assessments of drug activity; such studies have an implied comparator of prior trials or clinical experience. Alternatively, random-ized studies may be conducted, comparing the experimental arm with either a placebo, a standard therapy control arm, another experimental arm, or different doses of the experimental arm itself. The randomized study, while of limited power, may improve drug development by increasing the likelihood of selecting the best drug or dose for further development [8] . When a standard treatment arm is used as a comparator, that arm may serve as a barometer for the severity or nature of the disease in the overall study cohort. Excellent or poor results in the experimental arm are interpreted in light of the control arm.

A more recent study type, the randomized discontinuation study, begins with a lead - in period in which all subjects receive the experimental arm. After a predeter-mined period, subjects are randomized between continuing the study drug and receiving a placebo or no therapy. The lead - in period eliminates noncompliant sub-jects and unresponsive disease, increasing the likelihood of differences being observed in the randomized portion of the study. The cost is in the greater number of patients required for the study due to drop - out in the initial nonrandomized period [9] .

Results As noted, the clinical endpoints vary widely based upon disease and agent type. If a drug effect was seen, it must be considered whether the effect was suffi ciently interesting in light of existing therapies or other study arms. If a clinical effect was not seen, one must assess whether this could be explained by any biologi-cal surrogates or pharmacokinetic studies also undertaken. The clinical effi cacy must

be assessed in the face of observed toxicities. More severe toxicities might be accept-able for lifesaving therapies but not for agents directed at minor ailments. At the end of the phase II study, the investigator should have an initial assessment of a new agent ’ s impact on a disease as well as a better understanding of the toxicity profi le.

Two important and frequently used statistical concepts should be introduced here. The fi rst is power. In clinical terms, power is the probability that a study will fi nd that a drug is effective when the drug truly is effective. Statistically, it may be described as Power = 1 − β , where β is the probability of a study fi nding a drug inef-fective despite the truth being that the drug is effective — β is therefore also called the β error. A related term, the α error, represents the opposite mistake; it is the chance that a study will fi nd a drug effective when in truth the drug is ineffective. By general agreement, the value of α is usually set at 0.05. Power increases with larger studies (i.e., more patients) and when more prespecifi ed clinical events occur. Phases I and II trials typically employ small numbers of patients, which tends to increase error rates and limit statistical options. Nevertheless, statistics can inform us of the limitations of our knowledge. For example, if we observed 3 of 25 patients with cancer to have tumor responses, we could determine that — with 95% likeli-hood — the true response rate was from about 3 – 30% [10] . If we had hoped for better, we would need to carefully consider any next trial. Phases III and IV studies, described below, rely heavily on thoughtful consideration of α and β errors.

1.3.3 Introduction to Phase III Trials

Purpose Phase III studies are typically large randomized studies designed to demonstrate useful clinical activity in a specifi c disease setting. The process of ran-domizing patients between different treatment arms is fundamental to avoiding biased interpretations of outcomes.

Methods The design of phase III studies is critical both in addressing a specifi c hypothesis and in the pragmatic sense of making a drug useful in clinical practice. Fundamentally, this means that an appropriate patient population must be selected, all treatments must be clinically relevant, and the expected improvement in outcome must be both clinically meaningful and statistically measurable. Eligibility crite-ria — those criteria that determine which patients may join the study — must defi ne a population that is both adequately generalizable to include patients repre-sentative of the diseased cohort but also homogeneous enough to retain statistical power and to be applicable to a usefully recognizable disease group. For example, studies may be diffi cult to interpret when they include both early - and late - stage patients. If a study is positive, to which population is it best applied? If negative, might it be positive in one of the disease subpopulations if a study were done only in that group.

Treatment arms cannot ignore previously existing therapies. With respect to heart failure, a new drug must take into account that many patients will also be on ACE (angiotensin - converting enzyme) inhibiters, β - blockers, diuretics, antiplatelet agents, and possibly other medications. Excluding these medications may make the study uninterpretable in the real - world clinical context and, more importantly, it may be unethical.

INTRODUCTION TO PHASE I–IV CLINICAL TRIALS 5

6 INTRODUCTION TO CLINICAL TRIALS

The endpoint of a phase III study should be an accepted and clinically relevant one that is specifi ed before the trial is conducted. For example, in many cancers, an improvement in response rate is not considered an adequate phase III endpoint, whereas improvements in survival or disease - free survival may be accepted. Second-ary endpoints — quality of life, for example — may be employed but must be recog-nized as such at study completion.

A common diffi culty with phase III studies is inadequate power. This is often due to an overly optimistic estimate of improvement in a clinical outcome, an estimate that may be a product of resource limitations. A lesser and potentially meaningful improvement may be missed if too few patients are accrued to the study or follow - up is too short.

Results The primary and any secondary clinical outcomes must be assessed and interpreted as planned. In circumstances where the primary outcome is of border-line signifi cance or where the primary and secondary clinical outcomes are dispa-rate, explanations may be considered and used as hypotheses for future study. Post hoc analyses are frequently conducted but can only be hypothesis generating.

1.3.4 Introduction to Phase IV Trials

Purpose Phase IV studies, sometimes called pharmacoepidemiologic studies, are those that are conducted after a drug has been approved for marketing. Such studies, often large, may assess a drug for uncommon toxicities that may be undetectable in smaller phases I – III studies, or they may establish the activity or tolerability of a drug in a particular population or practice setting.

Studies conducted to assess new methods of drug administration, combinations with other agents, or activity in other diseases — that is, studies seeking a new mar-keting indication — are better described and conducted as the phases I – III studies they represent. Similarly, a distinction can be made between trials seeking to answer a specifi c postmarketing question and those conducted solely to increase market share, so - called seeding trials. In the latter, there may be an incentive for the involved physicians to prescribe the drug in question and there may be no intent to publish the results [11, 12] .

Methods Phase IV studies may be conducted in several ways.

1. Descriptive studies, sometimes collections of drug toxicities captured over time, may identify new problems. These may range from case studies to series of patients collected by companies or regulatory bodies. Although resource intensive, large prospective cohort studies may also be conducted to capture infrequent adverse events.

2. Randomized studies may be used to compare an agent to other similar agents or to confi rm earlier results.

3. Case – control studies or retrospective cohort studies can be conducted after data on a drug has accumulated. This would typically be done to assess for unusual side effects or associations of a drug with the development of a sub-sequent disease, such as malignancies or autoimmune sequelae.

PRINCIPLES OF TRIALS DEVELOPMENT 7

4. Cross - sectional studies, although perhaps less useful, assess drug exposure and outcomes in a population at a specifi c time. Causality may be more diffi cult to assess if a sequential temporal relationship cannot be determined [12] .

Results The results of phase IV studies may be required to fulfi ll regulatory requirements after accelerated approval of a new drug. The additional numbers and prolonged follow - up provided by postmarketing studies may also be crucial in revealing important but infrequent toxicities. On occasion, these fi ndings may lead to the withdrawal of a drug from the market, as, for example, after cardiovascular complications were associated with the anti - infl ammatory drug rofecoxib [13, 14] .

1.4 PRINCIPLES OF TRIALS DEVELOPMENT

1.4.1 Big Picture, Small Picture

Overall Goal: Improved Patient Care The details involved in protocol design and regulatory requirements can be overwhelming. Remembering the fundamental goal of clinical research — improved patient care — can be an aid; study design and decision making should be infl uenced by the consideration of what is best for patients.

Patients seek relief from suffering. The investigator should therefore choose the most relevant endpoint for a given trial. Studies of rhinitis may reasonably examine patient reporting of nasal discharge and congestion [15] , while studies of pancreatic cancer must consider an agent ’ s impact on survival or more relevant measures of symptoms or quality of life. Research protocols must be designed with these param-eters in mind. The outcome of interest must be described in suffi cient detail that it may be easily replicated, a matter as important in assessing a study ’ s value in support of regulatory approval as it is to an understanding of what benefi t a drug may be to future patients. Any clinical trial must assess the toxicities associated with treat-ment. Known adverse effects must be clearly described and provisions made for the adjustment of treatment to mitigate such toxicities should they occur. Of course, for suffi ciently severe toxicities, a warning system must be in place to inform patients, investigators, and the companies and agencies overseeing the study. The details of such reporting requirement may vary, but the act of sharing such information is sensible.

Quality After careful protocol development comes the messy process of admin-istering a protocol. Invariably, aspects of the protocol appear to be open to inter-pretation, and at some point there will be lapses in study conduct or paperwork. The maintenance of quality in a study means always trying to adhere to the letter and spirit of the protocol. It means that the responsible investigator must be avail-able to arbitrate whether patients are actually eligible and whether protocol viola-tions have occurred. It means that study coordinators must vigorously pursue the complete assessment of patients and the related documentation. Every effort must be made to follow patients to the completion of study. A poorly followed or docu-mented study may be diffi cult to interpret and may not be acceptable to regulatory agencies or other entities overseeing the trial.

8 INTRODUCTION TO CLINICAL TRIALS

Nothing in Isolation —The Bench and the Bedside The present era is one of exciting new agents, many directed at specifi c targets in the disease process. Even while such agents must undertake the staged clinical trials process, they may evoke interesting biological questions with implications for ongoing or future studies. The prospective collection, banking, and analysis of biological specimens may reveal subsets of patients for whom a new agent may have particular benefi t.

For example, small - molecule tyrosine kinase inhibitors directed at the endothelial growth factor receptor (EGFR) have been investigated in patients with non – small cell lung cancer. Despite good preclinical data [16] , clinical studies demonstrated more limited benefi t, ultimately resulting in limitations of access to one such drug, gefi tinib, previously approved by the Food and Drug Administration (FDA)under accelerated approval [17] . The investigation of tumor samples, however, revealed that some tumors had mutations in the tyrosine kinase domain of the EGFR gene, with corresponding protein changes and apparent improvements in clinical responses [18, 19] . Unfortunately, this fi nding was made posthumously for gefi tinib, but the implications for future development of this class of drug are clear. When feasible, biological investigations and specimen preservation should continue during the clinical period of study.

1.4.2 Human Element

Differences between Mice and Humans Despite the fact that 99% of mouse genes have human counterparts [20] , several important issues separate the species. First, important differences in biology can mean signifi cantly different drug metabo-lism and elimination, such that pharmacokinetics can only be generally predicted [21] . Second, human xenografts planted in mice may respond to drug therapy, but such responses are not consistently predictive of response phase II clinical studies [22] . This supports the necessity of clinical studies. Third, ethics dictates that both the goals and conduct of preclinical and clinical studies must differ. In animals, while the suffering and distress of animals is to be minimized [23] , it is accepted that tox-icities must be observed in other species to understand new agents and protect the humans that are subsequently exposed. By contrast, the very structure of trials in humans is one of careful staging to avoid excessive toxicity or any death. Earlier studies establish safety while later studies assess for useful clinical activity of a drug.

Relevance of Ethics There are more and less obvious aspects of ethics involved in clinical drug development. We have fortunately recognized and codifi ed the obvious, so, for example, it is universally recognized that withholding effective treat-ment for the sole purpose of observing natural disease history is unethical [24] . But there are less fl agrant examples that affect study design.

The phase I study by its nature poses ethical conundrums. It is a study designed to assess toxicity and an acceptable dose for a drug, with clinical benefi t being a secondary consideration. Thus, subjects put themselves at risk for uncertain benefi t, and healthy volunteers stand no chance of clinical benefi t. But the phase I trial is accepted for several reasons. First and foremost, if one accepts that our society wishes to continue to make progress against disease, it becomes an unavoidable necessity. A new drug must at some point be introduced into the human population.