Guide to Drug Development: A Comprehensive Review & Assessment

1295 Pages·2008·11.626 MB·English

by  Bert Spilker

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Guide to
Drug Development
A Comprehensive Review and Assessment
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Books by Bert Spilker
Guide to Clinical Studies and Developing Protocols
(Raven Press, 1984)
Guide to Clinical Interpretation of Data
(Raven Press, 1986)
Guide to Planning and Managing Multiple Clinical Studies
(Raven Press, 1987)
Multinational Drug Companies: Issues in Drug Discovery
and Development
(Raven Press, 1989)
Inside the Drug Industry, with Pedro Cuatrecasas
(Prous Science Publishers, Barcelona, 1990)
Quality of Life Assessments in Clinical Trials, Editor
(Raven Press, 1990)
Presentation of Clinical Data, with John Schoenfelder
(Raven Press, 1990)
Patient Compliance in Medical Practice and Clinical Trials,
edited with Joyce Cramer
(Raven Press, 1991)
Guide to Clinical Trials
(Raven Press, 1991)
Data Collection Forms in Clinical Trials, with John
Schoenfelder
(Raven Press, 1991)
Patient Recruitment in Clinical Trials, with Joyce Cramer
(Raven Press, 1992)
Multinational Pharmaceutical Companies: Principles and
Practices, 2nd edition
(Raven Press, 1994)
Medical Dictionary in Six Languages
(Raven Press, 1995)
Quality of Life and Pharmacoeconomics in Clinical Trials,
2nd edition
(Lippincott-Raven, 1996)
Introduction to Quality of Life and Pharmacoeconomics,
with Joyce Cramer
(Lippincott-Raven, 1997)
80528_FM.QXD 6/18/08 12:09 AM Page iii
Guide to
Drug Development
A Comprehensive Review and Assessment
Bert Spilker, PhD, MD
Consultant
President of Bert Spilker & Associates, LLC
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Publisher:Charley Mitchell
Managing Editor: Sirkka E. Howes
Project Manager: Rosanne Hallowell
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© 2009 by Lippincott Williams & Wilkins, a Wolters Kluwer business
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All rights reserved. This book is protected by copyright. No part of this book may be reproduced in
any form or by any means, including photocopying, or utilizing by any information storage and re-
trieval system without written permission from the copyright owner, except for brief quotations em-
bodied in critical articles and reviews.
Printed in the United States
Spilker, Bert.
Guide to drug development : a comprehensive review & assessment / Bert Spilker.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-0-7817-7424-6 (alk. paper)
ISBN-10: 0-7817-7424-1 (alk. paper)
1. Drug development. I. Title.
[DNLM: 1. Drug Design. 2. Drug Evaluation, Preclinical—methods. 3. Drug Industry—metods.
4. Pharmaceutical Preparations. QV 744 S756g 2009]
RM301.25.S693 2009
615'.19—dc22
2008000008
Care has been taken to confirm the accuracy of the information presented and to describe generally
accepted practices. However, the authors, editors, and publisher are not responsible for errors or omis-
sions or for any consequences from application of the information in this book and make no war-
ranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents
of the publication. Application of this information in a particular situation remains the professional
responsibility of the practitioner.
The authors, editors, and publisher have exerted every effort to ensure that drug selection and
dosage set forth in this text are in accordance with current recommendations and practice at the time
of publication. However, in view of ongoing research, changes in government regulations, and the
constant flow of information relating to drug therapy and drug reactions, the reader is urged to check
the package insert for each drug for any change in indications and dosage and for added warnings
and precautions. This is particularly important when the recommended agent is a new or infrequently
employed drug.
Some drugs and medical devices presented in this publication have Food and Drug Administra-
tion (FDA) clearance for limited use in restricted research settings. It is the responsibility of health care
providers to ascertain the FDA status of each drug or device planned for use in their clinical practice.
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This book is dedicated to my loving wife,
Arlene.
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Contents
About the Author xi 24 Competitive Intelligence . . . . . . . . . . . . . . . . . . . . . .261
Preface xiii
25 Conflicts of Interest and Bias . . . . . . . . . . . . . . . . . .266
Acknowledgments xv
26 Crisis Management . . . . . . . . . . . . . . . . . . . . . . . . . .280
Abbreviations xvii
27 Mergers, Joint Ventures, and Alliances . . . . . . . . . . . .287
S E C T I O N 1 28 Pharmacopolitics . . . . . . . . . . . . . . . . . . . . . . . . . . .298
Introduction and Overview of a Company 29 Institutional Memory . . . . . . . . . . . . . . . . . . . . . . . .308
and the Industry 30 Differences among Pharmaceutical
Companies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .315
1 Introduction to Drug Development . . . . . . . . . . . . . . . .3
2 Pharmaceutical Industry: Definitions . . . . . . . . . . . . . . .8 S E C T I O N 4
3 The Big Picture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15 External Corporate Relationships
4 Standards: Types, Uses, and Issues . . . . . . . . . . . . . . .34 and Interactions
5 Pharma-think, Academic-think, and
31 Interactions and Relationships between
Government-think . . . . . . . . . . . . . . . . . . . . . . . . . . .45
Academicians and Industry . . . . . . . . . . . . . . . . . . . .331
6 Pharma Sense versus Common Sense . . . . . . . . . . . . .55
32 Investigator-sponsored Research Proposals
Submitted to Industry . . . . . . . . . . . . . . . . . . . . . . . .341
S E C T I O N 2
33 Technology Transfer from Academia to Industry . . . .345
Basic Principles, Strategies,
34 Interactions between Pharmaceutical Companies . . . .349
and Approaches
35 Interactions with Trade Associations . . . . . . . . . . . . .354
7 Overview of Factors Affecting Drug Discovery . . . . . . .61 36 Interactions with Legislators and Government
8 The Drug Discovery Process . . . . . . . . . . . . . . . . . . . .68 Agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .359
9 Golden Rules of Drug Discovery . . . . . . . . . . . . . . . . .97 37 Interactions and Relationships with Healthcare
Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .370
10 The Drug Development Process . . . . . . . . . . . . . . . .104
38 Interactions with Patients and the Public . . . . . . . . . .374
11 Golden Rules of Drug Development . . . . . . . . . . . . . .114
39 Patient Package Inserts . . . . . . . . . . . . . . . . . . . . . . .384
12 Biotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119
40 Interactions and Relationships with the Media . . . . . .391
13 Extrapolating Animal Safety and Efficacy
Data to Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . .132
S E C T I O N 5
14 Evaluating and Interpreting Data . . . . . . . . . . . . . . . .143
Research and Development Organization,
15 Stimulating Innovation and Increasing Efficiency
with the Right Questions, People, Milieu, Management, and Assessments
and Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . .151
41 Organizing Research and Development . . . . . . . . . . .401
16 A New Paradigm of Drug Development . . . . . . . . . . .167
42 Managing Research and Development
17 Future Environments for Drug Discovery and Avoiding Tangents . . . . . . . . . . . . . . . . . . . . . . .410
and Development . . . . . . . . . . . . . . . . . . . . . . . . . . .172
43 Personnel Issues in Drug Discovery
and Development . . . . . . . . . . . . . . . . . . . . . . . . . .429
S E C T I O N 3
44 Myths about the Pharmaceutical Industry
Corporate Organization and Management and Drug Development . . . . . . . . . . . . . . . . . . . . . .436
Issues 45 Fads and Fashions in Drug Development . . . . . . . . . .441
18 Models of International Operations . . . . . . . . . . . . . .183 46 The Many Facets of Reality: Approaches
to Issues and Problems . . . . . . . . . . . . . . . . . . . . . .446
19 Organization at the Corporate Level . . . . . . . . . . . . . .191
47 International Organization and Management . . . . . . .451
20 Corporate Management . . . . . . . . . . . . . . . . . . . . . .202
48 Project Management: Balancing Line Function
21 Reducing Pharmaceutical Risk . . . . . . . . . . . . . . . . . .225
and Matrix Approaches . . . . . . . . . . . . . . . . . . . . . .460
22 Enhancing Communication . . . . . . . . . . . . . . . . . . . .231 49 Choosing the Number and Types of Drugs
23 Personnel and Staffing Issues . . . . . . . . . . . . . . . . . .246 to Develop . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .475
vii
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viii CONTENTS
50 Choosing Standards for Developing Drugs . . . . . . . . .480 S E C T I O N 7
51 Creating and Using Benchmarks . . . . . . . . . . . . . . . .489 Regulatory Affairs Activities and Issues
52 Evaluating a Portfolio of Investigational Drug Projects 496
85 Introduction to Regulatory Affairs . . . . . . . . . . . . . . .841
53 Compassionate Use Programs . . . . . . . . . . . . . . . . . .529
86 Negotiating and Interacting with Regulatory
54 Virtual Drug Development . . . . . . . . . . . . . . . . . . . .533
Agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .859
55 Developing and Marketing Orphan Drugs 87 Learning Which Regulatory Guidances
for Rare Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . .544
and Standards May Be Modified . . . . . . . . . . . . . . . .867
56 Productivity and Project Success . . . . . . . . . . . . . . . .553 88 Preparing for and Holding Meetings
57 Overview of Safety and Risk Management . . . . . . . .569 with Regulatory Agencies . . . . . . . . . . . . . . . . . . . . .873
58 Developing Standard Operating Procedures . . . . . . . .578 89 Food and Drug Administration Advisory
Committee Meetings . . . . . . . . . . . . . . . . . . . . . . . .884
90 Regulatory Applications for Marketing
S E C T I O N 6
Approval and Global Interactions
Clinical Activities and Issues with Regulators . . . . . . . . . . . . . . . . . . . . . . . . . . . .891
59 Introduction to Clinical Trials . . . . . . . . . . . . . . . . . .589 91 Regulatory Strategies in Real-life Product
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .902
60 Creating a Clinical Strategy and Development
Plan for a New Drug or Indication . . . . . . . . . . . . . .603
61 Designing and Implementing a Clinical Trial . . . . . . .615 S E C T I O N 8
62 Questions to Ask about a Clinical Trial Protocol . . . . .640 Marketing Activities, Issues, and Interactions
63 Dose-response Relationships in Clinical Trials . . . . . . .644 with Medical Affairs
64 Collecting and Interpreting Life Events 92 Overview of Marketing Activities and Issues . . . . . . . .911
Data in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . .655
93 Corporate Issues Regarding the Medical–Marketing
65 Quality of Life and Pharmacoeconomics
Interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .946
in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . .662
94 Organizational and Staffing Issues Regarding the
66 Overview of Phase 4 and Postapproval Clinical
Medical–Marketing Interface . . . . . . . . . . . . . . . . . . .954
Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .677
95 Marketing Needs, Wants, and Issues
67 Phase 4 Trials and Postapproval Pharmacovigilance
in Developing Drugs . . . . . . . . . . . . . . . . . . . . . . . .963
Methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . .685
96 Joint Medical and Marketing Activities . . . . . . . . . . .972
68 Feasibility of Multinational Trials . . . . . . . . . . . . . . . .693
97 Switching Prescription Drugs to Over-the-counter
69 Groups that Influence Protocol Design . . . . . . . . . . . .707
Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .986
70 Monitoring and Auditing a Clinical Trial . . . . . . . . . . .712 98 Costs and Pricing . . . . . . . . . . . . . . . . . . . . . . . . . . .993
71 Electronic Data Collection and E-clinical Trials . . . . . .721 99 Providing Product Information to Healthcare
72 Principles of Patient Recruitment and Retention . . . . .733 Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1007
73 Surrogate Endpoints and Biomarkers . . . . . . . . . . . . .737
74 Contract Research Organizations and Outsourcing S E C T I O N 9
Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .746
Functional Activities and Issues
75 Conducting Clinical Trials Efficiently and Rapidly . . . .756
76 Clinical Significance . . . . . . . . . . . . . . . . . . . . . . . . .765 100 Information Management . . . . . . . . . . . . . . . . . . . .1021
77 Incorporating Benefit-to-risk Determinations 101 Selected Statistical Issues . . . . . . . . . . . . . . . . . . .1038
in Drug Development . . . . . . . . . . . . . . . . . . . . . . . .771 102 Data Management . . . . . . . . . . . . . . . . . . . . . . . .1049
78 Interactions between Clinicians and Statisticians 103 Toxicology Activities and Issues . . . . . . . . . . . . . . .1058
for Analysis and Interpretation of Clinical Data . . . . .780
104 Animal Testing and Animal Welfare . . . . . . . . . . . .1065
79 The Concept of Normalcy . . . . . . . . . . . . . . . . . . . . .787
105 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . .1072
80 Recruiting and Training Clinical Investigators . . . . . . .797
106 Licensing Activities and Issues . . . . . . . . . . . . . . . .1077
81 Human Subject Protection and Ethical Issues
107 Technical Development Activities
in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . .807
and Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1102
82 Improving the Standards of Clinical Trial Publications .819
108 Production Activities and Issues . . . . . . . . . . . . . . .1119
83 Registries and Directories of Clinical Trials,
109 Patent Activities and Issues . . . . . . . . . . . . . . . . . .1144
plus Disclosure of Their Results and Archiving
Their Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .823 110 Legal Activities and Issues . . . . . . . . . . . . . . . . . . .1159
84 Clinical Trials Come of Age . . . . . . . . . . . . . . . . . . . .832 111 Financial Activities and Issues . . . . . . . . . . . . . . . . .1172
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CONTENTS ix
S E C T I O N 10 S E C T I O N 11
Overview of Current and Future Development Case Studies in Clinical Development,
112 Poor Development and Corporate Regulatory Affairs, and the Management
Practices: Threats to a Pharmaceutical of Drug Development
Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1191
116 Clinical Case Studies . . . . . . . . . . . . . . . . . . . . . . .1231
113 Keys for Pharmaceutical and Development
Success . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1201 117 Regulatory Affairs Case Studies . . . . . . . . . . . . . . .1237
114 Computer Simulations and Modeling . . . . . . . . . . .1214 118 Management of Drug Development Case Studies . .1244
115 The Future of Drug Discovery
and Development . . . . . . . . . . . . . . . . . . . . . . . . .1221 Index 1251
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