Table Of ContentCLINICAL
DEVELOPMENT
Strategic,
Pre-Clinical,
Clinical, and
Regulatory Issues
Janice Steiner
Boca Raton London New York
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ISBN 13: 978-1-57491-028-5( hbk)
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Library of Congress Card Number 96-41276
Library of Congress Cataloging-in-Publication Data
Steiner, Janice, 1946-
Clinical development: strategic, pre-clinical, clinical, and regulatory issues / Janice Steiner.
p. cm.
Includes bibliographical references and index.
ISBN 1-57491-028-0
I. Drugs-Research-United States. 2. Pharmaceutical industry-United States. 3. Drugs-Law
and legislation-United States. I. Title.
[DNLM: I. Drug Approval-methods. QV 771 S822c 1997]
RM301.25.S74 1997
615'. l 9'0973-dc20
DNLM/DLC 96-41276
Contents
PREFACE ix
CHAPTER 1. STRATEGY 1
What is a Development Plan? 1
Drivers and Goals 3
Purpose 5
The Elements of Strategy 6
Evaluating the Market 6
Strengths, Weaknesses, Opportunities, and Threats
(SWOT) Analysis 9
Setting Direction 11
Assessing Risk 11
Identifying and Obtaining Resources 14
Setting Strategy 15
Defining Goals 15
Decision Points 16
Critical Path Analysis 17
Setting Priorities 18
iii
iv Clinical Development
What are the Criteria of Success 18
Musts, Nice to Have, and Unimportant 18
Timelines 20
Budgets 20
Where Are the Decision Points 21
Go/No Go Decision Points 21
Decisions Between Competing Projects 22
Summary 23
References 23
CHAPTER 2. THE MARKET 25
Market Definition and Competition 25
Economic Indicators 25
Pricing Considerations 26
Increasing the Value of a Product: Product
Differentiation 28
Mass and Niche Markets 28
Indication and Demography 30
The Cost of Competition 32
Market Segmentation 33
Who Pays 34
Pharmacoeconomic Analyses 35
Price Competition 37
What Is the Intention of the Development? 38
Bringing a Product to Market 38
Differentiating Between Products in the Marketplace 39
Adding Value 40
Contents v
Summary 41
References 41
CHAPTER 3. THE CLINICAL PLAN 43
How to Support the Market Without Going
Overboard 45
The Outline of the Plan 46
Choice of Infrastructure—Make or Buy 48
Database Choices 50
What Are Valid Endpoints? 51
Clinical Endpoin ts 51
Surrogate Endpoints 54
Quality of Life 55
Economic Outcome Measures 56
Phase III 57
Phase II 58
Phase I 59
Summary 61
CHAPTER 4. THE PRECLINICAL PLAN 63
Pharmacology 63
Mechanisms ofA ction 65
Efficacy, Specificity, and Potency 66
Dose Finding 66
Understanding and Interpreting Pharmacological Data 67
Chemistry and Pharmacy 72
Drug Metabolism, Distribution, and
Pharmacokinetics 74
vi Clinical Development
Toxicology 85
Summary 87
CHAPTER 5. REGULATORY ISSUES 89
The Registration Approval Process 89
Which Authorities? 89
Choice of Routes to Clinical Trails in Europe 94
Insurance 97
Conformity with Good Practices 98
Differences Between the U.S. and Europe 98
Digital Submissions 100
Sources of Information: Guidelines, ICH, and Approval
Documents 100
Significance of the Summary of Product
Characteristics 103
Issues Associated with the Global Dossier 103
Setting a Regulatory Strategy 104
Taking Advantage of Intercountry Differences 106
How Not to Get Caught in Local Traps 107
Interacting Between the U.S. and Europe 114
Summary 116
References 116
CHAPTER 6. GOOD CLINICAL PRACTICE-
INCORPORATING IT AND ITS MANAGEMENT
INTO THE CLINICAL PLAN 117
Institutional Review Board/Ethics Committee 119
Investigator Requirements 122
Contents vii
Sponsor Responsibilities 127
Clinical Trial Design 127
Quality Assurance and Quality Con trol 130
Investigational Site Management 132
Communications with the Regulatory Authorities 133
Allowing for the Practical Impact 134
How to Implement GCP 136
What to Do When Things Go Wrong 138
Harmonising Between the U.S. and Europe 140
Summary 141
CHAPTER 7. PROJECT MANAGING THE PLAN 143
What Is the Organisation 143
Centralised Versus Decentralised Structures 147
Start-Up and Virtual Organisations 150
Contracting In and Out 152
Planning and Management as a Function of Structure
and Project 154
Matrix Versus Functional Management 156
Multidisciplinary Teams 158
What Are the Constraints? 159
Time 159
Money 161
Personnel 164
Material Supplies 166
Infrastructure 167
Management of Risk and Uncertainty 167
Setting a Project Management Strategy 171
viii Clinical Development
CASE STUDY: MIRACULO CORPORATION 177
Preclinical Pharmacology 181
The Project Team 184
The Project Starts 186
The First Real Project Team Meeting 188
Development Begins in Earnest 190
Dose Response Curves 194
Testing for Safety 196
The Clinical Development Plan 198
Revising the Plan 200
Presenting the Plan to Management 206
Evaluating the Safety Data 208
The Entiy to Clinic 212
Getting into Phase II 216
Phase II 220
Phase III 222
Choosing Trial Locations 224
The Final Outcome 226
Index 227
Preface
This book is intended for all those who are approaching clinical development,
not from a position of total ignorance, but from a desire to understand how
the whole is derived from the parts. More importantly, it is for those who
would want to consider how to plan and implement drug development
programmes that produce coherent commercial products without making
fundamental mistakes.
I have spent years working in clinical development groups in both large and
small companies, teaching junior members of the pharmaceutical industry
about the objectives and implementation of clinical development and ex-
amining physicians for their qualifying examinations in pharmaceutical
medicine.
My experience repeatedly has taught me that many individuals, even at quite
senior level, fail to understand the overall purpose and interrelationships of
what they are doing. This frequently happens because they are cut off from
the larger corporation or because they have been inadequately trained. Clearly,
they would be in a position to do a better job and to gain more job satisfaction
if they were able to understand properly the requirements, problems, and
achievements of disciplines other than their own.
As the pharmaceutical industry approaches the millennium, as demands for
ever greater research and development productivity become the norm, and
as the timelines to the marketplace become progressively shortened, this
overall understanding of the process will become more vital to all involved.
This will apply as much to large corporations as to small concerns. Indeed,
one of the phenomena of the last 20 years has been the rise of a new start up
pharmaceutical industry, populated often by those who are unfamiliar with
the procedures and pitfalls inherent in their activities.
ix
