Development of FDA regulated medical products a translational approach, second edition

Development of
FDA-Regulated
Medical Products


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Development of
FDA-Regulated
Medical Products
A Translational Approach
Second Edition
Elaine Whitmore

ASQ Quality Press
Milwaukee, Wisconsin


American Society for Quality, Quality Press, Milwaukee 53203
© 2012 by ASQ
All rights reserved. Published 2012
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Library of Congress Cataloging-in-Publication Data
Whitmore, Elaine.
  Development of FDA-regulated medical products : a translational approach / Elaine
  Whitmore.—2nd ed.
  p. cm.
  Includes bibliographical references and index.
  ISBN 978-0-87389-833-1 (hard cover : alk. paper)
  1. Drug approval—United States.  2. Biological products—Standards—United States.
  3. Medical instruments and apparatus—Standards—United States.  4. United States.
  Food and Drug Administration.  I. Title.
  RA401.5.W47 2012

 615.1'9—dc23

2011051569

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Table of Contents

List of Figures and Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Acronyms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii

Part I  Unique Challenges in Medical Product
Development
Chapter 1  Pushing the Pipeline: Translational Research
and Product Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Productivity Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Translational R&D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Valley of Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Translational Research and FDA Initiatives . . . . . . . . . . . 13
Driving Biomedical Innovation . . . . . . . . . . . . . . . . . . . . . 14
Chapter 2  Healthcare in the United States . . . . . . . . . . . . . . . . 19
Chapter 3  It’s Not Your Father’s FDA: The “Modernization”
of Medical Product Regulation . . . . . . . . . . . . . . . . . . . . . . . . . 25
Food and Drug Administration Modernization Act of 1997
(FDAMA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Prescription Drug User Fees . . . . . . . . . . . . . . . . . . . . . . . 27
Information on Off-Label Use and Economics . . . . . . . . . 28
Risk-Based Regulation of Medical Devices . . . . . . . . . . . . 28
Standards for Medical Products . . . . . . . . . . . . . . . . . . . . . 29
The New FDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29
Chapter 4  Classifying Medical Products . . . . . . . . . . . . . . . . . . 35
Drugs and Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

vii

viii   Table of Contents

Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
FDA Consolidation of Drugs and Biologics . . . . . . . . . . . . 41
Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Combination Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Chapter 5  Product Liability and Product Development . . . . . 53
Preemption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Basis of Product Liability . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Design Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Warning Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Manufacturing Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
The Role of Product Development Planning . . . . . . . . . . . 57

Part II  Bringing a New Medical Product
to Market
Chapter 6  Overview of the Approval Processes for
Drugs, Biologics, and Medical Devices . . . . . . . . . . . . . . . . . . 63
Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Preclinical Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Investigational New Drug Application . . . . . . . . . . . . . . . . 65
Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
New Drug Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Inspections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Generic Drugs and Abbreviated New Drug

Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Biosimilar Products (Follow-On Biologics) . . . . . . . . . . . . 68
Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
General Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71
Special Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Premarket Notification . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Premarket Approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Chapter 7  Quality by Design . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Design Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Design and Development Planning . . . . . . . . . . . . . . . . . . 81
Design Input . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Design Output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Design Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84




Table of Contents   ix

Design Verification and Validation . . . . . . . . . . . . . . . . . . 84
Design Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Design Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Design History File (DHF) . . . . . . . . . . . . . . . . . . . . . . . . .85
Other Considerations in Design Controls . . . . . . . . . . . . . . . . . 85
Chapter 8  Designing-Out Disaster: Risk Analysis . . . . . . . . . . 87
Quality Risk Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Risk Analysis Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Chapter 9  Recalls, Withdrawals, ­and Revocations . . . . . . . . . . 95
Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Firm-Initiated Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
FDA-Requested Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
FDA-Ordered Recalls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Withdrawals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Revocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Influence of Product Development Planning . . . . . . . . . . . . . . 100
Chapter 10  Human Factors and Usability Engineering:
Minimizing Medical Errors . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Chapter 11  Is It Safe and Does It Work? Evaluating Safety
and Efficacy in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . 115
Preclinical Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Drugs and Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .122
Endpoints and Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123
Medical Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Diversity in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Chapter 12  How Much Is the Product Really Worth?
Outcomes Research, Pharmacoeconomics, and
Managed Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Pharmacoeconomics and Economic Outcomes . . . . . . . . . . . . 131
Quality-of-Life Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Comparative Effectiveness Research . . . . . . . . . . . . . . . . . . . . 133
Outcomes and Product Development Planning . . . . . . . . . . . . . 134

Part III  Product Development Planning
Chapter 13  Models and Metaphors: Product Development
and the Product Development Organization . . . . . . . . . . . . . . 139
Swimming Against the Stream . . . . . . . . . . . . . . . . . . . . . . . . . 140

x   Table of Contents

The Cross-Functional Organization . . . . . . . . . . . . . . . . . . . . . 141
Chapter 14  Components of Product Development
Planning: The Product Development Process . . . . . . . . . . . . . 149
Stage 1—Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Stage 2—Feasibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Stage 3—Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Stage 4—Demonstration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Stage 5—Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Stage 6—Launch and Follow-Through . . . . . . . . . . . . . . . . . . . 160
Chapter 15  Components of Product Development
Planning: Development Portfoliio Management . . . . . . . . . . . 161
Killing a Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Chapter 16  Components of Product Development
Planning: Technology Assessment . . . . . . . . . . . . . . . . . . . . . . 175
Chapter 17  Components of Product Development
Planning: Technology Forecasting . . . . . . . . . . . . . . . . . . . . . . 183
Chapter 18  Better Double-Check That: A Guide for the
Risk-Averse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Planning for Promotional Opportunities . . . . . . . . . . . . . . . . . . 193
Speed to Market versus Product Promotional Preferences . . . . 195
Intellectual Property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Don’t Forget the Budget . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Conflict Resolution: What About Game Theory? . . . . . . . . . . . 199
Decision-Making Games . . . . . . . . . . . . . . . . . . . . . . . . . . 200
Global Games . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Product Development Ecosystem Games . . . . . . . . . . . . . . 201
Quality Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

Chapter 19  Where Do We Go From Here? . . . . . . . . . . . . . . . . 207
In Closing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
Appendix: Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Endnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231


List of Figures and Tables

Figure 1.1

Pharmaceutical industry R&D spending. . . . . . . . . . . . . . . . . 5

Table 1.1

New molecular entities: applications and approvals. . . . . . . . . 5

Figure 1.2 Drug development pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 1.3 Preapproval capitalized cost per approved NME. . . . . . . . . . . 7
Figure 1.4 Some definitions of translational research. . . . . . . . . . . . . . . . 9
Figure 1.5 Sources of funding and support for translational research
and development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Table 1.2

Three dimensions of the critical path. . . . . . . . . . . . . . . . . . . . 14

Figure 1.6 Sampling of schools with programs related to medical
product development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 2.1 Product development planning is an integrative approach. . . . 23

Figure 2.2 Product development planning. . . . . . . . . . . . . . . . . . . . . . . . . 24
Table 3.1

Chronology of significant regulations relevant to
healthcare product development. . . . . . . . . . . . . . . . . . . . . . . . 26

Figure 3.1 Examples of recent FDA initiatives affecting product
development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Table 4.1

Not all products of biological source are regulated
by CBER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Figure 4.1 Definition of a drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Figure 4.2a Minimum information included in an IND. . . . . . . . . . . . . . . 38
Figure 4.2b Clinical trial testing phases. . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Figure 4.3 Definition of a biological product. . . . . . . . . . . . . . . . . . . . . . . 39
Figure 4.4 Definition of a medical device. . . . . . . . . . . . . . . . . . . . . . . . . 45
Figure 4.5 Minimum information included in an IDE. . . . . . . . . . . . . . . . 46
Figure 4.6 Definition of a combination product. . . . . . . . . . . . . . . . . . . . . 47

xi


xii   List of Figures and Tables

Table 4.2

Number of original drug and biologics applications
filed with CDER and CBER. . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Table 4.3

Major medical device submissions received by CDRH. . . . . . 48

Table 4.4

Examples of NMEs approved in 2011. . . . . . . . . . . . . . . . . . . . 49

Table 4.5

Some recent biologics approvals. . . . . . . . . . . . . . . . . . . . . . . . 50

Table 4.6

Recent medical device approvals and clearances. . . . . . . . . . . 51

Table 5.1

Examples of U.S. national class action product liability
settlements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Figure 5.1

Establishing product defects for product liability. . . . . . . . . . . 56

Figure 5.2 Responsibilities of product development planning in
minimizing future product liability problems. . . . . . . . . . . . . 58
Figure 5.3 Primary considerations for product development
planning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Figure 6.1 Phases of clinical testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Figure 6.2 Mean time (months) from receipt to approval of priority
NDA/BLA submissions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Figure 6.3 Medical device classification panels. . . . . . . . . . . . . . . . . . . . . 70
Figure 6.4 Examples of reserved Class I devices. . . . . . . . . . . . . . . . . . . . 73
Figure 7.1

The 1-10-100 rule. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Figure 7.2

Class I devices subject to design controls. . . . . . . . . . . . . . . . . 81

Figure 7.3

Examples of items to include in a design controls
checklist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

Figure 8.1 Examples of potential interactions of risk elements. . . . . . . . . 89
Figure 8.2 Objectives of risk assessment and management. . . . . . . . . . . . 90
Figure 8.3 Example of FMECA matrix. . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Table 9.1

Examples of safety-based withdrawals of product
approvals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Figure 9.1

CDER recall statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Figure 9.2 CDRH recall statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Figure 9.3 CBER recall statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Table 10.1 Outline of device HFE/UE report. . . . . . . . . . . . . . . . . . . . . . . 104
Figure 10.1 CDRH comments on human factors. . . . . . . . . . . . . . . . . . . . . 106
Figure 10.2 Examples of FDA publications on the topic of human
factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Table 10.2 Examples of easily confused drug names. . . . . . . . . . . . . . . . . 108
Figure 10.3 Examples of general questions relative to demography
and products. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111




Table 11.1

List of Figures and Tables   xiii

Initial evaluation tests for consideration: biological
evaluation of medical devices. . . . . . . . . . . . . . . . . . . . . . . . . . 118

Table 11.2 Supplementary evaluation tests for consideration:
biological evaluation of medical devices. . . . . . . . . . . . . . . . . 119
Figure 11.1 Principles of ICH GCP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Figure 11.2 Drug development pathway. . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Figure 11.3 Diagrammatic representation of the ICH Common
Technical Document. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Table 12.1 Common pharmacoeconomic methods. . . . . . . . . . . . . . . . . . 132
Table 12.2 Examples of quality-of-life domains. . . . . . . . . . . . . . . . . . . . . 132
Figure 12.1 Questions applicable to CER. . . . . . . . . . . . . . . . . . . . . . . . . . 134
Figure 13.1 Stylized new product development funnel. . . . . . . . . . . . . . . . 140

Figure 13.2 Internal impediments to medical product development that
can be controlled or influenced by a product development
organization (salmon swimming upstream analogy). . . . . . . . 142
Figure 13.3 Internal impediments to medical product development that
are not usually controlled or significantly influenced by
a product development organization (salmon swimming
upstream analogy). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Figure 13.4 External impediments to medical product development that
can be controlled or influenced by a product development
organization (salmon swimming upstream analogy). . . . . . . . 143
Figure 13.5 External impediments to medical product development that
are not usually controlled or influenced by a product
development organization (salmon swimming upstream
analogy). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Figure 13.6 What a product development organization requires. . . . . . . . . 144
Figure 14.1 The product development process is an integral component
of product development planning. . . . . . . . . . . . . . . . . . . . . . . 149
Table 14.1 Six-step healthcare product development process. . . . . . . . . . 152
Figure 14.2 The product development process. . . . . . . . . . . . . . . . . . . . . . . 153
Figure 14.3 Questions to consider when evaluating ideas. . . . . . . . . . . . . . 155
Figure 14.4 Examples of idea evaluation criteria. . . . . . . . . . . . . . . . . . . . . 156
Figure 15.1 Development portfolio management is an integral
component of product development planning. . . . . . . . . . . . . . 162
Table 15.1 Framework for basic assessment of ideas, projects, and
future opportunities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Figure 15.2 A simple portfolio map matrix. . . . . . . . . . . . . . . . . . . . . . . . . 166
Table 15.2 Additional characteristics for project mapping. . . . . . . . . . . . . 166


xiv   List of Figures and Tables

Figure 15.3 An example of a technology portfolio matrix. . . . . . . . . . . . . . 167
Figure 15.4 Portfolio map matrix showing types of projects. . . . . . . . . . . . 168
Figure 15.5 A project map for a fictitious company: is it good or bad? . . . 168
Figure 15.6 Signs that a project should be killed. . . . . . . . . . . . . . . . . . . . . 173
Figure 16.1 Technology assessment is an integral component of
product development planning. . . . . . . . . . . . . . . . . . . . . . . . . 175
Figure 16.2 Considerations in technology assessment. . . . . . . . . . . . . . . . . 176
Figure 16.3 Examples of critical skills and knowledge base for
informed technology assessment. . . . . . . . . . . . . . . . . . . . . . . 178
Table 16.1 Framework for basic assessment of ideas, projects, and
future opportunities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Figure 16.4 Additional issues relevant to technology assessment. . . . . . . . 181
Figure 17.1 Technology forecasting is an integral component of
product development planning. . . . . . . . . . . . . . . . . . . . . . . . . 184
Figure 17.2 The relationship between science, technology, and
market. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Figure 17.3 Some factors contributing to the emergence of new diseases
and the reemergence of previously controlled diseases. . . . . . 188
Figure 17.4 Considerations for technology forecasting. . . . . . . . . . . . . . . . 189
Figure 17.5 Some areas of interest at FDA for the twenty-first
century. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
Figure 18.1 A non-comprehensive alphabetical list of risks. . . . . . . . . . . . 194
Table 18.1 Types of intellectual property. . . . . . . . . . . . . . . . . . . . . . . . . . 196
Figure 18.2 Important factors influencing IP value in medical product
development planning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Table 18.2 Some basic costs associated with obtaining a U.S.
patent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Table 18.3 FY 2012 FDA user fees. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Figure 18.3 The customer/quality continuum. . . . . . . . . . . . . . . . . . . . . . . 205

Acronyms and
Abbreviations

BLA—Biologics License Application
CBER—Center for Biologics Evaluation and Research
CDC—Centers for Disease Control and Prevention
CDER—Center for Drug Evaluation and Research
CDRH—Center for Devices and Radiological Health
CEA—cost-effectiveness analysis
CER—comparative effectiveness research
CPI—critical path initiative
CRO—contract research organization
FDA FD&C Act—Food, Drug, and Cosmetic Act
FDAMA—Food and Drug Administration Modernization Act
510(k)—Premarket Notification application
FMECA—failure mode effects and criticality analysis
FTA—fault tree analysis
GCP—good clinical practice
GLP—good laboratory practice
GMP—good manufacturing practice
HFE—human factors engineering
ICH—International Conference on Harmonization

xv


xvi   Acronyms and Abbreviations

IDE—Investigational Device Exemption
IND—Investigational New Drug application
IP—intellectual property
ISO—International Organization for Standardization
MDUFMA—Medical Device User Fee and Modernization Act
NDA—New Drug Application
NIH—National Institutes of Health
NME—new molecular entity
NSF—National Science Foundation
OCP—Office of Combination Products
PDUFA—Prescription Drug User Fee Act
PHS Act—Public Health Service Act
PMA—Premarket Approval
QFD—quality function deployment
QOL—quality of life
SMDA—Safe Medical Devices Act
TQM—total quality management


Preface

T

he years since the publication of the previous edition of this book
have seen profound changes in the actions and attitudes of patients,
insurers, manufacturers, and the Food and Drug Administration
regarding the streamlining of medical product development and approval.
What those years have not seen is a concomitant increase in innovative
treatments with profound benefits to patients.
Over the past decade, the path to the development of new drugs, biologics, and medical devices in the United States has become increasingly

inefficient, costly, and strewn with formidable obstacles. Despite enormous
investments in research by both private and public sources and a surge in
scientific and technological advances, new medical products barely trickle
into the marketplace. For a variety of reasons, applied sciences necessary
for medical product development are not keeping pace with the tremendous
advances in basic sciences.
Not surprisingly, industry and academia are under substantial pressure to transform discoveries and innovations from the laboratory into safe
and effective medical products to benefit patients and improve health. This
evolution—from bench to bedside—has become known as translational
research and development.
Translating promising discoveries and innovations into useful, marketable medical products demands a robust process to guide nascent products
through a tangle of scientific, clinical, regulatory, economic, social, and
legal challenges. There are so many human and environmental elements
involved in shepherding medical advances from lab to launch that the field
of medical product development has been referred to as an ecosystem. The
purpose of this book is to help provide a shared foundation from which
cross-functional participants in that ecosystem can negotiate the product

xvii


xviii  Preface

development labyrinth and accomplish the goal of providing both groundbreaking and iterative new medical products. This book is intended for anyone in industry, the public sector, or academia—regardless of functional
specialty, workplace, or seniority—who is interested in medical product
development.


Part I
Unique Challenges

in Medical Product
Development


(This page intentionally left blank)


1
Pushing the Pipeline
Translational Research and Product
Development

How wonderful that we have met with a paradox. Now
we have some hope of making progress.
—Niels Bohr

The U.S. healthcare product pipeline needs major plumbing repair.
There is no lack of innovation or shortage of important scientific discoveries in this country, but our ability to transform scientific advances
into new and effective medical products has been disappointing. Despite a
steady increase in the amount of money invested in research and development, there is a serious gap in making the transition from the research lab to
the patient. Novelty and innovation are the goals of academic and corporate
research funding and honors. But to have an impact on healthcare, innovations must be shepherded through challenging stages subject to rigorous
Food and Drug Administration (FDA) requirements, as well as through
business development–related scrutiny. It is not an easy or intuitively obvious road from lab to launch, and productivity in terms of the introduction
of new, innovative drugs, biologics, and medical devices has not kept pace
with opportunities or expectations. The pipeline needs a big push.

Productivity Gap
Although the productivity gap certainly exists for biological products and
medical devices, as well as prescription drugs, for the sake of simplicity,

let us examine U.S. industry expenditure on research and development of
pharmaceuticals relative to the number of new, innovative drugs that have
been approved by FDA during the same time period. To dissect innovation
from elaboration or imitation, only new molecular entities (NMEs) will be

3


4  Part I: Unique Challenges in Medical Product Development

examined. The distinction between NMEs and other traditional drugs is
summarized below:
• Innovation = NMEs, which are defined as active ingredients that
have never before been marketed in the United States in any form.
This is the category that comprises truly new therapeutic products.
• Elaboration = Non-NME new drugs, which include incremental
modifications of existing drugs, such as changes in formulation or
new indications (additional health conditions for which an existing
drug can be prescribed). Although clinical trials are required to
gain FDA approval, since the initial discovery and preclinical and
clinical safety testing of the active drug component have already
been done, the development costs and regulatory review times are
usually substantially lower than for NMEs.
• Imitation = Generic drugs, which are the same as a brandname drug in dosage, safety, strength, administration, quality,
performance, and intended use. FDA requires specific scientific
data on the therapeutic equivalence of generic drugs to the
branded drug, but does not require clinical trials. Consequently,
development costs are not even in the same league as for NMEs
or non-NME new drugs.
According to the U.S. Congressional Budget Office, the pharmaceutical industry is one of the most research-intensive industries in the United

States.1 Pharmaceutical firms invest as much as five times more in research
and development (R&D), relative to their sales, than the average U.S. manufacturing firm. Government-funded research institutes and agencies such
as National Institutes of Health (NIH), NSF, and the Centers for Disease
Control and Prevention (CDC) have ramped up R&D spending. Publicly
and privately funded academic R&D activity at universities and hospitals is
continuing at a pace commensurate with funding. Despite this, the rate at
which U.S. innovators have been able to bring new drugs from the research
pipeline into the market has slowed considerably over the past decade.
Figure 1.1 shows the estimated amount of money spent on R&D by
the private pharmaceutical sector. In Table 1.1, we see that the number
of NME approvals has essentially stagnated. Furthermore, applications for
NME approvals are not increasing, and candidate products did not appear
to be any more likely to advance to the stage of final FDA review in 2011
than in 2000. Some new therapeutic biological products are considered to
be NMEs, and are included here in the discussions of NMEs.
A myriad of explanations can be presented. Blame has been placed
on outdated clinical trial models and inefficient regulatory review and


Chapter 1: Pushing the Pipeline   5



Parmaceutical Industry R&D Spending
70.00
60.00

$ Billions

50.00

40.00
30.00
20.00
10.00

2004

2005

2006

2007
2008
Year

2009

2010

Figure 1.1 Pharmaceutical industry R&D spending.
Source: PhRMA 2011 Industry Profile.

Table 1.1

New molecular entities: applications and approvals.

Calendar year

NME applications filed

NMEs approved

2004

32

36

2005

38

20

2006

26

22

2007

35

18

2008

34

24

2009

37

26

2010

23

21

Source: FDA Center for Drug Evaluation and Research.

approval processes. Costs are often cited as an impediment. Indeed, costs
are a significant problem, but if investments are being made with dwindling
numbers of deliverables, blame also must be directed to the way the money
is being spent. While individual elements do contribute to failure, the most
egregious problem lies within the product development process itself.


6  Part I: Unique Challenges in Medical Product Development

It is estimated that development of a therapeutic new molecular entity
to the point of approval takes up to 15 years (see Figure 1.2). Recent estimates place the cost of developing a commercialized NME at over $1.3
billion (Figure 1.3).2 The numbers in Figure 1.3 include costs associated
with R&D and the costs of failed projects, which are capitalized and time
adjusted. These are disheartening figures, and the associated productivity

gap has become a concern to industry, academia, FDA and other government agencies, lawmakers, public and private funding sources, and patient
advocacy groups. Of course, there are the concerned patients themselves,
who hear or read reports on a daily basis about exciting discoveries that
hold promise for diagnosis, treatment, cure, or prevention of diseases—but
who rarely get to hear about, or benefit from, the availability of any breakthrough products.
Because of the great diversity within medical devices, and because
there are different regulatory pathways for various types of devices, estimates of product development time and costs are less readily analyzed, but
the overall trend holds true. A recent report says that taking a mediumrisk medical device cleared for marketing through the Premarket Notification 510(k) process requires $31 million on average, and that bringing

Developing a new medicine takes an average of 10–15 years.

5,000–10,000
compounds

Preclinical

Clinical trials

250

FDA review

Scale-up to
manufacturing

Post-marketing
monitoring and
research

5

3–6 years

Phase
1

Phase
2

Phase
3

Number of volunteers
20–100 100–500 1,000–5,000
6–7 years

NDA submitted

One FDAapproved
drug

IND submitted

Pre-discovery

Drug discovery

0.5–2 years

Indefinite

Figure 1.2 Drug development pathway.
Source: Pharmaceutical Research and Manufacturers of America, Drug Discovery
and Development: Understanding the R&D Process, www.Innovation.org.


Chapter 1: Pushing the Pipeline   7



Capitalized Pre-approval Costs
1400

Cost (Millions $)

1200
1000
800
600
400
200
0

Preclinical

Clinical
Phase of drug development

Total

Figure 1.3 Preapproval capitalized cost per approved NME.
Source: DiMasi and Grabowski 2007.

a ­high-risk device approved for marketing through the more rigorous premarket approval (PMA) process burns up about $94 million.3 About threequarters of those costs are related to stages linked to FDA. The devices in
the report are likely to be innovative new medical technologies requiring
clinical data, rather than simply extensions or products demonstrated to be
substantially equivalent to low or intermediate risk devices.
From a regulatory perspective, biologics may function as either
drugs—including but not limited to NMEs—or medical devices, and are
similarly affected by the productivity gap. Distinctions in drug, medical
device, and biologic product categorization and classification are discussed
elsewhere in this book.

Translational R&D
Moving a scientific idea, discovery, or design from the research stage,
through the product development process, to a viable and marketable medical product can be a formidable challenge. Surmounting the obstacles calls
for a revision in attitudes and processes related to medical product development. Enter translational research. Translational research—also frequently called translational science or translational development—refers