40
Development of FDA-Regulated Medical Products Prescription Drugs, Biologics, and Medical Devices
Development ofFDA-Regulated
Medical Products
Prescription Drugs, Biologics,and Medical Devices
Also available from ASQ Quality Press:
The FDA and Worldwide Quality System Requirements Guidebook for Medical DevicesKimberly A.Trautman
The Quality Auditor’s HACCP HandbookASQ Food, Drug, and Cosmetic Division
Mastering and Managing the FDA MazeGordon Harnack
Product Recall Planning Guide, Second EditionASQ Product Safety and Liability Prevention Interest Group
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ASQ Quality PressMilwaukee, Wisconsin
Development ofFDA-Regulated
Medical Products
Prescription Drugs, Biologics,and Medical Devices
Elaine Whitmore
American Society for Quality, Quality Press, Milwaukee 53203© 2004 by ASQAll rights reserved. Published 2003Printed in the United States of America
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Library of Congress Cataloging-in-Publication Data
Whitmore, Elaine.Development of FDA-regulated medical products : prescription drugs,
biologics, and medical devices / Elaine Whitmore.—2nd ed.p. cm.
Previously published under the title: Product development planning forhealth care products regulated by the FDA.Includes bibliographical references and index.ISBN 0-87389-613-0 (hardcover, case bound)1. Drug approval—United States. 2. New products—Standards—United
States. 3. United States. Food and Drug Administration. I. Whitmore,Elaine. Product development planning for health care products regulatedby the FDA. II. Title.
RA401.5.W48 2003615'.19—dc22 2003023464
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For Don, Andy, and Laura—as always.
vii
Table of Contents
List of Figures and Tables . . . . . . . . . . . . . . . . . . . . . ix
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
Preface to Previous Edition . . . . . . . . . . . . . . . . . . . . . xvii
Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix
Part I Unique Challenges in Medical ProductDevelopment
Chapter 1 Healthcare in the United States . . . . . . . . . . . . 3
Chapter 2 It’s Not Your Father’s FDA: The “Modernization”of Medical Product Regulation . . . . . . . . . . . . . . . . . 11
Chapter 3 Product Liability and Product Development . . . . 33
Part II Bringing a New Medical Product to Market
Chapter 4 Overview of the Approval Processes for Drugs,Biologics, and Medical Devices . . . . . . . . . . . . . . . . . 43
Chapter 5 Designing-in Quality . . . . . . . . . . . . . . . . . . 55
Chapter 6 Designing-Out Disaster: Risk Analysis . . . . . . . . 63
Chapter 7 Recalls, Revocations, and Withdrawals . . . . . . . 71
Chapter 8 Human Factors and the Nature of Relationships:Minimizing Medical Errors . . . . . . . . . . . . . . . . . . . 77
Chapter 9 Is It Safe and Does It Work? Evaluating Safety andEfficacy in Clinical Trials . . . . . . . . . . . . . . . . . . . . 87
viii Table of Contents
Chapter 10 How Much Is the Product Really Worth? OutcomesResearch, Pharmacoeconomics, and Managed Care . . . . . 101
Part III Product Development Planning
Chapter 11 Models and Metaphors: Product Development and the Product Development Organization . . . . . . . . . . 109
Chapter 12 Components of Product Development Planning:The Product Development Process . . . . . . . . . . . . . . . 119
Chapter 13 Components of Product Development Planning:Development Portfolio Management . . . . . . . . . . . . . . 131
Chapter 14 Components of Product Development Planning:Technology Assessment . . . . . . . . . . . . . . . . . . . . . . 145
Chapter 15 Components of Product Development Planning:Technology Forecasting . . . . . . . . . . . . . . . . . . . . . . 153
Chapter 16 More for the Laundry List: Marketing, Patents,Budgets, Games, and Quality . . . . . . . . . . . . . . . . . . 163
Chapter 17 Where Do We Go from Here? . . . . . . . . . . . . 175
Endnotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
ix
List of Figures and Tables
Figure 1.1 U.S. healthcare expenditures and projections. . . . . . . . 4Figure 1.2 U.S. prescription drug expenditures and projections. . . . 4Figure 1.3 Product development planning is an integrative
approach. . . . . . . . . . . . . . . . . . . . . . . . . . . 8Figure 1.4 Product development planning. . . . . . . . . . . . . . . . 9Table 2.1 Chronology of significant regulations relevant to
healthcare product development. . . . . . . . . . . . . . . 12Figure 2.1 Definition of a drug. . . . . . . . . . . . . . . . . . . . . 18Figure 2.2 Minimum information included in an IND. . . . . . . . . 18Figure 2.3 Definition of a biological product. . . . . . . . . . . . . . 19Figure 2.4 Definition of medical device. . . . . . . . . . . . . . . . . 22Figure 2.5 Minimum information included in an IDE. . . . . . . . . . 23Table 2.2 Major drug review activity. . . . . . . . . . . . . . . . . . 23Table 2.3 Major biologics review activities. . . . . . . . . . . . . . 23Table 2.4 Major medical device submissions received
by CDRH. . . . . . . . . . . . . . . . . . . . . . . . . . . 24Table 2.5 Recent new molecular entities approved by CDER. . . . . 24Table 2.6 Some recent BLA approvals. . . . . . . . . . . . . . . . . 25Table 2.7 Recent device actions. . . . . . . . . . . . . . . . . . . . 27Figure 2.6 Definition of a combination product. . . . . . . . . . . . . 28Table 2.8 Some outdated proposals and other actions that FDA
plans to withdraw. . . . . . . . . . . . . . . . . . . . . . . 31Table 3.1 Examples of recent product liability settlements. . . . . . 34Figure 3.1 Establishing product defects for product liability. . . . . . 35Figure 3.2 Responsibilities of product development planning
in minimizing future product liability problems. . . . . . . 37Figure 3.3 Primary considerations for product development
planning. . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Figure 4.1 Drug approval time. . . . . . . . . . . . . . . . . . . . . . 47Figure 4.2 Mean approval times for new biologics. . . . . . . . . . . 48
Figure 4.3 Medical device classification panels. . . . . . . . . . . . . 49
Figure 4.4 Examples of reserved Class I devices. . . . . . . . . . . . 52
Figure 5.1 The 1–10–100 rule. . . . . . . . . . . . . . . . . . . . . . 58
Figure 5.2 Class I devices subject to design controls. . . . . . . . . . 59
Figure 5.3 Examples of items to include in a design controls checklist. . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Figure 6.1 Examples of risk. . . . . . . . . . . . . . . . . . . . . . . 65
Figure 6.2 Objectives of risk assessment and management. . . . . . . 66
Table 6.1 Example of FMECA matrix. . . . . . . . . . . . . . . . . 69
Table 7.1 Recent safety-based drug withdrawals. . . . . . . . . . . . 74
Figure 7.1 CDRH five-year recall statistics. . . . . . . . . . . . . . . 74
Figure 7.2 CDER five-year recall statistics. . . . . . . . . . . . . . . 75
Figure 7.3 CBER five-year recall statistics. . . . . . . . . . . . . . . 75
Figure 8.1 CDRH comments on human factors. . . . . . . . . . . . . 79
Figure 8.2 Examples of FDA publications on the topic of human factors. . . . . . . . . . . . . . . . . . . . . . . . . 80
Table 8.1 Medication errors by cause during May 2001. . . . . . . . 81
Figure 8.3 Examples of general questions relative to demography and products. . . . . . . . . . . . . . . . . . . . . . . . . 83
Table 9.1 Initial evaluation tests for consideration: biological evaluation of medical devices. . . . . . . . . . . . . . . . 90
Table 9.2 Supplementary evaluation tests for consideration:biological evaluation of medical devices. . . . . . . . . . 91
Figure 9.1 Principles of ICH GCP. . . . . . . . . . . . . . . . . . . . 92
Figure 9.2 Overview of the new drug clinical development process. . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Figure 9.3 Diagrammatic representation of the ICH common technical document. . . . . . . . . . . . . . . . . . . . . . 96
Table 10.1 Pharmacoeconomic methods. . . . . . . . . . . . . . . . . 104
Table 10.2 Examples of quality of life domains. . . . . . . . . . . . . 104
Figure 11.1 Stylized new product development funnel. . . . . . . . . . 110
Figure 11.2 Internal impediments to healthcare product development that can be controlled or influenced by a product development organization (salmon swimming upstream analogy). . . . . . . . . . . . . . . . . . . . . . 112
Figure 11.3 Internal impediments to healthcare product development that are not usually controlled or significantly influenced by a product development organization (salmon swimmingupstream analogy). . . . . . . . . . . . . . . . . . . . . . 113
Figure 11.4 External impediments to healthcare product development that can be controlled or influenced by a product development organization (salmon swimming upstream analogy). . . . . . . . . . . . . . . . . . . . . . 114
x List of Figures and Tables
Figure 11.5 External impediments to healthcare product development that are not usually controlled or influenced by a productdevelopment organization (salmon swimming upstream analogy). . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Figure 11.6 What a product development organization needs. . . . . . 115Figure 12.1 The product development process is an integral
component of product development planning. . . . . . . . 120Table 12.1 Six-step healthcare product development process. . . . . . 122Figure 12.2 The product development process. . . . . . . . . . . . . . 123Figure 12.3 Questions to consider when evaluating ideas. . . . . . . . 125Figure 12.4 Examples of idea evaluation criteria. . . . . . . . . . . . . 126Figure 13.1 Development portfolio management is an integral
component of product development planning. . . . . . . . 132Table 13.1 Framework for basic assessment of ideas, projects, and
future opportunities. . . . . . . . . . . . . . . . . . . . . . 134Figure 13.2 A simple generic portfolio map matrix. . . . . . . . . . . 136Table 13.2 Additional characteristics for project mapping. . . . . . . 136Figure 13.3 An example of a technology portfolio matrix. . . . . . . . 137Figure 13.4 Portfolio map matrix showing types of projects. . . . . . . 138Figure 13.5 A project map for a fictitious company: is it good
or bad? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Figure 13.6 Signs that a project should be killed. . . . . . . . . . . . . 143Figure 14.1 Technology assessment is an integral component of
product development planning. . . . . . . . . . . . . . . . 146Figure 14.2 Considerations in technology assessment. . . . . . . . . . 146Figure 14.3 Examples of critical skills and knowledge base for
informed technologies assessment. . . . . . . . . . . . . . 149Table 14.1 Framework for basic assessment of ideas, projects, and
future opportunities. . . . . . . . . . . . . . . . . . . . . . 151Figure 14.4 Additional issues relevant to technology assessment. . . . 151Figure 15.1 Technology forecasting is an integral component of
product development planning. . . . . . . . . . . . . . . . 154Figure 15.2 The relationship between science, technology,
and market. . . . . . . . . . . . . . . . . . . . . . . . . . 155Figure 15.3 Factors contributing to the emergence of new diseases and
the reemergence of previously controlled diseases. . . . . 158Figure 15.4 Considerations for technology forecasting. . . . . . . . . . 160Figure 15.5 Areas of inerest at the FDA for the 21st century. . . . . . . 161Table 16.1 Types of intellectual property (IP). . . . . . . . . . . . . . 165Figure 16.1 Important factors influencing IP value in medical product
development planning. . . . . . . . . . . . . . . . . . . . 166Table 16.2 Some budget considerations. . . . . . . . . . . . . . . . . 167Figure 16.2 The customer/quality continuum. . . . . . . . . . . . . . . 172
List of Figures and Tables xi
xiii
Foreword
Healthcare cost, quality and access, and the question of “Who pays?”have taken center stage in the United States. By focusing on thepolitical, economic, and societal influences on medical product
development in updating her 1997 book, Elaine Whitmore directs us to thecritical wave of change that has rolled across the pharmaceutical industry.The drug development industry has experienced sometimes gut-wrenchingtransformation in the past decade and, as far as anyone can tell, this trans-formation will continue to evolve as strong outside influences on productdevelopment continue to exert tremendous pressures.
Will the latest push to cut the cost of prescription drugs, biotechnology,or new medical technology result in dampening innovation in the regulatedindustries? We all hope it won’t, but the truth is we don’t know. This vol-ume helps put focus on the various issues that impact this concern:
• When will the regulatory environment change again?
• How has the focus on patient outcomes affected productdevelopment?
• How will increased social pressures to manage medical costs affect marketing objectives and the product lifecycle?
• Will the United States adopt European pricing practices? How might this impact product development and patient care?
As a business leader in the pharmaceutical industry whose career hasbeen intimately tied to the product development process, I find Developmentof FDA-Regulated Medical Products to be comprehensive, inclusive andwell organized. The first step in mastering this changing environment is tobetter understand it.
For those who have made a career in pharmaceuticals, or are involvedin the product development cycle, Elaine’s text is suitable as a helpful day-to-day guide. It offers insight as to how internal and external pressures
influence the modern medical product development process, and how thesepressures interact with one another. With this knowledge, medical productdevelopment professionals will be better able to synthesize the elements ofthe new development process, and achieve the ultimate objective of bring-ing an effective product to market.
Elaine’s text also gives us an excellent basis from which to begin ananalysis of product development decision making. And it is my hope thatothers outside the industry, especially those who are striving to betterunderstand how we work, will leave with a better understanding of why andhow product decisions are made, and the very significant level of risk andchallenge inherent in the process.
In my mind, the real insight that Elaine Whitmore can offer us comesthrough in her very last chapter entitled, “Where Do We Go from Here?” Init, she talks about a great many practical issues that revolve around manag-ing expectations at all levels of the company, managing interactionsbetween members of the development team, and the key role of technologyin the development process.
But the real issue remains: “Where do we go from here?” Dr. Whitmoreacknowledges that the medical product development landscape is constantlyevolving, and provides stimulus for future discussion and debate that shouldoccur across our industry.
With the tremendous challenges, risks, and external pressures ofdeveloping new medicines and devices in the 21st century, it is still a won-der that new products are developed at all. That said, it would be a tragedyif they were not. And that is the very reason why Elaine Whitmore’s workis so critical.
Carrie S. CoxPresident, Global Pharmaceuticals
Schering-PloughKenilworth, New Jersey
xiv Foreword
xv
Preface
Since the predecessor to this book on product development was pub-lished in 1997, under the rather unwieldy title Product DevelopmentPlanning for Healthcare Products Regulated by the FDA, there have
been revolutionary changes to the classification and regulation of prescrip-tion drugs, biologics, and medical devices. One effect of the modernizationof the Food and Drug Administration (FDA) has been a leveling of theplaying field in the 21st century, with both regulators and industry experi-encing the uncertainties and growing pains that accompany significant gov-ernment reorganization.
While focus and missions in medical product development will alwaysbe functions, to some extent, of political and social change, certain princi-ples remain intact: there is a need for new medical products that are safe andeffective, designed and developed with quality, and that meet the needs ofcustomers. Efficiently and productively fulfilling these objectives requireseffective coordination of product development processes and activities.
Much new information has been added, including a review of the sig-nificant changes within the FDA that affect the requirements and review ofmedical products; updated facts and figures; expansion of subjects thathave grown more critical, such as clinical outcomes, human factors, andmarketing objectives; and new topics, such as the role of product develop-ment in hazard analysis, recalls, and product liability. The basic philosoph-ical message of the earlier volume and the intended audience of anyoneinterested in or active in medical product development—regardless of cor-porate function—remain the same.
xvii
Preface to Previous Edition*
This book is about maximizing the efficiency of developing newhealthcare products—such as medical devices, biologics, anddrugs—that are regulated by the FDA. This book is not intended to
emphasize that product development is important, that businesses need newproducts to survive and to grow, or that the results of poorly executed prod-uct development are costly or disastrous. Anyone interested in productdevelopment already knows this.
After several years of searching for a volume or two that would offerinformation helpful to my product development endeavors in this field, Idiscovered that conventional product development literature simply doesnot address topics of significance to healthcare products. Why is the devel-opment of medical devices, drugs, and biologics unique enough to warranta dedicated, up-to-date examination? There are many reasons, not the leastof which involves regulations. The requirements of the FDA, coupled withthose of emerging international regulatory and quality standards, differen-tiate healthcare products from the products that are the subjects of mostproduct development literature. Testing programs required by regulatoryagencies before healthcare products can be marketed impose special con-straints on development time lines, as do the often lengthy regulatoryreview processes. Managed care, as well, is exerting a profound influence,by requiring demonstration of superior clinical, cost, and quality-of-lifeoutcomes. Other factors such as cultural differences in attitudes, practices,and preferred outcomes of medicine and surgery pose special challenges toglobalizing product development efforts and new product introductions.
Organizational challenges exist, too. Product development must go onthrough restructuring, reorganization, mergers, divestitures, and thesequential adoption of the latest trends in organizational philosophy. Theway a particular company is structured or managed may or may not be
* Whitmore, Elaine. Product Development Planning for Health Care Products Regulated bythe FDA. Milwaukee: ASQ Quality Press, 1997.
optimal for product development in that company at a given time. Generallyspeaking, though, those individuals actively involved in product develop-ment do not have the authority to make substantial changes in organizationalstructure. Consequently, it is important for healthcare product developmentguidelines to be applicable to most, if not all, corporate structures, and notto require force-fitting.
This book is intended to form a foundation for anyone—regardless offunctional specialty or organizational echelon—who is a student of, isabout to embark upon, is active in, or has management responsibility forproduct development and business development decisions in the medicaldevice and pharmaceuticals industry. This book is also appropriate forupper management persomnel not personally active in product develop-ment activities, because it raises and explains issues pertinent to the successof healthcare product development efforts. Although not arranged in text-book format, the material is well-suited for classroom use in advancedmanagement or specialty management programs.
This is not a how-to manual, for the scope of FDA-regulated healthcareproducts is too vast to address in any single volume using a step-by-stepapproach. Rather than teaching readers how to do things, this book instructsreaders about the nature of the things that need to be done for the success-ful development and commercialization of new healthcare products. Thereare requirements that apply to product development of FDA-regulatedhealthcare products that are never encountered or considered in the devel-opment of other categories of new products. After reading this book, indi-viduals involved in the development of new FDA-regulated healthcareproducts, regardless of background or functional discipline, will understandthe reasons and significance of these special requirements and appreciate thevalue of product development planning.
This book will provide readers with: (1) the basic background materialthat will allow cross-functional participants in product development, as wellas managers not directly involved with the day-to-day activities of productdevelopment, to have a mutual understanding of regulations, guidelines,time lines, process implementation, and expectations; (2) a common vocab-ulary for all functions and all organizational levels; and (3) an introductionto methods and exercises that will facilitate quality-oriented healthcareproduct development. Through establishing a shared vision among diversegroups and individuals, product development planning can make healthcareproduct development activities less fractious and more productive.
xviii Preface to Previous Edition
xix
Abbreviations
510(k)—premarket notification application
ANDA—abbreviated new drug application
BLA—biologics license application
CBA—cost/benefit analysis
CBER—Center for Biologics Evaluation and Research
CDER—Center for Drug Evaluation and Research
CDRH—Center for Devices and Radiological Health
CEA—cost-effectiveness analysis
cGMP—current good manufacturing practice
CMA—cost minimization analysis
CRO—contract research organization
CTD—common technical document
CUA—cost/utility analysis
FDA—Food and Drug Administration
FDAMA—Food and Drug Administration Modernization Act
FD&C Act—Food, Drug, and Cosmetic Act
FMEA—failure mode and effects analysis
FMECA—failure mode and effects 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 (of technical requirements for registration of pharmaceuticals for human use)
IDE—investigational device exemption
IND—investigational new drug application
IP—intellectual property
IRB—Institutional Review Board
ISO—International Organization for Standardization
IVD—in vitro diagnostics
MDUFMA—Medical Device User Fee and Modernization Act
NCE—new chemical entity
NDA—new drug application
NME—new molecular entity
PDUFA—Prescription Drug User Fee Act
PHS Act—Public Health Service Act
PMA—premarket approval application
QOL—quality of life
QSR—quality systems regulations
SMDA—Safe Medical Devices Act
TQM—total quality management
xx Abbreviations
Part I
Unique Challengesin Medical Product
Development
1Healthcare in the
United States
The first wealth is health.
—Ralph Waldo Emerson
A billion here, a billion there, and pretty soon you’retalking about real money.
—Everett Dirksen
Those involved in medical product development share the same pri-mary goal: to discover, develop, and bring to market new productsthat enable people to live healthier, more productive, more comfort-
able lives. Nowhere in the world is this goal more enthusiastically endorsedby the population than in the United States. Yet from day one in the prod-uct development process, medical products manufacturers face challengesthat other industries never have to confront.
The United States leads the world in healthcare spending.1 Health andwell-being are so important in this country that by 2001, annual nationalhealth expenditures represented 14.1 percent of the gross domestic product,or about $5000 per person. This means that in 2001, Americans spent morethan $1.4 trillion on healthcare—more than five times the amount spent in1980.2 Government projections anticipate that this spending will exceed $3trillion by 2012 (see Figure 1.1).
In recent years, spending on prescription drugs has grown at a faster ratethan any other type of health expenditure. Prescription drug expenditures
3
alone accounted for fully 10 percent of the money spent in the United Stateson healthcare in 2001. By 2012, spending on prescription drugs is expectedto represent 15 percent of the total U.S. healthcare expenditure. As shownin Figure 1.2, the dollar amount spent on prescription drugs in 2012 willmore than triple the 2001 prescription drug expenditure. Unlike prescriptiondrug expenditures, spending on medical devices and biologics is not specif-ically tracked by the U.S. Department of Health and Human Services.
4 Part I: Unique Challenges in Medical Product Development
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
1998 2000 2002 2004 2006 2008 2010 2012
$ Tr
illio
ns
Year
Total U.S. Healthcare Spending
Figure 1.1 U.S. healthcare expenditures and projections.Source: Centers for Medicare and Medicaid Services
050
100150200250300350400450500
1998 2000 2002 2004 2006 2008 2010 2012
$ B
illio
ns
Year
U.S. Healthcare Spending—Prescription Drugs
Figure 1.2 U.S. prescription drug expenditures and projections.Source: Centers for Medicare and Medicaid Services
Industry estimates suggest that medical device sales in the United Stateswere about $78 billion in 2000.3 The biologics market may be about $40 bil-lion and is rapidly rising.
Add up the numbers and it becomes clear that the market for prescrip-tion drugs and other healthcare products, including medical devices andbiological products, is staggeringly huge. Continued growth and profitabil-ity, however, depend on a delicate balance of managed care initiatives, fed-eral and international regulatory requirements, generic challenges, liabilityissues, and the ability of industry suppliers and manufacturers to shortenproduct development cycles.
Product development in the healthcare field, especially product devel-opment of medical devices and certain biologics, has all too often been aseat-of-the-pants endeavor, short-changed in terms of support and under-standing by management and by the individuals charged with getting thejob done. But with recent developments in healthcare management andwith sweeping changes in global clinical, regulatory, and quality require-ments, manufacturers will no longer be able to effectively compete in thearena of healthcare products without making equally sweeping changes inthe way they develop new products. The Food and Drug Administration(FDA) has taken on a new role in enabling these changes, as will be dis-cussed in chapter 2.
Manufacturers of medical products today are obligated to do more thansimply provide evidence to the FDA that their products are safe and effica-cious. Growing concerns about the cost and quality of healthcare in theUnited States will dictate that in order for a new product to be accepted,reimbursed, and perhaps even approved, the use of that product will have toprovide favorable outcomes in terms of:
• Clinical utility in uncontrolled real-life use situations
• Quality of life for the patient, following the treatment
• Cost-effectiveness
Thus, a successful product development process will need to factor intherapeutic, humanistic, and economic performance.
It takes a lot of money and time to develop and launch a medical prod-uct. It is estimated that in the United States, about 10 to 15 years and morethan $800 million are needed to develop and obtain approval for a newdrug.4 Investments in the development of new therapeutic biologics are sim-ilar. Because the medical device area is much more diverse and complex, itis difficult to come up with average development times. Average time fromconcept to commercialization for medical devices ranges from two years toseven years, depending on the type of regulatory application required.5
Chapter One: Healthcare in the United States 5
Regulatory requirements and quality standards are becoming moredemanding, in part because of the desire to market new products outside ofthe United States. The shrinking of the world through globalization of med-ical product businesses is a fact of life for a variety of reasons: (1) thedomestic market is becoming increasingly saturated, so that going global isone of the few remaining ways to grow; (2) the pressures of managed careand cost containment in the United States are making it more difficult toincrease domestic sales of products that do not have demonstrated out-comes advantages when compared with available lower-priced alternatives;(3) small companies partner with or get acquired by large companies, theoverwhelming majority of which have a multinational presence; and (4)large, multinational companies want products that they can market globally.Yet many healthcare companies are poorly prepared to integrate into theirproduct development plans the elements of cultural biases and preferencesin medical and surgical practices, differing expectations of acceptable clin-ical outcomes, and variability in regulatory and quality requirements.
Harmonization of domestic requirements, as defined by the FDA, withthose set forth by the International Conference on Harmonization (ICH)directives will be a process requiring ongoing evolution and refinement.One thing is certain: harmonization will directly affect the way productdevelopment is planned, executed, and documented.
Because of the enormous investments required for regulated medicalproduct development, a shotgun approach often used with nonmedical prod-uct categories—in which large numbers of new products are introduced inhopes of ending up with at least one big winner—is not possible. Extraordi-nary focus and foresight are necessary. Evaluation of a myriad of ideas andopportunities against well-defined criteria will help assure that resourcesare directed at a select few of those opportunities—those that will lead tosuccessful and profitable new products.
Even though the pharmaceutical/medical device industry spends pro-portionately more on research and development (R&D), as a percent ofsales, than other industries, much of that money ends up being misdirectedinto activities that do not yield either information that is useful or new prod-ucts that are profitable. Industrial R&D intensity and expenditure do notguarantee success. The R&D efforts must be coupled to product andprocess developments that will sustain the company through the presentand into the future. It is not uncommon for 50 percent or more of what iscalled R&D or product development activity to be delegated to workrelated to neither research nor development. Requests for technical fixes forexisting products with design flaws usually top the list. Responding to fieldsales forces when help is needed with customer questions or problems, andrevalidating processes and products after the company makes changes in
6 Part I: Unique Challenges in Medical Product Development
materials, equipment, or manufacturing location, are also typical. Add tothis the time spent on general administrative tasks, various updates and pre-sentations, and training programs, and it’s clear that not much time may beleft for developing new products or technologies.
For a healthcare company to attain or sustain leadership will require thetimely development and launch of new products that are safe and effective,meet both recognized and unarticulated user needs, and provide necessaryand desirable outcomes. Creating and using a system of product develop-ment planning will substantially increase the probability of achieving thesegoals. Product development planning should be thought of as the applicationof total quality management (TQM) principles to new medical products.
Product development planning is an integrative approach to addressingboth long-term and short-term needs and requirements for new products(see Figure 1.3). Although each component section of product developmentplanning will be discussed separately in this book, in practice the compo-nents are inseparable. Each component draws upon, as well as contributesto, every other component.
Product development planning defines a technology strategy by linkingtechnology forecasting—as a vision of the future—with an ongoing assess-ment of existing, new, emerging, and embryonic technologies. The technol-ogy strategy, in turn, provides the foundation and direction for a portfolio ofproduct development project opportunities. Finally, quality management ofthis development portfolio depends upon successful implementation of asound product development process. The major components of productdevelopment process, development portfolio management, technologyassessment, and technology forecasting overlap in their contributions toshort-, medium-, and long-term strategy for the growth and evolution of thecompany (see Figure 1.4).
Firmly anchored in the present, the product development process dealswith the immediacy of identified active projects; its impact on the future isdependent upon the development time line of each project. Portfolio man-agement assures the proper mix of product development projects and oftheir sequence and phasing; its impact is linked to the present and near-future through monitoring and management of active ongoing projects, andto the mid-term future through staged application of the product develop-ment process to other identified projects. Technology assessment spans thenear- to mid-term future by encompassing evaluation of existing, emerging,embryonic, and new technology opportunities. Finally, the mid- to long-term future is most influenced by the imaginative, visionary exercise oftechnology forecasting.
Product development planning, especially through the implementationof the principles of the product development process, will allow healthcare
Chapter One: Healthcare in the United States 7
companies to break out of the trap of technical service disguising itself asR&D and undermining bona fide product development activities. Productdesign deficiencies and manufacturing problems will be identified and cor-rected early, making it much less likely for a costly problem to turn up late inthe game. The lack of clarity or comfort in the handling and use of the prod-uct will be minimized or eliminated, reducing the demands for technicalassurances, explanations, and support to users of the products. Furthermore,
8 Part I: Unique Challenges in Medical Product Development
Development
PlanningPro
duct
Productdevelopment
process
Developmentportfolio
management
Technologyforecasting
Technologyassessment
Productdevelopment
process
Developmentportfolio
management
Technologyforecasting
Technologyassessment
Figure 1.3 Product development planning is an integrative approach.
a company will be less likely to suffer the embarrassment and cost of launch-ing a product that is later discovered to have problems with properties suchas usability, stability, or packaging. Most importantly, however, product-associated risks to patients will be reduced.
A few of the techniques and procedural suggestions that follow areespecially tailored for the development of one or another category of med-ical product. For the most part, though, the principles and philosophy arealso applicable to all categories of FDA-regulated medical products thatare the focus of this book: drugs, biologics, and medical devices. A funda-mental knowledge and understanding of all three categories of regulatedmedical products is unavoidably important, since new and more sophisti-cated technological approaches to meet customer needs have blurred thedistinctions between drugs, biologics, and devices. While there may bedifferences in costs and development times, and in the nature and extentof regulatory and clinical requirements between the various categories ofhealthcare products, a program of formal and organized product develop-ment planning will bring focus and direction to everyone involved in med-ical product development and will add value and profitability to theproducts being developed.
Chapter One: Healthcare in the United States 9
Technology forecasting
Present
Component
Technology assessment
Portfolio management
Product development process
Future
Figure 1.4 Product development planning.
Aabbreviated new drug application
(ANDA), 48access to care, managing, 102animal testing, 29, 45, 87–89approval processes, 16–23, 43–54
biologics, 47–48drugs, 44–47generic drugs, 48–49medical devices, 49–54new drugs, 48–49
approval time,biologics, 48generic drugs, 48–49medical devices, 54new drugs, 44
Bbenefits, medical product, 64, 65biocompatibility, 89biologic devices, 20biologic product, license, 16biological evaluations, medical
devices, 89, 90–91biological product, PHS Act
definition, 19biologics,
FDA approval, 47–48FDA definition, 16
IND application, 89–92biologics license application (BLA),
16, 47, 94, 96recent approvals, 25–26
biologics market, 5biotechnological advances, 102blinding, 97budget, product development, 167–68
CCenter for Biologics Evaluation and
Research (CBER), 17ICH sponsor, 92mission, 19product classes, 19–20
Center for Devices and RadiologicalHealth (CDRH), 20, 22
clinical data, 96human factors engineering team,
78ICH guideline, 92major medical device submissions,
24Center for Drug Evaluation and
Research (CDER), 17ICH sponsor, 92
claims, unsubstantiated, 106clinical data, mutual acceptance, 92clinical endpoints, 99clinical need, 148
Index
195
clinical outcomes, 103clinical research compared to
outcomes research, 102clinical safety and effectiveness, 129clinical studies,
Class II medical device 510(k)submissions, 97
quality assurance, 92–93clinical testing on human subjects,
128clinical trials,
Class III devices, 96–97design, 101, 105diversity, 98–99drugs and biologics, 87, 89–98evaluating safety and efficacy,
87–99failures, 87medical devices, 97–98phases, 94, 98purpose, 45–46
clinical utility, 101closed formularies, 102cognitive factors, 82combination products, 26–28
CDRH definition, 28common technical document (CTD),
94–96competitors, 124compounded drug products, 14computer software, 59, 60concept testing, 127concurrent engineering, 116consolidation of drugs and biologics,
16–20contract research organization (CRO),
98controls, 97Cooper, Theodore, 21copyrights, 164–65core competencies, 124cosmetic appeal, 82cost/benefit analysis (CBA), 103cost-containment, 101, 102cost-effectiveness, 101cost-effectiveness analysis (CEA), 103cost-minimization analysis (CMA),
103cost of care, managing, 102cost/utility analysis (CUA), 103
coverage of medical treatments, 102cross-functional organization, 113–17cultural biases, 86current good manufacturing practices
(cGMP), 46, 56requirements for medical devices,
82–83customer feedback, 84customer observation, 84–85customers, 83–86, 148customers’ needs, 123, 124, 150
DDeclaration of Helsinki, 92demographics, 81demonstration, 122, 129design and development planning,
59–60design changes, 59, 61–62design controls, 57–62, 171–73
feasibility, 127–28requirements, 121
design controls implementation,FDA regulations, 59–62
design defects, 35, 36, 57, 64design for foreseeable risks, 37design history file, 59, 62design input, 59, 61design, medical devices, 56–62design output, 59, 61design results, assessing, 61design review, 59, 61, 62
committee, 128design transfer, 59, 61design verification and validation, 59,
61development initiation proposal, 126development portfolio management,
7–9, 131–44number of projects, 141–42portfolio assessment, 132,
133–41projects, discontinuing, 142–43requirements, 132–33
development scientists, 115direct observation, 84–85discovery, 122–27dispensing errors, 78
196 Index
document search and retrievalresources, 116
documentation, submitting, 30, 129dose-ranging, 89drugs,
FDA definition, 16IND application, 89–92
drugs, FDA approval,approval time, 46–47clinical trials, 45–46IND application, 45inspections, 46NDA, 46preclinical testing, 45screening, 44–45
drugs, new,FDA approval process, 44–47
Eeconomic analyses of healthcare
products, 102–3economic information about products,
14electronic submissions, 29end users, 148ergonomics, 81establishment license application
(ELA), 16exploratory searches, 123
Ffacilitator. See team leaderfailure mode analysis, 62, 67–69failure mode and effects analysis
(FMEA), 67failure mode and effects criticality
analysis (FMECA), 62, 67,68–69
fault tree analysis (FTA), 62, 67FDA approval processes,
biologics, 16drugs, 16medical devices, 20–22
FDA-approved indicated uses, 163–64feasibility, 110, 122, 127–28
studies, 98
Federal Food, Drug, and Cosmetic(FD&C) Act of 1938, 11
amendment of 1962, 20drug definition, 17, 18medical device amendments, 21Safe Medical Devices Act
(SMDA), 21Food and Drug Administration
(FDA), 5consolidation of drugs and
biologics, 16–20medical devices, 20–23medical product regulation, 11–31mission, 11
Food and Drug AdministrationInitiatives and Programs, 13–14
Food and Drug AdministrationModernization Act (FDAMA),11–16
funding resources, limited, 101
Ggame theory, 168–70gene mapping, 155–56general controls, medical devices,
50–52requirements, 51
generic drugs, 102approval process, 48–49
globalization, 6, 169globalization trend in product
development, 85–86good clinical practices (GCPs), 92,
171–72principles of ICH, 92–93
good laboratory practice (GLP)regulations, 88–89, 171–72
good manufacturing practice (GMP),56–58, 62
Gore, Al, 13guide. See team leader
Hharmonization of requirements, 6,
92, 94Hatch-Waxman Act, 166
Index 197
hazards, 63–64, 72health status of patient, 103healthcare, cost and quality, 5healthcare expenditures, 101healthcare market, 5healthcare product development,
internal impediments, 111–13healthcare products, development to
approval, 5healthcare spending, U.S., 3–5healthcare trends, affected by other
trends, 157human factors, 77–86, 128
analyses, 82–86human factors engineering (HFE), 79human genome project, 155–56human subjects, studies involving,
92–93human testing, 45human trials, advancing to, 88
Iimmunity to product liability, 34individual errors, 78–80industry analysis, 124innovator drug, approval process,
48–49institutional review board (IRB),
92–94instructions, inadequate, 35, 36insurance program, 102intellectual property (IP), 164–67internal review, 121International Conference on
Harmonization (ICH), 92investigational device exemption
(IDE), 22, 23, 92, 97, 128investigational new drug (IND)
application, 17, 18, 45, 89–92,128
ISO 10993 Part 1, 89
Llabeling, 36, 78laboratories, 89
laboratory tests, 44–45, 87launch and follow-through, 122, 130lawsuits, product liability, 34,
68, 81licenses, 16
cancellation, 73life-quality factors, 104
Mmanaged care, 102management responsibility, high-
level, 117manufacturers, medical product,
design controls, 57–62federal regulations, 55–56
manufacturing defects, 35, 36, 64manufacturing facility, license, 16manufacturing process, validation,
129manufacturing specifications, 36mapping, 134–41market,
failures, 150needs, 177withdrawals, 72–73, 74
market pull ideas, 176–77marketing,
biologic product, 16–17new drug, 16–17
marketing, planning,163–64quicker path, 164
McClellan, Mark, 26medical device,
classification, 49–50clinical trials, 97–98definition, 21–22expenditures, 4–5manufacturers, 51recalls, 57
Medical Device Amendments, 21,34, 50
medical device regulatory controls,50–54
general controls, 50–52premarket approval, 53–54premarket notification, 53special controls, 53
198 Index
medical device studies, blinding, 97Medical Device User Fee and
Modernization Act of 2002(MDUFMA), 29
medical devices,biological evaluations, 89, 90–91categories, 49–50classification panels, 49–50concept to commercialization, 5design, 98design review, 122faulty, 34–35IDE, 92implantable and absorbable, 88minimum requirements, 50–52operation, 98regulation of, 20–23, 50–54surveillance, 29
medical devices, Class I,design controls implementation,
59examples, 51premarket notification
requirements, 51–52reserved, 51–52
medical devices, Class II, 53clinical studies, 97design controls implementation,
59product development phases, 122
medical devices, Class III, 53–54clinical trials, 96–97design controls implementation,
59product development phases, 122
medical errors, minimizing, 77–86medical procedures, proved effective,
101medical product development, 55–62
design controls, 57–62successful, 54
medical products,classifications, 15–22clinical benefits, 103purpose, 105regulation, 11–31standards, 15–16use, 102–3
metabolic processes, 88
molecular modeling, 88multicultural markets, 86
Nnew chemical entities (NCEs), 24new drug application (NDA), 16, 17,
46, 94, 96new drug development and approval
process, 94–95new molecular entities (NMEs), 24nonclinical testing, 88nondomestic customers, 148nonsignificant-risk devices, 97non-zero-sum games, 168–69
Oobsolescence, premature, 150off-label indications, 14, 163–64Office of Combination Products
(OCP), 26–28Office of Generic Drugs at CDER, 481–10–100 rule, 57, 58optimization, 122, 128–29outcomes evaluations, 105–6outcomes measures, 105outcomes research, 102–3
compared to clinical research, 102
Pparallel development, 116patents, 164–65patient injuries, 21patient population, 98patient safety, 9, 14–15, 20–21,
29, 64patient-oriented factors, evaluations,
104penalties, product liability findings, 34pharmaceutical therapy interventions,
evaluation, 103pharmaceuticals, 16pharmaceuticals manufacturing, risk-
based approach, 29–30
Index 199
pharmacoeconomics, 103–4analyses, 103–4
pharmacogenetic research, 99pharmacy compounding, 14phases, clinical trials, 94, 98physical environment, 103pilot studies, 98pilot-scale manufacturing, 129pioneer drug, 48pivotal studies, 98political agendas and technology
forecasting, 158portfolio analysis, 121portfolio assessment, 132, 133–41
ideas, projects, opportunities, andpossibilities, 133–34
mapping, 134–41project evaluation, 135purpose, 133
post-marketing surveillance, 103, 130practitioners, experience, 103preamendment devices, 50, 53preclinical program, identifying, 45preclinical testing, 45, 88–89predicate device, 53preliminary efficacy studies, 89premarket approval (PMA), 22,
35, 98medical devices, 53–54
premarket notification [510(k)], 22,35, 51–54, 98
prepaid health plan, 102prescribing errors, 78prescription drug expenditures, 3–4Prescription Drug User Fee Act of
1992 (PDUFA), 13user fees, 13, 29, 46, 47
primary-care physicians, 102procedural advances, 102product,
defects, 64failure, 81misuse, 81portfolio, 13promotion, 164real-life effectiveness, 103recalls, 57, 64, 68, 71–72, 73,
74–75success, 130testing, 37
product development,concurrent engineering, 116cross-functional activity, 115path, 177phases, 122–23successful, 116teams, 37–38TQM, 170–72upper management responsibility,
117worldwide markets, 85–86
product development continuum,steps, 120–21
product development funnel, new,109–10
product development organization,needs, 115
product development planning, 7–9,36–39, 76, 99
core qualities, 133–34development portfolio
management, 131–44outcomes, 105–6product development process,
119–30team, 105technology assessment, 145–52technology forecasting, 153–61
product development process, 7–9,119–30
demonstration, 122, 129development phases, 122–23discovery, 122–27feasibility, 122, 127–28launch and follow-through, 122,
130objective of establishing, 121optimization, 122, 128–29production, 122, 130review system, 122–23successful, 5
product development teams, 37–38product ideas, 124–25
evaluation criteria, 126product liability, 33–39
defects, 35–36FDA approval, 34–35lawsuits, 34, 64, 68penalties, 34prevention, 36–39
200 Index
vulnerability to litigation, 33–34product license application
(PLA), 16production, 122, 130project evaluation, 135project management software
packages, 127–28project mapping characteristics,
134–36project team, 127–28project-focusing process, 110projects, discontinuing, 142–43proposals, outdated, 30–31prototype, 127Public Health Service (PHS) Act, 19
Qquality, 55–62
designed and built-in, 55–56quality assurance requirements, 88
clinical studies, 92–93quality challenges, 170–73quality of care, managing, 102quality of life, 101
measurements, 102quality of life (QOL) assessments,
104–5quality requirements,
FDA, 56quality standards, 116–17quality system regulations (QSRs),
56, 122
Rradiation-emitting products, 20reasonable confidence, 87recalls, 57, 64, 68, 71–72, 73, 74–75regulatory approval, 129regulatory controls, medical devices,
50–54regulatory issues, 116–17Reinventing Government program,
13–14research and development, 115
expenditures, 6–7research, government-funded, 159
reserved criteria, 51review jurisdiction, 17, 27–28review system, product development,
122–23revocations, 73reward and recognition, 128risk analysis, 63–69risk assessment, 65–67risk–benefit ratios, 102risk management, 66risk, medical product, 64
sources, 64–67risk, minimizing, 66risk of injury, assessing, 37risk-based regulation of medical
devices, 14–15risks, foreseeable, 37
SSafe Medical Devices Act (SMDA)
of 1990, 21safety and efficacy, evaluations, 88safety risks, 37–38safety-based withdrawals, 73, 74salmon swimming upstream analogy,
111–14scientists and technology forecasting,
157–58screening, 89side effects, 64–65significant-risk devices, 97simplification, 142simulated-use testing, 88special controls, medical devices, 53standards,
acceptance and coverage ofmedical treatments, 102
outcomes evaluations, 102steward. See team leadersubmission for approval, 30subscriptions, periodicals, 116
Tteam leader, 127technical feasibility, 110technological advances, 102
Index 201
technological opportunities, assessingvalue, 148–50
technology assessment, 7–9, 115–16,145–52
additional issues, 150–52basic scheme for evaluation,
150–51critical skills, 148–49objective, 145scientific opportunities, 147technological opportunities,
assessing value, 148–50technology forecasting, 7, 153–61
areas of interest, FDA, 161conclusion of a session, 159considerations, 160information sources, 156–57objective, 160political agendas, 158scientists, 157–58trends that affect healthcare
trends, 157technology, new,
attractiveness, 150technology push ideas, 176–77technology readiness and novelty, 150technology strategy, 7
formation, 145therapeutic agents, 102
total quality management (TQM), 7,55, 62
product development, 170–72trade secrets, 164–65trademarks, 164–65
Uuncontrollable factors, 103unidentifiable factors, 103universities, preclinical studies, 89U.S. Supreme Court decisions, 34, 57use errors, 65–67, 78user fees, 13, 167user, identifying, 84user needs and expectations, 84–85
Wwarning defects, 35, 36, 64withdrawals, safety-based, 73, 74worldwide markets, 85–86
Zzero-sum games, 168
202 Index
