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Development of FDA-Regulated Medical Products

A Translational Approach

Second Edition

Elaine Whitmore

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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

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

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

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

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 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

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

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

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

The 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, logics, 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

bio-Not surprisingly, industry and academia are under substantial sure to transform discoveries and innovations from the laboratory into safe and effective medical products to benefit patients and improve health This

pres-evolution—from bench to bedside—has become known as translational research and development

Translating promising discoveries and innovations into useful, able 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

market-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

Preface

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

ground-Part I

Unique Challenges

in Medical Product Development

How wonderful that we have met with a paradox Now

we have some hope of making progress.

—Niels BohrThe U.S healthcare product pipeline needs major plumbing repair

There is no lack of innovation or shortage of important scientific coveries 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 develop-ment, 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, innova-tions 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 obvi-ous road from lab to launch, and productivity in terms of the introduction

dis-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

1

Pushing the Pipeline

Translational Research and 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

brand-name 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 cal 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 man-ufacturing firm Government-funded research institutes and agencies such

pharmaceuti-as National Institutes of Health (NIH), NSF, and the Centers for Disepharmaceuti-ase 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

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

Figure 1.1 Pharmaceutical industry R&D spending.

Source: PhRMA 2011 Industry Profile.

Table 1.1 New molecular entities: applications and approvals.

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 mates 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 govern-ment 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 break-through products

esti-Because of the great diversity within medical devices, and because there are different regulatory pathways for various types of devices, esti-mates of product development time and costs are less readily analyzed, but the overall trend holds true A recent report says that taking a medium-risk medical device cleared for marketing through the Premarket Notifi-cation 510(k) process requires $31 million on average, and that bringing

Drug discovery Preclinical Clinical trials FDA review manufacturing Scale-up to Post-marketing monitoring and

Number of volunteers 6–7 years

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

Indefinite 0.5–2 years

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.

a high-risk device approved for marketing through the more rigorous market approval (PMA) process burns up about $94 million.3 About three-quarters 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

pre-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 medi-cal product can be a formidable challenge Surmounting the obstacles calls for a revision in attitudes and processes related to medical product devel-

opment Enter translational research Translational research—also quently called translational science or translational development—refers

Figure 1.3 Preapproval capitalized cost per approved NME.

Source: DiMasi and Grabowski 2007.

to concepts and practices intended to advance scientific discoveries from the lab to the patient The approach is typically described as “bench to bedside.”

As a relatively new and evolving discipline, translational research and development has somewhat different meanings depending on the particular institution or interest group engaged in its applications to medical products

or healthcare practices Examples of these definitions are shown in Figure 1.4 For the purposes of this book, with its focus on the development of mar-ketable prescription drugs, biologics, medical devices, and combinations thereof, the definition of translational research proposed by the Coulter Foundation seems most suitable:

• The research results generally include intellectual property that can be protected by patents

• It involves clinical application as a goal, and therefore requires

a transition (a translation) of the research from the research

laboratory to the clinic (“bench to bedside”)

• It involves commercialization as a goal, and therefore requires a transition (a translation) of the technology (technology transfer) from the academic institution to a commercial entity for final product development, manufacturing, and sales.4

In addition to the existence of diverse definitions of translational research, there are other complicating terminology factors Translational research

is sometimes divided into two stages or phases, sometimes into three, and sometimes into four In the most general sense, the first stage (T1) is the advancement of research laboratory discoveries to clinical studies, and the second (T2) is focused on moving knowledge gained from clinical trials into the community via clinical practice and treatment strategies However, even among researchers using, for example, a two-stage concept, there is disagreement as to when T1 ends and T2 begins Sometimes, T1 is con-sidered bench through early clinical trials, and T2 is considered pivotal

Definition: Translational research is the application of discoveries from basic biomedical and behavioral research toward the diagnosis, treatment, or

prevention of human disease, with the ultimate goal of improving public health.

Source: National Institutes of Health.

Definition: Translational research—the two-way transfer between work at the laboratory bench and patient care.

Source: Burroughs Wellcome Fund

Definition: Translational research is research that has some or all of the

following characteristics:

• It is driven primarily by considerations of use and practical applications

of the research results, as opposed to basic research, which is driven primarily by a quest for knowledge.

• It envisions the development of a practical solution that addresses a particular clinical problem or unmet clinical need.

• It often envisions as an endpoint the development of a particular product.

• The research results generally include intellectual property that can be protected by patents.

• It involves clinical application as a goal, and therefore requires a transition (a translation) of the research from the research laboratory to the clinic (“bench to bedside”).

• It involves commercialization as a goal, and therefore requires a transition (a translation) of the technology (technology transfer) from the academic institution to a commercial entity for final product development,

manufacturing, and sales.

Source: Coulter Foundation.

Definition: Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence, morbidity, and mortality.

Source: National Cancer Institute.

Definition: Translational research includes two areas of translation One is the process of applying discoveries generated during research in laboratory, and

in preclinical studies, to the development of trials and studies in human studies The second area of translation concerns research aimed at enhancing the adoption of best practices in the community.

Source: Bausell, R B 2006 “Translation Research: Introduction to the Special Issue.” Evaluation in the Health Professions 29 (1): 3–6.

Figure 1.4 Some definitions of translational research.

clinical trials to approval and beyond; sometimes, T1 is considered bench through completion of clinical trials, and T2 is application of clinical data

to real-world use Further subdivision of translational research into T3 and T4—which involve such things as developing standards of care, population- based clinical effectiveness, comparative costs and outcomes evaluations—

is at risk of vague, subjective, and inconsistent definitions

Furthermore, since the objective begins with research, but requires the involvement of disciplines other than strictly research or science, it would

seem that the term translational product development more clearly reflects

the requirement for a multidisciplinary approach to take a project from the lab to the patients and practitioners Focusing on “research” or “ science”

as the nouns to which the adjective “transitional” is applied may not quately foster the awareness and acceptance of other necessary skills and activities, which will not help to repair the medical product pipeline It is important, though, that the gestalt of translational research and product development not become overshadowed by semantic differences The dis-cipline is about transitioning biomedical breakthroughs and inventions into innovative, clinically effective products that improve healthcare As the field grows and translational concepts of “bench to bedside” continue to be implemented, terminology is likely to become more standardized

ade-At a minimum, the complex process of shepherding an idea or ery from bench to bedside involves:

discov-• Scientific discovery related to the pathogenesis of a disease

Definition: Traditional boundaries between basic research, clinical research, and patient-oriented research are yielding to a single, continuous, bidirectional spectrum commonly termed “translational research” or “translational medicine.”

Source: Hörig, E., E Marincola, and F M Marincola 2005 “Obstacles and Opportunities in Translational Research.” Nature Medicine 11: 705–8.

Definition: It’s the bridge from discovery to delivery It has a clinical goal or target in mind, which isn’t the case for basic research.

Source: Columbia University Medical Centre

Definition: Translational research is generally described as the process of applying ideas, insights, and discoveries generated through basic scientific inquiry to the treatment or prevention of disease or injury It is bidirectional

in nature, working from the laboratory to the clinic, and from the clinic back to the laboratory Translational research is, therefore, an inherently collaborative and interdisciplinary area of research.

Source: Ontario Neurotrauma Foundation.

Figure 1.4 Continued.

• Initial scientific assessment of the potential of the discovery to lead to a clinical advance in the diagnosis, treatment, or prevention

of a disease

• Initial/prototype development of a candidate drug, biologic,

medical device, or combination product

• Proof of concept and optimization of the candidates in preclinical bench testing

• Safety and efficacy testing in in vitro and in vivo preclinical testing

• Application for approval for clinical evaluation

• Clinical trials

• Regulatory submissions and FDA’s review of the data to determine the suitability for approval

• Post-market assessment of the new approved product for safety and effectiveness in real-world settings

Additional troublesome steps may include (in no particular order) mining patent position and applying for intellectual property protection; identifying cross-functional product development teams; implementing usability engineering; managing risk; developing and selecting preclinical models that have reasonable correlation with humans for the expected use

deter-of the product; designing clinical models with meaningful endpoints; tifying clinical investigators, recruiting patients, and monitoring the clini-cal trials; establishing an acceptable manufacturing process and facility; holding many meetings with FDA; acquiring funding for all of the above, and then some It is also a two-way street, with information gained at one step providing feedback to previous steps to allow optimization of the new product design, effectiveness, and appropriate use Medical product devel-opment is clearly an interactive and cooperative process dependent on a wide range of skills

iden-valley of Death

According to the NIH, 80 to 90% of research projects fail before they ever get tested on humans, and industry statistics suggest that the number is far higher The failure-plagued period of development from scientific discov-ery to initial clinical evaluations on humans has come to be known as the

“valley of death.”5,6

Scientific discoveries typically occur in academic settings Few, if any, academic researchers have the financial resources or experience to conduct

all of the studies needed to develop a new healthcare product It takes many years and many millions of dollars to traverse the preclinical develop- ment stage Overall capitalized time-adjusted costs for preclinical devel- opment of an approved NME have been estimated at $439 million, includ-ing discovery and failed project costs For 510(k) devices, it is in the range

of $7 million, and for PMA devices, $19 million

For economic and other reasons, investors and industry have been reluctant to commit the funding required to advance to and through clini-cal trials without substantial validation of the potential clinical utility of

a discovery But those involved in the discovery phase often don’t have the large sums of money to do additional testing to satisfy investors No money, no testing, no money Small start-up research companies face the same dilemma So, scientists publish, apply for new grants, and go on with basic research, and, consequently, potentially important treatments and cures are lost

The NIH has taken a lead role in drawing attention to the preclinical valley of death and to the objectives of translational research The agency also has programs to help fund translational research, as well as to provide scientific resources to translational efforts Other public funding, at the fed-eral and state levels, and from private and industry sources, is becoming available to help in the transition of scientific innovation from bench to bedside (see Figure 1.5)

• Federal

– National Institutes of Health

– Other federal (for example, National Science Foundation, Department of Defense, Centers for Disease Control and Prevention, Agency for

Healthcare Research and Quality, Small Business Administration)

• Industry: pharmaceutical, medical device, biotechnology

• Private research foundations

• Private charities and advocacy groups

• State and local government

• Venture capital and other investment groups

• Academic institutions

Figure 1.5 Sources of funding and support for translational research and

development

Translational Research and FDA initiatives

Critical Path Initiative

After much time on the receiving end of criticism for its part in the new product stagnation problem, FDA is joining the movement to accelerate the development of innovative medical products In 2004, FDA instituted

the Critical Path Initiative (CPI), described as FDA’s national strategy to

drive innovation in scientific processes through which medical products are developed, evaluated, and manufactured The original focus was on drug development, but quickly expanded to embrace biologics and medi-cal devices, and it now applies to all medical products regulated by FDA.Concurrent with the launch of CPI, FDA released a landmark report presenting the agency’s analysis of the reasons for the widening gap between scientific discoveries that have unlocked the potential to prevent and cure some of today’s biggest medical challenges and their translation into inno-vative medical treatments.7 In that report, FDA explained that the goal

of CPI is more-efficient medical product development and evaluation, as well as improved quality, safety, and effectiveness of products regulated by FDA The report concluded that collective action involving industry, acade-mia, and government agencies is needed to modernize scientific and techni-cal tools, as well as harness information technology to evaluate and predict the safety, effectiveness, and manufacturability of medical products.Two years after the launch of CPI, the FDA commissioner announced the release of a follow-up document.8 Created with broad contribution from the public, this publication eloquently described specific topics where the sciences of product development, from FDA’s perspective, had the greatest need for early attention and improvement They are:

Topic 1: Better evaluation tools—developing new biomarkers and disease models

Topic 2: Streamlining clinical trials

Topic 3: Harnessing bioinformatics

Topic 4: Moving manufacturing into the twenty-first century

Topic 5: Developing products to address urgent public health

needs

Topic 6: At-risk populations—pediatrics

FDA has identified scientific and technical dimensions along the cal path (Table 1.2) In describing the dimensional concept, FDA explains

criti-that—whether working with devices, drugs, or biologics—medical product developers must negotiate three crucial, interdependent scientific/technical dimensions on the critical path from scientific innovation to commercial product: assessing safety, demonstrating medical utility, and industrializa-tion The vast majority of medical product development costs are attribut-able to these three dimensions

Driving Biomedical innovation

In late 2011, FDA outlined steps to spur biomedical innovation, addressing concerns about sustainability of the medical product development pipeline

Table 1.2 Three dimensions of the critical path.

Assessing Show that product is • Preclinical: show that safety adequately safe for each product is safe enough

stage of development for early human testing

Demonstrating Show that the product • Preclinical: Select

medical utility benefits people appropriate design

Source: FDA 2004 “Innovation or Stagnation: Challenge and Opportunity on the

Critical Path to New Medical Products.”

which, as we have seen, is slowing down despite record investments in R&D The plan seeks to implement initiatives to facilitate translation of scientific opportunities into safe and effective medical products by focus-ing on:

• Rebuilding FDA’s small business outreach services

• Building the infrastructure to drive and support personalized medicine

• Creating a rapid drug development pathway for important targeted therapies

• Harnessing the potential of data mining and information sharing while protecting patient privacy

• Improving consistency and clarity in the medical device review process

• Training the next generation of innovators

• Streamlining and reforming FDA regulations9

There are indications that the number of FDA approvals of innovative new products began to increase in 2011, and that the review times may be improving This might represent statistical noise, but there is optimism that

it is a real trend arising from the positive influence of translational research and development measures

As the primary centers for basic research, universities have begun to take note of the importance of translational techniques and the multidisci-plinary requirements for medical product development Many schools have courses, programs, or departments devoted to fields such as regulatory affairs, clinical trial design, medical device bioengineering, drug develop-ment, and translational research (Figure 1.6) It is also vital that university technology transfer offices that license new technologies from the school

to venture capital groups (frequently for early-stage funding), or to private industry (often at stages beyond proof-of-concept), as well as the fund-ing entities themselves, attain an adequate comfort level with translational research and product development techniques Clearly, a thorough under-standing of the requirements and the processes involved in the translation

of scientific and technical discoveries into clinically relevant medical ucts is a top priority in fostering the innovative climate needed to maintain U.S competitiveness in diagnosing, treating, and preventing disease.Not all medical product development concerns itself with disruptive technologies such as new molecular entities, significant new biologics, radically innovative medical devices, or combinations of these While, in

prod-Arizona Arizona State University

California Stanford University

University of California San Francisco San Diego State University—Center for Bio/Pharm and Biodevice Development

University of Southern California

Colorado Colorado State University

Connecticut University of Connecticut

Florida University of South Florida

University of Florida College of Pharmacy

Georgia Georgia Technical Institute

Emory University University of Georgia, College of Pharmacy

Illinois Illinois Institute of Technology

Indiana Purdue University

Massachusetts Boston University

Northeastern University, School of Professional and Continuing Studies

Regis College Massachusetts College of Pharmacy and Health Sciences

Maryland Johns Hopkins University

University of Maryland, Baltimore Hood College

Michigan University of Michigan

Case Western Reserve University

Minnesota University of St Thomas

St Cloud State University

North Carolina Campbell University School of Pharmacy

Duke University

New Jersey Rutgers, The State University of New Jersey

Figure 1.6 Sampling of schools* with programs related to medical product

development.**

* Not a complete list

** Including regulatory affairs, preclinical development, clinical development, science and technology management, translational research, bioengineering

concept, translational research is most visibly applied to these truly new healthcare products, its principles are valuable in optimizing development

of products that are not so unique For example, repurposing old drugs for treatment of other target diseases, iterative changes to drug formulation, synthesis versus extraction of active biological agents, and design changes

to increase the effectiveness of medical devices in a vastly different graphic setting all have great potential to improve healthcare All require product development planning, utility assessment, demonstration of pre-clinical and clinical safety and efficacy, analysis of regulatory and intel-lectual property impact, market factors analysis, and other activities that benefit from translational approaches applied beyond the very early basic research phase of development Regardless of the nature or uniqueness of the product, changes in the way those products are developed will be neces-sary for the United States to effectively compete in this arena The objective

demo-of the following chapters is to help establish intellectual, scientific, cal, and terminological common ground to foster interdisciplinary collabo-ration in crossing the bridge from research to medical practice

logisti-New York Long Island University—Arnold and Marie Schwartz

College of Pharmacy

St John’s University

Oregon Oregon Health and Science University

Pennsylvania Lehigh University

Drexel University Temple University

University of Pennsylvania University of Pittsburgh

Rhode Island University of Rhode Island

Tennessee Vanderbilt University

Virginia University of Virginia

Washington University of Washington

Wisconsin University of Wisconsin

Figure 1.6 Continued.

Health is worth more than learning.

—Thomas Jefferson

Medical product development in the United States has been

belea-guered by uncontrollably escalating costs, embarrassingly low productivity, clinical failures, legal nightmares ranging from product liability to patent litigation, and oversight by an understaffed and underbudgeted federal regulatory body

Those involved in medical product development share the same mary goal: to discover, develop, and bring to market new products that enable people to live healthier, more productive, more comfortable lives Nowhere in the world is this goal more enthusiastically endorsed by the population than in the United States Yet, from day one in the product development process, medical products manufacturers face challenges that other industries never have to confront

pri-The United States leads the world in healthcare spending.1 Health and well-being are so important in this country that in 2012, annual national health expenditures will exceed 17% of the gross domestic product (GDP),

or about $9000 per person This means that in 2012 Americans will have spent over $2.9 trillion on healthcare—about twice the amount spent in

2002 Government projections anticipate that average annual health ing growth will outpace average annual growth in the overall economy

spend-By 2019, national health spending is expected to reach $4.5 trillion and comprise nearly 20% of GDP.2 Prescription drug expenditures alone have accounted for 10% of the money spent in the United States on healthcare since 2001, and the projections indicate that this percentage will remain relatively stable

Unlike prescription drug expenditures, spending on medical devices

is not specifically tracked by the U.S Department of Health and Human

2

Healthcare in the

United States

Services, but in 2009, the latest year studied, estimated sales of medical devices and in vitro diagnostics totaled $147.0 billion, or 5.9% of total national health expenditures.3 Biologics represent a substantial segment of the U.S drug market, and sales were expected to be approximately $60 billion in 2010.4 Add up the numbers and it becomes clear that the market for prescription drugs and other healthcare products, including medical devices and biological products, is staggeringly huge Continued growth and profitability, however, depend on a delicate balance of managed care initiatives, federal and international regulatory requirements, generic chal-lenges, liability issues, and the ability of industry suppliers and manufac-turers to shorten product development cycles while controlling costs.Product development in the healthcare field, especially development

of medical devices and certain biologics, has all too often been a the-pants endeavor, shortchanged in terms of support and understanding

seat-of-by management and seat-of-by the individuals charged with getting the job done But with recent developments in healthcare management, and with sweep-ing changes in global clinical, regulatory, and quality requirements, man-ufacturers will no longer be able to effectively compete in the arena of healthcare products without making equally sweeping changes in the way they develop new products FDA has taken on a new role in enabling these changes, which will be discussed in Chapter 3

Manufacturers of healthcare products today are obligated to do more than simply provide evidence to FDA that their products are safe and effi-cacious Growing concerns about the cost and quality of healthcare in the United 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 to provide favorable outcomes in terms of attributes such as:

complex, it is difficult to estimate average development times Average time from concept to commercialization for medical devices can range from two years to 10 years depending on the type of regulatory application required.Regulatory requirements and quality standards are becoming more demanding, in part because of the desire to market new products outside

of the United States The shrinking of the world through globalization of medical product businesses is a fact of life, for a variety of reasons: (1) the domestic market is becoming increasingly saturated, so that going global is one of the few remaining ways to grow; (2) the pressures of man-aged care and cost containment in the United States are making it more difficult to increase domestic sales of products that do not have demon-strated outcomes advantages when compared with available lower-priced alternatives; (3) small companies partner with or get acquired by large companies, the overwhelming majority of which have a multinational pres-ence; and (4) large, multinational companies want products that they can market globally Yet many healthcare companies are poorly prepared to integrate their product development plans with the elements of cultural biases and preferences in medical and surgical practices, differing expec-tations of acceptable clinical outcomes, and variability in regulatory and quality requirements

Harmonization of domestic requirements, as defined by FDA, with those 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 product development is planned, executed, and documented

Because of the enormous investments required for regulated care product development, a shotgun approach often used with nonmedical product categories—in which large numbers of new products are intro-duced in hopes of ending up with at least one big winner—is not possible Extraordinary focus and foresight are necessary Evaluation of a myriad of ideas and opportunities against well-defined criteria will help ensure that resources are directed at a select few of those opportunities—those that will lead to successful and profitable new products

health-Even though the pharmaceutical/medical device industry spends portionately more on R&D as a percentage of sales than other industries, much of that money ends up being misdirected into activities that do not yield information that is useful or new products that are profitable Indus-trial R&D intensity and expenditure do not guarantee success The R&D efforts must be coupled to product and process developments that will sus-tain the company through the present and into the future It is not uncommon for 50% or more of what is called R&D activity to be delegated to work that is not research or development related Requests for technical fixes for

pro-existing products with design flaws usually top the list Responding to field sales forces when help is needed with customer questions or problems, and revalidating processes and products after the company makes changes in materials, equipment, or manufacturing location are also typical Add to this the time taken up in general administrative tasks, various updates and presentations, and training programs, and it’s clear that not much time may

be left for developing new products or technologies

For a healthcare company to attain or sustain leadership, it will require the timely development and launch of new products that are safe and effec-tive, meet both recognized and unarticulated user needs, and provide nec-

essary and desirable outcomes Creating and using a system of product development planning will substantially increase the probability of achiev-ing these goals Product development planning should be thought of as the application of total quality management (TQM) principles to new health-care products

Product development planning is an integrative approach to addressing both long-term and short-term needs and requirements for new products (see Figure 2.1) Although each component section of product development planning will be discussed separately in this book, in actual practice the components are inseparable Each component draws on, as well as contrib-utes to, every other component

Product development planning defines a technology strategy by ing technology forecasting—as a vision of the future—with an ongoing assessment of existing, new, emerging, and embryonic technologies The technology strategy, in turn, provides the foundation and direction for a portfolio of product development project opportunities Finally, quality management of this development portfolio depends on successful imple-mentation of a sound product development process The major components

link-of the product development process, development portfolio management, technology assessment, and technology forecasting overlap in their contri-butions to short-, medium-, and long-term strategy for the growth and evo-lution of the company (see Figure 2.2)

Firmly anchored in the present, the product development process deals with the immediacy of identified active projects; its impact on the future

is dependent on the development timeline of each project Portfolio agement ensures the proper mix of product development projects and of their sequence and phasing; its impact is linked to the present and near future through monitoring and management of active ongoing projects, and

man-to the mid-term future through staged application of the product ment process to other identified projects Technology assessment spans the near to mid-term future by encompassing evaluation of existing, emerg-ing, embryonic, and new technology opportunities Finally, the mid- to