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

Development of FDA-Regulated Medical Products Also available from ASQ Quality Press: Medical Device Design and Regulation Carl T DeMarco CAPA for the FDA-Regulated Industry José Rodríguez-Pérez The FDA and Worldwide Quality System Requirements Guidebook for Medical Devices, Second Edition Amiram Daniel and Ed Kimmelman The Certified HACCP Auditor Handbook ASQ Food, Drug, and Cosmetic Division Root Cause Analysis: Simplified Tools and Techniques, Second Edition Bjørn Andersen and Tom Fagerhaug HALT, HASS, and HASA Explained: Accelerated Reliability Techniques, Revised Edition Harry W McLean The Quality Improvement Handbook, Second Edition ASQ Quality Management Division; John E Bauer, Grace L Duffy, and Russell T Westcott, editors The Quality Toolbox, Second Edition Nancy R Tague Root Cause Analysis: The Core of Problem Solving and Corrective Action Duke Okes The Certified Quality Engineer Handbook, Third Edition Connie M Borror, editor To request a complimentary catalog of ASQ Quality Press publications, call 800-248-1946, or visit our website at www.asq.org/quality-press Development of FDA-Regulated Medical Products A Translational Approach Second Edition Elaine Whitmore ASQ Quality Press Milwaukee, Wisconsin American Society for Quality, Quality Press, Milwaukee 53203 © 2012 by ASQ All rights reserved Published 2012 Printed in the United States of America 18 17 16 15 14 13 12 Library of Congress Cataloging-in-Publication Data Whitmore, Elaine   Development of FDA-regulated medical products : a translational approach / Elaine   Whitmore.—2nd ed   p cm   Includes bibliographical references and index   ISBN 978-0-87389-833-1 (hard cover : alk paper)   Drug approval—United States.  Biological products—Standards—United States   Medical instruments and apparatus—Standards—United States.  United States   Food and Drug Administration.  I Title   RA401.5.W47 2012  615.1'9—dc23 2011051569 ISBN: 978-0-87389-833-1 No part of this book may be reproduced in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher Publisher: William A Tony Acquisitions Editor: Matt T Meinholz Project Editor: Paul Daniel O’Mara Production Administrator: Randall Benson ASQ Mission: The American Society for Quality advances individual, organizational, and community excellence worldwide through learning, quality improvement, and knowledge exchange Attention Bookstores, Wholesalers, Schools, and Corporations: ASQ Quality Press books, video, audio, and software are available at quantity discounts with bulk purchases for business, educational, or instructional use For information, please contact ASQ Quality Press at 800-248-1946, or write to ASQ Quality Press, P.O Box 3005, Milwaukee, WI 53201-3005 To place orders or to request ASQ membership information, call 800-248-1946 Visit our website at http://www.asq.org/quality-press   Printed on acid-free paper In loving memory of Emma and James Peters (This page intentionally left blank) 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 Productivity Gap Translational R&D Valley of Death 11 Translational Research and FDA Initiatives 13 Driving Biomedical Innovation 14 Chapter 2  Healthcare in the United States 19 Chapter 3  It’s Not Your Father’s FDA: The “Modernization” of Medical Product Regulation 25 Food and Drug Administration Modernization Act of 1997 (FDAMA) 25 Prescription Drug User Fees 27 Information on Off-Label Use and Economics 28 Risk-Based Regulation of Medical Devices 28 Standards for Medical Products 29 The New FDA 29 Chapter 4  Classifying Medical Products 35 Drugs and Biologics 36 Drugs 37 vii viii   Table of Contents Biologics 38 FDA Consolidation of Drugs and Biologics 41 Medical Devices 43 Combination Products 46 Chapter 5  Product Liability and Product Development 53 Preemption 54 Medical Devices 54 Drugs 55 Basis of Product Liability 56 Design Defects 56 Warning Defects 57 Manufacturing Defects 57 The Role of Product Development Planning 57 Part II  Bringing a New Medical Product to Market Chapter 6  Overview of the Approval Processes for Drugs, Biologics, and Medical Devices 63 Drugs 64 Screening 64 Preclinical Testing 64 Investigational New Drug Application 65 Clinical Trials 65 New Drug Application 66 Inspections 66 Generic Drugs and Abbreviated New Drug Applications 67 Biologics 68 Biosimilar Products (Follow-On Biologics) 68 Medical Devices 69 General Controls 71 Special Controls 72 Premarket Notification 73 Premarket Approval 75 Chapter 7  Quality by Design 77 Design Controls 78 Design and Development Planning 81 Design Input 83 Design Output 83 Design Review 84 Table of Contents   ix Design Verification and Validation 84 Design Transfer 85 Design Changes 85 Design History File (DHF) 85 Other Considerations in Design Controls 85 Chapter 8  Designing-Out Disaster: Risk Analysis 87 Quality Risk Management 90 Risk Analysis Techniques 91 Chapter 9  Recalls, Withdrawals, ­and Revocations 95 Recalls 95 Firm-Initiated Recalls 96 FDA-Requested Recalls 96 FDA-Ordered Recalls 96 Withdrawals 97 Revocations 97 Influence of Product Development Planning 100 Chapter 10  Human Factors and Usability Engineering: Minimizing Medical Errors 103 Chapter 11  Is It Safe and Does It Work? Evaluating Safety and Efficacy in Clinical Trials 115 Preclinical Testing 116 Clinical Trials 120 Drugs and Biologics 122 Endpoints and Biomarkers 123 Medical Devices 124 Diversity in Clinical Trials 127 Chapter 12  How Much Is the Product Really Worth? Outcomes Research, Pharmacoeconomics, and Managed Care 129 Clinical Outcomes 131 Pharmacoeconomics and Economic Outcomes 131 Quality-of-Life Outcomes 131 Comparative Effectiveness Research 133 Outcomes and Product Development Planning 134 Part III  Product Development Planning Chapter 13  Models and Metaphors: Product Development and the Product Development Organization 139 Swimming Against the Stream 140 x   Table of Contents The Cross-Functional Organization 141 Chapter 14  Components of Product Development Planning: The Product Development Process 149 Stage 1—Discovery 152 Stage 2—Feasibility 156 Stage 3—Optimization 158 Stage 4—Demonstration 159 Stage 5—Production 159 Stage 6—Launch and Follow-Through 160 Chapter 15  Components of Product Development Planning: Development Portfoliio Management 161 Killing a Project 172 Chapter 16  Components of Product Development Planning: Technology Assessment 175 Chapter 17  Components of Product Development Planning: Technology Forecasting 183 Chapter 18  Better Double-Check That: A Guide for the Risk-Averse 193 Planning for Promotional Opportunities 193 Speed to Market versus Product Promotional Preferences 195 Intellectual Property 195 Don’t Forget the Budget 198 Conflict Resolution: What About Game Theory? 199 Decision-Making Games 200 Global Games 201 Product Development Ecosystem Games 201 Quality Challenges 202 Chapter 19  Where Do We Go From Here? 207 In Closing 208 Appendix: Resources 211 Endnotes 219 Glossary 225 Index 231 Endnotes  223 Chapter 11 Pharmaceutical Research and Manufacturers of America, Pharmaceutical Industry Profile 2011 (Washington, DC: PhRMA, April 2011) “New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible,” Federal Register 67, no 105 (May 31, 2002) U.S Department of Health and Human Services, Food and Drug Administration, Good Laboratory Practice for Nonclinical Laboratory Studies, 21 C.F.R Ch 1, Part 58, as updated U.S Department of Health and Human Services, Food and Drug Administration, Office of Device Evaluation, Use of International Standard ISO-10993, “Biological Evaluation of Medical Devices Part 1: Evaluation and Testing,” General program memorandum G95-1, May 1995 International Conference on Harmonisation, “Good Clinical Practice: Consolidated Guideline,” Federal Register 62 25692 (May 9, 1997) J Arrowsmith “Trial Watch: Phase II Failures: 2008–2010.” Nature Reviews Drug Discovery 10 (May 2011): 328–29 J Arrowsmith “Trial Watch: Phase III and Submission Failures: 2007–2010.” Nature Reviews Drug Discovery 10 (February 2011): 87 International Conference on Harmonisation, “Draft Guidance on M4 Common Technical Document; Availability,” Federal Register 65 (165) 51621–24 (August 24, 2000) Food and Drug Administration, Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff: Design Considerations for Pivotal Clinical Investigations for Medical Devices (Washington, D.C.: U.S Department of Health and Human Services, August 15, 2011) 10 Food and Drug Administration, Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials (Washington, D.C.: U.S Department of Health and Human Services, September 2005) 11 Food and Drug Administration, Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics (Draft) (Washington, D.C.: U.S Department of Health and Human Services, February 2010) 12 Food and Drug Administration, Guidance for Industry, Non-Inferiority Clinical Trials (Draft) (Washington, D.C.: U.S Department of Health and Human Services, March 2010) Chapter 12 M Zitter, “Outcomes Assessment: True Customer Focus Comes to Health Care,” Medical Interface (May 1992): 32–37 J A Cramer and B Spilker, Quality of Life & Pharmacoeconomics: An Introduction (Philadelphia: Lippincott-Raven, 1998) 224  Endnotes Federal Coordinating Council for Comparative Effectiveness Research, Report to the President and Congress, (Washington, D.C.: U.S Department of Health and Human Services, June 30, 2009) Chapter 13 C J Nuese, Building the Right Things Right (New York: Quality Resources, 1995) S C Wheelwright and K B Clark, Revolutionizing Product Development (New York: The Free Press, 1992) Chapter 17 Food and Drug Administration, Center for Drug Evaluation and Research, “FDA Approves First Antibiotic Treatment for Ulcers,” April 19, 1996 K J Kelley, “Using Host Defenses to Fight Infectious Diseases,” Nature Biotechnology 14, no (1996): 587–90 Chapter 18 Pharmaceutical Research and Manufacturers of America, Delivering the Promise of Pharmaceutical Innovation: The Need to Maintain Strong and Predictable Intellectual Property Rights, white paper on the intersection of intellectual property and antitrust law in the pharmaceutical industry (submitted to Federal Trade Commission) (Washington, D.C.: PhRMA, April 22, 2002) Leahy–Smith America Invents Act, H.R 1249, amending Title 35, United States Code, 112th Cong (2011) F C Zagare, Game Theory: Concepts and Applications (Newbury Park, CA: Sage Publications, 1984) M A Nowak, C E Tarnita, and T Antal, “Evolutionary Dynamics in Structured Populations,” Philosophical Transactions of the Royal Society B 365, no 1537 (2010): 19–30 Food and Drug Administration, Driving Biomedical Innovation: Initiatives to Improve Products for Patients (Washington, D.C.: U.S Department of Health and Human Services, October 2011) Chapter 19 W R Stumpe, “What the Research Manager Should Know About New Product Psychology,” Research Management 22 (1979): 13–17 Glossary Abbreviated New Drug Application (ANDA)—An application for approval of a generic drug adaptive clinical trials—Trials designed to allow the use of interim clinical data to modify and improve the study design in a preplanned manner biologic—A biological product; a preparation made from living organisms and their products applicable to the prevention, treatment, or cure of diseases or injuries; the category of biologics includes vaccines, blood products, certain diagnostic products, and biotechnology-derived products Biologics License Application (BLA)—An application for approval of a new biological product biosimilar—A biological product demonstrated to be highly similar to or interchangeable with an FDA-approved biological product current good manufacturing practice (cGMP)—See good manufacturing practice (GMP) clinical trials—The evaluation of a product in studies involving human subjects combination products—Complex medical products, such as drug-device, drug-biologic, and device-biologic combinations Common Technical Document (CTD)—An international harmonized format for submissions for approval of pharmaceuticals for human use The CTD does not replace the BLA or NDA, but provides a standardization of the presentation of content 225 226  Glossary comparative effectiveness research (CER)—Research comparing the benefits and harms of different interventions and strategies to prevent, diagnose, treat, and monitor health conditions in real-world settings design controls—A system to ensure that a new medical device can be used safely and effectively while meeting customer needs; a requirement of current GMPs for medical devices development portfolio—The collection of projects available to or being developed by a company development portfolio management—One of the four integral components of product development planning; a way to maximize control and minimize risks by keeping a company’s strategy for new products compatible with its business objectives device—See medical device disruptive technology—A new technology that changes things so profoundly that it typically displaces an established technology drug—An article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and that is intended to affect the structure or function of the body failure mode analysis—A determination of malfunction symptoms that appear immediately before or immediately after a failure of a critical parameter in a system or product Federal Food, Drug, and Cosmetic (FD&C) Act—The basic law in the United States governing foods, drugs for animals and humans, cosmetics, and medical devices With its numerous amendments, it is the most extensive law of its kind in the world; also referred to as the “Act.” Food and Drug Administration Modernization Act (FDAMA)—A federal act making numerous changes to the rules governing FDA and industries regulated by FDA generic drugs—Approved drugs that are no longer protected by patents and that are approved for marketing by companies without the need for clinical trials; generic drugs are bioequivalent to the original approved drugs good clinical practice (GCP)—Regulations and policies governing clinical research Glossary  227 good manufacturing practice (GMP)—Regulations that establish the minimum requirements for the methods, facilities, and controls used in the manufacturing of medical products human factors—The discipline that seeks to analyze and optimize the relationship between human beings and any technology; the interfaces may be physical, perceptual, or cognitive intellectual property—Intellectual assets, including patents, copyrights, trademarks, and trade secrets Investigational Device Exemption (IDE)—An exemption to the rules prohibiting a medical device that has not been cleared or approved for marketing from being shipped and tested in human subjects Investigational New Drug (IND)—An application for permission to test an unapproved drug or biologic in human subjects; an IND provides exemption to rules prohibiting the shipment of unapproved drugs managed care—Healthcare provided by a prepaid health plan or covered by an insurance program, in which medical services are reviewed and coordinated to manage access to care, quality of care, and cost of care medical device—An article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or other condition and that does not depend on chemical action within or on the body and is not dependent on being metabolized to achieve its primary intended purpose medical products—Drugs, biologics, and medical devices; these products are regulated by FDA new chemical entity (NCE)—See new molecular entity New Drug Application (NDA)—An application to FDA for approval to market a new drug new molecular entity (NME)—An active drug substance that has never been previously approved by FDA off-label use—Use of a medical product for an indication not approved or cleared by FDA outcomes research—Studies to determine whether use of a technology increases survival, reduces morbidity, improves quality of life, and provides benefits that justify the cost of its use 228  Glossary pharmacoeconomics—The application of economic principles to the evaluation of pharmaceutical interventions portfolio—See development portfolio preclinical studies—Evaluations of safety and/or efficacy in in vitro, ex vivo, or in vivo systems other than in human beings Premarket Approval (PMA) application—An application made to FDA for approval to market certain types of medical devices (Class III) that are considered life-supporting, life-sustaining, or of substantial importance in preventing impairment of human health Premarket Notification application [510(k)]—A submission made to FDA to gain clearance for commercial distribution and marketing of certain types of medical devices (Class II and some Class I); clearance may be gained by a finding that the device is substantially equivalent to another Class II or Class I device that is already on the market in the United States product development planning—An integrative approach to addressing both long-term and short-term needs and requirements for new products The four main components are product development process, development portfolio management, technology assessment, and technology forecasting product development process—One of the four integral components of product development planning; it describes the stages of healthcare product development (discovery, feasibility, optimization, demonstration, production, and launch and follow-through), as well as the associated tasks, reviews, and deliverables for each stage Public Health Service (PHS) Act—A federal act covering a broad spectrum of health concerns, including the regulation of biological products for human use quality—What the customer wants; the characteristic of a product or service that meets customer expectations and is free from defects Quality System Regulation (QSR)—Medical device GMPs recall—The removal or correction, by a firm, of a marketed product because the product is considered to be in violation of laws administered by FDA Glossary  229 risk assessment—The process of identifying, estimating, and evaluating the nature and severity of risks associated with a product; also called risk analysis or hazard analysis technology assessment—One of the four integral components of product development planning; it is an ongoing identification and evaluation of existing, new, emerging, and embryonic technologies technology forecasting—One of the four integral components of product development planning; anticipating the future to allow the formation of a suitable and planned technology strategy total quality management (TQM)—The application of quality principles to all company endeavors, with an emphasis on customer satisfaction and continuous improvement translational research—Research and development activities geared to turning a scientific idea, discovery, or design into a viable and marketable product usability engineering—The application of human factors principles to the design of devices and systems user fees—Fees paid to FDA by manufacturers for the review of applications for clearance or approval of new drugs, biologics, and medical devices The fees provide additional funds to FDA to improve the product review process (This page intentionally left blank) Index A Abbreviated New Drug Application (ANDA), 68 adaptive studies, 128 advertising restrictions, on medical products, 193–95 America Invents Act, 197 animal data, in medical product approval, 31 biomarkers, in clinical trials, 123–24 biomedical innovation, driving, 14–17 biosimilar products, 68–69 Bismarck, Otto von, 25 blinding, in clinical trials, 122, 125 Bohr, Niels, 3, 183 budgeting, for medical product development, 198–99 Buffett, Warren, 87 Butler, Samuel, 139 B C Best Pharmaceuticals for Children Act of 2002 (BPCA), 29 biocompatibility, 117 biologics classification of, 38–40 clinical trials of, 122 definition, 39 and drugs, FDA consolidation of, 41–43 overview of approval process, 68–69 Biologics License Application (BLA), 41, 68, 124 Biologics Price Competition and Innovation Act of 2009 (BPCI Act), 68–69 Carroll, Lewis, 149, 193 Center for Biologics Evaluation and Research (CBER), 38–40, 41–42, 120 Center for Devices and Radiological Health (CDRH), 43 and human factors engineering, 105 Center for Drug Evaluation and Research (CDER), 30, 37, 39, 41–42, 120 chemical action, in medical devices, FDA guidance on, 45 Class I medical device, 70, 71–72, 80 Class I recall, 96 Class II medical device, 72, 80 231 232  Index Class II recall, 96 Class III medical device, 75, 80 Class III recall, 97 clinical outcomes, 131 and medical product development, 20 and product development planning, 134–35 clinical trials, 120–22 diversity in, 127–28 of drugs, 65 evaluating safety and efficacy in, 115–28 cognitive factors, in human factors engineering, 109–10 cognitive walk-through, 112 combination products, classification of, 46–48 Common Technical Document (CTD), 124 comparative effectiveness research (CER), 133–34 concurrent engineering, 145 contract research organization (CRO), 127 Cooper, Theodore, 44 Cooper committee findings, 44 copyrights, 195 cost, to develop new medical products, 4, 5–7, 12, 14, 64, 67, 79, 130–31, 198 cost/benefit analysis (CBA), 131 cost-effectiveness analysis (CEA), 131 cost-minimization analysis (CMA), 131 cost/utility analysis (CUA), 131 Critical Path Initiative (CPI), 13–14, 30 cross-functional organization, 141–47 cultural bias, 21, 114, 179, 201 current good manufacturing practice (cGMP), 77–78 in human factors engineering, 110–11 customer in human factors engineering, 110–12, 113, 114 needs and requirements, 77, 79–80, 153–54, 161, 179, 204–5, 208–9 D decision-making games, 200–201 DeMille, Nelson, 207 demonstration, stage of product development process, 159 design and development planning (design control), 81–82 design changes (design control), 85 design controls, 78–86, 204 design defects, in product liability, 56–57 design history file (DHF) (design control), 85 design input (design control), 83 design output (design control), 83–84 design review (design control), 84 design transfer (design control), 85 design verification and validation (design control), 84 development portfolio, management of, 161–73 discovery, stage of product development process, 152–56 disruptive technologies, 153–54 diversity, in clinical trials, 127–28 Doyle, Arthur Conan, 77 draft proposals, withdrawal of outdated, 32 drugs and biologics, FDA consolidation of, 41–43 classification of, 36–37 clinical trials of, 122 cost to develop new, development pathway, development timeline, non-NME, versus NMEs, off-label use of, 28 overview of approval process, 64–68 and product liability, 55–56 duodenal ulcer treatment, technology forecasting example, 187–88 E economic analyses, of costs, 130–31 ecosystem, medical product development as, 201–2 Edison, Thomas Alva, 175 effectiveness, versus efficacy, 129 efficacy versus effectiveness, 129 evaluating in clinical trials, 115–28 Einstein, Albert, 129 endpoint, of clinical trials, 123–24 ergonomics, 103, 109 establishment license application (ELA), 41 extrinsic factors, in medical treatment, 127 F failure mode analysis, 91 failure mode and effects analysis (FMEA), 91 failure mode effects and criticality analysis (FMECA), 85, 91–93 failure rate, of clinical trials, 115, 123 fault tree analysis, 85, 91 FDA-ordered recalls, 96 FDA-requested recalls, 96 feasibility, stage of product development process, 156–58 feasibility studies, 126 Federal Food, Drug, and Cosmetic (FD&C) Act of 1938, 25 definition of drug under, 37 medical device regulation under, 43 firm-initiated recalls, 96 Food and Drug Administration (FDA) consolidation of drugs and biologics, 41–43 human factors violations, 105–8 modernization of, 25–33 strategic plan, 32 Food and Drug Administration Amendments Act of 2007 (FDAAA), 30 Food and Drug Administration Modernization Act of 1997 (FDAMA), 25–33 Index  233 formative evaluations, in medical product development, 112–13 funding, of medical product development, 4, 12, 15 funnel model, of product development, 139–40, 152 G game theory, in medical product development, 199–202 General Controls, for medical devices, 71–72 generic drugs, versus NMEs, globalization game theory and, 201 and human factors engineering, 113–14 and intellectual property, 197–98 good clinical practice (GCP), 120, 204 good laboratory practice (GLP), 204 regulations, 116–17 good manufacturing practice (GMP), 77–78 guidances, versus regulations, 33 H harmonization, of medical product development, 21 Hatch–Waxman Act, 196 hazards, in medical products, 87 healthcare expenditures, U.S., 19–20 in United States 19–24 Holmes, Sherlock, 77 human engineering See human factors engineering human factors, 103, 105 human factors engineering, 103–14 I in vitro diagnostic product (IVD), 72–73 innovator drug, 67–68 234  Index inspection, of drug manufacturing plant, 66–67 Institute of Medicine (IOM) medical errors report, 108 Premarket Notification study, 74–75 Institutional Review Board (IRB), 120 intellectual property (IP), 195–98 International Conference on Harmonization (ICH), 21, 120, 124 intrinsic factors, in medical treatment, 127 Investigational Device Exemption (IDE), 45, 120, 158 Investigational New Drug (IND) application, 37, 45, 65, 68, 120, 158 ISO 10993 Biological evaluation of medical devices—Part I, 117 J Jefferson, Thomas, 19 L launch and follow-through, stage of product development process, 160 M managed care, 130 manufacturing defects, in product liability, 57 mapping, in portfolio assessment, 164–69 market pull, model of innovation, 208–9 market withdrawal, 97 Medical Device Amendments to FD&C Act, 44, 55, 70 Medical Device User Fee and Modernization Act of 2002 (MDUFMA), 29 medical devices approval process, overview of, 69–76 classification of, 43–45, 70–71 clinical trials of, 124–27 cost to develop, 6–7 off-label use of, 28 and product liability, 55 risk-based regulation of, 28 surveillance of, 30–31 medical product development challenges in, 1–60 costs of, 67 designing-in quality, 77–86 discontinuing a project, 172–73 as ecosystem, 201–2 future of, 207–9 human development analogy, 150 impediments to, 142–44 process, 149–60 cynic’s take on, 207–8 and product development organization, 139–47 product liability and, 53–60 versus R&D, 142 role in product liability, 57–60 stage 1—discovery, 152–56 stage 2—feasibility, 156–58 stage 3—optimization, 158–59 stage 4—demonstration, 159 stage 5—production, 159–60 stage 6—launch and followthrough, 160 steps in, 150–51 medical products classifying, 35–48 new, bringing to market, 61–135 standards for, 29 medication errors, 108 N Nabokov, Vladimir, 63 New Drug Application (NDA), 37, 66, 124 new molecular entities (NMEs), 3–7 nonclinical testing See preclinical testing non-inferiority studies, 128 non-zero-sum games, 200 O Office of Biotechnology Products (OBP), 42 Office of Combination Products (OCP), 30, 47 Office of Drug Evaluation VI, 42 Office of New Drugs (CDER), 42 Office of Translational Sciences (OTS), 30 off-label use of drugs and medical devices, 28, 193–94 1–10–100 rule, in medical product development, 79 optimization, stage of product development process, 158–59 outcomes, clinical See clinical outcomes outcomes research, 129–31 P parallel development See concurrent engineering patents, 195–96 Patient Protection and Affordable Care Act (PPACA), 68–69 patient-centered outcomes research (PCOR), 133–34 patients in human factors engineering, 109–10 in pilot studies, 126 and product liability, 53 risks to, 24, 28, 113 safety of, 31, 43, 90 Pediatric Research and Equity Act of 2003 (PREA), 29 “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach,” 31–32 pharmaceutical industry, R&D spending, pharmaceutical manufacturing, riskbased approach, 31–32 pharmacoeconomics, 131 pilot studies, 126 pioneer drug See innovator drug pivotal trial, 126 Index  235 portfolio development, management of, 160–73 post-marketing studies, 127 preamendment devices, 70 preclinical testing, 116–20 of drugs, 64–65 preemption, in medical product liability, 54, 55–56 Premarket Approval (PMA), 45, 126–27 in medical device approval process, 75–76 Premarket Notification 510(k), 45 in medical device approval process, 73–75 Prescription Drug User Fee Act of 1992 (PDUFA), 27–28, 66 product development See medical product development product development ecosystem games, 201–2 product development organization, and medical product development, 139–47 product development planning, 22–24, 137–209 components of development portfolio management, 161–73 product development process, 149–60 technology assessment, 175–80 technology forecasting, 183–91 core qualities of, 163 influence on recalls, 100–101 and outcomes evaluations, 134–35 role in product liability, 57–60 product liability basis of, 56 and product development, 53–60 role of product development in, 57–60 product license application (PLA), 41 product promotional preferences, versus speed to market, 195 production, stage of product development process, 159–60 236  Index productivity gap, in medical product development, 3–17 promotional restrictions on medical products, 193–95 Q quality definitions of, 204 designing-in, 77–86 quality challenges, in medical product development, 202–5 quality continuum, 204 quality function deployment (QFD), 77 quality risk management, 90 Quality System Regulations (QSRs), 78 quality-of-life (QOL) outcomes, 131– 33, 135 R recalls, 95–97 influence of product development planning on, 100–101 regulations, versus guidances, 33 regulations, healthcare product chronology, 26–27 and product development planning, 146 risk-based, 28 research and development (R&D), versus product development, 142 revocations, license, 97–98 risk in medical product development, 193–205 in medical products, sources of, 88 risk analysis, 87–93 techniques, 91–93 risk assessment, 89 risk control, 92 risk-based regulation, of medical devices, 28 S Safe Medical Devices Act (SMDA) of 1990, 44, 78 safety, evaluating in clinical trials, 115–28 safety-based withdrawal, 97 salmon swimming upstream model, of product development, 140–41 science, relationship with technology, 184–85 screening, of drug candidates, 64 simplification, in portfolio assessment, 172 simulated use testing, 112–13 speed to market, versus product promotional preferences, 195 standards, for medical products, 29 T team leader, use of term, 157 technology, relationship with scientific discovery, 184–85 technology assessment, in product development planning, 145, 175–80 technology forecasting, in product development planning, 183–91 technology portfolio matrix, 167 technology push, model of innovation, 208–9 Thoreau, Henry David, 172 timeline, drug development, total quality management (TQM), 202–4 trade secrets, 195 trademarks, 195 translational development See translational research and development translational product development, 10–11 translational research and development, xvii, 7–11 definitions of, and FDA initiatives, 13–14 translational science See translational research and development U United States, healthcare in, 19–24 United States Supreme Court, 55, 79 universities, role in medical product development, 15 usability engineering See human factors engineering usability testing See simulated use testing user fees, FDA, 198–99 user testing See simulated use testing users, medical product, in human factors engineering, 111–12 Index  237 V validation, definition, 84 “valley of death,” in medical product development, 11–12, 65, 117 verification, definition, 84 W warning defects, in product liability, 57 William of Ockham, 161 withdrawals, product, 97 Z zero-sum games, 200 ... website at www.asq.org/quality-press Development of FDA- Regulated Medical Products A Translational Approach Second Edition Elaine Whitmore ASQ Quality Press Milwaukee, Wisconsin American Society... the obstacles calls for a revision in attitudes and processes related to medical product development Enter translational research Translational research—also frequently called translational science... 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