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The Process of New Drug Discovery and Development Second Edition © 2006 by Informa Healthcare USA, Inc.

The Process of New Drug Discovery and Development

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The Process of New Drug Discovery and DevelopmentSecond Edition 2006 by Informa Healthcare USA, Inc.The Process of New Drug Discovery and DevelopmentEdited byCharles G. Smith Ph.D.James T. ODonnell Pharm.D.Second Edition 2006 by Informa Healthcare USA, Inc.Informa Healthcare USA, Inc.270 Madison AvenueNew York, NY 10016 2006 by Informa Healthcare USA, Inc.Informa Healthcare is an Informa businessNo claim to original U.S. Government worksPrinted in the United States of America on acid-free paper10 9 8 7 6 5 4 3 2 1International Standard Book Number-10: 0-8493-2779-2 (Hardcover)International Standard Book Number-13: 978-0-8493-2779-7 (Hardcover)Library of Congress Card Number 2005036791This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the valid-ity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers.01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.Library of Congress Cataloging-in-Publication DataThe process of new drug discovery and development / editors, Charles G. Smith and James T. ODonnell.-- 2nd ed.p. ; cm.Rev. ed. of: The process of new drug discovery and development / Charles G. Smith. c1992.Includes bibliographical references and index.ISBN-13: 978-0-8493-2779-7 (alk. paper)ISBN-10: 0-8493-2779-2 (alk. paper)1. Drugs--Research--History. 2. Drugs--Design--History.[DNLM: 1. Drug Design. 2. Drug Evaluation, Preclinical. 3. Drug Evaluation. QV 744 P9645 2006] I. Smith, Charles G. (Charles Giles) II. ODonnell, James T., Pharm. D. RM301.25.S55 2006615.19--dc22 2005036791Visit the Informa Web site atand the Informa Healthcare Web site at 2006 by Informa Healthcare USA, Inc.www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.informa.comwww.informahealthcare.com As was the case with the first edition, this book is dedicated to my irreplaceable wife, Angeline,who persisted in encouraging me in this and other scientific efforts that often left little time forrecreational activities. In addition, I dedicate it to my daughter, Tracy, whose strongencouragement and occasional harassment convinced me to write the first edition.Charles G. SmithTo my wife, Sylvia, and my children, Kimberly and Jim, who make my life worth living.James T. ODonnell 2006 by Informa Healthcare USA, Inc.AcknowledgmentsSincere appreciation is expressed to Mr. S. Zollo at CRC Press/Taylor & Francis, whosestrong solicitation resulted in my decision to participate in the second edition of this book.The role of my coeditor, Dr. James T. ODonnell, without whose expertise and organiza-tional abilities this work could not possibly have been accomplished, deserves my mostheartfelt thanks and appreciation. The participation of many excellent authors has madethis book, in my opinion, a truly valuable contribution to the scientific literature in thefield of drug discovery and development. I am honored to end a most enjoyable careerwith this contribution.Charles G. Smith 2006 by Informa Healthcare USA, Inc.EditorsCharles G. Smith earned the B.S. degree (1950) in chemistry from the Illinois Institute ofTechnology, the M.A. degree (1952) in biochemistry from Purdue University, and the Ph.D.degree (1954) in biochemistry from the University of Wisconsin. He joined The UpjohnCompany in 1954 and worked in fermentation biochemistry for several years. In 1962, hewas appointed head of the biochemistry department at Upjohn and initiated a major anti-cancer effort therein. Dr. Smith moved to E. R. Squibb & Sons pharmaceutical company in1968, where he became vice president for research. He joined the Revlon Health CareGroup in 1975 as vice president for research and development. In 1986, he retired fromindustry and became a pharmaceutical consultant. During his tenure in the major phar-maceutical companies, Dr. Smith was intimately involved with projects in the fields ofinfectious diseases, cancer, cardiovascular diseases, central nervous system diseases, andpharmaceutical products from blood plasma. Since 1986, he has consulted with manybiotechnology companies that work in a broad cross-section of pharmaceutical research.He was a cofounder of Vanguard Medica in the United Kingdom in 1991 and namedadjunct professor in the Department of Natural Sciences at San Diego State University inthe same year. Dr. Smith is the author of 49 publications and the first edition of this book(1992), and remains a pharmaceutical consultant in the biotechnology field. James T. ODonnell earned the B.S. degree in pharmacy from the University of Illinois(1969) and the Doctor of Pharmacy degree from the University of Michigan (1971) as wellas the M.S. degree in clinical nutrition from Rush University (1982). He completed aresidency in clinical pharmacy at the University of Illinois Research Hospitals and hasbeen a registered pharmacist in Illinois since 1969. Dr. ODonnell spent 17 years in clinicalpractice at both the Cook County Hospital and the Rush University Medical Center inChicago. Dr. ODonnell is currently an associate professor of pharmacology at the RushUniversity Medical Center and is a member of the Graduate College, involved in theteaching of new drug development and regulations. Also, Dr. ODonnell is a lecturer in theDepartment of Medicine at the University of Illinois College of Medicine, Rockford. He isa Diplomate of the American Board of Clinical Pharmacology and Board of NutritionalSpecialties, a fellow of the American College of Clinical Pharmacology and the AmericanCollege of Nutrition, and a member of several professional societies. Dr. ODonnell is theauthor of 257 publications, and he is the founding editor of the Journal of Pharmacy Practice,a co-editor of Pharmacy Law, and the editor of Drug Injury: Liability, Analysis, andPrevention, First and Second Editions. In addition to his academic and editorial endeavors,Dr. ODonnell regularly consults in drug and pharmaceutical matters to industry, govern-ment, and law, and serves as pharmacologist consultant to the State of Illinois Departmentof Public Health. 2006 by Informa Healthcare USA, Inc.ContributorsLoyd V. Allen University of Oklahoma College of Pharmacy, Edmond, Oklahoma, U.S.Donald C. Anderson Pharmacia Corporation, Kalamazoo, Michigan, U.S.Timothy Anderson Pfizer, Inc., Groton, Connecticut, U.S.Stephen Barrett Quackwatch, Inc., Allentown, Pennsylvania, U.S.Joanne Bowes Safety Assessment UK, AstraZeneca R&D Alderley Park, Macclesfield,Cheshire, U.K.Irwin A. Braude Compass Pharmaceuticals, LLC, Charlotte, North Carolina, U.S.Celia Brazell Genetics Research, GlaxoSmithKline, Greenford, Middlesex, U.K.Jerry Collins Food and Drug Administration, Center for Drug Evaluation and Research,Office of Testing and Research, Rockville, Maryland, U.S.William T. Comer TorreyPines Therapeutics, Inc., La Jolla, California, U.S.Mark Crawford Cerep, Redmond, Washington, U.S.Andrew Dorner Wyeth Research, Andover, Maryland, U.S.David Essayan Food and Drug Administration, Center for Biologics Evaluation andResearch, Office of Therapeutics, Division of Clinical Trial Design and Analysis,Rockville, Maryland, U.S.Pauline Gee Department of Predictive Biology, MDS Pharma Services, Bothell,Washington, U.S.Baltazar Gomez-Mancilla Pharmacia Corporation, Kalamazoo, Michigan, U.S.Henry Grabowski Duke University, Durham, North Carolina, U.S.Howard E. Greene Rancho Santa Fe, CAJoseph Hackett Food and Drug Administration, Center for Devices and RadiologicalHealth, Office of In Vitro Diagnostic Device Evaluation and Safety, Rockville, Maryland,U.S. 2006 by Informa Healthcare USA, Inc.Jeff M. Hall Department of Cell Biology, Genoptix, Inc., San Diego, California, U.S.Tim G. Hammond Safety Assessment UK, AstraZeneca R&D Alderley Park,Macclesfield, Cheshire, U.K.Valrie Hamon Cerep, Paris, FranceIsmael J. Hidalgo Absorption Systems, LP, Exton, Pennsylvania, U.S.Carol Ann Homon Boehringer Ingelheim Pharmaceuticals, Inc., Medicinal ChemistryDepartment, Ridgefield, Connecticut, U.S.Shiew-Mei Huang Food and Drug Administration, Center for Drug Evaluation andResearch, Office of Clinical Pharmacology and Biopharmaceutics, Rockville,Maryland, U.S.Susan Ide National Institute of Health, NHGRI, and Novartis, Gaithersburg,Maryland, U.S.Vincent Idemyor College of Medicine, University of Illinois, Chicago, Illinois, U.S.Thierry Jean Cerep, Paris, FranceIlona Kariv Applications Research and Development, Genoptix Inc., San Diego,California, U.S.Joanne Killinger Wyeth Research, Chazy, New York, U.S.Harold J. Kwalwasser MDS Pharma Services, Bothell, Washington, U.S.John Leighton Food and Drug Administration, Center for Drug Evaluation andResearch, Office of New Drugs, Rockville, Maryland, U.S.Lawrence J. Lesko Food and Drug Administration, Center for Drug Evaluation andResearch, Office of Clinical Pharmacology and Biopharmaceutics, Rockville,Maryland, U.S.Jibin Li Absorption Systems, LP, Exton, Pennsylvania, U.S.Elizabeth Mansfield Food and Drug Administration, Center for Devices andRadiological Health, Office of In Vitro Diagnostic Device Evaluation and Safety,Rockville, Maryland, U.S.Phillip J. Marchand Optical Systems, Genoptix Inc., San Diego, California, U.S.Patricia A. McNeeley Genoptix Inc., San Diego, California, U.S.Robert Meyer Food and Drug Administration, Center for Drug Evaluation andResearch, Office of New Drugs, Rockville, Maryland, U.S.Justina A. Molzon U.S. Food and Drug Administration, Center for Drug Evaluation andResearch, Rockville, Maryland, U.S. 2006 by Informa Healthcare USA, Inc.Daniel Mufson Apotherx LLC, Napa, California, U.S.Richard M. Nelson Boehringer Ingelheim Pharmaceuticals, Inc., Medicinal ChemistryDepartment, Ridgefield, Connecticut, U.S.Lori Nesbitt Discovery Alliance International, Inc., Sugarland, Texas, U.S.Sarfaraz K. Niazi Pharmaceutical Scientists, Inc., Deerfield, Illinois, U.S.F. Richard Nichol Nichol Clinical Technologies Corporation, Newport Beach, California,U.S.Tina S. Nova Genoptix Inc., San Diego, California, U.S.James T. ODonnell Department of Pharmacology, Rush Medical College, RushUniversity Medical Center, Chicago, ILMark Paich Lexidyne, LLC, Colorado Springs, Colorado, U.S.Corey Peck Lexidyne, LLC, Colorado Springs, Colorado, U.S.Madhu Pudipeddi Technical Research and Development, Novartis PharmaceuticalsCorporation, Mumbai, India Michael H. Rabinowitz Johnson & Johnson Pharmaceutical Research & DevelopmentLLC, San Diego, California, U.S.Mitchell E. Reff Biogen Idec, Inc., Oncology, Cambridge, Massachusetts, U.S.Frederick E. Reno Reno Associates, Merritt Island, Florida, U.S.Michael G. Rolf Safety Assessment UK, AstraZeneca R&D Alderley Park, Macclesfield,Cheshire, U.K.Stephen G. Ryan AstraZeneca Pharmaceuticals, Wilmington, Delaware, U.S.Ronald A. Salerno WorldWide Regulatory Affairs, Wyeth Research, St. Davids,Pennsylvania, U.S.Richard H.C. San Genetic Toxicology, BioReliance, Rockville, Maryland, U.S.Virginia Schmith GlaxoSmithKline, Research Triangle Park, North Carolina, U.S.Abu T.M. Serajuddin Novartis Pharmaceutical Corporation, Pharmaceutical andAnalytical Development, East Hanover, New Jersey, U.S.Nigel Shankley Johnson & Johnson Pharmaceutical Research & Development, LLC,Merryfield Row, San Diego, California, U.S.Peter Shaw Department of Pharmacogenomics and Human Genetics, Bristol-MeyersSquibb, Princeton, New Jersey, U.S. 2006 by Informa Healthcare USA, Inc.Frank Sistare Food and Drug Administration, Center for Drug Evaluation and Research,Office of Testing and Research, Rockville, Maryland, U.S.Charles G. Smith Rancho Santa Fe, CAKirk Solo Lexidyne, LLC, Colorado Springs, Colorado, U.S.John C. Somberg Chief Division of Clinical Pharmacology, Department of Medicine &Pharmacology, Rush University, Chicago, Illinois, U.S.Brian B. Spear Abbott Laboratories, Department of Pharmacogenetics, Abbott Park,Illinois, U.S.Jason Valant Lexidyne, LLC, Colorado Springs, Colorado, U.S.Jean-Pierre Valentin Safety Assessment UK, AstraZeneca R&D Alderley Park,Macclesfield, Cheshire, U.K.Gnl Velielebi Research and Drug Discovery, TorreyPines Therapeutics, Inc., La Jolla,California, U.S.Daniel D. Von Hoff Translational Genomics Institute, Phoenix, Arizona, U.S.Heather L. Wallace Scientific Communications, ICON Clinical Research, North Wales,PennsylvaniaMark Watson Clinical Genomics, Merck and Co., Inc., West Point, Pennsylvania, U.S.Janet Woodcock U.S. Food and Drug Administration, Center of Drug Evaluation andResearch, Rockville, Maryland, U.S.Alexandra Worobec Food and Drug Administration, Center for Biologics Evaluationand Research, Office of Therapeutics, Division of Clinical Trial Design and Analysis,Rockville, Maryland, U.S. 2006 by Informa Healthcare USA, Inc.Contents1. Introduction..........................................................................................................................1Charles G. SmithSection I General Overview2. Overview of the Current Process of New Drug Discovery and Development ........................................................................................................................7Charles G. Smith and James T. ODonnell3. Integrated Drug Product Development From Lead Candidate Selection toLife-Cycle Management ...................................................................................................15Madhu Pudipeddi, Abu T.M. Serajuddin, and Daniel MufsonSection II Scientific Discoveries Application in New DrugDevelopment4. The Impact of Combinatorial Chemistry on Drug Discovery .................................55Michael H. Rabinowitz and Nigel Shankley5. High-Throughput Screening: Enabling and Influencing theProcess of Drug Discovery ..............................................................................................79Carol Ann Homon and Richard M. Nelson6. Pharmacological and Pharmaceutical Profiling: New Trends................................103Joanne Bowes, Michael G. Rolf, Jean-Pierre Valentin, Valrie Hamon, Mark Crawford, and Thierry Jean7. Cell-Based Analysis of Drug Response Using Moving Optical Gradient Fields ...............................................................................................................135Jeff M. Hall, Ilona Kariv, Patricia A. McNeeley, Phillip J. Marchand, and Tina S. Nova8. Patient-Derived Primary Cells in High-Throughput DifferentialAntitumor Screens: Let the Patients Be the Guide...................................................149Irwin A. Braude9. The Evolving Role of the Caco-2 Cell Model to Estimate IntestinalAbsorption Potential and Elucidate Transport Mechanisms..................................161Jibin Li and Ismael J. Hidalgo10. The Promise of Metabonomics in Drug Discovery..................................................187Harold J. Kwalwasser and Pauline Gee 2006 by Informa Healthcare USA, Inc.11. Pharmacogenetics and Pharmacogenomics in Drug Development andRegulatory Decision-Making: Report of the First FDAPWGPhRMADruSafe Workshop.........................................................................................199Lawrence J. Lesko, Ronald A. Salerno, Brian B. Spear, Donald C. Anderson, Timothy Anderson, Celia Brazell, Jerry Collins, Andrew Dorner, David Essayan,Baltazar Gomez-Mancilla, Joseph Hackett, Shiew-Mei Huang, Susan Ide,Joanne Killinger, John Leighton, Elizabeth Mansfield, Robert Meyer,Stephen G. Ryan, Virginia Schmith, Peter Shaw, Frank Sistare, Mark Watson,and Alexandra Worobec12. Drugs from Molecular Targets for CNS and Neurodegenerative Diseases ........225William T. Comer and Gnl Velielebi13. Safety Pharmacology: Past, Present, and Future.......................................................243Jean-Pierre Valentin and Tim G. Hammond14. Nonclinical Drug Safety Assessment..........................................................................291Frederick E. Reno15. Preclinical Genotoxicity Testing Past, Present, and Future ...............................305Richard H.C. SanSection III Standard Drug Developmental Issues: Updated16. The Need for Animals in Biomedical Research........................................................315Charles G. Smith17. Defining the Actual Research Approach to the New Drug Substance ................329Charles G. Smith18. Pharmacokinetics Pharmacodynamics in New Drug Development................335Sarfaraz K. Niazi19. Pharmaceutics and Compounding Issues in New DrugDevelopment and Marketing........................................................................................377Loyd V. Allen20. Late Stage and Process Development Activities.......................................................401Charles G. SmithSection IV Clinical Development21. Contract Research Organizations: Role and Function in New DrugDevelopment ....................................................................................................................407F. Richard Nichol22. The Front Lines of Clinical Research: The Industry................................................419Lori Nesbitt23. Horizons for Cancer Chemotherapy (and Nonchemotherapy) ..............................445Daniel D. Von Hoff 2006 by Informa Healthcare USA, Inc.24. Human Immunodeficiency Virus/Acquired Immune DeficiencySyndrome: Clinical Testing Challenges......................................................................459Vincent IdemyorSection V Regulatory and Legal Issues Affecting Drug Development25. Common Technical Document: The Changing Face of theNew Drug Application...................................................................................................473Justina A. Molzon26. Electronic Publishing......................................................................................................481Heather L. Wallace27. The Important Role of Pharmacists in a Complex Risk-ManagementSystem: Managing the Risks from Medical Product Use by Focusingon Patient Education, Monitoring, and Adverse Event Reporting ......................483Justina A. Molzon28. Liability, Litigation, and Lessons in New Drug Development..............................489James T. ODonnell29. Problems in the Nondrug Marketplace ......................................................................521Stephen Barrett30. Patents and New Product Development in the Pharmaceutical andBiotechnology Industries...............................................................................................533Henry Grabowski31. The Pharmaceutical Revolution: Drug Discovery and Development ..................547John C. SombergSection VI Case Histories32. The Discovery of Rituxan..............................................................................................565Mitchell E. Reff33. Funding the Birth of a Drug: Lessons from the Sell Side.......................................585Howard E. Greene34. Innovations for the Drug Development Pathway: What IsNeeded Now.....................................................................................................................603Janet Woodcock35. Managing R&D Uncertainty and Maximizing the Commercial Potential ofPharmaceutical Compounds Using the Dynamic Modeling Framework........................................................................................................................617Mark Paich, Corey Peck, Jason Valant, and Kirk Solo 2006 by Informa Healthcare USA, Inc.11IntroductionCharles G. SmithPrior to the 20th century, the discovery of drug substances for the treatment of humandiseases was primarily a matter of hit or miss use in humans, based on folklore andanecdotal reports. Many, if not most, of our earliest therapeutic remedies were derivedfrom plants or plant extracts that had been administered to sick humans (e.g., quininefrom the bark of the cinchona tree for the treatment of malaria in the mid-1600s and digi-talis from the foxglove plant in the mid-1700s for the treatment of heart failure, to nametwo). Certainly, some of these early medications were truly effective (e.g., quinine anddigitalis) in the sense that we speak of effective medications today. On the other hand,based on the results of careful studies of many such preparations over the years, eitherin animals or man, one is forced to come to the conclusion that most likely, the majorityof these plant extracts was not pharmacologically active, but rather they were perceivedas effective by the patient because of the so-called placebo effect. Surprisingly, placebos(substances that are known not to be therapeutically efficacious, but that are adminis-tered so that all the psychological aspects of consuming a medication are presented tothe patient) have been shown to exert positive effects in a wide range of disease states,attesting to the power of suggestion under certain circumstances. There still exist todaypractitioners of so-called homeopathic medicine, which is based on the administrationof extremely low doses of substances with known or presumed pharmacologic activities.For example, certain poisons, such as strychnine, have been used as a tonic for years invarious countries at doses that are not only nontoxic but that in the eyes of most scien-tifically trained medical and pharmacological authorities, could not possibly exert anactual therapeutic effect. Homeopathy is practiced not only in underdeveloped coun-tries, but also in certain well-developed countries, including the United States, albeit ona very small scale. Such practices will, most likely, continue since a certain number ofpatients who require medical treatment have lost faith, for one reason or another, in theso-called medical establishment. More will be said about proving drug efficacy inChapters 8 to 10.Pioneers in the field of medicinal chemistry such as Paul Ehrlich (who synthesized sal-varsan, the first chemical treatment for syphilis, at the turn of the 20th century), wereinstrumental in initiating the transition from the study of plants or their extracts with pur-ported therapeutic activities to the deliberate synthesis, in the laboratory, of a specific drugsubstance. Certainly, the discovery of the sulfa drugs in the 1930s added great momentumto this concept, since they provided one of the earliest examples of a class of pure chemi-cal compounds that could be unequivocally shown to reproducibly bring certain infec-tious diseases under control when administered to patients by mouth. During World War II,1 2006 by Informa Healthcare USA, Inc.2 The Process of New Drug Discovery and Developmentthe development of penicillin stimulated an enormous and highly motivated industryaimed at the random testing (screening) of a variety of microbes obtained from soil sam-ples for the production of antibiotics. This activity was set into motion by the discovery ofAlexander Fleming and others in England in 1929 that a Penicillium mold produced tinyamounts of a substance that was able to kill various bacteria that were exposed to it in atest tube. When activity in experimental animal test systems and in human patients wasdemonstrated, using extremely small amounts of purified material from the mold broth(penicillin), it was immediately recognized that antibiotics offered a totally new route totherapeutic agents for the treatment of infectious diseases in human beings. In addition tothe scientific interest in these findings, a major need existed during World War II for newmedications to treat members of the armed forces. This need stimulated significant activ-ity on the part of the United States Government and permitted collaborative efforts amongpharmaceutical companies (which normally would be highly discouraged or prohibitedby antitrust legislation from such in-depth cooperation) to pool resources so that the rateof discovery of new antibiotics would be increased. Indeed, these efforts resulted in accel-erated rates of discovery and the enormous medical and commercial potential of theantibiotics, which were evident as early as 1950, assured growth and longevity to thisimportant new industry. Major pharmaceutical companies such as Abbott Laboratories,Eli Lilly, E. R. Squibb & Sons, Pfizer Pharmaceuticals, and The Upjohn Company in theUnited States, to name a few, were particularly active in these endeavors and highly suc-cessful, both scientifically and commercially, as a result thereof (as were many companiesin Europe and Japan). From this effort, a wide array of new antibiotics, many with totallyunique and completely unpredictable chemical structures and mechanisms of action,became available and were proven to be effective in the treatment of a wide range ofhuman infectious diseases.In the 1960s and 1970s, chemists again came heavily into the infectious diseases arenaand began to modify the chemical structures produced by the microorganisms, givingrise to the so-called semi-synthetic antibiotics, which form a very significant part of thephysicians armamentarium in this field today. These efforts have proved highly valu-able to patients requiring antibiotic therapy and to the industry alike. The truly impres-sive rate of discovery of the semi-synthetic antibiotics was made possible by thefinding that, particularly in the penicillin and cephalosporin classes of antibiotics, a por-tion of the entire molecule (the so-called 6-APAin the case of penicillin and 7-ACAin thecase of cephalosporin) became available in large quantities from fermentation sources.These complex structures were not, in and of themselves, able to inhibit the growth ofbacteria, but they provided to the chemist the central core of a very complicated mole-cule (via the fermentation process), which the chemist could then modify in a variety ofways to produce compounds that were fully active (hence the term semi-syntheticantibiotics). Certain advantages were conferred upon the new molecules by virtue of thechemical modifications such as improved oral absorption, improved pharmacokineticcharacteristics and expanded spectrum of organisms that were inhibited, to name a few.Chemical analogs of antibiotics, other than the penicillin and cephalosporins, have alsobeen produced. The availability of truly efficacious antibiotics to treat a wide variety ofsevere infections undoubtedly represents one of the primary contributors to prolonga-tion of life in modern society, as compared to the situation that existed in the early partof this century.Coincidental with the above developments, biomedical scientists in pharmaceutical com-panies were actively pursuing purified extracts and pure compounds derived from plantsand animal sources (e.g., digitalis, rauwolfia alkaloids, and animal hormones) as humanmedicaments. Analogs and derivatives of these purified substances were also investigated 2006 by Informa Healthcare USA, Inc.Introduction 3intensively in the hope of increasing potency, decreasing toxicity, altering absorption, secur-ing patent protection, etc. During this period, impressive discoveries were made in thefields of cardiovascular, central nervous system, and metabolic diseases (especially dia-betes); medicinal chemists and pharmacologists set up programs to discover new and,hopefully, improved tranquilizers, antidepressants, antianxiety agents, antihypertensiveagents, hormones, etc. Progress in the discovery of agents to treat cardiovascular and cen-tral nervous system diseases was considerably slower than was the case with infectious dis-eases. The primary reason for this delay is the relative simplicity and straightforwardnessof dealing with an infectious disease as compared to diseases of the cardiovascular systemor of the brain. Specifically, infectious diseases are caused by organisms that, in many cases,can be grown in test tubes, which markedly facilitates the rate at which compounds thatinhibit the growth of, or actually kill, such organisms can be discovered. Not only was thetesting quite simple when carried out in the test tube but also the amounts of compoundsneeded for laboratory evaluation were extremely small as compared to those required foranimal evaluation. In addition, animal models of infectious diseases were developed veryearly in the history of this aspect of pharmaceutical research and activity in an intact ani-mal as well as toxicity could be assessed in the early stages of drug discovery and devel-opment. Such was not the case in the 1950s as far as cardiovascular, mental, or certain otherdiseases were concerned because the basic defect or defects that lead to the disease in manwere quite unknown. In addition, early studies had to be carried out in animal test systems,test systems which required considerable amounts of the compound and were much moredifficult to quantitate than were the in vitro systems used in the infectious-disease field. Thesuccesses in the antibiotic field undoubtedly showed a carry-over or domino effect inother areas of research as biochemists and biochemical pharmacologists began to search forin vitro test systems to provide more rapid screening for new drug candidates, at least in thecardiovascular and inflammation fields. The experimental dialog among biochemists, phar-macologists, and clinicians studying cardiovascular and mental diseases led, in the 1960s,to the development of various animal models of these diseases that increased the rate ofdiscovery of therapeutic agents for the treatment thereof. Similar research activities in thefields of cancer research, viral infections, metabolic diseases, AIDS, inflammatory disease,and many others have, likewise, led to in vitro and animal models that have markedlyincreased the ability to discover new drugs in those important fields of research. With theincreased discovery of drug activity came the need for increased regulation and, from theearly 1950s on, the Food and Drug Administration (FDA) expanded its activities andenforcement of drug laws with both positive and negative results, from the standpoint ofdrug discovery. In the later quarter of the 20th century, an exciting new technology emerged into thepharmaceutical scene, namely, biotechnology. Using highly sophisticated, biochemicalgenetic approaches, significant amounts of proteins, which, prior to the availability ofso-called genetic engineering could not be prepared in meaningful quantities, becameavailable for study and development as drugs. Furthermore, the new technologypermitted scientists to isolate, prepare in quantity, and chemically analyze receptors inand on mammalian cells, which allows one to actually design specific effectors of thesereceptors. As the drug discovery process increased in intensity in the mid- to late 20th century, pri-marily as a result of the major screening and chemical synthetic efforts in the pharmaceu-tical industry in industrialized countries worldwide, but also as a result of thebiotechnology revolution, the need for increased sophistication and efficacy in (1) how todiscover new drugs, (2) how to reproducibly prepare bulk chemicals, (3) how to determinethe activity and safety of new drug candidates in preclinical animal models prior to their 2006 by Informa Healthcare USA, Inc.4 The Process of New Drug Discovery and Developmentadministration to human beings and, finally, (4) how to establish their efficacy and safetyin man, became of paramount importance. Likewise, the ability to reproducibly prepareextremely pure material from natural sources or biotechnology reactors on a large scaleand to deliver stable and sophisticated pharmaceutical preparations to the pharmacistsand physicians also became significant.The above brief history of early drug use and discovery is intended to be purely illus-trative and the reader is referred to an excellent treatise by Mann1to become well informedon the history of drug use and development from the earliest historic times to the presentday.Reference1. Mann, R.D., Modern Drug Use: An Enquiry on Historical Principles, MTP Press, Lancaster,England, 1984, pp. 1769. 2006 by Informa Healthcare USA, Inc.Section IGeneral Overview 2006 by Informa Healthcare USA, Inc.2Overview of the Current Process of New DrugDiscovery and Development Charles G. Smith and James T. ODonnellCONTENTS2.1 Basic Scientific Discovery and Application to New Drug Development ..................112.2 Regulation of New Drug Development ..........................................................................122.3 Liability and Litigation ......................................................................................................12References ......................................................................................................................................12The first edition1of this book was published approximately 13 years ago. Its primaryobjective was to present an overview and a roadmap of the process of new drug discov-ery and development, particularly oriented to individuals or companies entering the phar-maceutical field. It was written by one of the authors (Smith), with no contributors, anddrawn on Smiths experiences in the industry and field over the course of nearly 40 years.In the second edition, the scope of the first book has been expanded and technical details inthe form of hard data have been included. In addition to the editors own commentary andcontributions, the major part of the book is the result of contributions of experts in the indus-try. New chapters on risk assessment, international harmonization of drug development andregulation, dietary supplements, patent law, and entrepreneurial startup of a new pharma-ceutical company have been added. Some of the important, basic operational aspects of drugdiscovery and development (e.g., organizational matters, staff requirements, pilot plantoperations, etc.) are not repeated in this book but can be found in the first edition. In the 1990s and the new millennium, major changes have occurred in the pharmaceuti-cal industry from the vantage points of research and development as well as commercialoperations. New technologies and processes such as high throughput screening andcombinatorial chemistry were widely embraced and developed to a high state of per-formance during this period. The very impressive rate of throughput testing the hundredsof thousands of compounds required micronization of operations, resulting in the reduc-tion of screening reaction mixtures from milliliters to microliters. The systems are generallycontrolled by robots, and testing plates can accommodate a wide spectrum of biologicaltests. Combinatorial chemistry, a process in which a core molecule is modified with a broadspectrum of chemical reactions in single or multiple reaction vessels, can produce tens ofthousands of compounds for screening. The objective of both approaches is to provide verylarge numbers of new chemical entities to be screened for biological activity in vitro. The useof computers to design new drug candidates has been developed to a significant level ofsophistication. By viewing on the computer, the active site to which one wants the drug7 2006 by Informa Healthcare USA, Inc.candidate to bind, a molecule can often be designed to accomplish that goal. The trueimpact of these approaches on the actual rate of discovering new drugs is yet to be estab-lished. Some have questioned the utility of these new screening methods, claiming that nonew molecular entities (NME) have resulted from these new screening methodologies,despite hundreds of millions invested by the industry. Studies in the last few years in the fields of genomics and proteomics have made availableto us an unprecedented number of targets with which to search for new drug candidates.While knowledge of a particular gene sequence, for example, may not directly point to aspecific disease when the sequences are first determined, investigations of their presencein normal and diseased tissues could well lead to a quantitative in vitro test system that isnot available today. The same can be said for the field of proteomics, but final decisions onthe value of these new technologies cannot be made for some years to come. Thanks to advances in genomics, animal models can now be derived using gene manip-ulation and cloning methods that give us never-before available in vivo models to be usedin new drug screening and development. Alarge number of mammalian cell culture sys-tems have also been developed not only to be used in primary screening but also forsecondary evaluations. For example, the in vitro Caco 2 system shows some very interest-ing correlation with drug absorption in vivo. Atest such as this is mandatory when one isdealing with several thousands of compounds or mixtures in a given experiment. Moretime will be needed to be absolutely certain of the predictability of such test systems but,appropriately, Caco 2 is widely used today in screening and prioritizing new drug candi-dates. As is always the case, the ultimate predictability of all the in vitro tests must awaitextensive studies in humans, which will occur several years henceforth.In addition to the discussion are metabonomics that relate to their unique positionwithin the hierarchy of cell function and their propensity to cross membranes and organs.Thus, many metabolites are found in bodily fluids that are accessible to measurement inhumans using relatively noninvasive technologies. The study of metabolomics providesthe pragmatic link from the macromolecular events of genomics and proteomics to thoseevents recognized in histology. Applications of such strategies can potentially translatediscovery and preclinical development to those metabolites measured traditionally, asfirst-in-human studies are performed earlier in drug discovery and development process,especially where no animal models are adequate.During the past decade, clinical trial methodology has been expanded, improved, and,in large measure, standardized. The clinical testing phase of new drug development is themost expensive single activity performed. In addition to cost, it is very time consumingsince, with chronic diseases, one must investigate the new drug candidate in a significantnumber of patients over a period of months or years, in randomized, double-blind,placebo- or active-drug-controlled studies. The search for surrogate endpoints continues,as it should, because a surrogate endpoint can markedly increase the rate of progressionin clinical investigations with new drug candidates in certain disease states. Modernadvances in molecular biology, receptor systems, cellular communication mechanisms,genomics, and proteomics will, according to our belief, provide researchers with newapproaches to the treatment of a variety of chronic diseases. Significantly improved pre-scription medications are sorely needed in many fields. In the past decade, we have wit-nessed very impressive advances in the treatment of AIDS, for example. There is noquestion that life expectancy has been increased, albeit accompanied by significant drugtoxicity and the need to use a cocktail of drugs in combination. The ability of the AIDSvirus to mutate and become drug resistant presents a major and imminent threat to allpatients afflicted with this disease. Serious efforts are under way in the pharmaceuticalindustry to find new drugs, across the entire infections diseases spectrum, which are notcross-resistant with existing therapies. 8 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.Cancer and AIDS vaccines are also under investigation using new technologies and,hopefully, the day will come when we can prevent or ameliorate some of these debilitat-ing and fatal diseases by vaccination. In the cancer field, new methodologies in sciencehave, again, given us new targets with which to search for chemotherapeutic agents. Thehumanization of monoclonal antibodies has resulted in the marketing of some trulyimpressive drugs that are much better tolerated by the patient than are cytotoxic agents.In the case of certain drug targets in cancer, impressive results have been seen in the per-centage of leukemia and lymphoma patients who can be brought into complete remis-sion. In addition, biological medications to increase red and white blood cells have becomeavailable. Unfortunately, drug resistance once again plagues the cancer field, as are thecases with AIDS and various infectious diseases. As a result, researchers are seeking com-pounds that are not cross-resistant with existing therapies. Very significant advances indrug discovery are also expected to be seen in central nervous system, cardiovascular, andother chronic diseases as a result of breakthrough research in these fields. Although the focus of this book is the research and development side of the pharma-ceutical industry, certain commercial considerations are worth mentioning because of themajor impact they may have on new drug research. These opinions and conclusions arebased solely on decades of experience in the field by editors, working in the industrywithin companies and as an independent consultant (Smith), and also as a health careworker and academic (ODonnell). No financial incentive for these statements has beenreceived from the pharmaceutical industry. As the result of the very complicated nature ofdrug discovery and development, unbelievable costs accrue in order to bring a new ther-apeutic agent to market. Increasing costs are incurred, in part, from (1) shifting disease tar-gets from more rapidly evaluable, acute diseases to those with poor endpoints andchronicity and (2) the emergence and rapid spread of serious diseases in society (e.g.,AIDS, certain cancers, hepatitis C, etc.). In addition to increasing cost, the time required togather sufficient data to be able to prove, to a statistically valid endpoint, that the drug hasindeed been effective in a given disease has risen. The cost for the development of a majordrug has been widely stated to be US $800 million per new therapeutic agent placed onthe market.1This figure incorporates, of course, the cost of lost compounds that did notmake the grade during preclinical or clinical testing. It has recently been reported that,while historically 14% of drugs that entered phase I clinical trials eventually wonapproval, now only 8% succeed. Furthermore, 50% of the drug candidates fail in the latestage of phase III trials compared to 20% in past years. More details on these points can befound in the literature (cf., Refs. 28).The average time from the point of identifying a clinical candidate to approval of a newdrug is approximately 10 years. There is an understandable clamor in the population andin our legislative bodies to lower the price of prescription drugs. The cost of some pre-scription drugs is, to be sure, a serious problem that must be addressed but some of thesolutions, suggested and embraced by certain legislators, could have serious negativeimpact on new drug discovery and development in the future. For example, allowing the importation of prescription drugs from Canada or other non-U.S. countries (25 around the world have been mentioned) may well reduce the price of new drugs in this countryto the point of significantly decreasing profits that are needed to support the tremendouscost of new drug discovery and development. The record clearly shows that countries thatcontrol drug prices, frequently under socialist governments, do not discover and developnew prescription drugs. The reason is obvious since the cost and time factors for new drugdiscovery can only be borne in countries in which the pharmaceutical companies areclearly profitable. Our patent system and lack of price controls are the primary reasons forthe huge industrial success of new product development in this country, in and out of thepharmaceutical arena. If we undercut that system in the prescription drug field, the costOverview of the Current Process of New Drug Discovery and Development 9 2006 by Informa Healthcare USA, Inc.of drugs will certainly go down in the United States in the short term but, without the nec-essary profits to invest heavily in new drug discovery and development, the latter willalso surely drop. Since it requires a decade from the time of initial investigation to mar-keting of a new drug, this effect would not be evident immediately after (1) allowing re-importation, (2) overriding patent protection, or (3) implementing price controls but,within a period of 5 to 10 years, we would certainly see pipelines of new medicationsbeginning to dry up. Indeed, if such a system were allowed to continue for several years,new drug development as we know it would, in our opinion, be seriously impeded. Whenlegislators look to Canada as an example of successful government subsidy of drugs, theyshould also consider whether a country like Canada could ever produce a steady streamof major new drugs, as does the United States. Research budgets have never been larger,we have never had as many innovative and exciting targets on which to focus, and thisenormous effort cannot be afforded unless the companies selling the drugs can realize anadequate profit. If our pipelines of new prescription drugs dry up, you can be rest assuredthat the deficit will not be satisfied elsewhere in the world. It has been reported that, 10years ago drug companies in Europe produced a significantly greater percentage of pre-scription drugs than is the case today. Society simply cannot afford to risk a marked reduc-tion in new drug discovery in this country. Patients must join the fight to see that activitiesto impose price controls, which will inevitably reduce the rate of discovery of many poten-tial drugs, are not based on political motives on the part of legislators. At this point in his-tory, U.S. science stands in the forefront of new drug discovery and development. Asnoted above, never before have we had such an array of biological targets and syntheticand biotechnological methods with which to seek new medications. Hopefully, our gov-ernment, in collaboration with the pharmaceutical industry, will find more suitable meth-ods to solve the question of the cost of new pharmaceuticals than to impose price controlsequal to those in countries that have socialized medicine. There can be no question as towhether the primary loser in such moves will be patients. In addition to the question of the rate of drug discovery and development, we must beconcerned about the quality of drugs available by mail or over the internet. The Food andDrug Administration (FDA) cannot possibly afford to check all drugs flowing into Americafrom as many as 25 foreign countries from which our citizens might be allowed to buy pre-scription drugs. It will be interesting to compare the regulatory requirements for FDAapproval in the United States with those of the least stringent of the foreign countries fromwhich some of our legislators want to approve importation of drugs. Would Congress beprepared to mandate a lowering of FDAstandards to the same level in order to reduce thecost of drug discovery and development in this country? We certainly hope not! Indeed,there have been reports that drugs imported and sold on the internet are counterfeit, and fre-quently contain little or no labeled active ingredients, and further, may contain adulterants. Another new topic chapter in the second edition of this book discusses the so-calleddietary supplements, contributed by a recognized authority in Health Fraud. Over thepast few years and, especially, since the passage of the DSHEAAct by Congress,9the useof such products has increased dramatically and they are made widely available to thepublic with little or no FDA regulation. Although the law prevents manufacturers frommaking a medical treatment claim on the label of these preparations, such products gen-erally have accompanying literature citing a variety of salutary effects in patients with var-ious ills, the majority of which have not been proven by FDA type-randomized,double-blind, placebo-controlled clinical studies, of the kind that must be performed onprescription drugs and some over-the-counter drugs in this country. Published studieson quality control defects in some of these dietary supplement products (cf.ConsumerLab.com) indicate the need for tightening up of this aspect of product develop-ment. FDA is currently promulgating GMPs for dietary supplements. An enhanced10 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.enforcement of the dietary supplement regulations now exists.9A small segment of thedietary supplement industry has been calling for GMPs and increased FDAregulation.102.1 Basic Scientific Discovery and Application to New Drug DevelopmentIn an apparent attempt to determine whether the American taxpayer is getting fair bene-fits from research sponsored by the federal government, the Joint Economic Committee ofbasic research has been funded by the NIH and various philanthropic foundations to dis-cover new concepts and mechanisms of bodily function, in addition to training scientists.The role of industry has been to apply the basic research findings to specific treatments orprevention of disease. This is the appropriate manner in which to proceed. The industrycannot afford to conduct sufficient basic research on new complicated biological processesin addition to discovering new drugs or vaccines. The government does not have themoney, time, or required number of experts to discover and develop new drugs. The process that plays out in real life involves the focus of pharmaceutical industryscientists on desirable biological targets that can be identified in disease states, and toset up the program to discover specific treatments that will show efficacy in human dis-ease. The compounds that are developed successfully become drugs on which the com-pany holds patents. In this manner, the enormous cost of discovering and developing anew drug (estimated at $800 million plus over a period of some 10 years1) as notedabove can be recouped by the founding company since no competitors can sell the prod-uct as long as the patent is in force. Without such a system in place, drug companies sim-ply could not, in our opinion, afford to bring new prescription drugs to the market.In the course of reviewing the matter, the Joint Economic Committee examined a list of21 major drugs, which was put together apparently as an example of drug products thatmight justify royalty to the government. One of these agents, captopril (trade nameCapoten), was discovered and developed by E.R. Squibb & Sons in the 1970s. At that time,Charles Smith (one of the authors/editors) was vice president for R&D at The SquibbInstitute for Medical Research. One of Squibbs academic consultants, Professor Sir JohnVane of the Royal College of Surgeons in London brought the idea of opening a new path-way to treat the so-called essential hypertension by inhibiting an enzyme known as theangiotensin converting enzyme (ACE). This biochemical system was certainly known atthat time but, in Squibbs experience in the field of hypertension treatment, was not gen-erally thought to play a major role in the common form of the disease, then known asessential hypertension. The company decided to gamble on finding a treatment that wasnot used at the time and that would be proprietary to the company. Professor Vane (Nobellaureate in medicine in 1982) had discovered a peptide in snake venom that was a potentinhibitor of ACE. Squibb decided to pursue the approach he espoused, resulting in thedevelopment of a unique treatment for this very prevalent and serious disease.In the first phase of their research, Squibb tested a short-chain peptide isolated from thevenom of the viper Bothrops jararaca, with which Vane was working in the laboratory, inhuman volunteers and showed that it did, indeed, inhibit the conversion of angiotensin Ito angiotensin II after intravenous injection. The peptide was also shown to reduce bloodpressure in patients when injected. Since the vast majority of peptides cannot be absorbedfrom the GI tract, Squibb scientists set out to prepare a nonpeptide compound that couldbe used orally and manufactured at acceptable cost. The design of a true peptidomimeticthat became orally active had not been accomplished at that time. Squibb then carried outOverview of the Current Process of New Drug Discovery and Development 11 2006 by Informa Healthcare USA, Inc.the U.S. Senate (for history see Ref. 7) has been considering this question. Historically,a full-blown clinical program on a worldwide basis, which led to FDA approval ofSquibbs drug Capoten (captopril), an ACE inhibitor. Mark also marketed an ACEinhibitor in the same time frame. This work opened a new area of research that hasresulted in a bevy of new drugs that share this mechanism of action for use as antihyper-In the minds of pharmaceutical researchers and, hopefully, the public at large, the aboveexample illustrates the unique role of pharmaceutical companies in making good use ofbasic research to discover new treatments for serious diseases. The huge costs to discoverand develop a new drug could not be borne unless the companies knew that, if their gam-ble worked (which is not the case in the majority of situations), they would be assured ofa good financial return for their shareholders. This system has served the country well inmany fields of endeavor, in and out of the drug arena, and should be retained as such. 2.2 Regulation of New Drug DevelopmentDrug development will come to a crashing halt without approval of the U.S. FDA, author-ized by Congress to approve, license, and monitor the drugs sold to the American public.We are fortunate to have two contributors from the FDA, an acting associate commissionerfor operations, and also CDERs (Center for Drug Evaluation and Research) associatedirector for International Conference on Harmonisation (ICH). These authors describe theFDAs new critical pathway initiative, pharmacists risk management contributions, aswell as the Common Technical Document (eCTD), which will enable a sponsor to file inone of the cooperating ICH partners, and receive approval for almost global marketing ofthe new agent. A very important chapter on pharmacogenetics and pharmacogenomicsincludes numerous FDAcontributers.2.3 Liability and LitigationLast and the most unpopular topic in any industry, especially in the pharmaceutical indus-try, is the topic of liability and litigation. We have elected to include a chapter on this topicso that workers from all scientific disciplines involved in drug discovery and developmentcan learn from history, and, hopefully, avoid being involved in the devastation of life (dueto toxicity of inadequately manufactured drugs or drugs with inadequate warnings forsafe use) and destruction of companies and careers that follows in the aftermath of drugproduct litigation.References1. Smith, C.G., The Process of New Drug Discovery and Development, 1st ed., CRC Press, BocaRaton, FL, 2002.2. Di Masi, J.A., Hansen, R.W., and Grabowski, H.G., The price of innovation: new estimates ofdrug development costs, J. Health Econ., 22, 151185, 2003.12 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.tensive drugs (for more detail, see Refs. 1115).3. Reichert, J.M. and Milne, C.-P., Public and private sector contributions to the discovery anddevelopment of impact drugs, Am. J. Therapeut., 9, 543555, 2002.4. Di Masi, J., Risks in new drug development. Approval success rates for investigational drugs,Clin. Pharmacol. Therapeut., 69, 297307, 2001.5. Di Masi, J., New drug development in the United States from 1963 to 1999, Clin. Pharmacol.Therapeut., 69, 286296, 2001.6. Grabowski, H., Vernon, J., and Di Masi, J.A., Returns on research and development for 1990snew drug introductions, Pharmacol. Econ., 20 (suppl. 3), 1129, 2002.7. Reichert, J.M. and Milne, C.-P., Public and private sector contributions to the discovery anddevelopment of impact drugs, A Tufts Center for the Study of Drug Development WhitePaper, May 2002.8. Hardin, A., More compounds failing phase I, Scientist Daily News, Aug. 6, 2004, p. 1.9. Dietary Supplement Health and Education Act of 1994, Publ. no. 103-417, 108 Stat. 4325codified 21 U.S.C. 321, et seq. (suppl. 1999).10.11. Smith, C.G. and Vane, J.R., The discovery of captopril, FASEB J., 17, 788789, 2003.12. Gavras, H., The discovery of captopril: Reply, FASEB J., 18, 225, 2004.13. Erdas, E.G., The discovery of captopril: Reply, FASEB J., 18, 226, 2004.14. Pattac, M., From vipers venom to drug design: treating hypertension, FASEB J., 18, 421, 2004.15. Smith, C.G. and Vane, J.R., The discovery of captopril: Reply, FASEB J., 18, 935, 2004.Overview of the Current Process of New Drug Discovery and Development 13 2006 by Informa Healthcare USA, Inc.FDA links: (a) http://www.cfsan.fda.gov/~dms/ds-warn.html (b) http://www.cfsan.fda.gov/~lrd/ hhschomp.html (c) http://www.fda.gov/ola/2004/dssa0608.html3Integrated Drug Product Development From LeadCandidate Selection to Life-Cycle ManagementMadhu Pudipeddi, Abu T.M. Serajuddin, and Daniel MufsonCONTENTS3.1 Introduction ........................................................................................................................163.2 Developability Assessment ..............................................................................................173.2.1 Evolution of the Drug Discovery and Development Interaction ..................183.2.2 Screening for Drugability or Developability ....................................................183.2.2.1 Computational Tools ..............................................................................193.2.2.2 High-Throughput Screening Methods ................................................203.2.2.3 In-Depth Physicochemical Profiling ....................................................213.3 Overview of Dosage-Form Development and Process Scale-Up ................................223.4 Preformulation ....................................................................................................................223.4.1 Preformulation Activities: Independent of Solid Form ..................................233.4.1.1 Dissociation Constant ............................................................................233.4.1.2 Partition or Distribution Coefficient ....................................................243.4.1.3 Solution Stability Studies ...................................................................... 243.4.2 Preformulation Activities: Dependent on Solid Form ....................................253.4.2.1 Solubility ..................................................................................................253.4.2.2 Salt-Form Selection ................................................................................253.4.2.3 Polymorphism..........................................................................................263.4.2.4 Solid-State Stability ................................................................................273.4.2.5 Drug-Excipient Interactions ..................................................................273.4.2.6 Powder Properties of Drug Substance ................................................283.5 Biopharmaceutical Considerations in Dosage-Form Design ......................................293.5.1 Physicochemical Factors ......................................................................................303.5.1.1 Solubility ..................................................................................................303.5.1.2 Dissolution ..............................................................................................303.5.2 Physiological Factors ............................................................................................323.5.2.1 Assessment of In Vivo Performance ....................................................333.5.2.2 In VitroIn Vivo Correlation ..................................................................333.6 Clinical Formulation Development: Clinical Trial Materials ......................................333.6.1 Phase I Clinical Trial Material ..............................................................................343.6.2 Phase II Clinical Trial Material ............................................................................363.6.3 Phase III Clinical Trial Material ..........................................................................3815 2006 by Informa Healthcare USA, Inc.3.7 Nonoral Routes of Administration ..................................................................................393.7.1 Parenteral Systems ................................................................................................393.7.2 Inhalation Systems ................................................................................................403.8 Drug-Delivery Systems ......................................................................................................413.9 Product Life-Cycle Management ......................................................................................443.10 Summary ..............................................................................................................................45References ......................................................................................................................................463.1 IntroductionHistorically, medicines have been administered through the obvious portals following theirpreparation first by the shaman and then by the physician and later by the apothecary.These natural products were ingested, rubbed-in, or smoked. For the past century, the per-son diagnosing the disease no longer prepares the potion, eliminating, no doubt, some ofthe power of the placebo, and as a consequence, drug discovery, development, and manu-facturing have grown into a separate pharmaceutical industry. In particular, the last 50years have been a period of astounding growth in our insight of the molecular function ofthe human body. This has led to discovery of medicines to treat diseases that were not evenrecognized a half-century ago. This chapter reflects the role of pharmaceutics and the diver-sity of the approaches taken to achieve these successes, including approaches that wereintroduced within recent years, and describes how the role of the industrial pharmacisthas evolved to become the technical bridge between discovery and development activitiesand, indeed, commercialization activities. No other discipline follows the progress of thenew drug candidate as far with regard to the initial refinement of the chemical lead throughpreformulation evaluation to dosage-form design, clinical trial material (CTM) preparation,process scale-up, manufacturing, and then life-cycle management (LCM).The pharmaceutical formulation was once solely the responsibility of the pharmacist,first in the drugstore and later in an industrial setting. Indeed, many of todays majordrug companies, such as Merck, Lilly, Wyeth, and Pfizer components Searle, Warner-Lambert, and Parke-Davis, started in the backrooms of drugstores. During the secondhalf of the 20th century, physicochemical and biopharmaceutical principles underlyingpharmaceutical dosage forms were identified and refined, thanks to the pioneeringworks by Higuchi,1Nelson,2Levy,3Gibaldi,4and their coworkers. Wagner,5Wood,6andKaplan7were among the earliest industrial scientists to systematically link formulationdesign activities and biology. Nevertheless, until recently, formulations were developedsomewhat in isolation with different disciplines involved in drug development operatingindependently. For example, during the identification and selection of new chemical enti-ties (NCEs) for development, not much thought was given into how they would be for-mulated, and during dosage-form design, adequate considerations of in vivo performanceof formulations was lacking. Wagner5first termed our evolving understanding of therelationship between the dosage form and its anatomical target, biopharmaceutics inthe early 1960s. Since then it has been apparent that careful consideration of a moleculesphysical chemical properties and those of its carrier, the dosage form, must be under-stood to enhance bioavailability, if given orally, and to enhance the ability of drug to reachthe desired site of action, if given by other routes of administration. This knowledgeallows for a rational stepwise approach in selecting new drug candidates, developing16 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.optimal dosage forms, and, later when it is necessary, making changes in the formulationor manufacturing processes. During the last decade or so, the basic approach of dosage-form development in the pharmaceutical industry has changed dramatically. Dosage-form design is now an integrated process starting from identification of drug moleculesfor development to their ultimate commercialization as dosage forms. This is oftenperformed by a multidisciplinary team consisting of pharmacists, medicinal chemists,physical chemists, analytical chemists, material scientists, pharmacokineticists, chemicalengineers, and other individuals from related disciplines.In its simplest terms the dosage form is a carrier of the drug. It must further be repro-ducible, bioavailable, stable, readily scaleable, and elegant. The skill sets employed todesign the first units of a dosage form, for example, a tablet, are quite different than thoserequired to design a process to make hundreds of thousands of such units per hour, repro-ducibly, in ton quantities, almost anywhere in the world. Nevertheless, it is important thatdesign for manufacturability considerations are made early although resource con-straints and minimal bulk drug supply may not favor them. The manufacturability situa-tion becomes understandably more complex as the dosage form becomes moresophisticated or if a drug-delivery system (DDS) is needed.The level of sophistication in dosage-form design has been keeping pace with advancesin discovery methods. New excipients, new materials, and combination products that con-sist of both a drug and a device have arisen to meet new delivery challenges. For example,many of the NCEs generated by high-throughput screening (HTS) are profoundly water-insoluble. What was considered a lower limit for adequate water solubility7(~0.1 mg/mL)in the 1970s has been surpassed by at least an order of magnitude due to changes in theway drug discovery is performed. Traditional methods such as particle size reduction toimprove the aqueous dissolution rate of these ever more insoluble molecules are notalways sufficient to overcome the liability. New approaches have evolved to meet thesechallenges ranging from cosolvent systems8to the use of lipidwater-dispersible excipi-ents9and to the establishment of numerous companies with proprietary methods toincrease bioavailability.Many literature sources describing formulation and manufacture of different pharma-ceutical dosage forms are available.10,11The primary objective of this chapter is to describean integrated process of drug development, demonstrating how all activities from leadselection to LCM are interrelated. Various scientific principles underlying these activitiesare described.A survey of new drug approvals (NDAs) during the last 5 years (1999 to mid-2004)showed that nearly 50% of them are oral dosage forms. The percentage is higher ifAbbreviated NDAs for generics are included. Therefore, the primary focus of this chapteris the development of oral dosage forms with a few other dosage forms described onlybriefly. However, many of the principles described in this chapter are common to alldosage forms.3.2 Developability AssessmentThe dosage-form design is guided by the properties of the drug candidate. If an NCEdoes not have suitable physical and chemical properties or pharmacokinetic attributes,the development of a dosage form (product) may be difficult and may sometimes beeven impossible. Any heroic measures to resolve issues related to physicochemical andbiopharmaceutical properties of drug candidates add to the time and cost of drugIntegrated Drug Product Development From Lead Candidate Selection to LCM 17 2006 by Informa Healthcare USA, Inc.development. Therefore, in recent years, the interaction between discovery and devel-opment scientists increased greatly to maximize the opportunity to succeed.123.2.1 Evolution of the Drug Discovery and Development InteractionThe traditional (i.e., pre-1990s) drug discovery process involved initial lead generation onthe basis of natural ligands, existing drugs, and literature leads. New compounds wouldbe synthesized and tested for biological activity, and structureactivity relationshipswould be established for optimization of leads using traditional medicinal chemistry tech-niques. Promising compounds would then be promoted for preclinical and clinical testingand therefore passed along to the product development staff. While often there was littlecollaboration between research and development, a few organizations had recognized theimportance of discovery-development teams to assess development issues related to newdrug candidates.7The current (post-1990s) drug discovery process typically involves:13Target identificationTarget validationLead identificationCandidate(s) selectionA drug target can be a receptor/ion channel, enzyme, hormone/factor, DNA, RNA,nuclear receptor, or other, unidentified, biological entity. Once drug targets are identi-fied, they are exposed to a large number of compounds in an in vitro or cell-based assayin an HTS mode. Compounds that elicit a positive response in a particular assay arecalled hits. Hits that continue to show positive response in more complex models riseto leads (lead identification). Aselected few of the optimized leads are then advancedto preclinical testing. The traditional discovery process has not been discontinued butstill occurs in a semiempirical fashion depending on the chemists or biologists experi-ence and intuition. With the application of HTS technologies, compound handling indiscovery has shifted to the use of organic stock solutions (dimethylsulfoxide) for invitro and in vivo testing from the traditional use of gum tragacanth suspensions in ratsby the pharmacologist.Use of combinatorial chemistry and HTS technologies have resulted in the generationand selection of increasingly lipophilic drug molecules with potential biopharmaceuticalhurdles in downstream development.14Particularly, the use of organic solvents such asdimethylsulfoxide has contributed to the increase in water-insoluble drugs. Analysis ofcompound attrition in pharmaceutical development indicated that poor pharmacokineticfactors, i.e., absorption, elimination, distribution, and metabolism (ADME) contributed toabout 40% of failed candidates, and for those that moved forward, the development time-lines significantly slowed down.15To reduce attrition of compounds later in development,pharmaceutical companies began to conduct pharmaceutical, pharmacokinetic, and safetyprofiling of late- as well as early-phase discovery compounds.163.2.2 Screening for Drugability or DevelopabilityCompounds with acceptable pharmaceutical properties, in addition to acceptable biolog-ical activity and safety profile, are considered drug-like or developable. Typical accept-able pharmaceutical properties for oral delivery of a drug-like molecule include sufficientaqueous solubility, permeability across biological membranes, satisfactory stability to18 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.metabolic enzymes, resistance to degradation in the gastrointestinal (GI) tract (pH andenzymatic stability), and adequate chemical stability for successful formulation into a sta-ble dosage form. Anumber of additional barriers, such as efflux transporters17(i.e., exportof drug from blood back to the gut) and first-pass metabolism by intestinal or liver cells,have been identified that may limit oral absorption. A number of computational andexperimental methods are emerging for testing (or profiling) drug discovery compoundsfor acceptable pharmaceutical properties.In this section, discussion of physicochemical profiling is limited to solubility, perme-there are other physicalmechanical properties that must also be considered). For conven-ience, methods available for physicochemical profiling are discussed under the followingcategories: computational tools (sometimes referred to as in silico tools), HTS methods, andin-depth physicochemical profiling.163.2.2.1 Computational ToolsMedicinal chemists have always been adept in recognizing trends in physicochemicalproperties of molecules and relating them to molecular structure. With rapid increase inthe number of hits and leads, computational tools have been proposed to calculate molec-ular properties that may predict potential absorption hurdles. For example, LipinskisRule of 514states that poor absorption or permeation are likely when:1. There are more than five H-bond donors (expressed as the sum of NH and OHgroups).2. The molecular weight is more than 500.3. log P5 (or c log P4.5).4. There are more than ten H-bond acceptors (expressed as the sum of Ns and Os)If a compound violates more than two of the four criteria, it is likely to encounter oralabsorption issues. Compounds that are substrates for biological transporters and pep-tidomimetics are exempt from these rules. The Rule of 5 is a very useful computationaltool for highlighting compounds with potential oral absorption issues. Anumber of addi-tional reports on pharmaceutical profiling and developability of discovery compoundshave been published,18since the report of Rule of 5. Polar surface area (PSA) and numberof rotatable bonds have also been suggested as means to predict oral bioavailability. PSAis defined as the sum of surfaces of polar atoms in a molecule. Arotatable bond is definedas any single bond, not in a ring, bound to a nonterminal heavy (i.e., non-hydrogen) atom.Amide bonds are excluded from the count. It has been reported that molecules with thefollowing characteristics will have acceptable oral bioavailability:191. Ten or fewer rotatable bonds.2. Polar surface area equal to or less than 140 2(or 12 or fewer H-bond donors andacceptors).Aqueous solubility is probably the single most important biopharmaceutical propertythat pharmaceutical scientists are concerned with. It has been the subject of computationalprediction for several years.2023The overall accuracy of the predicted values can beexpected to be in the vicinity of 0.5 to 1.0 log units (a factor of 3 to 10) at best. Although adecision on acceptance or rejection of a particular compound cannot be made only on thebasis of predicted parameters, these predictions may be helpful to direct chemical librarieswith improved drug-like properties.24Integrated Drug Product Development From Lead Candidate Selection to LCM 19 2006 by Informa Healthcare USA, Inc.ability, drug stability, and limited solid-state characterization (as we will see in Section 3.4,3.2.2.2 High-Throughput Screening MethodsHigh-throughput drug-like property profiling is increasingly used during lead identifica-tion and candidate selection. HTS pharmaceutical profiling may include:Compound purity or integrity testing using methods such as UV absorbance,evaporative light scattering, MS, NMR, etc.25Solubility.Lipophilicity (log P).Dissociation constant (pKa).Permeability.Solution/solid-state stability determination.Compound purity (or integrity testing) is important to ensure purity in the early stagesbecause erroneous activity or toxicity results may be obtained by impure compounds. It isinitiated during hit identification and continued into lead and candidate selection.Solubility is measured to varying degrees of accuracy by HTS methods. Typical methodsin the lead identification stage include determination of kinetic solubility by precipitationof a drug solution in dimethylsulfoxide into the test medium. Since the solid-state form ofthe precipitate (crystalline or amorphous) is often not clearly known by this method, themeasured solubility is approximate and generally higher than the true (equilibrium) solu-bility. Kinetic solubility, however, serves the purpose of identifying solubility limitations inactivity or in vitro toxicity assays or in identifying highly insoluble compounds. Lipinski etal.14observed that, for compounds with a kinetic solubility greater than 65 g/mL (in pH 7non-chloride containing phosphate buffer at room temperature), poor oral absorption isusually due to factors unrelated to solubility. The acceptable solubility for a drug com-pound depends on its permeability and dose. This point will be further elaborated later.Methods to improve solubility in lead optimization have been reviewed.26Estimation or measurement of pKais important to understand the state of ionization ofthe drug under physiological conditions and to evaluate salt-forming ability.27Log P deter-mines the partitioning of a drug between an aqueous phase and a lipid phase (i.e., lipidbilayer). Log P and acid pKacan be theoretically estimated with reasonable accuracy.14,28,29High-throughput methods are also available for measurement of log P30and pKa.31Physical flux of a drug molecule across a biological membrane depends on the product ofconcentration (which is limited by solubility) and permeability. High-throughput artificialmembrane permeability (also called Parallel Artificial Membrane Permeability Assay) hasbeen used in early discovery to estimate compound permeability.32This method measuresthe flux of a compound in solution across an artificial lipid bilayer deposited on a microfil-ter. Artificial membrane permeability is a measure of the actual flux (rate) across an artificialmembrane whereas log P or log D as mentioned earlier represent equilibrium distri-bution between an aqueous and a lipid phase. Sometimes the term intrinsic permeabilityis used to specify the permeability of the unionized form. Artificial membrane permeabilitycan be determined as a function of pH. The fluxes across the artificial membrane in theabsence of active transport have been reported to relate to human absorption through ahyperbolic curve. The correlation of permeability through artificial membranes may dependon the specific experimental conditions such as the preparation of the membranes and pH.Therefore, guidelines on what is considered acceptable or unacceptable permeability mustbe based on the individual assay conditions. For example, Hwang et al.33ranked compoundpermeation on the basis of the percent transport across the lipid bilayer in 2 h: 2% (low), 2to 5% (medium), and 5% (high), respectively.Caco-2 monolayer, a model for human intestinal permeability, is commonly used in drugdiscovery to screen discovery compounds.34,35The method involves measurement of flux of20 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.the compound dissolved in a physiological buffer through a monolayer of human coloniccells deposited on a filter. Caco-2 monolayer permeability has gained considerableacceptance to assess human absorption. Compounds with a Caco-2 monolayer perme-ability (Papp) similar to or greater than that of propranolol (~30 106cm/sec) are con-sidered highly permeable, while compounds with Pappsimilar to or lower than that ofranitidine (1 106cm/sec) are considered poorly permeable. Hurdles associated withdetermination of permeability of poorly soluble compounds using Caco-2 method havebeen reviewed.363.2.2.3 In-Depth Physicochemical ProfilingOnce compounds enter the late lead selection or candidate selection phase, more in-depthphysicochemical profiling is conducted. The extent of characterization may vary fromcompany to company; however, it likely includes:Experimental pKaand log P (as a function of pH, if necessary)Thermodynamic solubility (as a function of pH)Solution/suspension stabilitySolid-state characterizationSolid-state characterization typically involves:Solid-state stabilityFeasibility of salt formationPolymorph characterizationParticle size, hygroscopicityDissolution rateIn a more traditional pharmaceutical setting, this characterization would be done dur-ing preformulation studies. With the availability of automation and the ability to conductmost of these experiments with small quantities of material, more preformulation activi-ties are being shifted earlier into drug discovery. Recently, Balbach and Korn37reported a100 mg approach to pharmaceutical evaluation of early development compounds.Additional absorption, metabolism, distribution, elimination, and toxicity38screens mayalso be conducted at this stage.Overall, the scientific merit of physicochemical profiling is clear. It provides a betterassessment of development risks of a compound early on. The important question is howcan pharmaceutical companies utilize the vast amount of physicochemical information toadvance the right drug candidates to preclinical and clinical testing? Scorecards or flagsmay be used to rank drug candidates for their physicochemical properties. These scores orflags, however, have to be appropriately weighted with biological activity, safety, and phar-macokinetic profiling of compounds. The relative weighting of various factors depends onthe specific issues of a discovery program. However, the basic question of how does it helpreduce attrition due to unacceptable physicochemical properties remains to be answered ina statistical sense. In 1997, Lipinski et al.14reported that a trend had been seen since theimplementation of the Rule of 5 toward more drug-like properties in Pfizers internal drugbase. Overall, the goal of a discovery program is to steer the leads in the right directionusing computational and HTS approaches and then utilize the in-depth screening tools toselect the most optimal compound without undue emphasis on a single parameter such asbiological activity. The overall success of a compound is a function of its biological and bio-pharmaceutical properties.Integrated Drug Product Development From Lead Candidate Selection to LCM 21 2006 by Informa Healthcare USA, Inc.3.3 Overview of Dosage-Form Development and Process Scale-UpOnce a compound is selected for development, the pharmaceutics group begins a series ofstudies to further evaluate the salient physical-chemical and physical-mechanical proper-ties of NCEs to guide the actual design (formulation, recipe) of the dosage form that willcarry the drug. These investigations consist of the following steps that span the years thatthe molecule undergoes clinical evaluation:PreformulationConsideration of its biopharmaceutical aspectsDosage-form designCTMs manufactureScale-up studies including technical transfer to manufacturing sitesInitiation of long-term stability studies to guide the setting of the expiration dateProduction of biobatchesValidation and commercial batchesLife-cycle managementWhile there is a natural desire to front-load these evaluations, this must be balancedagainst the sad fact that many molecules fail to survive clinical testing: sufficient charac-terization is performed to help select the right molecule to minimize losses at the later,and much more costly, clinical evaluation stages. Great thought and planning are requiredto optimize the level of effort expended on a single molecule when so many are known tofail during clinical evaluation.There are many reference on the design10,11and scale-up39of pharmaceutical dosageforms. It is appropriate to mention that the design of the dosage form be well documentedfrom its inception as this information is required at the NDA stage to explain the devel-opment approach. The FDA and its global counterparts are seeking documentation thatthe product quality and performance are achieved and assured by design of effective andefficient manufacturing processes. The product specifications should be based upon amechanistic understanding of how the formulation and processing factors impact theproduct performance. As we describe later, it is important that an ability to effect contin-uous improvement to the production process with continuous real-time assessment ofquality must be incorporated in drug development. Recent regulatory initiatives requirethat the product/process risks are assessed and mitigated. In this respect, GMP regula-tions for drugs are moving toward quality standards already required for devices.3.4 PreformulationIn the pre-1990s development scenario, preformulation activities would start when a com-pound had been chosen as the lead candidate by the drug discovery unit and advancedfor preclinical development prior to testing in man. In the current integrated discovery-development scenario, many of the classical preformulation activities are conducted whilescreening compounds are in the lead identification or compound selection stage.Irrespective of the actual timing of preformulation studies, preformulation lays the foun-dation for robust formulation and process development. The purpose of preformulation isto understand the basic physicochemical properties of the drug compound so that the22 The Process of New Drug Discovery and Development 2006 by Informa Healthcare USA, Inc.challenges in formulation are foreseen and appropriate strategies are designed. Somephysicochemical properties are independent of the physical form (i.e., crystal form) butsimply are a function of the chemical nature of the compound. They include chemical struc-tur