drug approval process
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New Drug Approval ProcessStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
DRUGS AND THE PHARMACEUTICAL SCIENCES
Executive EditorJames SwarbrickAAI, Inc.Wilmington, North Carolina
Advisory Board
Larry L. AugsburgerUniversity of Maryland
Baltimore, Maryland
David E. NicholsPurdue UniversityWest Lafayette, Indiana
Douwe D. BreimerGorlaeus Laboratories
Leiden, The Netherlands
Stephen G. SchulmanUniversity of FloridaGainesville, Florida
Trevor M. JonesThe Association of the
British Pharmaceutical IndustryLondon, United Kingdom
Jerome P. SkellyCopley Pharmaceutical, Inc.Canton, Massachusetts
Hans E. JungingerLeiden/Amsterdam Center
for Drug ResearchLeiden, The Netherlands
Felix TheeuwesAlza CorporationPalo Alto, California
Vincent H. L. LeeUniversity of Southern California
Los Angeles, California
Geoffrey T. TuckerUniversity of SheffieldRoyal Hallamshire HospitalSheffield, United Kingdom
Peter G. WellingInstitut de Recherche Jouveinal
Fresnes, France
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DRUGS AND THE PHARMACEUTICAL SCIENCES
A Series of Textbooks and Monographs
1. Pharmacokinetics, Milo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig,Murray M. Tuckerman, and William S. Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz
9. Activated Charcoal: Antidotal and Other Medical Uses, David 0. Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Karch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts, Biomedical Assessments, Yie W.Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi and Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Second Edition,Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV
17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited by Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. NashStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
24. Anticancer and Interferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and GeorgeB. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzinowicz, Burrows T.Younkin, Jr., and Michael J. Gudzinowicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition, Revised and Expanded, editedby Joseph R. Robinson and Vincent H. Lee
30. New Drug Approval Process: Clinical and Regulatory Management, edited by Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W Chien
32. Drug Delivery Devices: Fundamentals and Applications, edited by Praveen Tyle
33. Pharmacokinetics: Regulatory Industrial · Academic · Perspectives, edited by Peter G. Welling andFrancis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives, edited by Jonathan Hadgraftand Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by Isaac GhebreSellassie
38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang
40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by Gilbert S. Banker andChristopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and Production Technology, edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne and Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications, Second Edition, Revised and Expanded,Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark Chasin and Robert Langer
46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S. Tse and James J. Jaffe
47. HPLC in the Pharmaceutical Industry, edited by Godwin W Fong and Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S. Tse, and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
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50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, Yie W Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto and Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Third Edition, editedby Sidney H. Willig and James R. Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan
54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J. Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D. Nunn
56. New Drug Approval Process: Second Edition, Revised and Expanded, edited by Richard A. Guarino
57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded, edited by Ira R. Berry andRobert A. Nash
58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra
59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters and Jonathan Hadgraft
60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck
61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by Alain Rolland
62. Drug Permeation Enhancement: Theory and Applications, edited by Dean S. Hsieh
63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan
64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jörg Kreuter
67. Pharmacokinetics: Regulatory · Industrial · Academic Perspectives, Second Edition, edited by Peter G.Welling and Francis L. S. Tse
68. Drug Stability: Principles and Practices, Second Edition, Revised and Expanded, Jens T. Carstensen
69. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded, edited by Sandy Weinberg
70. Physical Characterization of Pharmaceutical Solids, edited by Harry G. Brittain
71. Pharmaceutical Powder Compaction Technology, edited by Göran Alderborn and Christer Nyström
72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by Gilbert S. Banker andChristopher T. Rhodes
73. Microencapsulation: Methods and Industrial Applications, edited by Simon Benita
74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone
75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt and Michael MontagneStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness, edited by Peter G. Welling,Louis Lasagna, and Umesh V. Banakar
77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen andHoward Bernstein
78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revisedand Expanded, Sidney H. Willig and James R. Stoker
79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition, Revised and Expanded,edited by James W McGinity
80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition, Sanford Bolton
81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh
82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded, edited by William R. Strohl
83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and Richard H. Guy
84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpe
85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by John A. Bontempo
86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation · Production · Quality Control,edited by Donald C. Monkhouse and Christopher T. Rhodes
88. Development and Formulation of Veterinary Dosage Forms: Second Edition, Revised and Expanded, editedby Gregory E. Hardee and J. Desmond Baggot
89. Receptor-Based Drug Design, edited by Paul Leff
90. Automation and Validation of Information in Pharmaceutical Processing, edited by Joseph F. deSpautz
91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts and Kenneth A. Walters
92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and Roger Phan-Tan-Luu
93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III
94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy, David E. Bugay andW. Paul Findlay
95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain
96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, edited by Louis Rey and Joan C.May
97. Percutaneous Absorption: Drugs-Cosmetics-Mechanisms-Methodology, Third Edition, Revised andExpanded, edited by Robert L. Bronaugh and Howard I. Maibach
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98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development, edited by EdithMathiowitz, Donald E. Chickering III, and Claus-Michael Lehr
99. Protein Formulation and Delivery, edited by Eugene J. McNally
100. New Drug Approval Process: Third Edition, The Global Challenge, edited by Richard A. Guarino
101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid
102. Transport Processes in Pharmaceutical Systems, edited by Gordon Amidon, Ping I. Lee, and ElizabethM. Topp
103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A. Kotkoskie
104. The Clinical Audit in Pharmaceutical Development, edited by Michael R. Hamrell
ADDITIONAL VOLUMES IN PREPARATION
Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud and Gilberte Marti-Mestres
Oral Drug Absorption, edited by Jennifer B. DressmanStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page i
New Drug Approval ProcessThird Edition
The Global Challenge
edited byRichard A. Guarino, M.D.
Oxford Pharmaceutical Resources, Inc.Totowa, New Jersey
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Page ii
The first and second editions were published as New Drug Approval Process (1987) and New Drug ApprovalProcess: Second Edition, Revised and Expanded (1992).
ISBN: 0-8247-0308-1
This book is printed on acid-free paper.
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Copyright © 2000 by Marcel Dekker, Inc. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic ormechanical, including photocopying, microfilming, and recording, or by any information storage and retrievalsystem, without permission in writing from the publisher.
Current printing (last digit):10 9 8 7 6 5 4 3 2 1
PRINTED IN THE UNITED STATES OF AMERICAStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page iii
To my family and friends,who never left my side during good and crisis situations.Their dedication, support, and love will remain with me always.Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page v
Preface
New drug, device, and biological product development in the United States has changed drastically since thetime of the Kefauver Amendments in 1962. Regulations now demand that both safety and efficacy be evidentbefore products can be marketed with FDA's stamp of approval. The mechanics involved in the drug approvalprocess have had a tremendous impact on how new products are developed globally. Good Clinical Practicesand ICH guidelines must be followed meticulously for FDA and other worldwide regulatory agencies to allowpharmaceutical products to be marketed bearing labels that show safety as well as efficacy. As we forge into the21st century with the need to develop a larger array of pharmaceuticals, consideration of the rules, regulations,and guidelines in the new drug approval development process must become part of a company's strategic plan inbringing these products to market.
New Drug Approval Process, Third Edition addresses all the latest information and methodologies on themechanics of preparing INDs and NDAs. New ways to expedite this process are detailed. The organization ofthis edition is very different from that of previous editions. The text is now divided into sections, eachrepresenting an essential step in the new drug development process. Our intention is to help readers identify andanswer specific questions related to their areas of interest and expertise while using the text as a desk reference.Although each step of the process is considered separately, the text as a whole covers every aspect of how tobring pharmaceutical products to market.
The selection of authors to address the drug development process was based on their ability to present factualdata in a manner that the reader can readily comprehend. In Part I, Regulatory Aspects of New DrugDevelopment, the authors mesh their years of experience in IND and NDA development. The essential aspectsof the nonclinical and clinical development of products are carefully considered along with the regulatoryrequirements necessary for regulatory agencies' approval. Having dealt with these regulations for many years, theauthors are able to suggest ways to expedite the new drug approval process. Other specialized areas, such as,ELAs, PLAs, and ANDAs, that often are not addressed, are covered in this section. Special attention is given tobiotechnology, manufacturing, and control requirements for NDAs and ANDAs.Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page vi
Part II, Clinical Research Development, and Part III, Good Clinical Practices, detail the necessary steps in theclinical development process. The authors help the reader clearly understand and absorb the regulatoryrequirements. Special attention is given to IRBs, informed consents, ADR handling and reporting, and programmanagement. Also, GCP regulations of the investigator, sponsor, and monitor obligations are approachedpractically and applied to clinical research. A discusion of the importance of quality assurance and its growingrole in drug development as it relates to the changing industry completes these sections.
Part IV, The Orphan Drug and the Rx to OTC Switch, are addressed by specialists who have had great successgetting FDA approval for products in these areas. The development of orphan drugs through biotechnology isaddressed. It is inevitable that more products will undergo an Rx to OTC switch because of the changesoccurring in medical care and costs globally.
The last topics in Part V, Effective Methodology in Expediting NDA Approval, present all new information notreferred to in earlier editions. The changes that have occurred throughout the pharmaceutical industry in new drugdevelopment processes have added a new dimension to the marketing process. FDA liaison and datapresentation for FDA submissions have given new challenges to industries developing new drug, device, andbiological applications. The evolving CRO and SMO companies, as well as the ''computer world haven," haveinfluenced new product development. Again, authors of these chapters have combined information with insight onthe mechanics of getting new product approvals globally.
My appreciation and thanks are extended to all the authors, who have worked diligently in the preparation of thisthird edition of New Drug Approval Process. Special thanks go to Patricia Blaine, Lisa Butkowski, SharonMirowsky, and Catherine Juliano for their continuous endeavors in the preparation of this book.
RICHARD A. GUARINO, M.D.Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page vii
Introduction
The discovery and approval of new drugs during the next millennium will revolutionize the entire health careindustry. Bureaucratic agencies throughout the world are becoming more homogeneous and resourceful in theirways of accepting and approving new products that will benefit patients suffering from diseases. The increasingdemands by consumers for nonprescription drugs, as a result of the rapidly changing health care programs, willstimulate the ethical companies to switch their prescription (Rx) products to over-the-counter (OTC) ones.
Pharmaceutical companies are seeking ways to meet the national and international requirements of the changinghealth care market. Mergers, acquisitions, and licensing all play an important role in what and how products willcome to market in the next 10 to 15 years. In many instances, decisions regarding these new products will bebased on economics and social demands rather than on scientific discovery. The research into new productdevelopment has made a 180-degree turn. Companies are decreasing their internal drug development staffs andare outsourcing a large part of research and development responsibilities to CROs. As a result, both CROs andSMOs have boomed in the last 10 years and have put new demands on pharmaceutical companies' managementteams.
Notwithstanding these drastic changes in the philosophy of new product development, the basic rules,regulations, and guidelines remain firm and must be adhered to if manufacturers intend to get approval for theirnew products. Regulatory requirements throughout the world continue to include stringent regulations to confirmsafety and efficacy of drugs, biologics, and devices.
The FDA and similar agencies in Europe are collaborating to bring these regulations to a global acceptancethrough the International Committee on Harmonization. It is hoped that these efforts will allow companies toachieve global approval of new products.
At present, in the United States, the FDA approves INDs that contain sufficient information about theinvestigational drug to show that it is safe for human testing. NDAs are approved only if the applicantdemonstrates through adequate scientific evidence that the drug is safe and by substantial evidenceStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
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that the drug is effective for the conditions prescribed, recommended, or suggested in the product's proposedlabeling. The content of the FDA/ICH regulations define substantial evidence of effectiveness and safety as thatwhich is demonstrated by adequate and well-controlled clinical investigations. Additionally, to obtain FDAapproval, an applicant must show that the methods used in manufacturing and control, processing, and packagingof the drug are adequate to preserve its identity, strength, quality, and purity. Good Manufacturing Practices(GMPs) play an important role in completing this process.
As simple and procedural as this process for an IND and NDA may seem, to achieve the final goal of bringing anew product to market, a vast amount of in-depth understanding of the drug approval process is necessary.
Good Laboratory Practices (GLPs), Good Clinical Practices (GCPs), and Investigational Review Boards (IRBs)regulations have become more precise and efficient to ensure that within new drug development, subjectsenrolled in new product investigations are used wisely and safety measures are implemented to minimize risks.FDA's concentration on "orphan" drugs and the new trend to bring more prescription drugs to OTC status haveput new demands on the strategic planning to implement the process.
This third edition of New Drug Approval Process will give an innovative prospectus to all individuals involved innew drug development. Also, the aura of the changing industry will be reflected throughout the book with theintention of recasting traditional methodologies as a basis for successful implementation of current and future newproduct development.
RICHARD A. GUARINO, M.D.Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page ix
Contents
Preface v
Introduction vii
Contributors xiii
Acronyms and Initialisms xv
Part I. Regulatory Aspects of New Drug Development
1. Drug Development TeamsDuane B. Lakings
1
2. Nonclinical Drug Development: Pharmacology, Drug Metabolism, and ToxicologyDuane B. Lakings
17
3. The Investigational New Drug Application and the Investigator's BrochureWilliam M. Troetel
55
4. General Considerations of the NDAMartha R. Charney
93
5. Specific Requirements, Content, and Format of an NDARichard A. Guarino and Patricia Blaine
103
6. The Biologic License Application (BLA)Albert A. Ghignone and Douglas Testa
157
7. Chemistry, Manufacturing and Control Requirements of the NDA, and ANDAIvy Bautista
189
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Part II. Clinical Research Development
8. Clinical Research ProtocolsRichard A. Guarino
219
9. Adverse Reactions and Interactions of DrugsRichard A. Guarino
247
10. Institutional Review Board/Independent Ethics Committee and Informed Consent:Protecting Subjects Throughout the Clinical Research ProcessRochelle L. Goodson
271
11. Statistical and Data Management: Collaboration in Clinical ResearchLaurent M. Kassalow
289
12. The Management of Clinical StudiesIleana Maria Alexander
311
Part III. Good Clinical Practices
13. Obligations of the Investigator, Sponsor, and MonitorRichard A. Guarino
325
14. Preparing for FDA Inspections: Manufacturing SitesTimothy Urschel
335
15. Quality AssuranceEarl W. Hulihan
349
Part IV. The Orphan Drug and the Rx to OTC Swith
16. Orphan DrugsJohn T. Zenno
361
17. Clinical Development, Regulations, and Trends for OTC DrugsWilliam E. Gilbertson and Steven A. Francesco
375
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Part V. Effective Methodology in Expediting NDA Approval
18. Industry and FDA LiaisonWilliam M. Troetel
393
19. Data Presentation for FDA Submissions: Text and Tabular ExpositionPatricia Blaine
415
20. The Computer World in New Drug DevelopmentChris Clauss
423
21. Working with a CRODuane B. Lakings and Alexandra D. J. Mancini
439
22. The Evolving SMO in the United StatesKenneth A. Getz
455
Index 465
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Page xiii
Contributors
Ileana Maria Alexander, R.N. Department of Medical Affairs, Warner-Lambert Consumer Healthcare, MorrisPlains, New Jersey
Ivy Bautista, M.B.A. Department of Drug Regulatory Affairs, Berlex Laboratories, Inc., Montville, New Jersey
Patricia Blaine, R.R.T., M.Ed. Blaine Pharmaceutical Services, Inc., Matawan, New Jersey
Martha R. Charney, Ph.D. Consultant, Menlo Park, California
Chris Clauss Networks Computer Consulting, Oakland, New Jersey
Steven A. Francesco, M.B.A. Francesco International, South Orange, New Jersey
Kenneth A. Getz, M.S., M.B.A. CenterWatch, Inc., Boston, Massachusetts
Albert A. Ghignone, M.S., RAC Regulated Technologies, Inc., Phillipsburg, New Jersey
William E. Gilbertson, Pharm.D. Center for Drug Evaluation and Research, Food and Drug Administration,Rockville, Maryland
Rochelle L. Goodson R. L. Goodson Consulting, Inc., Forest Hills, New York
Richard A. Guarino, M.D., K.M. Oxford Pharmaceutical Resources, Inc., Totowa, New Jersey
Earl W. Hulihan, M.Ed. EduQuest, Inc., Rockville, Maryland
Laurent M. Kassalow, M.S. Data Management and Biostatistics, Target Research Associates, Inc., ScotchPlains, New JerseyStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page xiv
Duane B. Lakings, Ph.D. Drug Safety Evaluation Consulting, Inc., Birmingham, Alabama
Alexandra D. J. Mancini, M.Sc. Department of Regulatory Affairs, QLT PhotoTherapeutics, Inc., WestVancouver, British Columbia, Canada
Douglas Testa, Ph.D. Regulated Technologies, Inc., Phillipsburg, New Jersey
William M. Troetel, Ph.D. Regulatory Affairs Consultant, Mount Vernon, New York
Timothy Urschel, M.B.A. Department of Regulatory Affairs, Novo Nordisk Pharmaceuticals, Inc., Princeton,New Jersey
John T. Zenno Worldwide Regulatory Affairs, The Liposome Company, Inc., Princeton, New JerseyStart of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page xv
Acronyms and Initialisms
The Medical Communications Department of Oxford Pharmaceutical Resources, Inc. has been collectingacronyms and initialisms throughout the professional careers of its individual members. We have obtained about600 items through workshops, conventions, professional publications, and the other chapters in this book. Theauthor of two of the chapters in this book, William M. Troetel, Ph.D., graciously allowed us to merge a large listfrom one of his chapters into this list. We gratefully acknowledge his contribution.
The following list should be used as your reference for acronyms and initialisms throughout this book.
AAAS American Association for the Advancement of ScienceAABB American Association of Blood BanksAACR American Association for Cancer ResearchAADAAbbreviated Antibiotic Drug Application (FDA) (used primarily for generics)AAFP American Academy of Family PhysiciansAAI American Academy of ImmunologistsAAP American Association of PathologistsAAPP American Academy of Pharmaceutical PhysiciansAAPS American Association of Pharmaceutical ScientistsABPI Association of the British Pharmaceutical IndustryACCP American College of Clinical PharmacologyACE Adverse Clinical EventACIL American Council of Independent LaboratoriesACP Associates of Clinical Pharmacology (USA), a group that certifies clinical research
associates (CRAs) and clinical research coordinators (CRCs)ACPU Association of Clinical Pharmacology UnitsACRA Associate Commissioner for Regulatory Affairs (FDA)ACRPIAssociation for Clinical Research in the Pharmaceutical Industry (UK)
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ACS American Chemical SocietyACT Applied Clinical Trials magazineACTG AIDS Clinical Trials Group (NIAID)ACTU AIDS Clinical Trials Unit (NIH)AD Alzheimer's disease; antidepressantADAMHAAlcohol, Drug Abuse, and Mental Health Administration (no longer exists)ADAS Alzheimer's Disease Assessment ScaleADASCOG
Alzheimer's Disease Assessment Scale, Cognitive Subscale
ADE Adverse Drug Experience/Effect/EventADI Acceptable Daily IntakeADME Absorption, Distribution, Metabolism, EliminationADP Automated Data ProcessingADR Adverse Drug ReactionADRS Adverse Drug Reporting SystemAE Adverse Event/ExperienceAE ApprovableAED Antiepileptic DrugAEGIS ADROIT Electronically Generated Information ServiceAERS Adverse Event Reporting System (FDA)AESGP Association Européenne des Specialités Grand Public (European Proprietary
Medicines Manufacturers Association)AFCR See AFMRAFDO Association of Food and Drug OfficialsAFMR American Federation for Medical Research, formerly known as the American
Federation for Clinical Research (AFCR)AHA Area Health Authority (UK)AHCPR Agency for Health Care Policy Research (NIH)AICRC Association of Independent Clinical Research Contractors (UK)AIDS Acquired Immune Deficiency Syndrome. See also HIV and SIDAAIM Active Ingredient ManufacturerAIP Abbreviated Inspection ProgramAMA American Medical AssociationAMA-DE AMA Drug EvaluationsAMC Academic Medical CentersAMF Administrative Management of the FilesAmFAR American Foundation for AIDS ResearchAMG Arzneimittelgesetz (German Drug Law)AMI Acute myocardial infarction
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ANADAAbbreviated New Animal Drug ApplicationANDA Abbreviated New Drug Application (for a generic drug)ANOVAAnalysis of varianceAOAC Association of Official Analytical ChemistAOAC Association Pharmaceutique Belge (Belgium)AP Approved (COMIS term)APhA American Pharmaceutical AssociationAPHIS Animal and Plant Health Inspection ServiceAQL Acceptable Quality LevelARC AIDSrelated complexARDS Adult respiratory distress syndromeARENA Applied Research Ethics National AssociationASA American Statistical AssociationASAP Administrative Systems Automation Project (FDA)ASCII American Standards Code for Information Interchange (computer files)ASCO American Society for Clinical OncologyASCPT American Society for Clinical Pharmacology and TherapeuticsASM American Society for MicrobiologyASQC American Society for Quality ControlAT Active (COMIS term)ATF Bureau of Alcohol, Tobacco, and FirearmsAUC Area under the curve (an expression of exposure)AZT Zidovudine (HIV treatment)BARQABritish Association of Research Quality AssuranceBB Bureau of Biologics (now CBER)BCE Beneficial Clinical EventBEUC European Bureau of Consumer UnionsBfArM Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs
and Medical Devices, Germany)BGA Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizinn
(Federal Institute for Health Protection of Consumers and Veterinary Medicine,Germany)
BGVV Bundesgesundheitsamt (former German public health agency)BID Two times per dayBIND Biological Investigational New DrugBIO Biotechnology Industry OrganizationBIRA British Institute of Regulatory AffairsBLA Biologic License Application
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BMB Bioresearch Monitoring BranchBMI Body mass indexBPAD Bipolar affective disorderBPI Bundesverband der Pharmazeutischen Industrie EV (Germany)BPM Beats Per MinuteBrAPP British Association of Pharmaceutical PhysiciansBRB Biomedical Research BranchBSA Body surface areaBVC British Veterinary CodexC & S Culture and SensitivityCA Chemical AbstractsCA Competent Authority (regulatory body charged with monitoring compliance with
European member state national statutes and regulations)CAC Carcinogenicity Assessment CommitteeCACE Committee for Advancement of Chemistry EducationCAD Coronary artery diseaseCANDA Computer-Assisted New Drug Application. See NDACAPLA Computer-Assisted Product License Application. See PLACAPLARComputer-Assisted Product License Agreement Review (FDA)CAPRA Canadian Association of Pharmaceutical Regulatory AffairsCAS Chemical Abstracts ServiceCBC Complete blood countCBCTN Community Based Clinical Trials NetworkCBER Center for Biologics Evaluation and Research (FDA)CBF Cerebral blood flowCCASE Coordinating Committee for Advancement of Scientific EducationCCC Compliance Coordinating Committee (CDER)CCD Canadian Drugs DirectorateCCDS Company Core Data SheetsCCI Committee on Clinical Investigations. See also IRBCCRA Certified Clinical Research Associate. See also ACPCCRC Certified Clinical Research Coordinator. See also ACPCDC Centers for Disease Control (Atlanta, GA)CDER Center for Drug Evaluation and Research (FDA)CDRH Center for Devices and Radiological Health (FDA)CE Continuing education
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CE Mark signifying compliance with EU harmonized standards and directivesCEN Comité Européen de Normalisation (European Committee for Standardization)CESS CDER Executive Secretariat StaffCFR Code of Federal Regulations (usually cited by part and chapter, as 21 CFR
211)CFSAN Center of Food Safety and Applied NutritionCGMP Current Good Manufacturing PracticesCH Clinical HoldCHD Coronary heart diseaseCIB Clinical Investigator's BrochureCID CTFA Cosmetic Ingredient DictionaryCIOMS Council for International Organisations of Medical Sciences (postapproval
international ADR reporting, UK)CIR Cosmetic Ingredient ReviewCIS Commonwealth of Independent StatesCLIA Clinical Laboratory Improvements AmendmentsCMC Chemistry, Manufacturing and ControlsCMCCC Chemistry and Manufacturing Controls Coordinating Committee (CDER)CME Continuing medical educationCNS Central nervous systemCOA Commissioned Officers AssociationCOA Certificates of AnalysisCOE Code of EthicsCOIMS Centerwide Oracle Management Information System(FDA)COMIS Center Office Management Information SystemCOSTARTCoding Symbols for a Thesaurus of Adverse Reaction TermsCP Compliance ProgramCPMP Committee for Proprietary Medicinal Products (EU)CPSC Consumer Product Safety Commission (USA)CR Cross Reference (COMIS term)CRA Clinical Research AssociateCRADA Cooperative Research and Development Agreement (with NIH)CRC Clinical Research Coordinator. See also CCRCCRF Case Report Form
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CRO Contract Research Organization. See also IPROCS Civil ServiceCS Clinically significantCSDD Center for the Study of Drug DevelopmentCSI Consumer Safety InspectorCSM Commission for Safety of Medicines (UK Regulatory Agency) Committee on
Safety of Medicines (UK)CSO Consumer Safety Officer (FDA)Project ManagerCSR Clinical Study ReportCCSI Company Core Safety InformationCT Computerized tomographyCT Clinical trialCTC Clinical Trial CertificateCTEP Clinical Therapeutics Evaluation Program (NCI)CTX Clinical Trial Exemption Certification (MCA)CV Curriculum vitaeCVM Center for Veterinary Medicine (FDA)CXR Chest X-rayDAS Drug Abuse StaffDAWN Drug Abuse Warning NetworkDB Double-blindDD Department of Drugs (Swedish regulatory agency)ddC Dideoxycytidine, a cytidine nucleoside analogddC Didanosine, a purine nucleoside analogueDDIR Division of Drug Information ResourcesDDMAC Division of Drug Marketing, Advertising, and CommunicationsDEA Drug Enforcement Administration (USA)DEN Drug Experience NetworkDES Division of Epidemiology and SurveillanceDESI Drug Efficacy Study Implementation Notice (FDA, to evaluate drugs in use
before 1962)DGD Now OGD (formerly CBER's Division of Genetic Drugs)DHEW Department of Health, Education, and Welfare (USA, now split into HHS and
Department of Education)DHHS Department of Health and Human Services (USA)DIA Drug Information AssociationDISD Division of Information Systems DesignDMF Drug Master FileDoD Department of Defense (USA)DPC-PTRAct
Drug Price Competition and Patent Term Restoration Act of 1984 (also knownas Waxman-Hatch bill)
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DRG Diagnosis Related GroupsDRG Division of Research Grants (NIH)DSI Division of Scientific Investigations (FDA)DSM Diagnostic and Statistical Manual (of the American Psychiatric Association)DSMB Data and Safety Monitoring BoardDSNP Development of Standardized Nomenclature Project (FDA)DUR Drug Utilization ReviewEA Environmental assessmentEAB Ethical Advisory Board (term used in some nations for groups similar to IRBs and
IECs)EBSA European Biosafety AssociationEC European Commission (in documents older than the mid-1980s, EC may mean
European Community)ECG ElectrocardiogramECJ European Court of JusticeECPHINEuropean Community Pharmaceutical Products Information NetworkECU European Currency UnitED Effective doseEEC European Economic Community (old term for EC, now EU)EEG ElectroencephalogramEEO Equal Employment OpportunityEER Establishment Evaluation RequestEFGCP European Forum on Good Clinical Practice (Evere, Belgium)EFPIA European Federation of Pharmaceutical Industries' AssociationsEFTA European Free Trade AssociationEIA Establishment Inspection ReportsEIR Establishment Inspection Report (FDA)ELA Establishment License Application (biologics)EMEA European Medicines Evaluations Agency (UK)EMS Electronic Mail ServiceEO Executive OrderEOP1 End-of-Phase 1EOP2 End-of-Phase 2EORTC European Organization for Research and Treatment of CancerEOS End of StudyEP European Parliament
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EPA Environmental Protection AgencyEPAR European Public Assessment ReportEPL Effective Patent LifeEPMS Employee Performance Management SystemEPO European Patent OfficeEPRG European Pharmacovigilance Research GroupER Essential Requirements (EU)ESRA European Society of Regulatory AffairsESS Executive Secretary and StaffETT Exercise tolerance testEU European UnionEUP Experimental Use PermitFACA Federal Advisory Committee Act 1972FÄPI Fachgesellschaft der Ärzte in der Pharmazeutischen Industrie e.V. (German
Association of Physicians in the Pharmaceutical Industry)FarmindustriaThe Association of the Italian Pharmaceutical ManufacturersFAX FacsimileFCC Federal Communications CommissionFCCSET Federal Coordinating Council for Science, Engineering and TechnologyFD & C Act Federal Food, Drug and Cosmetic ActFD 1571 Form Used to Submit INDFD 1572 Statement of Investigator Form (accompanies IND)FD 1639 Form Used to Submit Drug Experience ReportFD 2252 Form Used to Submit NDA Annual ReportFD 2253 Form Used for Promotional Advertising or LabelingFD 356H Form Used to Submit NDAFD 483 Form Issued by FDA upon Adverse Findings of InspectionFDA Food and Drug Administration (USA)FDA-SRS Spontaneous Reporting System of the Food and Drug AdministrationFDLI Food and Drug Law InstituteFFDCA Federal Food Drug & Cosmetic ActFFPM Fellow of the Faculty of Pharmaceutical Medicine (UK)FMD Field Management DirectivesFOI Freedom of InformationFOIA Freedom of Information ActFONSI Finding of no significant impactFPIF The Finnish Pharmaceutical Industry AssociationFPL Final Printed Labeling
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FR Federal RegisterFRC Federal Records Center (Suitland)FRCP Fellow of the Royal College of Physicians, sometimes followed by a place namefor
example, FRCP (Edin.)that indicates a university medical schoolFSIS Food Safety and Inspection ServiceFTC Federal Trade Commission (USA)FUR Follow-Up RequestGAO General Accounting Office (US government)GATT General Agreement of Tariffs and TradeGC General Counsel (FDA)GC Gas chromatographyGCP Good Clinical PracticeGI GastrointestinalGLP Good Laboratory PracticeGMP Good Manufacturing PracticeGP General practitionerGPRA Government Performance and Results ActGRAS Generally Recognized as SafeGRASE Generally Recognized as Safe and EffectiveGRP Good Review PracticeHAACPHazard Analysis and Critical Control Point (inspection technique)HAI Health Action InternationalHCFA Health Care Financing Administration (HHS)HF Routing code for mail to the Office of the Commissioner of the FDAHFD Routing code for mail to CDERHFM Routing code for mail to CBERHFS Routing code for mail to CFSANHFT Routing code for mail to NCTRHFV Routing code for mail to CVMHFZ Routing code for mail to CDRHHHS Department of Health and Human Services (USA, also called DHHS)HIMA Health Industry Manufacturer's Association (devices)HIS Indian Health ServiceHIV Human immunodeficiency virusHIV+ HIV-positive; HIV-infectedHIV-1 Human immunodeficiency virus Type 1HMO Health Maintenance OrganizationHPB Health Protection Branch (Canada's equivalent of the FDA)
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HPLC High pressure liquid chromatographyHRG Health Research GroupHRRC Human Research Review committeeHRSA Health Resources and Services AdministrationHX HistoryI.V. IntravenousIACUC Institutional Animal care and Use CommitteeIARC International Agency for Research on CancerIC Informed consentIC Chemistry Information Amendment (COMIS) termICD Informed Consent DocumentICH International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human UseICPEMCInternational commission for Protection Against Mutagens and carcinogensICTH International Committee on Thrombosis and HemostasesIDB Investigational Drug BrochureIDE Investigational Device Exemption (FDA)IDR Idiosyncratic Drug ReactionIDSMB Independent Data Safety Monitoring BoardIEC Independent Ethics committee. see also EAB, IRB, NRBIFPMA International federation of Pharmaceutical Manufacturers' AssociationsIG Office of the Inspector GeneralIKS Interkantonale Kontrollstelle für Heilmittel (Switzerland)IM Clinical Information Amendment (COMIS term)IM IntramuscularINAD Investigational New Animal DrugIND Investigational New drug application (FDA). see also TINDINDA Investigational New Drug ApplicationINDC Investigational New Drug CommitteeINN International Nonproprietary NameIOM Institute of Medicine (national Academy of Science, USA)IPCS International Program for Chemical SafetyIPRA International Product Registration documentIPRO Independent Pharmaceutical Research Organization. see also CROIRB Institutional Review Board, sometimes Independent Review Board. see also IEC,
EAB, NRBIRC Institutes Review Committee
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IRD International Registration DocumentIRG Initial Review GroupsIRS Identical, related, or similarIS Information systemsISCB International Society for Clinical BiostatisticsISO International Organisation for StandardisationISPE International Society for PharmacoepidemiologyIT Toxicology Information Amendment (COMIS term)IT Information technologyITCC Information Technology Coordinating Committee (CDER)IV InterviewIVD In vitro device; in vitro diagnosticsIVF In vitro fertilizationIVF/ET In vitro fertilization/embryo transferJCAH Joint Commission for the Accreditation of HospitalsJCAHOJoint Commission of Accreditation of Health Care OrganizationsJCPT Journal of Clinical Pharmacology and TherapeuticsJCRDDJournal of Clinical Research and Drug DevelopmentJCRP Journal of Clinical Research and PharmacoepidemiologyJPMA Japan Pharmaceutical Manufacturers' AssociationKS Kaposi's SarcomaL & D Labor and deliveryLAN Local Area NetworkLD Lethal doseLD50 Lethal dose (50%)LEAA Law Enforcement Assistance AdministrationLERN Library Electronic Reference NetworkLIF Swedish Pharmaceutical Industry AssociationLKP Leiter der klinischen Prüfungunder the German Drug Law, the physician who is head
of clinical testingLNC Labeling and Nomenclature CommitteeLOA Letter of AgreementLOC Level of ConcernLOCF Last observation carried forwardLOD Loss on dryingLRC Lipid research clinicLRI Lower respiratory infectionLTE Less than effectiveLVP Large volume parenteralsMA Marketing AuthorizationMAA Marketing Authorization Application (EC)
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MAH Marketing Authorization HoldersMAPP Manual of Policy and ProceduresMBC Minimum bactericidal concentrationMCA Medicines Control Agency (UK)MDA Medical Devices Agency (UK)MDD Medical Device Directives (EU)MDI Metered-dose inhaler; manic-depressive illnessMDR Medical Device ReportingMDV Medical Device VigilanceMECU Million ECUMEDDRA Medical Dictionary for Drug Regulatory AffairsMEDLARS Medical Literature Analysis and Retrieval SystemMEDWATCHMedWatch Adverse Event Reporting SystemMEFA Association of the Danish Pharmaceutical IndustryMEMO Medicines Evaluation and Monitoring OrganisationMEP Member of the European ParliamentMHW Ministry of Health and Welfare (Koseisho, Japan's drug regulatory agency)MI Myocardial infarctionMIC Minimum Inhibitory ConcentrationMOU Memorandum of Understanding (between FDA and a regulatory agency in
another country) that allows mutual recognition of inspectionsMPCC Medical Policy Coordinating Committee (CDER)MRA Medical Research AssociateMRI Magnetic resonance imagingMTD Maximum tolerated doseNA Not approvableNABR National Association for Biomedical ResearchNADA New Animal Drug ApplicationNAF Notice of Adverse Findings (FDA postaudit letter)NAFTA North American Free Trade AgreementNAHC National Advisory Health CouncilNAI No Action Indicated (most favorable FDA postinspection classification)NAS National Academy of SciencesNAS New Active SubstanceNAS-NRC National Academy of SciencesNational Research CouncilNATRIK National Reporting and Investigation Centre (UK)NCCLS National Committee for Clinical Laboratory StandardsNCE New Chemical Entity
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NCHGR National Center for Human Genome Research (NIH)NCHS National Center for Health Statistics (in CDC)NCI National Cancer Institute (NIH)NCPIE National Council on Patient Information and Education(Washington, DC)NCRP Northwest Clinical Research Professionals (Portland, OR)NCRR National Center for Research Resources (NIH)NCS Not clinically significantNCTR National Center for Toxicological ResearchNCVIA National Childhood Vaccine Injury Act (1986)NDA New Drug Application (FDA)NDE New Drug EvaluationNDS New Drug Study (Canada's new drug application)NEFARMA Dutch Association of the Innovative Pharmaceutical IndustryNEI National Eye Institute (NIH)NEJM New England Journal of MedicineNF National FormularyNHLBI National Heart, Lung, and Blood Institute (NIH)NHS National Health Service (UK)NHW National Health and Welfare Department (Canada's equivalent of DHHS)NIA National Institute on Aging (NIH)NIAAA National Institute on Alcohol Abuse and Alcoholism (NIH)NIAID National Institute of Allergies and Infectious Diseases (NIH)NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH)NIAMSD National Institute of Arthritis and Musculoskeletal and Skin DiseasesNICHD National Institute of Child Health and Human Development (NIH)NIDA National Institute on Drug Abuse (NIH)NIDCD National Institute on Deafness and Other Communication Disorders (NIH)NIDDKD National Institute of Diabetes and Digestive and Kidney DiseasesNIDR National Institute of Dental Research (NIH)NIEHS National Institute of Environmental Health Sciences (NIH)NIGMS National Institute of General Medical Sciences (NIH)NIH National Institutes of Health (DHHS)NIMH National Institute of Mental Health (NIH)
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NINDSNational Institute of Neurological Disorders & Stroke (NIH)NINR National Institute of Nursing Research (NIH)NLEA Nutrition Labeling and Education Act (1990)NLM National Library of Medicine (NIH)NME New Molecular EntityNMR Nuclear magnetic resonanceNOEL No observed effect levelNon-Mem
Non-linear Mixed Effect Model
NR No Reply Necessary (COMIS term)NRB Noninstitutional Review Board, also known as an Independent Review Board. See
also EAB, IEC, IRB -NRC National Research CouncilNRC Nuclear Regulatory CommissionNSAIDNonsteroidal anti-inflammatory drugNSF National Science FoundationNSR Nonsignificant riskNTP National Toxicology ProgramOAI Official Action Indicated (serious FDA postinspection classification)OAM Office of Alternative Medicine (NIH)OASH Office of the Assistant Secretary for HealthOB-GYN
Obstetrics and Gynecology
OC Office of the CommissionerOC Office of Compliance (CDER)OCD Office of the Center Director (CDER)OCPB Office of Clinical Pharmacology and Biopharmaceutics (CDER)OCR Optical Character RecognitionOD Right eyeODB Observational DatabaseODE Office of Drug Evaluation (CDER now has five such offices: ODE I, II, III, IV, and
V)-OEA Office of External AffairsOEB Office of Epidemiology and Biostatistics (CDER)OECD Organization for Economic Cooperation and DevelopmentOGC Office of the General CounselOGD Office of Generic Drugs (CDER, formerly DGB)OGE Office of Government Ethics (formerly part of Office of Personnel Management,
separate executive branch in 1989)OHA Office of Health AffairsOHRMOffice of Human Resource Management
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OJC Office Journal of the EU-C Series (Information)OJL Office Journal of the EU-L Series (Legislation)OLA Office of Legislative AffairsOM Office of Management (CDER)OMB Office of Management and Budget (USA)ONDC Office of New Drug Chemistry (CDER)OP Open (COMIS term)OP Office of PolicyOPA Office of Public AffairsOPD Orphan Products Division DirectorateOPM Office of Personnel ManagementOPRR Office of Protection from Research Risks (NIH)OPS Office of Pharmaceutical Science (CDER)ORA Office of Regulatory AffairsORM Office of Review Management (CDER)ORO Office of Regional OperationsOS Left eyeOSHA Occupational Safety and Health Administration (USA)OTA Office of Technology Assessment (USA; abolished by Congress, Fall 1995)OTC Over-the-Counter (refers to nonprescription drugs)OTCOM Office of Training and Communications (CDER)OTR Office of Testing and Research (CDER)OU Both eyesP PriorityPAHO Pan American Health OrganizationPAI Preapproval inspectionPAITS Pre-Approval Inspection Tracking SystemPAR Postapproval researchPC Personal computerPC Protocol Amendment-Change (COMIS term)PCC Parklawn Computer CenterPCC Poison Control CenterPCP Pneumocystis carinii pneumoniaPD Position descriptionPD PharmacodynamicsPDA Parenteral Drug AssociationPDQ Physicians' Data Query (NCI-sponsored cancer trial registry)PDR Physicians' Desk ReferencePDUFA Prescription Drug User Fee Act (of 1992, USA)PEM Prescription Event Monitoring
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PEP Performance Evaluation PlanPERI Pharmaceutical Education & Research Institute, division of PhRMAPET Positron emission tomographyPFT Pulmonary function testsPhRMA Pharmaceutical Research and Manufacturers of America(previously PMA)PHS Public Health Service (USA)PI Package insert (approved product labeling)PI Principal InvestigatorPI Protocol Amendment-New Investigator (COMIS term)PK PharmacokineticsPLA Product License Application (biologics) (UK)PLA/ELAProduct License Application/Establishment License ApplicationPM Project ManagerPMA Pre-Market Approval Application (FDA); Pharmaceutical Manufacturers
Association (now PhRMA) (equivalent to NDA for Class III Devices)PMCC Project Management Coordinating Committee (CDER)PMDIT Project managementPMS Postmarketing surveillancePN Protocol AmendmentNew Protocol (or Pending Review) (COMIS term)PO Per os (by mouth)PPA Poison Prevention ActPPI Patient package insertPPM Physician Practice Management OrganizationsPPO Preferred Provider Organization; Policy and Procedure OrderPR Pulse ratePR Public relationsPRIM&RPublic Responsibility in Medicine and Research (Boston, MA)PRN As neededPROG Peer-Review Oversight Group (NIH)PSUR Periodic Safety Update ReportsPTCC Pharmacology/Toxicology Coordinating Committee (CDER)PUD Peptic ulcer diseaseQA Quality assuranceQAU Quality Assurance Unit
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QC Quality controlQD Once dailyQID Four times a dayQL Quality of lifeQNS Quantity not sufficientQOD Every other dayQOL Quality of lifeQSAR Quantitative SARR&D Research and developmentR&TD Research and technological developmentRAC Reviewer Affairs Committee (CDER)RADARRisk Assessment of DrugsAnalysis and ResponseRAPS Regulatory Affairs Professional's SocietyRCC Research Coordinating Committee (CDER)RCH Remove Clinical HoldRCT Randomized clinical trialsRD Response to Request for Information (COMIS term)RDE Remote data entryRDRC Radioactive Drug Research CommitteeRDT Rising-dose toleranceRFA Request for approvalRIF Reduction in forceRKI Robert-Koch-Institut, Bundesinstitut für Infektionskrankheiten und nich-über
tragbare Krankheiten (Federal Institute for Infectious and Non-communicableDiseases, Germany)
RL Regulatory Letter (FDA postaudit letter)RMO Regulatory Management OfficerRTF Decision by the FDA to refuse to file an applicationRTF Refuse to FileRUG Resource Utilization GroupRx PrescriptionS StandardSAE Serious adverse eventSAL Sterility assurance levelSAR Structure-activity RelationshipSBA Summary Basis of ApprovalSBIR Small Business Innovative Research Program (USA)SC SubcutaneousSC Study coordinator. See also CCRC, CRCSCSO Supervisory Consumer Safety OfficerSCT Society for Clinical Trials
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SD Standard deviationSDAT Senile dementia of the Alzheimer's typeSE Standard errorSEA Single European Act of 1987SEER Surveillance, Epidemiology, and End Results (Registry of NCI)SES Senior Executive ServiceSIDA Spanish (síndrome inmunodeficiencia adquirida), Italian, and French acronym for
AIDS. See AIDSSMART Submission Management and Review Tracking (FDA)SMDA Safe Medical Devices Act (1990)SME Significant medical eventSMO Site Management OrganizationSmPC Summary of Product CharacteristicsSNDA Supplemental New Drug ApplicationSNIP Syndicat National de l'Industrie Pharmaceutique (France)SoCRA Society of Clinical Research AssociatesSOMD Safety of Medicines Department (UK)SOP Standard operating procedureSPM Society of Pharmaceutical MedicineSQ SubcutaneousSRS Spontaneous Reporting SystemSSCT Swedish Society for Clinical TrialsSSFA Società di Scienze Farmacologiche Applicate (Italy)SSM Skin surface microscopySTD Sexually transmitted diseaseSTT Short-term testsSUD Sudden unexpected deathSUPAC Scale up and post approval changesSVP Small volume parenteralsSX SymptomsTB TuberculosisTGA Thermographic AnalysisTID Three times a dayTIND Treatment IND. See also INDTK ToxicokineticsTMO Trial Management OrganizationTOP TopicalTSH Thyroid stimulating hormoneUA UrinalysisUKCCRUK Coordinating Committee on Cancer Research
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UNESCO United Nations Educational Science and Cultural OrganizationUSAN US Adopted Names CouncilUSC United States Code (book of laws)USCA U.S. Code AnnotatedUSDA United States Department of AgricultureUSP United States PharmacopeiaUSPC U.S. Pharmacopeial ConventionUSP-DI United States PharmacopeiaDrug InformationUSP-NF United States PharmacopeiaNational FormularyUSUHS Uniformed Services University of the Health SciencesVA Veterans Administration (officially, United States Department of Veterans Affairs)VAERS Vaccine Adverse Event Reporting SystemVAI Voluntary Action Indicated (FDA postaudit inspection classification)WD Withdrawn (COMIS term)WHO World Health Organization (also used to refer to WHO glossary for coding AEs)WHOARTWorld Health Organization Adverse Reaction TerminologyWI Inactive (COMIS term)WL Warning Letter (most serious FDA postaudit letter, demands immediate action
within 15 days)WNL Within normal limitsWRAIR Walter Reed Army Institute of Research (DoD)WTO World Trade Organization
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Page 465
Index
A
Abbreviated New Drug Application (ANDA), 150, 214
Chemistry, Manufacturing and Controls Section, 189, 194-214
DESI Review, 376
drug product requirements, 215
drug substance sources, 214
expiration dates, 216
guidelines, 150
specifications, 215
summary, 214
Addenda, 244
Absorption, Distribution, Metabolism Excretion Studies (ADMEs), 113, 124, 127
Acute toxicology studies, 31
Adverse Drug Reactions/Events, (ADRs) (ADEs), 118, 247-270, 434
ADRs vs. ADEs, 262
alert reports, 265
assessment of, 266
classification of, 248
collection of ADRs, 260, 261
dose-dependent, 248
in fetus, 48
in geriatrics, 252
liver disease, 254
in pediatrics, 252
in pregnant women, 249
renal disease, 254
drug interactions, 256
beneficial effects, 259
mechanisms, 256
pharmacokinetic pathways, 257
evaluation of ADRs, 260, 309
patient information, 262
post-marketing ADEs, 261, 265
reporting of ADEs, 239, 260, 262, 434
unexpected AEs, 265
Advisory committee meetings, 407
Amendments, 81, 185, 243
American Medical Centers (AMCs), 461
Analytical data for NDA, 147, 201, 204, 206
Animal pharmacokinetics, 29
Animal studies, 17-54
Annual reports, 83
Antibiotics, 198
Antibiotic applications, 104
B
Benefit-to-risk ratio (B/R), 118
integrated summary B/R, 141
Bioanalytical chemistry, 35
Bioanalytical method, 25
Bioavailability studies, 35, 114, 124, 178
Biologic License Application (BLAs), 157-187
amendments, 185
application, 163-167
assembling BLA, 186
contents, 160-185
history, 158
introduction, 157, 159
nonclinical pharmacology, 177
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[Biologic Licence Application (BLAs)]
supplements, 185
toxicology, 118
Biostatistics, 287-310
Blinding techniques, 223-225
placebo, 298
C
Carcinogenicity studies, 50, 121
Case report forms, 148, 236, 238
in BLAs, 182
content, 236
design, 432
NDA submission of, 149
tabulations of, 148
Center for Drug Evaluation and Research Organization (CDER), 396
consumer, industry inquiries, 400, 401
other information, 400
Chemistry, Manufacturing, and Controls (CMC), 189-218, 194
drug product, 193, 203-211, 215
drug substance, 191, 194-203
for INDs, 61
methods validation package, 212
samples, 211
Clinical chemistry, 43
Clinical data analysis, 306
Clinical drug development, 14
Clinical holds, 84
Clinical pharmacology, 132
Clinical research
management, 289, 311-323
closure, 321
initiation, 316
monitoring, 320
prestudy, 313
orphan drugs, 369
phases of clinical research, 59
phase 1, 7, 59, 60, 61, 221, 291
phase 2, 7, 67, 221
phase 3, 7, 67, 221
phase 3b, 221
phase 4, 221
protocols (see Protocol design), 219-246, 292, 296
rare diseases, 362
Clinical Research Associate (CRA) (see also Monitor), 242, 320
Closure visit, 321
Code of Federal Regulations, 55, 94, 103, 104, 150, 194, 271, 312, 325, 345
Computer Assisted New Drug Applications (CANDAs), 436
Computers in New Drug Development, 423
automatic data collection, 433
extranets, 427
groupwork, 425
hardware, 429
internet, 426, 427
networking, 424
security, quality assurance, 429
software, 430
trials management, 436
Concomitant medication, 235
Contract Research Organizations (CROs), 439
clinical, 448
monitoring, 445
nonclinical, 440
selection of CROs, 440, 449
working relationships, 452
Controlled studies, 116, 128, 132, 222
Crossover studies, 225
D
Data collection, 433
Data entry, 432
Data flow, 323
Data management in clinical research, 289
Data presentations for FDA submissions, 415
tabular presentation, 419
text exposition, 418
Data sets, 144
Drug Efficacy Study Implementation (DESI), 376
Document management, 435
Dose range studies, 32Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page 467
Dose tolerability studies, 32
Double blind studies, 222
Drug abuse and overdose information, 140
Drug development assessment, 23, 33
Drug development teams, 1-9, 290
clinical, 6
preclinical, 4
project, 2, 8
Drug discovery and development, 10-16
logic plan, 8
Drug interactions, 140, 256
Drug metabolism, 30, 36, 46
Drug product labeling, 56, 147, 234
E
Efficacy results, 144, 307
Emergency use/investigational products, 282
Environmental assessment, 79, 211
Establishment License Applications (ELAs), 157
Evaluation Procedures (CRFs), 236
laboratory assessments, 238
objective, subjective, 238
F
FDA
accelerated reviews, 409
adverse reaction reporting, 239, 260, 262, 434
approval process, 408
contacts, 399
drug approval, 408
forms
356(h), 163, 166
1571, 68, 69-71
1572, 74, 75
guidelines, 291
industry liaison, 393-395
inquiries, 393
inspections
GMP, 335
PAI, 335-348
liaison with industry, 400, 401
meetings, 401, 406
orphan drugs, 367, 372
phase 2 conference, 403-406
pre IND meetings, 401
pre NDA meetings, 406
statistical statement, 301
submissions to, 415
tabular presentation, 419
text exposition, 416
Final study reports, 307
Formulation analyses, 41
Freedom of Information (FOI), 410-413
act, 411
fees, 412
public information, 410
requests, 412
G
Genotoxicity, 39
Good Clinical Practices (GCPs), 325-334
investigator obligations, 326, 328
monitor obligations, 330
sponsor obligations, 329-330
Good Laboratory Practices (GLPs), 34
H
Hematology, 43
Histopathology, 43
Historical controls study design, 129, 135
Human pharmacokinetics, 178
Human rights, 241
I
ICH guidelines, 32, 39, 42, 45, 50, 51
Immunogenicity, 44
Independent ethics committee, 271
Industry and FDA liaison, 393
Informed consent, 241, 271, 278
audits/inspections, 285-286
elements of, 279
emergency use, 283
forms, 278
oral consent, 282
regulatory requirements, 284
Initiation visit, 316
investigator qualifications, 322
investigator obligations, 326, 328
Inspections, 285, 394Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page 468
Institutional Review Board (IRB), 240, 271-278, 328
advertising, 276
auditing, 285
continuing review, 277
document approval, 277
documentation, 274
expedited reviews, 278
membership, 273
operations, 274
required information, 275
responsibilities, 273
Integrated clinical/statistical report, 142
Integrated summary of efficacy, 130, 136
Integrated summary of safety, 130, 137
Interim analyses, 305, 309
Internet, 426, 437
Investigational New Drug Application (IND), 6, 55-85
annual reports, 83
background history and information 55-58
clinical research, 59
clinical holds, 84
content and format, 72
exemptions, 56
format, 58
labeling, 56
pre IND meeting, 401
safety reports, 82
statistics, 291
treatment IND, 409
waivers, 57
withdrawals, 84
Investigational drugs, 232
Investigator brochure, 85-91
contents, 87
Investigator disqualification, 322
Investigator meetings, 315
Investigators obligations, 131, 243, 326
Investigator selection, 312
Investigator's site, 319
K
Kefauver-Harris amendments, 376
L
Labeling
IND, 56
NDA, 147
study drugs, 234
Laboratory assessments, 238
Literature review, 296
M
Manufacturing and control requirements (NDAs and ANDAs), 15, 189-218
ANDAs, 214
antibiotics and fermented products, 198
chemistry, 194-198
container/closure systems, 192, 193, 203, 208
dosage forms/composition, 193, 204
drug product, 193-194, 203-211, 215
drug substance, 194, 197, 199, 214
environmental impact analysis, 211
expiration dates, 209, 216
method of manufacturing, 192, 193, 196, 205
methods validation data, 212-214
NDA summary, 191, 192
process control, 199
reference standard, 200, 202
samples, 211
specifications and analytical methods, 192, 193, 201, 204, 215
stability, 191, 193, 195, 209
test formulations, 194
Metabolism, 30
Microbiology, 125
Mock inspections, 338
Monitor obligations, 330
Monitoring, 242, 320-321
clinical research organization (CRO) monitoring, 445
clinical study execution, 304, 445
Mutagenicity studies, 124
N
National Academy of Sciences/National Research Council (NAS/NRC), 376Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page 469
New Drug Application (NDAs), 103-155
amendment, 107
annotated package insert, 109
application content, 108, 109
application format, 104
archival copy, 104
review copy, 105
approval times, 101
assembling and submitting, 104-108
chemistry, manufacturing and controls (CMC), 110-112, 119
clinical data, 115, 127
clinical study overview, 116
contents and format, 95, 103
controlled clinical studies, 116
general considerations, 93
human pharmakinetics & bioavailability, 114
methods validation, 147
microbiology, 115, 125
NDA review copy, 149
NDA review guide, 151
NDA summary format and content, 109, 191
nonclinical pharmacology and toxicology, 27, 112, 119, 132
other studies, 117
pharmacologic class, 110
post-marketing reports, 107
pre NDA meetings, 406
regulations, 94
review process, 98
safety summary, 117
samples, 147
sections of an NDA, 95
statistical analysis, 115
supplements, 107
technical sections, 119-149
acute toxicology, 121
ADME, 124
bioavailability, 124
clinical data, 127-136
controlled studies, 132
uncontrolled studies, 135
human pharmacokinetics, 124
carcinogenicity, 121
mutagenicity, 124
pharmacology, 121
reproduction, 123
uncontrolled clinical studies, 117
Nonclinical drug development, 13, 17-53
acute toxicology studies, 31, 38
background and history, 17, 19
bioanalytical methods, 25, 35
bioavailability, 35
drug candidate selections, 33
early nonclinical formulation, 27
pharmacology, 20, 119, 177
preliminary animal pharmacokinetics, 29, 35
preliminary drug metabolism, 30, 36
preliminary evaluations, 25
toxicology, 119, 177
O
Obligations of
investigator, 326
monitor, 330
sponsor, 329, 330
Orphan Drug Act, 361
Orphan drugs, 361-374
clinical studies, 369
FDA review, 372
product designation, 365
rare diseases, conditions, 362
requests, 367
submission requirements, 372
scientific/technical review, 371
OTC drugs, 375-391
advisory panel, 377
background, 375
clinical development, 375
FDA review, phases 1-3, 378-379
''Max the Molecule", 385
monograph
active ingredients, 379
provisions, 379
labeling, 380
testing, 382
nonmonograph, 382Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation
Page 470
[OTC drugs]
switches, 383
aging population, 387
impact on industry, 388
reimbursement, 389
Rx to OTC trends, 383-391
publication, 379
P
Parallel studies, 225, 300
Pharmacokinetics, 45, 114, 124, 257
Pharmacokinetic experiments, 35
in animals, 29
Pharmacology studies, 25, 121
Phase 2 conference, preparation, summary, 403-406
Phases of clinical research, 59, 61, 67, 221
phase 1, 60
phase 2, 67
phase 3, 67
phase 3b, 221
phase 4, 221
Placebo, 298
Post-marketing studies, 118
Pre-Approval Inspection (PAI). 335-348
audit strategy, 338
general inspection coverage, 337
mock PAIs, 338-347
post PAIs, 347
withholding approval, 338
Preclinical drug development, 12, 34
Pre IND meetings, 401
Pre NDA meetings, 406
Pre-study Investigational site Visit (PSIV), 313
Product License Application (PLA), 157
Product safety, 395
Protocol design (see also Clinical phases), 61, 219-246, 300
amendments, 81
blinding techniques, 223
controlled studies, 222
crossover studies, 225
elements of, 226
general considerations, 221
investigational drugs, 232
materials and methods, 230
open studies, 364
parallel studies, 225
statistical section, 292
study objective, 220, 228
uncontrolled studies, 225
Q
Quality Assurance (QA), 349-360
departments, 350
corporate structure, outcomes, 350-353
operations, 352
early phase QA, 1-3 353-357
endnotes, 358
Pre-Approval Inspection (PAI), 345
R
Randomization, 299
Reproductive studies, 123
Reproductive toxicology, 48
segment I-fertility, 48
segment II-teratology, 49
segment III-perinatal and postnatal development, 49
Research evaluation (see Nonclinical drug development), 17-53
Review copy of NDA, 149
Risk vs. benefit, 118, 229
S
Sample size, 297
Safety considerations (see also Adverse reactions)
alert reports, 265
pharmacology, 39
reports, 82
results, 145
updates, 141, 181, 308
Significant difference, 297
Site Management Organization (SMOs), 455-463
corporate model, 458
hybrid model, 460
loose affliliation model, 460
physician model, 459
Sponsor obligations, 329
Stability, 195, 209Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation