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title: author: publisher: isbn10 | asin: print isbn13: ebook isbn13: language: subject publication date: lcc: ddc: subject:

New Drug Approval Process

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DRUGS AND THE PHARMACEUTICAL SCIENCES Executive Editor James Swarbrick AAI, Inc. Wilmington, North Carolina Advisory Board Larry L. Augsburger University of Maryland Baltimore, Maryland Douwe D. Breimer Gorlaeus Laboratories Leiden, The Netherlands Trevor M. Jones The Association of the British Pharmaceutical Industry London, United Kingdom Hans E. Junginger Leiden/Amsterdam Center for Drug Research Leiden, The Netherlands Vincent H. L. Lee University of Southern California Los Angeles, California David E. Nichols Purdue University West Lafayette, Indiana Stephen G. Schulman University of Florida Gainesville, Florida Jerome P. Skelly Copley Pharmaceutical, Inc. Canton, Massachusetts Felix Theeuwes Alza Corporation Palo Alto, California Geoffrey T. Tucker University of Sheffield Royal Hallamshire Hospital Sheffield, United Kingdom

Peter G. Welling Institut de Recherche Jouveinal Fresnes, France Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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. Nash Start 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 George B. 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, edited by 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 and Francis 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 Hadgraft and 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 and Christopher 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, edited by 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 and Robert 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 Jrg 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 Gran Alderborn and Christer Nystrm 72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher 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 Montagne Start 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 and Howard Bernstein 78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and 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, edited by 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 and W. 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 and Expanded, edited by Robert L. Bronaugh and Howard I. Maibach Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development, edited by Edith Mathiowitz, 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 Elizabeth M. 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. Dressman Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page i

New Drug Approval Process

Third Edition The Global Challenge
edited by Richard A. Guarino, M.D. Oxford Pharmaceutical Resources, Inc. Totowa, New Jersey

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The first and second editions were published as New Drug Approval Process (1987) and New Drug Approval Process: Second Edition, Revised and Expanded (1992). ISBN: 0-8247-0308-1 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. 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 or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, 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 AMERICA Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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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 the time of the Kefauver Amendments in 1962. Regulations now demand that both safety and efficacy be evident before products can be marketed with FDA's stamp of approval. The mechanics involved in the drug approval process have had a tremendous impact on how new products are developed globally. Good Clinical Practices and ICH guidelines must be followed meticulously for FDA and other worldwide regulatory agencies to allow pharmaceutical products to be marketed bearing labels that show safety as well as efficacy. As we forge into the 21st 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 in bringing these products to market. New Drug Approval Process, Third Edition addresses all the latest information and methodologies on the mechanics of preparing INDs and NDAs. New ways to expedite this process are detailed. The organization of this edition is very different from that of previous editions. The text is now divided into sections, each representing an essential step in the new drug development process. Our intention is to help readers identify and answer 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 to bring pharmaceutical products to market. The selection of authors to address the drug development process was based on their ability to present factual data in a manner that the reader can readily comprehend. In Part I, Regulatory Aspects of New Drug Development, the authors mesh their years of experience in IND and NDA development. The essential aspects of the nonclinical and clinical development of products are carefully considered along with the regulatory requirements necessary for regulatory agencies' approval. Having dealt with these regulations for many years, the authors 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 to biotechnology, manufacturing, and control requirements for NDAs and ANDAs. Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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Part II, Clinical Research Development, and Part III, Good Clinical Practices, detail the necessary steps in the clinical development process. The authors help the reader clearly understand and absorb the regulatory requirements. Special attention is given to IRBs, informed consents, ADR handling and reporting, and program management. Also, GCP regulations of the investigator, sponsor, and monitor obligations are approached practically and applied to clinical research. A discusion of the importance of quality assurance and its growing role 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 success getting FDA approval for products in these areas. The development of orphan drugs through biotechnology is addressed. It is inevitable that more products will undergo an Rx to OTC switch because of the changes occurring in medical care and costs globally. The last topics in Part V, Effective Methodology in Expediting NDA Approval, present all new information not referred to in earlier editions. The changes that have occurred throughout the pharmaceutical industry in new drug development processes have added a new dimension to the marketing process. FDA liaison and data presentation for FDA submissions have given new challenges to industries developing new drug, device, and biological applications. The evolving CRO and SMO companies, as well as the ''computer world haven," have influenced new product development. Again, authors of these chapters have combined information with insight on the 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 this third edition of New Drug Approval Process. Special thanks go to Patricia Blaine, Lisa Butkowski, Sharon Mirowsky, 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 care industry. Bureaucratic agencies throughout the world are becoming more homogeneous and resourceful in their ways of accepting and approving new products that will benefit patients suffering from diseases. The increasing demands by consumers for nonprescription drugs, as a result of the rapidly changing health care programs, will stimulate 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 changing health care market. Mergers, acquisitions, and licensing all play an important role in what and how products will come to market in the next 10 to 15 years. In many instances, decisions regarding these new products will be based on economics and social demands rather than on scientific discovery. The research into new product development has made a 180-degree turn. Companies are decreasing their internal drug development staffs and are outsourcing a large part of research and development responsibilities to CROs. As a result, both CROs and SMOs have boomed in the last 10 years and have put new demands on pharmaceutical companies' management teams. 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 their new products. Regulatory requirements throughout the world continue to include stringent regulations to confirm safety and efficacy of drugs, biologics, and devices. The FDA and similar agencies in Europe are collaborating to bring these regulations to a global acceptance through the International Committee on Harmonization. It is hoped that these efforts will allow companies to achieve global approval of new products. At present, in the United States, the FDA approves INDs that contain sufficient information about the investigational drug to show that it is safe for human testing. NDAs are approved only if the applicant demonstrates through adequate scientific evidence that the drug is safe and by substantial evidence Start 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 proposed labeling. The content of the FDA/ICH regulations define substantial evidence of effectiveness and safety as that which is demonstrated by adequate and well-controlled clinical investigations. Additionally, to obtain FDA approval, an applicant must show that the methods used in manufacturing and control, processing, and packaging of 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 a new 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, subjects enrolled 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 have put 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 in new drug development. Also, the aura of the changing industry will be reflected throughout the book with the intention of recasting traditional methodologies as a basis for successful implementation of current and future new product development. RICHARD A. GUARINO, M.D. Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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Contents
Preface Introduction Contributors Acronyms and Initialisms Part I. Regulatory Aspects of New Drug Development 1. Drug Development Teams Duane B. Lakings 2. Nonclinical Drug Development: Pharmacology, Drug Metabolism, and Toxicology Duane B. Lakings 3. The Investigational New Drug Application and the Investigator's Brochure William M. Troetel 4. General Considerations of the NDA Martha R. Charney 5. Specific Requirements, Content, and Format of an NDA Richard A. Guarino and Patricia Blaine 6. The Biologic License Application (BLA) Albert A. Ghignone and Douglas Testa 7. Chemistry, Manufacturing and Control Requirements of the NDA, and ANDA Ivy Bautista Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation 1 17 55 93 103 157 189 v vii xiii xv

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Part II. Clinical Research Development 8. Clinical Research Protocols Richard A. Guarino 9. Adverse Reactions and Interactions of Drugs Richard A. Guarino 10. Institutional Review Board/Independent Ethics Committee and Informed Consent: Protecting Subjects Throughout the Clinical Research Process Rochelle L. Goodson 11. Statistical and Data Management: Collaboration in Clinical Research Laurent M. Kassalow 12. The Management of Clinical Studies Ileana Maria Alexander Part III. Good Clinical Practices 13. Obligations of the Investigator, Sponsor, and Monitor Richard A. Guarino 14. Preparing for FDA Inspections: Manufacturing Sites Timothy Urschel 15. Quality Assurance Earl W. Hulihan Part IV. The Orphan Drug and the Rx to OTC Swith 16. Orphan Drugs John T. Zenno 17. Clinical Development, Regulations, and Trends for OTC Drugs William E. Gilbertson and Steven A. Francesco Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation 361 375 325 335 349 219 247 271

289 311

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Part V. Effective Methodology in Expediting NDA Approval 18. Industry and FDA Liaison William M. Troetel 19. Data Presentation for FDA Submissions: Text and Tabular Exposition Patricia Blaine 20. The Computer World in New Drug Development Chris Clauss 21. Working with a CRO Duane B. Lakings and Alexandra D. J. Mancini 22. The Evolving SMO in the United States Kenneth A. Getz Index Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation 393 415 423 439 455 465

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Contributors
Ileana Maria Alexander, R.N. Department of Medical Affairs, Warner-Lambert Consumer Healthcare, Morris Plains, 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., Scotch Plains, New Jersey Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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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., West Vancouver, 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 Jersey Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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Acronyms and Initialisms

The Medical Communications Department of Oxford Pharmaceutical Resources, Inc. has been collecting acronyms and initialisms throughout the professional careers of its individual members. We have obtained about 600 items through workshops, conventions, professional publications, and the other chapters in this book. The author of two of the chapters in this book, William M. Troetel, Ph.D., graciously allowed us to merge a large list from 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 Science AABB American Association of Blood Banks AACR American Association for Cancer Research AADAAbbreviated Antibiotic Drug Application (FDA) (used primarily for generics) AAFP American Academy of Family Physicians AAI American Academy of Immunologists AAP American Association of Pathologists AAPP American Academy of Pharmaceutical Physicians AAPS American Association of Pharmaceutical Scientists ABPI Association of the British Pharmaceutical Industry ACCP American College of Clinical Pharmacology ACE Adverse Clinical Event ACIL American Council of Independent Laboratories ACP Associates of Clinical Pharmacology (USA), a group that certifies clinical research associates (CRAs) and clinical research coordinators (CRCs) ACPU Association of Clinical Pharmacology Units ACRA Associate Commissioner for Regulatory Affairs (FDA) ACRPIAssociation for Clinical Research in the Pharmaceutical Industry (UK) Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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ACS American Chemical Society ACT Applied Clinical Trials magazine ACTG AIDS Clinical Trials Group (NIAID) ACTU AIDS Clinical Trials Unit (NIH) AD Alzheimer's disease; antidepressant ADAMHAAlcohol, Drug Abuse, and Mental Health Administration (no longer exists) ADAS Alzheimer's Disease Assessment Scale ADAS Alzheimer's Disease Assessment Scale, Cognitive Subscale COG ADE Adverse Drug Experience/Effect/Event ADI Acceptable Daily Intake ADME Absorption, Distribution, Metabolism, Elimination ADP Automated Data Processing ADR Adverse Drug Reaction ADRS Adverse Drug Reporting System AE Adverse Event/Experience AE Approvable AED Antiepileptic Drug AEGIS ADROIT Electronically Generated Information Service AERS Adverse Event Reporting System (FDA) AESGP Association Europenne des Specialits Grand Public (European Proprietary Medicines Manufacturers Association) AFCR See AFMR AFDO Association of Food and Drug Officials AFMR 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 SIDA AIM Active Ingredient Manufacturer AIP Abbreviated Inspection Program AMA American Medical Association AMA-DE AMA Drug Evaluations AMC Academic Medical Centers AMF Administrative Management of the Files AmFAR American Foundation for AIDS Research AMG Arzneimittelgesetz (German Drug Law) AMI Acute myocardial infarction Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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ANADAAbbreviated New Animal Drug Application ANDA Abbreviated New Drug Application (for a generic drug) ANOVAAnalysis of variance AOAC Association of Official Analytical Chemist AOAC Association Pharmaceutique Belge (Belgium) AP Approved (COMIS term) APhA American Pharmaceutical Association APHIS Animal and Plant Health Inspection Service AQL Acceptable Quality Level ARC AIDSrelated complex ARDS Adult respiratory distress syndrome ARENA Applied Research Ethics National Association ASA American Statistical Association ASAP Administrative Systems Automation Project (FDA) ASCII American Standards Code for Information Interchange (computer files) ASCO American Society for Clinical Oncology ASCPT American Society for Clinical Pharmacology and Therapeutics ASM American Society for Microbiology ASQC American Society for Quality Control AT Active (COMIS term) ATF Bureau of Alcohol, Tobacco, and Firearms AUC Area under the curve (an expression of exposure) AZT Zidovudine (HIV treatment) BARQABritish Association of Research Quality Assurance BB Bureau of Biologics (now CBER) BCE Beneficial Clinical Event BEUC European Bureau of Consumer Unions BfArM Bundesinstitut fr Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical Devices, Germany) BGA Bundesinstitut fr gesundheitlichen Verbraucherschutz und Veterinrmedizinn (Federal Institute for Health Protection of Consumers and Veterinary Medicine, Germany) BGVV Bundesgesundheitsamt (former German public health agency) BID Two times per day BIND Biological Investigational New Drug BIO Biotechnology Industry Organization BIRA British Institute of Regulatory Affairs BLA Biologic License Application Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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BMB BMI BPAD BPI BPM BrAPP BRB BSA BVC C&S CA CA

Bioresearch Monitoring Branch Body mass index Bipolar affective disorder Bundesverband der Pharmazeutischen Industrie EV (Germany) Beats Per Minute British Association of Pharmaceutical Physicians Biomedical Research Branch Body surface area British Veterinary Codex Culture and Sensitivity Chemical Abstracts Competent Authority (regulatory body charged with monitoring compliance with European member state national statutes and regulations) CAC Carcinogenicity Assessment Committee CACE Committee for Advancement of Chemistry Education CAD Coronary artery disease CANDA Computer-Assisted New Drug Application. See NDA CAPLA Computer-Assisted Product License Application. See PLA CAPLARComputer-Assisted Product License Agreement Review (FDA) CAPRA Canadian Association of Pharmaceutical Regulatory Affairs CAS Chemical Abstracts Service CBC Complete blood count CBCTN Community Based Clinical Trials Network CBER Center for Biologics Evaluation and Research (FDA) CBF Cerebral blood flow CCASE Coordinating Committee for Advancement of Scientific Education CCC Compliance Coordinating Committee (CDER) CCD Canadian Drugs Directorate CCDS Company Core Data Sheets CCI Committee on Clinical Investigations. See also IRB CCRA Certified Clinical Research Associate. See also ACP CCRC Certified Clinical Research Coordinator. See also ACP CDC 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 Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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CE CEN CESS CFR

Mark signifying compliance with EU harmonized standards and directives Comit Europen de Normalisation (European Committee for Standardization) CDER Executive Secretariat Staff Code of Federal Regulations (usually cited by part and chapter, as 21 CFR 211) CFSAN Center of Food Safety and Applied Nutrition CGMP Current Good Manufacturing Practices CH Clinical Hold CHD Coronary heart disease CIB Clinical Investigator's Brochure CID CTFA Cosmetic Ingredient Dictionary CIOMS Council for International Organisations of Medical Sciences (postapproval international ADR reporting, UK) CIR Cosmetic Ingredient Review CIS Commonwealth of Independent States CLIA Clinical Laboratory Improvements Amendments CMC Chemistry, Manufacturing and Controls CMCCC Chemistry and Manufacturing Controls Coordinating Committee (CDER) CME Continuing medical education CNS Central nervous system COA Commissioned Officers Association COA Certificates of Analysis COE Code of Ethics COIMS Centerwide Oracle Management Information System(FDA) COMIS Center Office Management Information System COSTARTCoding Symbols for a Thesaurus of Adverse Reaction Terms CP Compliance Program CPMP Committee for Proprietary Medicinal Products (EU) CPSC Consumer Product Safety Commission (USA) CR Cross Reference (COMIS term) CRA Clinical Research Associate CRADA Cooperative Research and Development Agreement (with NIH) CRC Clinical Research Coordinator. See also CCRC CRF Case Report Form Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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CRO CS CS CSDD CSI CSM

Contract Research Organization. See also IPRO Civil Service Clinically significant Center for the Study of Drug Development Consumer Safety Inspector Commission for Safety of Medicines (UK Regulatory Agency) Committee on Safety of Medicines (UK) CSO Consumer Safety Officer (FDA)Project Manager CSR Clinical Study Report CCSI Company Core Safety Information CT Computerized tomography CT Clinical trial CTC Clinical Trial Certificate CTEP Clinical Therapeutics Evaluation Program (NCI) CTX Clinical Trial Exemption Certification (MCA) CV Curriculum vitae CVM Center for Veterinary Medicine (FDA) CXR Chest X-ray DAS Drug Abuse Staff DAWN Drug Abuse Warning Network DB Double-blind DD Department of Drugs (Swedish regulatory agency) ddC Dideoxycytidine, a cytidine nucleoside analog ddC Didanosine, a purine nucleoside analogue DDIR Division of Drug Information Resources DDMAC Division of Drug Marketing, Advertising, and Communications DEA Drug Enforcement Administration (USA) DEN Drug Experience Network DES Division of Epidemiology and Surveillance DESI 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 Association DISD Division of Information Systems Design DMF Drug Master File DoD Department of Defense (USA) DPC-PTR Drug Price Competition and Patent Term Restoration Act of 1984 (also known Act as Waxman-Hatch bill) Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxi

DRG DRG DSI DSM DSMB DSNP DUR EA EAB

Diagnosis Related Groups Division of Research Grants (NIH) Division of Scientific Investigations (FDA) Diagnostic and Statistical Manual (of the American Psychiatric Association) Data and Safety Monitoring Board Development of Standardized Nomenclature Project (FDA) Drug Utilization Review Environmental assessment Ethical Advisory Board (term used in some nations for groups similar to IRBs and IECs) EBSA European Biosafety Association EC European Commission (in documents older than the mid-1980s, EC may mean European Community) ECG Electrocardiogram ECJ European Court of Justice ECPHINEuropean Community Pharmaceutical Products Information Network ECU European Currency Unit ED Effective dose EEC European Economic Community (old term for EC, now EU) EEG Electroencephalogram EEO Equal Employment Opportunity EER Establishment Evaluation Request EFGCP European Forum on Good Clinical Practice (Evere, Belgium) EFPIA European Federation of Pharmaceutical Industries' Associations EFTA European Free Trade Association EIA Establishment Inspection Reports EIR Establishment Inspection Report (FDA) ELA Establishment License Application (biologics) EMEA European Medicines Evaluations Agency (UK) EMS Electronic Mail Service EO Executive Order EOP1 End-of-Phase 1 EOP2 End-of-Phase 2 EORTC European Organization for Research and Treatment of Cancer EOS End of Study EP European Parliament Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxii

EPA EPAR EPL EPMS EPO EPRG ER ESRA ESS ETT EU EUP FACA FPI

Environmental Protection Agency European Public Assessment Report Effective Patent Life Employee Performance Management System European Patent Office European Pharmacovigilance Research Group Essential Requirements (EU) European Society of Regulatory Affairs Executive Secretary and Staff Exercise tolerance test European Union Experimental Use Permit Federal Advisory Committee Act 1972 Fachgesellschaft der rzte in der Pharmazeutischen Industrie e.V. (German Association of Physicians in the Pharmaceutical Industry) FarmindustriaThe Association of the Italian Pharmaceutical Manufacturers FAX Facsimile FCC Federal Communications Commission FCCSET Federal Coordinating Council for Science, Engineering and Technology FD & C Act Federal Food, Drug and Cosmetic Act FD 1571 Form Used to Submit IND FD 1572 Statement of Investigator Form (accompanies IND) FD 1639 Form Used to Submit Drug Experience Report FD 2252 Form Used to Submit NDA Annual Report FD 2253 Form Used for Promotional Advertising or Labeling FD 356H Form Used to Submit NDA FD 483 Form Issued by FDA upon Adverse Findings of Inspection FDA Food and Drug Administration (USA) FDA-SRS Spontaneous Reporting System of the Food and Drug Administration FDLI Food and Drug Law Institute FFDCA Federal Food Drug & Cosmetic Act FFPM Fellow of the Faculty of Pharmaceutical Medicine (UK) FMD Field Management Directives FOI Freedom of Information FOIA Freedom of Information Act FONSI Finding of no significant impact FPIF The Finnish Pharmaceutical Industry Association FPL Final Printed Labeling Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxiii

FR Federal Register FRC 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 school FSIS Food Safety and Inspection Service FTC Federal Trade Commission (USA) FUR Follow-Up Request GAO General Accounting Office (US government) GATT General Agreement of Tariffs and Trade GC General Counsel (FDA) GC Gas chromatography GCP Good Clinical Practice GI Gastrointestinal GLP Good Laboratory Practice GMP Good Manufacturing Practice GP General practitioner GPRA Government Performance and Results Act GRAS Generally Recognized as Safe GRASE Generally Recognized as Safe and Effective GRP Good Review Practice HAACPHazard Analysis and Critical Control Point (inspection technique) HAI Health Action International HCFA Health Care Financing Administration (HHS) HF Routing code for mail to the Office of the Commissioner of the FDA HFD Routing code for mail to CDER HFM Routing code for mail to CBER HFS Routing code for mail to CFSAN HFT Routing code for mail to NCTR HFV Routing code for mail to CVM HFZ Routing code for mail to CDRH HHS Department of Health and Human Services (USA, also called DHHS) HIMA Health Industry Manufacturer's Association (devices) HIS Indian Health Service HIV Human immunodeficiency virus HIV+ HIV-positive; HIV-infected HIV-1 Human immunodeficiency virus Type 1 HMO Health Maintenance Organization HPB Health Protection Branch (Canada's equivalent of the FDA) Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxiv

HPLC HRG HRRC HRSA HX I.V. IACUC IARC IC IC ICD ICH

High pressure liquid chromatography Health Research Group Human Research Review committee Health Resources and Services Administration History Intravenous Institutional Animal care and Use Committee International Agency for Research on Cancer Informed consent Chemistry Information Amendment (COMIS) term Informed Consent Document International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICPEMCInternational commission for Protection Against Mutagens and carcinogens ICTH International Committee on Thrombosis and Hemostases IDB Investigational Drug Brochure IDE Investigational Device Exemption (FDA) IDR Idiosyncratic Drug Reaction IDSMB Independent Data Safety Monitoring Board IEC Independent Ethics committee. see also EAB, IRB, NRB IFPMA International federation of Pharmaceutical Manufacturers' Associations IG Office of the Inspector General IKS Interkantonale Kontrollstelle fr Heilmittel (Switzerland) IM Clinical Information Amendment (COMIS term) IM Intramuscular INAD Investigational New Animal Drug IND Investigational New drug application (FDA). see also TIND INDA Investigational New Drug Application INDC Investigational New Drug Committee INN International Nonproprietary Name IOM Institute of Medicine (national Academy of Science, USA) IPCS International Program for Chemical Safety IPRA International Product Registration document IPRO Independent Pharmaceutical Research Organization. see also CRO IRB Institutional Review Board, sometimes Independent Review Board. see also IEC, EAB, NRB IRC Institutes Review Committee Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxv

IRD International Registration Document IRG Initial Review Groups IRS Identical, related, or similar IS Information systems ISCB International Society for Clinical Biostatistics ISO International Organisation for Standardisation ISPE International Society for Pharmacoepidemiology IT Toxicology Information Amendment (COMIS term) IT Information technology ITCC Information Technology Coordinating Committee (CDER) IV Interview IVD In vitro device; in vitro diagnostics IVF In vitro fertilization IVF/ET In vitro fertilization/embryo transfer JCAH Joint Commission for the Accreditation of Hospitals JCAHOJoint Commission of Accreditation of Health Care Organizations JCPT Journal of Clinical Pharmacology and Therapeutics JCRDDJournal of Clinical Research and Drug Development JCRP Journal of Clinical Research and Pharmacoepidemiology JPMA Japan Pharmaceutical Manufacturers' Association KS Kaposi's Sarcoma L & D Labor and delivery LAN Local Area Network LD Lethal dose LD50 Lethal dose (50%) LEAA Law Enforcement Assistance Administration LERN Library Electronic Reference Network LIF Swedish Pharmaceutical Industry Association LKP Leiter der klinischen Prfungunder the German Drug Law, the physician who is head of clinical testing LNC Labeling and Nomenclature Committee LOA Letter of Agreement LOC Level of Concern LOCF Last observation carried forward LOD Loss on drying LRC Lipid research clinic LRI Lower respiratory infection LTE Less than effective LVP Large volume parenterals MA Marketing Authorization MAA Marketing Authorization Application (EC) Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxvi

MAH Marketing Authorization Holders MAPP Manual of Policy and Procedures MBC Minimum bactericidal concentration MCA Medicines Control Agency (UK) MDA Medical Devices Agency (UK) MDD Medical Device Directives (EU) MDI Metered-dose inhaler; manic-depressive illness MDR Medical Device Reporting MDV Medical Device Vigilance MECU Million ECU MEDDRA Medical Dictionary for Drug Regulatory Affairs MEDLARS Medical Literature Analysis and Retrieval System MEDWATCHMedWatch Adverse Event Reporting System MEFA Association of the Danish Pharmaceutical Industry MEMO Medicines Evaluation and Monitoring Organisation MEP Member of the European Parliament MHW Ministry of Health and Welfare (Koseisho, Japan's drug regulatory agency) MI Myocardial infarction MIC Minimum Inhibitory Concentration MOU Memorandum of Understanding (between FDA and a regulatory agency in another country) that allows mutual recognition of inspections MPCC Medical Policy Coordinating Committee (CDER) MRA Medical Research Associate MRI Magnetic resonance imaging MTD Maximum tolerated dose NA Not approvable NABR National Association for Biomedical Research NADA New Animal Drug Application NAF Notice of Adverse Findings (FDA postaudit letter) NAFTA North American Free Trade Agreement NAHC National Advisory Health Council NAI No Action Indicated (most favorable FDA postinspection classification) NAS National Academy of Sciences NAS New Active Substance NAS-NRC National Academy of SciencesNational Research Council NATRIK National Reporting and Investigation Centre (UK) NCCLS National Committee for Clinical Laboratory Standards NCE New Chemical Entity Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxvii

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 significant NCTR National Center for Toxicological Research NCVIA National Childhood Vaccine Injury Act (1986) NDA New Drug Application (FDA) NDE New Drug Evaluation NDS New Drug Study (Canada's new drug application) NEFARMA Dutch Association of the Innovative Pharmaceutical Industry NEI National Eye Institute (NIH) NEJM New England Journal of Medicine NF National Formulary NHLBI 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 Diseases NICHD 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 Diseases NIDR 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) Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxviii

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 Entity NMR Nuclear magnetic resonance NOEL No observed effect level Non- Non-linear Mixed Effect Model Mem 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 Council NRC Nuclear Regulatory Commission NSAIDNonsteroidal anti-inflammatory drug NSF National Science Foundation NSR Nonsignificant risk NTP National Toxicology Program OAI Official Action Indicated (serious FDA postinspection classification) OAM Office of Alternative Medicine (NIH) OASH Office of the Assistant Secretary for Health OB- Obstetrics and Gynecology GYN OC Office of the Commissioner OC Office of Compliance (CDER) OCD Office of the Center Director (CDER) OCPB Office of Clinical Pharmacology and Biopharmaceutics (CDER) OCR Optical Character Recognition OD Right eye ODB Observational Database ODE Office of Drug Evaluation (CDER now has five such offices: ODE I, II, III, IV, and V)OEA Office of External Affairs OEB Office of Epidemiology and Biostatistics (CDER) OECD Organization for Economic Cooperation and Development OGC Office of the General Counsel OGD 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 Affairs OHRM Office of Human Resource Management Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxix

OJC Office Journal of the EU-C Series (Information) OJL Office Journal of the EU-L Series (Legislation) OLA Office of Legislative Affairs OM 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 Policy OPA Office of Public Affairs OPD Orphan Products Division Directorate OPM Office of Personnel Management OPRR Office of Protection from Research Risks (NIH) OPS Office of Pharmaceutical Science (CDER) ORA Office of Regulatory Affairs ORM Office of Review Management (CDER) ORO Office of Regional Operations OS Left eye OSHA 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 eyes P Priority PAHO Pan American Health Organization PAI Preapproval inspection PAITS Pre-Approval Inspection Tracking System PAR Postapproval research PC Personal computer PC Protocol Amendment-Change (COMIS term) PCC Parklawn Computer Center PCC Poison Control Center PCP Pneumocystis carinii pneumonia PD Position description PD Pharmacodynamics PDA Parenteral Drug Association PDQ Physicians' Data Query (NCI-sponsored cancer trial registry) PDR Physicians' Desk Reference PDUFA Prescription Drug User Fee Act (of 1992, USA) PEM Prescription Event Monitoring Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxx

PEP Performance Evaluation Plan PERI Pharmaceutical Education & Research Institute, division of PhRMA PET Positron emission tomography PFT Pulmonary function tests PhRMA Pharmaceutical Research and Manufacturers of America(previously PMA) PHS Public Health Service (USA) PI Package insert (approved product labeling) PI Principal Investigator PI Protocol Amendment-New Investigator (COMIS term) PK Pharmacokinetics PLA Product License Application (biologics) (UK) PLA/ELAProduct License Application/Establishment License Application PM Project Manager PMA 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 management PMS Postmarketing surveillance PN Protocol AmendmentNew Protocol (or Pending Review) (COMIS term) PO Per os (by mouth) PPA Poison Prevention Act PPI Patient package insert PPM Physician Practice Management Organizations PPO Preferred Provider Organization; Policy and Procedure Order PR Pulse rate PR Public relations PRIM&RPublic Responsibility in Medicine and Research (Boston, MA) PRN As needed PROG Peer-Review Oversight Group (NIH) PSUR Periodic Safety Update Reports PTCC Pharmacology/Toxicology Coordinating Committee (CDER) PUD Peptic ulcer disease QA Quality assurance QAU Quality Assurance Unit Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxxi

QC Quality control QD Once daily QID Four times a day QL Quality of life QNS Quantity not sufficient QOD Every other day QOL Quality of life QSAR Quantitative SAR R&D Research and development R&TD Research and technological development RAC Reviewer Affairs Committee (CDER) RADARRisk Assessment of DrugsAnalysis and Response RAPS Regulatory Affairs Professional's Society RCC Research Coordinating Committee (CDER) RCH Remove Clinical Hold RCT Randomized clinical trials RD Response to Request for Information (COMIS term) RDE Remote data entry RDRC Radioactive Drug Research Committee RDT Rising-dose tolerance RFA Request for approval RIF Reduction in force RKI Robert-Koch-Institut, Bundesinstitut fr Infektionskrankheiten und nich-ber tragbare Krankheiten (Federal Institute for Infectious and Non-communicable Diseases, Germany) RL Regulatory Letter (FDA postaudit letter) RMO Regulatory Management Officer RTF Decision by the FDA to refuse to file an application RTF Refuse to File RUG Resource Utilization Group Rx Prescription S Standard SAE Serious adverse event SAL Sterility assurance level SAR Structure-activity Relationship SBA Summary Basis of Approval SBIR Small Business Innovative Research Program (USA) SC Subcutaneous SC Study coordinator. See also CCRC, CRC SCSO Supervisory Consumer Safety Officer SCT Society for Clinical Trials Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxxii

SD SDAT SE SEA SEER SES SIDA

Standard deviation Senile dementia of the Alzheimer's type Standard error Single European Act of 1987 Surveillance, Epidemiology, and End Results (Registry of NCI) Senior Executive Service Spanish (sndrome inmunodeficiencia adquirida), Italian, and French acronym for AIDS. See AIDS SMART Submission Management and Review Tracking (FDA) SMDA Safe Medical Devices Act (1990) SME Significant medical event SMO Site Management Organization SmPC Summary of Product Characteristics SNDA Supplemental New Drug Application SNIP Syndicat National de l'Industrie Pharmaceutique (France) SoCRA Society of Clinical Research Associates SOMD Safety of Medicines Department (UK) SOP Standard operating procedure SPM Society of Pharmaceutical Medicine SQ Subcutaneous SRS Spontaneous Reporting System SSCT Swedish Society for Clinical Trials SSFA Societ di Scienze Farmacologiche Applicate (Italy) SSM Skin surface microscopy STD Sexually transmitted disease STT Short-term tests SUD Sudden unexpected death SUPAC Scale up and post approval changes SVP Small volume parenterals SX Symptoms TB Tuberculosis TGA Thermographic Analysis TID Three times a day TIND Treatment IND. See also IND TK Toxicokinetics TMO Trial Management Organization TOP Topical TSH Thyroid stimulating hormone UA Urinalysis UKCCRUK Coordinating Committee on Cancer Research Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page xxxiii

UNESCO United Nations Educational Science and Cultural Organization USAN US Adopted Names Council USC United States Code (book of laws) USCA U.S. Code Annotated USDA United States Department of Agriculture USP United States Pharmacopeia USPC U.S. Pharmacopeial Convention USP-DI United States PharmacopeiaDrug Information USP-NF United States PharmacopeiaNational Formulary USUHS Uniformed Services University of the Health Sciences VA Veterans Administration (officially, United States Department of Veterans Affairs) VAERS Vaccine Adverse Event Reporting System VAI 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 Terminology WI Inactive (COMIS term) WL Warning Letter (most serious FDA postaudit letter, demands immediate action within 15 days) WNL Within normal limits WRAIR Walter Reed Army Institute of Research (DoD) WTO World Trade Organization Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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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

Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

Page 466

[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, 32 Start 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, 394 Start 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), 376 Start 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, 382 Start 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, 209 Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation