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

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

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

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

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.

HeadquartersMarcel Dekker, Inc.270 Madison Avenue, New York, NY 10016tel: 212-696-9000; fax: 212-685-4540

Eastern Hemisphere DistributionMarcel Dekker AGHutgasse 4, Postfach 812, CH-4001 Basel, Switzerlandtel: 41-61-261-8482; fax: 41-61-261-8896

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The publisher offers discounts on this book when ordered in bulk quantities. For more information, write toSpecial Sales/Professional Marketing at the headquarters address above.

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

Page viii

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

2. Nonclinical Drug Development: Pharmacology, Drug Metabolism, and ToxicologyDuane B. Lakings

3. The Investigational New Drug Application and the Investigator's BrochureWilliam M. Troetel

4. General Considerations of the NDAMartha R. Charney

5. Specific Requirements, Content, and Format of an NDARichard 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 ANDAIvy Bautista

Page x

Part II. Clinical Research Development

8. Clinical Research ProtocolsRichard A. Guarino

9. Adverse Reactions and Interactions of DrugsRichard A. Guarino

10. Institutional Review Board/Independent Ethics Committee and Informed Consent:Protecting Subjects Throughout the Clinical Research ProcessRochelle L. Goodson

11. Statistical and Data Management: Collaboration in Clinical ResearchLaurent M. Kassalow

12. The Management of Clinical StudiesIleana Maria Alexander

Part III. Good Clinical Practices

13. Obligations of the Investigator, Sponsor, and MonitorRichard A. Guarino

14. Preparing for FDA Inspections: Manufacturing SitesTimothy Urschel

15. Quality AssuranceEarl W. Hulihan

Part IV. The Orphan Drug and the Rx to OTC Swith

16. Orphan DrugsJohn T. Zenno

17. Clinical Development, Regulations, and Trends for OTC DrugsWilliam E. Gilbertson and Steven A. Francesco

Page xi

Part V. Effective Methodology in Expediting NDA Approval

18. Industry and FDA LiaisonWilliam M. Troetel

19. Data Presentation for FDA Submissions: Text and Tabular ExpositionPatricia Blaine

20. The Computer World in New Drug DevelopmentChris Clauss

21. Working with a CRODuane B. Lakings and Alexandra D. J. Mancini

22. The Evolving SMO in the United StatesKenneth A. Getz

Index 465

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)

Page xvi

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

Page xvii

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

Page xix

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

Page xx

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)

Page xxi

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

Page xxii

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

Page xxiii

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)

Page xxiv

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

Page xxv

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)

Page xxvi

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

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 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)

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 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

Page xxix

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

Page xxx

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

Page xxxi

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

Page xxxii

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

Page xxxiii

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

Document

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

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

[Biologic Licence Application (BLAs)]

supplements, 185

toxicology, 118

Biostatistics, 287-310

Blinding techniques, 223-225

placebo, 298

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

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

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

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

accelerated reviews, 409

adverse reaction reporting, 239, 260, 262, 434

approval process, 408

contacts, 399

drug approval, 408

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

Genotoxicity, 39

Good Clinical Practices (GCPs), 325-334

investigator obligations, 326, 328

monitor obligations, 330

sponsor obligations, 329-330

Good Laboratory Practices (GLPs), 34

Hematology, 43

Histopathology, 43

Historical controls study design, 129, 135

Human pharmacokinetics, 178

Human rights, 241

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

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

Kefauver-Harris amendments, 376

Labeling

IND, 56

NDA, 147

study drugs, 234

Laboratory assessments, 238

Literature review, 296

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

National Academy of Sciences/National Research Council (NAS/NRC), 376Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]2000[/DP]End of Citation

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

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

[OTC drugs]

switches, 383

aging population, 387

impact on industry, 388

reimbursement, 389

Rx to OTC trends, 383-391

publication, 379

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

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

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

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

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