FDA FDA 7 IND FDA FDA DMF DMF DMF Regulatory Affairs

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2 FDA FDA 7 IND FDA FDA DMF DMF DMF Regulatory Affairs

3 CIP / ISBN Ⅰ. Ⅱ. Ⅲ.1 2 Ⅳ. 1R954 2D CIP A ISBN /R

4 WTO 90% FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA com

5 GMP 20 GMP FDA FDA IND IND IND GMP FDA FDA 10 FDA GMP FDA

6 2 NDA FDA IND ANDA OTC DMF FDA FDA

7 Kefauver - Harris FDA IND FDA IND 77 IND GCP 99 IND 100 IND 101 IND 108 IND 110 IND 110 IND 111 IND 111 FDA 113 FDA

8 2 NDA 125 NDA 127 NDA 128 NDA 135 NDA FDA NDA NDA NDA ANDA Kefauver - Harris ANDA 217 ANDA 217 / ANDA 232 FDA 232 ANDA 234 FDA OTC 251 OTC OTC OTC 254 OTC 270 OTC 271 OTC Monographs Rx/OTC OTC 283 OTC 287 DMF 296 FDA DMF 296

9 3 DMF 296 DMF 300 DMF 302 DMF 303 FDA DMF 307 DMF 312 CTD 3.2. S 312 DMF FDA 390 CDER 462

10 Food and Drug Administration FDA FDA FDA FDA Kefauver - Harris % University of Pennsylvania School of Medicine 1-1

11 Patent Office - Samuel Lee 1796 Bilious Pill Samuel H. P. Lee Bilious Pills Samuel Lee Samuel H. P. Bilious Pills Samuel Lee caveat emptor

12 3 - USP U. S. Pharmacopeia USP USP USP USP American Medical Association AMA American Pharmaceutical Association APhA National Formulary USP USP 30% Drs. Mixer 19

13 4 Dr. Lin Chinese Blood Pills Dr. Drake Canton Chinese Hair Cream Journal of the American Medical Association FDA Drug Importation Act USP 1862 Chemical DivisionU. S. Department of Agriculture Bureau FDA 19 70

14 Harvey W. Wiley 1-3 Wiley FDA Wiley Wiley Wiley Wiley Paddock bill American Pharmaceutical Association Wiley 1902

15 6 Hygienic Table Poison Squad 1-4 Wiley Crusader 1-4 Wiley Colliers The Patent Medicine Conspiracy Against the Freedom of the Press Ladies Home Journal Edward Bok ThePatent - Medicine Curse

16 7 Pierces Pierces Pierces Mark Sullivan Pierces Pierces Pierce Colliers 1-5 The Great America Fraud Ladies Home Journal Samuel Hopkins Adams Colliers The Great America Fraud 1-5 ~ 1-6 smoothing syrup Colliers Colliers Colliers Upton Sinclair

17 8 The Jungle 1-7 Sinclair 1-7 The Jungle Pure Food and Drugs Act PFDA Wiley Wiley PFDA adulterated USP USP USP / U. S. Pharmacopoeia /National Formulary misbranded alcohol morphine opium cocaine heroin alpha beta eucaine chloroform cannabis chloral hydrate acetanilide PFDA PFDA PFDA PFDA PFDA 1930 Food and Drug Administration FDA - FDA PFDA

18 PFDA PFDA PFDA PF- DA Sherley Amendment O. A. Johnson Kansas 1911 misbranded Dr. Johnson PFDA PFDA 1906 PFDA 1912 Sherley Sherley Amendment ~ 2000 Cato Journal 20 80% 1922

19 % 1929 FTC PFDA FDA 30 FDA 1906 PFDA FDA PFDA Banbar Lash - Lure Radithor Wilhide Exhaler FDA Tugwell Rexford 1933 Tugwell self - medication Copeland FDA Massengil 1937 Elixir Sulfanilamide Elixir Sulfanilamide 1906 PFDA Elixir Sulfanilamide 11 Elixir Sulfanilamide PF- DA Massengill FoodDrugsand Cosmetic Act FDCA 1906 PFDA FDCA 1-9 FDA 1 FDA FDA FDA 2 New Drug Application NDA

20 FDA NDA 60 FDA 3 Sherley FDA FDCA 1906 PFDA misbranded FDCA FDA sulfas FDA / FDA FDA 1951 Prescription Drug Amendment Durham - Humphrey

21 Kefauver - Harris % 1951 FDA Estes Kefauver 8% Kefauver FDA PMA AMA AMA Kefauver Kefauver Richardson - Merrell 1957 thalidomide Kevadon FDA Frances Kelsey FDA FDA thalidomide Richardson - Merrell

22 13 60 Richardson - Merrell phocomelia 1-10 Thalidomide thalidomide thalidomide 10 Richardson - Merrell FDA 1-10 ~ thalidomide 1-11 Thalidomide Richardson - Merrell thalidomide FDA FDA

23 Thalidomide Kelsey 1962 Distinguished Federal Civil Service Award 1-13 Kefauver - Harris Kefauver Kefauver - Harris Kefauver - Harris Amendments 1-14 FDA FDA Kefauver - Harris 60 FDA FDA FDA FDA Investigational New Drug IND IND FDA FDA FDA IND

24 FDA Kefauver - Harris New Drug Application NDA FDA 1966 National Academy of Sci- ences NAS National Research Council NRC Drug Efficacy Study Implementation DESI NRC DESI NRC DESI 1962 Kefauver - Harris FDA Food and Drug Administration Modernization Act FDA FDA FDA FDA FDA FDA

25 16 FDA FDA Vaccine Act U. S. Pharmacopeia USP USP 1848 Drug Importation Act 1862 Lincoln Charles M. Wetherill FDA - Bureau of Chemistry 1880 Peter Collier 1883 Harvey W. Wiley Wiley Biologics Control Act - BLA BLA Federal Hygienic Laboratory 1887 National Institutes of Health NIH 1906 Pure Food and Drugs Act 6 30 Theodore Roosevelt adulterated misbranded 1911 Johnson U. S. v. JOHNSON Sherley Sherley Amendment 1914 Harrison Harrison Narcotic Act

26 FoodDrugand In- secticide Administration Bureau Of Chemistry and Soils 1930 agricultural appropriations act Food and Drug Administration FDA 1933 FDA 1906 Pure Food and Drugs Act FDA 1937 ELIXIR OF SULFANILAMIDE diethylene glycol FoodDrugand Cosmetic Act FDA 1940 FDA Federal Security Agency Walter G. Campbell Commissioner of Food and Drugs 1941 Insulin Amendment FDA Phenobarbital 300 FDA GMP 1944 Public Health Service Act 1945 Penicillin Amendment FDA U. S. v. Sullivan FDA FDA 1949 FDA GUIDANCE TO INDUSTRY- Procedures for the Appraisal of the Toxicity of Chemicals in Food black book 1950 Alberty Alberty Food Products Co. v. U. S directions for use purpose 1951 Prescription Drug Amendment Durham - Humphrey Durham - Humphrey Amendment Rx OTC FDA 1962

27 Cardiff U. S. v. CARDIFF 1938 FDA FDA FDA Consumer Consultants FDA FDA 180 FDA American Society of Hospital Pharmacists American Association of Medical Record Librarians American Medical Association 1953 FDA Department of HealthEducationand WelfareHEW Factory Inspection Amendment FDA 1955 Oveta Culp Hobby 14 FDA FDA polio vaccine 260 Division of Biologics Control National Institutes of Health 1958 > Food Additives Amendment FDA Delaney FDA Federal Register Substances Generally Recognized As SafeGRAS Color Additive Amendment 1962 Kefauver - Harris Kefauver - Harris Drug Amendments FDA FDA FDA 1963 Kefauver - Harris FDA Advisory Committee on Investigational New Drugs FDA 1965 Drug Abuse Control Amendments 1966 FDA National Academy of Science/ National Research Council Fair Packaging And Labeling Act FDA 1968 FDA FDA Bureau Of Drug Abuse Control Treasury Department Bu- reau of Narcotics Department of Justice Bureau of Narcotics and Dangerous DrugsBNDD FDA Public Health Service FDA Drug Efficacy Study Implementation DESI Animal Drug Amendments 512

28 Upjohn Finch 1962 FDA Comprehensive Drug Abuse Prevention And Control Act Environmental Protection Agency EPA FDA 1971 PHS Bureau Of Radiological Health FDA National Center For Toxicological Research 1972 Over - the - Counter Drug Review Drug Listing Act NIH FDA 1974 National Research Act 1976 Medical Device Amendments FDA - GMP GMP FDA FDA Vitamins And Minerals Amendments Proxmire FDA FDA 1982 FDA Tamper - Resistant Packaging Regulations Tylenol FDA Red Book 1949 black book Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food 1983 Orphan Drug Act 20 Federal Anti - Tampering Act 1984 Drug Price Competition And Patent Term Restoration Act Waxman - Hatch Act 5 ANDA FDA 5 FDA 1985 FDA AIDS TEST FOR BLOOD

29 Childhood Vaccine Act FDA Drug Export Amendment Act 1 / FDA 1987 FDA IND 1988 Food And Drug Administration Act FDA Department of Health and Human Services FDA Commissioner of Food and Drugs Prescription Drug Marketing Act Generic Animal Drug And Patent Term Restoration Act Eosinophilia - Myalgia Syndrome EMS L - L - Tryptophan FDA 100 mg L Nutrition Labeling And Education Act health claims food ingredient panel serving sizes Safe Medical Devices Act FDA FDA 1991 Accelerate The Review Of Drugs 1992 Generic Drug Enforcement Act 1989 FDA Debarment FDA Prescription Drug User Fee Act NDA BLA 5 FDA FDA 2.5 ~ 8 FDA 1.5 X- Mammography Quality Standards Act X - FDA

30 Dietary Supplement Health And Education Act FDA FDA Uruguay Round Agreements Act Animal Medicinal Drug Use Clarification Act 1996 Animal Drug Availability Act FDA FDA FDA Export Reform and Enhancement Act 1997 Food And Drug Administration Modernization Act FDA Best Pharmaceuticals for Children Act 2003 Medicare Prescription Drug And Modernization Act 1965 FDA FDA FDA FDA FDA 1-15

31 United State of America USA United States Constitution 1Legislative 2Judicial 3 Executive

32 23 Legislative Congress Senate 100 Committees Congressional Budget Office General Accounting Office Government Printing Office

33 24 Office of Compliance for Legislative Branch Employees Office of Technology Assessment Stennis Center for Public Service 2. House 435 Committees House OrganizationsCommissions and Task Forces Office of the Clerk Office of Inspector General Library of Congress Judicial judicial review 1869 Supreme Court of the United States U. S. Judicial Circuit Courts of Appeal U. S. Court of Appeals for the Federal Circuit U. S. Court of Federal Claims U. S. Court of Appeals for the Armed Forces U. S. Court of Appeals for Veterans Claims U. S. Tax Court U. S. Court of International Trade U. S Federal Courts U. S. Sentencing Commission Federal Judicial Center State Courts 11 FDA Executive

34 25 Executive Office of the President The White House Office Office of the Vice President of the United States Office of Management and Budget Council of Economic Advisers National Security Council Office of United States Trade Representatives Office of Policy Development Office of Science and Technology Policy Council on Environmental Quality Office of National Drug Control Policy Office of Administration Cabinet Department Department of Agriculture Department of Commerce Department of Defense Department of Education Department of Energy Department of Health and Human Services HHS Department of Housing and Urban Development Department of the Interior Department of Justice Department of Labor Department of State Department of Transportation Department of the Treasury Department of Veterans Affairs HHS HHS 2004 S 548 billion 9 25% HHS National Institutes of Health NIH 2 Food and Drug Administration FDA 3 Centers for Disease Control and Prevention 4 Agency for Toxic Substances and Disease Registry 5 Indian Health Service 6 Health Resources and Services Administration 7 Substance Abuse and Mental Health Services

35 26 8 Agency for Healthcare Research and Quality 9 Centers for Medicare & Medicaid Services 10 Administration for Children and Families 11 Administration on Aging HHS HHS http/ /www. hhs. gov/about /whatwedo. html / FDA Food and Drug Administration FDA FDA FDA MD Rockville FDA FDA S 1.7 billion FDA FDA FDA 1 Office of the CommissionerOC- FDA FDA 2 CDER- 3 CBER- 4 CDRH- 5 CFSAN- 6 CVM- 7 NCTR- FDA FDA 8 ORA- FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA Web http/ /www. fda. gov/

36 27 1. CDER FDA CDER CDER CDER CDER FDA FDA CDER CDER CDER CDER CDER Manual of Policies and Procedures MaPPs MaPPs IND NDA AN- DA CDER Good Review Practices GRP CDER 9 1 Office of Executive Programs 2 Office of New Drugs IND NDA OTC 3 OPaSS 4 Office of Management FDA 5 Office of Regulatory Policy FDA 6 Office of Pharmaceutical Science ANDA 7 Office of Clinical Pharmacology and Biopharmaceutics 8 Office of Medical Policy 9 Office of Counter Terrorism CDER 1 85 IND NDA FDA 2002 Office of Pharmacoepidemiology and Statistical Science OPaSS 180 OPaSS

37 28 FDA CDER FDA OPaSS OPaSS Office of Drug Safety ODS Office of Biostatistics CDER ODS MedWatch ODS ODS ODS Division of Drug Risk Evaluation DDRE DDRE Division of Medication Errors and Technical Support DMETS CDER Division of SurveillanceResearchand Communication Support SRCS SRCS MedWatch Medication Guides 3 Office of Pharmaceutical Science OPS CDER OPS OPS OPS 1 Office of New Drug Chemistry 20 CDER 2 Office of Generic Drugs ANDA 3 Office of Biotechnology Products 4 Office of Testing and Research

38 29 OPS / 4 Office of New Drugs CDER IND NDA ODE ⅠODE ⅡODE ⅢODE ⅣODE Ⅴ ODE Ⅵ IND NDA ODE Ⅰ Neuropharmacological Drug Products Division of Oncology Drug Products Division of Cardio - Renal Drug Products ODE Ⅱ Division of Metabolic and Endocrine Drug Products Division of Pulmonary Drug Products Division of AnestheticCritical Care and Addiction Drug Products ODE Ⅲ Division of GastroIntestinal Coagulation Drug Products Division of Reproductive and Urologic Drug Products Division of Medical Imaging and Radiopharmaceutical Drug Products ODE Ⅳ Division of Anti - Infective Drug ProductsHFD Division of Anti - Viral Drug Products Division of Special Pathogen and Immunologic Drug Products Drug Shortages Program Antimicrobial Resistance Initiative ODE Ⅴ Division of Anti - Inflammatory Analgesic and Ophthalmologic Drug Products Division of Dermatologic and Dental Drug Products Division of Over - the - Counter Drug Products Botanical Review Team ODE Ⅵ Division of Therapeutic Biological Internal Medicine Products Division of Therapeutic Biological Oncology Products Division of Review Management and Policy FDA FDA 25%FDA FDA FDA

39 30 NDA BLA ANDA New Molecular Entity - OTC NDA FDA CDER 1 IND NDA OTC ANDA CBER CDER 21 CFR FDA CBER CBER CBER CBER CBER CDER 1 USP NF 2 3

40 31 X - - X X - CT FDA FDA FDA CDRH FDA FDA CFSAN dietary supplement 1994 Dietary Supplement Health and Education Act DSHEA dietary ingredient - FDA FDA FDA 80% S 15 billion FDA FDA 1 2 FDA FDA FDA FDA FDA Center for Veterinary Medicine CVM

41 32 CVM BSE FDA % Drug - eluting stents FDA FDA CDER FDA FDA Office of Combination Products FDA CDERCBER CDRH FDA FDA FDA sodium pentobarbital FDA FDA FDA 1. Rx OTC OTC Monographs OTC 1FDA OTC 2 OTC 3 OTC OTC generics OTC

42 33 NDA FDA CBER FDA CDER generics Follow On Biologics FDA Rx OTC FDA 353 b l FDA NDA OTC OTC Rx OTC OTC 2. FDA 21 U. S. C. 801 Controlled Substances Act CSA CSA anabolic steroids - Drug SchedulingCSA21 U. S. C. 812 Schedule Ⅰ- Schedule Ⅱ- Schedule Ⅲ- Schedule Ⅳ- Schedule Ⅴ- Drug Enforcement Administration DEA FDA FDA FDA DEA DEA DEA 3. OTC OTC FDA DESI Homeopathic Samuel Hahnemann 1796 like cures like

43 Homeopathic Pharmacopeia FDA GMP FDA OTC Pharmacy compounding FDA FDA FDA FDA Compliance Policy Guide FDA FDA FDA FDA FDA DESI 1938 FDA Drug Efficacy Study Implementation DESI 1. FDA FDA Orange Book

44 35 Approved Drug Products with Therapeutic Equivalence Evaluations FDA FDA Cumulative Supplement FDA http/ /www. fda. gov/cder /ob /default. htm Patents exclusivity 1 FDA Patent Trademark Office PTO PTO Uruguay Rounds Agreements Act Drug Price Competition and Patent Term Restoration Act FDA 60 PTO FDA PTO PTO FDA NDA FDA 30 FDA ANDA FDA form 3542a FDA form FDA 505 c 3 D 505 j 5 D 21 CFR

45 36 FDA FDA FDA NCE FDA FDA FDA FDA FDA NCE 5 NCE FDA FDA NCE 5 5 FDA 5 NCE FDA Eli Lilly AlimtaFDA NCE NCE FDA FDA 1993 ~ 2004 NDA NCE % % % % % % % % % % % % % 2004 CBER CDER

46 37 3 FDA Huntingtons Disease Myoclonus Lou Gehrigs Disease Tourette Syndrome Muscular Dystrophy 80 FDA 1983 The Orphan Drug Act 50% 7 orphan drug FDA FDA Interleukin - 2 vascular leak syndrome ALS Oxandrolone FDA

47 38 5 ~ 10 mg 1989 Searle Laboratories 1995 Bio - Technology General Corp FDA HIV FDA 7 Bio - Technology General Corp Searle Laboratories 2.5 mg 20mg S 0.30 S FDA FDA FDA Tamoxifen Best Pharmaceuticals for Children Act 6 FDA Drug Price Competition and Patent Term Restoration Act Waxman - Hatch 180 FDA 70% % ANDA

48 Drug Listing Act / FDA Establishment Licenses 5 FDA 2656 FDA 2656E 2656E 30 FDA OTC IND FDA GMP API GMP FDA DMF FDA FDA API DMF API FDA FDA FDA FDA Drug Listing FDA form FDA 6 12 FDA National Drug Code NDC NDC NDC FDA FDA NDC 1 FDA FDA FDA mg Ranitidine NDC FDA 2657 FDA 2657 FDA / establishment licences product fees Prescription Drug User Fee Act PDUFA FDA FDA FDA FDA standard reviews 6 priority reviews

49 % 50% 75% 2 / establishment fees 3 product fees 1 31 IND FDA IND PDUFA 5 5 PDUFA 5 PDUFA ~ 1997 PDUFA ~ 2002 PDUFA ~ 2007 PDUFA Public Health Security and Bioterrorism Response Act FDA NDA FDA 2005 NDA NDA S S / 5 S NDA S S PDUFA allergenic extract PHS 351 NDA FDA - FDA - FDA - / - /

50 41 - / - FDA OTC FDA NDABLA ANDA Drug Registration Listing FDA 1 FDA FDA FDA FDA FDA FDA FDA API FDA FDA 1996 FDA Operational and Administrative System for Import Support OASIS FDA FDA Automated Commercial System ACS ACS ACS FDA FDA FDA OASIS OASIS FDA FDA FDA OASIS FDA

51 42 FDA FDA FDA / / FDA API FDA FDA FDA FDA FDA FDA Notice of Detention and Hearing 21 CFR Part 1subpart E / FDA FDA drug registration product listing FDA FDA FDA Notice of Refusal of Admission GMP FDA Import Alert Detention Without Physical Examination DWPE GMP FDA GMP GMP FDA GMP http/ /www. customs. ustreas. gov/xp /cgov/import /

52 Bioterrorism Act Secretary of Health and Human Services Title ⅢProtecting Safety and Security of Food and Drug Supply 321 section Import for Export d Personal Importation FDA FDA ORA 9 / Import Operations /Actions FDA 4

53 44 Tier I countries FDA FDA FDA FDAFDA Certificates of Exportation FDA FDA FDA FDA FDA ActsRegulations Guidance to Industry Guide FDA FDA FDA FDA ActsRegulations FDCA Code of Federal Regulations CFR 1. FDCA U. S. C. 21 FDCA 9 Chapter Ⅰ - Short Title Chapter Ⅱ - Definitions Subchapter Ⅲ - Prohibited Acts and Penalties Chapter Ⅳ - Food Chapter Ⅴ - Drugs And Devices Chapter Ⅵ - Cosmetics Chapter Ⅶ - General Authority Chapter Ⅷ - Imports And Exports Chapter Ⅸ - Miscellaneous 1 Chapter V - Drugs And Devices A - - Section 501 Adulterated Drugs and Devices - Section 502 Misbranded Drug and Devices

54 45 - Section 503 Exemptions and Consideration for certain DrugsDevicesand Biological Products - Section 505 New Drugs - Section 506 Certification of Drugs Containing Insulin - Section 507 Certification of Antibiotics - Section 510 Registration of Producers of Drugs and Devices B - - Section 525 Recommendations for Investigations of Drugs for Rare Diseases or Conditions - Section 526 Designation of Drugs for Rare Diseases or Conditions - Section 527 Protection for Drugs for Rare Diseases or Conditions - Section 528 Open Protocols for Investigations of Drugs for Rare Diseases or Conditions C - D - E - 2 Chapter Ⅷ - Imports And Exports - Section 801 Imports and Exports - Section 802 Exports of certain unapproved products - Section 803 Office of international relations 2. Food and Drug Administration Modernization Act1997 Administrative Procedures Act Animal Drug User Fee Act2003 Best Pharmaceuticals for Children Act Bioterrorism Act of 2002PDF 297 KB Controlled Substances Act Controlled Substances Import and Export Act Drug Listing Act Dietary Supplement Health and Education Act Fair Packaging and Labeling Act Federal Anti - Tampering Act Generic Animal Drug and Patent Term Restoration Act Medical Device User Fee and Modernization Act Miscellaneous Provisions Relating to Orphan Drugs The National Environmental Policy Act The Orphan Drug Act Pediatric Research Equity Act Prescription Drug User Fee Act 3. Code of Federal Regulations CFR 21 Title 21

55 http/ /www. access. gpo. gov/nara /cfr /index. html 21 Ⅰ FDA 1-99 HHS Ⅱ DEA Ⅲ 21 Title 21Food and Drugs 2004 Chapter Ⅰ - Ⅰ- Food And Drug AdministrationDepartment Of Health And Human Services A - Subchapter A- General 1 General enforcement regulations 2 General administrative rulings and decisions 3 Product jurisdiction 5 Organization 7 Enforcement policy 10 Administrative practices and procedures 11 Electronic recordselectronic signatures 12 Formal evidentiary public hearing 13 Public hearing before a public board of inquiry 14 Public hearing before a public advisory committee 15 FDA Public hearing before the commissioner 16 FDA Regulatory hearing before the food and drug administration 17 Civil money penalties hearings 19 Standards of conduct and conflicts of interest 20 Public information 21 Protection of privacy 25 Environmental impact considerations 26 Mutual recognition of pharmaceutical good manufacturing practice reportsmedical device quality system audit reportsand certain medical device product evaluation reportsunited states and the European community 50 Protection of human subjects 54 Financial disclosure by clinical investigators 56 Institutional review boards 58 Good laboratory practice for nonclinical laboratory studies 60 Patent term restoration 70 Color additives 71 Color additive petitions 73 Listing of color additives exempt from certification 74 Listing of color additives subject to certification 80 Color additive certification 81 General specifications and general restrictions for provisional color additives for use in foodsdrugsand cosmetics 82 Listing of certified provisionally listed colors and specifications

56 47 Chapter Ⅰ - Ⅰ- Food And Drug AdministrationDepartment Of Health And Human Services A - Subchapter A- General 99 Dissemination of information on unapproved /new uses for marketed drugsbiologicsand / devices B - Subchapter B- Food For Human Consumption C - Subchapter C- DrugsGeneral 200 General 201 Labeling 202 Prescription drug advertising 203 Prescription drug marketing 205 Guidelines for state licensing of wholesale prescription drug distributors 206 Imprinting of solid oral dosage form drug products for human use 207 Registration of producers of drugs and listing of drugs in commercial distribution 208 Medication guides for prescription drug products 210 Current good manufacturing practice in manufacturingprocessingpackingor holding of drugsgeneral 216 Pharmacy compounding 225 Current good manufacturing practice for medicated feeds 211 Current good manufacturing practice for finished pharmaceuticals 250 Special requirements for specific human drugs 290 Controlled drugs 299 Drugsofficial names and established names 226 A Current good manufacturing practice for type a medicated articles D - Subchapter D- Drugs For Human Use 300 General 310 New drugs 312 Investigational new drug application 314 FDA Applications for FDA approval to market a new drug 315 Diagnostic radiopharmaceuticals

57 48 Chapter Ⅰ - Ⅰ- Food And Drug AdministrationDepartment Of Health And Human Services D - Subchapter D- Drugs For Human Use 316 Orphan drugs 320 Bioavailability and bioequivalence requirements 328 Over - the - counter drug products intended for oral ingestion that contain alcohol 330 Over - the - counterotchuman drugs which are generally recognized as safe and effective and not misbranded 331 Antacid products for over - the - counterotchuman use 332 Antiflatulent products for over - the - counter human use 333 Topical antimicrobial drug products for over - the - counter human use 335 Antidiarrheal drug products for over - the - counter human use 336 Antiemetic drug products for over - the - counter human use 338 Nighttime sleep - aid drug products for over - the - counter human use 340 Stimulant drug products for over - the - counter human use 341 Coldcoughallergybronchodilatorand antiasthmatic drug products for over - the - counter human use 343 Internal analgesicantipyreticand antirheumatic drug products for over - the - counter human use 344 Topical otic drug products for over - the - counter human use 346 Anorectal drug products for over - the - counter human use 347 Skin protectant drug products for over - the - counter human use 348 External analgesic drug products for over - the - counter human 349 Ophthalmic drug products for over - the - counter human use 350 Antiperspirant drug products for over - the - counter human use 352 Sunscreen drug products for over - the - counter human use use stayed indefinitely 355 Anticaries drug products for over - the - counter human use 357 Miscellaneous internal drug products for over - the - counter human use

58 49 Chapter Ⅰ - Ⅰ- Food And Drug AdministrationDepartment Of Health And Human Services D - Subchapter D- Drugs For Human Use 358 Miscellaneous external drug products for over - the - counter human use 361 Prescription drugs for human use generally recognized as safe and effective and not misbrandeddrugs used in research 369 Interpretative statements re warnings on drugs and devices for over - the - counter sale E - Subchapter E - Animal DrugsFeedsAnd Related Products 500 General 501 Animal food labeling 502 Common or usual names for nonstandardized animal foods 509 Unavoidable contaminants in animal food and food - packaging material 510 New animal drugs 511 New animal drugs for investigational use 514 New animal drug applications 515 Medicated feed mill license 520 Oral dosage form new animal drugs 522 Implantation or injectable dosage form new animal drugs 524 Ophthalmic and topical dosage form new animal drugs 526 Intramammary dosage forms 529 Certain other dosage form new animal drugs 530 Extralabel drug use in animals 556 Tolerances for residues of new animal drugs in food 558 New animal drugs for use in animal feeds 570 Food additives 571 Food additive petitions 573 Food additives permitted in feed and drinking water of animals 579 Irradiation in the productionprocessingand handling of animal feed and pet food 582 Substances generally recognized as safe 584 Food substances affirmed as generally recognized as safe in feed and drinking water of animals 589 Substances prohibited from use in animal food or feed

59 50 Chapter Ⅰ - Ⅰ- Food And Drug AdministrationDepartment Of Health And Human Services F - Subchapter f - biologics 600 Biological productsgeneral 601 Licensing 606 Current good manufacturing practice for blood and blood components 607 Establishment registration and product listing for manufacturers of human blood and blood products 610 General biological products standards 630 General requirements for bloodblood componentsand blood derivatives 640 Additional standards for human blood and blood products 660 Additional standards for diagnostic substances for laboratory 680 Additional standards for miscellaneous products G - Subchapter G- Cosmetics tests 700 General 701 Cosmetic labeling 710 Voluntary registration of cosmetic product establishments 720 Voluntary filing of cosmetic product ingredient composition statements 740 Cosmetic product warning statements H - Subchapter H - Medical Devices 800 General 801 Labeling 803 Medical device reporting 806 Medical devicesreports of corrections and removals 807 Establishment registration and device listing for manufacturers and initial importers of devices 808 Exemptions from federal preemption of state and local medical device requirements 809 In vitro diagnostic products for human use 810 Medical device recall authority 812 Investigational device exemptions 814 Premarket approval of medical devices

60 51 Chapter Ⅰ - Ⅰ- Food And Drug AdministrationDepartment Of Health And Human Services H - Subchapter H - Medical Devices 820 Quality system regulation 821 Medical device tracking requirements 822 Postmarket surveillance 860 Medical device classification procedures 861 Procedures for performance standards development 862 Clinical chemistry and clinical toxicology devices 864 Hematology and pathology devices 866 Immunology and microbiology devices 868 Anesthesiology devices 870 Cardiovascular devices 872 Dental devices 874 Earnoseand throat devices Gastroenterology - urology devices 878 General and plastic surgery devices 880 General hospital and personal use devices 882 Neurological devices 884 Obstetrical and gynecological devices 886 Ophthalmic devices 888 Orthopedic devices 890 Physical medicine devices 892 Radiology devices 895 Banned devices 898 Performance standard for electrode lead wires and patient cables I - Subchapter I - Mammography Quality Standards Act 900 Mammography J - Subchapter J - Radiological Health L - Subchapter L - Regulations Under Certain Other Acts Administered By The Food And Drug Administration Ⅱ- Chapter Ⅱ - Drug Enforcement AdministrationDepartment Of Justice 1300 Definitions 1301 Registration of manufacturersdistributorsand dispensers of controlled substances

61 52 Ⅱ- Chapter Ⅱ - Drug Enforcement AdministrationDepartment Of Justice 1302 Labeling and packaging requirements for controlled substances 1303 Quotas 1304 Records and reports of registrants 1305 Order forms 1306 Prescriptions 1307 Miscellaneous 1308 Schedules of controlled substances 1309 Ⅰ Registration of manufacturersdistributorsimporters and exporters of list I chemicals 1310 Records and reports of listed chemicals and certain machines 1312 Importation and exportation of controlled substances 1316 Administrative functionspracticesand procedures 1313 Importation and exportation of precursors and essential chemicals Ⅲ- Chapter Ⅲ - Office of National Drug Control Policy CFR CFR NDA ANDA FDA 483 CFR FDA FDA Guidances FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA http/ /www. fda. gov/cder /guidance /guidlist. pdf

62 53 FDA FDA CBER http/ /www. fda. gov/cber /guidelines. htm CDRH http/ /www. fda. gov/cdrh /guidance. html CDER http/ /www. fda. gov/cder /guidance /guidance. htm CFSAN http/ /vm. cfsan. fda. gov/ ~ dms /guidance. html CVM http/ /www. fda. gov/cvm/guidance /guidance. html ORA http/ /www. fda. gov/ora / FDA Guide FDA Manual of Policies and Procedures MaPPs CDER http/ /www. fda. gov/cder /mapp. htm ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH ICH EU ICH FDA PhRMA EU EFPIA MHLW JPMA WHO EFTA HC IFPMA ICH ICH Safety 2Efficacy 3Quality 4 Regulatory Communications FDA ICH ICH FDA ICH FDA FDA FDA ICH 21 ICH FDA ICH

63 54 Safety S1A The Need for Long - term Rodent Carcinogenicity Studies of Pharmaceuticals S1B Testing for Carcinogenicity of Pharmaceuticals S1C Dose Selection for Carcinogenicity Studies of Pharmaceuticals S1CR Guidance on Dose Selection for Carcinogenicity Studies of PharmaceuticalsAddendum on a Limit Dose and Related S2A Notes Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals S2B S3A S3B S4A S5A S5B GenotoxicityA Standard Battery for Genotoxicity Testing of Pharmaceuticals ToxicokineticsThe Assessment of Systemic Exposure in Toxicity Studies PharmacokineticsGuidance for Repeated Dose Tissue Distribution Studies Duration of Chronic Toxicity Testing in AnimalsRodent and Nonrodent Toxicity Testing Detection of Toxicity to Reproduction for Medicinal Products Detection of Toxicity to Reproduction for Medicinal Products Addendum on Toxicity to Male Fertility S6 Preclinical Safety Evaluation of Biotechnology - Pharmaceuticals Derived S7A Safety Pharmacology Studies for Human Pharmaceuticals / M2 M3 M4 ectd ectdelectronic Common Technical Document Specification Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals Common Technical Document for the Registration of Pharmaceuticals for Human Use Efficacy E1A E2A E2B The Extent of Population Exposure to Assess Clinical Safety For Drugs Intended for Long - term Treatment of Non - Life - Threatening Conditions Clinical Safety Data ManagementDefinitions and Standards for Expedited Reporting ICH International Conference on HarmonisationGuidance on Data Elements for Transmission of Individual Case Safety Re- ports

64 55 Efficacy E2C E3 E4 E5 E6 E7 Clinical Safety Data ManagementPeriodic Safety Update Reports for Marketed Drugs ICH E2C Addendum to ICH Clinical Safety Data Management Periodic Safety Update Reports for Marketed Drugs Structure and Content of Clinical Study Reports - Dose - Response Information to Support Drug Registration Ethnic Factors in the Acceptability of Foreign Clinical Data Questions and Answers GLP Good Clinical PracticeConsolidated Guideline Studies in Support of Special PopulationsGeriatrics E8 General Considerations for Clinical Trials E9 E10 E11 Statistical Principles for Clinical Trials Choice of Control Group and Related Issues in Clinical Trials Clinical Investigation of Medicinal Products in the Pediatric Population Quality Q1AR2 Q1B Stability Testing of New Drug Substances and Products Photostability Testing of New Drug Substances and Products Q1C Stability Testing for New Dosage Forms Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F Q2A Q2B Stability Data Package for Registration Applications in Climatic Zones III and IVrevision 1 Text on Validation of Analytical Procedures Validation of Analytical ProceduresMethodology Q3A Impurities in New Drug Substances Q3BR Impurities in New Drug Products Q3C ImpuritiesResidual Solvents Tables and List Q5A Q5B Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin Quality of Biotechnological ProductsAnalysis of the Expression Construct in Cells Used for Production of r - DNA De- rived Protein Products

65 56 Quality Q5C Q5D Q6A Q6B Q7A / Quality of Biotechnological ProductsStability Testing of Biotechnological /Biological Products / Quality of Biotechnological /Biological ProductsDerivation / and Characterization of Cell Substrates Used for Production of Biotechnological /Biological ProductsAvailability ICHQ6A International Conference on HarmonisationGuidance on Q6A SpecificationsTest Procedures and Acceptance Criteria for New Drug Substances and New Drug ProductsChemical Substances / SpecificationsTest Procedures and Acceptance Criteria for Biotechnological /Biological Products GMP Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients ICH ICH FDA CDER http/ /www. fda. gov/cder /guidance /index. htm 2004 Merck Vioxx FDA Regulatory Affairs

66 1-1 HHS

67 1-2 FDA

68 1-3 CDER 59

69 1-4 CBER

70 1-5 CDRH

71 1-6 CFSAN

72 1-7 CVM

73 OPS

74 1-9 OPaSS

75 1-10 FDA OC

76 1-11 OND 67

77 1-12 ONPLDS

78 IND Investigational New Drug IND IND IND IND d / / / I N D 20 ~ ~ ~ 5000 NDA N D A IND < 1 /5000 < 20% ~ 70% ~ 33% ~ 27% PhRMA FDA 10 ~ 20% 2.5 ~ 250 / % ~ 8 S 500 ~ S 800 million

79 70 IND 70% 80% IND IND FDA 12 IND GlaxoSmithKline Retrovir AZT FDA AZT 1987

80 71 / DNA FDA IND Pharmacology pharmacon logos in vivo in vitro in situ ex vivo PD PK

81 72 IND PD - Primary Pharmacodynamic Secondary Pharmacodynamic Safety Pharmacology PK PK Absorption Distribution Metabolism Excretion ADME - AUC C max T max PK 2 2 ~ / FDA IND Toxicology Acetaminophen LD 50 50% LD 50 = 25mg/kg LD 50 = mg/kg LD 50 = mg/kg LD 50 > 2000 mg/kg

82 73 IND FDA / FDA 2 / LD 50 2 MTD NOEL 3 4 FDA / NOEL % ~ ~ > 6 6

83 74 IND > 3 6 / % ICH 9 FDA 9 IND 6 6 IND FDA 12 Carcinogenicity / 24 IND ICH FDA Reproductive Toxicity

84 75 FDA / / / 16 FDA IND FDA / Genotoxicity/ Mutagenicity Ames ICH ICH Guideline on Specific Aspects of Regulatory Genotoxicity Tests Toxicokinetic

85 76 IND PK/ADME FDA DNA ADME - / FDA

86 77 IND FDA IND FDA IND FDA IND IND IND IND IND IND IND IND IND IND Investigator IND IND 21 CFR IND Emergency use of an investigational new drug FDA 21CFR IND FDA FDA IND IND FDA CBER IND Division of Biological Investigational New DrugsHFB CDER Document Management and Reporting BranchHFD - 53 FDA IND IND 30 FDA IND FDA IND Treatment IND

87 78 IND FDA FDA CFR IND E IND Parallel Track FDA IND FDA FDA National Cancer InstituteNCI IND FDA FDA FDA NDA FDA IND 21 CFR CFR 56 GMP FDA IND FDA FDA FDA

88 79 NDA FDA FDA FDA / IND 21 CFR 50 FDA Commissioner IND FDA / IND IND - 21 CFR FDA IND FDA FDA IND 30 FDA IND Form FDA 1571 IND FDA IND IND FDA IND IND

89 80 IND IND IND IND IND FDA IND IND IND IND IND FDA FDA Fluconazole FDA B IND FDA IND IND FDA IND 1 FDA IND2 3 HIV IND NDA IND 21 CFR FDA IND FDA IND Exploratory IND Studies IND IND FDA IND IND

90 81 IND 7 IND IND IND IND FDA IND Guidance for IndustryInvestigatorsand ReviewersExploratory IND Studies IND IND IND IND IND IND 20 ~ 100 ~ 70% 100 ~ 200 ~ 33% > 2000 ~ 25 ~ 30%

91 82 IND 20 ~ 100 FDA 100 ~ 300 NDA / 1000 ~ FDA

92 83 FDA NDA BLA Lasser et. Al. JAMA cerivastatin Warner - Lambert Troglitazone Merck Vioxxrofecoxib 27% Vioxx FDA Vioxx Vioxx FDA IND FDA

93 84 IND FDA - Randomized controlled trialsrct -

94 85 Cross - over study A B B A A B cohort study case - controlled trial odds - ratio

95 86 IND - - Dose - Response Studies Nuremberg Code The Nuremberg War Crimes Tribunal Doctors Trial / / X

96

97 88 IND 2-3 Andrew Ivy Leo Alexander Nuremberg Code

98 World Medical Association Declaration of Helsinki A. B. C. A

99 90 IND B

100 91 27 C Somerset West thalidomide Kefauver - Harris FDA 1964 NIH IRB FDA IRB IRB

101 92 IND 60 Henry Breecher 1966 Ethics and Clinical Research Armed Forces Epidemiological Board Willowbrook / NIH DHEW Tuskegee Syphilis Study S PHS DHEW 1973

102 DHEW National Research Act National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research Belmont Report IRB DHEW

103 94 IND DHHS CFR 4621 CFR IRB IRB FDA IND IRB / 1986 Edward J. Markey - American Nuclear Guinea PigsThree Decades of Radiation Experiments on U. S. Citizens Ronald Reagan FDA 21CFR IRB 1966 DHEW FDA FDA / 21 CFR

104 95 FDA FDA 5 FDA 21 CFR CFR FDA 6 7 8

105 96 IND 21 CFR U. S. C f FDA FDA IND - - -

106 FDA / / proxy consent 18 / American Academy of Pediatrics National Commission for Protection of Human Subjects of Biomedical and Behavioral Research 7 informed permission FDA FDA DHHS 21 CFR 50Subpart D DHHS

107 98 IND John Moore 6 1 UCLA Golde Golde 15 Golde UCLA Golde Golde Golde Golde Golde Golde Golde Golde Golde Golde 1979 MO Genetics Institute UCLA Golde S Golde Sandoz Golde S Golde Golde MO

108 99 Golde Golde Golde GCP Good Clinical Practice GCP GCP FDA ICH GCP FDA FDA IND 1 2 FDA FDA GCP GCP GCP GCP FDA ICH NDA ICH GCP FDA NDA FDA IND FDA IND IND CRO FDA IND IND IND

109 100 IND IND 21 CFR 50 FDA FDA FDA GCP principal investigator FDA FDA IND IND IND FDA IND IND IND IND IND FDA FDA IND FDA IND IND FDA 21 CFR IND ICH GCP - E6 FDA IND IND 21 CFR a 1 ix IND IND IND

110 IND 101 IND IND FDA 1571 FDA 1572 IND IND IND IND IND 000 FDA CFR IND FDA Food and Drug Administration Center for Drug Evaluation and Research Central Document Room B Ammendale Rd. BeltsvilleMd CDER Therapeutic Biological Products Document Room Center for Drug Evaluation and Research Food and Drug Administration Wilkins Avenue RockvilleMD IND 1 Cover Letter 2 Form FDA IND - 21 CFR 56 IRB CFR

111 102 IND - - IND 3 Table of Contents FDA IND IND 5 6 Investigators Brochure ICH Clinical Protocols

112 IND FDA - - FDA GCP CMC 21 CFR a 7 i CMC FDA IND IND IND GMP NDA CMC

113 104 IND FDA CMC FDA IND FDA CMC CMC FDA IND NDA CMC CMC CMC 1 IND FDA CMC 2 / FDA

114 IND 105 IND IR IND IND IND 3 - NF ACS IND IND

115 106 IND CautionNew Drug - Limited by Federal or United Stateslaw to investigational use 6 21 CFR 25 FDA FDA Guidance for Industry for the Submission of Environmental Assessments for Human Drug Applications and SupplementsNovember1995 FDA FDA 1 2 FDA FDA FDA CFR a 8 i 1 2 IND FDA IND CFR a 8 ii a

116 IND 107 FDA IND IND GLP FDA IND FDA IND FDA FDA 120 FDA 21 CFR FDA CNS FDA GLP 21 CFR a 8 iii GLP GLP 21 CFR 58 GLP

117 108 IND IND FDA IND IND NDA FDA IND IND IND IND FDA FDA IND 30 IND IND FDA IND IND FDA IND IND IND 1. IND IND

118 IND 109 Amendment FDA IND IND FDA IND FDA IND IND FDA 30 FDA FDA IND FDA 2. IND 21 CFR IND FDA IND IND 15 FDA 7 IND FDA 3. IND 21 CFR FDA IND IND 60 IND 1 IND 2IND

119 110 IND IND 3 IND IND 4 IND FDA IND IND IND IND FDA IND FDA IND RR RR 30 IND FDA IND PT PT 30 IND FDA IND IND 21 CFR IND IND FDA 21 CFR IND IND FDA IND IND FDA IND IND IND IND IND IND FDA FDA 21 CFR IND FDA IND 21 CFR IND

120 IND 111 IND 21 CFR IND 21 CFR FDA 21 CFR IND 5 FDA FDA IND FDA IND FDA INDFDA 30 FDA FDA FDA FDA IND IND IND IND FDA IND inactive status FDA FDA FDA FDA IND IND 30 FDA IND IND 21 CFR IND IND FDA IND 21 CFR IND 30 FDA IND IND 2-5

121 112 IND 2-5 IND FDA IND IND IND NDA FDA IND IND IND IND FDA IND FDA IND FDA / 1 FDA

122 IND 113 FDA IND 2 / 3 / IND 1 2 IND / IND NDA FDA 1980 FDA FDA IND FDA 30 FDA FDA IND 31 FDA IND FDA FDA FDA FDA FDA 1. IND Clinical Hold FDA 30 FDA FDA FDA IND FDA IND IND IND

123 114 IND FDA IND IND CLINICAL HOLD RESPONSE IND IND IND NDA FDA 30 IND FDA IND FDA IND FDA FDA FDA FDA FDA FDA FDA FDA FDA AB C A A A FDA 30 FDA B NDA FDA FDA FDA B FDA 60 FDA NDA BLA B FDA C AB C FDA 75 FDA FDA FDA 60 FDA 14 FDA FDA

124 IND 115 FDA FDA 1. FDA IND FDA IND FDA IND FDA FDA FDA FDA FDA FDA FDA b 1 FDA 3. FDA FDA FDA FDA IND FDA FDA FDA FDA FDA FDA 4. NDA BLA NDA BLA

125 116 IND FDA FDA NDA NDA FDA FDA FDA FDA Formal Meetings With Sponsors and Applicants for PDUFA Products 2000 FDA MAPP Formal Meetings Between CDER And CDERs External Constituents 21 CFR CFR IND cgmpglpgcp CFR 312 IND 21 CFR 312 IND IND IND IND 21 CFR CFR CFR Part CFR Part CFR Part Subpart A - Subpart B - IND IND IND IND IND IND Subpart C -

126 IND IND IND IND Subpart D Subpart E Subpart F IND IND Subpart G - FDA 21 CFR Part CFR Part CFR Parts 210 and 211 FDA IND 21 CFR

127 118 IND Investigational New DrugsExport Requirements for Unapproved New Drug Products FDA FDA FDA Export Reform and Enhancement Act FDA 9 / Regulatory Procedures Manual Chapter 9 - Import Operations /Actions - FDA FDA CDER CBER FDA ICH FDA ICH FDA ICH ICH ICH ICH E6 ICH - Guidance for IndustryE6 Good Clinical PracticeConsolidated GuidanceFinal 4 /1996 ICH E2C ICH - Guidance for IndustryE2C Clinical Safety Data ManagementPeriodic Safety Update Reports for Marketed DrugsFinal 01 - Nov ICH E2C ICH Guideline Topic V1 Step 4Addendum to ICH E2C Clinical Safety Data Management Periodic Safety Update Reports for Marketed Drugs2 /2003 ICH Guidelines on Clinical Data Safety Monitoring Boards - ICH E3E9E10www. ich. org CDER /CBER FDA FDA IND IND Content and Format of Investigational New Drug ApplicationsINDsfor Phase 1 Studies of Drugs Acceptance of Foreign Clinical Studies3 /2001 IND Content and Format of Investigational New Drug ApplicationsINDsfor Phase 1 Studies of DrugsIncluding Well - CharacterizedTherapeuticBiotechnology - derived Products Establishing Pregnancy Exposure 8 /2002 Format and Content of the Clinical and Statistical Sections of an Application 7 /1988 General Considerations for the Clinical Evaluation of Drugs General Considerations for the Clinical Evaluation of Drugs in Infants and Children 9 /77 Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products 5 /1998 Study and Evaluation of Gender Differences in the Clinical

128 IND 119 Evaluation of Drugs 7 /1993 Study of Drugs Likely to be used in the Elderly 11 /1989 The Use of Clinical Holds Following Clinical Investigator Misconduct IND Guidance for IndustryInvestigatorsand ReviewersExploratory IND Studies 4 /2005 NIH AAALAC FDA ICH 1 Developing Medical Imaging Drug and Biological Products Part 1Conducting Safety Assessments6 /2004 / Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application 3 /1998 Immunotoxicology Evaluation of Investigational New Drugs 10 / 2002 Single Dose Acute Toxicity Testing for Pharmaceuticals Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers 1 /2003 Integration of Study Results to Assess Concerns about Human Reproductive and Developmental Toxicities 11 /2001 Nonclinical Safety Evaluation of Pediatric Drug Products 1/2003 Recommended Approaches to Integration of Genetic Toxicology Study Results11 /2004 Statistical Aspects of the DesignAnalysisand Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals 5 /2001 FDA www. fda. gov/cder /guidance /index. htm 2002 S 32 billion NIH 1998 S 13.7 billion 2003 S 27.2 billion 5 15% % IND FDA IND

129 120 IND 2-5 IND IND 1986 ~ 2004 IND IND CBER CDER IND FDA IND ICH IND IND

130 IND IND FDA 1571

131 122 IND

132 IND FDA 1572

133 124 IND

134 NDA New Drug Application NDA FDA FDA FDA NDA NDA FDA FDA FDA Zidovudine Azidothymidine AZT AZT 19 AZT FDA 1987 FDA 107 FDA AZT FDA - FDA - FDA Clozaril 20 Clozaril 30% FDA Clozaril Sandoz Sandoz 1987 Clozaril WBC CPMS CPMS Caremark CPMS Clozaril WBC

135 126 NDA Roche Clozaril Clozaril Caremark WBC Sandoz FDA Clozaril Sandoz Clozaril WBC FDA CPMS 1989 Clozaril Clozaril CPMS 99% FDA FDA Clozaril - FDA Risk Management Program RMP FDA Clozaril RMP Clozaril ThalomidTrovanTikosynActiqXyremMifeprex TracleerLotronex FDA FDA FDA FDA FDA NDA FDA NDA FDA FDA NDA 3-1 FDA FDA FDA NDA FDA NDA NDA NDA FDA NDA FDA Singulair 1992 IND NDA FDA NDA FDA 28 FDA NDA 2004 NCE 24.7

136 NDA FDA NDA NDA FDA NDA 21 CFR FDA NDA FDA NDA CMC GLP GCP CMC cgmp NDA FDA CDER CBER Biologic Licensing Application

137 128 NDA BLA 2003 CBER CDER FDA 2002 Office of Combination Products / / / FDA CDERCBER CDRH FDA 21 CFR 314 FDA Applications for FDA Approval to Market a New Drug D Drugs for Human Use A General Provisions FDA NDA Aarticles recognized in the official United States Pharmacopoeiaofficial Homoeopathic Pharmacopoeia of the United Statesor official National Formularyor any supplement to any of themand Barticles intended for use in the diagnosiscuremitigation treatmentor prevention of disease in man or other animalsand Carticlesother than foodintended to affect the structure or any function of the body of man or other animalsand Darticles intended for use as a component of any article specified in clausea B orc. A food or dietary supplement for which a claimsubject to sections 403 r 1 Band 403 r 3 of this title or sections 403 r 1 Band 403 r 5 Dof this title is made in accordance with the requirements of section 403 rof this title is not a drug solely because the label or the labeling contains such a claim. A fooddietary ingredientor dietary supplement for which a truthful and not misleading statement is made in accordance with section 403 r 6of this title is not a drug under clausecsolely because the label or the labeling contains such a statement. 1Any drugexcept a new animal drug or an animal feed bearing or containing a new animal drug the composition of which is such that such drug is not generally recognizedamong experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugsas safe and effective for use under the conditions prescribedrecommendedor suggested in the labeling thereofexcept that such a drug not so recognized shall not be deemed to be anew drugif at any time prior to the enactment of this Act it was subject to the Food and Drugs Act of June as amendedand if at such time its labeling contained the same representations concerning the conditions of its useor 2Any drugexcept a new animal drug or an animal feed bearing or containing a new animal drug the composition of which is such that such drugas a result of investigations to determine its safety and effectiveness for use under such conditionshas become so recognizedbut which has nototherwise than in such investigationsbeen used to a material extent or for a material time under such conditions

138 NDA CFR Drug product means a finished dosage formfor exampletabletcapsulesolutionetc. that contains an active drug ingredient generallybut not necessarilyin association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo. 21 CFR Bulk drug substance means any substance that is represented for use in a drug and thatwhen used in the manufacturingprocessingor packaging of a drugbecomes an active ingredient or a finished dosage form of the drugbut the term does not include intermediates used in the synthesis of such substances. bulk pharmaceutical chemical BPC active pharmaceutical ingredient API ICH Q3A new drug substance new molecular entitynme new chemical entity NCE as a designated therapeutic moiety that has not been previously registered in a region or member state. The definition also states that a new drug substance may be a complexa simple esteror a salt of a previously approved drug substance. NDA FDA NCE FDA FDA 3-1 FDA 1992 Prescription Drug User Fee Act priority drug Food and Drug Modernization Act of 1997 Fast Track FDA fast track priority review accelerated approval Priority Review FDA NDA FDA NDA FDA FDA Mapp NDA

139 130 NDA 3-1 CDER NDA 1993 ~ 2004 FDA FDA NDA NDA CBER CDER Accelerated Approval FDA NDA FDA Subpart H Accelerated Approval of New Drugs for Serious or Life - Threatening Illnesses FDA Subpart H 21 CFR surrogate endpoint CD4 FDA FDA clinical endpoint FDA chronic myeloid leukemia CML Gleevec ima-

140 NDA 131 tinib mesylate Novartis NDA FDA Novartis Gleevec CML progression - free survival Gleevec 95% Gleevec 88% 85% Gleevec 91% FDA Gleevec HIV FDA clinical endpoints Clinical endpoints Clinical endpoints Clinical endpoints accelerated approval fast track fast track FDA 1997 FDA IND IND 21 CFR Subpart E - Drugs Intended to Treat Life - threatening and Seriously Debilitating Illnesses FDA FDA FDA NDA FDA Fast Track Drug Development Programs - Designation Developmentand Application Review Subpart E 1 FDA Pre - IND

141 132 NDA FDA FDA 2 FDA treatment protocol FDA 3 NDA NDA 4 surrogate endpoints 5 NDA FDA - FDA / FDA NDA FDA IND FDA PDUFA FDA FDA FDA 1 - PDUFA Continuous Marketing ApplicationsPilot 1 - Reviewable Units for Fast Track Products Under PDUFA 2 - PDUFA Continuous Marketing ApplicationsPilot 2 - Scientific Feedback and Interactions During Development of Fast Track Products under PDUFA Parallel Track Parallel track 1992

142 NDA 133 IND IND Treatment IND HIV HIV FDA NDA FDA FDA FDA 1969 National Environmental Policy Act NEPA FDA 21 CFR 25 IND NDA ANDA BLA Environmental Assessments 21 CFR CFR 25 C FDA Environmental Assessment of Human Drug and Biologics Applications FDA Finding of No Significant Impact FONSI Pharmacogenomics pharmacogenomics FDA FDA CDER CBER CDRH Pharmacogenomic Data Submissions FDA FDA FDA FDA FDA IND Form FDA 1571 IND CDER CBER Request for Fast Track Designation NDA Form FDA 356h 1. 1

143 134 NDA 2 FDA FDA FDA FDA IND FDA IND IND 2. FDA FDA 60 1 Designation letter- FDA Designation letter Non - designation letter- FDA Non - designation letter FDA FDA FDA FDA Orphan Drugs Orphan Drugs NDA FDA 1 2 / 3

144 NDA IND NDA FDA CFR 316 A B C FDA D E F FDA Office of Orphan Products Development Orphan Drug Act FDA IND NDA IND NDA FDA CDER CBER NDA NDA 21 CFR NDA ICH Common Technical Document CTD DMF NDA IND NDA ANDA DMF FDA

145 136 NDA CTD GMPGLP GCP ICH Steering Committee Common Technical Document CTD CTD CTD ICH ICH CTD CTD ICH CTD CTD CTD CTD DMF CTD CTD 2 5 CTD FDA ICH - CTD - Submitting Marketing Applications According to the ICH - CTD Format - General Considerations B CTD NDA ANDA BLA CTD CTD

146 NDA 137 CTD CTD ICH CTD NDA 1. 1 Module CTD Form FDA 356h Debarment certification NDA Form FDA 3397 Claimed exclusivity - 2. CTD 2 Module CTD CTD Table of Contents 2.2 CTD CTD Introduction 2.3 Quality Overall Summary 2.4 Nonclinical Overview 2.5 Clinical Overview 2.6 Nonclinical Written and Tabulated Summary - Pharmacology - Pharmacokinetics - Toxicology 2.7 Clinical Summary CTD 3 Module 3 Quality 3.1 Module 3 Table of Contents 3.2 Body of Data 3.2. S DMF 3.2. P P.1

147 138 NDA USPEP BP ICH Q6A Q6B P.2 / / / / P / 4 ph 5 ICH Q6B 1 -

148 NDA ICH Q2AQ2BQ6A Q6B Process Validation / ICH Q6B P.4 ICH Q6AQ3C Q6B ICH Q2AQ2B Q6B ICH Q5AQ5D Q6B adventitious agents 1 nonviral adventitious agents ICH Q5AQ5D Q6B 2 viral adventitious agents ICH Q5AQ5D Q6B P.5 ICH Q3BQ6A Q6B ICH Q2AQ2B Q6B ICH Q3B Q3CQ6A Q6B ICH Q3BQ5CQ6A Q6B P.6 ICH Q6A Q6B P.7 / P.8 ICH Q1AQ1BQ3BQ5C Q6A

149 140 NDA NDA 6 Accelerated Stability Testing FDA3 FDA ICH Q1A Q5C FDA 30 FDA 1 2 A. B. C. ph D. ph 4 ~ 45 E. ph F. ph G. H.

150 NDA 141 ph 3.5mg I. ph J. ph K ICH Q1AQ1BQ2AQ2B Q5C 3.3 Literature References 4. CTD 4 Module Module 4 Table of Contents 4.2 Study Reports Pharmacology Pharmacokinetics - - Absorption - Distribution - Metabolism - Excretion Toxicology In vitro In vivo -

151 142 NDA CTD 5 Module BA - BA BE - In Vitro- In Vivo PK - PK - PK - PK - PK - PK PD - PD PK/PD - PD PK/PD Integrated Analyses Meta - Analyses Bridging Analyses CRF 5.4 Literature References CTD

152 NDA 143 CTD modules ICH FDA CTD Quality Safety Efficacy CTD Module 2Quality Overall Summary QOS Module 3 CTD - M4QThe CTD - Quality 2 Module 2the Nonclinical Overview and thenonclinical Written and Tabulated Summaries CTD - M4SThe CTD - Safety 2 Module 2 the Clinical Overview and the Clinical Summaryand Module 5 CTD - M4EThe CTD - Efficacy NDA NDA NDA NDA ICH FDA e - CTD ICH e - CTD M2 e - CTD- 3.0 M2 e - CTD - Electronic Common Technical Document SpecificationVersion 3.0 ICH CTD e - CTD XML CTD web browser FDA FDA Draft Guidance for Industry Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions CTD FDA FDA NDA BLA DMF IND NDA ANDA 3-3 FDA /

153 144 NDA 3-3 FDA / NDA FDA D 314 FDA 21 - > D - > FDA Subpart A - Subpart B

154 NDA Subpart C - Abbreviated Applications Subpart D - FDA FDA Subpart E - Subpart F Subpart G DMF Subpart H Subpart I - 2. FDA FDA CDER FDA http/ /www. fda. gov/cder /guidance /index. htm NDA - - Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations

155 146 NDA NDA IND BA BE ANDA BE NDA ANDA - NDA ANDA Changes to an Approved NDA or ANDA NDA ANDA - Changes to an Approved NDA or ANDAQuestions and Answers Container Closure Systems for Packaging Human Drugs and Biologics Format and Content of the ChemistryManufacturing and Controls Section of an Application Format and Content of the Microbiology Section of an Application - Format and Content of the Clinical and Statistical Sections of an Application Format and Content of the Summary for New Drug and Antibiotic Applications FormattingAssembling and Submitting New Drug and Antibiotic Applications Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances - Submitting Documentation for the Stability of Human Drugs and Biologics Submitting Samples and Analytical Data for Methods Validation - Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Products - NDAsImpurities in Drug Substances Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products Drug Master Files FDA INDNDAANDA DMF Required Specifications for FDAs INDNDAand ANDA Drug Master File Binders - Qualifying for Pediatric Exclusivity PET - ANDA Drug Applications - Content and Format for NDAs and ANDAs Refusal to File CDER NDA - MaPP DIDP Procedures for Processing NDA and NDA Supplement Approval Letters and Action Packages to Be Posted on the Internet NDA

156 NDA MaPP Review of the Same Supplemental Change to More than One NDA or ANDA in More Than One Review Division NDA ANDA MaPP NDAsFiling Review IssuesNDA MaPP Action Packages for NDAs and Efficacy Supplements NDA MaPP Refusal to Accept Application for Filing From Applicants in Arrears MaPP Drug Application Approval 501 bpolicy 501 b MaPP Requesting and Accepting Non - Archivable Electronic Records for New Drug Applications MaPP Priority Review Policy NDA FDA NDA NDA NDA FDA NDA FDA FDA FDA NDA NDA NDA FDA NDA NDA NDA NDA

157 148 NDA FDA NDA FDA FDA NDA FDA FDA FDA FDA FDA FDA FDA FDA 30 / / 1972 FDA 21 CFR Part A

158 NDA B 3 C 4 D 5 E 6 F 7 G 8 H 1997 CDER CBER FDA 1. NDA FDA NDA Approval Letter FDA Drug Approval Packages FDA NDA FDA approvable not approvable approvable NDA not approvable NDA GMP FDA FDA FDA NDA 2. NDA 1 21 CFR FDA FDA NDA FDA Duract FDA 10 FDA FDA

159 150 NDA 3 FDA S 20 million FDA CDER NDA FDA / FDA NDA FDA 505 c FDA k 507 g 21 CFR CFR CFR FDA FDA FDA 510 j 2 5 FDA NDA NDA 58 NDA / 21 CFR CFR FDA FDA Federal Register 505 j 6

160 NDA 151 FDA FDA FDA FDA FDA 2 21 CFR CFR FDA FDA FDA FDA FDA FDA FDA FDA 3 FDA 21 CFR CFR / 21 CFR NDA FDA NDA FDA NDA FDA - / - 21 CFR FDA FDA - NDA NDA FDA

161 152 NDA FDA 25% post - marketing surveillance FDA FDA 15 FDA FDA FDA FDA MedWatch OTC MedWatch Vaccine Adverse Event Reporting System MedWatch MedWatch FDA Baycol Bayer 2001 Duract Wyeth - Ayerst 1998 Fen - phen Wyeth - Ayerst 1998 Lotronex GlaxoSmithKline Propulsid Janssen 2000 Raplon Organon 2001 Rezulin Parke - Davis /Warner - Lambert 2000 Seldane Hoechst 1998 Serzone Bristol - Myers Squibb 2003 Trovan Pfizer Zyflo Abbott Vioxx Merck 2004 Bextra Pfizer FDA NDA FDA NDA

162 NDA FDA NDA NDA

163 154 NDA FDA NDA FDA NDA 60 NDA FDA refuse - to - file NDA FDA NDA FDA NDA FDA CDER NDA 5% FDA NDA 30 FDA NDA PDUFA FDA CDER 3-3 NDA FDA FDA FDA FDA priority Standard 0 60 FDA NDA - / 45 FDA FDA NDA FDA NDA FDA CDER 3-5 ~ 3-30 FDA

164 NDA NDA 3-6 NDA

165 156 NDA NDA - NDA NDA - Priority Review Fast TrackNDA FDA NDA Rolling NDA NDA - FDA

166 NDA NDA 3-12 NDA

167 158 NDA 3-13 NDA NDA NDA Fast Track NDA Rolling NDA FDA FDA NDA 3-14 NDA

168 NDA NDA 3-16 NDA

169 160 NDA NDA Gantt Chart / DSINDA 3-17 NDA 3-18

170 NDA 161 CRF 10 CRF NDA

171 162 NDA ~

172 NDA ~ ~

173 164 NDA ~ ~ 180 NDA NDA FDA FDA FDA NDA FDA NDA Pre - Approval Inspection PAI 3-31 NDA GMP FDA FDA % NDA GMP GMP NDA CDER Bioresearch Monitoring Program BiMo DSI IRB CRO FDA Division of Scientific Investigations DSI CRF DSI DSI / FDA DSI official action indicated Notice of Initiation of Disqualification Proceedings and Opportunity to Explain NIDPOE NIDPOE CDER 3%

174 NDA FDA NDA 3.1 FDA Fast Track 1998 ~ Pegasys peginterferon alfa - 2a Hoffmann - La Roche 2005 Alone or in combination with ribavirin Copegusfor treatment of chronic hepatitis C in patients co - infected with HIVwho have clinically stable HIV disease lamivudine /zidovudine /nevirapine Aspen Pharmacare 2005 Treatment of HIV Abraxanepaclitaxel protein - bound particles for injectable suspension Clolar clofarabine Macugen pegaptanib sodium American BioScience 2005 Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy Genzyme 2004 Treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens Eyetech 2004 Treatment of exudativewetage - related macular degeneration

175 166 NDA Kepivance palifermin Amgen 2004 Decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving Levaquin levofloxacin Ortho McNeil 2004 Treatment of inhalational anthraxpost - exposure Tarcevaerlotinib OSI 2004 Treatment of locally advanced or metastatic Non Small - myelotoxic therapy requiring hematopoietic stem cell support Cell Lung Cancer after failure of at least one prior chemotherapy regimen Alimtapemetrexed Lilly 2004 Treatment of non - small cell lung cancer Vidazaazacitidine Pharmion 2004 Treatment of patients with certain subtypes of myelodysplastic syndrome Apokynapomorphine Bertek 2004 Treatment of acuteintermittent hypomobility off episodes end - of - dose wearing offand unpredictable on /offepisodesassociated with advanced Parkinsons disease Avastinbevacizumab Genentech 2004 For the first - line treatment of patients with metastatic carcinoma of the colon and rectumin combination with intravenous 5 - fluorouracil - based chemotherapy Erbituxcetuximab ImClone Systems 2004 Treatment of EGFR - expressingmetastatic colorectal carcinoma in patients who are refractory to irinotecan - based chemotherapy in combination with irinotecan treatment of EGFR - expressingmetastatic colorectal carcinoma in patients who are intolerant to irinotecan - based chemotherapyadministered as a single agent Alimtapemetrexed disodium Lilly 2004 Treatment of malignant pleural mesothelioma Lexivafosamprenavir calcium GSK 2003 Treatment of HIV Zavescamiglustat Actelion 2003 Treatment of type I Gaucher disease Emtrivaemtricitabine Gilead 2003 Treatment of HIV Bexxartositumomab and iodine I 131 tositumomab Corixa 2003 Treatment of patients with CD20 positivefollicularnon - Hodgkins lymphomawith and without transformation whose disease is refractory to Rituximab and has relapsed following chemotherapy. Velcadebortezomib Millennium 2003 Treatment of relapsed /refractory multiple myeloma Iressagefitinib AstraZeneca 2003 Treatment of non - small cell lung cancer Aldurazyme laronidase Biomarin 2003 Treatment of patients with Hurler and Hurler - Scheie forms of Mucopolysacchar - idosis IMPS Iand for patients with the Scheie form who have moderate to severe symptoms

176 NDA 167 Fabrazymeagalsidase beta Genzyme 2003 Use in patients with Fabry disease to reduce globo - triaosylceramidegl - 3deposition in capillary endothelium of the kidney and certain other cell types Somavertpegvisomant Pharmacia and Upjohn 2003 Treatment of acromegaly Fuzeonenfuvirtide Hoffmann - La Roche 2003 Treatment of HIV Pegasyspeginterferon alfa - 2a Hoffmann - La Roche 2002 PEGASYSpeginterferon alfa - 2aalone or in combination with COPEGUSfor the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha Arimidexanastrozole AstraZeneca 2002 Adjuvant treatment of early breast cancer in postmenopausal women Eloxatinoxaliplatin Sanofi - Synthelabo 2002 Treatment of colorectal cancer Zevalin ibritumomab tiuxetan IDEC 2002 Treatment of patients with relapsed or refractory low - gradefollicularor transformed B- cell non - Hodgkins lymphoma not acc. app.including patients with RituximabRituxanrefractory follicular non - Hodgkins lymphoma Orfadinnitisinone Swedish Orphan 2002 Treatment of hereditary tyrosinemia type I Viread tenofovir disoproxil fumarate Gilead 2001 Treatment of HIV Gleevec imatinib mesylate Novartis 2001 Treatment of Chronic Myeloid Leukemia Campathalemtuzumab ILEX 2001 Treatment of B- cell chronic lymphocytic leukemiab - CLLin patients who have been treated with alkylating agents and who have failed fludarabine therapy Candidascaspofungin acetate Merck 2001 Treatment of aspergillus infections for patients who are refractory to or intolerant of other therapies Remicade infliximab Centocor 2000 Expand the indication to include the inhibition of progression of structural damage in patients with rheumatoid arthritis who have had an inadequate response to methotrexate Trisenoxarsenic trioxide Cell Therapeutics 2000 Treatment of acute promyelocytic leukemia Kaletra lopinavir /ritonavir Abbott 2000 Treatment of HIV Actimmune interferon gamma - 1b InterMune 2000 Delaying time to disease progression in patients with severemalignant osteopetrosis Taxoteredocetaxel Aventis 1999 For the treatment of locally advanced or metastatic non - small cell lung cancer Ageneraseamprenavir Glaxo 1999 Treatment of HIV Ziagenabacavir sulfate Glaxo 1998 Treatment of HIV Enbreletanercept Immunex 1998 Treatment of rhuematoid arthritis

177 168 NDA Herceptin trastuzumab Genentech 1998 Treatment of metastatic breast cancer Sustivaefavirenz DuPont 1998 Treatment of HIV 3.2 Accelerated Approval 1992 ~ NDA Clolarclofarabine 2004 Provides for the use of Clolarclofarabineintravenous infusion for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens Luveris lutropin alfa 2004 Provides for the use of Luveris 75IUlutropin alfa for injection concomitantly administered with Gonal - f follitropin alfa for injectionfor stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiencylh < 1.2 IU/L Truvadaemtricitabinetenofovir 2004 Provides for the use of Truvada TM emtricitabine200 mgand tenofovir disoproxil fumarate300 mg Tablets in combination with other antiretroviral agentssuch as nonnucleoside reverse transcriptase inhibitors or protease inhibitorsfor the treatment of HIV- 1 infection in adults Plenaxisabarelix 2003 Provides for the use of Plenaxisabarelix for injectable suspension100 mg for the palliative treatment of men with advanced symptomatic prostate cancerin whom LHRH agonist therapy is not appropriate and who refuse surgical castrationand have one or more of the following 1risk of neurological compromise due to metastases 2ureteral or bladder outlet obstruction due to local encroachment or metastatic diseaseor3severe bone pain from skeletal metastases persisting on narcotic analgesia Velcadebortezomib 2003 Provides for the use of Velcadebortezomibfor Injection for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy Iressagefitinib 2003 Provides for the use of IRESSAgefitinib tabletsas monotherapy for the treatment of patients with locally advanced or metastatic non - small cell lung cancer after failure of both platinum- based and docetaxel chemotherapies Gleevec imatinib mesylate 2003 Provides for the use of Gleevecimatinib mesylate100 mg and 400 mg tablets for the treatment of patients with chronic myeloid leukemiacmlin blast crisisaccelerated phaseor in chronic phase after failure of interferon - alpha therapy Fuzeonenfuvirtide 2003 Provides for the use of Fuzeonenfuvirtidefor injectionin combination with other antiretroviral agentsfor the treatment of HIV - 1 infection in treatment experienced patients with evidence of HIV - 1 replication despite ongoing antiretroviral therapy

178 NDA 169 Eloxatinoxaliplatin 2002 Provides for the use of Eloxatinoxaliplatinfor Injection in combination with infusional 5 - FU/LV for the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed during or within 6 months of completion of first line therapy with the combination of bolus 5 - FU/LV and irinotecan Xyremsodium oxybate 2002 Provides for the use of Xyrem Oral Solution for the treatment of cataplexy associated with narcolepsy Remodulin treprostinil sodium 2002 Provides for the use of Remodulintreprostinil sodiuminjection and 10.0 mg/ml for the treatment of pulmonary arterial hypertension PAH Tracleerbosentan 2001 Treatment of pulmonary arterial hypertension Viread tenofovir disoproxil fumarate 2001 In combination with other antiretroviral agents for the treatment of HIV - 1 infection in adults Gleevec imatinib mesylate 2001 Provides for the use of Gleevec imatinib mesylate50 and 100 mg capsules Trizivirabacavir sulfatelamivudineand zidovudine for the treatment of patients with chronic myeloid leukemiacmlin blast crisisaccelerated phaseor in chronic phase after failure of interferon - alpha therapy 2000 Provides for the use of Trizivir either alone or in combination with other antiretroviral agents for the treatment of HIV- 1 infection Mifeprexmifepristone 2000 For medical termination of intrauterine pregnancy through 49 days pregnancy Kaletra lopinavir /ritonavir 2000 Kaletra in combination with other antiretroviral agents for the treatment of HIV- 1 infection in adults and pediatric patients age six months and older Mylotarggemtuzumab ozogamicin 2000 Treatment of patients with CD33 positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy Synercidquinupristin /dalfopristin 1999 Treatment of vancomycin resistant Enterococcus faecium Temodar temozolomide 1999 Treatment of adult patients with refractory anaplastic astrocytoma i. e. patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine Ageneraseamprenavir 1999 Provides for the use of Ageneraseamprenavir in combination with other antiretroviral agentsfor the treatment of HIV- 1 infection DepoCytcytarabine 1999 Depocyt is indicated for the intrathecal treatment of lymphomatous meningitis Ziagenabacavir sulfate 1998 Provides for the use of Ziagenabacavir sulfate in combination with other antiretroviral agentsfor the treatment of HIV- 1 infection Actiqfentanyl citrate 1998 For the management of breakthrough cancer pain in patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain Sustivaefavirenz 1998 Provides for the use of efavirenz in combination with other antiretroviral agents for the treatment of HIV- 1 infection

179 170 NDA Viramunenevirapine 1998 Provides for an oral suspensionwhich is indicated for use in combination therapy with other antiretroviral agents for the treatment of HIV- 1 infection Thalomid thalidomide 1998 Thalomid is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosumenland as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrences Priftinrifapentine 1998 Priftin is indicated for the treatment of pulmonary tuberculosistb Sulfamylonmafenide acetate 1998 Indicated for use as an adjunctive topical antimicrobial agent to control bacterial infection when used under moist dressings over meshed autografts on excised burn wounds Xelodacapecitabine 1998 Treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline - containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy may be contraindicated Rescriptordelavirdine mesylate 1997 Treatment of HIV infection in combination with appropriate antiretroviral agents when therapy is warranted Viraceptnelfinavir mesylate 1997 Treatment of HIV infection when therapy is warranted Viraceptnelfinavir mesylate 1997 Treatment of HIV infection when therapy is warranted ProAmatinemidodrine hydrochloride 1996 Treatment of symptomatic orthostatic hypotension Serostimsomatropin 1996 Treatment of AIDS wasting associated with catabolism loss or cachexia Viramunenevirapine 1996 Combination with nucleoside analogues for the treatment of HIV - 1 infected adults who have experienced clinical and /or immunologic deterioration Camptosar irinotecan hydrochloride 1996 Treatment of refractory colorectal cancer Taxoteredocetaxel 1996 Treatment of patients with locally advanced or metastatic breast cancer who have progressed or relapsed during anthracycline based therapy Crixivan indinavir sulfate 1996 Treatment of HIV infection in adults Norvirritonavir 1996 In combination with nucleoside analogues or as monotherapy for the treatment of HIV infection Invirasesaquinavir mesylate 1995 Treatment of advanced HIV infection in selected patients in combination with nucleoside analogues Epivir lamivudine 1995 Treatment of HIV infection in selected patients Doxildoxorubicin hydrochloride 1995 Treatment of AIDS - related Kaposis sarcoma in patients with disease that has progressed on prior combination chemotherapy or in patients who are intolerant to such therapy Casodexbicalutamide 1995 Use in combination therapy with a Luteinizing - Hormone Releasing Hormone LHRHanalogue for the treatment of advanced prostate cancer Zinecarddexrazoxane 1995 To reduce the incidence and severity of cardiomyopathy associated with doxorubicin administration in certain breast cancer patients Zeritstavudine 1994 Treatment of adults with advanced HIV infection - alternative therapy

180 NDA 171 Biaxinclarithromycin 1993 Treatment of disseminated mycobacterial infections due to Mycobacterium avium and Mycobacterium intracellular Hividzalcitabine 1992 Combination therapy with zidovudine in advanced HIV infection 1992 ~ Remodulin treprostinil sodium 2004 Provides for adding the infusion of Remodulin treprostinil sodium & 10 mg/ml Injection via an indwelling central venous catheter to the labeling Levaquin levofloxacin 2004 Provides for the use of Levaquin tablets for the treatment of inhalational anthraxpost - exposure Femara letrozole 2004 Provides for the use of Femara for the extended adjuvant treatment of early breast cancer in postmenopausal women who have received five years of adjuvant tamoxifen therapy. Alimtapemetrexed 2004 Provides for the use of Alimta pemetrexed for injectionas a single - agent for the treatment of patients with locally advanced or metastatic non - small cell lung cancer after prior chemotherapy. Gleevec imatinib mesylate 2003 Provides for the use of Gleevec imatinib mesylatetablets for the treatment of pediatric patients with Ph + chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon alpha therapy. There are no controlled trials demonstrating a clinical benefitsuch as improvement in disease - related symptoms or increased survival. Gleevec imatinib mesylate 2002 Provides for the use of Gleevec imatinib mesylate 100 mg capsules for the treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemiacml. Follow- up is limited. Arimidexanastrozole 2002 Provides for the use of ARIMIDEXanastrozoleTablets for adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer Lotronexalosetron hydrochloride 2002 Provides for the use of Lotronex only for women with severe diarrhea - predominant irritable bowel syndromeibswho havechronic IBS symptoms generally lasting 6 months or longer had anatomic or biochemical abnormalities of the gastrointestinal tract excludedand failed to respond to conventional therapy Gleevec imatinib mesylate 2002 Provides for the use of Gleevec imatinib mesylatefor the treatment of patients with KitCD117positive unresectable and /or metastatic malignant gastrointestinal stromal tumorsgist Ciprociprofloxacin hydrochlorid 2000 Provides for the use of CIPRO for inhalational anthraxpost - exposure Celebrexcelecoxib 1999 To reduce the number of adenomatous colorectal polyps in Familial Adenomatous PolyposisFAP as an adjunct to usual care

181 172 NDA Doxildoxorubicin hydrochloride 1999 Treatment of metastatic carcinoma of the ovary in patients with disease that is refractory to both paclitaxel - and platinum- based chemotherapy regimens Viramunenevirapine 1998 Provides for the inclusion of pediatric information into the labeling Ethyolamifostine 1996 Provides for modification of Ethyol indicationsto include treatment of patients with non - small cell lung cancer Biaxinclarithromycin 1993 Provides for the treatment of disseminated mycobacterial infections due to Mycobacterium avium and Mycobacterium intracellular 3.3 FDA 1983 ~ FDA 269 FDA 1465 FDA acetylcysteine Acetadote For the intravenous treatment of moderate to severe acetaminophen overdose Albendazole Albenza Treatment of hydatid disease cystic echinococcosis due to E. granulosus larvae or alveolar echinococcosis due to E. multilocularis larvae. 10 /19 / /23 / /17 / /11 /1996 Albendazole Albenza Treatment of neurocysticercosis due to Taenia 1 /18 / /11 /1996 solium as1chemotherapy of parenchymal subarachnoidal and racemosecysts in spinal fluidneurocysticercosis in symptomatic cases and 2prophylaxis of epilepsy and other sequelae in asymptomatic neurocysticercosis Aldesleukin Proleukin Treatment of metastatic melanoma 9 /10 / /9 /1998 Aldesleukin Proleukin Treatment of metastatic renal cell carcinoma 9 /14 / /5 /1992 alemtuzumab Campath Treatment of chronic lymphocytic leukemia 10 /20 / /7 /2001 Alglucerase injection Ceredase For replacement therapy in patients with Gauchers disease type I. Alitretinoin Panretin Topical treatment of cutaneous lesions in patients with AIDS- related Kaposis sarcoma. 3 /11 / /5 / /24 / /2 /1999 Allopurinol sodium Aloprim for In- Management of patients with leukemialym- 10 /16 / /17 /1996 jection phomaand solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels and who cannot tolerate oral therapy.

182 NDA 173 Alpha1 - proteinase inhibitor Prolastin For replacement therapy in the alpha proteinase inhibitor congenital deficiency state. Altretamine Hexalen Treatment of advanced adenocarcinoma of the ovary. 12 /7 / /2 / /9 / /26 /1990 Amifostine Ethyol Reduction of the incidence of moderate to severe 5 /12 / /24 /1999 xerostomia in patients undergoing post - operative radiation treatment for head and neck cancer. Amifostine Ethyol For use as a chemoprotective agent for cisplatin 5 /30 / /8 /1995 in the treatment of advanced ovarian carcinoma Aminosalicylic acid Paser Granules Treatment of tuberculosis infections. 2 /19 / /30 /1994 Amiodarone HCl Cordarone For the acute treatment and prophylaxis of life - threatening ventricular tachycardia or ventricular fibrillation. 3 /16 / /3 /1995 Amphotericin B lipid Abelcet Treatment of invasive fungal infections 12 /5 / /18 /1996 complex Anagrelide Agrylin Treatment of essential thrombocythemia 1 /27 / /14 /1997 Antihemophilic factor recombinant Antihemophilic factor recombinant Antihemophilic factor / von Willebrand factor complex driedpasteurized ReFacto Kogenate For the control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia Acongenital factor Ⅷ deficiency or classic hemophilia. Prophylaxis and treatment of bleeding in individuals with hemophilia A or for prophylaxis when surgery is required in individuals with hemophilia A. Humate - P Treatment and prevention of bleeding in hemophilia Aclassical hemophiliain adult patientsand treatment of spontaneous and trauma - induced bleeding episodes in severe von Willebrand diseaseand in mild and moderate von Willebrand disease where use of desmopressin is known or suspected to be inadequate in adult and pediatric patients. 2 /8 / /25 / /25 / /16 / /1 /1999 Antithrombin Ⅲ human Thrombate Ⅲ For replacement therapy in congenital deficiency of AT - III for prevention and treatment 11 /26 / /30 /1991 of thrombosis and pulmonary emboli. Antithrombin Ⅲ human ATnativ For the treatment of patients with hereditary antithrombin III deficiency in connection with 2 /8 / /13 /1989 surgical or obstetrical procedures or when they suffer from thromboembolism.

183 174 NDA Antivenincrotalidae polyvalent immune Fab ovine CroFab Treatment of envenomations inflicted by North American crotalid snakes. Apomorphine HCl Apokyn Treatment of the on - off fluctuations associated with late - stage Parkinsons disease. 1 /12 / /2 / /22 / /20 /2004 Aprotinin Trasylol For prophylactic use to reduce perioperative blood loss and the homologous blood transfusion requirement in patients undergoing cardiopulmonary bypass surgery in the course of repeat coronary artery bypass graft surgery and in selected cases of primary coronary artery bypass graft surgery where the risk of bleeding is especially high impaired hemostasisor where transfusion is unavailable or unacceptable. 11 /17 / /29 /1993 Arsenic trioxide Trisenox Treatment of acute promyelocytic leukemia 3 /3 / /25 /2000 Atovaquone Mepron Treatment of AIDS associated Pneumocystis Carinii Pneumonia 9 /10 / /25 /1992 Atovaquone Mepron Prevention of Pneumocystis carinii pneumonia 8 /14 / /5 /1999 PCPin high - riskhiv- infected patients defined by a history of one or more episodes of PCP and /or a peripheral CD4 + T4 helper / inducerlymphocyte count less than or equal to200 /mm 3. azacitidine Vidaza Treatament of myelodysplastic syndromes 12 /3 / /19 /2004 Baclofen Lioresal Intrathecal Treatment of intractable spasticity caused by spinal cord injurymultiple sclerosisand other spinal diseases including spinal ischemiaspinal tumortransverse myelitis cervical spondylosisand degenerative myelopathy. 11 /10 / /25 /1992 Basiliximab Simulect Prophylaxis of solid organ rejection. 12 /12 / /12 /1998 Benzoate and phenylacetate Ucephan For adjunctive therapy in the prevention and treatment of hyperammonemia in patients with urea cycle enzymopathy due to carbamylphosphate 1 /21 / /23 /1987 synthetaseornithinetranscarbamylase or argininosuccinate synthetase deficiency. benzoate /phenylacetate Ammonul Treatment of acute hyperammonemia and associated encephalopathy in patients with deficiencies in enzymes of the urea cycle. 11 /22 / /17 /2005

184 NDA 175 Beractant Survanta intra- Prevention of neonatal respiratory distress syn- 2 /5 / /1 /1991 tracheal drome. Beractant Survanta intra- Treatment of neonatal respiratory distress syn- 2 /5 / /1 /1991 tracheal drome. Betaine Cystadane Treatment of homocystinuria 5 /16 / /25 /1996 Bexarotene Targretin Treatment of cutaneous manifestations of cutaneous T - cell lymphoma in patients who are refractory to at least one prior systemic therapy 6 /18 / /29 /1999 Bleomycin sulfate Blenoxane Treatment of malignant pleural effusion 9 /17 / /20 /1996 bortezomib VELCADE To treat multiple myeloma 1 /15 / /13 /2003 Bosentan Tracleer Treatment of pulmonary arterial hypertension. 10 /6 / /20 /2001 Botulinum toxin type A Botox Treatment of cervical dystonia. 8 /20 / /21 /2000 Botulinum toxin type A Botox Treatment of blepharospasm associated with dystonia in adultspatients 12 years of age and above. Botulinum toxin type A Botox Treatment of strabismus associated with dystonia in adults patients 12 years of age and above. 3 /22 / /29 / /22 / /29 /1989 Botulinum toxin type B Myobloc Treatment of cervical dystonia 1 /16 / /8 /2000 Botulism immune globulin Buffered intrathecal electrolyte /dextrose Buprenorphine hydrochloride Buprenorphine in combination with naloxone BabyBIG Treatment of infant botulism 1 /31 / /23 /2003 Elliotts B Solutiotration For use as a diluent in the intrathecal adminis- 8 /24 / /27 /1996 of methotrexate and cytarabine for the prevention or treatment meningeal leukemia and lymphocytic lymphoma Subutex Treatment of opiate addiction in opiate users 6 /15 / /8 /2002 Suboxone Treatment of opiate addiction in opiate users 10 /27 / /8 /2002 Busulfan Busulfex As preparative therapy in the treatment of malignancies with bone marrow transplantation. 7 /28 / /4 /1999 Caffeine Cafcit Treatment of apnea of prematurity 9 /20 / /21 /1999 Calcitonin - human for injection Cibacalcin Treatment of symptomatic Pagets diseaseosteitis deformans. 1 /20 / /31 /1986 Calcium acetate Phos - Lo Treatment of hyperphosphatemia in end stage renal failure. 12 /22 / /10 /1990 Ceramide trihexosidase /alpha - galactosidase A Fabrazyme Treatment of Fabrys disease 1 /19 / /24 /2003

185 176 NDA Chenodiol Chenix For patients with radiolucent stones in well opacifying gallbladdersin whom elective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age cinacalcet Sensipar Treatment of hypercalcemia in patients with parathyroid carcinoma 9 /21 / /28 / /12 / /8 /2004 Citric acidglucono - Renacidin Irri- Treatment of renal and bladder calculi of the 8 /28 / /2 /1990 delta - lactone and gation apatite or struvite variety. magnesium carbonate Cladribine Leustatin Injection Treatment of hairy cell leukemia. 11 /15 / /26 /1993 clofarabine Clolar Treatment of acute lymphoblastic leukemia 2 /7 / /28 /2004 Clofazimine Lamprene Treatment of lepromatous leprosyincluding dapsone - resistant lepromatous leprosy and lepromatous leprosy complicated by erythema nodosum leprosum. Clonidine Duraclon For continous epidural administration as adjunctive therapy with intraspinal opiates for the treatment of pain in cancer patients tolerant toor unresponsive tointraspinal opiates Coagulation factor Ⅸ Mononine Replacement treatment and prophylaxis of the hemorrhagic complications of hemophilia B. 6 /11 / /15 / /24 / /2 / /27 / /20 /1992 Coagulation Factor Ⅸ AlphaNine For use as replacement therapy in patients 7 /5 / /31 /1990 human with hemophilia B for the prevention and control of bleeding episodesand during surgery to correct defective hemostasis. Coagulation Factor Ⅸ recombinant BeneFix Treatment of hemophilia B. 10 /3 / /11 /1997 Coagulation factor Ⅶ a NovoSeven Treatment of bleeding episodes in hemophilia 6 /6 / /25 /1999 recombinant A or B patients with inhibitors to Factor Ⅷ or Factor Ⅸ. Colfosceril palmitateexosurf Neonatal for Intratra- cetyl alcoholtyloxapol cheal Colfosceril palmitateexosurf Neonatal for Intratra- cetyl alcoholtyloxapol cheal Prevention of hyaline membrane diseasealso known as respiratory distress syndrome in infants born at 32 weeks gestation or less Treatment of established hyaline membrane disease at all gestational ages. 10 /20 / /2 / /20 / /2 /1990 Corticorelin ovine tri- Acthrel For use in differentiating pituitary and ectopic 11 /24 / /23 /1996 flutate production of ACTH in patients with ACTH - dependent Cushings syndrome.

186 NDA 177 Cromolyn sodium Gastrocrom Treatment of mastocytosis 3 /8 / /22 /1989 Cromolyn sodium 4% Opticrom 4% Treatment of vernal keratoconjunctivitis 7 /24 / /3 /1984 ophthalmic solution ophthalmic solution Cysteamine Cystagon Treatment of nephropathic cystinosis 1 /25 / /15 /1994 Cytarabine liposomal DepoCyt Treatment of neoplastic meningitis. 6 /2 / /1 /1999 Cytomegalovirus immune CytoGam Prevention or attenuation of primary cy- 8 /3 / /4 /1998 globulin tomegalovirus disease in immunosuppressed recipients of organ transplants Daclizumab Zenapax Prevention of acute renal allograft rejection. 3 /5 / /10 /1997 Daunorubicin citrate li- DaunoXome Treatment of patients with advanced HIV- as- 5 /14 / /8 /1996 posome injection sociated Kaposis sarcoma Denileukin diftitox Ontak Treatment of patients with persistent or recurrent cutaneous T - cell lymphoma whose malignant cells express the CD25 component of the IL - 2 receptor. Desmopressin acetate DDAVP Treatment of mild hemophilia A and von Willebrands disease. administration. 8 /21 / /5 / /22 / /7 /1994 Diazepam viscous solution for rectal administration DIASTAT Dexrazoxane Zinecard For the prevention of cardiomyopathy associated with doxorubicin 12 /17 / /26 /1995 For the management of selectedrefractory2 /25 / /29 /1997 patients with epilepsyon stable regimens of antiepileptic drugsaeds who require intermittent use of diazepam to control bouts of increased seizure activity. Diethyldithiocar bamate Imuthiol Treatment of AIDS. 4 /3 /1986 Diethylenetriaminepentaacetic acid DTPA Digoxin immune Ovine FAB Digibind Treatment of patients with known or suspected internal contamination with plutoniumamericiumor curium to increase the rates of elimination. Treatment of potentially life threatening digitalis intoxication in patients who are refractory to management by conventional therapy. Dornase alfa Pulmozyme To reduce mucous viscosity and enable the clearance of airway secretions in patients with cystic fibrosis. 4 /28 / /11 / /1 / /22 / /16 / /30 /1993 Doxorubicin liposome Doxil Treatment of ovarian cancer. 11 /4 / /28 /1999 Dronabinol Marinol For the stimulation of appetite and prevention of weight loss in patients with a confirmed diagnosis of AIDS. 1 /15 / /22 /1992

187 178 NDA Eflornithine HCl Ornidyl Treatment of Trypanosoma brucei gambiense infectionsleeping sickness. 4 /23 / /28 /1990 Epirubicin Ellence Treatment of breast cancer 9 /14 / /15 /1999 Epoetin alfa Epogen Treatment of anemia associated with HIV infection or HIV treatment. Epoetin alfa Epogen Treatment of anemia associated with end stage renal disease. 7 /1 / /31 / /10 / /1 /1989 Epoprostenol Flolan Treatment of secondary pulmonary hypertension 3 /22 / /14 /2000 due to intrinsic precapillary pulmonary vascular disease. Epoprostenol Flolan Treatment of primary pulmonary hypertension. 9 /25 / /20 /1995 Etanercept Enbrel Reduction in signs and symptoms of moderately to severely active polyarticular - course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more disease - modifying anti - rheumatic drugs. 10 /27 / /27 /1999 Ethanolamine oleate Ethamolin Treatment of patients with esophageal varices that have recently bledto prevent rebleeding. Etidronate disodium Didronel Treatment of hypercalcemia of malignancy inadequately managed by dietary modification and /or oral hydration. Exemestane Aromasin Treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy. 3 /22 / /22 / /21 / /21 / /19 / /21 /1999 Felbamate Felbatol Treatment of Lennox - Gastaut syndrome. 1 /24 / /29 /1993 Filgrastim Neupogen Reduction in the duration of neutropenia11 /7 / /2 /1998 feverantibiotic useand hospitalizationfollowing induction and consolidation treatment for acute myeloid leukemia. Filgrastim Neupogen For use in the mobilization of peripheral blood progenitor cells for collection in patients who will receive myeloablative or myelosuppressive chemotherapy. Filgrastim Neupogen Treatment of patients with severe chronic neutropeniaabsolute neutrophil count less than 500 /mm 3. Filgrastim Neupogen Treatment of neutropenia associated with bone marrow transplants 7 /17 / /28 / /7 / /19 / /1 / /15 /1994

188 NDA 179 Fludarabine phosphate Fludara Treatment of chronic lymphocytic leukemia Follitropin alfarecombinant Gonal - F CLL including refractory CLL. For the initiation and re - initiation of spermatogenesis in adult males with reproductive failure due to hypothalamic or pituitary dysfunctionhypogonadotropic hypogonadism. AMENDED indication 6 /27 /00For the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure. Fomepizole Antizole Treatment of methanol or ethylene glycol poisoning. Fosphenytoin Cerebyx For the acute treatment of patients with status epilepticus of the grand mal type. 4 /18 / /18 / /21 / /24 / /22 / /8 / /22 / /4 / /4 / /5 /1996 Gallium nitrate injection Fomepizole Antizole Treatment of methanol or ethylene glycol poisoning. Ganite Treatment of hypercalcemia of malignancy. 12 /5 / /17 /1991 Ganciclovir intravitreal implant Vitrasert Implant Treatment of cytomegalovirus retinitis. 6 /7/ /4 /1996 Ganciclovir sodium Cytovene Treatment of cytomegalovirus retinitis in immunocompromised patients with AIDS. Gemtuzumab zogamicin Mylotarg Treatment of CD33 - positive acute myeloid leukemia. 10 /31 / /23 / /24 / /17 /2000 Glatiramer acetate Copaxone Treatment of multiple sclerosis 11 /9 / /20 /1996 Glutamine NutreStore For use with human growth hormone in the treatment of short bowel syndrome nutrient malabsorption from the gastrointestinal tract resulting from an inadequate absorptive surface. Gonadorelin acetate Lutrepulse For induction of ovulation in women with hypothalamic amenorrhea due to a deficiency or absence in the quantity or pulse pattern of endogenous GnRH secretion. Halofantrine Halfan Treatment of mild to moderate acute malaria caused by susceptible strains of P. falciparum and P. vivax. 3 /6 / /10 / /22 / /10 / /4 / /24 /1992

189 180 NDA Hemin Panhematin Amelioration of recurrent attacks of acute intermittent porphyriaaiptemporarily related to the menstrual cycle in susceptible women and similar symptoms which occur in other patients with AIPporphyria variegata and hereditary coproporphyria. 3 /16 / /20 /1983 Histrelin acetate Supprelin Treatment of central precocious puberty. 8 /10 / /24 /1991 Hydroxyurea Droxia Treatment of patients with sickle cell anemia as shown by the presence of hemoglobin S. ibritumomab tiuxetan Zevalin Treatment of B - cell non - Hodgkins lymphoma. 10 /1 / /25 / /6 / /19 /2002 Icodextrin 7.5% with Extraneal Treatment of those patients having end stage 7 /18 / /20 /2002 Electrolytes Peritoneal renal disease and requiring peritoneal dialysis Dialysis Solution treatment. Idarubicin HCl for injectioso Idamycin Treatment of acute myelogenous leukemiaal- 7 /25 / /27 /1990 referred to as acute nonlymphocytic leukemia. Ifosfamide Ifex Treatment of testicular cancer. 1 /20 / /30 /1988 Iloprost inhalation solution Ventavis Treatment of pulmonary arterial hypertension 8 /17 / /29 /2004 Imatinib Gleevec Treatment of chronic myelogenous leukemia 1 /31 / /10 /2001 imatinib mesylate Gleevec Treatment of gastrointestinal stromal tumors 11 /1 / /1 /2002 Imiglucerase Cerezyme Replacement therapy in patients with types Immune globulin intravenous Gamimune N ⅠⅡand Ⅲ Gauchers disease Infection prophylaxis in pediatric patients affected with the human immunodeficiency virus. Infliximab Remicade Treatment of moderately to severely active Crohns disease for the reduction of the signs and symptoms in patients who have an inadequate response to conventional therapyand treatment of patients with fistulizing Crohns disease for the reduction in the number of draining enterocutaneous fistulas. 11 /5 / /23 / /18 / /27 / /14 / /24 /1998 Interferon alfa - 2a Roferon A Treatment of chronic myelogenous leukemia. 6 /6 / /19 /1995 Interferon alfa - 2a recombinant Roferon - A Treatment of AIDS related Kaposis sarcoma. 12 /14 / /21 /1988 Interferon alfa - 2b recombinant Intron A Treatment of AIDS - related Kaposis sarcoma. 6 /24 / /21 /1988 Interferon beta - 1a Avonex Treatment of multiple sclerosis. 12 /16 / /17 /1996

190 NDA 181 Interferon beta - 1b Betaseron Treatment of multiple sclerosis. 11 /17 / /23 /1993 Interferon gamma 1 - b Actimmune Treatment of chronic granulomatous disease. 9 /30 / /20 /1990 Interferon gamma - 1b Actimmune Delaying time to disease progression in patients with severeosteopetrosis. malignant 9 /30 / /10 /2000 Iobenguane Sulfate Ⅰ 131 For use as a diagnostic adjunct in patients with pheochromocytoma. 11 /14 / /21 /1990 ironⅢ- hexacyanoferrateⅡ ed Radiogardase Treatment of patients with known or susupect- 5 /1 / /2 /2003 internal contamination with radioactive or non - radioactive cesium or thallium Lamotrigine Lamictal Treatment of Lennox - Gastaut syndrome. 8 /23 / /24 /1998 laronidase Aldurazyme Treatment of patients with mucopolysaccharidosis - Ⅰ. Lepirudin Refluden Treatment of heparin - associated thrombocytopenia type Ⅱ. 9 /24 / /30 / /13 / /6 /1998 Leucovorin Leucovorin cal- For rescue use after high dose methotrexate 8 /17 / /31 /1988 cium therapy in the treatment of osteosarcoma. Leucovorin Leucovorin calcium For use in combination with 5 - fluorouracil 12 /8 / /12 /1991 for the treatment of metastatic colorectal can- cer. Leuprolide acetate Lupron Treatment of central precocious puberty. 7 /25 / /16 /1993 Levocarnitine Carnitor Treatment of manifestations of carnitine deficiency 9 /6 / /15 /1999 in patients with end stage renal disease who require dialysis Levocarnitine Carnitor Treatment of genetic carnitine deficiency. 2 /28 / /10 /1986 Levocarnitine Carnitor Treatment of primary and secondary carnitine deficiency of genetic origin. 7 /26 / /16 /1992 Levomethadyl acetate Orlaam Treatment of heroin addicts suitable for main- 1 /24 / /9 /1993 hydrochloride tenance on opiate agonists. Liothyronine sodium injection Lidocaine patch 5% Lidoderm Patch For relief of allodyniapainful hypersensitivity and chronic pain in postherpetic neuralgia 10 /24 / /19 /1999 Triostat Treatment of myxedema coma /precoma. 7 /30 / /31 /1991 Liposomal amphotericin B Liposomal amphotericin B AmBisome Treatment of cryptococcal meningitis 12 /10 / /11 /1997 AmBisome Treatment of visceral leishmaniasis 12 /6 / /11 /1997 Lodoxamide Alomide Oph- Treatment of vernal keratoconjunctivitis 10/16 / /23 /1993 tromethamine thalmic Solution

191 182 NDA Mafenide acetate solution Sulfamylon solution For use as an adjunctive topical antimicrobial agent to control bacterial infection when used under moist dressings over meshed autografts on excised burn wounds. Mefloquine HCl Lariam Treatment of acute malaria due to Plasmodium falciparum and Plasmodium vivax. Mefloquine HCl Lariam Prophylaxis of Plasmodium falciparum malaria which is resistant to other available drugs. 7 /18 / /5 / /13 / /2 / /13 / /2 /1989 Megestrol acetate Megace Treatment of patients with anorexiacachexia4 /13 / /10 /1993 Melphalan Alkeran For Injection or significant weight loss= / > 10% of baseline body weightand confirmed diagnosis of AIDS. Treatment of patients with multiple myeloma for whom oral therapy is inappropriate. Mesna Mesnex For use as a prophylactic agent in reducing the incidence of ifosfamide - induced hemorrhagic cystitis. 2 /24 / /18 / /14 / /30 /1988 Methotrexate sodium Methotrexate Treatment of osteogenic sarcoma 10 /21 / /7 /1988 Metronidazole topicalmetrogel Treatment of acne rosacea. 10 /22 / /22 /1988 Midodrine HCl Amatine Treatment of patients with symptomatic orthostatic hypotension. 12 /5 / /6 /1996 miglustat Zavesca Treatment of Gaucher disease. 5 /29 / /31 /2003 Mitoxantrone Novantrone Treatment of progressive - relapsing multiple sclerosis Mitoxantrone Novantrone Treatment of secondary - progressive multiple sclerosis. Mitoxantrone Novantrone Treatment of hormone refractory prostate cancer. Mitoxantrone HCl Novantrone Treatment of acute myelogenous leukemiaalso referred to as acute nonlymphocytic leukemia. Modafinil Provigil Treatment of excessive daytime sleepiness in narcolepsy. Monooctanoin Moctanin For dissolution of cholesterol gallstones retained in the common bile duct. Morphine sulfate concentrate Infumorph For use in microinfusion devices for intraspinal administration in the treatment of intractable chronic pain. 8 /13 / /13 / /13 / /13 / /21 / /13 / /13 / /23 / /15 / /24 / /30 / /31 / /12 / /19 /1991

192 NDA 183 multi - vitiam infusion without vitamin K M. V. I Prevention of vitamin deficiency and thromboembolic complications in people receiving home parenteral nutrition and warfarin - type anticoagulant therapy 3 /8 / /9 /2004 Nafarelin acetate Synarel Nasal Treatment of central precocious puberty. 7 /20 / /26 /1992 Solution Naltrexone HCl Trexan For blockade of the pharmacological effects of 3 /11 / /30 /1984 exogenously administered opioids as an adjunct to the maintenance of the opioid - free state in detoxified formerly opioid - dependent individuals. nitazoxanide Alinia Treatment of intestinal giardiasis 2 /14 / /22 /2002 Nitazoxanide Alinia Treatment of cryptosporidiosis. 12 /12 / /22 /2002 Nitisinone Orfadin Treatment of tyrosinemia type 1. 5 /16 / /18 /2002 Nitric oxide INOmax Treatment of persistent pulmonary hypertension in the newborn. 6 /22 / /23 /1999 Octreotide Sandostatin LAR Treatment of diarrhea associated with vasoactive intestinal peptide tumorsvipoma. 8 /24 / /25 /1998 Octreotide Sandostatin LAR Treatment of acromegaly. 8 /24 / /25 /1998 Octreotide Sandostatin Treatment of severe diarrhea and flushing as- 8 /24 / /25 /1998 LAR sociated with malignant carcinoid tumors. Ofloxacin Ocuflox Ophthalmic Treatment of bacterial corneal ulcers. 4 /18 / /22 /1996 Solu- tion Oprelvekin Neumega Prevention of severe chemotherapy - induced 12 /17 / /25 /1997 thrombocytopenia. Oxybate Xyrem Treatment of narcolepsy. 11 /7 / /17 /2002 Paclitaxel Taxol Treatment of AIDS - related Kaposis sarcoma. 3 /25 / /4 /1997 Pegademase bovine Adagen For enzyme replacement therapy for ADA deficiency 5 /29 / /21 /1990 in patients with severe combined im- munodeficiency. Pegaspargase Oncaspar Treatment of acute lymphocytic leukemia. 10 /20 / /1 /1994 Pegvisomant Somavert Treatment of acromegaly 6 /24 / /25 /2003 pemetrexed disodium Alimta Treatment of malignant pleural mesothelioma 8 /28 / /4 /2004 Pentamidine isethionate Nebupent Prevention of Pneumocystis carinii pneumonia 1 /12 / /15 /1989 in patients at high risk of developing this disease. Pentamidine isethionate Pentam 300 Treatment of Pneumocystis carinii pneumonia. 2 /28 / /16 /1984

193 184 NDA Pentastarch Pentaspan As an adjunct in leukapheresis to improve the 8 /28 / /19 /1987 harvesting and increase the yield of leukocytes by centrifugal means. Pentosan polysulfate Elmiron Treatment of interstitial cystitis. 8 /7 / /26 /1996 sodium Pentostatin for injection Nipent Treatment of hairy cell leukemia. 9 /10 / /11 /1991 Pilocarpine Salagen Treatment of xerostomia induced by radiation 9 /24 / /22 /1994 therapy for head and neck cancer. Pilocarpine HCl Salagen Treatment of xerostomia and keratoconjunctivitis sicca in Sjogrens syndrome patients. 2 /28 / /11 /1998 polifeprosan 20 with Gliadel Treatment of malignant glioma. 12 /13 / /23 /1996 carmustine polifeprosan 20 with Gliadel Treatment of malignant glioma 12 /13 / /25 /2003 carmustine porfimer Photofrin For the ablation of High - Grade Dysplasia in Barretts Esophagus in patients who are not considered to be candidates for esophagectomy 10 /19 / /1 /2003 Porfimer sodium Photofrin For the photodynamic therapy of patients with 6 /6 / /27 /1995 primary or recurrent obstructingeither partially or completelyesophageal carcinoma. Potassium citrate Urocit - K Prevention of calcium renal stones in patients 9 /16 / /30 /1985 with hypocitraturia. Potassium citrate Urocit - K For avoidance of the complication of calcium 9 /12 / /30 /1985 stone formation in patients with uric lithiasis. Potassium citrate Urocit - K Prevention of uric acid nephrolithiasis. 11 /1 / /30 /1985 Potassium Iodide Oral Solution ThyroShield For use as a thyroid blocking agent in pediatric patients exposed to radiactive iodine Pulmonary surfactant Curosurf For the treatment and prevention of respiratory replacementporcine distress syndrome in premature infants. rasburicase Elitek Treatment of malignancy - associated or chemotherapy - induced hyperuricemia. Recombinant human luteinizing hormone For use in association with recombinant human follicle stimulating hormone for the treatment of women with chronic anovulation due to hypogonadotropic hypogonadism. Respiratory syncytial Respigam Prophylaxis of respiratory syncytial virus lower virus immune globulin respiratory tract infections in infants and young children at high risk of RSV disease. RhoDimmune globulin WinRho SD Treatment of immune thrombocytopenic purpura. intravenous 11 /17 / /2 / /18 / /11 / /12 /2002 Luveris 10 /7 / /27 / /18 / /9 / /24 /1995

194 NDA 185 ribavirin REBETOL Treatment of chronic hepatitis C in pediatric patients Rifabutin Mycobutin Prevention of disseminated Mycobacterium avium complex disease in patients with advanced HIV infection. Rifampin Rifadin I. V. For antituberculosis treatment where use of the oral form of the drug is not feasible. RifampinisoniazidRifater For the short - course treatment of tuberculosis. pyrazinamide 4 /4 / /29 / /18 / /23 / /9 / /25 / /12 / /31 /1994 Rifapentine Priftin Treatment of pulmonary tuberculosis. 6 /9 / /22 /1998 Riluzole Rilutek Treatment of amyotrophic lateral sclerosis. 3 /16 / /12 /1995 Rituximab Rituxan Treatment of non - Hodgkins B - cell lymphoma. Sacrosidase Sucraid Treatment of congenital sucrase - isomaltase deficiency. 6 /13 / /26 / /10 / /9 /1998 Sargramostim Leukine To reduce neutropenia and leukopenia and decrease 3 /6 / /15 /1995 the incidence of death due to infection in patients with acute myelogenous leukemia. Sargramostim Leukine Treatment of neutropenia associated with bone 5 /3 / /5 /1991 marrow transplantfor the treatment of graft failure and delay of engraftmentand for the promotion of early engraftment. Satumomab pendetide Oncoscint CR/ OV Detection of ovarian carcinoma. 9 /25 / /29 /1992 Selegiline HCl Eldepryl As an adjuvant to levodopa and carbidopa treatment of idiopathic Parkinsons disease paralysis agitans postencephalitic Parkinsonismand symptomatic Parkinsonism. Sermorelin acetate Geref Treatment of idiopathic or organic growth hormone deficiency in children with growth failure. sodium phenylbutyrate Buphenyl Treatment of urea cycle disorderscarbamylphosphate synthetase deficiencyornithine transcarbamylase deficiencyand arginiosuccinic acid synthetase deficiency. Somatrem for injection Protropin For long - term treatment of children who have growth failure due to a lack of adequate endogenous growth hormone secretion. Somatropin Genotropin Treatment of adults with growth hormone deficiency. 11 /7 / /5 / /14 / /26 / /22 / /30 / /9 / /17 / /6 / /31 /1997

195 186 NDA Somatropin Humatrope Treatment of short stature associated with Turner syndrome. Somatropin Nutropin For use in the long - term treatment of children who have growth failure due to a lack of adequate endogenous growth hormone secretion. SomatropinrDNA origin Nutropin Depot Long - term treatment of children who have growth failure due to a lack of adequate en- dogenous growth hormone secretion. SomatropinrDNA origin mone Saizen Treatment of idiopathic or organic growth horure. deficiency in children with growth fail- SomatropinrDNA origininjection Norditropin Treatment of growth failure in children due to inadequate growth hormone secretion. 5 /8 / /30 / /6 / /17 / /28 / /22 / /6 / /8 / /10 / /20 /2000 Somatropinr - DNA Zorbtive For use alone or in combination with glutamine in the treatment of short bowel syndrome. 3 /6 / /1 /2003 somatropinrdna Genotropin Treatment of growth failure in children who were born small for gestational age. SomatropinrDNA Genotropin Treatment of short stature in patients with Prader - Willi syndrome. Somatropin for injection Nutropin As replacement therapy for growth hormone deficiency in adults after epiphyseal closure. Somatropin for injection Serostim Treatment of AIDS - associated catabolism/ weight loss. Somatropin for injection Nutropin Treatment of growth retardation associated with chronic renal failure. Somatropin for injection Nutropin Treatment of short stature associated with Turners syndrome. Somatropin for injection Humatrope For the long - term treatment of children who have growth failure due to inadequate secretion of normal endogenous growth hormone. Sotalol HCl Betapace Treatment of life - threatening ventricular tachyarrhythmias. 12 /27 / /25 / /6 / /20 / /18 / /15 / /15 / /23 / /4 / /17 / /23 / /30 / /12 / /8 / /23 / /30 /1992 Sterile talc powder Sclerosol Treatment of malignant pleural effusion. 9 /18 / /24 /1997 Intrapleural Aerosol Succimer Chemet Treatment of lead poisoning in children. 5 /9 / /22 /1988 Sulfadiazine Sulfadiazine For use in combination with pyrimethamine for the treatment of Toxoplasma gondii encephalitis in patients with and without AIDS. 3 /14 / /29 /1994

196 NDA 187 Surface active extract of Infasurf Treatment and prevention of respiratory failure 6 /7 / /1 /1998 saline lavage of bovine due to pulmonary surfactant deficiency in lungs preterm infants. Synthetic human secretin For use in the diagnosis of gastrinoma associ- 6 /16 / /9 /2004 ated with Zollinger - Ellison syndrome. Synthetic porcine secretin For use in conjunction with diagnostic proce- 3 /7 / /4 /2002 dures for pancreatic disorders to increase pancreatic fluid secretion. Synthetic porcine secretin For use in the evaluation of exocrine pancreas 6 /18 / /1 /2002 function. Synthetic porcine secretin For use in the diagnosis of gastrinoma associ- 6 /18 / /4 /2002 ated with Zollinger - Ellison syndrome. Temozolomide Temodar Treatment of recurrent malignant glioma. 10 /5 / /11 /1999 temozolomide Temodar Treatment of malignant glioma 10 /5 / /15 /2005 Teniposide Vumon Treatment of refractory childhood acute lymphocytic leukemia. 11 /1 / /14 /1992 Teriparatide Parathar Diagnostic agent to assist in establishing the diagnosis in patients presenting with clinical and laboratory evidence of hypocalcemia due 1 /9 / /23 /1987 to either hypoparathyroidism or pseudohypoparathyroidism. Thalidomide Thalomid Treatment of erythema nodosum leprosum. 7 /26 / /16 /1998 Thyrotropin alpha Thyrogen As an adjunct in the diagnosis of thyroid cancer. 2 /24 / /30 /1998 tinidazole Tindamax Treatment of giardiasis 4 /18 / /17 /2004 Tinidazole Tindamax Treatment of amebiasis 8 /20 / /17 /2004 Tiopronin Thiola Prevention of cystine nephrolithiasis in patients with homozygous cystinuria. 1 /17 / /11 /1988 Tobramycin for inhalation TOBI Treatment of bronchopulmonary infections of 10 /13 / /22 /1997 Pseudomonas aeruginosa in cystic fibrosis pa- tients. Topiramate Topamax Treatment of Lennox - Gastaut syndrome. 11 /25 / /28 /2001 Toremifene Fareston Hormonal therapy of metastatic carcinoma of the breast. 9 /19 / /29 /1997 Tositumomab and iodine Bexxar Treatment of non - Hodgkins B - cell lym- 5 /16 / /27 /2003 I 131 tositumomab phoma. Tranexamic acid Cyklokapron Treatment of patients with congenital coagulopathies who are undergoing surgical procedurese. g. dental extractions. 10 /29 / /30 /1986 treprostinil Remodulin Treatment of pulmonary arterial hypertension. 6 /4 / /21 /2002

197 188 NDA Tretinoin Vesanoid Treatment of acute promyelocytic leukemia. 10 /24 / /22 /1995 Trientine HCl Syprine Treatment of patients with Wilsons disease 12 /24 / /8 /1985 who are intolerantor inadequately responsive to penicillamine. Trimetrexate Neutrexin Treatment of Pneumocystis carinii pneumonia 5 /15 / /17 /1993 glucuronate in AIDS patients. Urofollitropin Metrodin For induction of ovulation in patients with 11 /25 / /18 /1986 polycystic ovarian disease who have an elevated LH/FSH ratio and who have failed to respond to adequate clomiphene citrate therapy. Ursodiol URSO Treatment of patients with primary biliary cirrhosis. 6 /20 / /10 /1997 Vaccinia Immune GlobulinHumanIntravenous Treatment of severe complications from the smallpox vaccine 6 /18 / /18 /2005 Valrubicin Valstar Treatment of carcinoma in situ of the urinary 5 /23 / /25 /1998 bladder. Zalcitabine Hivid Treatment of AIDS. 6 /28 / /19 /1992 Zidovudine Retrovir Treatment of AIDS related complex. 3 /19 / /12 /1987 Zidovudine Retrovir Treatment of AIDS. 7 /17 / /19 /1987 Zinc acetate Galzin Treatment of Wilsons disease 11 /6 / /28 /1997 Zoledronate ZometaZabel Treatment of tumor induced hypercalcemia. 8 /18 / /20 /2001

198 ANDA Generics genus % % 8% ANDA 30%60% FDA 2003 Waxman - Hatch Act

199 190 ANDA FDA Kefauver - Harris FDA NDA FDA Kefauver - Harris FDA FDA FDA % 1984 FDA FDA 1984 Drug Price Competition and Patent Term Restoration Act Waxman - Hatch Act Orrin Hatch Henry Waxman 505 j 1984 Waxman - Hatch 5 FDA NDA

200 191 Bioequivelence Abbreviated New Drug Application ANDA Waxman - Hatch ANDA Waxman - Hatch 180 FDA ANDA Paragraph IV certification FDA FDA ANDA % FDA ANDA 1984 FDA FDA 180 ANDA FDA 30 FDA FDA FDA ANDA Amend- ment FDA FDA FDA Hatch - Waxman Hatch - Waxman Hatch - Waxman 5 NDA NCE

201 192 ANDA FDA 5 NDA Hatch - Waxman 30 Hatch - Waxman ANDA 1 paragraph IV certification Medicare Prescription Drug And Modernization Act ANDA 20 ANDA FDA FDA ANDA 30 FDA 30 FDA ANDA FDA ANDA tentatively approved 30 FDA ANDA 30 FDA FDA FDA Hatch - Waxman 1984 Hatch - Waxman Act 180 Bolar ANDA 3. Hatch - Waxman Act Bolar

202 193 ANDA 4. Hatch - Waxman Abbreviated New Drug Application ANDA Hatch - Waxman FDA FDA Hatch - Waxman Act 1984 Hatch - Waxman Act 12% % Hatch - Waxman Act FDA FDA 1989 FDA FDA FDA Charles Y. Chang FDA Vitarin FDA

203 194 ANDA FDA Par Pharmaceutical Inc. Quad Pharmaceuticals Inc FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA 38 FDA FDA 38 FDA FDA FDA FDA FDA FDA FDA FDA Generic Drug Enforcement Act FDA 306 d 4 FDA Debarment FDA FDA

204 195 Debarment Debarment FDA FDA FDA Federal Register FDA FDA FDA FDA FDA FDA FDA FDA S 1 million Permissive Debarment FDA 5 FDA mandatory debarment permissive debarment 10 FDA FDA FDA 1984 Hatch - Waxman Act FDA

205 196 ANDA FDA 1984 Hatch - Waxman Act FDA FDA Approved Drug Products with Therapeutic Equivalence Evaluations Orange Book FDA FDA FDA A A B A AA - AN - AO - AP - AT - AB FDA AB 2003 FDA FDA FDA FDA http/ /www. fda. gov/cder /ob /default. htm 1 2 FDA NDA OTC 3 FDA 4 FDA FDA 30 FDA FDA FDA FDA FDA FDA

206 197 FDA ANDA FDA Reference Listed Drug RLD FDA FDA FDA 505 j 21 CFR FDA FDA PK Bioequivalence 21 CFR 211 GMP FDA FDA FDA FDA FDA FDA FDA

207 198 ANDA FDA FDA f 2 FDA FDA FDA SUPAC 1937 FDA FDA FDA FDA Inactive Ingredient Database FDA FDAFDA FDA Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients FDA FDA FDA FDA FDA 1. Patent Trademark Office PTO FDA Uruguay Round Agreements Act

208 Drug Price Competition and Patent Term Restoration Act FDA ANDA 2. FDA FDA 5 5 FDA IND FDA FDA 3 FDA NCE Hatch - Waxman Act ANDA FDA ANDA FDA FDA FDA 1

209 200 ANDA FDA 45 FDA Bayer Cipro 501 j Drug Price Competition And Patent Term Restoration Act Food And Drug Administration Modernization Act Medicare Prescription Drug And Modernization Act CFR CFR CFR CFR CFR CFR CFR 320 D 314 FDA Subpart C

210 201 OGD FDA FDA ANDA FDA FDA ANDA Day Exclusivity When Multiple ANDAs Are Submitted on the Same Day ANDA Alternate Source of the Active Pharmaceutical Ingredient in Pending ANDAs ANDA ANDAsImpurities in Drug Substances Hatch - Waxman ANDA 180 Court DecisionsANDA Approvalsand Day Exclusivity Under the Hatch - Waxman Act Amendments to the Federal FoodDrugand Cosmetic Act Handling and Retention of BA and BE Testing Samples OGD ICH Letter announcing that the OGD will now accept the ICH long - term storage conditions as well as the stability studies conducted in the past CDER ORA CDER ORA Letter describing efforts by the CDER and the ORA to clarify the responsibilities of CDER chemistry review scientists and ORA field investigators in the new and abbreviated drug approval process in order to reduce duplication or redundancy in the process OGD Letter on incomplete Abbreviated ApplicationsConvictions Under GDEAMultiple Supplements Annual Reports for Bulk AntibioticsBatch Size for Transdermal DrugsBioequivalence ProtocolsResearch Deviations from OGD Policy ANDA Letter on the Provision of new information pertaining to new bioequivalence guidelines and refuse - to - file letters Letter on the provision of new procedures and policies affecting the generic drug review process Letter on the request for cooperation of regulated industry to improve the efficiency and effectiveness of the generic drug review processby assuring the completeness and accuracy of required information and data submissions Letter on the response to 12 /20 /1984 letter from the Pharmaceutical Manufacturers Association about the Drug Price Competition and Patent Term Restoration Act Letter to all ANDA and AADA applicants about the Generic Drug Enforcement Act of 1992 GDEA and the Office of Generic Drugs intention to refuse - to - file incomplete submissions as required by the new law /

211 202 ANDA Letter to regulated industry notifying interested parties about important detailed information regarding labeling scale - uppackagingminor /major amendment criteria and bioequivalence requirements MajorMinorand Telephone Amendments to Abbreviated New Drug Applications ANDA Organization of an ANDA ANDA Revising ANDA Labeling Following Revision of the RLD Labeling Skin Irritation and Sensitization Testing of Generic Transdermal Drug Products ANDA Variations in Drug Products that May Be Included in a Single ANDA Hatch - Waxman FDA MaPP FDA CDER Manual of Policies and Procedures MaPP MaPP Chapter Generic Drugs Responding to Telephone Inquiries in the Office of Generic Drugs Collection of Documents in Docket for Agency Policy StatementsSpeeches and Policy and Procedure Guides Addressing Human Generic Drugs Issuing and Tracking of Consults OGD Reassignment of Bioequivalence Reviews Productivity Documentation in the Division of Bioequivalence Review Responsibility for Bioequivalence Studies with Clinical Endpoints Submitted in an Abbreviated New Drug Application Review of Investigational New Drug Applications Bio - INDsby the Office of Generic Drugs Bio - IND Procedures for Review of Bioequivalence Study Protocols Inspections of Clinical Facilities and Analytical Laboratories Review of Dissolution Data in Supplemental ANDAs ANDA Requesting Methods Validation for ANDAs ANDA Scoring Configuration of Generic Drug Products Guidance on the Packaging of Test Batches Consistent Container Information in an Abbreviated Application Reaffirmation of Expiration Dating Period for Abbreviated Applications

212 Availability of Labeling Guidelines Review of Generic Drug Product Labeling Requiring Input From Multiple FDA Components FDA Requests for Expedited Review of Supplements to Approved ANDAs and AADAs Restatement of the Office of Generic Drugs First - infirst - reviewedpolicy and Modification of the Exceptions to the Policy Regarding Minor Amendments Telephone Requests by the Division of Bioequivalence Telephone Requests by the Divisions of Chemistry Handling and Processing Requests for Global Reviews FDA FDA FDA FDA FDA FDA FDA FDA FDA 30 FDA 350 FDA 2004 FDA drug formularies 60

213 204 ANDA FDA Public Health Service Medicaid Medicare %

214 Hatch - Waxman Act %80% 50% Barr Prozac fluoxetine hydrochloride20mg 180 S 311 million 2001 S S 4.63 Barr 12 70% MOVA 1998 CounsellorDevelopments In Intellectual Property Law And PracticeVOL.4 NO.2 Mova 180 Mova Glyburide Upjohn Mova FDA ANDA Upjohn Glynase 2007 Mova Glynase Glyburide Glynase Glyburide Upjohn Upjohn Glyburide 70% Upjohn Glyburide Upjohn 1984 FDA Hatch - Waxman FDA FDA Mova 70% Glyburide 163 Mova Upjohn 70%

215 206 ANDA Mova Mova 49% 163 Mova FDA Glynase % FDA ANDA Upjohn 49% 163 Mova FDA Glynase ANDA Upjohn Upjohn Mova 45 San JuanPuerto Rico Mova Glynase Puerto Rico Upjohn Mova Mova Mova Upjohn Mova Upjohn Glynase Mova Upjohn Upjohn Mova Upjohn Mylan ANDA Upjohn 45 Mylan Mylan Upjohn Mova Mylan FDA Mylan Glyburide Mylan ANDA Mova Glyburide FDA Glyburide Mova Mova FDA Mylan Mylan FDA Mylan FDA 180 Mova Mova FDA FDA 21 U. S. C. 355 j 4 B iv Mylan ANDA Mova Upjohn Mova 180 FDA Mylan Mylan FDA Mova FDA Mylan Mylan FDA ANDA Mylan Mova Upjohn Upjohn Mova Mova Mova Upjohn Mova Upjohn Upjohn 163 Mova 163 Upjohn Mova Mova Upjohn Mova Upjohn 163 Glyburide

216 207 Hatch - Waxman Upjohn Mova Upjohn Glyburide Mova Glyburide Mylan Mova Upjohn 163 FDA Mova Glyburide 10 8 S Astra Zeneca 53% Pfizer 30%Merck 40% Glaxo Smith Kline 28%Bristol Myers Squibb 27% FDA FDA 1. FDA 45 FDA FDA FDA FDA 45

217 208 ANDA FDA FDA GSK Paxil paroxetine hydrochloride Paxil S 2.67 billion Apotex 1998 ANDA GSK GSK 30 FDA FDA FDA AstraZeneca Prilosec omeprazole Prilosec 2001 S 5.7 billion FDA Andrx Andrx FDA FDA Andrx AstraZeneca Andrx GlaxoSmithKline GSK Augmentin Geneva Augmentin 2017 GSK 2002 GSK Geneva Geneva Hatch - Waxman - FDA ANDA FDA Bristol - Myers Squibb Platinol 3

218 Platinol S S 250 million GlaxoSmithKline Paxil Paxil Apotex 1998 GlaxoSmithKline FDA Paxil Apotex 65 Apotex 2003 Bristol - Myers Squibb Taxol FDA 24 Ivax FDA Ivax Bristol - Myers Squibb BuSpar Bristol - Myers Squibb BuSpar 12 FDA BuSpar Buspirone BuSpar BuSpar 7 Warner - Lambert Pfizer Neurontin Warner Neurontin Neurontin gabapentin 1998 Neurontin Neurontin Warner - Lambert Pfizer S 2 billion Warner - Lambert FDA FDA 2008 gabapentin Alzheimers disease Huntingtons disease Parkinsons disease FDA gabapentin gabapentin Warner - Lambert FDA Apotex 2002 gabapentin Warner - Lambert Apotex gabapentin lactam 30 gabapentin FDA 54

219 210 ANDA FDA ANDA 505 b 2 30 FDA FDA FDA FDA 180 FTC K - Dur FTC Schering - Plough Upsher - Smith AHP K - Dur 20 K - Dur Upsher - Smith FDA AHP K - Dur 20 Upsher - Smith AHP Upsher - Smith Upsher - Smith Upsher - Smith AHP AHP K - Dur 20 K - Dur AHP 2006 K - Dur 20 K - Dur 20 AHP FDA AHP AHP FTC AHP FDA Upsher - Smith AHP K - Dur S 228 million 1999 S 251 million 2000 S 290 million % S 216 million K - Dur 20

220 211 FTC K - Dur 20 Hytrin Hytrin Abbott Laboratories Abbott Hytrin terazosin Abbott FDA Hytrin S 500 and S 750 million Terazosin Geneva FDA Abbott 45 Abbott 30 Hytrin Geneva Abbott Abbott Geneva S 4.5 million Geneva Geneva 180 Geneva 180 Abbott % Geneva Abbott Geneva Hytrin terazosin 3. Authorised generics 180 Barr Johnson & Johnson Ortho Tri - Cyclen 180 Johnson & Johnson Watson Barr Barr Paxil paroxetinglucotrol XLWellbutrin SR Glucophage XR FTC FDA FDA

221 212 ANDA FDA FDA FDA FDA FDA FDA FDA FDA FDA FDA Hytrin FDA FDA Aredia FDA - - FDA - FDA -

222 213 FDA Neurontin neurodegenerative FDA FDA FDA FDA FDA ~ billions Pravastatin Pravachol BMS S Sertraline HCl Zoloft Pfizer S Simvastatin Zocor Merck & Co S Amlodipine besylate Norvasc Pfizer S Oxycodone HCl Oxycontin Purdue Pharma S Zolpidem tartrate Ambien Lorax S Sumatriptan Imitrex Oral GSK S Cetirizine hcl Zyrtec Pfizer S Alendronate sodium Fosamax Merck & Co S

223 214 ANDA 2004 billions Risperidone Risperdal Janssen S Venlafaxine hcl Effexor XR Wyeth S Divalproex sodium Depakote Abbott S Gabapentin Neurontin Pfizer S lamotrigine Lamictal GSK S Rosiglitazone maleate Avandia SB Pharmco S Rabeprazole sodium Aciphex Eisai S Lansoprazole Prevacid TAP Pharma S Atorvastatin Lipitor Pfizer S escitalopram Lexapro Forest S Levofloxacin Levaquin Ortho McNeil S Pioglitazone hcl Actos Takeda S Olanzapine Zyprexa Eli Lilly S Montelukast sodium Singulair Merck & Co S Oestrogen Premarin Tabs Wyeth S Sildenafil citrate Viagra Pfizer S Bupropion hcl Wellbutrin SR GSK S Celecoxib Celebrex Searle S Fexofenadine hcl Allegra Aventis S S FDA NDCHealth DNA FDA

224 ~ 2006 Cerezyme or Ceredase Imiglucerase Alglucerase Genzyme 2001 Ceredase Alglucerase Genzyme 2001 Cerezyme Imiglucerase Genzyme 2001 Humulin Human insulin Eli Lilly 2001 Novolin Human insulin Novo Nordisk 2002 Intron A Interferon alpha - 2b Schering - Plough 2002 Avonex Interferon beta - 1a Biogen 2003 Humatrope Somatropin Eli Lilly 2003 Nutropin Somatropin Genentech 2003 Epogen Epoetin alfa Amgen 2004 Geref Sermorelin Acetate Serono 2004 Procrit Epoetin alfa Amgen /J&J 2004 Synagis Palivizumab Abbott 2005 Novolin Human insulin Novo Nordisk 2005 Activase Alteplase Genentech 2005 Protropin Somatrem Genentech 2005 Neupogen Filgrastim Amgen and Roche 2006 Albutein Human albumin Enzon 2006 FDA 100 FDA genetically engineered proteins Roche /Genentech

225 216 ANDA Herceptin FDA FDA FDA FDA BIO FDA FDA FDA Sicor Biotechna U. A. B alpha - 2b Sicor Teva Pharmaceutical Industries Teva 1999 N. J. Bio - Technology General Corp. Miami Ivax Indiana Protein Technologies Stada Arzneimittel AG DSM Biologics Stada S 100 million PEGylated Abbott Abbott AltaRex OvaRex Cambridge Antibody Technology Genzyme lerdelimumab CAT Abbott adalimumab Immunomedics Amgen epratuzumab

226 ANDA 217 ANDA FDA CDER / FDA FDA 21 CFR CFR ANDA FDA ANDA FDA 356h FDA 1984 Abbreviated New Drug Application ANDA FDA 21 CFR c d f FDA NDA 21 CFR FDA 505 J 2 C 21 CFR FDA FDA FDA ANDA Checklist 4.2FDA 356h

227 218 ANDA / 4.3FDA FDA 3455 FDA FDA 21 CFR FDA Organization of an ANDA - Drug Master Files DMF FDA FDA FDA FDA NDA FDA 356h / FDA FDA Adobe Acrobat PDF FDA FDA FDA FDA FDA Cover Letter Cover Letter International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Common Technical Document CTD CTD FDA NDA CTD CTD FDA 22 ANDA CTD e - CTD / 50

228 ANDA 219 Congressional Office of Technology Assessment OTA 1974 BA BE BA BE FDA Part Bioavailability and Bioequivalence Requirementswhich contain subparts AGeneral Provisionsand B Procedures for Determining the Bioavailability or Bioequivalence of Drug Products NDA 1984 Hatch - Waxman Act ANDA ANDA PE BE FDA / FDA FDA BA BE FDA 21 CFR Bioavailability BA the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstreamba may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. 4-3

229 220 ANDA % systemic exposure profile FDA FDA Pharmaceutical equivalence PE Therapeutic equivalence TE FDA 21 CFR Bioequivalence BE the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study 4-4

230 ANDA PE / BA/BE FDA FDA SUPAC BA BE / CFR PK 2 PD 3 comparative clinical trials 4 FDA / FDA FDA 1 PK systemic exposure AUC C max T max Effect - Time curve

231 222 ANDA 3 5 dissolution profiles FDA USP USP FDA ph PK / 1. PK PK - / FDA Nonreplicate Wash - out Period FDA buccal sublingual FDA FDA

232 ANDA 223 FDA Average Bioequivalence Population Bioequivalence FDA FDA 60 FDA FDA FDA ANDA FDA ANDA ANDA1990 FDA ANDA ANDA 4 FDA ANDA BE FDA FDA FDA ANDA FDA BE ANDA ANDA 505 b 2 NDA ANDA / 2. 1 Food - Effect Studies / FDA / FDA single - dose two - period two - se- quence FDA 2 FDA 21 CFR b 1 i parent drug

233 224 ANDA - FDA FDA 3 Enantiomers FDA achiral Racemates markers of peak total exposure FDA FDA BA BE 5 24 nonreplicate gastrointestinal transit 2 3 C max AUC 72 AUC AUC 0-72 AUC 0 - t AUC 0 - AUC FDA 6 narrow therapeutic ranges NTR NTR FDA SUPAC Aminophylline extended - release Carbamazepine Clindamycin Hydrochloride

234 ANDA 225 Clonidine Hydrochloride Clonidine Transdermal Dyphylline Disopyramide Phosphate Ethinyl Estradiol /Progestin Guanethidine Sulfate Isoetharine Mesylate Isoproterenol Sulfate Lithium Carbonate Metaproterenol Sulfate Minoxidil Oxtriphylline PhenytoinSodium Prazosin Hydrochloride Primidone Procainamide Hydrochloride Quinidine Sulfate CapsulesTablets Quinidine Gluconate Tablets Theophylline Capsules Tablets Valproic Acid Syrup DivalproexSodium WarfarinSodium 3. BA BE AUC AUC 0 - t AUC 0 - FDA

235 226 ANDA AUC 0 - t AUC 0 - C max AUC AUC 0 - T AUC 0 - C max pharmacodynamic endpoints FDA 20% 80% 125% C max AUC 90% 80%125% ANOVA 90% C max AUC 80%125% 90% 1 C max AUC 90% power FDA AUC 3.5% JAMASept.41987Vol.258No ANDA 127 AUC 0 - t % SD 2.84 AUC % SD 2.97 C max % SD 3.72 JAMADec.11999Vol.282No % FDA 2001 Statistical Approaches

236 ANDA 227 to Establishing Bioequivalence average population individual FDA 1 Two - way crossover study 290% 80% ~ 125% AUC C max 3CBS FDA 20% 20% 20% 20% 20% FDA FDA 4. / FDA FDA 5 5 FDA FDA FDA / FDA FDA FDA

237 228 ANDA BA/BE 1974 OTA FDA BA BE BA BE FDA BA BE FDA 1962 FDA / FDA BCS FDA Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate - Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System biopharmaceutics classification system BCS BCS dissolution solubility intestinal permeability BCS BCS ANDA FDA BCS ph %

238 ANDA USP 100 rpm 50 rpm N HCl USP 2pH 4.5 3pH 6.8 USP 30 85% 4 BA/BE FDA f {[ ] 100} f 2 = 50LOG /n n t = 1 R t - T t R T f FDA f 2 50 f 2 f % f 2 BA/BE FDA f 2 BA/BE 2. BA /BE FDA BCS BE

239 230 ANDA BCS f 2 > 50 BCS elixirs syrups tinctures BA/BE FDA - 80polysorbate 80 mannitol sorbitol FDA FDA IIG FDA FDA IIG BCS FDA Narrow Therapeutic Range Drugs FDA / / FDA - Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations 2003 Food - Effect Bioavailability and Fed Bioequivalence Studies 2002 Statistical Approaches to Establishing Bioequivalence 2001 Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate - Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System 2000 Bioequivalence Protocols ResearchDeviations from OGD Policy 1998 Handling and Retention of BA and BE Testing Samples 2002 FDA Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action Statistical Information from the June 1999 Draft Guidance and Statistical Information for In Vitro Bioequivalence Data 2003 Bioequivalence Studies Data and Detailed Statistical

240 ANDA 231 Methodology 1998 AveragePopulationand Individual Approaches to Establishing Bioequivalence 1999 Bioanalytical methods validation for human studies 2001 Food - Effect Bioavailability and Fed Bioequivalence Studies 2003 NDA ANDA - Topical dermatological drug product NDAs and ANDAs - bioavailabilitybioequivalencein vitro releaseand associated studies 1998 In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Studies 1997 / WHO ICH ICH CTD BA BE CTD Module 2 G/1 biopharmaceutics ICH WHO ICH BA BE replicate designs BCS BCS 21 CFR CFR FDA FDA FDA 1998 FDA FDA FDA FDA FDA FDA

241 232 ANDA FDA FDA - CBE CFR a 8 iv ANDA ANDA FDA FDA ANDA NDA ANDA CDER Office of Generic Drugs OGD FDA NDA ANDA RLD FDA / 2004 FDA FDA 4-4 Office of Generic Drugs OGD FDA CDER OGD OGD 2004 ANDA CMC 1989 FDA ANDA OGD 2005 Division of Labeling and Program Support Division of Bioequivalence

242 ANDA 233 / Division of Chemistry Ⅰ Antihypertensives ACE Inhibitors Diruetics Vasodilators - Prostiglandins Potassium Salts Radiopharmaceutics Radiopaques Non - Steriodal Anti - InflammatoriesNSAIDS Estrogens /Progestins Gonadotropins LVPs Oncology Agents Hormonal Agents Diabetic Agents Inhalation Corticosteriods Respiratory Agents Surgical - Dental Hematologic Agents Anti - Anxiety Agents Seditives Dermatolgics Otics Ophthalmics Antifungal Agents Anti - Infectives Antiprotozoal Agents Simon Eng Peter Chen Ann Vu Diuretics Estrogens Sedatives Antifungals Corticosteroids Anti - Infectives Division of Chemistry Ⅱ Benjamin Danso Anti - Ulcer Anticonvulsants Antimotility/Antispasmodics Anticholinergics Anorexics CNS Agents Fibrinolytics /Thromboembolics Diagnostics Yoon Kong

243 234 ANDA Beta Blockers Calcium Channel Blockers Anti - Arrhythmics Drug Abuse Agents Vasodilators Antidepressants Antivirals Anesthetics Analgesics Respiratory Stimulants Narcotic Agonists Opthalmic Steroid /Antibiotics Antidepressants Anti - Alcoholism agents Nicotine /Anti - nicotine agents Coagulants /Anticoagulants Division of Chemistry Ⅲ Antipsychotics Vitamins Antihistamines - Cough Preps Muscle Relaxants Contraceptive Agents Anabolic Steroids Dental Products Antibiotics Antifungals Antineoplastic Antibiotics Immuno - Suppressants Fermentation derived Stanley Shepperson Ted Palat Tom Hinchliffe Sarah Park Ryan Nguyen ANDA NDA NDA ANDA NDA ANDA NDA ANDA

244 ANDA 235 NDA ANDA ANDA ANDA

245 236 ANDA 1 FDA FDA 5 USP USP FDA 6 7 GMP FDA GMP 8 FDA FDA ANDA OGD ANDA OGD ANDA acknowledgment letter ANDA ANDA ANDA ANDA / 6 1. FDA FDA SAS Transport BCS FDA 1 2 OGD 2. / /

246 ANDA 237 / NDA 3. FDA FDA FDA 4. ANDA ANDA OGD OGD OGD NDA FDA ANDA FDA 505 j ANDA ANDA 180 NDA 10 Request for Plant Inspection ANDA OGD FDA Office of Compliance 21 CFR 211 ANDA / GMPGLP GCP Office of Compliance ANDA ANDA PAI GMP ANDA Office of Compliance ANDA ANDA ANDA OGD ANDA 483 FDA ANDA FDA FDA ANDA ANDA OGD ANDA OGD approval tentative approval ANDA GMP

247 238 ANDA ANDA ANDA PAI FDA FDA ANDA OGD OGD 48 ANDA OGD 48 FDA X OGD ANDA CMC OGD FDA SUPAC OGD ANDA 1 Major Amendment 2 Minor Amendment 3 Telephone Amendment review clock 10 OGD FDA review clock OGD OGD ANDA 6 ANDA 1. OGD 1 -

248 ANDA metered dose inhalers CFR CMC CMC 2. ANDA 1 DMF 2 GMP ANDA ANDA OGD ANDA ANDA CMC

249 240 ANDA FDA ANDA CMC CMC OGD OGD OGD 10 OGD FDA OGD ANDA FDA 1995 ~ ANDA ANDA ANDA ANDA FDA FDA ANDA FDA 1995 ~ 2004