1. The FDA Process for Approving Generic Drugs Gary J. Buehler, R.Ph.Dale Conner, Pharm. D. DirectorDirector, Division of Bioequivalence Office of Generic Drugs

2. Center for Drug Evaluation & Research U.S. Food & Drug Administration 2 Did you know that generic drugs... Are safe and effective alternatives to brand name prescriptionsAre safe and effective alternatives to brand name prescriptions Can help both consumers and the government reduce the cost of prescription drugsCan help both consumers and the government reduce the cost of prescription drugs Are currently used in 50% of all prescriptions dispensedAre currently used in 50% of all prescriptions dispensed Save an average of $50 for every prescription soldSave an average of $50 for every prescription sold

3. Center for Drug Evaluation & Research U.S. Food & Drug Administration 3 Hatch-Waxman Amendments to FFD&C Act - 1984 Considered one of the most successful pieces of legislation ever passedConsidered one of the most successful pieces of legislation ever passed Created the generic drug industryCreated the generic drug industry Increased availability of genericsIncreased availability of generics 1984 12% prescriptions were generic1984 12% prescriptions were generic 2000 44% prescriptions were generic - yet only 8% of revenue for prescription drugs2000 44% prescriptions were generic - yet only 8% of revenue for prescription drugs Compromise legislation to benefit both brand and generic firmsCompromise legislation to benefit both brand and generic firms Continued

4. Center for Drug Evaluation & Research U.S. Food & Drug Administration 4 Hatch-Waxman Amendments to FFD&C Act - 1984 Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials)Allowed generic firms to rely on findings of safety and efficacy of innovator drug after expiration of patents and exclusivities (do not have to repeat expensive clinical and pre-clinical trials) Allowed patent extensions and exclusivities to innovator firmsAllowed patent extensions and exclusivities to innovator firms

5. Center for Drug Evaluation & Research U.S. Food & Drug Administration 5 Brand Name DrugGeneric Drug NDA RequirementsANDA Requirements1. Chemistry2. Manufacturing3. Controls4. Labeling5. Testing 6. Animal Studies 7. Clinical Studies6. Bioequivalence 8. Bioavailability NDA vs. ANDA Review Process

6. Center for Drug Evaluation & Research U.S. Food & Drug Administration 6 What are the requirements for a generic drug? LabelingLabeling Chemistry/MicrobiologyChemistry/Microbiology BioequivalenceBioequivalence LegalLegal

7. Center for Drug Evaluation & Research U.S. Food & Drug Administration 7 How do we assure the quality of generic drugs? First 5 steps of review process are identical to NDA processFirst 5 steps of review process are identical to NDA process Bioequivalence for complicated products is discussed with the same staff that reviewed the brand productBioequivalence for complicated products is discussed with the same staff that reviewed the brand product FDA has experience with the productFDA has experience with the product Scientific literature publishedScientific literature published Product is known to be safeProduct is known to be safe

8. Center for Drug Evaluation & Research U.S. Food & Drug Administration 8 Generic Drug Review Process Bioequivalence Review Labeling Review Chemistry & Micro Review Request for Plant Inspection APPLICANT ANDA Acceptable & Complete Application Review N Chem/Micro OK? Labeling OK? Bioequivalence OK? PreApproval Inspection Results OK? Not Approvable Letter Approval Withheld until Results Satisfactory Bio Deficiency Letter APPROVED ANDA N N N N YY Y Y Y Refuse to Receive Letter

9. Center for Drug Evaluation & Research U.S. Food & Drug Administration 9 What are the requirements for a generic drug? Same active ingredient(s) Same active ingredient(s) Same route of administration Same route of administration Same dosage form Same dosage form Same strength Same strength Same conditions of use Same conditions of use Compared to reference listed drug (RLD) - (brand name product)

10. Center for Drug Evaluation & Research U.S. Food & Drug Administration 10 Labeling “Same” as brand name labeling“Same” as brand name labeling May delete portions of labeling protected by patent or exclusivityMay delete portions of labeling protected by patent or exclusivity May differ in excipients, PK data and how suppliedMay differ in excipients, PK data and how supplied

11. Center for Drug Evaluation & Research U.S. Food & Drug Administration 11 Chemistry Components and compositionComponents and composition Manufacturing and controlsManufacturing and controls Batch formulation and recordsBatch formulation and records Description of facilitiesDescription of facilities Specs and testsSpecs and tests PackagingPackaging StabilityStability

12. Center for Drug Evaluation & Research U.S. Food & Drug Administration 12 Manufacturing Compliance Programs Purpose - To assure quality of marketed drug productsPurpose - To assure quality of marketed drug products Mechanisms - Product TestingMechanisms - Product Testing –Surveillance –Manufacturing/Testing plant inspections –Assess firm’s compliance with good manufacturing processes

13. Center for Drug Evaluation & Research U.S. Food & Drug Administration 13 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH OFFICE OF GENERIC DRUGS APPROVED DRUG PRODUCTS WITH THERAPEUTIC EQUIVALENCE EVALUATIONS 23 rd EDITION THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER SECTION 505 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT. 2003 Electronic Orange Book - http://www.fda.gov/cder/ob/

14. Center for Drug Evaluation & Research U.S. Food & Drug Administration 14 All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s)All FDA approved drug products listed (NDA’s, OTC’s & ANDA’s) –Therapeutic equivalence codes  “A” = Substitutable  “B” = Inequivalent, NOT Substitutable –Expiration dates: patent and exclusivity –Reference Listed Drugs/brand drugs identified by FDA for generic companies to compare with their proposed products Orange Book “ Orange Book ”

15. Center for Drug Evaluation & Research U.S. Food & Drug Administration 15 Definition of Bioequivalence Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions

16. Center for Drug Evaluation & Research U.S. Food & Drug Administration 16 Purpose of BE Therapeutic equivalence (TE)Therapeutic equivalence (TE) Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoringBioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring The most efficient method of assuring TE is to assure that the formulations perform in an equivalent mannerThe most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner

17. Center for Drug Evaluation & Research U.S. Food & Drug Administration 17 Model of Oral Dosage Form Performance Therapeutic Effect Dosage Form Gut Wall Drug in Solution Blood Site of Activity Pharmacokinetic Measurement Dosage Form Performance Clinical/PD Measurement ln Dose Dose

18. Center for Drug Evaluation & Research U.S. Food & Drug Administration 18 Clinical/PD Dose-Response Clinical/PD Response Log Dose

19. Center for Drug Evaluation & Research U.S. Food & Drug Administration 19 Plasma Concentration-Dose Dose Plasma Conc.

20. Center for Drug Evaluation & Research U.S. Food & Drug Administration 20 Approaches to Determining Bioequivalence (21 CFR 320.24) In vivo measurement of active moiety or moieties in biologic fluidIn vivo measurement of active moiety or moieties in biologic fluid In vivo pharmacodynamic comparisonIn vivo pharmacodynamic comparison In vivo limited clinical comparisonIn vivo limited clinical comparison In vitro comparisonIn vitro comparison Any other approach deemed appropriate by FDAAny other approach deemed appropriate by FDA FeV 1 Albuterol Blanching Study Topical Corticosteroid Topicals Nasal Suspensions Questran - Binding Studies Nasal Solutions-Sprayer Evaluation Propofol - Droplet Size

21. Center for Drug Evaluation & Research U.S. Food & Drug Administration 21 Single-dose, two-way crossover, fastedSingle-dose, two-way crossover, fasted Single-dose, two-way crossover, fedSingle-dose, two-way crossover, fed AlternativesAlternatives –Single-dose, parallel, fasted –Single-dose, replicate design –Multiple-dose, two-way crossover, fasted –Clinical endpoint study Study Designs Long Half-Life (wash-out) Amiodarone, Etidronate Highly Variable Drugs Less Sensitive Clozapine (Patient Trials) Chemotherapy Trials Topicals Nasal Suspensions

22. Center for Drug Evaluation & Research U.S. Food & Drug Administration 22 Waivers of In Vivo Study Requirements DefinitionDefinition Criteria (21 CFR 320.22)Criteria (21 CFR 320.22) –In vivo bioequivalence is self-evident –Parenteral solutions –Inhalational anesthetics –Topical (skin) solution –Oral solution –Different proportional strength of product with demonstrated BE

23. Center for Drug Evaluation & Research U.S. Food & Drug Administration 23 Statistical Analysis (Two One-sided Tests Procedure) AUC and CmaxAUC and Cmax –90% Confidence Intervals (CI) must fit between 80%-125%

24. Center for Drug Evaluation & Research U.S. Food & Drug Administration 24 Statistical Analysis 80 - 125 % What does this mean?What does this mean? Can there be a 46% difference?Can there be a 46% difference? What is a point estimate?What is a point estimate? What is a confidence interval?What is a confidence interval?

25. Center for Drug Evaluation & Research U.S. Food & Drug Administration 25 Statistical Analysis Bioequivalence criteriaBioequivalence criteria –Two one-sided tests procedure Test (T) is not significantly less than referenceTest (T) is not significantly less than reference Reference (R) is not significantly less than testReference (R) is not significantly less than test Significant difference is 20% ( = 0.05 significance level)Significant difference is 20% ( = 0.05 significance level) –T/R = 80/100 = 80% –R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)

26. Center for Drug Evaluation & Research U.S. Food & Drug Administration 26 Possible BE Results (90% CI) T/R (%) 80% 125%

27. Center for Drug Evaluation & Research U.S. Food & Drug Administration 27 Narrow Therapeutic Range (NTI) Drugs Drug Products that are subject to therapeutic drug concentration or pharmacodynamic monitoringDrug Products that are subject to therapeutic drug concentration or pharmacodynamic monitoring –Examples are: Digoxin, Lithium, Phenytoin, Warfarin Traditional bioequivalence limit of 80- 125% is unchanged for these productsTraditional bioequivalence limit of 80- 125% is unchanged for these products

28. Center for Drug Evaluation & Research U.S. Food & Drug Administration 28 Contacting the OGD Contact: Office of Generic Drugs FDA/CDER (HFD-600) 7500 Standish Place Rockville, MD 20855 phone: 301-827-5845 Web site: www.fda.gov/cder/ogd/index.htm