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Guidance for IndustryBioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) October 2000 BP

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G u i d a n c e fo r In d u stryB ioavailability a n d B i o e q u iva lence S tu d ies fo r O rally A d m inistered D r u g P r o d u c ts - G e n e ral C o n sid e ratio n s

Additional copies a r e available from the. D r u g Information B r a n c h (HFD-210), Centerfor D r u g Evaluation a n d R e s e a r c h (CDER), 5 6 0 0 Fishers L a n e , Rockville, M D 2 0 8 5 7 , (Tel) 3 0 1 - 8 2 7 - 4 5 7 3 Internet at http://www.fda.gov/cder/guidance/index.htm

U .S . D e p a r tm e n t o f Health a n d H u m a n Services F o o d a n d D r u g A d m inistration C e n ter for D r u g E v a l u a tio n a n d R e s e a r c h( C D E R ) O c to b e r 2 0 0 0

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Table of Contents

L IL A. B. C. . A. B. C. D. Iv. V. A. B. C. D. E VL A. B. C. D. E F.

fNTRODUCTfON BACKGROUND..

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2 GENERAL ........................................................................................................................................................................... 3 BIOAVAILABILITY ........................................................................................................................................................... 4 ............................................................................................................................................................ BIOEQUIVALENCE METHODS TO DOCUMENT BA AND BE ...................................................................................................................... 6

6 PHARMACOKINETIC STUDIES ........................................................................................................................................ lo PHARMACODYNAMIC STUDIES ................................................................................................................................... lo COMPARATIVE CLINICAL STUDIES ............................................................................................................................ 10 IN VITRO STUDIES ......................................................................................................................................................... COMPARISON 11 OF BA MEASURES IN BE STUDIES ................................................................................................ OF BA AND BE ............................................................................................................................ 11

DOCUMENTATION

12 SOLUTIONS ...................................................................................................................................................................... 12 SUSPENSIONS.................................................................................................................................................................. 12 ............................................................................... IMMEDIATE-RELEASE PRODUCTS CAPSULES AND TABLETS 14 MODIFIED-RELEASEPRODUCTS ................................................................................................................................. 17 MISCELLANEOUS DOSAGE FORMS .............................................................................................................................. 17 SPECIAL TOPICS .............................................................................................................................................................. 17 FOOD-EFFECT STUDIES ................................................................................................................................................. . MOIETIESTOBEMEASURED ...... ............................................................................................................................... 18 19 LONG HALF-LIFE DRUGS............................................................................................................................................... 20 FIRSTPOINTCMAX ....................................................................................................................................................... 20 ORALLY ADMINISTERED DRUGS INTENDED FOR LoCAL ACTION ....................................................................... 20 NARROW THERAPEUTIC RANGE DRUGS.................................................................................................................... 1: List of Guidances That Will Be Replaced ..................................................................................................... 22 2: General Pharmacokinetic Study Design and Data Handling . .. . .. . .. . . . . . . .. . .. . . . . . . .. . .. . . . . .. . . . . .. . . . . .. . .. . . . . .. . . . .. .. .. . 23

APPENDM APPENDIX

GUIDANCE FOR INDUSTRY Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations

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This guidance represents the Food and Drug Administration current thinking on this topic. It does s not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations.

INTRODUCTION

This guidanceis intendedto provide recommendations sponsors to and/or applicantsplanning to include bioavailability(BA) and bioequivalence (BE) infomration for orally administered drug productsin investigational new drug applications(IN&), new drug applications@IDAs), abbreviatednew drug applications(ANDAs), and their supplements.This guidanceaddresses to meet the BA and BE how requirementsset forth in 21 CFR part 320 as they apply to dosageforms intended for oral . . admrm&ation2 The guidanceis also generally applicableto non-orally administereddrug products where reliance on systemicexposuremeasuresis suitableto documentBA and BE (e.g., transdermal delivery systemsand certainrectal and nasal drug products). The guidanceshould be useful for applicantsplanning to conductBA and BE studiesduring the IND period for an NDA, BE studies intendedfor submissionin an ANDA, and BE studiesconductedin the postapprovalperiod for certain changesin both NDAs and ANDAs.~ This guidanceis designedto reducethe need for FDA drug-specificBABE guidances.As a result,this guidancereplacesa number of previously issuedFDA drug-specificBE guidances(seethe list in Appendix 1). On rare occasions, FDA may decide to provide additional BABE guidancesfor specific drug products.

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BACKGROUND

This guidance has been prepared by the Biopharmaceutics Coordinating Committee in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA). These dosage forms include tablets, capsules, solutions, suspensions, conventional/immediate modified (extended, delayed) release drug products. release, and

3 Other Agency guidances are available that consider specific scale-up and postapproval changes (SUPAC) for different types of drug products to help satisfy regulatory requirements in both 2 1 CFR part 320 and 2 1 CFR 3 14.70.

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General

Studiesto measureBA and/or establishBE of a product are important elementsin supportof INDs, NDAs, ANDAs, and their supplements.As part of INDs and NDAs for orally administereddrug products,BA studiesfocus on determiningthe processby which a drug is releasedfrom the oral dosageform and moves to the site of action. BA dataprovide an estimateof the traction of the drug absorbed,as well as its subsequent distriiution and elimination. BA can be generallydocumented a systemicexposure by profile obtainedby measuringdrug and/ormetaboliteconcentration the systemiccirculationover time. The in systemicexposureprofile determinedduring clinical trials in the IND period can serveas a benchmarkfor subsequent studies. BE Studiesto establishBE betweentwo products are important for certain changesprior to approval for a pioneer product in NDA and ANDA submissions, in the presenceof certain and postapprovalchangesin NDAs and ANDAs. In BE studies,an applicantcomparesthe systemicexposureprofile of a test drug product to that of a referencedrug product. For two orally administereddrug productsto be bioequivalent,the active drug ingredientor active moiety in the test product should exhibit the samerate and extent of absorptionas the reference drug product. Both BA and BE studiesare requiredby regulations,dependingon the type of applicationbeing submitted. Under 21 CFR 3 14.94,BE information is requiredto ensuretherapeutic equivalencebetweena pharmaceuticallyequivalenttest drug product and a referencelisted drug. Regulatoryrequirements documentationof BA and BE are provided in 21 CFR part for 320, which containstwo subparts. SubpartA covers generalprovisions,while SubpartB contains18 sectionsdelineatingthe following generalBABE requimrnents: Requirementsfor submissionof BA and BE data (320.21) Criteria for waiver of an in vivo BA or BE study (320.22) Basis for demonstrating vivo BA or BE (320.23) in Types of evidenceto establishBA or BE (320.24) Guidelinesfor conductof in vivo BA studies(320.25) Guidelineson designof