Guidance for Industry

Bioavailability 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 stry
B 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.

II.

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 single-dose studies(320.26) BA Guidelineson designof multiple-dosein vivo BA studies(320.27) Correlationsof BA with an acutepharmacologicaleffect or clinical evidence (320.28) Analytical methodsfor an in vivo BA study (320.29) Inquiries regardingBA and BE requirementsand review of protocolsby FDA (320.30) Applicability of requirements regardingan IND application(320.31) Proceduresfor establishingand amendinga BE requirement(320.32) Criteria and evidenceto assess actual or potential BE problems(320.33) Requirementsfor batch testing and certification by FDA (320.34) 2

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Requirements in vitro batch testingof eachbatch (320.35) for Requirements maintenance recordsof BE testing (320.36) for of Retentionof BA samples(320.38) Retentionof BE samples(320.63) Bioavailability

B.

Bioavailability is definedin 21 CFR 320.1 as ‘ rate and extentto which the activeingredient the or activemoiety is absorbedfrom a drug product and becomesavailableat the site of action. For drug products that are not intendedto be absorbedinto the bloodstream,bioavailability may be assessed measurements by intendedto reflect the rate and extentto which the active ingredientor activemoiety becomesavailableat the site of action.” This definition focuseson the processes which the active ingredientsor moieties are releasedfrom an oral dosageform by and move to the site of action. From a pharmacokinetic perspective, data for a given formulationprovide an estimateof the BA relative traction of the orally administered dosethat is absorbed the systemiccirculation into when comparedto the BA data for a solution, suspension, intravenousdosageform (21 CFR or 320.25 (d) (2) and (3)). In addition, BA studiesprovide other useful pharmacokinetic informationrelatedto distribution,elimination,the effectsof nutrientson absorptionof the drug, doseproportionality,linearity in pharmacokinetics the activemoietiesand, where of appropriate, inactivemoieties. BA datamay also provide information indirectly aboutthe propertiesof a drug substance prior to entry into the systemiccirculation,suchas permeability and the intluenceof presystemicenzymesand/or transporters(e.g., p-glycopmtein). BA for orally administered drug productsmay be documented developinga systemic by exposureprofile obtainedfrom m easuringthe concentration activeingredientsandor active of moietiesand, when appropriate,its activemetabohtes over time in samplescolk&ed from the systemiccirculation. Systemicexposurepatternsreflect both releaseof the drug substance from the drug product and a seriesof possiblepresystemic/systemic actionson the drug substance after its releaset?om the drug product. Additional comparativestudiesshouldbe performedto understandthe relative contribution of theseprocesses the systemicexposurepattern. to One regulatoryobjective is to assess, through appropriatelydesignedBA studies,the performanceof the formulationsusedin the clinical trials that provide evidenceof safetyand efficacy (21 CFR 320.25(d)(l)). The performanceof the clinical trial dosageform may be optimized,in the contextof demonstrating safetyand efficacy,before marketinga drug product. The systemicexposureprofiles of clinical trial materialcan be usedas a benchmarkfor subsequent formulation changesand may thus be useful as a referencefor Uure BE studies. Although BA studieshavemany pharmacokinetic objectivesbeyond formulationperformance as describedabove,it shouldbe noted that subsequent sectionsof this guidancefocus on using

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relative BA (referredto as product quality BA) and, in particular, BE studiesas a meansto to documentproduct quality. In vivo performance,in terms of BABE, may be considered be one aspectof product quality that provides a link to the performanceof the drug product used in clinical trials and thus to the database containingevidenceof safetyand efficacy. C. Bioequivalence

Bioequivalence defined at 21 CFR 320.1 as “the absence a significant differencein the rate is of and extentto which the active ingredientor activemoiety in pharmaceutical equivalents or pharmaceutical alternatives becomesavailableat the site of drug action when administered the at samemolar doseunder similar conditionsin an appropriatelydesignedstudy.” As noted in the statutorydefinitions,both BE and product quality BA focus on the releaseof a drug substance from a drug product and subsequent absorptioninto the systemiccirculation. For this mason, similar approaches m easuringBA in an NDA shouldgenerallybe followed in demonstrating to BE for an NDA or an ANDA. Establishingproduct quality BA is a benchmarkingeffort with comparisons an oral solution, oral suspension, an intravenousformulation. In contrast, to or demonstrating is usually a more formal comparativetest that usesspecifiedcriteria for BE comparisons predetermined limits for the criteria. and BE 1.
IiVDhJDAs

BE documentation may be useful during the INDNDA period to establishlinks between(1) early and late clinical trial formulations;(2) formulationsusedin clinical trial and stability studies,if different; (3) clinical trial formulationsand to-be-marketed drug product; and (4) other comparisons,as appropriate. In each comparison,the new formulation or new method of manufactureis the test product and the prior formulation or method of manufactureis the referenceproduct. The need to redocumentBE during the IND period is generallyleft to the judgment of the sponsor,who may wish to use the principlesof relevantguidances(in this guidance,seesectionsII.C.3, Postapproval Changes,and IILD, In Vitro Studies)to determinewhen changesin components, composition,and/or method of manufacturesuggesta needto perform further in vitro andor in vivo studies. A test product may fail to meet BE limits because test product has higher or lower the measuresof rate and extent of absorptioncomparedto the referenceproduct or becausethe performanceof the test or referenceis more variable. In some cases, nondocumentation BE may arisebecause inadequate of of numbersof subjectsin the study relativeto the magnitudeof inttasubjectvariability, and not because eitherhigh of or low relative BA of the test product. Adequatedesign and executionof a BE study will facilitateunderstanding the causes nondocumentation BE. of of of Where the test product generates plasmalevels that are substantiallyabovethoseof the referenceproduct, the regulatory concernis not therapeuticfailure, but the adequacyof
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the safety database from the test product. Where the test product has levels that are substantiallybelow those of the referenceproduct, the regulatory concernbecomes themlxutic efficacy. When the variability of the test product rises,the regulatory concernrelatesto both safety and efficacy, becauseit may suggestthat the test product does not perform as well as the referenceproduct, and the test product may be too variableto be clinically useful. Propermapping of individual dose-response concentration-response or curvesis useful in situationswhere the drug product has plasmalevelsthat are either higher or lower than the referenceproduct and am outsideusual BE limits. In the absence individual of data, population dose-response concentration-response acquired over a range or data of doses,including dosesabove the recommended therapeuticdoses,may be sufficient to demonstrate the increasein plasmalevels would not be accompanied that by additionalrisk. Similarly, population dose-or concentration-response relationships observedover a lower range of doses,including dosesbelow the recommended therapeuticdoses,may be able to demonstrate reducedlevels of the test product that comparedto the referenceproduct are associated with adequateefficacy. In either event,the burden is on the sponsorto demonstrate adequacyof the clinical trial the dose-response concentration-response to provide evidenceof therapeutic or data equivalence.In the absence this evidence,a failure to documentBE may suggesta of need for a reformulation,a changein the method of manufacturefor the test product, and/or a repeatof the BE study.
2. ANDAs

BE studiesare a critical componentof ANDA submissions.The purposeof these studiesis to demonstrate betweena pharmaceutically BE equivalentgenericdrug product and the correspondingreferencelisted drug (21 CFR 314.94 (a)(7)). Together with the determination pharmaceutical of equivalence, establishingBE allows a regulatoryconclusionof therapeuticequivalence.
3. Postapproval Changes

Information on the types of in vitro dissolutionand in vivo BE studiesthat shouldbe conductedfor immediate-release modified-release and drug products approvedas eitherNDAs or ANDAs in the presenceof specifiedpostapprovalchangesis provided in the FDA guidances industry entitled SUPAC-IR: Immediate Release Solid Oral for
Dosage Forms: Scale-Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (November 1995); and SUPAC-MR: ModiJied Release Solid Oral Dosage Forms: Scale- Up and Post-Approval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (September1997). In the presenceof certain 5

major changesin components, composition,and/or method of manufactureafter approval,in vivo BE shouldbe redemonstrated. For approvedNDAs, the drug product after the changeshould be comparedto the drug product before the change. For approved ANDAs, the drug product atler the changeshould be comparedto the referencelisted drug. Under section 506A(t)(2)(B) of the FederalFood, Drug, and Cosmetic Act, postapprovalchangerequiring completionof studiesin accordance with 21 CFR part 320 must be submittedin a supplementand approvedby FDA before distriiuting a drug product made with the change.

III.

METHODS TO DOCUMENT BA AND BE

As noted at 21 CFR 320.24, severalin vivo and in vitro methodscan be used to measureproduct quality BA and establishBE. In descendingorder of preference,theseinclude pharmacokinetic, are in pharmacodynamic, clinical, and in vitro studies. Thesegeneralapproaches discussed the following sectionsof this guidance. Productquality BA and BE frequentlyrely on pharmacokinetic measuressuch as AUC and Cmax that are reflective of systemicexposure. A. Pharmacokinetic Studies 1.
General Considerations

The statutorydefinitions of BA and BE, expressed terms of rate and extent of in absorptionof the active ingredientor moiety to the site of action,emphasizethe use of pharmacokinetic measures an accessible in biological matrix such as blood, plasma, and/or serumto indicatereleaseof the drug substance t?omthe drug product into the systemiccirculation.4This approachrestson an understanding measuringthe active that moiety or ingredientat the site of action is generallynot possibleand furthermore,that somerelationshipexistsbetweenthe efficacy/safetyand concentration active moiety of and/or its irnIwtant metaboliteor metabolitesin the systemiccirculation. To measure product quality BA and establishBE, relianceon pharmacokinetic measurements may be viewed as a bioassaythat assesses releaseof the drug substance from the drug product into the systemiccirculation. A typical study is conductedas a crossoverstudy. In this type of study, clearance, volume of distribution,and absorption,as determined by physiologicalvariables(e.g. gastricemptying,motility, pH), are assumed have less to interoccasion variability comparedto the variability arisingt?omformulation performance. Therefore,differencesbetweentwo productsdue to formulation factors can be determined.

4 If serial measurements of the drug or its metabolites in plasma, serum, or blood cannot be accomplished, measurement of urinary excretion may be used to document BE.

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2.

Pilot Study

If the sponsorchooses,a pilot study in a small number of subjectscan be carried out before proceedingwith a full BE study. The study can be usedto validateanalytical methodology,assess variability, optimize samplecollectiontime intervals,and provide other information. For example,for conventionalimmediate-release products,careful timing of initial samples may avoid a subsequent finding in a full-scalestudy that the first samplecollection occursafler the plasma concentrationpeak. For modified-release products,a pilot study can help determinethe samplingscheduleto assess time and lag dosedumping. A pilot study that documentsBE may be acceptable, provided that its designand executionare suitableand a sufficient number of subjects(e.g., 12) have completedthe study. 3. Pivotal Bioequivalence Studies

Generalrecommendations a standardBE study basedon pharmacokinetic for measurements provided in Appendix 2. are 4. Nonreplicate Study Designs

Nonreplicatestudy designsare recommendedfor BE studiesof most orally administered,immediate-release dosageforms. However, sponsorsand/or applicants have the option of using replicatedesignsfor BE studiesof thesedrug products. These studiesare descrii in sectionIRA.5 below. The recommended method of analysis of nonmplicateor replicatestudiesto establishBE is discussed sectionIV. General in recommendations nonreplicatestudy designsare provided in Appendix 2. for 5. Replicate Study Designs

Replicatestudy designsare recommendedfor BE studiesof modified-release dosage forms and highly variabledrug products(within-subjectcoefficientof variation 2 30%), including thosethat are immediaterelease,modified-release, other orally and administereddrug products. The recommended method of analysisof replicatestudies to establishBE is discussed sectionIV. in Replicatestudy designsoffer severalscientific advantages comparedto nonreplicate designs. The advantages replicatestudy designsare that they (1) allow comparisons of of within-subject variancesfor the test and referenceproducts; (2) indicate whether a testproduct exhibits higher or lower within-subjectvariability in the bioavailability measureswhen comparedto the referenceproduct; (3) suggestwhether a subject-byformulation (S*F) interactionmay be present;(4) provide more information about factorsunderlying formulationperformance;and (5) reducethe number of subjects neededin the BE study. 7

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Study Population

Unless otherwise indicated by a specific guidance, subjects recruited for in vivo BE studies should be 18 years of age or older and capable of giving informed consent. This guidance recommends that iu vivo BE studies be conducted in iudividuals representative of the general population, taking into account age, sex, and race factors. If the drug product is inteuded for use iu both sexes,the sponsor should attempt to include similar proportions of males and females in the study. If the drug product is to be used predominantly iu the elderly, the sponsor should attempt to include as many subjects of 60 years of age or older as possible. The total number of subjects in the study should provide adequatepower for BE demonstration,but it is not expectedthat there will be sufficient power to draw conclusions for each subgroup. Statistical analysis of subgroups is not recommended. Restrictionson admissioninto the study shouldgenerally be basedsolely on safety considerations.In someinstances,it may be useful to admit patientsinto BE studiesfor whom a drug product is intended. In this situation, sponsors and/or applicantsshould attempt to enterpatientswhose disease processis stablefor the durationof the BE study. In accordance with 21 CFR 320.3 1, for some products that will be submitted in ANDAs, au IND may be required for BE studies to ensurepatient safety.

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Single-Dose/Multiple-Dose Studies

Instances where multipledose studies may be usetil are defiued at 21 CFR 320.27(a)(3). However, this guidauce generally recommends single-dose pharmacokinetic studies for both immediate- and modified-release drug products to demonstrate BE because they are generally more sensitive in assessingreleaseof the drug substancefrom the drug product into the systemic circulation (see section V). If a multiple-dose study design is necessary,appropriate dosageadministration and sampling should be carried out to document attainment of steady state.

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Bioanalytical Methodology

Bioanalytical methods for BA and BE studies should be accurate,precise, selective, sensitive, and reproducible. A separateFDA guidance entitled Bioanalytical Methods Validation for Human Studies (published in drawlin December 1998) will be available, when f?nalized,to assist sponsorsiu validating bioanalytical methods.

9.

Pharmacokinetic Measures of Systemic Exposure

Both direct (e.g., rate constar& rate profile) and indirect (e.g., Cmax, Tmax, mean absorption time, mean residence time, Cmax normalized to AUC) pharmacokiuetic measuresare limited in their ability to assessrate of absorption. This guidance,

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therefore,recommendsa changein focus from thesedirect or indirect measures of absorptionrate to measuresof systemicexposure. Cmax and AUC can continueto be used as measures product quality BA and BE, but more in terms of their capacityto for assess exposurethan their capacity to reflect rate and extent of absorption. Relianceon systemicexposuremeasuresshould reflect comparablerate and extent of absorption, which in turn should achievethe underlying statutoryand regulatoryobjectiveof ensuringcomparabletherapeuticeffects. Exposuremeasures defined relative to are early, peak, and total portions of the plasma,serum,or blood concentrationtime profile, as follows: a. Early Exposure

For orally administeredimmediate-release products,BE may generallybe drug demonstrated measurements peak and total exposure. An early exposure by of measuremay be indicatedon the basisof appropriate clinical efficacy/safetytrials and/or pharmacokinetic/pharmacodynamic studiesthat call for better control of drug absorptioninto the systemiccirculation (e.g.,to ensurerapid onsetof an analgesiceffect or to avoid an excessivehypotensiveaction of an antihypenensive).In this setting,the guidancerecommendsuse of partial AUC as an early exposuremeasure. The partial areashouldbe truncatedat the populationmedian of Tmax valuesfor the reference formulation. At leasttwo quantifiablesamplesshouldbe collectedbefore the expected peak time to allow adequateestimationof the partial area. b. Peak Exposure

Peak exposureshould be assessed measuringthe peak drug concentration(Cmax) by obtaineddirectly from the datawithout interpolation.
C.

Total Exposure

For single-dosestudies,the measurement total exposureshould be: of
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Area under the plasma/serum/blood concentration-time curve from time zero to time t (AU&), where t is the last time point with measurable concentration for individualformuation. Area under the plasma/scrumMoodconcentration-time curve from time zero to time i&nitty (AUC&,), where AU& = AU&, + C&, Ct is the last measurabledrug concentrationand h, is the terminal or eliminationrate constant calculatedaccordingto an appropriate method. The tem~inalhalf-life (t& of the drug should also be reported.

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For steady-state studies,the measurement total exposureshould be the areaunder of the plasma,serumor blood concentration-time curve t?omtime zero to time z over a dosing interval at steadystate(AU&), where z is the length of the dosinginterval. B. Pharmacodynamic Studies

Pharmacodynamic studiesare not recommended orally administereddrug productswhen the for drug is absorbedinto the systemiccirculation and a pharmacokineticapproachcan be used to assess systemicexposureand establishBE. However, in thoseinstanceswhere a pharmacokineticapproachis not possible,suitably validatedpharmacodynamic methodscan be used to demonstrate BE. C. Comparative Clinical Studies

Where them are no other means,well-controlledclinical trials in humansmay be useful to provide supportiveevidenceof BA or BE. However, the use of comparativeclinical trials as an approachto demonstrate is generallyconsideredinsensitiveand should be avoidedwhere BE possible(21 CFR 320.24). The use of BE studieswith clinical trial endpointsmay be appropriateto demonstrate for orally administereddrug productswhen measurement the BE of active ingredientsor activemoietiesin an accessible biological fluid (pharmacokineticapproach) or pharmacodynamic approachis infeasible. D. In Vitro Studies

Under certain circumstances, product quality BA and BE can be documentedusing in vitro approaches CFR 320.24). For highly soluble,highly permeable, (21 rapidly dissolving,orally administemddrug products,documentationof BE using an in vitro approach(dissolution studies)is appropriatebasedon the biopharmaceutics classificationsystern5 This approach may also be suitableunder somecircumstances assessing during the IND period, for in BE NDA and ANDA submissions, in the presenceof certain postapprovalchangesto and approved NDAs and ANDAs. In addition, in vitro approaches documentBE for to nonbioproblem drugs approvedprior to 1962 remain acceptable(21 CFR 320.33). Dissolution testing is also usedto assess batch-to-batchquality, where the approachmay become one of the tests,with defined procedures,in a drug product specificationto allow batch release. Dissolution testing is also used to (1) provide processcontrol and quality assurance, and (2) assess need for further BE studiesrelative to minor postapprovalchanges,where the dissolutioncan functionas a signalof bioinequivalence.In vitro dissolutioncharacterization is encouraged all product formulationsinvestigated(includingprototypeformulations), for
5 See the FDA guidance for industry on Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classijication System (August 2000). This document provides complementary information on the BiopharmaceuticsClassification System (BCS).

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particularly if in vivo absorptionchamcteristics being defined for the different product are formulations. Such efforts may enablethe establishment an in vitro-in vivo correlation. When of an in vitro-in vivo correlationor associationis available(21 CFR 320.22),the in vitro test can servenot only as a quality control specificationfor the manufacturingprocess,but also as an indicator of how the product will perform in vivo. The following guidances provide recommendations the developmentof dissolutionmethodology,settingspecifications, the on and regulatoryapplicationsof dissolutiontesting: (1) Dissolution Testing of Immediate Release Solid Oral Dosage Forms (August 1997); and (2) Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations (September 1997). This guidancerecommends dissolutiondata from threebatchesfor both NDAs and that ANDAs be usedto set dissolutionspecificationsfor modified-release dosageforms, including extended-release dosageforms.

Iv.

COMPARISON OF BAMEASURES IN BE STUDIES

An equivalenceapproachhas been and continuesto be recommended BE comparisons. The for recommendedapproachrelies on (1) a criterion to allow the comparison,(2) a confidenceinterval for the criterion, and (3) a BE limit. Log-transformationof exposuremeasures prior to statisticalanalysisis recommended. BE studiesare performed as single-dose,crossoverstudies. To comparemeasuresin thesestudies,data have been analyzedusing an averageBE criterion. This guidancerecommends continueduse of an averageBE criterion to compareBA measures replicateand nonreplicateBE for studiesof both immediate-and modified-release products.However, sponsorshave the option to explain why they would use anothercriterion (e.g.,an individual BE criterion for replicatedesignstudies of highly variable drug products). Sponsorsshould documentselectionof the criterion in the study protocol. Sponsorsandor applicantswishing further informationon this approachshouldcontactthe appropriateCDER review division. The criteria to allow comparisonof BE measures be provided will in a separate FDA guidancefor industry.6 When the individual or populationBE criterion is used,in addition to meetingthe BE limit basedon confidencebounds,the point estimateof the geometric test/reference mean ratio should fall within SO-125%.

V.

DOCUMENTATION

OF BA AND BE

An in vivo study is generallyrecommended all solid oral dosageforms approvedafter 1962and for for bioproblem drug products approvedprior to 1962. Waiver of in vivo studiesfor different strengths of a drug product may be grantedunder 21 CFR 320.22 (d)(2) when (1) the drug product is in the same
‘ Average, Population, and Individual Approaches to Establishing Bioequivalence (draft guidance published August 1999). When finalized, this guidance will provide recommendations on criteria for comparison of BE measures.

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dosageform, but in a different strength;(2) this d&rent strengthis proportionally similar in its active and inactive ingredientsto the sttengthof the product for which the samemanufacturer conducted has an acceptable vivo study; and (3) the new strengthmeetsan appropriatein vitro dissolutiontest. This in guidancedefinesproportionally similar in two ways: Definition 1: All active and inactive ingredientsare in exactly the sameproportion between di&rent strengths(e.g.,a tablet of 50-mg strengthhas all the inactive ingredients, exactly half that of a tablet of lOO-mgstrength,and twice that of a tablet of 25mg strength). Definition 2: The total weight of the dosageform remainsnearly the samefor all strengths (within f 5 percentof the total weight of the strengthon which a bio-study was performed),the sameinactive ingredientsare usedfor all strengths, the changein any strengthis obtainedby and altering the amount of the active ingredientand one or more of the inactiveingredients.7For example,with respectto an approved5-mg tablet, the total weight of new l- and 2.5-mg tabletsremainsnearly the same,and the changesin the amountof active ingredientare offset by a changein one or more inactiveingmdients. This definition is generallyapplicableto highpotency drug substances where the amount of active drug substance the dosageform is in relatively low (e.g.,_<5 mg). k Solutions

For oral solutions,elixirs, syrups,tinctures,or other solubilizedforms, BA and/or BE can be demonstrated using nonclinical studies(21 CFR 320.22(b)(3)(i)). Generally,in vivo BE studies are waived for solutionson the assumptionthat releaseof the drug substance from the drug product is selfevident and that the solutionsdo not contain any excipientthat significantlyaffects drug absorption (21 CFR 320.22 (b) (3) (iii)). H owever, there are certain excipients,such as sorbitol or mannitol,that can reducethe bioavailabilityof drugswith low intestinalpermeability in amountssometimes usedin oral liquid dosageforms. B. Suspensions

BA and BE for a suspension should generallybe established for immediate-release oral as solid dosageforms, and both in vivo and in vitro studiesare recommended. C. Immediate-Release Products: Capsules and Tablets 1. General Recommendations

For product quality BA and BE studies,where the focus is on releaseof the drug substance from the drug product into the systemiccirculation,a single-dose, fasting
’ The changes in the inactive ingredients should be within the limits defined by the SUPAC -IR and SUPAC-MR guidances.

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study should be performed. In vivo BE studiesshouldbe accompanied in vitro by dissolutionprofiles on all skengthsof eachproduct. For ANDAs, the BE study should be conductedbetweenthe test product and referencelisted drug using the strength specifiedin Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). 2. a. Waivers of In Vivo BE Studies (Biowaivers) INDs, NDAs, and ANDAs: Preapproval

When the drug product is in the samedosageform, but in a different strength,and is proportionallysimilar in its active and inactiveingmdients,an in vivo BE demonstration of one or more lower strengthscan be waived basedon dissolutiontestsand an in vivo study on the higheststrength.* For an NDA, biowaivers of a higher strengthwill be determinedto be appropriate basedon (1) clinical safetyand/or efficacy studiesincluding data on the doseand the desirabilityof the higher &err& (2) linear eliminationkineticsover the therapeutic dose range;(3) the higher strengthbeing proportionallysimilar to the lower &en& and (4) the samedissolutionprocedures being used for both strengthsand similar dissolution resultsobtained. A dissolutionprofile shouldbe generated all strengths. for The fi test should be usedto compareprofiles from the different strengths the of product. An & value_>50 indicatesa sufficiently similar dissolutionprofile suchthat further in vivo studiesare not necessary.For an fi value < 50, further discussions with CDER review staff may help to determinewhetheran in vivo study is important(2 1 CFR 320.22 (d)(2)(ii)). The $ approachis not suitablefor rapidly dissolvingdrug products (e.g., _>85% dissolvedin 15 minutesor less). For an ANDA, conductingan in vivo study on a strengththat is not the highestmay be appropriatefor reasonsof safety, subjectto approval by review staff. In addition, as with an NDA, the Agency will considera waiver requestfor a recentlyapprovedhigher strengthwhen an in vivo BE study was performedon a lower strengthof the samedrug product submittedin an ANDA under the following circumstances:
l

Linear elimination kinetics has been shown over the therapeuticdoserange. The higher strengthis proportionallysimilar to the lower strength.

l

’ This recommendation modifies a prior policy of allowing blowaivers for only three lower strengths on ANDAs.

13

l

Comparative dissolutiontestingon the higherstrength the test and reference of drug productis submittedand found acceptable. The sponsor initiatedthe BE studyon the lower strength within five working daysof the approvaldateof a higher strength the reference of listed drug. A studyis considered initiated when the first subjectis dosed.

l

Sponsors ANDAs wishing to submita biowaiverrequestunderthesecircumstances of shouldfirst contactthe RegulatorySupportBranch,Office of GenericDrugs, for advice on the proper filing procedure. b. NDAs and ANLIAs: Postapproval

Informationon the typesof in vitro dissolution in vivo BE studies irnmediateand for releasedrug productsapprovedas either NDAs or ANDAs in the presence of specified postapproval changes providedin an FDA guidancefor industryentitled are SUPAC-IR: Immediate ReleaseSolid Oral DosageForms: Scale-Up and PostApproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing,and In Vivo BioequivalenceDocumentation(November 1995). For postapproval changes, in vitro comparison the shouldbe madebetweenthe prechange and postchange products. In instances wheredissolution profile comparisons are recommended, fi test shouldbe used. An t$ valueof 150 suggests sufliciently an a similar dissolution profile andno furtherin vivo studies needed.W h e n in vivo BE ate studiesare recommended, comparison the shouldbe madefor NDAs betweenthe prechange postchange and products,and for ANDAs betweenthe postchange and reference listed drug products. D. Modified-Release Products

Modified-release productsinclude delayed-release productsand extended (controlled)-release products. As definedin the U.S. Pharmacopeia (USP), delayed-release productsare dosage drug forms that release drugsat a tim e later than immediatelyafter administration thesedrug the (i.e., productsexhibit a lag tim e in quantifiable plasmaconcentrations). Typically, coatings (e.g., entericcoatings) intendedto delaythe release medication are of until the dosage form has passed throughthe acidic medium of the stomach.In vivo testsfor delayed-release drug productsare similar thosefor to extended-release products. In vitro dissolutiontestsfor drug theseproductsshoulddocumentthat they are stableunderacidic conditionsand that they release drug only in a neutralmedium (e.g.,pH 6.8). the

14

Extended-release products are dosageforms that allow a reduction in dosing t?equency drug as comparedto when the drug is presentin an immediate-release dosageform. Thesedrug products can also be developedto reduce fluctuationsin plasma concentrations.Extendedreleaseproducts can be capsules,tablets,granules,pellets, and suspensions.If any part of a drug product includesan extended-release component,the following recommendations apply. I. NDAs: BA and BE Studies

An NDA can be submittedfor a previously unapprovednew molecular entity, or for a new salt, new ester,prodrug, or other noncovalentderivativeof a previously approved new molecularentity, formulatedas a modified-release drug product. The first modified-release drug product for a previously approvedimmediate-release drug product should be submittedas an NDA. Subsequent modified-releaseproductsthat are pharmaceutically equivalentand bioequivalentto the listed drug product should be submittedas ANDAs. BA recommendations the NDA of an extended-release for product are consideredat 21 CFR 320.25(f). The purpose for an in vivo BA study for which a controlled-release claim is made is to determineif all of the following conditions are met:
0

The drug product meetsthe controlledreleaseclaims made for it. The BA profile established the drug product rules out the occurrenceof any for dosedumping. The drug product’ steady-state s performanceis equivalentto a currently marketednoncontrolledreleaseor controlled-release drug product that contains the sameactive drug ingredientor therapeuticmoiety and that is subjectto an approvedfull new drug application. The drug product’ formulation providesconsistentpharmacokinetic s performancebetweenindividual dosageunits.

0

0

0

As noted at 21 CFR 320.25 (f) (2), the reference material(s) for such a BA study shall be chosen to permit an appropriate scientific evaluation of the controlled release claims madefor the drug product, such as:
0

A solutionor suspension the active drug ingredientor therapeuticmoiety of A currently marketednoncontrolled-release product containingthe same drug active drug ingredientor therapeuticmoiety and administeredaccordingto the dosagerecommendations the labeling in

0

15

a

A currently marketed controlled-releasedrug product subjectto an approved full new drug applicationcontainingthe sameactive drug ingredient or therapeuticmoiety and administeredaccordingto the dosagerecommendations in the labeling

To satisfy the CFR recommendationsfor BA studiesfor an extended-release drug product submitted as an NDA, this guidancerecommendsthe following studies:
0

A single-dose,fasting study on all strengthsof tablets/capsules highest and strength of beaded capsules A single-dose,f&-effect study on the highest strength

0

0

A steady-state study on the highest strength

When substantialchangesin the components/composition and/or method of manufacture for an extended-release drug product occur between the to-be-marketed NDA dosageform and the clinical trial material, BE studiesare recommended. 2. ANDAs: BE Studies

For extended-release products submitted as ANDAs, the following studiesare recommended: (1) a single-dose,replicate, fasting study comparing the highest strength of the test and reference listed drug product; and (2) a food-effect, nonreplicate study comparing the highest strengthof the test and referenceproduct (section VIA). Becausesingle-dosestudiesare consideredmore sensitivein addressingthe primary question of BE (i.e., releaseof the drug substance from the drug product into the systemiccirculation), multiple-dose studiesam generally not recommended,even in instanceswhere nonlinear kinetics are present 3. a. Waivers of In Vivo BE Studies (Biowaivers): NDAs and ANDAs Beaded Capsules- Lower Strength

For extended-release beaded capsuleswhere the strengthdiffers only in the number of beadscontaining the active moiety, a single-dose,fasting BE study should be carried out only on the highest strength,with waiver of in vivo studiesfor lower strengthsbasedon dissolutionprofiles. A dissolutionprofile should be generatedfor each strengthusing the recommendeddissolutionmethod. The f2 test should be used to compareprofiles from the different strengthsof the product. An G value of 2 50 can be used to confirm that fbrther in vivo studiesare not needed.

16

b.

Tablets - Lower Strength

For extended-release tablets,when the drug product is in the samedosageform but in a different skngth, is proportionallysimilar in its active and inactiveingredients, has and the samedrug releasemechanism, in vivo BE determination one or more lower an of strengthscan be waived basedon dissolutionprofile comparisons, with an in vivo study only on the higheststrength. The drug productsshouldexhibit similar dissolutionprofiles betweenthe highest strengthand the lower strengthsbasedon the 6 test in at leastthree dissolution media (e.g.,pH 1.2,4.5 and 6.8). The dissolutionprofile shouldbe generatedon the test and referenceproducts of all strengths. 4. Postapproval Changes

Information on the types of in vitro dissolutionand in vivo BE studiesfor extendedreleasedrug products approvedas either NDAs or ANDAs in the presenceof specifiedpostapprovalchangesare provided in an FDA guidancefor industry entitled SUPAC-MR: ModiJied ReleaseSolid Oral Dosage Forms: Scale-Up and PostApproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (September 1997). For postapprovalchanges,the in vitro comparisonshould be made betweenthe pmchange and postchangeproducts. In instanceswhere dissolutionprofile comparisons are recommended,an fi test should be used. An & valueof _>50 suggests similar a dissolutionprome. A failure to demonstrate similar dissolutionprofilesmay result in the needto perform an in vivo BE study. When in vivo BE studiesam conducted, the comparisonshould be made for NDAs betweenthe prechangeand postchange products, and for ANDAs betweenthe postchange product and referencelisted drug. E. Miscellaneous Dosage Forms

Rapidly dissolvingdrug products,such as buccal and sublingualdosageforms, should be tested for in vitro dissolutionand in vivo BA and/orBE. Chewabletabletsshouldalso be evaluated for in vivo BA and/or BE. Chewabletablets(as a whole) shouldbe subjectto in vitro dissolutionbecausethey might be swallowedby a patient without proper chewing. In general, in vitro dissolutiontest conditionsfor chewabletabletsshouldbe the sameas for nonchewable tabletsof the sameactive ingredient/moiety.Infrequently,different test conditionsor acceptance criteria may be indicatedfor chewableand nonchewabletablets,but thesedifferences,if they exist, shouldbe resolvedwith the appropriate review division. VI. SPECIAL TOPICS A. Food-Effect Studies

17

Coadministrationof food with oral drug productsmay influence drug BA and/or BE. Foodeffect BA studiesfocus on the effectsof food on the releaseof the drug substance from the drug product as well as the absorptionof the drug substance.BE studieswith food focus on demonstratingcomparableBA betweentest and referenceproductswhen coadministemd with meals. Usually, a single-dose,two-period, two-treatment,two-sequence crossoverstudy is recommendedfor both food-effect BA and BE studies. B. Moieties to Be Measured I. Parent Drug VersusMetabolites

The moietiesto be measured biological fluids collectedin BA and BE studiesare in eitherthe active drug ingredientor its activemoiety in the administered dosageform (parent drug) and, when appropriate,its active metabolites(21 CFR 320.24(b)(l)(i)).9 This guidancerecommendsthe following approaches BA and BE studies. for For BA studies(seesectionIIB), determinationof moietiesto be measuredin biological fluids should take into accountboth concentration activity. and Concentration refers to the relative quantity of the parent drug or one or more metabolites a given volume of an accessible in biological fluid suchas blood or plasma. Activity refersto the relative contributionof the parentdrug and its metabolite(s) the in biological fluids to the clinical safetyand/orefficacy of the drug. For BA studies,both the parentdrug and its major active metabolitesshouldbe measured, analytically if feasible. For BE studies,measurement only the parentdrug releasedf?om the dosageform, of ratherthan the metabolite,is generallyrecommended.The rationalefor this recommendation that the concentration-time is profile of the parentdrug is more sensitiveto changesin formulationperformance than a metabolite,which is mom reflectiveof metaboliteformation,distribution,and elimination. The following am exceptionsto this generalapproach.
l

Measurementof a metabolitemay be preferredwhen parent drug levels are too low to allow reliable analyticalmeasurem in blood, plasma,or serum for an adequate ent length of time. The metabolitedata obtainedfrom thesestudiesshouldbe subjectto a confidenceinterval approachfor BE demonstration.If there is a clinical concern relatedto efficacy or safety for the parentdrug, sponsorsand/or applicantsshould

9A dosage form contains active and, usually, inactive ingredients. The active ingredient may be a prodrug that requires further transformation in vivo to become active. An active moiety is the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt, or other noncovalent derivative of the molecule, responsible for the physiological or pharmacological action of the drug substance.

18

contactthe appropriatereview division to determinewhether the parentdrug should be measuredand analyzedstatistically.
l

A metabolitemay be formed as a result of gut wall or other presystemic metabolism. Ifthe metabolitecontributes meaningfullyto safetyand/orefficacy,the metaboliteand the parent drug shouldbe measured.When the relative activity of the metaboliteis low and doesnot contributemeaningfullyto safetyand/orefficacy, it doesnot need to be measured. The parent drug measuredin theseBE studies shouldbe analyzedusing a confidenceinterval approach. The metabolitedata can be used to provide supportiveevidenceof comparabletherapeuticoutcome. Enantiomers VersusRacemates

2.

For BA studies,m easmment of individual enantiomers may be important. For BE using an achiral assay. studies,this guidancerecommends easumnentof the racemate m Measurement individual enantiomers BE studiesis recommended when all of of in only the following conditionsare met: (1) the enantiomers exhibit diffemnt phannacodynamic characteristics; the enantiomers (2) exhibit difherent pharmacokinetic characteristics; (3) primary efficacy/safety activity resideswith the minor enantiomer,and (4) nonlinear absorptionis present(as expressed a changein the enantiomerconcentration by ratio with changein the input rate of the drug) for at leastone of the enantiomers.In such cases,BE criteria should be applied to the enantiomers separately. 3. Drug Products with Complex Mixtures as the Active Ingredients

Certain drug productsmay contain complex drug substances active moietiesor (i.e., active ingtedientsthat are mixtures of multiple syntheticand/ornaturalsource components).Some or all of the componentsof thesecomplex drug substances may not be charac$er&dwith regardto chemicalstructureand/orbiological activity. Quantificationof all active or potentiallyactivecomponents pharmacokineticstudies in to documentBABE is neither necessary desirable. Rather,BA and BE studies nor shouldbe basedon a small number of markersof rate and extent of absorption. Although necessarilya case-by-ease determination, criteria for marker selectioninclude amountof the moiety in the dosageform, plasmaor blood levels of the moiety, and biological activity of the moiety relativeto othermoietiesin the complexmixture. Where pharmacokineticapproaches not feasibleto assess and extent of absorptionof are rate a drug substance from a drug product, in vitro approaches may be preferred. Phamracodynamic clinical approaches be called for ifno quantifiablemoieties or may are availablefor in vivo pharmacokineticor in vitro studies. C. Long Half-Life Drugs

19

In a BA/pharmacokineticstudy involving an oral product with a long half-life drug, adequate characterization the half-life calls for blood samplingover a long period of time. For a BE of determinationof an oral product with a long half-life drug, a nonreplicate,single-dose,crossover study can be conducted,provided an adequatewashout period is used. If the crossoverstudy is problematic,a BE study with a parallel design can be used. For either a crossoveror parallel study, samplecollection time shouldbe adequate ensurecompletionof gastrointestinal to transit (approximately2 to 3 days) of the drug product and absorptionof the drug substance.Cmax, and a suitably truncatedAUC can be used to characterize peak and total drug exposure, respectively. For drugs that demonstrate intra-subjectvariability in distribution and low clearance,an AUC truncatedat 72 hours (AU&72 r,J may be usedin place of AU&, or high i&a-subject variability in distriiution and clearance, AU&,. For drugs demonstrating AUC truncationwarrantscaution. In such cases,sponsorsand/or applicantsshould consult the appropriatereview staff. D. First Point Cmax

The first point of a concentration-time curve in a BE study basedon blood and/orplasma measurements sometimes highestpoint, which raisesa questionaboutthe measurement is the of true Cmax because insufficientearly samplingtimes. A carefullyconducted of pilot study may avoid this problem. Collection of an early time point between5 and 15 minutesafter dosing followed by additionalsamplecollections(e.g.,two to five) in the first hour aI?erdosing may be sufficient to assess early peak concentrations.If this samplingapproachis followed, data sets should be consideredadequate, even when the highest observedconcentrationoccurs at the first time point. E. Orally Administered Drugs Intended for Local Action

Documentationof product quality BA for NDAs where the drug substance producesits effects by local action in the gastmintestinal can be achievedusing clinical efficacy and safety tract studiesand/orsuitably designedand validatedin vitro studies. Similarly, documentation BE of for ANDAs, and for both NDAs and ANDAs in the presence certain postapprovalchanges, of can be achievedusing BE studieswith clinical efficacy and safetyendpointsand/or suitably designedand validatedin vitro studiesif the latter studiesare eitherreflectiveof important clinical effectsor are more sensitiveto changesin product performancecomparedto a clinical study. To ensurecomparablesafety,additional studieswith and without food may help to understand degreeof systemicexposurethat occursfollowing administrationof a drug the product intendedfor local action in the gastrointestinal tract. F. Narrow Therapeutic Range Drugs

20

This guidancedefinesnarrow therapeutic range” drug productsas thosecontainingcertain drug substances are subjectto therapeuticdrug concentrationor pharmacodynamic that monitoring, and/or where product labeling indicatesa narrow therapeuticrange designation.Examples includedigoxin,lithium,phenytoin,theophylline,and warfarin. Becausenot all drugs subjectto therapeuticdrug concentrationor pharmacodynamic monitoring are narrow therapeuticrange drugs, sponsorsand/or applicantsshould contactthe appropriatereview division at CDER to determinewhether a drug should or should not be consideredto have a narrow therapeutic range. This guidancerecommendsthat sponsors consideradditionaltesting and/orcontrols to ensure the quality of drug productscontainingnarrow therapeuticrangedrugs. The approachis designedto provide increased assurance interchangeability drug productscontaining of for specifiednarrow therapeuticrange drugs. It is not designedto influencethe practice of medicine or pharmacy. Unlessotherwiseindicatedby a specificguidance,this guidancerecommends the traditional that BE limit of 80-125% for non-narrowtherapeutic range drugs remain unchangedfor the bioavailability measures (AUC and Cmax) of narrow therapeuticrange drugs.

lo This guidance uses the term “narrow therapeutic range” instead of “narrow therapeutic index” drug, although the latter is more commonly used.

21

APPENDIX 1 List of Guidances That Will Be Replaced

1. 2.

Guidelinesfor the Evaluation of Controlled ReleaseDrug Products (April 1984). Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design (July 1992). Oral Extended (Controlled) ReleaseDosage Form: In Vivo Bioequivalence and In Vitro Dissolution Testing (September 1993). Drafi Guidancefor Industry In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches (October 1997). Drug specificbioequivalence guidances hrn the Division of Bioequivalence, Office of Generic Drugs, Office of Pharmaceutical Science,Centerfor Drug Evaluationand Research, FDA.

3.

4.

5.

22

APPENDIX 2 General Pharmacokinetic Study Design and Data Handling

For both replicate and nonreplicate, vivo phamracokinetic studies,the following general in BE approaches recommendedrecognizingthat the elementsmay be adjustedfor certain drug are substances drug products. and Study conduct:
0

The test or referenceproducts should be administeredwith about 8 ounces(240 ml) of water to an appropriatenumber of subjectsunder fasting conditions,unlessthe study is a foodeffect BABE study. Generally,the highestmarketedsnengthshouldbe administered a single unit If as necessary analyticalreasons, for multiple units of the higheststrengthcan be administeredproviding the total single-dose remainswithin the labeleddoserange. An adequate washoutperiod (e.g.,more than 5 half lives of the moietiesto be measured)should separateeach treatment. The lot numbersof both test and referencelisted productsand the expiration date for the referenceproduct should be stated. The drug contentof the test product should not differ fi-omthat of the referencelisted product by more than 5 percent. The sponsor should include a statementof the compositionof the test product and, if possible,a side-by-sidecomparisonof the compositionsof test and referencelisted products. In accordance with 21 CFR 320.38, samplesof the test and referencelisted product must be retainedfor 5 years. prior to and during each study phase,subjectsshould (1) be allowed water as desired except for one hour before and after drug administration;(2) be provided standard mealsno lessthan 4 hours afler drug admi&ratiom (3) abstainfrom alcohol for 24 hours prior to each study period and until after the last samplefrom eachperiod is collected.

0

l

0

0

Samplecollectionand samplingtimes: a Under normal circumstances, blood, rather than urine or tissue,should be used. In most cases,drug, or metabolitesare measuredin serumor plasma. However, in certain caseswhole blood may be more appropriatefor analysis. Blood samplesshouldbe 23

drawn at appropriatetimes to describethe absorption,distribution, and elimination phasesof the drug. For most drugs, 12 to 18 samples,including a predose sample, should be collectedper subjectper dose. This samplingshould continue for at least threeor more terminal half lives of the drug. The exacttiming for samplecollection dependson the natureof the drug and the input from the administereddosageform. The samplecollection shouldbe spacedin sucha way that the maximum concentration of the drug in the blood (Cmax) and terminal eliminationrate constant(Q can be estimatedaccurately. At leastthree to four samplesshouldbe obtainedduring the terminal log-linearphaseto obtain an accurateestimateof h, fkom linear regression. The actualclock time when samplesare drawn as well as the elapsedtime relatedto drug administrationshould be recorded. Subjectswith predoseplasma concentrations:
0

If the predoseconcentrationis less than or equal to 5 percentof Cmax value in that subject,the subject’ data without any adjustments be included in all s can pharmacokinetic measurements calculations. If the predosevalue is greaterthan 5 and percentof Cmax, the subjectshouldbe droppedfrom all BE study evaluations.

Data deletiondue to vomiting:
l

Data fi-om subjectswho experienceemesisduring the courseof a BE study for immediate-release productsshouldbe deletedftom statisticalanalysisif vomiting occurs at or before 2 times median Tmax. In the caseof modified-release products,the data from subjectswho experienceemesisany time during the labeleddosinginterval should be deleted.

The following pharmacokinetic informationis recommended submission: for
0

0
l

Plasmaconcentrations time points and Subject,period, sequence, treatment

AUC,,,AUC,,,Cmax,Tmax,h,,andt1/2
Intersubject,inttasubject, and/ortotal variability, if available Subject-by-formulation interactionvariancecomponent(on’ if individual BE criterion ), is used Cmin (concentration the end of a dosing interval),Cav (averageconcentrationduring at a dosing interval), degreeof fluctuation [(Cmax-Cmin)/Cav],and swing [(CrnaxCmin)/Cmin] if steady-state studiesare employed Partial AUC, requestedonly as discussedin sectionIII. A.9.a. AU&,, and Cmax:

0
0 0

0

In addition,the following statisticalinformation shouldbe provided for AU&,

24

.

l l l l

Geometricmean Arithmetic mean Ratio of means Confidenceintervals

Logarithmic transformationshouldbe provided for measures usedfor BE demonstration. Roundingoff of confidenceintervalvalues:
l

Confidenceinterval (CI) valuesshouldnot be roundedoff; therefore,to passa CI limit of 80-125, the value should be at least 80.00 and not more than 125.00.

25

MEMORANDUM

DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

DATE: FROM: Director Division Material

of for

OTC Drug Docket

Products, No. /y

HFD-560

SUBJECT: TO:

74fl-Q52N. HFA-305

m
q

Dockets

Management

Branch,

The attached material should be placed on public display under the above referenced Docket No. This material Comment No. should be cross-referenced to

Charles

J.

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