New Guidlines

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

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fNTRODUCTfON

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BACKGROUND..

1 ..................................................................................................................................................................

A. B. C. .

2 GENERAL ........................................................................................................................................................................... 3 BIOAVAILABILITY ........................................................................................................................................................... 4 ............................................................................................................................................................ BIOEQUIVALENCE METHODS

A. B. C. D.

TO DOCUMENT

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

Iv.

COMPARISON

V.

DOCUMENTATION A. B. C. D. E

BA AND BE ...................................................................................................................... 6

OF BA AND BE ............................................................................................................................ 11

12 SOLUTIONS ...................................................................................................................................................................... 12 SUSPENSIONS.................................................................................................................................................................. 12 ............................................................................... IMMEDIATE-RELEASE PRODUCTS CAPSULES AND TABLETS 14 MODIFIED-RELEASEPRODUCTS ................................................................................................................................. 17 MISCELLANEOUS DOSAGE FORMS .............................................................................................................................. 17 SPECIAL TOPICS ..............................................................................................................................................................

VL A. B. C. D. E F.

17 FOOD-EFFECT STUDIES ................................................................................................................................................. MOIETIESTOBEMEASURED ...... . ............................................................................................................................... 18 19 LONG HALF-LIFE DRUGS............................................................................................................................................... 20 FIRSTPOINTCMAX ....................................................................................................................................................... ORALLY ADMINISTERED DRUGS INTENDED FOR LoCAL ACTION .......................................................................20 20 NARROW THERAPEUTIC RANGE DRUGS....................................................................................................................

APPENDM

1: List of Guidances That Will Be Replaced ..................................................................................................... 22

APPENDIX

2: General Pharmacokinetic

Study Design and Data Handling . .. . .. . .. . . . . . . .. . .. . . . . . . .. . .. . . . . .. . . . . .. . . . . .. . .. . . . . .. . . . .. .. .. . 23

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’s current thinking on this topic. It does 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.

I.

INTRODUCTION

This guidanceis intendedto provide recommendationsto sponsorsand/or applicantsplanning to include bioavailability(BA) and bioequivalence(BE) infomration for orally administereddrug productsin investigationalnew drug applications(IN&), new drug applications@IDAs), abbreviatednew drug applications(ANDAs), and their supplements.This guidanceaddresseshow to meet the BA and BE 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 subsequentdistriiution and elimination. BA can be generallydocumentedby a systemicexposureprofile obtainedby measuringdrug and/ormetaboliteconcentrationin the systemiccirculationover time. The systemicexposureprofile determinedduring clinical trials in the IND period can serveas a benchmarkfor subsequentBE studies. Studiesto establishBE betweentwo products are important for certain changesprior to approval for a pioneer product in NDA and ANDA submissions,and in the presenceof certain 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. Regulatoryrequirementsfor documentationof BA and BE are provided in 21 CFR part 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 demonstratingin vivo BA or BE (320.23) Types of evidenceto establishBA or BE (320.24) Guidelinesfor conductof in vivo BA studies(320.25) Guidelineson designof single-doseBA studies(320.26) 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 requirementsregardingan IND application(320.31) Proceduresfor establishingand amendinga BE requirement(320.32) Criteria and evidenceto assessactual or potential BE problems(320.33) Requirementsfor batch testing and certification by FDA (320.34) 2

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Requirementsfor in vitro batch testingof eachbatch (320.35) Requirementsfor maintenanceof recordsof BE testing (320.36) Retentionof BA samples(320.38) Retentionof BE samples(320.63)

B.

Bioavailability

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Bioavailability is definedin 21 CFR 320.1 as ‘the rate and extentto which the activeingredient 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 by measurementsintendedto reflect the rate and extentto which the active ingredientor activemoiety becomesavailableat the site of action.” This definition focuseson the processesby which the active ingredientsor moieties are releasedfrom an oral dosageform and move to the site of action. From a pharmacokineticperspective,BA data for a given formulationprovide an estimateof the relative traction of the orally administereddosethat is absorbedinto the systemiccirculation when comparedto the BA data for a solution, suspension,or intravenousdosageform (21 CFR 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 pharmacokineticsof the activemoietiesand, where appropriate,inactivemoieties. BA datamay also provide information indirectly aboutthe propertiesof a drug substanceprior to entry into the systemiccirculation,suchas permeability and the intluenceof presystemicenzymesand/or transporters(e.g., p-glycopmtein). BA for orally administereddrug productsmay be documentedby developinga systemic exposureprofile obtainedfrom m easuringthe concentrationof activeingredientsandor active moietiesand, when appropriate,its activemetabohtesover time in samplescolk&ed from the systemiccirculation. Systemicexposurepatternsreflect both releaseof the drug substancefrom 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 theseprocessesto the systemicexposurepattern. 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 demonstratingsafetyand efficacy,before marketinga drug product. The systemicexposureprofiles of clinical trial materialcan be usedas a benchmarkfor subsequentformulation changesand may thus be useful as a referencefor Uure BE studies. Although BA studieshavemany pharmacokineticobjectivesbeyond formulationperformance as describedabove,it shouldbe noted that subsequentsectionsof this guidancefocus on using

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

Bioequivalence

Bioequivalenceis defined at 21 CFR 320.1 as “the absenceof a significant differencein the rate and extentto which the active ingredientor activemoiety in pharmaceuticalequivalentsor pharmaceuticalalternativesbecomesavailableat the site of drug action when administeredat the 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 subsequentabsorptioninto the systemiccirculation. For this mason, similar approachesto m easuringBA in an NDA shouldgenerallybe followed in demonstrating BE for an NDA or an ANDA. Establishingproduct quality BA is a benchmarkingeffort with comparisonsto an oral solution, oral suspension,or an intravenousformulation. In contrast, demonstratingBE is usually a more formal comparativetest that usesspecifiedcriteria for comparisonsand predeterminedBE limits for the criteria. 1.

IiVDhJDAs

BE documentationmay 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-marketeddrug 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 becausethe test product has higher or lower measuresof rate and extent of absorptioncomparedto the referenceproduct or becausethe performanceof the test or referenceis more variable. In some cases, nondocumentationof BE may arisebecauseof inadequatenumbersof subjectsin the study relativeto the magnitudeof inttasubjectvariability, and not becauseof eitherhigh or low relative BA of the test product. Adequatedesign and executionof a BE study will facilitateunderstandingof the causesof nondocumentationof BE. Where the test product generatesplasmalevels that are substantiallyabovethoseof the referenceproduct, the regulatory concernis not therapeuticfailure, but the adequacyof 4

the safety databasefrom 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-responseor concentration-response curvesis useful in situationswhere the drug product has plasmalevelsthat are either higher or lower than the referenceproduct and am outsideusual BE limits. In the absenceof individual data, population dose-responseor concentration-response data acquired over a range of doses,including dosesabove the recommendedtherapeuticdoses,may be sufficient to demonstratethat the increasein plasmalevels would not be accompaniedby additionalrisk. Similarly, population dose-or concentration-response relationships observedover a lower range of doses,including dosesbelow the recommended therapeuticdoses,may be able to demonstratethat reducedlevels of the test product comparedto the referenceproduct are associatedwith adequateefficacy. In either event,the burden is on the sponsorto demonstratethe adequacyof the clinical trial dose-responseor concentration-responsedata to provide evidenceof therapeutic equivalence.In the absenceof this evidence,a failure to documentBE may suggesta 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 demonstrateBE betweena pharmaceuticallyequivalentgenericdrug product and the correspondingreferencelisted drug (21 CFR 314.94 (a)(7)). Together with the determinationof pharmaceuticalequivalence,establishingBE allows a regulatoryconclusionof therapeuticequivalence. 3.

Postapproval Changes

Information on the types of in vitro dissolutionand in vivo BE studiesthat shouldbe conductedfor immediate-releaseand modified-releasedrug products approvedas eitherNDAs or ANDAs in the presenceof specifiedpostapprovalchangesis provided in the FDA guidancesfor industry entitled SUPAC-IR: Immediate Release Solid Oral 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 accordancewith 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, pharmacodynamic,clinical, and in vitro studies. Thesegeneralapproachesare discussedin 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, expressedin terms of rate and extent of absorptionof the active ingredientor moiety to the site of action,emphasizethe use of pharmacokineticmeasuresin an accessiblebiological matrix such as blood, plasma, and/or serumto indicatereleaseof the drug substancet?omthe drug product into the systemiccirculation.4This approachrestson an understandingthat measuringthe active moiety or ingredientat the site of action is generallynot possibleand furthermore,that somerelationshipexistsbetweenthe efficacy/safetyand concentrationof active moiety and/or its irnIwtant metaboliteor metabolitesin the systemiccirculation. To measure product quality BA and establishBE, relianceon pharmacokineticmeasurementsmay be viewed as a bioassaythat assessesreleaseof the drug substancefrom 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 assumedto have less interoccasionvariability 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,assessvariability, optimize samplecollectiontime intervals,and provide other information. For example,for conventionalimmediate-release products,careful timing of initial samplesmay avoid a subsequentfinding in a full-scalestudy that the first samplecollection occursafler the plasma concentrationpeak. For modified-release products,a pilot study can help determinethe samplingscheduleto assesslag time and 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

Generalrecommendationsfor a standardBE study basedon pharmacokinetic measurementsare provided in Appendix 2. 4.

Nonreplicate Study Designs

Nonreplicatestudy designsare recommendedfor BE studiesof most orally administered,immediate-releasedosageforms. However, sponsorsand/or applicants have the option of using replicatedesignsfor BE studiesof thesedrug products. These studiesare descrii in sectionIRA.5 below. The recommendedmethod of analysis of nonmplicateor replicatestudiesto establishBE is discussedin sectionIV. General recommendationsfor nonreplicatestudy designsare provided in Appendix 2. 5.

Replicate Study Designs

Replicatestudy designsare recommendedfor BE studiesof modified-releasedosage forms and highly variabledrug products(within-subjectcoefficientof variation 2 30%), including thosethat are immediaterelease,modified-release,and other orally administereddrug products. The recommendedmethod of analysisof replicatestudies to establishBE is discussedin sectionIV. Replicatestudy designsoffer severalscientific advantagescomparedto nonreplicate designs. The advantagesof replicatestudy designsare that they (1) allow comparisons 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

6.

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 diseaseprocessis 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.

7.

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.

8.

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 measuresof absorptionrate to measuresof systemicexposure. Cmax and AUC can continueto be used as measuresfor product quality BA and BE, but more in terms of their capacityto assessexposurethan 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. Exposuremeasuresare defined relative to early, peak, and total portions of the plasma,serum,or blood concentrationtime profile, as follows: a.

Early Exposure

For orally administeredimmediate-releasedrug products,BE may generallybe demonstratedby measurementsof peak and total exposure. An early exposure measuremay be indicatedon the basisof appropriateclinical 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 assessedby measuringthe peak drug concentration(Cmax) obtaineddirectly from the datawithout interpolation. C.

Total Exposure

For single-dosestudies,the measurementof total exposureshould be: 0

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Area under the plasma/serum/bloodconcentration-timecurve from time zero to time t (AU&), where t is the last time point with measurableconcentrationfor individualformuation. Area under the plasma/scrumMoodconcentration-timecurve 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 appropriatemethod. The tem~inalhalf-life (t& of the drug should also be reported.

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

Pharmacodynamic Studies

Pharmacodynamicstudiesare not recommendedfor orally administereddrug productswhen the drug is absorbedinto the systemiccirculation and a pharmacokineticapproachcan be used to assesssystemicexposureand establishBE. However, in thoseinstanceswhere a pharmacokineticapproachis not possible,suitably validatedpharmacodynamicmethodscan be used to demonstrateBE. 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 demonstrateBE is generallyconsideredinsensitiveand should be avoidedwhere possible(21 CFR 320.24). The use of BE studieswith clinical trial endpointsmay be appropriateto demonstrateBE for orally administereddrug productswhen measurementof the active ingredientsor activemoietiesin an accessiblebiological fluid (pharmacokineticapproach) or pharmacodynamicapproachis infeasible. D.

In Vitro Studies

Under certain circumstances,product quality BA and BE can be documentedusing in vitro approaches(21 CFR 320.24). For highly soluble,highly permeable,rapidly dissolving,orally administemddrug products,documentationof BE using an in vitro approach(dissolution studies)is appropriatebasedon the biopharmaceuticsclassificationsystern5 This approach may also be suitableunder somecircumstancesin assessingBE during the IND period, for NDA and ANDA submissions,and in the presenceof certain postapprovalchangesto approved NDAs and ANDAs. In addition, in vitro approachesto documentBE for nonbioproblem drugs approvedprior to 1962 remain acceptable(21 CFR 320.33). Dissolution testing is also usedto assessbatch-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) assessthe need for further BE studiesrelative to minor postapprovalchanges,where dissolutioncan functionas a signalof bioinequivalence.In vitro dissolutioncharacterizationis encouragedfor all product formulationsinvestigated(includingprototypeformulations), 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 absorptionchamcteristicsare being defined for the different product formulations. Such efforts may enablethe establishmentof an in vitro-in vivo correlation. When 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 guidancesprovide recommendationson the developmentof dissolutionmethodology,settingspecifications,and the 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 guidancerecommendsthat dissolutiondata from threebatchesfor both NDAs and ANDAs be usedto set dissolutionspecificationsfor modified-releasedosageforms, including extended-releasedosageforms.

Iv.

COMPARISON OF BAMEASURES IN BE STUDIES

An equivalenceapproachhas been and continuesto be recommendedfor BE comparisons. The recommendedapproachrelies on (1) a criterion to allow the comparison,(2) a confidenceinterval for the criterion, and (3) a BE limit. Log-transformationof exposuremeasuresprior 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 measuresfor replicateand nonreplicateBE studiesof both immediate-and modified-releaseproducts.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 measureswill be provided in a separateFDA 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/referencemean ratio should fall within SO-125%.

V.

DOCUMENTATION

OF BA AND BE

An in vivo study is generallyrecommendedfor all solid oral dosageforms approvedafter 1962and for bioproblem drug products approvedprior to 1962. Waiver of in vivo studiesfor different strengthsof 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 samemanufacturerhas conducted an acceptablein vivo study; and (3) the new strengthmeetsan appropriatein vitro dissolutiontest. This 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,and the changein any strengthis obtainedby 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 substanceswhere the amount of active drug substancein the dosageform is relatively low (e.g.,_<5 mg). k

Solutions

For oral solutions,elixirs, syrups,tinctures,or other solubilizedforms, BA and/or BE can be demonstratedusing nonclinical studies(21 CFR 320.22(b)(3)(i)). Generally,in vivo BE studies are waived for solutionson the assumptionthat releaseof the drug substancefrom 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 amountssometimesusedin oral liquid dosageforms. B.

Suspensions

BA and BE for a suspensionshould generallybe establishedas for immediate-releasesolid oral 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 substancefrom 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 accompaniedby in vitro 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.

Waivers of In Vivo BE Studies (Biowaivers)

a.

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 therapeuticdose range;(3) the higher strengthbeing proportionallysimilar to the lower &en& and (4) the samedissolutionproceduresbeing used for both strengthsand similar dissolution resultsobtained. A dissolutionprofile shouldbe generatedfor all strengths. The fi test should be usedto compareprofiles from the different strengthsof the product. An & value_>50 indicatesa sufficiently similar dissolutionprofile suchthat further in vivo studiesare not necessary.For an fi value < 50, further discussionswith 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.

l

The higher strengthis proportionallysimilar to the lower strength.

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

13

l

l

Comparativedissolutiontestingon the higherstrengthof the test and referencedrug productis submittedand found acceptable. The sponsorinitiatedthe BE studyon the lower strengthwithin five working daysof the approvaldateof a higher strengthof the referencelisted drug. A studyis consideredinitiated when the first subjectis dosed.

Sponsorsof ANDAs wishing to submita biowaiverrequestunderthesecircumstances shouldfirst contactthe RegulatorySupportBranch,Office of GenericDrugs, for advice on the proper filing procedure. b.

NDAs and ANLIAs: Postapproval

Informationon the typesof in vitro dissolutionand in vivo BE studiesfor irnmediatereleasedrug productsapprovedas either NDAs or ANDAs in the presenceof specifiedpostapprovalchangesareprovidedin an FDA guidancefor industryentitled 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 postapprovalchanges,the in vitro comparisonshouldbe madebetweenthe prechange and postchangeproducts. In instanceswheredissolutionprofile comparisonsare recommended,an fi test shouldbe used. An t$ valueof 150 suggests a sufliciently similar dissolutionprofile andno furtherin vivo studiesate needed.W h e n in vivo BE studiesare recommended,the comparisonshouldbe madefor NDAs betweenthe prechangeand postchangeproducts,and for ANDAs betweenthe postchangeand referencelisted drug products. D.

Modified-Release Products

Modified-releaseproductsinclude delayed-release productsand extended(controlled)-release products. As definedin the U.S. Pharmacopeia (USP), delayed-release drug productsare dosageforms that releasethe drugsat a tim e later than immediatelyafter administration(i.e., thesedrug productsexhibit a lag tim e in quantifiableplasmaconcentrations).Typically, coatings(e.g., entericcoatings)are intendedto delaythe releaseof medicationuntil the dosageform has passedthroughthe acidic medium of the stomach.In vivo testsfor delayed-release drug productsare similar thosefor to extended-release drug products. In vitro dissolutiontestsfor theseproductsshoulddocumentthat they are stableunderacidic conditionsand that they releasethe drug only in a neutralmedium (e.g.,pH 6.8).

14

Extended-releasedrug products are dosageforms that allow a reduction in dosing t?equencyas comparedto when the drug is presentin an immediate-releasedosageform. 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 recommendationsapply. 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-releasedrug product. The first modified-releasedrug product for a previously approvedimmediate-releasedrug product should be submittedas an NDA. Subsequentmodified-releaseproductsthat are pharmaceuticallyequivalentand bioequivalentto the listed drug product should be submittedas ANDAs. BA recommendationsfor the NDA of an extended-release 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.

0

The BA profile establishedfor the drug product rules out the occurrenceof any dosedumping.

0

The drug product’s steady-stateperformanceis equivalentto a currently marketednoncontrolledreleaseor controlled-releasedrug product that contains the sameactive drug ingredientor therapeuticmoiety and that is subjectto an approvedfull new drug application.

0

The drug product’s formulation providesconsistentpharmacokinetic performancebetweenindividual dosageunits.

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 suspensionof the active drug ingredientor therapeuticmoiety

0

A currently marketednoncontrolled-release drug product containingthe same active drug ingredientor therapeuticmoiety and administeredaccordingto the dosagerecommendationsin the labeling

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-releasedrug product submitted as an NDA, this guidancerecommendsthe following studies: 0

A single-dose,fasting study on all strengthsof tablets/capsulesand highest strength of beaded capsules

0

A single-dose,f&-effect

0

A steady-statestudy on the highest strength

study on the highest strength

When substantialchangesin the components/compositionand/or method of manufacture for an extended-releasedrug product occur between the to-be-marketed NDA dosageform and the clinical trial material, BE studiesare recommended. 2.

ANDAs: BE Studies

For extended-releaseproducts 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 substancefrom the drug product into the systemiccirculation), multiple-dose studiesam generally not recommended,even in instanceswhere nonlinear kinetics are present 3.

Waivers of In Vivo BE Studies (Biowaivers): NDAs and ANDAs

a.

Beaded Capsules- Lower Strength

For extended-releasebeaded 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-releasetablets,when the drug product is in the samedosageform but in a different skngth, is proportionallysimilar in its active and inactiveingredients,and has the samedrug releasemechanism,an in vivo BE determinationof one or more lower 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 comparisonsare recommended,an fi test should be used. An & valueof _>50 suggestsa similar dissolutionprome. A failure to demonstratesimilar 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 postchangeproduct 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 appropriatereview 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 substancefrom the drug product as well as the absorptionof the drug substance.BE studieswith food focus on demonstratingcomparableBA betweentest and referenceproductswhen coadministemdwith meals. Usually, a single-dose,two-period, two-treatment,two-sequencecrossoverstudy is recommendedfor both food-effect BA and BE studies. B.

Moieties to Be Measured I.

Parent Drug VersusMetabolites

The moietiesto be measuredin biological fluids collectedin BA and BE studiesare eitherthe active drug ingredientor its activemoiety in the administereddosageform (parent drug) and, when appropriate,its active metabolites(21 CFR 320.24(b)(l)(i)).9 This guidancerecommendsthe following approachesfor BA and BE studies. For BA studies(seesectionIIB), determinationof moietiesto be measuredin biological fluids should take into accountboth concentrationand activity. Concentration refers to the relative quantity of the parent drug or one or more metabolitesin a given volume of an accessiblebiological fluid suchas blood or plasma. Activity refersto the relative contributionof the parentdrug and its metabolite(s)in the biological fluids to the clinical safetyand/orefficacy of the drug. For BA studies,both the parentdrug and its major active metabolitesshouldbe measured,if analytically feasible. For BE studies,measurementof only the parentdrug releasedf?om the dosageform, ratherthan the metabolite,is generallyrecommended.The rationalefor this recommendationis that the concentration-timeprofile of the parentdrug is more sensitiveto changesin formulationperformancethan 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 analyticalmeasurement in blood, plasma,or serum for an adequate 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

2.

A metabolitemay be formed as a result of gut wall or other presystemic metabolism. Ifthe metabolitecontributesmeaningfullyto 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

For BA studies,m easmment of individual enantiomersmay be important. For BE studies,this guidancerecommendsm easumnentof the racemateusing an achiral assay. Measurementof individual enantiomersin BE studiesis recommendedonly when all of the following conditionsare met: (1) the enantiomersexhibit diffemnt phannacodynamic characteristics;(2) the enantiomersexhibit difherentpharmacokineticcharacteristics;(3) primary efficacy/safetyactivity resideswith the minor enantiomer,and (4) nonlinear absorptionis present(as expressedby a changein the enantiomerconcentrationratio with changein the input rate of the drug) for at leastone of the enantiomers.In such cases,BE criteria should be applied to the enantiomersseparately. 3.

Drug Products with Complex Mixtures as the Active Ingredients

Certain drug productsmay contain complex drug substances(i.e., active moietiesor active ingtedientsthat are mixtures of multiple syntheticand/ornaturalsource components).Some or all of the componentsof thesecomplex drug substancesmay not be charac$er&dwith regardto chemicalstructureand/orbiological activity. Quantificationof all active or potentiallyactivecomponentsin pharmacokineticstudies to documentBABE is neither necessarynor desirable. Rather,BA and BE studies shouldbe basedon a small number of markersof rate and extent of absorption. Although necessarilya case-by-easedetermination,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 pharmacokineticapproachesare not feasibleto assessrate and extent of absorptionof a drug substancefrom a drug product, in vitro approachesmay be preferred. Phamracodynamicor clinical approachesmay be called for ifno quantifiablemoieties 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 characterizationof the half-life calls for blood samplingover a long period of time. For a BE 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 adequateto ensurecompletionof gastrointestinaltransit (approximately2 to 3 days) of the drug product and absorptionof the drug substance.Cmax, and a suitably truncatedAUC can be used to characterizepeak and total drug exposure, respectively. For drugs that demonstratelow intra-subjectvariability in distribution and clearance,an AUC truncatedat 72 hours (AU&72 r,J may be usedin place of AU&, or AU&,. For drugs demonstratinghigh i&a-subject variability in distriiution and clearance, AUC truncationwarrantscaution. In such cases,sponsorsand/or applicantsshould consult the appropriatereview staff. D.

First Point Cmax

The first point of a concentration-timecurve in a BE study basedon blood and/orplasma measurementsis sometimesthe highestpoint, which raisesa questionaboutthe measurementof true Cmax becauseof insufficientearly samplingtimes. A carefullyconductedpilot 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 assessearly 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 substanceproducesits effects by local action in the gastmintestinaltract can be achievedusing clinical efficacy and safety studiesand/orsuitably designedand validatedin vitro studies. Similarly, documentationof BE for ANDAs, and for both NDAs and ANDAs in the presenceof certain postapprovalchanges, 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 understandthe degreeof systemicexposurethat occursfollowing administrationof a drug product intendedfor local action in the gastrointestinaltract. F.

Narrow Therapeutic Range Drugs

20

This guidancedefinesnarrow therapeuticrange” drug productsas thosecontainingcertain drug substancesthat are subjectto therapeuticdrug concentrationor pharmacodynamicmonitoring, and/or where product labeling indicatesa narrow therapeuticrange designation.Examples includedigoxin,lithium,phenytoin,theophylline,and warfarin. Becausenot all drugs subjectto therapeuticdrug concentrationor pharmacodynamicmonitoring 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 sponsorsconsideradditionaltesting and/orcontrols to ensure the quality of drug productscontainingnarrow therapeuticrangedrugs. The approachis designedto provide increasedassuranceof interchangeabilityfor drug productscontaining specifiednarrow therapeuticrange drugs. It is not designedto influencethe practice of medicine or pharmacy. Unlessotherwiseindicatedby a specificguidance,this guidancerecommendsthat the traditional BE limit of 80-125% for non-narrowtherapeuticrange 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.

Guidelinesfor the Evaluation of Controlled ReleaseDrug Products (April 1984).

2.

Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design (July 1992).

3.

Oral Extended (Controlled) ReleaseDosage Form: In Vivo Bioequivalence and In Vitro Dissolution Testing (September 1993).

4.

Drafi Guidancefor Industry In Vivo Bioequivalence Studies Based on Population and Individual Bioequivalence Approaches (October 1997).

5.

Drug specificbioequivalenceguidanceshrn the Division of Bioequivalence,Office of Generic Drugs, Office of PharmaceuticalScience,Centerfor Drug Evaluationand Research,FDA.

22

APPENDIX 2 General Pharmacokinetic Study Design and Data Handling

For both replicate and nonreplicate,in vivo phamracokineticBE studies,the following general approachesare recommendedrecognizingthat the elementsmay be adjustedfor certain drug substancesand drug products. 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.

0

Generally,the highestmarketedsnengthshouldbe administeredas a single unit If necessaryfor analyticalreasons,multiple units of the higheststrengthcan be administeredproviding the total single-doseremainswithin the labeleddoserange.

l

An adequatewashoutperiod (e.g.,more than 5 half lives of the moietiesto be measured)should separateeach treatment.

0

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 accordancewith 21 CFR 320.38, samplesof the test and referencelisted product must be retainedfor 5 years.

0

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.

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’sdata without any adjustmentscan be included in all pharmacokineticmeasurementsand calculations. If the predosevalue is greaterthan 5 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-releaseproducts,the data from subjectswho experienceemesisany time during the labeleddosinginterval should be deleted.

The following pharmacokineticinformationis recommendedfor submission: 0

0

Plasmaconcentrationsand time points Subject,period, sequence,treatment

l

AUC,,,AUC,,,Cmax,Tmax,h,,andt1/2

0

Intersubject,inttasubject,and/ortotal variability, if available Subject-by-formulationinteractionvariancecomponent(on’), if individual BE criterion is used Cmin (concentrationat the end of a dosing interval),Cav (averageconcentrationduring a dosing interval), degreeof fluctuation [(Cmax-Cmin)/Cav],and swing [(CrnaxCmin)/Cmin] if steady-statestudiesare employed Partial AUC, requestedonly as discussedin sectionIII. A.9.a.

0 0

0

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

24

AU&,,

and Cmax:

.

l l l l

Geometricmean Arithmetic mean Ratio of means Confidenceintervals

Logarithmic transformationshouldbe provided for measuresusedfor 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

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

MEMORANDUM

DATE: FROM:

Director Division

of

OTC Drug

SUBJECT:

Material

for

Docket

TO:

Dockets

m

Management

Products, No.

/y

Branch,

HFD-560

74fl-Q52N. HFA-305

The attached material should be placed on public display under the above referenced Docket No.

q

This material Comment No.

should

be cross-referenced

Charles

J.

to