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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
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
.
Table of Contents
L fNTRODUCTfON . .. . . . . .. . . . .. . .. . .. . . . . .. . . . . . .. .. . . . . .. .. . . . . .. . . . . . . . . .. . . .. . . . . . .. . .. . . . ... . . . .. . . . . .. . . . .. . . . . . .. . .. . . . . . . . . . .. . . . . .. . . . . . .. . . . .. . . . .. . . . . .. . . . . .. . .. . . . .. . . . 1
IL BACKGROUND.. 1
..................................................................................................................................................................
A. 2
GENERAL ...........................................................................................................................................................................
B. BIOAVAILABILITY ........................................................................................................................................................... 3
C. BIOEQUIVALENCE 4
............................................................................................................................................................
. METHODS TO DOCUMENT BA AND BE ......................................................................................................................
6
A. PHARMACOKINETIC STUDIES ........................................................................................................................................ 6
B. PHARMACODYNAMIC STUDIES ................................................................................................................................... lo
C. COMPARATIVE CLINICAL STUDIES ............................................................................................................................ lo
D. 10
IN VITRO STUDIES .........................................................................................................................................................
Iv. COMPARISON 11
OF BA MEASURES IN BE STUDIES ................................................................................................
I
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 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 release, and
modified (extended, delayed) release drug products.
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.
k General
2
. .
B. Bioavailability
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.
3
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
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.
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.
2. ANDAs
3. Postapproval Changes
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.
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
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.
6
2. Pilot Study
7
6. Study Population
7. Single-Dose/Multiple-Dose Studies
8. Bioanalytical Methodology
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,
8
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
b. Peak Exposure
C. Total Exposure
9
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
D. In Vitro Studies
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).
10
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).
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.
11
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 high-
potency drug substanceswhere the amount of active drug substancein the dosageform is
relatively low (e.g.,_<5 mg).
k Solutions
B. Suspensions
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.
12
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).
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).
’ This recommendation modifies a prior policy of allowing blowaivers for only three lower strengths on ANDAs.
13
l Comparativedissolutiontestingon the higherstrengthof the test and referencedrug
productis submittedand found acceptable.
D. Modified-Release Products
Modified-releaseproductsinclude delayed-release
productsand extended(controlled)-release
products.
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.Extended-
releaseproducts can be capsules,tablets,granules,pellets, and suspensions.If any part of a
drug product includesan extended-release component,the following recommendationsapply.
0 The BA profile establishedfor the drug product rules out the occurrenceof any
dosedumping.
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:
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
2. ANDAs: BE Studies
16
b. Tablets - Lower Strength
4. Postapproval Changes
A. Food-Effect Studies
17
Coadministrationof food with oral drug productsmay influence drug BA and/or BE. Food-
effect 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
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.
2. Enantiomers VersusRacemates
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.
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.
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.
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
22
APPENDIX 2
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 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:
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.
In addition,the following statisticalinformation shouldbe provided for AU&, AU&,, and Cmax:
24
.
l Geometricmean
l Arithmetic mean
l Ratio of means
l Confidenceintervals
Roundingoff of confidenceintervalvalues:
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 of OTC Drug Products, HFD-560
m The attached
display under
material should be placed
the above referenced
on public
Docket No.
q This material
Comment No.
should be cross-referenced to
Charles J.