BIOEQUIVALENCE,BIOSIMILARDRUGPRODUCTS,ANDBCS

Idea about Bioequivalence, biosimilars and BCS

1. BIOEQUIVALENCE, BIOSIMILAR
DRUGPRODUCTS,ANDBCS
By
Dr.ChinmayaKeshariSahoo.M.Pharm,Ph.D
AssociateProfessor
CollegeofPharmaceuticalSciences,Puri
1

2. CONTENTS
1.Definitions
2.TypesofBioequivalence(BE)
3.WhenshouldBEstudyconducted
4.MethodsofstudyingBE
5.Designandevaluationofbioequivalencestudies
6.BEExperimentalStudyDesigns
7.BEStudyProtocol
8.StudySubmissionandDrugReviewProcess
9.ClinicalSignificanceofBEstudies
10.SpecialConcernsinBioavailabilityandBEStudies
11.GenericSubstitution
12.Biosimilardrugproducts
13.Biopharmaceuticsclassificationsystem(BCS)
2

3. DEFINITIONS
Bioavailability:
Bioavailabiltyisdefinedastherateandextenttowhichtheactiveingredientor
activemoietyisabsorbedfromadrugproductandbecomesavailableatthesite
ofaction.(AccordingtoFDA2003)
Bioequivalence:
Itisarelativetermwhichdenotesthatthedrugsubstanceintwoormore
identicaldosageforms,reachesthesystemiccirculationatthesamerelative
ratesandtothesamerelativeextenti.etheirplasmaconcentrationtimeprofiles
willbeidenticalwithoutthesignificantstatisticaldifferences.
InnovatorProduct:
Adrugproductsthathavebeenapprovedasnewdrugoradrugthat
correspondstoone.E.g.Efudex(Rochelaboratories)
GenericProducts:
Productsofwhichactiveingredients,strengths,dosageformsanddosage
regimensarethesameasthoseofinnovatorproduct.E.gNicip
Genericnomenclature:
Itreferstorecognized,nonproprietaryorcommonnameofanactivedruginadrug
product.E.gAcetaminophen(USA),Paracetamol(UK/India) 3

4. TYPES OF BIOEQUIVALENCE
Chemical equivalence:
Itindicatesthattwoormoredrugproductsthatcontainthesamelabelled
chemicalsubstanceasanactiveingredientinthesameamount.
Therapeutic equivalence:
Thistermindicatesthattwoormoredrugproductsthatcontainthesame
therapeuticallyactiveingredientelicitidenticalpharmacologicaleffectsandcan
controlthediseasetothesameextent.
Clinical equivalence:
Whenthesamedrugfrom2ormoredosageformsgivesidenticalinvivoeffects
asmeasuredbypharmacologicalresponseorbycontroloverasymptomora
disease.
Pharmaceutical equivalence:
Thetermimpliesthattwoormoredrugproductsareidenticalinstrength,
quality,purity,contentuniformity,disintegrationanddissolution
characteristics.Theymayhoweverdifferincontainingdifferentexcipients.
4

5. WHEN SHOULD BE STUDIES CONDUCTED
1.Whenagenericformulationistestedagainstan
innovatorbrand.
2.Whentheproposeddosageformisdifferentfrom
thatusedinclinicaltrails.
3.Whensignificantchangesaremadeinthe
manufactureofthemarketedformulation.
5

6. METHODS OF BIOEQUIVALENCE STUDIES
Methods of BE studies
I. In Vivo bioequivalence study
II. In vitro bioequivalence study
III. Pharmacodynamicstudies
IV. Comparative clinical trials
I. In Vivo bioequivalence study
1.Itrequiresdeterminationofrelativebioavailabilityafter
administrationofasingledoseoftestandreferenceformulationsbythe
samerouteinequaldoses,butatdifferenttimes.
2.Thereferenceproductisgenerallyapreviouslyapprovedproduct,
usuallyainnovator’sproductorsomesuitablereferencestandard.
3.Thestudyisperformedinfasting,young,healthy,adultmale
volunteerstoassurehomogeneityinthepopulation&tosparethe
patients,elderlyorpregnantwomenfromrigorsofsuchaclinical
investigation.
6

7. Contd.
II.InvitroBEstudy
Infollowingcircumstancesequivalencemaybeassessedbytheuseofinvitro
dissolutiontesting:
1.Drugsforwhichtheapplicantprovidedatatosubstantiateallofthe
following:
Highestdosestrengthissolublein250mlofanaqueousmediaoverthepH
rangeof1-7.5at37
0
C.
Atleast90%oftheadministeredoraldoseisabsorbedonmassbalance
determinationorincomparisontoanintravenousreferencedose.
Speedofdissolutionasdemonstratedbymorethan80%dissolutionwithin15
minutesat37
0
CusingIPapparatus1,at50rpmorIPapparatus2,at100rpmin
avolumeof900mlorlessineachofthefollowingmedia:
a.0.1Nhydrochloricacidorartificialgastricjuice(withoutenzymes)
b.ApH4.5buffer
c.ApH6.8bufferorartificialintestinaljuice(withoutenzyme)
7

8. Contd.
2.Differentstrengthofthedrugmanufacturedbythesame
manufacturer,whereallofthefollowingcriteriaarefulfilled:
1.Thequalitativecompositionbetweenthestrengthsisessentiallythesame.
2.Theratioofactiveingredientsandexcipientsbetweenthestrengthis
essentiallythesameorinthecaseofsmallstrength,theratiobetweenthe
excipientsisthesame.
3.Themethodofmanufactureisessentiallythesame.
4.Anappropriateequivalencestudyhasbeenperformedonatleastoneofthe
strengthoftheformulation(usuallythehigheststrengthunlessalowerstrength
ischosenforreasonsofsafety);and
5.Incaseofsystemicavailability-pharmacokineticshavebeenshowntobelinear
overthetherapeuticdoserange.
Invitrodissolutiontestingmayalsobesuitabletoconfirmunchangedproduct
qualityandperformancecharacteristicswithminorformulationor
manufacturingchangesafterapproval.
8

9. Contd.
III.Pharmacodynamicstudies
Studiesinhealthyvolunteersofpatientsusing
pharmacodynamicparametersmaybeusedfor
establishingequivalencebetweentwopharmaceutical
products.Thesestudiesmaybecomenecessary
1.Ifquantitativeanalysisofthedrugand/or
metabolite(s)inplasmaorurinecannotbemadewith
sufficientaccuracyandsensitivity.
2.Ifmeasurementofdrugconcentrationscannotbeused
assurrogateendpointsforthedemonstrationof
efficacyandsafetyoftheparticularpharmaceutical
producte.g.topicalproductswithoutanintended
absorptionofthedrugintothesystemiccirculation.
9

10. Contd.
IV. Comparative clinical trials
Itiscarriedoutwhen
1.Theplasmaconcentrationtime-profiledate
maynotbesuitabletoassessequivalence
betweentwoformulations.
2.Pharmacodynamicstudiescannotbeperformed
becauseoflackofmeaningfulpharmacodynamic
parameters,whichcanbemeasured.
3.Pharmacodynamicandpharmacokineticstudies
arenotfeasible.
10

11. ELEMENTS OF BE STUDY PROTOCOL
1.Title
2.StudyObjective
3.StudyDesign
a.Design
b.DrugProducts(Testproducts,Referenceproducts)
c.DosageRegimen
d.SampleCollectionSchedule
e.Housing
f.Fasting/mealsSchedule
g.Analyticalmethods
4.StudyPopulation
a.Subjects
b.Subjectselection(Medicalhistory,Physicalexam.,Lab.Tests)
c. Inclusion criteria/ Exclusion criteria
d. Restrictions/ Prohibitions
11

12. Contd.
5. Clinical procedures
a. Dosage and drug administration
b. Biological sampling schedule
c. Activity of subjects
6. Ethical consideration
a. Basic principles
b. Institutional Review Board
c. Informed consent
d. Indications for subject withdrawal
e. Adverse reactions and emergency procedure
7. Facilities
8. Data analysis
a. Analytical validation procedure,
b. Statistical treatment of data)
9. Drug accountability
10. Appendix
12

13. STUDY DESIGN
Basic design is determined by
Scientificquestionstobeanswered
Natureofthereferencematerialandthe
dosageformtobetested
Availabilityofanalyticalmethods
Benefit-riskconsiderationsinregardto
testinginhumans
13

14. Contd.
Criteriaforhumansubjects
Studiesshouldbeconductedinindividuals
representativeofthegeneralpopulation,taking
intoaccountage,sex,andrace.
Healthysubjects,above18yearsofage.
Choiceofgenderbasedonusage&safetycriteria
Pregnantwomenorthosetakingcontraceptives
shouldnotbeincludedinthetest
Thesubjectsaregenerallyfastedfor10to12h
(overnight)priortodrugadministrationandmay
continuesofastfora2to4hperiodafterdosing.
14

15. Contd.
Studydesignforsolidoraldosageforms
1.Fastingstudy
2.Foodinterventionstudy
3.Multiple-dose(steady-state)study
1.Fastingstudy
Requiredforallimmediatereleaseandmodifiedreleasedosage
form
Bothmaleandfemaleareusedinstudy
Bioequivalencestudiesareusuallyresolutebyasingle-dose,two-
period,two-treatment,two-sequence,andopen-label,randomized
crossoverdesigncomparingequaldosesofthetestandreference
productsinfasted,adult,healthysubjects.
15

16. Contd.
2.Foodinterventionstudy
Generallyconductedusingmealcondition
Thetestmealishighfatandhighcaloriemeal
Alcoholandanyoverthecounterdrugwasdiscontinued
foratleastthreedaysbeforethestartoftheexperiment
andthroughouttheexperimentperiod
3.Multiple-dose(steady-state)study
Comparingequaldoseoftestandreferenceproduct
Performedinadult,healthysubjects
16

17. BE EXPERIMENTAL STUDY DESIGNS
Various types of test designs are used to study of BE such as
1. Parallel design
2. Cross over design
1. Parallel design
Aparalleldesignisacompletelyrandomizeddesigninwhich
eachsubjectreceivesone&onlyoneformulationofadrugina
randomfashion.
Thesimplestparalleldesignisthetwo-groupparalleldesign,
whichcompares2formulationsofadrug.
Eachgroupcontainsequalnumberofsubjects.
Paralleldesignisusefuldrugswithlonghalf-lives(longerthan24
h)
17

18. Contd.
18

19. Contd.
2. Cross over design
Arrangementsinwhicheachsubjectreceivestwo
ormoredifferenttreatmentsonsuccessive
occasions,areknownascrossoverdesigns.
Inthisdesign,thenumberoftreatmentsissame
asthenumberofperiods.
Thisdesigncanbeusedwithanynumberof
treatments,subjectstotherestrictionthatthe
numberofsubjectsmustbeamultipleofthe
numberoftreatments.
19

20. Contd.
A)Latin Square Design
Eachformulationisadministeredjustoncetoeachsubjectandonceineach
studyperiod.
Inordertoallocatethetreatmenttotheexperimentalunitsinrowsandcolumns,
wetakethehelpfromLatinsquares.
ALatinsquareoforderpisanarrangementofpsymbolsinp
2
cellsarrangedin
prowsandpcolumnssuchthateachsymboloccursonceandonlyonceineach
rowandineachcolumn.
ExamplesofLatin-squarecrossoverdesignsforabioequivalencestudyin
humanvolunteers,comparingthreedifferentdrugformulations(A,B,C).
20
Subjects T1 T2 T3
1 A B C
2 B C A
3 C A B

21. Contd.
B)Replicated Crossover Study Design(RCSD)
RCSDisusedforthedeterminationofindividualbioequivalence,toestimate
within-subjectvarianceforboththeTestandReferencedrugproducts,andto
provideanestimateofthesubject-by-formulationinteractionvariance.
Generally,afour-period,two-sequence,two-formulationdesignis
recommendedbytheFDA.
Thesamereferenceandthesametestareeachgiventwicetothesamesubject.
Othersequencesarepossible.Inthisdesign,Reference-to-ReferenceandTest-
to-Testcomparisonsmayalsobemade.
WhereR=Reference,T=Test
21
Period 1 Period 2 Period 3 Period 4
Sequence 1 T R T R
Sequence 2 R T R T

22. Contd.
AdvantagesofCrossoverdesign:
Minimizeintersubjectvariabilityinplasmadruglevel.
Minimizeintrasubjectvariability
Minimizevariationduetotimeeffect.
Makeitmorepossibletofocusmoreonformulationvariableswhichisthekey
tosuccessforanybioequivalencestudy.
Drawbacksofcross-overdesign:
Takeslongtimesinceappropriatewashoutperiodbetween2administrationsis
essential.
Timemaybelongerifthedrughast1/2long.
Whentheno.offormulationstobetestedaremore,thestudybecomesmore
difficultandsubjectdropoutratemayincrease.
22

23. EVALUATION OF THE DATA
1.Analytical Method:
Theanalyticalmethodformeasurementofthedrug
mustbevalidatedforaccuracy,precision,sensitivity,
andspecificity.
Theuseofmorethanoneanalyticalmethodduringa
bioequivalencestudymaynotbevalid,because
differentmethodsmayyielddifferentvalues.
Datashouldbepresentedinbothtabulatedand
graphicformforevaluation.
Theplasmadrugconcentration–timecurveforeach
drugproductandeachsubjectshouldbeavailable.
23

24. Contd.
2.PharmacokineticEvaluationoftheData
Forsingle-dosestudies,includingafastingstudyorafood
interventionstudy,thepharmacokineticanalysesinclude
calculationforeachsubjectoftheareaunderthecurvetothe
lastquantifiableconcentration(AUC0–t)andtoinfinity
(AUC0–∞),Tmax,andCmax.
Additionally,theeliminationrateconstant(k),theelimination
half-life(t½),andotherparametersmaybeestimated.
Formultiple-dosestudies,pharmacokineticanalysisincludes
calculationforeachsubjectofthesteady-stateareaunderthe
curve,(AUC0–t),Tmax,Cmin,Cmax,andthepercent
fluctuation[100x(Cmax–Cmin)/Cmin].
Properstatisticalevaluationshouldbeperformedontheestimated
pharmacokineticparameters.
24

25. Contd.
3.StatisticalEvaluationoftheData
Aftercollectionofthedatastatisticalmethodmustbe
appliedtodeterminethelevelofsignificanceofany
observeddifferenceintherateandextentofabsorptionin
ordertoestablishBEbetweentwoormoredrugproducts.
Thecommonlyadoptedapproachestodeterminestatistical
differencesare
a)AnalysisofVariance(ANOVA)
ANOVAisastatisticalprocedureusedtotestthedatafor
differenceswithinandbetweentreatmentandcontrol
groups.
Abioequivalentproductshouldproducenosignificant
differenceinallpharmacokineticparameterstested.
25

26. Contd.
TheparameterstestedusuallyincludeAUC0–t,
AUC0–∞,tmax,andCmaxobtainedforeach
treatmentordosageform.
Astatisticaldifferencebetweenthepharmacokinetic
parametersobtainedfromtwoormoredrugproducts
isconsideredstatisticallysignificantifthereisa
probabilityoflessthan1in20timesor0.05
probability(p≤0.05)thattheseresultswouldhave
happenedonthebasisofchancealone.
Theprobability(p)isusedtoindicatethelevelof
statisticalsignificance.Ifp<0.05,thedifferences
betweenthetwodrugproductsarenotconsidered
statisticallysignificant.
26

27. Contd.
(b)TwoOne-SidedTestsProcedure/confidenceintervalapproach
ItisusedtodemonstrateifthebioavailabilityofthedrugfromtheTest
formulationistooloworhighincomparisontothatoftheReference
product.
The90%confidencelimitsareestimatedforthesamplemeansbasedon
aStudent'stdistributionofthedata.
A90%confidenceintervalabouttheratioofmeansofthetwodrug
productsmustbewithin±20%formeasurementoftherateandextentof
drugbioavailability(ParametersAUCorCmax).
Thelower90%confidenceintervalfortheratioofmeanscannotbeless
than0.80,andtheupper90%confidenceintervalfortheratioofthe
meanscannotbegreaterthan1.20.
Whenlog-transformeddataareused,the90%confidenceintervalisset
at80–125%.Theseconfidencelimitshavealsobeentermedthe
bioequivalenceinterval.The90%confidenceintervalisafunctionof
samplesizeandstudyvariability,includinginter-andintrasubject
variability
27

28. STUDYSUBMISSIONANDDRUGREVIEWPROCESS
ThecontentsofNewDrugApplications(NDAs)
andAbbreviatedNewDrugApplications
(ANDAs)aresimilarintermsofthequalityof
manufacture.
ThesubmissionforanNDAmustcontainsafety
andefficacystudiesasprovidedbyanimal
toxicologystudies,clinicalefficacystudies,and
pharmacokinetic/bioavailabilitystudies.
Forthegenericdrugmanufacturer,the
bioequivalencestudyisthepivotalstudyinthe
ANDAthatreplacestheanimal,clinical,and
pharmacokineticstudies.
28

29. Contd.
Brand Name Drug
(NDA) Requirements
Generic Drug
(ANDA) Requirements
1.Labeling
2.Pharm/Tox
3.Chemistry
4.Manufacturing
5.Controls
6.Microbiology
7.Inspection
8.Testing
9.Animal studies
10.Clinical studies
11.Bioavailability
1.Labeling
2.Pharm/Tox
3.Chemistry
4.Manufacturing
5.Controls
6.Microbiology
7.Inspection
8.Testing
9.Bioequivalence
29

30. Contd.
Theinvestigatorshouldbesurethatthestudyhas
beenproperlydesigned,theobjectivesareclearly
defined,andthemethodofanalysishasbeen
validated(i.e.,showntomeasurepreciselyand
accuratelytheplasmadrugconcentration).
Theresultsareanalyzedbothstatisticallyand
pharmacokinetically.
Theseresults,alongwithcasereportsand
variousdatasupportingthevalidityofthe
analyticalmethod,areincludedinthe
submission.
30

31. Proposed format and contents of an in vivo BE study
submission and accompanying in vitro data
TitlePage
1.Studytitle
2.Nameofsponsor
3.Nameandaddressofclinicallaboratory
4.Nameofprincipalinvestigator(s)
5.Nameofanalyticallaboratory
6.Datesofclinicalstudy(start,completion)
7.Signatureofprincipalinvestigator(anddate)
8.Signatureofclinicalinvestigator(anddate)
Table of Contents
I.Study Resume
1.Productinformation
2.Summaryofbioequivalencestudy
3.Summaryofbioequivalencedata
Plasma
Urinaryexcretion
4.Figureofmeanplasmaconcentration-time
profile
5.Figureofmeancumulativeurinary
excretion
6.Figureofmeanurinaryexcretionrates
II.ProtocolandApprovals
1.Protocol
2.LetterofacceptanceofprotocolfromFDA
3.Informedconsentform
4.LetterapprovalofInstitutionalReview
Board(IRB)
5.ListofmembersofIRB
III.Clinicalstudy
1.Summaryofthestudy
2.Detailsofthestudy
3.Demographiccharacteristicsofthe
subjects
4.Subjectassignmentinthestudy
5.Meanphysicalcharacteristicsofsubjects
arrangedbysequence
6.Detailsofclinicalstudy
7.Deviationsfromprotocol
8.Vitalsignsofsubjects
9.Adversereactionreport 31

32. IV.AssayMethodologyandValidation
1.Assaymethoddescription
2.Validationprocedure
3.Summaryofvalidation
4.Dataonlinearityofstandardsamples
5.Dataoninterdayprecisionandaccuracy
6.Dataonintradayprecisionandaccuracy
7.Figureforstandardcurve(s)forlow/high
ranges
8.Chromatogramofstandardandquality
controlsamples
9.Samplecalculation
V.PharmacokineticparametersandTests
1.Definitionandcalculation
2.Statisticaltests
3.Druglevelsateachsamplingtimeand
pharmacolineticparameters
4.Figureofplasmaconcentration-timeprofile
5.Figuresofindividualsubjectplasma
concentration-timeprofiles
6.Figureofmeancumulativeurinaryexcretion
7.Figuresofindividualsubjectmeancumulative
urinaryexcretion
8.Figureofmeanurinaryexcretionrates
9.Figuresofindividualsubjectmeanurinary
excretionrates
10.Tableofindividualsubjectdata
arranged bydrug,drug/period,
drug/sequence
VI.StatisticalAnalyses
1.Statisticalconsiderations
2.Summaryofstatisticalsignificance
3.Summaryofstatisticalparameters
4.ANOVA,leastsquareestimatesandleast
squaresmeans
VII.Appendices
1.RandomizationSchedule
2.Sampleidentificationcodes
3.Analyticalrawdata
4.Chromatogramofatleast20%subjects
5.Medicalrecordandclinicalreports
6.Clinicalfacilitiesdescription
7.Analyticalfacilitiesdescription
8.Curriculavitaeoftheinvestigators
VIII.InVitroTesting
1.Dissolutiontesting
2.Dissolutionassaymethodology
3.Contentuniformitytesting
4.Potencydetermination
IX.BatchsizeandFormulation
1.Batchrecord
2.Quantitativeformulation
32

33. CLINICAL SIGNIFICANCE OF BE STUDIES
Twoformulationswhoserateandextentofabsorptiondifferby
20%orlessareconsideredbioequivalent.
Differencesoflessthan20%inAUCandCmaxbetweendrug
productsareunlikelytobeclinicallysignificantinpatients.(BE
TaskForceReport)
TheBETaskForcestatesthatclinicalstudiesofeffectiveness
havedifficultyindetectingdifferencesindoseofeven50-100%.
Asmallstatisticallysignificantdifferenceindrugbioavailability
fromtwoormoredosageformsisdetectedifthestudyiswell
controlledandthenumberofsubjectsissufficientlylarge.
Whenthetherapeuticobjectivesofthedrugareconsideredan
equivalentclinicalresponseshouldbeobtainedfromthe
comparisonofdosageformsiftheplasmadrugconcentrations
remainaboveMECforanappropriateintervalanddonotreach
minimumtoxicconcentration(MTC).
33

34. Contd.
TheelderlyorpatientsondrugtherapyarenotusedforBE
studies.
NormalhealthyvolunteersarepreferredforBEstudiesduetoless
risk.
Theexcipientsinoneofthedosageformstestedmayposea
probleminthepatientwhousesthegenericdosageform.
Forthemanufactureofadosageformspecificationsaresetto
provideuniformityofdosageforms.
34

35. SPECIALCONCERNSINBIOAVAILABILITYAND
BIOEQUIVALENCE STUDIES
ThegeneralBEstudydesignsandevaluationsuchasthe
comparisonofAUC,Cmaxandtmaxmaybeusedfor
systemicallyabsorbeddrugsandconventionaloraldosageforms.
Howeverforcertaindrugsanddosageformssystemic
bioavailabilityandBEaredifficulttoascertain.
Drugsanddrugproducts(e.g.Cyclosporine,Chloropromazine,
Verapamiletc.)areconsideredtobehighlyvariableifthe
intrasubjectvariabilityinbioavailabilityparametersisgreaterthan
30%byanalysisofvariancecoefficientofvariation.
Fordrugswithverylongeliminationhalflivesoracomplex
eliminationphase,acompleteplasmadrugconcentrationVstime
curvemaybedifficulttoobtainforaBEstudyusingcrossover
design.
35

36. Contd.
Somedrugse.gbenzocaine,hydrocortisone,antiinfectivesare
intendedforlocaleffectformulatedastopicalointments,oral
suspensions,orrectalsuppositories.TheBEdeterminationfor
drugsthatarenotabsorbedsystemicallyfromthesiteof
applicationcanbedifficulttoassess.Forthesenonsystemic
absorbabledrugsasurrogatemarkerisneededforBE
determination.
Variousdrugdeliverysystemandnewerdosageformsare
designedtodeliverthedrugbynonoralroutewhichmayproduce
onlypartialsystemicbioavailability.
Drugshavingbiotransformation.
36

37. Contd.
Table : Problems in BA and BE
37
Drugswith high intrasubjectvariability
Long elimination half life drugs
Biotransformation of drugs
Stereoselectivedrug metabolites
Drugs with active metabolite
Drugs with polymorphic
metabolism
Nonbioavailabledrugs(forlocaleffect)
Antacids
Local anesthetics
Antiinfectives
Antinflamatorysteroids
Dosage forms for nonoral
administration
Transdermal
Inhalation
Ophthalmic
Intranasal
Bioavailabledrugsthatshouldnot
producepeakdruglevels
Hormonereplacementtherapy
Potassiumsupplements
Biotechnologyderiveddrugs
Erythromycininterferon
Proteaseinhibitors
Complexdrugsubstances
Conjugatedestrogens

38. Contd.
Table:PossiblesurrogateMarkersforBEStudies
38
DrugProduct Drug SurrogateMarker
MetereddoseinhalerAlbuterol Forced expiratory
volume
Topicalsteroid Hydrocortisone Skinblanching
AnionexchangeresinCholestyramine Bindingtobileacids
Antacids Magnesium and
aluminiumhydroxide
gel
Neutralizationofacid
Topicalantifungal Ketoconazole Druguptakeinto
stratumcorneum

39. GENERIC SUBSTITUTION
Tocontaindrugcosts,moststatehaveadoptedgeneric
substitutionlawstoallowpharmacisttodispenseagenericdrug
productforabrand-namedrugproductthathasbeenprescribed.
Somestateshaveadoptedpositiveformulary,whichlists
therapeuticallyequivalentorinterchangeabledrugproductthat
pharmacistmaydispense.
Othersuseanegativeformulary,whichlistsdrugproductsthat
arenottherapeuticallyequivalentorinterchangeofwhichis
prohibited.
Andifthedrugisnotnegativeformulary,theunlistedgeneric
drugproductsareassumedtobetherapeuticallyequivalentand
maynotbeinterchanged.
Theyserveaspublicinformationandadvicetohealthagencies,
prescribersandpharmaciststopromotepubliceducationinthe
areaofdrugproductselection.
39

40. Contd.
Orangebookwhichidentifiesdrugproductsapprovedonthebasis
ofsafetyandeffectiveness.
Orangebookcontainstherapeuticequivalenceevaluationsfor
approveddrugproductsmadebyvariousmanufacturers.These
marketeddrugproductsareevaluatedaccordingtospecific
criteria.
CDERpublishesannuallyalistingofapproveddrugproducts,
Approveddrugproductswiththerapeuticequivalenceevaluation.
Thedrugproductsaredividedintotwomajorcategories‘A’codes
applytodrugproductsconsideredtobetherapeutically
equivalenttootherpharmaceuticallyequivalentproducts,and
‘B’codesapplytodrugproducts.
40

41. Contd.
41
ACodes
AA-Productsinconventionaldosage
formsnotpresentingBEproblems
AB-Products meeting BE
requirements
AN-Solutionsandpowdersfor
aerosolization
AO-Injectableoilsolutions
AP-Injectableaqueoussolutionsand,
sometimes,intravenousnonaqueous
solutions
AT-Topicalproducts
BCodes
BC-Extendedreleasetablets,
extendedreleasecapsuleandextended
releaseinjectables
BD-Activeingredientsanddosage
formswithdocumentedBEproblems
BE-Delayedreleaseoraldosageforms
BN-Productsinaerosol-nebulizer
deliverysystem
BP-Activeingredientsanddosage
formswithpotentialBEproblems
BR-Suppositoriesorenemasfor
systemicuse
BT-TropicalproductswithBEissues
BX-Insufficientdata

42. GENERIC BIOLOGICS (BIOSIMILAR DRUG PRODUCTS)
BiosimilarProduct
Abiosimilarisabiologicalproductthatishighlysimilarandhasnoclinically
meaningfuldifferencesfromanexistingFDA-approvedreferenceproduct
Biological product
BiologicalproductsareregulatedbytheFoodandDrugAdministration(FDA)
andareusedtodiagnose,prevent,treat,andcurediseasesandmedicalconditions.
Biologicalproductsareadiversecategoryofproductsandaregenerallylarge,
complexmolecules.Theseproductsmaybeproducedthroughbiotechnologyin
alivingsystem,suchasamicroorganism,plantcell,oranimalcell,andareoften
moredifficulttocharacterizethansmallmoleculedrugs.
Reference product
Areferenceproductisthesinglebiologicalproduct,alreadyapprovedbyFDA,
againstwhichaproposedbiosimilarproductiscompared.Areferenceproductis
approvedbasedon,amongotherthings,afullcomplementofsafetyand
effectivenessdata.
Interchangeableproduct
Aninterchangeableproductisabiosimilarproductthatmeetsadditional
requirementsoutlinedbytheBiologicsPriceCompetitionandInnovationAct.
Aspartoffulfillingtheseadditionalrequirements,informationisneededto
showthataninterchangeableproductisexpectedtoproducethesameclinical
resultasthereferenceproductinanygivenpatient.
42

43. Contd.
Table:Comparisonofbiologic,andbiosimilarproducts
43
Process Biologic Biosimilar
Manufacturing
Clinical
development
Regulation
Producedbybiologicalprocessin
hostcelllines
Sensitivetoproductionprocess
changesexpensiveandspecialized
productionfacilities
Reproducibilitydifficultto
establish
Extensiveclinicalstudies,including
PhaseI–III
Pharmacovigilanceandperiodic
safetyupdatesneeded
Needs to demonstrate
comparability
Regulatory pathway defined by
Europe (EMEA)
Currently no automatic substitution
intended
Producedbybiological
processinhostcelllines
Sensitivetoproduction
processhangesexpensiveand
specializedproductionfacilities
Reproducibilitydifficultto
establish
Extensive clinical studies,
including Phase I–III
Pharmacovigilanceand periodic
safety updates needed
Needs to demonstrate similarity
Regulatory pathway defined by
Europe (EMEA)
No automatic substitution
allowed

44. Contd.
RegulatoryperspectivesforBiosimilarProducts
Existinggenericdefinitionisnotappropriatefor
biosimilar
Approvalofthebiosimilarproductshouldbebasedon
thedemonstrationofsimilaritytoasuitablereference
drugwithcomprehensivecomparativedata
Comprehensivecharacterizationandcomparisonat
qualitylevelshallprovideabasisforareductioninthe
non‐clinicalandclinicaldata
Afinaldeterminationofsimilaritycanbebasedona
combinationofquality,non‐clinicalandclinical
evaluation
44

45. Contd.
Requirements for Quality studies
FullCMCandcomparabilityexercisedatabetweenbiosimilarproduct
andreferenceproductarerequired
•Extensivesidebysidecharacterization
•Physicochemicalproperties(includingImmunochemicalproperties)
•Biologicalactivity
•Specification
•Impurities
•Stability
Analyticaltechniquesshouldbestateofarttodetectslightdifferences
inqualityattributes
Acceptancecriteriainsettingupthespecificationshouldbeestablished
andjustifiedbasedontheresultsofanumberofrepresentativelot
analyses
45

46. Contd.
Demonstration of Similarity
Thedemonstrationofcomparabilitydoesnot
necessarilymeanthatthequalityattributesofthe
twoproductswillbeidentical,buttheyarehighly
similarwithtwoconsequences
Minorstructuraldifferencessuchasvariabilityin
posttranslationalmodificationsmaybeacceptable
but,mustbejustified
Differencesinimpurityprofilesshouldbejustified
Theimpactofobserveddifferencesinthequality
attributesshouldbeassessedandthennon‐clinical
andclinicalstudiesshouldbedesignedand
conductedonthebasisoftheresults
46

47. Contd.
Requirements for Non‐clinical Studies
Comparativenon‐clinicalstudiesshouldbedesignedto
detectsignificantdifferencesbetweenthebiosimilar
productandthereferenceproduct
Invitrostudy
•Receptorbindingstudy
•Cellproliferationassay
Invivostudy
•Biological/Pharmacodynamicstudiesrelevanttothe
clinicalapplication
Toxicity
•Atleastonerepeatdosetoxicitystudyinarelevant
species,includingtoxicokineticstudy,antibody
measurement
47

48. Contd.
RequirementsforClinicalstudies
Comparativeclinicaltrialsarerequireddependingonthedata
intermsofqualityandnonclinicalstudies.
•PharmacokineticStudies/PharmacodynamicStudies
•ClinicalEfficacy&Safetytrials
•ConfirmatoryPK/PDstudies
Equivalencetrialispreferable,andmarginsshouldbe
pre‐specifiedandjustified
Extrapolationtootherindicationsofthereferencedrugmaybe
possibleifsimilarefficacyandsafetyestablishedina
‘sensitive’testmodelandscientificallyjustified
Pre‐approvalsafetydatafromsufficientnumberofpatientsand
studydurationshouldbeprovidedtocomparethenature,
severity,andfrequencyofadversereactions(including
immunogenicitystudy)
48

49. Contd.
Table : Biosimilarsapproved timeline
49
Biosimilar Reference Approvalyear
Omnitrope Somatropin2006
Valtropin Somatropin2006
Binocrit Epoetinalpha2007
Retacrit Epoetinzeta2007
Biograstim Filgrastim2008
Zarzio Filgrastim2009
Nivestim Filgrastim2010

50. THE BIOPHARMACEUTICS CLASSIFICATION
SYSTEM (BCS)
TheBCSisascientificframeworkforclassifyingdrug
substancesbasedontheirAqueousSolubilityAnd
IntestinalPermeability.
Whencombinedwiththedissolutionofthedrugproduct,
theBCStakesintoaccountthreemajorfactorsthat
governtherateandextentofdrugabsorptionfromIR
solidoraldosageforms.ThesefactorsareDissolution,
SolubilityandIntestinalPermeability.
TheaimoftheBCSistoprovidearegulatorytoolfor
thereplacementofcertainBEstudiesbyconducting
accurateinvitrodissolutiontests.
50

51. Contd.
AccordingtotheBCS(Amidonet.al),Drugsubstances
areclassifiedasfollows:
CLASS1:HighSolubility–HighPermeability
e.g.Metoprolol,Diltiazem,Verapamil,Propranolol
CLASS2:LowSolubility–HighPermeability
e.g.Glibenclamide,Ezetimibe,Phenytoin,Nifedipine
CLASS3:HighSolubility–LowPermeability
e.g.Cimetidine,Acyclovir,Captopril
CLASS4:LowSolubility–LowPermeability
e.gHydrochlorothiazide,Neomycin,Methotrexate
51

52. Contd.
High Aqueous Solubility
AnobjectiveoftheBCSapproachistodeterminetheequilibrium
solubilityofadrugunderapproximatephysiologicconditions.
Adrugsubstanceisconsideredhighlysolublewhenthehighestdose
(inmg)strengthissoluble(mg/ml)in250mlorlessofaqueous
mediumoverthepHrange1-7.5at37°C.(FDA/Indian)
HighPermeability
Studiesoftheextentofabsorptioninhumans,orintestinal
permeabilitymethodscanbeusedtodeterminethepermeabilityclass
membershipofadrug.
Tobeclassifiedashighlypermeable,atestdrugshouldhaveanextent
ofabsorption>90%inhumans.(FDA/Indian)
Rapidly Dissolving
When>85%ofthelabeledamountofdrugsubstancedissolveswithin
30minutesusingUSPapparatusIorIIinavolumeof<900mlbuffer
solutions.
52

53. Methods to determine permeability
Somemethodstodeterminethepermeabilityofadrugfrom
thegastrointestinaltractinclude
(1)Invivointestinalperfusionstudiesinhumans;
(2)Invivoorinsituintestinalperfusionstudiesinanimals;
(3)Invitropermeationexperimentsusingexcisedhumanor
animalintestinaltissues;
(4)Invitropermeationexperimentsacrossamonolayerof
culturedhumanintestinalcells.
Whenusingthesemethods,theexperimentalpermeabilitydata
shouldcorrelatewiththeknownextent-of-absorptiondatain
humans.
Afteroraldrugadministration,invivopermeabilitycanbe
affectedbytheeffectsofeffluxandabsorptivetransportersinthe
gastrointestinaltract,byfood,andpossiblybythevarious
excipientspresentintheformulation.
53

54. DISSOLUTION
Thedissolutionclassisbasedontheinvitrodissolutionrateofan
IRdrugproductunderspecifiedtestconditionsandisintendedto
indicaterapidinvivodissolutioninrelationtotheaveragerateof
gastricemptyinginhumansunderfastingconditions.
AnIRDrugproductisconsideredrapidlydissolvingwhennotless
than85%ofthelabelamountofdrugsubstancedissolveswithin
30minutesusingUSPapparatusIat100rpmorapparatusIIat50
rpminavolumeof900mlorlessineachofthefollowingmedia:
(1)acidicmediasuchas0.1NHClorsimulatedgastricfluidUSP
withoutenzymes,
(2)apH4.5buffer,and
(3)apH6.8bufferorsimulatedintestinalfluidUSPwithout
enzymes.TheFDAisintheprocessofrevisingtheBCSguidance
topermitbiowaiversforgenericformulationsofclass3drugs
54

55. Contd.
55

56. Significance of BCS
RegulatorytollforreplacementofcertainBEstudies.
Itcansavebothtimeandmoney—iftheimmediate-
release,orallyadministereddrugmeetsspecificcriteria,
theFDAwillgrantawaiverforexpensiveandtime
consumingbio-equivalencestudies.
Valuabletoolforformulationscientistforselectionof
designofformulateddrugsubstance.
Whenintegratedwithotherinformationprovidea
tremendoustoolforefficientdrugdevelopment.
ReducescostandtimeofapprovingScale-upandpost
approvalchallenges.
Applicableinbothpre-clinicalandclinicaldrug
developmentprocess.
Worksasaguidingtoolindevelopmentofvariousoral
drugdeliverysystems.
56

57. THANK YOU
57