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Outline

Whatispharmacokinetics Differenttypesandapplicationsofpharmacokineticstudies Bioequivalencestudies

DataqualitycheckandBiomedicalMonitoring

(BIMO)program

in

Office

of

Scientific

Investigations


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3

Outline



(BIMO)program

in

Office

of

Scientific

Investigations


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Pharmacokinetics(PK)

Astudyofmovementsofdrugswithinbiologicsystemsoveraperiodoftime;aquantitativeanalysisofthetimecourseofadrugdisposition

Absorption

Distribution

Metabolism

Excretion

Oftendescribedaswhatthebodydoestoadrug (vs.whatadrugdoestothebody)


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Pharmacodynamics (PD): HowitisrelatedtoPK

Absorption

Distribution

Metabolism Excretion

PharmacodynamicsDose Pharmacokinetics EffectConcentration-time profile

Study

of

the

effects

of

drugs

in

the

body

and

their

mechanisms

ofaction

Whatadrugdoestothebody

Pharmacodynamic markersindrugdevelopment


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RightDrug

SafeandEffective

Personalized

Medicine

RightPatients

RightDose

Safety (Adverse Event)

Curve

Efficacy Curve

Response(PD)

Dose (Exposure)Time

C

oncentration

Time Dose(exposure)

Response

Efficacy

AdverseEvents


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Singledose/multipledosePK

Massbalance(ADME) Bioavailability/bioequivalence

Foodeffect(oralformulations)

Specificpopulations age/gender

renalimpairment

hepaticimpairment

obesity

Drugdruginteractions

ThoroughQTc

(cardiacrepolarization)

Typesof

Phase

1PK

Studies


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SingleDosePKStudy

Oftenafistinhumanstudy Usuallyperformedinhealthymaleandfemalesubjects Toassessthepharmacokineticsofthecompoundacrossarangeofdoses(includingclinicallyrelevant

doses)

Determinelinearityanddoseproportionality


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Single

Dose

ConcentrationTimeProfiles


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SingleDose

PK

Parameters

Parameter 50 mg

(N=6)

100 mg

(N=6)

250 mg

(N=6)

500 mg

(N=6)

750 mg

(N=6)

1000 mg

(N=6)

Cmax(g/mL)

1.51 0.25 3.08 0.96 10.1 1.68 16.6 2.11 23.4 4.92 30.5 4.32

Tmax (h) 0.92

(0.90-1.08)

0.92

(0.92-1.10)

0.92

(0.92-1.25)

1.08

(0.92-1.08)

1.00

(0.92-1.08)

0.92

(0.92-1.02)AUCinf(ug*h/mL)

3.95 0.73 6.72 1.67 23.4 5.38 44.8 2.86 57.6 9.75 80.9 8.63

t1/2 (h) 2.03 0.15 2.23 0.42 2.33 0.26 2.53 0.28 2.62 0.29 2.90 0.14

CL (L/h) 11.5 2.33 13.7 2.94 9.87 2.35 9.89 0.63 11.8 2.07 11.0 1.17Vz (L) 33.4 4.46 42.9 4.19 32.8 7.17 35.9 3.45 44.4 8.08 46.0 5.23

AUCinf; area under concentration-time curve from time 0 to infinity; Cmax, maximum observed concentration; CL,plasma clearance; t1/2, elimination half-life; Tmax, time of Cmax; Vz, volume of distribution of terminal phase


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Doseproportionality

0

5

10

15

20

25

30

35

0 200 400 600 800 1000

Dose (mg)

Cmax(ug/m

l)

0

20

40

60

80

100

AUC(ug*h/ml)

Cmax

AUC


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MultipleDose

Concentration

Time

Profiles

(Day1)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-572_Cubicin_BioPharmr_P2.pdf


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MultipleDose

Concentration

Time

Profiles

(Day7)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-572_Cubicin_BioPharmr_P2.pdf


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MultipleDose

PK

Anesth Analg 2004;99:137986


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MassBalance

Study

(ADME)

Tounderstandtheroutesofeliminationofadrugandto

identifyits

circulatory

and

excretory

metabolites

Commonly14Cradiolabeleddrug

Usuallysingledose

Usuallyhealthyvolunteers

Providesvaluableinformationnotonlyonmetabolismandexcretionpathways,butalsoinsightsonhowrenalorhepatic

impairment

might

affect

drug

clearance,

especially

for

those

metabolizedandexcretedviarenal&hepaticmechanisms

Canbeperformedearlyindevelopment,butmaybeperformedatanystage


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MassBalance

(ADME)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200327Orig1s000ClinPharmR.pdf


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MassBalance

(ADME)

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200327Orig1s000ClinPharmR.pdf


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Bioavailability(BA)

Therateandextenttowhichtheactiveingredientoractivemoietyisabsorbedfromadrugproductandbecomesavailableatthesiteofaction

Canprovideanestimateoftherelativefractionoftheorallyadministereddosethatisabsorbedintothesystemiccirculationcomparedtoareference

material

(i.e.,

solution,

suspension,

or

intravenous

dosageform)


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Bioequivalence(BE)

Theabsenceofasignificantdifferenceintherateandextenttowhichtheactiveingredientoractivemoietybecomesavailableatthesiteofactionwhenadministeredatthesamemolardoseundersimilar

conditions

InplainEnglish...

Whentwodrugproductsachievesimilardrugconcentrationtimeprofileinthesystemicbloodcirculationfollowingadministrationofasamedose


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BEExample


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FoodEffect

Administrationoffoodwithoraldrugproductsmay

affectthe

BA

and/or

BE

Foodcanhaveinfluencesonthereleaseofthedrugsubstancefromthedrugproductaswellasthe

absorptionof

the

drug

substance

Usuallyasingledose,twoperiod,twotreatment,two

sequencecrossoverstudycomparingahighfathighcaloriemealtothefastedstate

Highfathighcaloriemeal=150,250,and500600caloriesfromprotein,carbohydrate,andfat,respectively


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FoodEffect

HighFatMeal


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SpecificPopulations

EvaluatestheimpactofanintrinsicfactoronthePKofthe

drug

Age(elderlyandpediatrics)

Gender(maleandfemalesubjects)

Renalorhepaticimpairment

Obesity

Pregnancy

Usuallyasingledosestudy

Recommended

to

perform

study

prior

to

Phase

3

Supportsdoseadjustmentsofthedruginthespecificpopulation


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SpecificPopulations

Age

Healthy elderly

Healthy young


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SpecificPopulations

RenalImpairment

0

10

20

30

40

50

60

70

80

0 12 24 36 48

Time (hrs)

P

lasmaConc

(mcg/mL)

>80 mL/min

50-80 mL/min

30-50 mL/min


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DrugDrug

Interaction

Studies

Evaluatesthepotentialofthedrugactingaseithera

pharmacokineticperpetrator

or

avictim

when

two

drugsarecoadministered

Supportsdoseadjustmentswhendruginteractionsobserved(eitherperpetratororvictimdrug)

Usuallyperformedinhealthymaleandfemale

subjects

Studydesigndependsonthemechanismsofdruginteractions,halflife,clinicaldosingregimen,etc


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Impactof

Ketoconazole


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Impactof

Rifampin


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Outline



(BIMO)program

in

Office

of

Scientific

Investigations


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Bioequivalence

Theabsenceofasignificantdifferenceintherateandextenttowhichtheactiveingredientoractivemoietybecomesavailableatthesiteofactionwhenadministeredatthesamemolardoseundersimilarconditions

Studiesareconductedtoassessthesamenessoftwodrugproducts,differentdosingregimens,etc(eg.,

formulation

change,

food

effects,

crushed

tablets)


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Howis

BE

Determined?

TypicallybasedonpharmacokineticmeasuresofCmaxand

AUCfor

systemically

available

drugs

Test(T)andReference(R)productsareconsideredbioequivalentwhenthe90%CIofthegeometricmeanratios

(T/R)of

Cmax

and

AUC

are

within

80%

to

125%

Typically,agroupofsubjects(n=1836)areadministeredtestandreferencedrugproductssequentiallyintwodosingperiods,whichareseparatedbyawashoutperiod

Serialsamplesofbiologicfluid(eg.,plasma,serum,urine)arecollectedatpredoseandatvarioustimepointsafterdosingandareanalyzedfordeterminationofdrugand/oractive

metaboliteconcentrations


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BioequivalenceEndpoints*

Invivotestinhumansinwhichtheconcentrationofthe

active

moiety

in

whole

blood,

plasma,

serum

or

otherappropriatebiologicalfluidismeasuredasafunctionoftime

Invivotestinhumansinwhichtheurinaryexcretionoftheactivemoietyismeasuredasafunctionoftime

This

is

not

appropriate

if

urinary

excretion

is

not

a

significantmechanismofelimination

*Indecreasingorderofaccuracy,sensitivity,andreproducibility


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BioequivalenceEndpoints

(cont.)

Invivotestinhumansinwhichanappropriateacute

pharmacologicaleffect

of

the

active

moiety

is

measured

as

afunctionoftimeifsucheffectcanbemeasuredwith

sufficientaccuracy,sensitivity,andreproducibility

Thisapproachmaybeapplicabletodosageformsthatarenot

intendedto

deliver

the

active

moiety

to

the

bloodstream

for

systemic

distribution

Well

controlled

clinical

trials

that

establish

the

safety

and

effectivenessofthedrugproduct,forpurposesofmeasuringbioavailability,orappropriatelydesignedcomparativeclinicaltrials,forpurposesofdemonstratingbioequivalence


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Outline



(BIMO)program

in

Office

of

Scientific

Investigations


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CDERBioresearch

Monitoring

(BIMO)

Program

Onsiteinspectionsofclinicalinvestigators,sponsors,IRBs,

CROs,GLP

and

BE

studies

Ensureadherencetoapplicableregulations

GoodLaboratoryPractice(GLP)

Bioequivalence

(BE)

GoodClinicalPractice(GCP)

Objectives

ToverifythequalityandintegrityofdatasubmittedtotheAgency

Toensuretherightsandwelfareofhumanresearchsubjectsareprotected

ToensurethatFDAregulatedresearchisconductedincompliance

withapplicableregulations


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BIMOProgram

InspectionTypes

ForCause(directed)

Surveillance

PrescriptionDrugUserFeeAct(PDUFA)related

Compliance

Classification

NAI(NoActionIndicated):Inspectedentityisincompliance

VAI(VoluntaryActionIndicated):Minordeviation(s)fromthe

regulations.Voluntary

correction

is

requested

OAI(OfficialActionIndicated):RequiresregulatoryoradministrativeactionbyFDAduetoseriousnoncomplianceissues


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BEprogram: OfficeofScientificInvestigations(OSI)

Uponrequest,OSIperformsinspectionswiththeOfficeofRegulatoryAffairs

(ORA)

of

the

bioanalytical

and/or

clinical

sites

of

the

BE

study

to

verifythequalityandintegrityofthedatasubmittedtotheAgency

OfficeofNewDrug

OfficeofGenericDrug

InspectionConsult

Inspectionassignment

Inspection

Clinicalsite Analyticalsite

FDA483/EIR

EIRReviewRecommendations


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Inspectionsof

Bioanalytical

Sites

Criticalpointsofinspectionofbioanalytical

sites:

Pre

study

analytical

method

validation

Runacceptancecriteriaduringsubjectsampleanalysis

Documentationofsamplehandling

Repeat

analysis

of

samples

Equipmentlogs,SOPs

Correspondencelogs

Confirmation

of

data

included

in

final

study

report

Confirmsthatdataaregulatorydecisionisreplieduponarevalidandaccurate


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Pointsto

Consider:

Method

Validation

PrecisionandAccuracy(inter andintrabatch) Selectivity interferencefromendogenous/exogenoussubstances Stabilityunderstudyconditions

Freeze/thaw

Longtermfrozenstorage

Benchtop,autosampler

Stocksolution

Reportallstudyresultsduringvalidation


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Pointsto

Consider:

SOP

Writtenprocedureswithaprioricriteria

Runacceptance/rejectioncriteria

Chromatographyacceptance/reintegrationcriteria

Repeatanalysis,datareporting


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Inspectionsof

Clinical

Sites

Critical

points

of

inspections

of

clinical

sites:

Subjectsafety

Dosing

Drugproducts

Blooddrawtimes

Sampleprocessing

Adverseevents

Protocoladherence

Reservesamples


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Pointsto

Consider:

Subject

Safety

Weretherights,health,andwelfareofthesubjects

protected

Wasinformedconsentobtained?

Wasadequatemedicalsupervisionprovided?

Werealladverseeventsreported?


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Pointsto

Consider:

Dosing

and

Blood

Sampling

Whoreceivedwhatandwhen?

Testversusreference

Actualtreatmentadministered

Was

the

randomization

scheme

adhered

to?

Actualdosingtime

Weresamplesprocessedandstoredaccordingto

theprotocol?

Temperature,processedwithinspecifiedtimeframe,etc.


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Pointsto

Consider:

Protocol

Adherence

Inclusion/exclusioncriteria

Were

inclusion/exclusion

criteria

met?

Wereprotocolrequiredscreeningactivitiesconducted?

e.g.,clinicalchemistry,hematology,pregnancytests,vitalsigns,ECGs,

physicalexams,

etc.

Wasadherencetoprotocolrestrictionsdocumentedateachdosingperiod?

Rx

and

OTC

drugs

prior

to

dosing

and

throughout

study

Caffeine/alcoholrestrictionspriortodosing


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Pointsto

Consider:

Reserve

Samples

Retainedsamplesthatarerepresentativeoftheactualdrug

productsused

in

the

study

Reservesamplesmustbe:

Randomlyselectedatthestudysite

Positively

identified

as

having

come

from

the

same

sample

used

in

thespecificBEstudy

Retainedforatleast5yearsfollowinganapproval,oriftheapplicationisnotapproved,atleast5yearsfollowingthedate

of

completionof

the

study

21CFR

320.28

Retention

of

bioavailability

samples

and

21

CFR

320.63

Retention

of

bioequivalencesamples


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Hepatic

Impairment?

RenalImpairment?DrugDrugInteractions

BioEquivalence

Pediatricpatients?

Elderly?

Race?

Gender?

FoodEffects?

BAStudies

Phase1PK

doseproportionality

doseaccumulation

ValidatedAnalyticalMethods

DrugProduct

Labeling

Phase2/3

Phase3 Safety&Efficacy

Phase3PK

Study

populationPK

exposure/response

Phase2

Phase1

CYP450/Pgp

substrates

inhibitors

inducers

ProteinBindingInVitroMetabolism

HumanMassBalance

NDA


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