Regulatory Requirements Scribd

7/31/2019 Regulatory Requirements Scribd

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Regulatory requirements for BA/BE-

A comparative approach

Presented by: Somsuvra Ghatak


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Various regulatory guidelines for BA-BE


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Others


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Parameter Brazil

Selection of subjects

Sample size Healthyvolunteer, n>12

Healthy volunteer,n>12

Healthy volunteer,nmin=12, but a

larger no. is oftenrequired

Should not be lessthan 16 unless

justified forethical reasons

n


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Parameter

Long half-life

drugs

cross-over

parallel

design

Relative

bioavailability

estimated using

truncated AUC

Not specified cross-over

parallel

design

alternative

collection

schedule upto 72

hrs, allowingdetermination

of area under

fragmented

curve

parallel design

Study design

ImmediateRelease:

Single dose

cross-over

study(fast/fed)

Modified

release:

Single dose

cross-over

study

(fast/fed)

ImmediateRelease:

Single dose

cross-over study

(fast/fed)

Modifiedrelease:

Single dose

cross-over study

(fast/fed)

ImmediateRelease:

Single dose

cross-over study

(fast/fed)

Modifiedrelease:

Single dose

cross-over study

(fast/fed)

cross-over

Latin square

design for

comparing 3

formulations

Balanced

incomplete

block design

for more than

3 formulations

single/multipledose, open,

random, cross-

over study

Parallel design


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Parameter

Need for a

steady state

study

No Yes, if the

formulation is a

prolonged

release or a

transdermal one

Yes, if the

AUCx/AUCinf

is less than 80%

Yes

Need for a

food effectstudy

Needed, if the

effect of foodis specified in

the labelling

Yes, for a

delayed releaseor a prolonged

releaseformulation

Needed for an

immediate

releaseformulation if

there is a food

effect reported

with the

reference

product

Yes, for a

modified releaseformulation

Needed for animmediate

release

formulation if

there is a foodeffect reported

with the

reference

product

Needed, if

there is apossibility of

effect of foodon

bioavailability


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Parameter

Strengths to

be tested

Reference Listed

Drug (RLD) inthe

Orange Book**usually thehighest strengthif formulationsareproportionallysimilar

Highest strengthof a drug product(if conditionsfrom Guidanceare fulfilled)

Highest strengthof a drug product(if conditionsfrom Guidanceare fulfilled)

Drugs withnon-linear PK

Not addressedin Guidelines

Refer to(RLD) in theOrange Book

Use strength withlargest sensitivity

to identifydifferences in

Formulation

Steady-state

study may berequired

Use strength withlargest sensitivity

to identifydifferences inFormulation

Fed study

requiredSteady-state

study may berequired

Steady-statestudy may berequired


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Parameter

Samples 12-18 samples,including a pre-dose

sample/subject/

dose, to becontinued for atleast 3 or moreterminal half-livesof the drug

3-4 samplesduring terminallog linear phase

Duration ofsampling toaccount for at

least 80% ofAUCI

At least 3elimination halflife of the drug

At least 3elimination halflife of the drug

At least 3sampling pointsduringabsorption phase

3-4 at theprojected Tmax

4 points during

eliminationphase

3-5 times theelimination halflife of the drug

Subjects with

pre-dose

plasmaconcentration

If pre-doseconcentration is5% of Cmax in

that subject, datato be included forpcokineticmeasurements

if >5% of cmax,subject to bedropped from allstudy evaluations

Not mentioned Not mentioned Not mentioned Not mentioned


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Parameter

Wash out

period

More than 5 t1/2 In steady state,

at least 3t1/2

Not less than

10t1/2

Not less than

5t1/2

Minimum 7t1/2

Narrow

therapeutic

range drugs

Additional

testing required

Acceptance

interval for

AUC & Cmax

ratio to be

tightened

Not mentioned Not mentioned Not mentioned

Blinding Not specified Yes Not specified

Fasting prior

to study

10 hrs before &

2 hrs after

Fasting

during night

Abstain

from food,

drinks & othermedicines

10 hrs before Single dose:

10 hrs before

& 4 hrs after

Multiple

dose:2 hrs before &after

8 hrs before &

4 hrs after

Water 8 ounce (240ml) 150ml at least 150ml at least


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Parameter

Position after

ingestion

Not specified Posture &physical

activity to be

standardized

Not allowed torecline until at

least 2 hrs after

ingestion of

drug

Not specified

Base line

collection

Not specified 30 mins before

drug

administration

Highly

variable

drugs

Replicate design Steady state/replicate

design

Widerinterval (75-133%) may be

acceptable

with safety and

efficacy

justification

Not specified Steady state/replicate

design

Intra-subjectvariability>30%

- Replicate

design


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Parameter

Statistical analysis

Metrics onwhich to

prove BE

CmaxAUC0-tAUCinfTmaxZ

t1/2

CmaxAUC0-t

CmaxAUC0-t

CmaxAUC0-tAUCinfTmaxZ

t1/2

CmaxAUC0-t

Acceptance

criteria for

BE

AUCt, AUCinf,

Cmax

90% CI must be

between 80.00-

125.00%

AUCt:

90% CI must be

between 80-125 %

Cmax:

90% C.I. must be

between 80-125 %

Wider interval may

be acceptable

(e.g.75-133%) with

proper efficacy and

safety justification

Tmax:

Non-parametricmethod

AUCt:

90% CI must be

between 80-125 %

Cmax:

Ratio must be

between 80-125 %

Add-on studies may

be allowed if intra-

CV greater than

expected

AUCt, AUCinf, Cmax

90% CI must be

between 80.00-

125.00%

Tmax:

Non-parametricmethod

90% CI for ratio of

population

mean (T/R)

for AUC0-t and

Cmax between

80-125 %.

For drugs with lowtherapeutic

range (e.g

carbamazepine)

include

AUCt,Cmax, &

Tmax Use 95 %

CI


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Parameter

Measurement of

metabolite

Not required,except:

Parent drug notmeasurable

Active pre-systemicmetabolism


Parent drugnot measurable

Activemetabolite

Non-linearpcokinetics


Parent drug notmeasurable

Required when:

a) Conc. Of drug too low

b) Limitations ofanalytical method

c) Unstable drugs

d) Short half l ifedrugs

e) Pro-drugs

Required when:

a) Limitationofanalytical

method

Measurement ofEnantiomers

Not requiredexcept:

Enantiomers

with unequal

PK and PD

Minor

enantiomerresponsible for

efficacy /safety

Non linear

Absorption

Not requiredexcept:

Enantiomerwith non linearPK

Usually notRequired

Absence of

recommendati

on in BE

guidelines

Recommendedwhen:

Enantiomers

with unequal PK

and PD

Minor

enantiomerresponsible for

efficacy /safety

Non linear

Absorption


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