regulatory requirements drs. jan welink training workshop: assessment of interchangeable multisource...

Regulatory requirements

Drs. Jan Welink

Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

Assessment of Interchangeable Multisource Medicines, Kenya, August 20092 |

BioequivalenceBioequivalence

in vivo comparison of products by means of volunteers serving as “in-vivo dissolution model”

Bioequivalence studies:

comparison of productcharacteristics to ensure therapeutic equivalence

‘biological quality control’


Regulatory requirements for BE studiesRegulatory requirements for BE studies

single dose, two-period, crossover

Golden standard study design:

Reference (comparator)/Test (generic)

healthy volunteers

90% CI AUC and Cmax:80 – 125%



Bioequivalence: Linear pharmacokinetics

Non narrow therapeutic drug

Non highly variable drug

Decision based upon parent drug data

Stereochemistry not an issue

Decision based upon plasma concentrations



Special cases: Dose- or time dependent pharmacokinetics

Specific food recommendations

Active metabolites

Pro-drugs

Enantiomers


Bioequivalence-non linear pharmacokineticsBioequivalence-non linear pharmacokinetics

select the strength with thelargest sensitivity to detect differences

in the two products

Goal: compare performance

2 formulations



Linear PK:

R TR T



AUC/Cmax increase lessthan dose proportional

exception:

solubility !



AUC/Cmax increase morethan dose proportional


Bioequivalence-narrow therapeutic drugsBioequivalence-narrow therapeutic drugs

Narrow Therapeutic Index Drugs


Bioequivalence-narrow therapeutic drugsBioequivalence-narrow therapeutic drugs

‘Critical dose drugs’– Small changes in dose may cause

• Serious therapeutic failure• Serious adverse events

– Individual dose-titration needed (TDM)

Narrow Therapeutic Index Drugs


Bioequivalence-narrow therapeutic drugBioequivalence-narrow therapeutic drug

Acceptance range for bioequivalence testingAcceptance range for bioequivalence testing

The 90%-CI should lie within the range of 0.8-1.25• AUC-ratio• Cmax-ratio

In cases of NTI drugs the acceptance range may need to be tightened (0.9 – 1.11)



The EU position

The current BE guideline does not specifically address NTI drugs

Narrowing of BE acceptance range allowed



The Canadian position:



Canadian guidance for NTI drugs

AUC: 90%-CI within 0.9-1.12

Cmax: 90%-CI within 0.8-1.25

Studies in both fasted and fed state

Steady-state studies on a case-by-case basis– Cmin: 90%-CI within 0.8-1.25


Bioequivalence – highly variable drugsBioequivalence – highly variable drugs



Highly variable drugs What are HVD?

HVD drugs and products

How to establish BE HVD



What are HVD?

HVD are medicinal products which show high inter occasional variability: CV > 30%

Occasion 1 Occasion 2

Not the ANOVA CV!



0200400600800

10001200

0 2 4 6

time (h)

Furo

se

mid

e (

ng

/ml)

HVD drugs and products

High Variable Drug

High variability caused by intrinsic intra- indiviudual variability in the pharmacokinetic response of the active compound

High Variable Product

High variability caused by intra indiviudual variability in the pharmacokinetic caused by formulation effects



How to establish HVD

Problem:

Difficult to establish bioequivalence with normal acceptance criteria (90 % CI)

45%

CV=15%

CV=30%

N=88 subjects


Bioequivalence-highly variable drugsBioequivalence-highly variable drugs

Increase number of subjects

Multiple dose (steady-state) studies

Replicate design to determine intra-individual variability

- widen goal post 80-125





Scaling

an example:

wr

w0

lower upper, limits, BE

223.0 EXP

* w0 is the SD at which the BE limits are permitted to be widened (set by an agency)

* wr is either the residual SD (ABE2) or the SD of the ref product (replicate design)



60

80

100

120

140

160

180

0,2 0,25 0,3 0,35 0,4 0,45 0,5

%The Black Box

Sw0=0.20

Sw0=0.25

Swr

80%

125%



Swr Sw0=0.20 Sw0=0.25

0.30 71.6-139.8 76.5-130.7

0.40 64.0-156.3 70.0-142.9

0.50 57.2-174.7 64.0-156.3


Bioequivalence – metaboliteBioequivalence – metabolite

Bioequivalence based on the metabolite

Parent = pro-drug

Analytical difficulties – too low concentration– unstable in matrix

Short elimination half-life parent drug

Metabolite contributes to the activity

Pharmacokinetics non-linear (parent + metab.)

Reasons:



0,01

0,1

1

10

100

0 5 10 15 20 25 30

TIME (HR)

CO

NC

(n

g/m

L)

Parent drug Metabolite

FORMATION RATE-LIMITED METABOLISM (IV) (FRL)

0.1

1.0

10.0

100.0

0 5 10 15 20 25 30

TIME (HR)

CO

NC

(n

g/m

L)

Parent drug Metabolite

ELIMINATION RATE-LIMITED METABOLISM (IV) (ERL)



Metabolite data can only be used if the Applicant presents convincing, state-of-the art arguments that measurements of the parent compound are unreliable.

Further considerations (1):

Cmax of the metabolite is less sensitive to differences in the rate of absorption than Cmax of the parent drug.

when the rate of absorption is considered of clinical importance, bioequivalence should, if possible, be determined for Cmax of the parent compound, if necessary at a higher dose.



Metabolite is more reflective of metabolite formation, distribution and elimination.

Further considerations (2):

Measurement inactive metabolite can be rarely justified.

When using metabolite data as a substitute for parent drug concentrations, the applicant should present data supporting the view that the parent drug exposure will be reflected by metabolite exposure dose.

Bioequivalence based upon confidence interval approach.



Example:

metabolite: 90% CI AUC and Cmax within 80 – 125%

but parent..!



Modified release (MR) oral dosage forms:

Plasma Conc.-Time curveimmediate/prolonged release

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Time (h)

Pla

sm

a C

on

c. m

g/L

Plasma Conc.-Time curveprolonged release

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Time (h)

Pla

sm

a C

on

c. m

g/L

Plasma Conc.-Time curvedelayed release

0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Time (h)

Pla

sm

a C

on

c. m

g/L



MR dosage forms

single unit formulations

multiple unit formulations

EC formulations



single dose, two-period, crossover, fasting

Modified release (MR) oral dosage forms:Requested BE studies for enteric coated formulations:

not statistical significant different


or

single dose, two-period, crossover, fed


pH!


Results of bioequivalence study obtained in bio-study for one strength to the other strengths based upon dose proportionality and dissolution data.

Fed and fast bioequivalence studies normally no problem


EC formulations

multiple unit formulations:


Results of bioequivalence study obtained in bio-study for one strength to the other strengths based upon dose dissolution data and proportionality, except for the enteric coating!!

Fed study mostly problematic!


EC formulations

single unit formulations:



EC formulations


0

500

1000

1500

2000

2500

3000

0 1 2 3 4 5 6 7 8 9 10

Time after dosing on Day 1 (hr)

treatment=T

04.210.8



EC formulations




single dose, two-period, crossover, fasting

Modified release (MR) oral dosage forms:Requested BE studies for controlled release formulations:


single dose, two-period, crossover, fed


multiple dose, two-period, crossover, fasting

-steady state conditions

-EU, not FDA

90% CI AUC and Cmax:80 – 125%;

Cmin and PTF! -dose dumping

- -FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002)



Cmax,ss

AUCss

Cmin,ss

PTF



MR oral dosage forms:

Single unit formulations:– Single dose study fasted state for every strength– Multiple dose study may be waived for lower strengths

If a product concerns several strengths:

Multiple unit formulations:– Single and multiple dose studies may be waived for lower

strengths in case of identical granules or pellets

In vitro dissolution studies



Fixed combination products…

in vivo comparison vs. appropriate comparator combination (or separate comparator products in specific cases)

general testing criteria apply to all active components

bioequivalence criteria apply to all active compounds 90% CI AUC and Cmax:80 – 125%


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regulatory requirements drs. jan welink training workshop: assessment of interchangeable multisource...

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