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![Page 1: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/1.jpg)
Regulatory requirements
Drs. Jan Welink
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
![Page 2: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/2.jpg)
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’
![Page 3: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/3.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 20093 |
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%
![Page 4: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/4.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 20094 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
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
![Page 5: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/5.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 20095 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
Special cases: Dose- or time dependent pharmacokinetics
Specific food recommendations
Active metabolites
Pro-drugs
Enantiomers
![Page 6: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/6.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 20096 |
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 20097 |
Bioequivalence-non linear pharmacokineticsBioequivalence-non linear pharmacokinetics
Linear PK:
R TR T
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Assessment of Interchangeable Multisource Medicines, Kenya, August 20098 |
Bioequivalence-non linear pharmacokineticsBioequivalence-non linear pharmacokinetics
AUC/Cmax increase lessthan dose proportional
exception:
solubility !
![Page 9: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/9.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 20099 |
Bioequivalence-non linear pharmacokineticsBioequivalence-non linear pharmacokinetics
AUC/Cmax increase morethan dose proportional
![Page 10: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/10.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200910 |
Bioequivalence-narrow therapeutic drugsBioequivalence-narrow therapeutic drugs
Narrow Therapeutic Index Drugs
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200911 |
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200912 |
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)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200913 |
Bioequivalence-narrow therapeutic drugBioequivalence-narrow therapeutic drug
The EU position
The current BE guideline does not specifically address NTI drugs
Narrowing of BE acceptance range allowed
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200914 |
Bioequivalence-narrow therapeutic drugBioequivalence-narrow therapeutic drug
The Canadian position:
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200915 |
Bioequivalence-narrow therapeutic drugBioequivalence-narrow therapeutic drug
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200916 |
Bioequivalence – highly variable drugsBioequivalence – highly variable drugs
![Page 17: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/17.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200917 |
Bioequivalence – highly variable drugsBioequivalence – highly variable drugs
Highly variable drugs What are HVD?
HVD drugs and products
How to establish BE HVD
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200918 |
Bioequivalence – highly variable drugsBioequivalence – highly variable drugs
What are HVD?
HVD are medicinal products which show high inter occasional variability: CV > 30%
Occasion 1 Occasion 2
Not the ANOVA CV!
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200919 |
Bioequivalence – highly variable drugsBioequivalence – highly variable drugs
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200920 |
Bioequivalence – highly variable drugsBioequivalence – highly variable drugs
How to establish HVD
Problem:
Difficult to establish bioequivalence with normal acceptance criteria (90 % CI)
45%
CV=15%
CV=30%
N=88 subjects
![Page 21: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/21.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200921 |
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
How to establish HVD
![Page 22: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/22.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200922 |
Bioequivalence-highly variable drugsBioequivalence-highly variable drugs
How to establish HVD
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)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200923 |
Bioequivalence-highly variable drugsBioequivalence-highly variable drugs
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%
![Page 24: Regulatory requirements Drs. Jan Welink Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009.](https://reader035.fdocuments.us/reader035/viewer/2022062422/56649ec55503460f94bcf6f1/html5/thumbnails/24.jpg)
Assessment of Interchangeable Multisource Medicines, Kenya, August 200924 |
Bioequivalence-highly variable drugsBioequivalence-highly variable drugs
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200925 |
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:
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200926 |
Bioequivalence – metaboliteBioequivalence – metabolite
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)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200927 |
Bioequivalence – metaboliteBioequivalence – metabolite
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200928 |
Bioequivalence – metaboliteBioequivalence – metabolite
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.
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200929 |
Bioequivalence – metaboliteBioequivalence – metabolite
Example:
metabolite: 90% CI AUC and Cmax within 80 – 125%
but parent..!
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200930 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200931 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
MR dosage forms
single unit formulations
multiple unit formulations
EC formulations
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200932 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
single dose, two-period, crossover, fasting
Modified release (MR) oral dosage forms:Requested BE studies for enteric coated formulations:
not statistical significant different
90% CI AUC and Cmax:80 – 125%
or
single dose, two-period, crossover, fed
90% CI AUC and Cmax:80 – 125%
pH!
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200933 |
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
Regulatory requirements for BE studiesRegulatory requirements for BE studies
EC formulations
multiple unit formulations:
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200934 |
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!
Regulatory requirements for BE studiesRegulatory requirements for BE studies
EC formulations
single unit formulations:
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200935 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
EC formulations
single unit 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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200936 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
EC formulations
single unit formulations:
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200937 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
single dose, two-period, crossover, fasting
Modified release (MR) oral dosage forms:Requested BE studies for controlled release formulations:
90% CI AUC and Cmax:80 – 125%
single dose, two-period, crossover, fed
90% CI AUC and Cmax:80 – 125%
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)
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200938 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
Cmax,ss
AUCss
Cmin,ss
PTF
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200939 |
Regulatory requirements for BE studiesRegulatory requirements for BE studies
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
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Assessment of Interchangeable Multisource Medicines, Kenya, August 200940 |
Regulatory requirements for BE studiesRegulatory requirements for BE 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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Assessment of Interchangeable Multisource Medicines, Kenya, August 200941 |
End End