Regulatory requirements
Drs. Jan Welink
Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
90% CI AUC and Cmax:
80 – 125%
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Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
Bioequivalence:
Linear pharmacokinetics
Non narrow therapeutic drug
Non highly variable drug
Decision based upon parent drug data
Decision based upon plasma concentrations
Stereochemistry not an issue
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Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
Special cases:
Dose- or time dependent pharmacokinetics
Specific food recommendations
Active metabolites
Pro-drugs
Enantiomers
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-non linear pharmacokinetics
Goal:
compare performance
2 formulations
select the strength with the
largest sensitivity to detect differences
in the two products
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-non linear pharmacokinetics
Linear PK:
R T
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Training workshop: Training of BE assessors, Kiev, October 2009
R T
Bioequivalence-non linear pharmacokinetics
AUC/Cmax increase less
than dose proportional
exception:
solubility!
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-non linear pharmacokinetics
AUC/Cmax increase more
than dose proportional
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-narrow therapeutic drugs
Narrow Therapeutic Index Drugs
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-narrow therapeutic drugs
Narrow Therapeutic Index Drugs
 ‘Critical dose drugs’
– Small changes in dose may cause
• Serious therapeutic failure
• Serious adverse events
– Individual dose-titration needed (TDM)
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-narrow therapeutic drug
Acceptance 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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – highly variable drugs
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – highly variable drugs
Highly variable drugs
What are HVD?
HVD drugs and products
How to establish BE HVD
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – highly variable drugs
What are HVD?
HVD are medicinal products which show
high inter occasional variability: CV > 30%
Not the ANOVA CV!
Occasion 1
15 |
Occasion 2
Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – highly variable drugs
High Variable Drug
High variability caused by intrinsic intraindiviudual variability in the pharmacokinetic
response of the active compound
Furosemide (ng/ml)
HVD drugs and products
1200
1000
800
600
400
200
0
0
2
4
time (h)
High Variable Product
High variability caused by intra indiviudual
variability in the pharmacokinetic caused by
formulation effects
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Training workshop: Training of BE assessors, Kiev, October 2009
6
Bioequivalence – highly variable drugs
How to establish HVD
CV=15%
Problem:
Difficult to establish bioequivalence with
normal acceptance criteria (90 % CI)
CV=30%
45%
N=88 subjects
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-highly variable drugs
How to establish HVD
 Increase number of subjects
 Multiple dose (steady-state) studies
 Replicate design to determine intra-individual variability
- widen goal post 80-125
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence-highly variable drugs
How to establish HVD
 Scaling
an example:
 0.223


BE limits, upper, lower  EXP 
  wr 
  w0

* 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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Training workshop: Training of BE assessors, Kiev, October 2009
180
160
Sw0=0.20
140
%
Sw0=0.25
120
125%
The Black Box
100
80
80%
60
0,2
0,25
0,3
0,35
0,4
0,45
0,5
Swr
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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
Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – metabolite
Bioequivalence based on the metabolite
Reasons:

Parent = pro-drug

Analytical difficulties
–
–
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too low concentration
unstable in matrix

Short elimination half-life parent drug

Metabolite contributes to the activity

Pharmacokinetics non-linear (parent + metab.)
Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – metabolite
FORMATION RATE-LIMITED METABOLISM (IV) (FRL)
ELIMINATION RATE-LIMITED METABOLISM (IV) (ERL)
100.0
CONC (ng/mL)
CONC (ng/mL)
100
10
1
0,1
0,01
1.0
0.1
0
5
10
15
20
25
30
TIME (HR)
Parent drug
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10.0
0
5
10
15
20
TIME (HR)
Metabolite
Training workshop: Training of BE assessors, Kiev, October 2009
Parent drug
Metabolite
25
30
Bioequivalence – metabolite
Further considerations (1):
Metabolite data can only be used if the Applicant
presents convincing, state-of-the art arguments that
measurements of the parent compound are unreliable.
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – metabolite
Further considerations (2):
Metabolite is more reflective of metabolite formation,
distribution and elimination.
Bioequivalence based upon confidence interval
approach.
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.
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – metabolite
Example:
metabolite: 90% CI AUC and Cmax within 80 – 125%
but parent..!
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Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
Modified release (MR) oral dosage forms:
Plasma Conc.-Time curve
prolonged release
Plasma Conc.-Time curve
delayed release
120
120
100
100
100
80
60
40
20
0
Plasma Conc. mg/L
120
Plasma Conc. mg/L
Plasma Conc. mg/L
Plasma Conc.-Time curve
immediate/prolonged release
80
60
40
20
0
0
10
20
30
40
Time (h)
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50
60
70
80
60
40
20
0
0
10
20
30
40
Time (h)
Training workshop: Training of BE assessors, Kiev, October 2009
50
60
70
0
10
20
30
40
Time (h)
50
60
70
Regulatory requirements for BE studies
MR dosage forms
multiple unit formulations
EC formulations
single unit formulations
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Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
Modified release (MR) oral dosage forms:
Requested BE studies for enteric coated formulations:
single dose, two-period,
crossover, fasting
single dose, two-period,
crossover, fed
90% CI AUC and Cmax:
80 – 125%
90% CI AUC and Cmax:
80 – 125%
or
not statistical
significant different
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Training workshop: Training of BE assessors, Kiev, October 2009
pH!
Regulatory requirements for BE studies
EC formulations
multiple unit formulations:
Fed and fast bioequivalence studies normally no problem
Results of bioequivalence study obtained in bio-study for
one strength to the other strengths based upon dose
proportionality and dissolution data.
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Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
EC formulations
single unit formulations:
Fed study mostly problematic!
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!!
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Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
EC formulations
single unit formulations:
3000
04.210.8
2500
treatment=T
2000
1500
1000
500
0
0
1
2
3
4
5
6
7
Time after dosing on Day 1 (hr)
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Training workshop: Training of BE assessors, Kiev, October 2009
8
9
10
Regulatory requirements for BE studies
EC formulations
single unit formulations:
32 |
Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
Modified release (MR) oral dosage forms:
Requested BE studies for controlled release formulations:
single dose, two-period,
crossover, fasting
multiple dose, two-period,
crossover, fasting
single dose, two-period,
crossover, fed
90% CI AUC and Cmax: 90% CI AUC and Cmax: 90% CI AUC and Cmax:
80 – 125%;
80 – 125%
80 – 125%
Cmin and PTF!
- dose dumping
- steady state conditions
- EU, not FDA
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Training workshop: Training of BE assessors, Kiev, October 2009
- FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December
2002)
Regulatory requirements for BE studies
Cmax,ss
AUCss
Cmin,ss
PTF
34 |
Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory requirements for BE studies
MR oral dosage forms:
If a product concerns several strengths:
 Single unit formulations:
– Single dose study fasted state for every strength
– Multiple dose study may be waived for lower 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
35 |
Training workshop: Training of BE assessors, Kiev, October 2009
Regulatory 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
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Training workshop: Training of BE assessors, Kiev, October 2009
90% CI AUC and Cmax:
80 – 125%
End
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Training workshop: Training of BE assessors, Kiev, October 2009