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%
2|

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

3|

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

4|

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

5|

Training workshop: Training of BE assessors, Kiev, October 2009

Bioequivalence-non linear pharmacokinetics

Linear PK:

R T

6|

Training workshop: Training of BE assessors, Kiev, October 2009

R T

Bioequivalence-non linear pharmacokinetics

AUC/Cmax increase less
than dose proportional

:exception

! solubility
7|

Training workshop: Training of BE assessors, Kiev, October 2009

Bioequivalence-non linear pharmacokinetics

AUC/Cmax increase more
than dose proportional

8|

Training workshop: Training of BE assessors, Kiev, October 2009

Bioequivalence-narrow therapeutic drugs

Narrow Therapeutic Index Drugs

9|

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)

10 |

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)

11 |

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

12 |

Training workshop: Training of BE assessors, Kiev, October 2009

Bioequivalence highly variable drugs

13 |

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

14 |

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

16 |

Training workshop: Training of BE assessors, Kiev, October 2009

Furosemide (ng/ml)

HVD drugs and products

1200
1000
800
600
400
200
0
0

4
time (h)

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

17 |

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

18 |

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)

19 |

Training workshop: Training of BE assessors, Kiev, October 2009

Sw0=0.20
Sw0=0.25
%

125%

The Black Box

80%

Swr

20 |

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

too low concentration

unstable in matrix

Short elimination half-life parent drug

Metabolite contributes to the activity
Pharmacokinetics non-linear (parent + metab.)
21 |

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

10

CONC (ng/mL)

CONC (ng/mL)

100

1
0,1
0,01

1.0
0.1

10

15

20

25

30

TIME (HR)
Parent drug

22 |

10.0

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.
23 |

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.
24 |

Training workshop: Training of BE assessors, Kiev, October 2009

Bioequivalence metabolite

Example:
metabolite: 90% CI AUC and Cmax within 80 125%
but parent..!

25 |

Training workshop: Training of BE assessors, Kiev, October 2009

Regulatory requirements for BE studies

:Modified release (MR) oral dosage forms

26 |

Training workshop: Training of BE assessors, Kiev, October 2009

Regulatory requirements for BE studies

MR dosage forms

multiple unit formulations

EC formulations
single unit formulations

27 |

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
28 |

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.

29 |

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!!
30 |

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

Time after dosing on Day 1 (hr)

31 |

Training workshop: Training of BE assessors, Kiev, October 2009

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 dumpingsteady state conditionsEU, not FDA-

33 |

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

36 |

Training workshop: Training of BE assessors, Kiev, October 2009

90% CI AUC and Cmax:

80 125%

End

37 |

Training workshop: Training of BE assessors, Kiev, October 2009