What is the experimental unit in premix bioequivalence ?

June 2010Didier Concordetd.concordet@envt.fr

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Bioequivalence concepts

Exposure

Close Concentration profiles Close effects

Concentrations

Effects

Time pionneer generic

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Bioequivalence concepts

Time

Close PK parametersAUC, Cmax

Cmax

Tmax

AUC

Close Concentration profiles Close effects

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Current definition of bioequivalence

Average Average Generic

Time

Con

cent

rati

onReference

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Current bioequivalence definition

The two formulations are considered as bioequivalent if theirconcentrations profiles are close in a virtual animal : the average animal.

Close population mean of AUC, Cmax.

Does implicitly assume that the population is homogeneous with no specific strata.Sampling randomly animals is enough to insure absence of bias

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Current bioequivalence definition

Time

Con

cent

rati

on

The average individual is not "well defined"

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What is the individual ?Individual : That cannot be divided into several (independent) pieces without altering what is observed.Can the animal be the individual when the drug is given in food?

Con

cent

rati

on

Time

Animal fed aloneThe same animal fed with others

Food intakes are not independent

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What is the individual ?

The individual could be the pen :

- size of the pen,- social behaviour on food intake,…

the breeder : - type of food,- modalities of meal preparation,- modalities of premix distribution,…

the pig company ?

If the animals' food intakes are not independent, the animal cannot be the individual.

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What you are thinking about right now …

The pen (size of pen, social behaviour) effect and the breeder effect (type of food, modalities of meal preparation, modalities of premix distribution)

impacts both the pioneer and the test premix in the same way.

So, why should we choose the pen or the breeder as the individual ?

It is probably true, but…maybe not important.It depends on what we mean exactly by bioequivalence.

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How to define the exposure for a pen, a breeder, a population ?

A pen

A b

reed

er =

an

indi

vidu

al

A population

A sample of individuals

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Exposures

Exposure

Time

Con

cent

rati

on

For a single animalFor a two animalsFor a pen

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Exposures

Exposure

For a pen

Exposure

For two pens

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Exposures

For a sample of pens

Exposure

For a breeder

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Exposures

Exposure

For a breederFor a sample of breedersFor a population

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Three main types of bioequivalence

Average bioequivalence :The pioneer and generic premix formulations should give close "average" exposures.

Population bioequivalence :The statistical distribution of the drug exposures of the two formulations among breeders/pen should be close

Individual bioequivalence :For most breeders/pen, the formulations should give close exposures.

Average bioequivalence :The pioneer and generic premix formulations should give close "average" exposures.

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Average bioequivalence

Exposure for the pioneer formulation

Exposure for the generic formulation Identity line

Population mean

Equivalencerange

Population mean

The two formulations are "average bioequivalent"

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Average bioequivalence

Exposure for the pioneer formulation

Exposure for the generic formulation Identity line

Population mean

Equivalencerange

Population mean

The two formulations are NOT "average bioequivalent"

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Average bioequivalence

Only the population means are involved in the ABE definition

- number of individuals = number of breeders (pens)

- need of a representative sample of individuals

- factors influencing PK profiles can be considered as

noise that render imprecise estimation of population means

- the study can be organised so that the between individual

variability is minimized

The argument that such or such factor impacts (or not) differentially the pioneer and the generic PK profiles is not meaningful in this case.

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Three main types of bioequivalence

Average bioequivalence :The pioneer and generic premix formulations should give close "average" exposures.

Population bioequivalence :The statistical distribution of the drug exposures of the two formulations among breeders/pen should be close

Individual bioequivalence :For most breeders/pen, the formulations should give close exposures.

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2.5%

2.5%

2.5% 2.5%

Population bioequivalence

Exposure for the pioneer formulation

Exposure for the generic formulation Identity line

Equivalenceranges

The two formulations are "population bioequivalent"

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Population bioequivalence

It refers to prescriptability : An ‘individual’ who take a product, for the first time, is expecting to obtain the same therapeutic efficacy whatever the selected formulation.Two formulations would not be “population bioequivalent” if a breeder (pen) that intents to use the new formulation cannot expect the same effect as another breeder (pen) that uses the pioneer one

- number of individuals = number of breeders (pens)- need of a representative sample of individuals- the between individual variability to be precisely estimated (the study should not be designed so that the between individual variability is minimized)-The possible existence of a formulation*breeder or formulation*pen interaction has no relevance when discussing prescriptability

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Three main types of bioequivalence

Average bioequivalence :The pioneer and generic premix formulations should give close "average" exposures.

Population bioequivalence :The statistical distribution of the drug exposures of the two formulations among breeders/pen should be close

Individual bioequivalence :For most breeders/pen, the formulations should give close exposures.

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2.5%

2.5%

2.5% 2.5%

Individual bioequivalence

Exposure for the pioneer formulation

Exposure for the generic formulation Identity line

Equivalenceranges

The two formulations are "individual bioequivalent"

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2.5%

2.5%

2.5% 2.5%

Individual bioequivalence

Exposure for the pioneer formulation

Exposure for the generic formulation Identity line

Equivalenceranges

The two formulations are NOT "individual bioequivalent"

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Individual bioequivalence

It refers to switchability : Two formulations of the same drug are ‘switchable’ if an individual (breeder/pen) using one formulation can expect the same therapeutic effect after being switched to the other formulation. Two formulations would not be “individual bioequivalent” if a there exists a formulation*breeder or formulation*pen interaction.

- number of individuals = number of breeders (pens)- need of a representative sample of individuals- the interaction individual*formulation variability to be precisely estimated (the study should not be designed so that the between individual variability is minimized)-The possible existence of a formulation*breeder or formulation*pen interaction is relevant when discussing switchability.

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Conclusion

Need to choose the individual- breeder - pen - pig company ?

Need to choose a definition of bioequivalence- average- population- individual.

Whatever the chosen individual and definition of bioequivalence, a population data analysis will necessarily be used.