What is the experimental unit in premix bioequivalence ?

1. What is the experimental unit in premix bioequivalence ? June 2010 Didier Concordet d.concordet@envt.fr

2. pionneer generic Bioequivalence concepts Close Concentration profiles Close effects Effects Concentrations Exposure Time

3. Bioequivalence concepts Close Concentration profiles Close effects Cmax Close PK parameters AUC, Cmax AUC Tmax Time

4. Average Generic Average Concentration Time Current definition of bioequivalence Reference

5. Current bioequivalence definition The two formulations are considered as bioequivalent if their concentrations 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

6. Concentration Time Current bioequivalence definition The average individual is not "well defined"

7. Animal fed alone The same animal fed with others Food intakes are not independent Concentration Time 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?

8. What is the individual ? If the animals' food intakes are not independent, the animal cannot be 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 ?

9. 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.

10. How to define the exposure for a pen, a breeder, a population ? A population A breeder = an individual A pen A sample of individuals

11. Exposures For a pen For a single animal For a two animals Concentration Exposure Time

12. Exposures For two pens For a pen Exposure Exposure

13. Exposures For a breeder For a sample of pens Exposure

14. Exposures For a population For a breeder For a sample of breeders Exposure

15. Three main types of bioequivalence Average bioequivalence : The pioneer and generic premix formulations should give close "average" exposures. 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.

16. Average bioequivalence Exposure for the pioneer formulation Population mean Equivalence range Population mean The two formulations are "average bioequivalent" Exposure for the generic formulation Identity line

17. Average bioequivalence Exposure for the pioneer formulation Population mean Equivalence range Population mean The two formulations are NOT "average bioequivalent" Exposure for the generic formulation Identity line

18. 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.

19. 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.

20. 2.5% 2.5% 2.5% 2.5% Population bioequivalence Exposure for the pioneer formulation Equivalence ranges Exposure for the generic formulation The two formulations are "population bioequivalent" Identity line

21. 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

22. 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.

23. 2.5% 2.5% 2.5% 2.5% Individual bioequivalence Exposure for the pioneer formulation Equivalence ranges Exposure for the generic formulation The two formulations are "individual bioequivalent" Identity line

24. 2.5% 2.5% 2.5% 2.5% Individual bioequivalence Exposure for the pioneer formulation Equivalence ranges Exposure for the generic formulation The two formulations are NOT "individual bioequivalent" Identity line

25. 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.

26. 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.