A-Bioéquivalence: considérations techniques et scientifiques

1. A-Bioéquivalence: considérations techniques et scientifiques

2. Une revue technique récente en français

3. A1-Bioequivalence :Origine du concept

4. Principe de l’essai de bioéquivalence ? = Approcheanalytiqque Equivalence pharmaceutique: 95-105% au moins 24 mois Levothyrox:ancienne formulation: 90-110% pour 36 mois

5. Principe de l’essai de bioéquivalence ? = Approche in vivo Concentrations plasmatiques Concentrations plasmatiques Bioéquivalence: ≤80-125% avec un risque <5%:

6. A2: Pourquoi des preuves pharmacocinétique (mesure des concentrations plasmatiques) pour démontrer la bioéquivalence plutôt qu’un essai clinique ou la mesure d’effets?

7. Essais cliniques • Coût prohibitif annulant l’intérêt des génériques • Coût> plusieurs 100M€ • Générique: beaucoup moins cher mais 32M€ pour le lévothyrox • Impossibilité statistique de démontrer une équivalence • On sait démontrer une non-infériorité mais pas une équivalence avec un intervalle 80-125% avec un risque de 5%

8. Pourquoi des concentrations plasmatiques et pas des effets L’hypothèse de base est que si les concentrations plasmatiques sont très proches (similaires) alors les tous effets seront “essentiellement” les mêmes.

9. DOSE Effects driven by plasma concentrations Plasma concentrations yes Basic assumption to bioequivalence Is there an univocal relationship between exposure and effect ? yes Yes yes Yes Effects not driven by plasma concentrations Plasma concentrations Yes/No ?

10. A3-Pourquoi utiliser le concept de biodisponibilité pour démontrer une bioéquivalence

11. Basic assumption to bioequivalence Similar plasma concentration profile  same effect ? Why ? Effect = Effect Substance property (efficacy) Emax Emax  Dose ED50 + Dose Dose ED50 Hybrid substance and formulation properties (Potency)

12. Basic assumption to bioequivalence Substance property Clearance  EC50 Bioavailability ED50 = Formulation property

13. Basic assumption to bioequivalence • Similar plasma concentration profile  same effect? substance properties Emax  Dose Clearance  EC50+ Dose F% Effect = Formulation properties

14. Basic assumption to bioequivalence • Similar plasma concentration  same effect? • Comparison of 2 formulations of the same drug Emax  Dose Clearance  EC50 F,ref Emax  Dose Clearance  EC50 F,test Vs. Effect,test = Effect, pioneer = + Dose + Dose Comparison of test and reference formulations rely on comparison of F%ref and F%test because only F% may differ Clearance, Emax and EC50 are substance' properties and are identical for a princeps and a generic

15. A4- Ne pas confondre essai de bioéquivalence et un essai de biodisponibilité

16. Bioequivalence vs. Bioavailability (I) • - Bioavailability trials must document • influence of different factors on the rate • and extent of drug absorption • • age • • sex • • route of administration • • disease • • •••••

17. Bioequivalence vs. Bioavailability (III) • Bioavailability trials : • Variability has to be introduced deliberately • Bioequivalence trials : • Variability must not be introduced deliberately • Bioequivalence trial must be performed on homomogeneous groups of subjects

18. Bioequivalence vs. Bioavailability (IV) Inference from a trial - Bioavailability No generalization from a subgroup of subjects to the population - Bioequivalence If B.E. is demonstrated in a particular subgroup of subjects, conclusion should be extended to whole population unless there is an interaction between formulation and a constitutional factor

19. Bioequivalence : Factor of variability to control (I) • Species • B.E. of two formulations has to be demonstrated in each species (interaction between formulation and species is systematically hypothesized ) • Food interactions • This factor of variability addresses questions essentially related to the pharmaceutical form and not related to the future patient population

20. A5-Does essentially the same plasma time curve leads to essentially the same effect whether toxic or therapeutic?

21. PK/PD relationship to discuss bioequivalence acceptance criteria Effect Drug with a large margin of safety Dose may be selected in the asymptotic part of the dose-effect relationship curve and a Δ of 20% for exposure is generally irrelevant in terms of effect Exposure ∆ = 20%

22. PK/PD relationship to discuss bioequivalence acceptance criteria Drug with a narrow margin of safety Dose cannot be selected in the asymptotic part of the dose-effect relationship curve and a Δ of 20% for exposure may be very relevant in term of effect depending of the slope of the curve Effect Exposure ∆ = 20%

23. Does essentially the same plasma time curve leads to essentially the same effect whether toxic or therapeutic? Effects identical ±40% very different AUC Systemic exposure ±20% ±20%

24. Conséquence d’une variation de ± 20 % de l’exposition sur l’amplitude des variations des effets désirés (courbe bleue) et des effets indésirables (courbe brune)

25. A6-Les différentes définitions statistiques possibles d’ une bioéquivalence

26. Average vs.population bioequivalencevs. individual bioequivalence

27. Different types of bioequivalence • Average (ABE) : mean • Population (PBE) : prescriptability • Individual (IBE) : switchability

28. EMA guideline

29. Average bioequivalence reference test AUC/ Cmax Same mean

30. Average bioequivalence Average B.E. refers to the location parameters Average B.E. may not be sufficient to guarantee that an individual patient could be switched from a reference to a generic formulation (e.g., more than 50 % of subjects may be outside the B.E. range when the average B.E. is actually demonstrated)

31. Average bioequivalence • Addresses only mean (center of distribution) but not variability (shape of distribution) • Does not address switchability • FDA : an approved generic can be a substitute for the reference drug product; however FDA did not indicate that the approved generic drug and the innovative can be used interchangeability (Chow et al: Some thoughts on drug interchangeability.)

32. Prescribability • Refer to the clinical setting in which a practitioner prescribes a drug product to a patient for the first time • He has no information on his patient • the prescriber needs to know the comparability of the 2 or n formulations in the population population bioequivalence

33. Interchangeability

34. Population bioequivalenceAUC distribution “Test” and “reference” are bioequivalent if the entire population distribution (mean and variability) are sufficiently similar with regard to AUC and Cmax No Yes

35. Bioéquivalence moyenne et fenêtre thérapeutique

36. Switchability • Refer to the clinical setting in which a practitioner transfers a patient from one drug product to another • We have information on the response of the patient to a particular formulation (princeps or a generic) and clinicians have titrated the dose to reach a particular goal • issue for drug of critical therapeutic categories, for elderly, debilitated patients etc.

37. Individual bioequivalence patient-by-formulation interaction YES No test reference Address switchability “Test” and “reference” are bioequivalent if the individual subject means and variabilities are sufficiently similar with regard to AUC and Cmax; Ce concept est pratiquement abandonné car trop difficile à mettre en évidence

38. Individual bioequivalence • The clinical relevance of a subject-by-formulation interaction has not clearly been demonstrated • e.g.: a pH-specific excipient effect associated with certain diazepam formulations result in producing unequivalence when administered to individuals with elevated gastric pH (like elderly)

39. The types of bioequivalence: summary Individual Average Population Pioneer Test Only guarantees on the mean Guarantees an overall distribution (mean and variance) Test of no interaction between patient and formulation guarantees an individual BE

40. Substitution entre les génériques

41. Guideline on the investigation of bioequivalence (2009) • It is said: Furthermore, this guideline does not cover aspects related to generic substitution as this is subject to national legislation. • Ce n’est pas un problème « scientifique » mais une mesure de gestion

42. IC de différents génériques et BE des génériques entre eux

43. Différences entre génériques: AUC

44. Différences entre génériques: Cmax

45. Possibilité théoriques de faire des méta-analyses pour vérifier que les génériques sont BE entre eux mais les résultats seraient ingérables en cas de différence Chow SC, Shao J. Bioequivalencereview for druginterchangeability. J Biopharm Stat 1999;9(3):485-97.

46. B-The Bioequivalence trial

47. B1-Types of Bioequivalence trials

48. Types of bioequivalence trials Metabolite PD1 Dose abs Drug C (t) Clinical efficacy PD2 Dissolution ..... Drug in urine PD PK Clinical in vitro testing in vivo testing

49. Types of bioequivalence trial in vivo : metabolite plasma profile (I) • When no analytical techniqueexists for drug but does exist for a primary inactive metabolite • The administered drug is a prodrug which is very rapidly transformed to an active metabolite

50. Pourquoi ne pas utiliser des effets ou des essais cliniques plutôt que des concentrations plasmatiques pour démontrer une BE?