1. Bioequivalence Studies Dr Sanet Aspinall, PhD Managing Director AddClin Research Pretoria 20 March 2009

2. Bioequivalence studies are usually done to compare pharmacokinetic parameters of generic drug products with those of a marketed formulation, typically an innovator drug product.

3. Bioequivalence = Comparative bioavailability

4. BIOAVAILABILITY: “Bioavailability means the rate and extent to which the active pharmaceutical ingredient or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action.” (FDA, EU CPMP, MCC)

5. BIOEQUIVALENCE: “The absence of a significant difference in the rate and extent to which the active pharmaceutical ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of action (bioavailability) when administered at the same molar dose under similar conditions in an appropriately designed study.” (FDA)

6. THERAPEUTIC EQUIVALENCE: Clinical (therapeutic) trials can be done to prove that safety and efficacy of two pharmaceutical products are essentially the same, at the same dose. These studies are usually avoided because they are time-consuming, expensive and exposed to difficulties. Clinical outcomes or pharmacodynamic parameters may be involved.

7. Proof of bioequivalence normally implies clinical / therapeutic equivalence and interchangeable use of pharmaceutical products.

8. Comparative bioavailability studies (bioequivalence testing): This is the cost-effective gold standard to predict clinical equivalence of like products.

9. Bioequivalence studies: Designed to obtain comparative in vivo pharmacokinetic data = plasma drug concentration versus time data Appropriate statistical analysis Interpretation of results according to guidelines produced by regulatory authorities

10. PK parameters used: AUC: Area Under the Curve Describes the total amount of drug present in the plasma, thus indicator of the extent of drug absorption.

11. PK parameters used: C max : the peak plasma drug concentration (this, together with t max, are indicators of rate of drug absorption.)

12. AUC and C max are regarded as PRIMARY pk parameters in bioequivalence studies

13. SECONDARY pk parameters include: t max : the time (from dosing) to reach C max. t½: terminal elimination half-life. This indicates the time required for the amount of drug in the body to decrease by half (50%).

15. Typical Study Design (two formulations): Two period Randomized and balanced Cross-over Single dose Laboratory-blind

16. Study subjects: Number of subjects: Must be sufficient to provide 80% of power for meeting and passing the acceptance criteria. Can be determined from published literature. Normally sample size is calculated by a biostatistician.

17. Selection of subjects: Usually healthy volunteers, with strict inclusion and exclusion criteria (age, BMI etc.) Enroll a few more to provide for drop-outs Seldom patients (only when risks/adverse events are unacceptable to healthy volunteers).

18. Study Standardisation: Fasting: dosing only on empty stomach (for most studies) Dosing: same time of day for each subject Fluid intake at dosing: critical to use same volume, e.g. 200ml

19. Study Standardisation (2): Food and fluid intake: standardised and supervised. Posture and activity: controlled and supervised No concomitant medicines, alcohol, caffeine or certain fruit juices allowed.

20. Blood sampling: Venous blood collected in heparinised or EDTA tubes at predetermined intervals over predetermined time. Sampling frequency depends on expected t max.

21. Blood sampling (2): Sampling duration depends on the expected t½ of the drug and the sensitivity of the bio-analytical method used. Usually blood samples are collected for 5 x t½ Minimum required by MCC is 3 x t½ (providing 80% of AUC 0-∞ )

22. Blood sampling (3): Blood volume withdrawal limitations usually means that a total of about 20 samples per period are allowed. Sampling points should be chosen carefully, to result in adequate profiles allowing accurate estimation of relevant pk parameters.

23. Other Issues: Informed consent (comprehensive). Allow an adequate washout period between profiles (>5 x t½). Steady-state (Css) studies (= multiple doses) are sometimes required. Usually single-dose studies are sufficient.

24. Fed vs Fasting: 1.Immediate release dosage forms: usually studied whilst fasting, unless pronounced food effects known. 2.Modified release dosage forms: - to check for any effects of food, studies are required under both fed and fasting conditions. - dosing occurs immediately after a high fat meal.

25. Bioanalysis: GLP, GCP, QC and SOPs. Only validated, reliable chromatographic methods with sufficient sensitivity to be used. Sometimes necessary to measure active metabolite(s) as well as parent compound. Adverse events documented

26. Acceptance range for pk parameters: AUC: 90% confidence intervals should usually be within 0,80-1,25 (80%-125%). C max : 90% confidence intervals should usually be within 0,75-1,33 (75%-133%). (In some cases 80%-125%). These are calculated using log-transformed data. Must be stated up-front in the protocol and may not be changed / added retrospectively.

27. Generic vs proprietary prescribing or dispensing in South Africa: Registration of generic products by MCC will not compromise safety and efficacy of pharmacotherapeutic regimens.

28. AddClin Research Phase 1 unit

32. CONTACT DETAILS: Phase 1 / BE Studies AddClin Research Phase 2-4 and Therapeutic Clinical Equivalence Studies Synexus SA Managing DirectorLaetitia Crause Dr Sanet AspinallBusiness Development Tel: (012) 803-7733083 253 1260