1. OVERVIEW OF DACA BIOEQUIVALENCE REPORT EVALUATION Presented by Solomon Shiferaw 31Augst 2010

2. Objectives To provide an overview on the bioequivalence requirement for registration. To highlight the application assessment for inter changeability of multi-source generic product in FMHACA To show the constraints for assessment of BE in FMHACA

3. Introduction Regulatory Authority Mission “To assure that Safe and Effective drugs are marketed in the country and are available to the people ”

4. Introduction Multi-source drug products need to conform to the same standards of quality, efficacy and safety required of the originator's products. A reasonable assurance must be provided that they are, as intended, clinically interchangeable with nominally equivalent market products.

5. Introduction cont. Assessment of equivalence will normally require  an in vivo study, or  a justification that such a study not be required in a particular case.

6. Documentation of equivalence for MA Pharmaceutically equivalent multi-source pharmaceutical products must be shown to be therapeutically equivalent to one another in order to be considered interchangeable

7. Documentation of equivalence for MA Bioequivalence: Approach for establishing equivalence Comparative CT BE study (In most case) In-vitro dissolution study Comparative PD study

8. Documentation of equivalence for MA Acceptance of any test procedure depends on factors like characteristics of the active drug substance and drug product concentrations in an accessible fluid (eg plasma) Evidence on vitro/in vivo correlation Solubility & Permeability of API, etc

9. General organization of the document for BE Names and affiliations of the responsible investigator (s) and analyst (s) Site of the study  Accreditation of the BE site by Local DRA  Detailed information on clinical and analytical facilities of the institution (s) Period of its execution of BE study

10. General organization of the document for BE cont. The names and B. No. of the products used in the study as well as the composition of the test product Analytical validation report The responsible investigator (s) should sign for their respective section of the report

11. General organization of the document for BE cont. The applicant should submit a signed statement confirming the identity of the test product with the pharmaceutical product, which is submitted for registration

12. The report of In-vivo BE should include Study Protocol Summary of the study Objectives

13. The report of In-vivo BE should include Subjects  subjects should be as homogeneous (healthy volunteers in order to reduce variability other than in the pharmaceutical products)  a clear criteria for inclusion/exclusion  non smokers & with out a history of alcohol or drug abuse problems

14. The report of In-vivo BE should include Subject cont.  volunteers screening standard laboratory tests, a medical history and physical examination Age range of 18-55 with a weight with normal range In most cases 18-24 subjects but NLT 12

15. The report of In-vivo BE should include Design considerations Minimize variability except attribute to formulation Minimize bias Compare performance of the two formulations

16. The report of In-vivo BE should include Study design  Cross over design Vs Parallel Design  Randomization  Standardization (exercise, diet, fluid intake, restriction of intake)  Single dose Vs Multiple dose  Number of treatment group  Treatment periods

17. The report of In-vivo BE should include Study design cont.  wash out period (NLT 5 t 1/2 )  Doses, rout of administration  Sampling times and method for collection of samples

18. The report of In-vivo BE should include Chemical Analysis  Method used to determine plasma conc. Of drugs  Should be  Accurate & Precise  Selective & Sensitive and  Reproducible  The results of Bioanalytical Method Validation

19. The report of In-vivo BE should include Test Product  Identical to the projected commercial pharmaceutical product  Bio-batch (industrial (ideal), pilot scale) Reference Product (comparators)  Innovator product  Market leader product( Registered in Ethiopia)

20. The report of In-vivo BE should include Results  All results (raw data)  Sufficiently detailed statistical and/or any other procedures for calculating the parameters used  Clinical findings  Representative chromatograms

21. The report of In-vivo BE should include Results cont. Pharmacokinetics Parameters AUC  Measure of the extent of absorption Criteria: 80 -120 C max  Measure of rate of absorption Criteria: 80 - 120 T max  Measure of rate of absorption

22. BE is not required for Aqueous solutions  Intravenous solutions  Intramuscular, subcutaneous solutions  Oral solutions  Ophthalmic or otic solutions  Nasal spray  Powder for reconstitution as a solution  Gases  Inhalation & nasal preparation  Topical products

23. BE study required for Systemic application of such product require BE study  Oral immediate release product  Non-oral and Non-parenteral products Eg. transdermal patches, suppositories  Sustained or modified release products  Fixed combination products

24. In-Vitro dissolution study Under certain conditions Like  Highly soluble and permeable BCS class I  Different strength of the same formulation ( BE done for 1 strength (usually for higher strength)  Same qualitative composition  Same ratio of active ingredients and excipients  Basket Or Paddle

25. In-Vitro dissolution study Media for comparative dissolution  pH 6.8 buffer  pH 4.5 buffer  pH 1.2 buffer or 0.1NHCl

26. In-Vitro dissolution study Difference factor(f 1 ) f 1 = sum IR t -T t I/sum R t x100 f1 should NMT 15 Similarity factor(f 2 ): f 2 = 50.Log( 1/ (1+1/nx sum(R t -T t ) 2 ) 1/2 x100) f 2 should NLT 50

27. Challenges in BE Evaluation Lack of adequate experience and training on BE evaluation Lack of comparators reference products The guideline is not exhaustive Limited access to the reference materials