Milan Smid, MD, PhD

1. Demonstration of Bioequivalence Milan Smid, MD, PhD Tutorial: WHO Prequalification Programme for Priority Medicines, Beijing, March, 2010

2. Proof of bioequivalence is required for multisource interchangeable medicines evaluated within WHO Prequalification Programme Why? How? Always?

3. Why?

4. Although medicines may contain same active ingredient in the same strength and dosage form, after administration to the organism due to pharmaceutical differences the release and absorption of active moiety may be different. Therapeutic effect is different. • In vitro tests provide valuable information but are not necessarily a reliable guide to the bioavailability or therapeutic performance of the product.

5. Bioequivalence Pharmaceutical Equivalent Products Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications)

6. Bioequivalence Two medicinal products are bioequivalent if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same.

7. Bioequivalence – bridging innovators and generics Innovative medicine Experimental data/ Literature Clinical data (Module V) Generic medicine Multisource interchangeable Preclinical data (Module IV) BIOEQUIVALENCE Pharmaceutical data (Module III) Administrative and summarizing data (Modules I and II) incl. GMP

8. Interchangeability Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use. Bioequivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring.

9. How?

10. Demonstration of bioequivalence Bioequivalence study or PD studies Clinical studies In vitro methods ONLY EXCEPTIONAL!

11. Tested product • GMP • batch size • pilot batch • commercial batch • not smaller than 100 000 units or 10 % of industrial batch size (whichever is higher) • difference regarding the content of the investigative products (T and R) should preferably not be more than 5 % • strength with the largest sensitivity to detect differences in the two products

12. Comparators for Prequalification Programme • Lists of recommended comparators available on WHO website. • Innovator product with established Q,S, and E sourced from well regulated market (ICH process countries). • Other comparators must be justified. Recommended to consult WHO.

13. Planning a BE StudyStudy Subjects • Selection of subjects • description of volunteers;smoker, vegetarian, phenotyping…. • verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure…) • number of volunteers depending on variability; at least 12(EU: healthy, 18-55y; FDA: both sexes, > 18y) • randomisation objective: minimising interindividual variability in order to detect product differences!

14. Design of bioequivalence studies Golden standard study design single dose, two-period, crossover healthy volunteers Reference (comparator)/ Test (generic)

15. Design of bioequivalence studies Standard approach BE study non-replicate single administration R and T average bioequivalence 90% CI AUC and Cmax: 80 – 125%

16. Planning a BE StudyStudy Samples • Sampling times • appr. 3 – 4 to describe drug “input” • appr. 3 sampling times around peak concentration • appr. 3 – 4 to describe elimination • sufficient to “describe” at least 80 % of total AUC - usually ~12– 18 samples • wash-out-phase (not less than 5 half-lives)  Minimum!

17. Specific bioeqivalence situations • Highly variable drugs • Narrow therapeutic index drugs • Food effect • Measurement of metabolites • Modified release formulations • Fixed combination products • Drugs with inherent toxicity

18. Analytical methods • FDA Guidance for Industry • Bioanalytical method validation, May 2001 • ICH Guidance for industry • Validation of analytical methods: definitions and terminology, June 1995 • Validation of analytical procedures: methodology, November 1996

19. Quality of Bioequivalence Studies Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trials subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

20. BTIFBioequivalence Trial Information Form http://who.int/prequal Information for Applicants Generics, ANNEX 7: Presentation of Bioequivalence Trial Information

21. BTIFBioequivalence Trial Information Form

22. Frequent GCP non-compliances • No informed consent, complex language • Ethics committee not independent • Dosing procedure is inadequately documented, no drug accountability • Certificates of analysis are not consistent with study products or not sufficiently detailed • No testing on addictive substances performed • Withdrawals are improperly documented • Meals not standardized and not documented • Storage of blood samples is not monitored • Method of calculation of PK parameters is not specified • Insufficient explanation of outliers • Chromatograms not consistent with data

23. Non-compliance Bioanalytical partCritical deviations in %

24. Always?

25. Bioequivalence Cases when pharmaceutical equivalence is enough: • Aqueous solutions • Intravenous solutions • Intramuscular, subcutaneous solutions • Oral solutions • Otic or ophthalmic solutions • Topical products prepared as solutions • Aqueous solution for nebulizer inhalation or nasal sprays • Powders for reconstitution as solution • Gases

26. Bioequivalence may be proven for one strength Immediate release (IR) oral dosage forms: If a product concerns several strengths and: • Same manufacturer and manufacturing proces • Linear pharmacokinetics • Same qualitative composition of different strengths (WHO) • Same ratio between active substance and excipients, or same excipients in case of low concentration active substance (less than 5%) • Similar dissolution profiles (WHO)

27. BCS-based biowaiver ” BE studies may be exempted if the absence of differences in the in vivo performance can be justified by satisfactory in vitro data.” Valid for oral immediate release dosage forms with systemic action! Biowaiver justification based on criteria derived from the concepts underlying the Biopharmaceutics Classification System

28. Basis for BCS-based Biowaiver Applications/Decisions • WHO – Technical Report Series No. 937, May 2006 Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms • FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000) • EU-guidance:“Note for Guidance on the Investigation of Bioavailability andBioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1

29. BCS-based biowaiver Biopharmaceutics Classification System (BCS) dissolution (both formulation and API) drug product  drug substance in solution membrane transport drug substance in the system simplified mechanistic view on bioavailability

30. BCS according to WHO Solubility at pH 1-6.8 CLASS I Highly permeable Highly soluble (very rapid dissolution or profile comparison) Eligible CLASS II Highly permeable Poorly soluble Eligible only if weak acids, highly soluble at pH 6.8,+dissolution Absorbed >85% CLASS III Poorly permeable Highly soluble Eligible if very rapidly dissolving CLASS IV Poorly permeable Poorly soluble Not eligible

31. BCS-based Biowaiver Application Form Active Pharmaceutical Ingredients (APIs) eligible for a BCS-based biowaiver application are identified by the WHO Prequalification of Medicines Programme. It is not necessary to provide data to support the BCS classification of the respective API(s) in the application i.e. data supporting the drug substance solubility or permeability class. Comparative dissolution of final product is necessary.

32. WHO BCS-based biowaiver Active substances selected for biowaiving by WHO TB: • Levofloxacin • Ofloxacin • Ethambutol • Isoniazid • Pyrazinamide HIV/AIDS: • Lamivudine • Stavudine • Zidovudine

33. BCS-based Biowaiver Application Form Designed to facilitate information exchange between the Applicant and the WHO Prequalification of Medicines Programme if the Applicant seeks to waive bioequivalence studies, based on the Biopharmaceutics Classification System (BCS). For further information, please study the respective WHO biowaiver guidance documents. This form is not to be used, if a biowaiver is applied for additional strength(s) of the submitted product(s), in which situation a separate "Biowaiver Application Form: Additional Strengths" should be used.

34. Information sources

35. Guidance documents http://who.int/prequal/ * Note to applicants on the choice of comparator products for the prequalification project * Guideline on generics - Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

36. Thank you for attention smidm@who.int