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WORKSHOP ON PREQUALIFICATION OF ARV: BIOEQUIVALENCE

WORKSHOP ON PREQUALIFICATION OF ARV: BIOEQUIVALENCE. Introduction to the Discussion of Bioequivalence Study Design and Conduct Presented by Hans Kemmler Consultant to WHO Swissmedic (Swiss drug regulatory authority). Background: First Product to Market. Innovator’s Product Quality

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WORKSHOP ON PREQUALIFICATION OF ARV: BIOEQUIVALENCE

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  1. WORKSHOP ON PREQUALIFICATION OF ARV: BIOEQUIVALENCE Introduction to the Discussion of Bioequivalence Study Design and Conduct Presented by Hans Kemmler Consultant to WHO Swissmedic (Swiss drug regulatory authority) Hanoi, 2006-19-01

  2. Background:First Product to Market • Innovator’s Product • Quality • Safety and efficacy • Based on extensive clinical trials • Expensive • Time consuming Hanoi, 2006-19-01

  3. Background:Other products with same medicinal ingredient • Subsequent-entry products • Generic products • Multisource products • How do these products gain marketing authorization? Hanoi, 2006-19-01

  4. Pharmaceutical equivalence • Same amount of the same active pharmaceutical ingredient • Salts, esters • Same dosage form • Comparable dosage forms • e.g., tablet vs. capsule • Same route of administration • Is pharmaceutical equivalence enough? Hanoi, 2006-19-01

  5. Sometimes pharmaceutical equivalence is enough • Aqueous solutions • Intravenous solutions • Intramuscular, subcutaneous • Oral solutions • Otic or ophthalmic solutions • Topical preparations • Solutions for nasal administration • Powders for reconstitution as solution • Gases Hanoi, 2006-19-01

  6. Sometimes it is not enough • Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence • Therapeutic equivalence: • Pharmaceutically equivalent • Same safety and efficacy profiles after administration of same dose Hanoi, 2006-19-01

  7. Pharmaceutical Equivalents Test Reference Possible Differences • Drug particle size • Excipients • Manufacturing Equipment or Process • Site of manufacture Could lead to differences in product performance in vivo Hanoi, 2006-19-01

  8. Additional data is required • Oral immediate release products with systemic action • Generally required for solid oral dosage forms • Critical use • Narrow therapeutic range • Bioavailability problems associated with the active ingredient • Problematic polymorphism, excipient interaction, or sensitivity to manufacturing processes Hanoi, 2006-19-01

  9. Additional data is required • Oral modified release products with systemic action • Fixed dose combination products with systemic action • When at least one component requires study • Non-oral / non-parental products with systemic action • Non-solution products with non-systemic action Hanoi, 2006-19-01

  10. Marketing authorization of multisource products • Extensive clinical trials to demonstrate safety and efficacy • Interchangeability? • Demonstration of equivalence to reference (comparator) product • Interchangeability • Therapeutic equivalence Hanoi, 2006-19-01

  11. Marketing authorization through equivalence • Suitable methods for assessing equivalence: • Comparative pharmacokinetic studies • Comparative pharmacodynamic studies • Comparative clinical trials • Comparative in vitro tests Hanoi, 2006-19-01

  12. Comparative Pharmacokinetic Studies • In vivo measurement of active ingredient • “Some” relationship between concentration and safety/efficacy • Product performance is the key • Comparative bioavailability Hanoi, 2006-19-01

  13. Bioavailability • The rate and extent to which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation.” Reference: intravenous administration = 100% bioavailability Hanoi, 2006-19-01

  14. Important Pharmacokinetic Parameters • AUC: area under the concentration-time curve  measure of the extent of bioavailability • Cmax: the observed maximum concentration of drug  measure of both the rate of absorption and the extent of bioavailability • tmax: the time after administration of drug at which Cmax is observed  measure of the rate of absorption Hanoi, 2006-19-01

  15. Plasma concentration time profile concentration Cmax AUC time Tmax Hanoi, 2006-19-01

  16. Bioequivalence Two products are bioequivalent if • they are pharmaceutically equivalent • bioavailabilities (both rate and extent) after administration in the same molar dose are similar to such a degree that their effects can be expected to be essentially the same Hanoi, 2006-19-01

  17. Therapeutic Equivalence • Therapeutic equivalence: • Pharmaceutically equivalent • Same safety and efficacy profiles after administration of same dose: bioequivalent • Interchangeability Hanoi, 2006-19-01

  18. Comparative Pharmacodynamic Studies • Not recommended when: • active ingredient is absorbed into the systemic circulation • pharmacokinetic study can be conducted • Local action / no systemic absorption Hanoi, 2006-19-01

  19. Comparative Clinical Studies • Pharmacokinetic profile not possible • Lack of suitable pharmacodynamic endpoint • Typically insensitive Hanoi, 2006-19-01

  20. Comparative in vitro Studies • May be suitable in lieu of in vivo studies under certain circumstances • Requirements for waiver to be discussed • Currently no “biowaiver” (waiving the requirement for a bioequivalence study) in prequalification project except for additional strength Hanoi, 2006-19-01

  21. When are bioequivalence studies employed? • Multisource product vs. Innovative product • Pre-approval changes • Bridging studies • Post-approval changes • Additional strengths of existing product Hanoi, 2006-19-01

  22. Bioequivalence Studies:Basic Design Considerations • Minimize variability not attributable to formulations • Minimize bias • REMEMBER: goal is to compare performance of the two products Hanoi, 2006-19-01

  23. “Gold Standard” Study Design • Single-dose, two-period, crossover • Healthy volunteers • Subjects receive each formulation once • Adequate washout Hanoi, 2006-19-01

  24. Multiple-dose Studies • More relevant clinically? • Less sensitive to formulation differences Hanoi, 2006-19-01

  25. Multiple-dose Studies may be employed when: • Drug is too potent/toxic for administration in healthy volunteers • Patients / no interruption of therapy • Extended/modified release products • Accumulation using recommended dosing interval • In addition to single-dose studies Hanoi, 2006-19-01

  26. Multiple-dose Studies may be employed when: • Non-linear pharmacokinetics at steady-state (e.g., saturable metabolism) • Assay not sufficiently sensitive for single-dose study Hanoi, 2006-19-01

  27. Crossover vs. Parallel Designs • Crossover design preferred • Intra-subject comparison • Lower variability • Generally fewer subjects required • Parallel design may be useful • Drug with very long half-life • Crossover design not practical Hanoi, 2006-19-01

  28. Parallel Design Considerations • Ensure adequate number of subjects • Adequate sample collection • Completion of Gastrointestinal transit / absorption process • 72 hours normally sufficient Hanoi, 2006-19-01

  29. Fasted vs. Fed Designs • Fasted study design preferred • Minimize variability not attributable to formulation • Better able to detect formulation differences Hanoi, 2006-19-01

  30. Fed Study Designs may be employed when: • Significant gastrointestinal (GI) disturbance caused by fasted administration • Product labeling restricts administration to fed state Hanoi, 2006-19-01

  31. Fed Study Design Considerations • Fed conditions depend on local diet and customs • Dependent on reason for fed design • Avoiding GI disturbance • Minimal meal to minimize impact • Required due to drug substance / dosage form • Modified-release products Hanoi, 2006-19-01

  32. Fed Study Design Considerations cont. • Required due to drug substance / dosage form • Complicated pharmacokinetics • Known effect of food on drug substance • Fed conditions designed to promote maximal perturbation • High fat • High Calorie • Warm Hanoi, 2006-19-01

  33. Replicate vs. non-replicate designs • Standard approach • Non-replicated • Single administration of each product • Average bioequivalence Hanoi, 2006-19-01

  34. Replicate Designs • Typically four-period design • Each product administered twice • Intra-subject variability • Subject X formulation interaction • Different approaches possible • Average bioequivalence • Individual bioequivalence Hanoi, 2006-19-01

  35. Replicate Designs • Advantages • More information available • Different approaches to assessment possible • Disadvantages • Bigger commitment for volunteers • More administrations to healthy volunteers • More expensive to conduct Hanoi, 2006-19-01

  36. Helpful Guidelines • FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000) • Canadian Guidance for Industry: “Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations used for systemic effects.” (1992) • EU “Note for Guidance on the Investigation ofBioavailability and Bioequivalence” • CPMP/EWP/QWP/1401/98 and related guidances and documents (www.emea.eu.int/pdfs/human/ewp ) • Many other related guidances, consider current scientific discussion Hanoi, 2006-19-01

  37. Discussion • Questions • Comments • Opinions Hanoi, 2006-19-01

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