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Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to regulatory authorities. Why are bioavailability / bioequivalence studies necessary? An Introduction to Bioequivalence Studies
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Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to regulatory authorities Why are bioavailability / bioequivalence studies necessary? An Introduction to Bioequivalence Studies Presented by: Hans Kemmler, Consultant to WHO Accra, 5.Nov. 2008
Background:First Product to Market • Innovator’s Product • Quality • Safety and efficacy • Based on extensive clinical trials • Expensive • Time consuming
Background:Other products with same medicinal ingredient • Subsequent-entry products • Generic products • Multisource products • How do these products gain marketing authorization?
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?
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
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
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
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
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
Marketing authorization of multisource products • Extensive clinical trials to demonstrate safety and efficacy • Interchangeability? • Demonstration of equivalence to reference (comparator) product • Interchangeability • Therapeutic equivalence
Marketing authorization through equivalence • Suitable methods for assessing equivalence: • Comparative pharmacokinetic studies • Comparative pharmacodynamic studies • Comparative clinical trials • Comparative in vitro tests
Comparative Pharmacokinetic Studies • In vivo measurement of active ingredient • “Some” relationship between concentration and safety/efficacy • Product performance is the key • Comparative bioavailability
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
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
Plasma concentration time profile concentration Cmax AUC time Tmax
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
Bioavailability • Absolute bioavailability (F): • Relative bioavailability (Frel)
Bioavailability: Same Dose • Absolute bioavailability (F): • Relative bioavailability (Frel)
Therapeutic Equivalence • Therapeutic equivalence: • Pharmaceutically equivalent • Same safety and efficacy profiles after administration of same dose: bioequivalent • Interchangeability
Comparative Pharmacodynamic Studies • Not recommended when: • active ingredient is absorbed into the systemic circulation • pharmacokinetic study can be conducted • Local action / no systemic absorption
Comparative Clinical Studies • Pharmacokinetic profile not possible • Lack of suitable pharmacodynamic endpoint • Typically insensitive
Comparative in vitro Studies • May be suitable in lieu of in vivo studies under certain circumstances • Requirements for waiver to be discussed
When are bioequivalence studies employed? • Multisource product vs. Innovative product • Pre-approval changes • Bridging studies • Post-approval changes • Additional strengths of existing product
Bioequivalence Studies:Basic Design Considerations • Minimize variability not attributable to formulations • Minimize bias • REMEMBER: goal is to compare performance of the two products
“Gold Standard” Study Design • Single-dose, two-period, crossover • Healthy volunteers • Subjects receive each formulation once • Adequate washout
Multiple-dose Studies • More relevant clinically? • Less sensitive to formulation differences
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
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
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
Parallel Design Considerations • Ensure adequate number of subjects • Adequate sample collection • Completion of Gastrointestinal transit / absorption process • 72 hours normally sufficient
Fasted vs. Fed Designs • Fasted study design preferred • Minimize variability not attributable to formulation • Better able to detect formulation differences
Fed Study Designs may be employed when: • Significant gastrointestinal (GI) disturbance caused by fasted administration • Product labeling restricts administration to fed state
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 • Complicated pharmacokinetics • Known effect of food on drug substance
Fed Study Design Considerations cont. • Fed conditions designed to promote maximal perturbation • High fat • High Calorie • Warm
Replicate vs. non-replicate designs • Standard approach • Non-replicated • Single administration of each product • Average bioequivalence
Replicate Designs • Typically four-period design • Each product administered twice • Intra-subject variability • Subject X formulation interaction • Different approaches possible • Average bioequivalence • Individual bioequivalence
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
Discussion • Questions • Comments • Opinions