Hanoi, 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, Background: First Product to Market Innovator’s Product Quality Safety and efficacy –Based on extensive clinical trials –Expensive –Time consuming

Hanoi, Background: Other products with same medicinal ingredient Subsequent-entry products Generic products Multisource products How do these products gain marketing authorization?

Hanoi, 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, 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, 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, Pharmaceutical Equivalents Possible Differences Drug particle size Excipients Manufacturing Equipment or Process Site of manufacture TestReference Could lead to differences in product performance in vivo

Hanoi, 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, 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, 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, Marketing authorization through equivalence Suitable methods for assessing equivalence: –Comparative pharmacokinetic studies –Comparative pharmacodynamic studies –Comparative clinical trials –Comparative in vitro tests

Hanoi, Comparative Pharmacokinetic Studies In vivo measurement of active ingredient “Some” relationship between concentration and safety/efficacy Product performance is the key Comparative bioavailability

Hanoi, 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, Important Pharmacokinetic Parameters AUC: area under the concentration-time curve  measure of the extent of bioavailability C max : the observed maximum concentration of drug  measure of both the rate of absorption and the extent of bioavailability t max : the time after administration of drug at which C max is observed  measure of the rate of absorption

Hanoi, Plasma concentration time profile C max T max AUC time concentration

Hanoi, 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, Therapeutic Equivalence Therapeutic equivalence: –Pharmaceutically equivalent –Same safety and efficacy profiles after administration of same dose: bioequivalent Interchangeability

Hanoi, 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, Comparative Clinical Studies Pharmacokinetic profile not possible Lack of suitable pharmacodynamic endpoint Typically insensitive

Hanoi, 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, When are bioequivalence studies employed? Multisource product vs. Innovative product Pre-approval changes –Bridging studies Post-approval changes Additional strengths of existing product

Hanoi, Bioequivalence Studies: Basic Design Considerations Minimize variability not attributable to formulations Minimize bias REMEMBER: goal is to compare performance of the two products

Hanoi, “Gold Standard” Study Design Single-dose, two-period, crossover Healthy volunteers Subjects receive each formulation once Adequate washout

Hanoi, Multiple-dose Studies More relevant clinically? Less sensitive to formulation differences

Hanoi, 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, 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, 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, Parallel Design Considerations Ensure adequate number of subjects Adequate sample collection –Completion of Gastrointestinal transit / absorption process –72 hours normally sufficient

Hanoi, Fasted vs. Fed Designs Fasted study design preferred –Minimize variability not attributable to formulation –Better able to detect formulation differences

Hanoi, Fed Study Designs may be employed when: Significant gastrointestinal (GI) disturbance caused by fasted administration Product labeling restricts administration to fed state

Hanoi, 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, 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, Replicate vs. non-replicate designs Standard approach –Non-replicated –Single administration of each product –Average bioequivalence

Hanoi, 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, 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, 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 of Bioavailability and Bioequivalence ” –CPMP/EWP/QWP/1401/98 and related guidances and documents ( ) Many other related guidances, consider current scientific discussion

Hanoi, Discussion Questions Comments Opinions