Hanoi, 2006-19-01 1

WORKSHOP ON PREQUALIFICATION OF ARV:

BIOEQUIVALENCE

Introduction to the Discussion of Bioequivalence Study

Design and Conduct

Presented byHans Kemmler

Consultant to WHOSwissmedic (Swiss drug regulatory authority)

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Background:First Product to Market

Innovator’s Product

Quality

Safety and efficacy– Based on extensive clinical trials– Expensive– Time consuming

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Background:Other products with same medicinal ingredient

Subsequent-entry products

Generic products

Multisource products

How do these products gain

marketing authorization?

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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?

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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

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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

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Pharmaceutical Equivalents

Possible Differences

Drug particle size

Excipients

Manufacturing

Equipment or

Process

Site of manufacture

Test Reference

Could lead to differences in product performance in vivo

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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

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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

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Marketing authorization of multisource products

Extensive clinical trials to

demonstrate safety and efficacy– Interchangeability?

Demonstration of equivalence to

reference (comparator) product– Interchangeability– Therapeutic equivalence

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Marketing authorization through equivalence

Suitable methods for assessing

equivalence:– Comparative pharmacokinetic studies– Comparative pharmacodynamic

studies– Comparative clinical trials– Comparative in vitro tests

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Comparative Pharmacokinetic Studies

In vivo measurement of active

ingredient

“Some” relationship between

concentration and safety/efficacy

Product performance is the key

Comparative bioavailability

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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

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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

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Plasma concentration time profile

Cmax

Tmax

AUC

time

concentration

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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

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Therapeutic Equivalence

Therapeutic equivalence:– Pharmaceutically equivalent– Same safety and efficacy profiles after

administration of same dose: bioequivalent

Interchangeability

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Comparative Pharmacodynamic Studies

Not recommended when:– active ingredient is absorbed into the

systemic circulation– pharmacokinetic study can be

conducted

Local action / no systemic absorption

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Comparative Clinical Studies

Pharmacokinetic profile not possible

Lack of suitable pharmacodynamic

endpoint

Typically insensitive

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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

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When are bioequivalence studies employed?

Multisource product vs. Innovative product

Pre-approval changes – Bridging studies

Post-approval changes

Additional strengths of existing product

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Bioequivalence Studies:Basic Design Considerations

Minimize variability not attributable to

formulations

Minimize bias

REMEMBER: goal is to compare

performance of the two products

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“Gold Standard” Study Design

Single-dose, two-period, crossover

Healthy volunteers

Subjects receive each formulation

once

Adequate washout

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Multiple-dose Studies

More relevant clinically?

Less sensitive to formulation

differences

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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

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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

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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

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Parallel Design Considerations

Ensure adequate number of subjects

Adequate sample collection – Completion of Gastrointestinal

transit / absorption process– 72 hours normally sufficient

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Fasted vs. Fed Designs

Fasted study design preferred– Minimize variability not attributable to

formulation– Better able to detect formulation

differences

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Fed Study Designs may be employed when:

Significant gastrointestinal (GI)

disturbance caused by fasted

administration

Product labeling restricts

administration to fed state

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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

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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

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Replicate vs. non-replicate designs

Standard approach– Non-replicated– Single administration of each product– Average bioequivalence

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Replicate Designs

Typically four-period design– Each product administered twice

Intra-subject variability

Subject X formulation interaction

Different approaches possible– Average bioequivalence– Individual bioequivalence

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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

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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 (www.emea.eu.int/pdfs/human/ewp )

Many other related guidances,

consider current scientific discussion

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Discussion

Questions

Comments

Opinions