1. Hanoi, 2006-19-01 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)

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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