Transcript training workshop on pharmaceutical quality, good manufacturing

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
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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
Reference
Test
Possible Differences

Drug particle size

Excipients

Manufacturing
Equipment or
Process

Site of manufacture
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
concentration
Cmax
AUC
time
Tmax
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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
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