kyiv, 2005-10-051 training workshop on pharmaceutical quality, good manufacturing practice &...
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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY,
GOOD MANUFACTURING PRACTICE & BIOEQUIVALENCE
Introduction to the Discussion of Bioequivalence Study
Design and Conduct
Presented byJohn Gordon, Ph.D.Consultant to WHO
e-mail: [email protected]
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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
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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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Discussion
Questions
Comments
Opinions