Download Introduction to Bioequivalence Studies

Training workshop on regulatory requirements for registration of Artemisinin
based combined medicines and assessment of data which are submitted to
regulatory authorities
Why are bioavailability / bioequivalence studies
necessary?
An Introduction to Bioequivalence Studies
Presented by: Hans Kemmler, Consultant to WHO
Accra, 5.Nov. 2008
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Artemisinin combined medicines, Kampala, February 2009
Background:
First Product to Market
 Innovator’s Product
 Quality
 Safety and efficacy
– Based on extensive clinical trials
– Expensive
– Time consuming
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Artemisinin combined medicines, Kampala, February 2009
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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Artemisinin combined medicines, Kampala, February 2009
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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Artemisinin combined medicines, Kampala, February 2009
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
•
•
•
•
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Critical use
Narrow therapeutic range
Bioavailability problems associated with the active ingredient
Problematic polymorphism, excipient interaction, or sensitivity
to manufacturing processes
Artemisinin combined medicines, Kampala, February 2009
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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Artemisinin combined medicines, Kampala, February 2009
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:
–
–
–
–
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Comparative pharmacokinetic studies
Comparative pharmacodynamic studies
Comparative clinical trials
Comparative in vitro tests
Artemisinin combined medicines, Kampala, February 2009
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
Tmax
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time
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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Bioavailability
 Absolute bioavailability (F):
AUCextravascular Doseint ravenous
F

AUCint ravenous Doseextravascular
 Relative bioavailability (Frel)
AUCextravascular1 Doseextravascular 2
Frel 

AUCextravascular 2 Doseextravascular1
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Bioavailability: Same Dose
 Absolute bioavailability (F):
AUCextravascular Doseint ravenous
F

AUCint ravenous Doseextravascular
 Relative bioavailability (Frel)
AUCextravascular1 Doseextravascular 2
Frel 

AUCextravascular 2 Doseextravascular1
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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
• Complicated pharmacokinetics
• Known effect of food on drug substance
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Fed Study Design Considerations cont.
 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
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