why are bioavailability / bioequivalence studies necessary?
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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 - PowerPoint PPT PresentationTRANSCRIPT
Artemisinin combined medicines, Kampala, February 20091 |
Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to
regulatory authorities
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 StudiesPresented by: Hans Kemmler, Consultant to WHO
Accra, 5.Nov. 2008
Artemisinin combined medicines, Kampala, February 20092 |
Background:Background:First Product to MarketFirst Product to Market
Background:Background:First Product to MarketFirst Product to Market
Innovator’s Product
Quality
Safety and efficacy– Based on extensive clinical trials– Expensive– Time consuming
Artemisinin combined medicines, Kampala, February 20093 |
Background:Background:Other products with same medicinal ingredientOther products with same medicinal ingredient
Background:Background:Other products with same medicinal ingredientOther products with same medicinal ingredient
Subsequent-entry products
Generic products
Multisource products
How do these products gain marketing authorization?
Artemisinin combined medicines, Kampala, February 20094 |
Pharmaceutical equivalencePharmaceutical 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?
Artemisinin combined medicines, Kampala, February 20095 |
Sometimes pharmaceutical equivalence is enough
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
Artemisinin combined medicines, Kampala, February 20096 |
Sometimes it is not enoughSometimes 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
Artemisinin combined medicines, Kampala, February 20097 |
Pharmaceutical EquivalentsPharmaceutical 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
Artemisinin combined medicines, Kampala, February 20098 |
Additional data is requiredAdditional 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
Artemisinin combined medicines, Kampala, February 20099 |
Additional data is requiredAdditional 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
Artemisinin combined medicines, Kampala, February 200910 |
Marketing authorization of multisource products
Marketing authorization of multisource products
Extensive clinical trials to demonstrate safety and efficacy
– Interchangeability?
Demonstration of equivalence to reference (comparator) product
– Interchangeability– Therapeutic equivalence
Artemisinin combined medicines, Kampala, February 200911 |
Marketing authorization through equivalence
Marketing authorization through equivalence
Suitable methods for assessing equivalence:– Comparative pharmacokinetic studies– Comparative pharmacodynamic studies– Comparative clinical trials– Comparative in vitro tests
Artemisinin combined medicines, Kampala, February 200912 |
Comparative Pharmacokinetic StudiesComparative Pharmacokinetic Studies
In vivo measurement of active ingredient
“Some” relationship between concentration and safety/efficacy
Product performance is the key
Comparative bioavailability
Artemisinin combined medicines, Kampala, February 200913 |
Bioavailability 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
Artemisinin combined medicines, Kampala, February 200914 |
Important Pharmacokinetic ParametersImportant 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
Artemisinin combined medicines, Kampala, February 200915 |
Plasma concentration time profilePlasma concentration time profile
Cmax
Tmax
AUC
time
concentration
Artemisinin combined medicines, Kampala, February 200916 |
BioequivalenceBioequivalence
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
Artemisinin combined medicines, Kampala, February 200917 |
BioavailabilityBioavailability
Absolute bioavailability (F):
Relative bioavailability (Frel)
larextravascu
ravenousint
ravenousint
larextravascu
DoseDose
AUCAUC
F
1larextravascu
2larextravascu
2larextravascu
1larextravascurel Dose
DoseAUCAUC
F
Artemisinin combined medicines, Kampala, February 200918 |
Bioavailability: Same DoseBioavailability: Same Dose
Absolute bioavailability (F):
Relative bioavailability (Frel)
larextravascu
ravenousint
ravenousint
larextravascu
DoseDose
AUCAUC
F
1larextravascu
2larextravascu
2larextravascu
1larextravascurel Dose
DoseAUCAUC
F
Artemisinin combined medicines, Kampala, February 200919 |
Therapeutic EquivalenceTherapeutic Equivalence
Therapeutic equivalence:– Pharmaceutically equivalent– Same safety and efficacy profiles after administration of same
dose: bioequivalent
Interchangeability
Artemisinin combined medicines, Kampala, February 200920 |
Comparative Pharmacodynamic StudiesComparative Pharmacodynamic Studies
Not recommended when:– active ingredient is absorbed into the systemic circulation– pharmacokinetic study can be conducted
Local action / no systemic absorption
Artemisinin combined medicines, Kampala, February 200921 |
Comparative Clinical StudiesComparative Clinical Studies
Pharmacokinetic profile not possible
Lack of suitable pharmacodynamic endpoint
Typically insensitive
Artemisinin combined medicines, Kampala, February 200922 |
Comparative in vitro StudiesComparative in vitro Studies
May be suitable in lieu of in vivo studies under certain circumstances
Requirements for waiver to be discussed
Artemisinin combined medicines, Kampala, February 200923 |
When are bioequivalence studies employed?
When are bioequivalence studies employed?
Multisource product vs. Innovative product
Pre-approval changes – Bridging studies
Post-approval changes
Additional strengths of existing product
Artemisinin combined medicines, Kampala, February 200924 |
Bioequivalence Studies:Basic Design Considerations
Bioequivalence Studies:Basic Design Considerations
Minimize variability not attributable to formulations
Minimize bias
REMEMBER: goal is to compare performance of the two products
Artemisinin combined medicines, Kampala, February 200925 |
“Gold Standard” Study Design“Gold Standard” Study Design
Single-dose, two-period, crossover
Healthy volunteers
Subjects receive each formulation once
Adequate washout
Artemisinin combined medicines, Kampala, February 200926 |
Multiple-dose StudiesMultiple-dose Studies
More relevant clinically?
Less sensitive to formulation differences
Artemisinin combined medicines, Kampala, February 200927 |
Multiple-dose Studies may be employed when:
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
Artemisinin combined medicines, Kampala, February 200928 |
Multiple-dose Studies may be employed when:
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
Artemisinin combined medicines, Kampala, February 200929 |
Crossover vs. Parallel DesignsCrossover 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
Artemisinin combined medicines, Kampala, February 200930 |
Parallel Design ConsiderationsParallel Design Considerations
Ensure adequate number of subjects
Adequate sample collection – Completion of Gastrointestinal transit / absorption process– 72 hours normally sufficient
Artemisinin combined medicines, Kampala, February 200931 |
Fasted vs. Fed DesignsFasted vs. Fed Designs
Fasted study design preferred– Minimize variability not attributable to formulation– Better able to detect formulation differences
Artemisinin combined medicines, Kampala, February 200932 |
Fed Study Designs may be employed when:
Fed Study Designs may be employed when:
Significant gastrointestinal (GI) disturbance caused by fasted administration
Product labeling restricts administration to fed state
Artemisinin combined medicines, Kampala, February 200933 |
Fed Study Design ConsiderationsFed 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
Artemisinin combined medicines, Kampala, February 200934 |
Fed Study Design Considerations cont.Fed Study Design Considerations cont.
Fed conditions designed to promote maximal perturbation
– High fat– High Calorie– Warm
Artemisinin combined medicines, Kampala, February 200935 |
Replicate vs. non-replicate designsReplicate vs. non-replicate designs
Standard approach– Non-replicated– Single administration of each product– Average bioequivalence
Artemisinin combined medicines, Kampala, February 200936 |
Replicate DesignsReplicate Designs
Typically four-period design– Each product administered twice
Intra-subject variability
Subject X formulation interaction
Different approaches possible– Average bioequivalence– Individual bioequivalence
Artemisinin combined medicines, Kampala, February 200937 |
Replicate DesignsReplicate Designs
Advantages– More information available– Different approaches to assessment possible
Disadvantages– Bigger commitment for volunteers– More administrations to healthy volunteers– More expensive to conduct