3 1a interchangeability study design
DESCRIPTION
InterchangebailityTRANSCRIPT
Interchangeability and study design
Drs. Jan Welink
Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
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Guidance documents
http://apps.who.int/prequal/
* Note to applicants on the choice of comparator products for the prequalification project
* Guideline on generics
- Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability)
- Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)
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Guidance documents
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Regulatory Authority Mission
“Assure that SAFE and EFFECTIVEdrugs are marketed in the country
and are available to the people”
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Bioavailability
Bioavailability
Bioavailability means the rate and extent to whichthe active substance or therapeutic moiety is
absorbed from a pharmaceutical form andbecomes available at the site of action.
plasma
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Bioavailability
relative bioavailability
absolute bioequivalence
food-effect different formulations
interactions
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Bioequivalence
Bioequivalence:Two medicinal products are bioequivalents if
they are pharmaceutical equivalents or alternativesand if their bioavailabilities (rate and extent) afteradministration in the same molar dose are similar
to such degree that their effects, with respectto both efficacy and safety, will be
essential the same.
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Bioequivalence
Bioequivalence
Bioavailability
Pharmaceutical equivalent
Pharmaceutical
alternatives
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Bioequivalence
Reference Test
Pharmaceutical EquivalentProducts
Possible DifferencesDrug particle size, ..
ExcipientsManufacturing process
EquipmentSite of manufacture
Batch size ….
Documented Bioequivalence= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)
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Bioequivalence
Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use.
Therapeutic equivalence of a multiscource product can be assured when the multiscource product is both pharmaceutically equivalent/alternative and bioequivalent.
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Bioequivalence
Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:
-difference excipients
-difference manufacturing process
-other variables
drug performance?
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Bioequivalence
Therapeutic equivalent does not necessarily imply bioequivalence:
-sensitivity
-different formulations (IR/CR)
-different active substance
equivalence?
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Bioequivalence
acceptance criteria: comparative rate and extent of absorption
pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
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Bioequivalence
BA and BE are generally required for approvals of innovator and generic (multiscource) products.
BE based on blood level determination of Cmax and AUC has become the most commonly used and successful biomarker for safety and efficacy of the drug product.
BE products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring.
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Bioequivalence
ref.
BRIDGING STUDIES
clinical batch comm.batch changed batch
scale up variations
ref. testtest
approval innovator
approval generic
acceptance variations
innovatorgeneric bioequiv.batch comm. batch changed batch
testtest ref.test
scale up variations
acceptance variations
ref.
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Bioequivalence
Studies necessary for :Oral Immediate Release products
– In general – Critical use medicines/Narrow therapeutic range drug products– Documented BA or BE problems related to API– Scientific evidence suggesting polymorphs of API, excipients,
and/or process affecting BA– Non-oral, non-parenteral products designed to act systemically
Oral Modified Release productsFixed-combination products with systemic absorption
where at least one of the API requires an in vivo study
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Bioequivalence
Cases when pharmaceutical equivalence is enough:Aqueous solutions
– Intravenous solutions– Intramuscular, subcutaneous solutions– Oral solutions– Otic or ophthalmic solutions– Topical products prepared as solutions– Aqueous solution for nebulizer inhalation or nasal sprays
Powders for reconstitution as solution
Gases
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Studies
PD studies clinicalstudies
in vitromethods
Different approach for establishing equivalence
ONLY IN EXCEPTIONAL CASE!!
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EXPERIMENTAL DESIGN
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Bioequivalence
Important PK parameters
AUC :
area under the concentration-time curve measure of the extent of absorption
Cmax: the observed maximum concentration of a drug
measure of the rate of absorption
tmax: time at which Cmax is observed
measure of the rate of absorption
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Plasma concentration time profile
Cmax
Tmax
AUC
time
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Bioequivalence – single dose
minimize variability not attributable to formulations
Basic design considerations:
goal: compare performance2 formulations
minimize bias
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Bioequivalence – single dose
single dose, two-period, crossover
Golden standard study design:
Reference (comparator)/Test (generic)
healthy volunteers
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Bioequivalence – single dose
Single dose, two-period crossover:Subjects receive in Period I and II Test/Reference
Subjects:
Healthy volunteers– randomisation– Inclusion/exclusion criteria– Number of subjects
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Bioequivalence – single dose
Number of subjects!!
- Sample size calculation: e.g. Eur J Drug Metab Pharmacokinet 30 (2005) 41
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Bioequivalence – fast/fed
Administration of Test/Reference:
Normally fasted state– overnight fast– drug administration ca. 240 ml water
If the SPC of the reference product contains specific recommendations in relation with food
intake related to food interaction effects the study should be designed accordingly
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Bioequivalence – fast/fed
Time (h)
Plas
ma
Con
c. m
g/L
Time (h)
Plas
ma
Con
c. m
g/L
Time (h)
Plas
ma
Con
c. m
g/L
Time (h)
Plas
ma
Con
c. m
g/L
no change in absorption: delay in absorption:
increase in absorption: decrease in absorption:
Food effect:
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Bioequivalence – fast/fed
If the recommendation of food intake is based on pharmacokinetic properties such as higher bioavailability, then a bioequivalence study under fed conditions is generally required
If the recommendation of food intake is intended to decrease adverse events or to improve tolerability, a bioequivalence study under fasting conditions is considered acceptable although it would be advisable to perform the study under fed conditions.
If the SPC leaves a choice between fasting and fed conditions, then bioequivalence should preferably be tested under fasting conditions as this situation will be more sensitive to differences in pharmacokinetics.
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Bioequivalence – fast/fed
In general:
follow SPC.
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Sampling
Number of samples.
Blood sampling:
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.
Sampling times (Cmax!). knowledge drug
substance
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Extrapolated AUC < 20%
time
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Extrapolated AUC < 20%
time
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Bioequivalence – multiple dose
More relevant clinically?
Multiple dose:
Less sensitive to formulation differences!
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Bioequivalence – multiple dose
Multiple dose studiesin case of….. Drug too potent/toxic for healthy
volunteers –patients/ no interruption therapy
Extended/modified release formulations – accumulation / unexpected behavior
Non-linear PK at steady state
Analytical assay sensitivity
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Bioequivalence – parallel design
Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required
Crossover: Parallel:
RR T
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Bioequivalence – parallel design
Parallel design may be useful:Drug with very long elimination half-life
– Crossover design not practical
Number of subjectsParallel design considerations:
Adequate sample collection– Complete absorption– 72 hours sufficient in general
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Bioequivalence – replicate vs. non-replicate
non-replicate
Standard approach BE study:
average bioequivalence
single administrationR and T
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Bioequivalence – replicate vs. non-replicate
T and/or R administered twice
Replicate
) RRTT or RRT or TTR:(
Subject X formulation interaction
Intra-subject variability
average bioequivalence/ individual bioequivalence
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Bioequivalence – replicate design
Scientific advantages: Comparison within-subject variances T and R
Indicate whether T exhibits lower or higher within-subject variability
More information (performance/S*F interaction)
Reduce number of subjects
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Bioequivalence – replicate design
Disadvantages: Bigger commitment volunteers
More administrations per subject
More expensive
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Bioequivalence
Single dose studies.
Most submitted bioequivalence studies are:
Crossover design.
Non replicate.
Fasted conditions. depends on drug
substance!
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End