Transcript Interchangeability and study design

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 EFFECTIVE
drugs are marketed in the country
and are available to the people”
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Bioavailability
Bioavailability
Bioavailability means the rate and extent to which
the active substance or therapeutic moiety is
absorbed from a pharmaceutical form and
becomes available at the site of action.
plasma
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Bioavailability
relative bioavailability
absolute
bioequivalence
different
formulations
food-effect
interactions
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Bioequivalence
Bioequivalence:
Two medicinal products are bioequivalents if
they are pharmaceutical equivalents or alternatives
and if their bioavailabilities (rate and extent) after
administration in the same molar dose are similar
to such degree that their effects, with respect
to 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
Pharmaceutical Equivalent
Products
Reference
Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution specifications)
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Bioequivalence
Therapeutic equivalence of a multiscource product can be
assured when the multiscource product is both
pharmaceutically equivalent/alternative and bioequivalent.
Concept of interchangeability includes the equivalence of the
dosage form as well as for the indications and instructions for
use.
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Bioequivalence
Pharmaceutical equivalent does not necessarily imply
therapeutic equivalence:
- difference excipients
- difference manufacturing process
- other variables
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drug
performance?
Bioequivalence
Therapeutic equivalent does not necessarily imply
bioequivalence:
- sensitivity
- different formulations (IR/CR)
- different active substance
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equivalence?
Bioequivalence
pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
acceptance criteria: comparative rate and extent of absorption
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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
BRIDGING STUDIES
variations
scale up
innovator
clinical batch
comm.batch
ref.
test
changed batch
ref.
test
acceptance
variations
approval
innovator
approval
generic
generic
test
ref.
acceptance
variations
test
bioequiv.batch
ref.
comm. batch
scale up
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Assessment of Interchangeable Multisource Medicines, Kenya, August 2009
changed batch
variations
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 products
 Fixed-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
Different approach for
establishing equivalence
PD studies
clinical
studies
in vitro
methods
ONLY IN EXCEPTIONAL CASE !!
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EXPERIMENTAL DESIGN
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Bioequivalence
Important PK parameters
Cmax:
the observed maximum concentration of a drug
 measure of the rate of absorption
AUC:
area under the concentration-time curve
 measure of the extent of absorption
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tmax:
time at which Cmax is observed
 measure of the rate of absorption
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Plasma concentration time profile
Cmax
AUC
Tmax
time
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Bioequivalence – single dose
Basic design considerations:
minimize variability not
attributable to formulations
minimize bias
goal: compare performance
2 formulations
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Bioequivalence – single dose
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
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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
Food effect:
delay in absorption:
Plasma Conc. mg/L
Plasma Conc. mg/L
no change in absorption:
Time (h)
Time (h)
decrease in absorption:
Plasma Conc. mg/L
Plasma Conc. mg/L
increase in absorption:
Time (h)
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Time (h)
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
Blood sampling:
Number of samples.
Sampling times (Cmax!).
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.
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knowledge
drug
substance
Extrapolated AUC < 20%
time
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Extrapolated AUC < 20%
time
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Bioequivalence – multiple dose
Multiple dose:
More relevant clinically?
Less sensitive to
formulation differences!
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Bioequivalence – multiple dose
Multiple dose studies
in 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:
Crossover design preferred:
- intra-subject comparison
- lower variability
- fewer subjects required
Parallel:
R
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T
Bioequivalence – parallel design
Parallel design may be useful:
 Drug with very long elimination half-life
– Crossover design not practical
Parallel design considerations:
 Number of subjects
 Adequate sample collection
– Complete absorption
– 72 hours sufficient in general
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Bioequivalence – replicate vs. non-replicate
Standard approach BE study:
non-replicate
single administration
R and T
average bioequivalence
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Bioequivalence – replicate vs. non-replicate
Replicate
(RRTT or RRT or TTR):
T and/or R administered twice
Intra-subject variability
Subject X
formulation interaction
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
Most submitted bioequivalence studies are:
Single dose studies.
Fasted conditions.
Crossover design.
Non replicate.
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depends on
drug
substance!
End
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