Transcript Training workshop: Training of BE assessors, Kiev, October 2009 9

Interchangeability
and study design
Drs. Jan Welink
Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Guidance documents
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Training workshop: Training of BE assessors, Kiev, October 2009
Guidance documents
Europe: http://www.emea.europa.eu
- Note for guidance on the investigation of
bioavailability and bioequivalence
- Note for guidance on modified release oral and
transdermal dosage form: section II.
- Question and answer documents
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence
Pharmaceutical Equivalent
Products
Reference
Test
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence
Pharmaceutical equivalent does not necessarily imply
therapeutic equivalence:
- difference excipients
- difference manufacturing process
- other variables
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Training workshop: Training of BE assessors, Kiev, October 2009
drug
performance?
Bioequivalence
Therapeutic equivalent does not necessarily imply
bioequivalence:
- sensitivity
- different formulations (IR/CR)
- different active substance
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Training workshop: Training of BE assessors, Kiev, October 2009
equivalence?
Bioequivalence
pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
acceptance criteria: comparative rate and extent of absorption
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence
Bioequivalence studies necessary for :
 Oral Immediate Release products
 Oral modified release products
 Fixed-combination products with systemic absorption
where at least one of the API requires an in vivo study
 Transdermal products with systemic action
 Inhalation products
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence
Cases when pharmaceutical equivalence is enough:
 Aqueous solutions
–
–
–
–
Intravenous solutions
Intramuscular, subcutaneous solutions
Oral solutions
Otic or ophthalmic solutions
 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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Training workshop: Training of BE assessors, Kiev, October 2009
EXPERIMENTAL DESIGN
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
tmax:
time at which Cmax is observed
 measure of the rate of absorption
Plasma concentration time profile
Cmax
AUC
Tmax
time
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – single dose
Basic design considerations:
minimize variability not
attributable to formulations
minimize bias
goal: compare performance
2 formulations
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – single dose
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – variability
Number of subjects: variability!!
Controllable variation:
- carry-over effects (use of other medicines etc.)
- time-factors (sampling time etc.)
- physiological factors (gastric emptying etc.)
Inescapable variation:
- subject difference (inter- and intra variability)
- formulations differences
- random error
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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – fast/fed
Administration of Test/Reference:
 Normally fasted state
– overnight fast
– drug administration ca. 240 ml water
SPC !!!!!
– with or without food
– reason:
• pharmacokinetic
• adverse events
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Training workshop: Training of BE assessors, Kiev, October 2009
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
Bioequivalence – multiple dose
Multiple dose:
More relevant clinically?
Less sensitive to
formulation differences!
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – parallel design
Crossover:
Crossover design preferred:
- intra-subject comparison
- lower variability
- fewer subjects required
Parallel:
R
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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
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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Training workshop: Training of BE assessors, Kiev, October 2009
Bioequivalence – replicate design
Bigger commitment
volunteers
Disadvantages:
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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