interchangeability and study design drs. jan welink training workshop: training of be assessors,...
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Interchangeability
and study designDrs. Jan Welink
Training workshop: Training of BE assessors, Kiev, October 2009
Training workshop: Training of BE assessors, Kiev, October 20092 |
Guidance documentsGuidance 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)
Training workshop: Training of BE assessors, Kiev, October 20093 |
Guidance documentsGuidance documents
Training workshop: Training of BE assessors, Kiev, October 20094 |
Guidance documentsGuidance 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 20095 |
BioequivalenceBioequivalence
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.
Training workshop: Training of BE assessors, Kiev, October 20096 |
BioequivalenceBioequivalence
Reference Test
Pharmaceutical EquivalentProducts
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence= Therapeutic Equivalence
Training workshop: Training of BE assessors, Kiev, October 20097 |
BioequivalenceBioequivalence
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.
Training workshop: Training of BE assessors, Kiev, October 20098 |
BioequivalenceBioequivalence
Pharmaceutical equivalent does not necessarily imply therapeutic equivalence:
-difference excipients
-difference manufacturing process
-other variables
drug performance?
Training workshop: Training of BE assessors, Kiev, October 20099 |
BioequivalenceBioequivalence
Therapeutic equivalent does not necessarily imply bioequivalence:
-sensitivity
-different formulations (IR/CR)
-different active substance
equivalence?
Training workshop: Training of BE assessors, Kiev, October 200910 |
BioequivalenceBioequivalence
acceptance criteria: comparative rate and extent of absorption
pharmaceutical equivalence
method: in principle comparative pharmacokinetics (AUC, Cmax)
Training workshop: Training of BE assessors, Kiev, October 200911 |
BioequivalenceBioequivalence
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.
Training workshop: Training of BE assessors, Kiev, October 200912 |
BioequivalenceBioequivalence
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
Training workshop: Training of BE assessors, Kiev, October 200913 |
BioequivalenceBioequivalence
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
Training workshop: Training of BE assessors, Kiev, October 200914 |
StudiesStudies
PD studiesclinicalstudies
in vitromethods
Different approach for
establishing equivalence
ONLY IN EXCEPTIONAL CASE!!
Training workshop: Training of BE assessors, Kiev, October 200915 |
EXPERIMENTAL DESIGNEXPERIMENTAL DESIGN
Training workshop: Training of BE assessors, Kiev, October 200916 |
BioequivalenceBioequivalence
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
Training workshop: Training of BE assessors, Kiev, October 200917 |
Plasma concentration time profilePlasma concentration time profile
Cmax
Tmax
AUC
time
Training workshop: Training of BE assessors, Kiev, October 200918 |
Bioequivalence – single doseBioequivalence – single dose
minimize variability not attributable to formulations
Basic design considerations:
goal: compare performance2 formulations
minimize bias
Training workshop: Training of BE assessors, Kiev, October 200919 |
Bioequivalence – single doseBioequivalence – single dose
single dose, two-period, crossover
Golden standard study design:
Reference (comparator)/Test (generic)
healthy volunteers
Training workshop: Training of BE assessors, Kiev, October 200920 |
Bioequivalence – single dose 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
Training workshop: Training of BE assessors, Kiev, October 200921 |
Bioequivalence – variabilityBioequivalence – 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
Training workshop: Training of BE assessors, Kiev, October 200922 |
Bioequivalence – fast/fed 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
Training workshop: Training of BE assessors, Kiev, October 200923 |
SamplingSampling
Number of samples.
Blood sampling:
Time of sampling (extrapolated AUC max. 20%).
Washout phase long enough.
Sampling times (Cmax!). knowledge drug
substance
Training workshop: Training of BE assessors, Kiev, October 200924 |
Bioequivalence – multiple doseBioequivalence – multiple dose
More relevant clinically?
Multiple dose:
Less sensitive to formulation differences!
Training workshop: Training of BE assessors, Kiev, October 200925 |
Bioequivalence – multiple doseBioequivalence – 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
Training workshop: Training of BE assessors, Kiev, October 200926 |
Bioequivalence – parallel design Bioequivalence – parallel design
Crossover design preferred: - intra-subject comparison - lower variability - fewer subjects required
Crossover: Parallel:
RR T
Training workshop: Training of BE assessors, Kiev, October 200927 |
Bioequivalence – parallel design Bioequivalence – parallel design
Parallel design may be useful:
Drug with very long elimination half-life– Crossover design not practical
Number of subjects
Parallel design considerations:
Adequate sample collection– Complete absorption– 72 hours sufficient in general
Training workshop: Training of BE assessors, Kiev, October 200928 |
Bioequivalence – replicate vs. non-replicateBioequivalence – replicate vs. non-replicate
non-replicate
Standard approach BE study:
average bioequivalence
single administrationR and T
Training workshop: Training of BE assessors, Kiev, October 200929 |
Bioequivalence – replicate vs. non-replicateBioequivalence – 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
Training workshop: Training of BE assessors, Kiev, October 200930 |
Bioequivalence – replicate designBioequivalence – 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
Training workshop: Training of BE assessors, Kiev, October 200931 |
Bioequivalence – replicate designBioequivalence – replicate design
Disadvantages: Bigger commitment volunteers
More administrations per subject
More expensive
Training workshop: Training of BE assessors, Kiev, October 200932 |
BioequivalenceBioequivalence
Single dose studies.
Most submitted bioequivalence studies are:
Crossover design.
Non replicate.
Fasted conditions. depends on drug
substance!