Transcript Evaluation of bioavailability/bioequivalence data

EVALUTION OF DOSSIERS IN WHOPREQUALIFICATION PROJECT
MULTISOURCE HIV/AIDS-DRUGS
Evaluation of
bioavailability/bioequivalence data
Based, with some changes on a presentation by Anna-Karin
Hamberg
Medical products agency, Sweden
Presented by
Hans Kemmler
Consultant to WHO
(Clinical Reviewer, Swissmedic, Switzerland)
Shanghai, 2005-02-28
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Why do we need
Bioequivalence studies?

No clinical studies have been performed in
patients with the Generic Product to support
its Efficacy and Safety.

With data to support similar in vivo
performance (= Bioequivalence)
Efficacy and Safety
data can be extrapolated from the Innovator
Product to the Generic Product.
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Overview

Definition of some important
Bioequivalence [BE] terms

Key issues in the WHO Manual Annex 3
“Guidelines on Requirements to
Establish Interchangeability”

Major Deficiencies in BE-Studies
identified within the WHO Procurement,
Quality and Sourcing Project: HIV/Aids
Drugs
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Overview

A Note on Choice of Reference
Products

Present new WHO Template for
Assessment of Bioequivalence data
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Bioavailability

“ .. the extent and the rate at 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
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Plasma concentration time
profile
concentration
Cmax
AUC
time
Tmax
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Important Pharmacokinetic
Parameters

AUC: area under the concentration-time
curve  measure of the extent of
bioavailability
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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
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Bioavailability

Absolute bioavailability (F):
AUCextravascular Doseint ravenous
F

AUCint ravenous Doseextravascular

Relative bioavailability (Frel)
AUC extravascular1 Doseextravascular 2
Frel 

AUC extravascular 2 Doseextravascular1
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Bioavailability: Same Dose

Absolute bioavailability (F):
AUCextravascular Doseint ravenous
F

AUCint ravenous Doseextravascular

Relative bioavailability (Frel)
AUC extravascular1 Doseextravascular 2
Frel 

AUC extravascular 2 Doseextravascular1
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Pharmaceutical Equivalents

contain the same amount of the same active
substance in the same dosage form

meet the same or comparable standards

intended to be administered by the same
route
Pharmaceutical equivalence by itself does not
necessarily imply therapeutic equivalence
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Pharmaceutical Equivalents
Reference
Test
Possible Differences

Drug particle size

Excipients

Manufacturing
Equipment or
Process

Site of manufacture
Could lead to differences in product performance in vivo
 Possible Bioinequivalence
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Bioequivalence
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
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Therapeutic equivalence
Two products are therapeutically equivalent if

pharmaceutically equivalent

their effects, with respect to both efficacy and
safety, will be essentially the same as derived
from appropriate studies
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bioequivalence studies
pharmacodynamic studies
clinical studies
in vitro studies
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Interchangeable
pharmaceutical products
If a product is demonstrated to be
therapeutically equivalent to a reference
product, then the products are considered
interchangeable.
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Bioanalytical Method Validation
Quantitative determinations of drugs
in biological samples, such as blood
or plasma, play a significant role in
evaluation and interpretation of
bioequivalence data.
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Bioanalytical Method Validation
Essential to use a well-characterised
and fully validated analytical method
to yield reliable results.
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Bioanalytical Method Validation
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Method Validation should include
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Accuracy
Precision
Sensitivity
Specificity
Recovery
Stability
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Bioanalytical Method Validation
Accuracy
Closeness of determined value to the
true value.
The acceptance criteria is mean value
 15% deviation from true value.
At LOQ, 20% deviation is acceptable.
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Bioanalytical Method Validation
Precision
The closeness of replicate
determinations of a sample by an
assay.
The acceptance criteria is  15% CV.
At LOQ, 20% deviation is acceptable.
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Bioanalytical Method Validation
Sensitivity
The limit of quantitation (LOQ)
is the lowest concentration
which can be measured with
acceptable accuracy and
precision.
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Bioanalytical Method Validation
Specificity (selectivity)
Ability of the method to measure
only what it is intended to measure
in the presence of other components
in the sample. Blank samples of the
biological matrix should be tested
for interfering peaks.
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Bioanalytical Method Validation
Recovery
The extraction efficiency of an analytical
process, reported as a percentage of the
known amount of an analyte carried
through the sample extraction and
processing steps of the method. Recovery
does not have to be 100%, but the extent of
recovery of an analyte and of the internal
standard should be consistent.
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Bioanalytical Method Validation
Stability
Stability of the drug in the biological
matrix during
the collection process,
the sample storage period and
sample analysis,
should be established.
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Bioanalytical Method Validation
Useful references:
FDA Guidance for Industry

Bioanalytical Method Validation (May 2001)
(http://www.fda.gov/cder/guidance/4252fnl.pdf)
Published Workshop Reports

Shah, V.P. et al, Pharmaceutical Research:
1992; 9:588-592
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Shah, V.P. et al, Pharmaceutical Research:
2000; 17: 1551-1557
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