Bioequivalence Requirements in Japan : …...Bioequivalence Requirements in Japan : Background...
Transcript of Bioequivalence Requirements in Japan : …...Bioequivalence Requirements in Japan : Background...
Bioequivalence Requirements in Japan : Background Concepts
Hiroyasu Ogata, Ph.D.
Professor Emeritus, Meiji Pharmaceutical University
Director, Japan Society of Generic Medicines
The 15th Annual IGPA Conference 2012, Kyoto, 12.5-7 (2012)
Session 6 Bioequivalence
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History of bioequivalence guideline in Japan
Brief overview of bioequivalence studies for products
administered orally in Japan
Participating subjects
Selection of subjects
Number of subjects
Dissolution tests(bio-waiver)
Conclusion
Outlines
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History of bioequivalence guideline in Japan
Brief overview of bioequivalence studies for products
administered orally in Japan
Participating subjects
Selection of subjects
Number of subjects
Dissolution tests(bio-waiver)
Conclusion
Outlines
3
History of bioequivalence guideline in Japan
Year Subjects Bioequivalence
range Statistics Dissolution
test(bio-waiver)
1974 dog, rabbit ー hypothesis test
1980 humans (dog)
80-120%: normal distribution
hypothesis test + power analysis(Δ = 0.2,1-β >0.8)
1997 humans(patients)
80-125%:log normal distribution
90% confidence interval
2001 humans(patients)
80-125%:log normal distribution
90% confidence interval
similarity, equivalence
2012 humans(patients)
80-125%:log normal distribution
90% confidence interval
similarity, equivalence
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Guideline for Bioequivalence Studies of Generic Products
(2012/02/29)
Guideline for Bioequivalence Studies of Generic Products for
Different Strengths of Oral Solid Dosage Forms (2012/02/29)
Guideline for Bioequivalence Studies for Formulation Changes
of Oral Solid Dosage Forms (2012/02/29)
Guideline for Bioequivalence Studies for Different Oral Solid
Dosage Forms (2012/02/29)
Bioequivalence Studies of Generic Products for Ethical
Combination Drug Products (2012/02/29)
Bioequivalence Studies for Different Strengths of Ethical
Combination Drug Products and Formulation Changes of
Ethical Combination Drug Products (2012/02/29)
Current Guidelines for Bioequivalence Studies of
Generic Products
Oral solid dosage forms
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http://www.nihs.go.jp/drug/DrugDiv-E.html
Guideline for Bioequivalence Studies of Generic Topical
Dermatological Drug Products (2006/11/24)
Guideline for Bioequivalence Studies for Different
Topical Dermatological Dosage Forms (2006/11/24)
Guideline for Bioequivalence Studies for Formulation
Changes of Topical Dermatological Drug Products
(2010/11/01)
Current Guidelines for Bioequivalence Studies of
Generic Products
Topical dermatological drug products
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History of bioequivalence guideline in Japan
Brief overview of bioequivalence studies for products
administered orally in Japan
Participating subjects
Selection of subjects
Number of subjects
Dissolution tests(bio-waiver)
Conclusion
Outlines
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8 8
◆healthy adult volunteers
◆2x2 cross-over design
◆administered under fasting conditions
◆unchanged active ingredient or a major active metabolite
◆Cmax, AUC
◆acceptance range for each parameter is 0.80 to 1.25
when expressed as the ratio of the parameter’s means
for the test product and reference one
◆90% confidence interval of difference in the average
values of logarithmic parameters to be assessed
between test and reference products is within the
acceptable range of log(0.80) - log(1.25)
Brief overview of bioequivalence studies for
products administered orally in Japan
History of bioequivalence guideline in Japan
Brief overview of bioequivalence studies for products
administered orally in Japan
Participating subjects
Selection of subjects
Number of subjects
Dissolution tests(bio-waiver)
Conclusion
Outlines
9
H.Ogata, N.Aoyagi, N.Kaniwa, M.Koibuchi, T.Shibazaki, A.Ejima, S.Tsuji and
Y.Kawazu, Int.J.Clin.Pharmacol.Ther.Toxicol., 20, 159-165 (1982).
Dissolution rates of diazepam from commercial products 10
pKa: 3.0
H.Ogata, N.Aoyagi, N.Kaniwa, M.Koibuchi, T.Shibazaki, A.Ejima, S.Tsuji and
Y.Kawazu, Int.J.Clin.Pharmacol.Ther.Toxicol., 20, 159-165 (1982).
Average diazepam serum concentration after oral administration
●high gastric acidity; ○low gastric acidity 11
H.Ogata, N.Aoyagi, N.Kaniwa, T.Shibazaki, A.Ejima, Y.Takagishi, T.Ogura, K.Tomita, S.Inoue and M.Zaizen, Int.J.Pharm., 23, 277-288 (1985).
Effect of pH on dissolution rates of metronidazole from sugar coated tablets
dissolution test method: OB:disintegration apparatus、PD:paddle、RB:rotating basket、RF: rotating flask
Serum concentration of metronidazole after oral administration of sugar coated tablets
● high gastric acidity
○ low gastric acidity
H.Ogata, N.Aoyagi, N.Kaniwa, T.Shibazaki, A.Ejima, Y.Takagishi, T.Ogura, K.Tomita, S.Inoue and M.Zaizen, Int.J.Pharm., 23, 277-288 (1985).
For evaluation of
pharmaceutical characteristics
dissolution rates of active ingredients
from solid products should be monitored
in place of “solubility” of active
ingredients.
The high rate of achlorhydric
subjects in the Japanese population
is an important factor for assessing
bioequivalence, as this parameter
indicate an ethnic difference that must
be considered in bioequivalence studies.
Participating subjects
Selection of subjects(I)
In principle, healthy adult volunteers should be used.
Drug use is limited to a specific population:
When the test and reference products show a significant
difference in dissolution under one or more of conditions of the
dissolution test, the bioequivalent studies should be performed
using subjects from the specified population.
However, as possible discrepancies between the
evaluations of healthy subjects and patients cannot be ruled
out, patients should participate in the studies.
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Drug use is not limited to a specific population:
When the test and reference products exhibit a significant
difference in dissolution at around pH 6.8 in the dissolution
test or between pH 3.0 and 6.8 for products containing
basic drugs, subjects with low gastric acidity (achlorhydric
subjects) should be used.
Participating subjects
Selection of subjects(II)
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Participating subjects
Number of subjects
A sufficient number of subjects is needed to assess
bioequivalence.
Add-on subject study
If bioequivalence cannot be demonstrated because of an
insufficient number of subjects, an add-on subject study can
be performed using no less than half the number of
subjects in the initial study.
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Standard Error: SE = s/√n s:sample standard deviation
n:number of subjects participated
80%< mean value ± tα・SE<125%
mean value of
test product 80% of
reference
product
125% of
reference
product
Assessment of bioequivalence using 90%
confidence interval
Subjects number:a sufficient number of subjects needed
to assess bioequivalence
:
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History of bioequivalence guideline in Japan
Brief overview of bioequivalence studies for products
administered orally in Japan
Participating subjects
Selection of subjects
Number of subjects
Dissolution tests(bio-waiver)
Conclusion
Outlines
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Assay and other factors
Pharmaceutical factor
Pharmacokinetic factor
Factors inducing the variability of parameters
when evaluating bioequivalence
Aim of bioequivalence study:
Evaluation of differences
between reference and test
products
Pharmacokinetic factor and
assay and other ones
should be cancelled in the
evaluation.
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Assay and other factors
Pharmaceutical factor
Pharmacokinetic factor
Factors inducing the variability of parameters
when evaluating bioequivalence
Assay and other factors:
Studies should be
performed under the same
conditions.
Pharmacokinetic factor:
By using cross-over
design,
inter-subject variability,
but not intra-subject
variability can be cancel.
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1) The total sample size of the initial bioequivalence study
should be no less than 20 (n=10/group) or the pooled
sample size of the initial and add-on subject studies should
be no less than 30
In the case that the confidence interval is not
within the acceptable range of log(0.80) - log(1.25):
pharmacokinetic intra-subject variability may be
notable: i.e., a highly variable drug
If additional data indicates a close similarity in the
dissolution profiles between the two products:
pharmaceutical factors can be neglected, 25
2) If the differences in the average values of the logarithmic
parameters being assessed for the two products are
between log(0.90) - log(1.11)
1) the total sample size of the initial bioequivalence study
should ne no less than 20 (n=10/group) or the pooled
sample size of the initial and add-on subject studies should
be no less than 30
2) the differences in the average values of the logarithmic
parameters being assessed for two products are between
log(0.90) - log(1.11)
In the case that the confidence interval is not
in acceptable range of log(0.80) - log(1.25)
pharmacokinetic intra-subject variability may be
notable: i.e., highly variable drug
i.w. additional data indicating the close similarity of
dissolution profiles between two products,
pharmaceutical factor can be neglected the test products is accepted as being
bioequivalent. 26
Dissolution tests in bioequivalence studies
for judging the situation of bio-waiver
Aim:
Pharmaceutical properties are evaluated as being
closely similar between the reference and the test
products from the view point of their dissolution rates.
High power for detecting the differences of pharmaceutical
properties between products:
row agitation
four different test solutions
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evaluations using the whole dissolution curve, and not just
one point: two points or f2 function
Dissolution tests in bioequivalence studies
Aim:
Pharmaceutical properties are evaluated as being similar
or equivalent between the reference and test products
from the view point of their dissolution rates.
Agitation (rpm)
pH
Acidic drugs Neutral or basic drugs, and
coated products
Poorly soluble drugs
Surfactants
50 (1)1.2 (1)1.2 (1)1.2 non
50 (2)5.5-6.5 (2)3.0-5.0 (2)4.0 non
50 (3)6.8-7.5 (3)6.8 (3)6.8 non
50 (4)water (4)water (4)water non
50 ー ー (5)1.2 polysorbate 80
50 ー ー (6)4.0 polysorbate 80
50 ー ー (7)6.8 polysorbate 80
100 (1),(2) or (3) (1),(2) or (3) (5),(6) or (7) polysorbate 80
Apparatus: JP paddle apparatus Volume of test solution: basically 900 mL
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Similarity
Acceptance criteria for similarity and
equivalence of dissolution profiles
Average dissolution of test
product is within that of the
reference product ± 15%
Equivalence
Average dissolution of test
product is within that of the
reference product ± 10%
Bio-waiver in
add-on subject
study with a
limited condition
Bio-waiver in
BE study for
formulation
change with a
limited range 29
f2>42
f2>50
Acceptance criteria for similarity of
dissolution profiles
15 30 min 15
85 %
85 %
0 15 30 min
10 min
±15%
60 %
40 %
0.5 6 hr
Levels of Changes in Uncoated Product
B C D
Disintegrating agents
Starch 3.0 6.0 9.0
Others 1.0 2.0 3.0
Binders 0.50 1.0 1.5
Lubricants・Polishers
Stearate salts 0.25 0.50 0.75
Others 1.0 2.0 3.0
Fluidizing agents
Talc 1.0 2.0 3.0
Others 0.10 0.20 0.30
Diluting agents 5.0 10 15
Others(Preservatives, Sweetners, Stabilizers, etc) 1.0 2.0 3.0
5.0 10 15Sum of absolute values of difference of content(%) of change components
Function of Excipient and Component
Difference of Content(%W/W)Compared to Standard
Bio-waiver in BE study for formulation change with a limited
range
A: changes of components described as “trace use”
Levels of formulation changes and required tests
LevelImmediate/Extended
ReleaseTherapeutic
rangePoorly
soluble/SolubleRapid/Non-
rapid disolution
A Immediate Release Non-narrow
BImmediate Release,
Enteric coated,Extended Release
Soluble
Poorly soluble
Rapid
Non-rapid
Poorly soluble
Non-narrow
Narrow
Rapid
Non-rapid
Poorly soluble
Narrow
Enteric coated,Extended Release
EImmediate Release,
Enteric coated,Extended Release
When the dissolution profiles are equivalent, they are judged as bioequivalent.
Non-narrow Soluble
Immediate Release
C
D
Narrow
Immediate Release,Enteric caoted
Extended Release
Non-narrow
Soluble
Levels of formulation changes and required tests
LevelImmediate/Extended
ReleaseTherapeutic
rangePoorly
soluble/SolubleRapid/Non-
rapid disolution
A Immediate Release Non-narrow
BImmediate Release,
Enteric coated,Extended Release
Soluble
Poorly soluble
Rapid
Non-rapid
Poorly soluble
Non-narrow
Narrow
Rapid
Non-rapid
Poorly soluble
Narrow
Enteric coated,Extended Release
EImmediate Release,
Enteric coated,Extended Release
When the dissolution profiles are equivalent, they are judged as bioequivalent.
Non-narrow Soluble
Immediate Release
C
D
Narrow
Immediate Release,Enteric caoted
Extended Release
Non-narrow
Soluble
Poorly soluble drug product: the average dissolution rate of the reference
product does not reach 85% within the designated test time in any of
the dissolution media without surfactant.
Levels of formulation changes and required tests
LevelImmediate/Extended
ReleaseTherapeutic
rangePoorly
soluble/SolubleRapid/Non-
rapid disolution
A Immediate Release Non-narrow
BImmediate Release,
Enteric coated,Extended Release
Soluble
Poorly soluble
Rapid
Non-rapid
Poorly soluble
Non-narrow
Narrow
Rapid
Non-rapid
Poorly soluble
Narrow
Enteric coated,Extended Release
EImmediate Release,
Enteric coated,Extended Release
When the dissolution profiles are equivalent, they are judged as bioequivalent.
Non-narrow Soluble
Immediate Release
C
D
Narrow
Immediate Release,Enteric caoted
Extended Release
Non-narrow
Soluble
Rapid dissolution product:
at 30 min, not less than 85% dissolution of the
reference product under all the testing conditions
Levels of formulation changes and required tests
LevelImmediate/Extended
ReleaseTherapeutic
rangePoorly
soluble/SolubleRapid/Non-
rapid disolution
A Immediate Release Non-narrow
BImmediate Release,
Enteric coated,Extended Release
Soluble
Poorly soluble
Rapid
Non-rapid
Poorly soluble
Non-narrow
Narrow
Rapid
Non-rapid
Poorly soluble
Narrow
Enteric coated,Extended Release
EImmediate Release,
Enteric coated,Extended Release
When the dissolution profiles are equivalent, they are judged as bioequivalent.
Non-narrow Soluble
Immediate Release
C
D
Narrow
Immediate Release,Enteric caoted
Extended Release
Non-narrow
Soluble
Conclusion Bioequivalence study guidelines have been revised
based on the progress of related sciences during the past
40 years.
The high rate of achlorhydric subjects in the Japanese
population is an important factor for assessing
bioequivalence, as this parameter indicate an ethnic
difference that must be considered in bioequivalence
studies.
The similarity of pharmaceutical properties can be
evaluated using the dissolution test, which has a high
power for detecting differences of pharmaceutical
properties between products, and can be used to judge
the need for a bio-waiver in add-on subject study with a
limited condition, and in BE study for formulation change
with a limited range 36