Bioequivalence Requirements in Japan : Background Concepts · 2014-10-14 · Bioequivalence...

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

1

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

2






Number of subjects


Conclusion

Outlines

3


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




similarity, equivalence




similarity, equivalence

4

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

5

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

6






Number of subjects


Conclusion

Outlines

7

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






Number of subjects


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.

H.Ogata, N.Aoyagi, et al., J.Pharm.Dyn., 7, 656-664 (1984)

15

16

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.


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.

18

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.


Selection of subjects(II)

19


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.

20

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

：

21






Number of subjects


Conclusion

Outlines

22

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.

23

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.

24

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

27

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



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

28

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


EImmediate 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



ReleaseTherapeutic

rangePoorly


rapid disolution


BImmediate Release,


Soluble

Poorly soluble

Rapid

Non-rapid

Poorly soluble

Non-narrow

Narrow

Rapid

Non-rapid

Poorly soluble

Narrow


EImmediate Release,



Non-narrow Soluble

Immediate Release

C

D

Narrow


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.



ReleaseTherapeutic

rangePoorly


rapid disolution


BImmediate Release,


Soluble

Poorly soluble

Rapid

Non-rapid

Poorly soluble

Non-narrow

Narrow

Rapid

Non-rapid

Poorly soluble

Narrow


EImmediate Release,



Non-narrow Soluble

Immediate Release

C

D

Narrow


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



ReleaseTherapeutic

rangePoorly


rapid disolution


BImmediate Release,


Soluble

Poorly soluble

Rapid

Non-rapid

Poorly soluble

Non-narrow

Narrow

Rapid

Non-rapid

Poorly soluble

Narrow


EImmediate Release,



Non-narrow Soluble

Immediate Release

C

D

Narrow


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

Bioequivalence Requirements in Japan: Background Concepts

Hiroyasu Ogata, Ph.D.

Thank you for your attention 37

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Bioequivalence Requirements in Japan : Background Concepts · 2014-10-14 · Bioequivalence...

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