Bioequivalence Requirements in Japan : Background Concepts

Transcription

1 Session 6 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, (2012) 1

2 Outlines 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 2

3 Outlines 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 3

4 History of bioequivalence guideline in Japan Year Subjects Bioequivalence range Statistics 1974 dog, rabbit ー hypothesis test 1980 humans (dog) humans(patien ts) humans(patien ts) humans(patien ts) %: normal distribution %:log normal distribution %:log normal distribution %:log normal distribution hypothesis test + power analysis(δ = 0.2,1-β >0.8) 90% confidence interval 90% confidence interval 90% confidence interval Dissolution test(bio-waiver) similarity, equivalence similarity, equivalence 4

5 Current Guidelines for Bioequivalence Studies of Generic Products Oral solid dosage forms 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) 5

6 Current Guidelines for Bioequivalence Studies of Generic Products Topical dermatological drug products 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) 6

7 Outlines 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 7

8 Brief overview of bioequivalence studies for products administered orally in Japan 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) 8

9 Outlines 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 9

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, (1982). Dissolution rates of diazepam from commercial products 10

11 H.Ogata, N.Aoyagi, N.Kaniwa, M.Koibuchi, T.Shibazaki, A.Ejima, S.Tsuji and Y.Kawazu, Int.J.Clin.Pharmacol.Ther.Toxicol., 20, (1982). Average diazepam serum concentration after oral administration high gastric acidity; low gastric acidity 11

12 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, (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

13 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, (1985). Serum concentration of metronidazole after oral administration of sugar coated tablets

14 For evaluation of pharmaceutical characteristics dissolution rates of active ingredients from solid products should be monitored in place of solubility of active ingredients.

15 H.Ogata, N.Aoyagi, et al., J.Pharm.Dyn., 7, (1984) 15

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17 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.

18 Participating subjects Selection of subjects(i) In principle, healthy adult volunteers should be used. However, as possible discrepancies between the evaluations of healthy subjects and patients cannot be ruled out, patients should participate in the studies. 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. 18

19 Participating subjects Selection of subjects(ii) 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. 19

20 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. 20

21 Assessment of bioequivalence using 90% confidence interval 80%< mean value ± tα SE<125% 80% of reference product mean value of test product 125% of reference product Standard Error: SE = s/ n s:sample standard deviation n:number of subjects participated Subjects number:a sufficient number of subjects needed to assess bioequivalence 21

22 Outlines 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 22

23 Factors inducing the variability of parameters when evaluating bioequivalence Pharmaceutical factor Pharmacokinetic factor Assay and other factors 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

24 Factors inducing the variability of parameters when evaluating bioequivalence Pharmaceutical factor Pharmacokinetic factor Assay and other factors Pharmacokinetic factor: By using cross-over design, inter-subject variability, but not intra-subject variability can be cancel. Assay and other factors: Studies should be performed under the same conditions. 24

25 In the case that the confidence interval is not within the acceptable range of log(0.80) - log(1.25): 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 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) 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

26 In the case that the confidence interval is not in acceptable range of log(0.80) - log(1.25) 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) 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

27 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 evaluations using the whole dissolution curve, and not just one point: two points or f2 function 27

28 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. ph Agitation (rpm) 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) (2) (2)4.0 non 50 (3) (3)6.8 (3)6.8 non 50 (4)water (4)water (4)water non 50 ー ー (5)1.2 polysorbate ー ー (6)4.0 polysorbate ー ー (7)6.8 polysorbate (1),(2) or (3) (1),(2) or (3) (5),(6) or (7) polysorbate Apparatus: JP paddle apparatus Volume of test solution: basically 900 ml

29 Acceptance criteria for similarity and equivalence of dissolution profiles Similarity Average dissolution of test product is within that of the reference product ± 15% f2>42 Equivalence Average dissolution of test product is within that of the reference product ± 10% f2>50 Bio-waiver in add-on subject study with a limited condition Bio-waiver in BE study for formulation change with a limited range 29

30 Acceptance criteria for similarity of dissolution profiles 85 % ±15% 60 % 10 min min % min 40 % hr

31 Bio-waiver in BE study for formulation change with a limited range Levels of Changes in Uncoated Product Function of Excipient and Component Difference of Content(%W/W) Compared to Standard B C D Disintegrating agents Starch Others Binders Lubricants Polishers Stearate salts Others Fluidizing agents Talc Others Diluting agents Others(Preservatives, Sweetners, Stabilizers, etc) Sum of absolute values of difference of content(%) of change components A: changes of components described as trace use

32 Levels of formulation changes and required tests Immediate/Extended Therapeutic Poorly Level Release range soluble/soluble A Immediate Release Non-narrow B Immediate Release, Enteric coated, Extended Release C D E Immediate Release, Enteric caoted Extended Release Immediate Release Enteric coated, Extended Release Immediate Release, Enteric coated, Extended Release Non-narrow Narrow Non-narrow Narrow Non-narrow Narrow Soluble Poorly soluble Soluble Poorly soluble Soluble Poorly soluble Rapid/Nonrapid disolution Rapid Non-rapid Rapid Non-rapid When the dissolution profiles are equivalent, they are judged as bioequivalent.

33 Levels of formulation changes and required tests Immediate/Extended Therapeutic Poorly Level Release range soluble/soluble A Immediate Release Non-narrow B Immediate Release, Enteric coated, Extended Release C Immediate Release, Enteric caoted Non-narrow Narrow Soluble Poorly soluble Soluble Rapid/Nonrapid disolution Rapid Non-rapid Poorly soluble Non-narrow Extended Release Narrow Rapid Non-narrow Soluble Non-rapid Immediate Release Poorly Poorly soluble D soluble drug product: the average dissolution rate of the reference product does not reach 85% within Narrowthe designated test time in any of the dissolution Enteric media coated, without surfactant. Extended Release Immediate Release, E Enteric coated, Extended Release When the dissolution profiles are equivalent, they are judged as bioequivalent.

34 Levels of formulation changes and required tests Immediate/Extended Therapeutic Poorly Level Release range soluble/soluble A Immediate Release Non-narrow B Immediate Release, Enteric coated, Extended Release C D E Immediate Release, Enteric caoted Extended Release Immediate Release Enteric coated, Extended Release Immediate Release, Enteric coated, Extended Release Non-narrow Narrow Non-narrow Narrow Non-narrow Narrow Soluble Poorly soluble Soluble Poorly soluble Soluble Poorly soluble Rapid/Nonrapid disolution Rapid Non-rapid Rapid Non-rapid Rapid dissolution product: at 30 min, not less than 85% dissolution of the reference product under all the testing conditions When the dissolution profiles are equivalent, they are judged as bioequivalent.

35 Levels of formulation changes and required tests Immediate/Extended Therapeutic Poorly Level Release range soluble/soluble A Immediate Release Non-narrow B Immediate Release, Enteric coated, Extended Release C D E Immediate Release, Enteric caoted Extended Release Immediate Release Enteric coated, Extended Release Immediate Release, Enteric coated, Extended Release Non-narrow Narrow Non-narrow Narrow Non-narrow Narrow Soluble Poorly soluble Soluble Poorly soluble Soluble Poorly soluble Rapid/Nonrapid disolution Rapid Non-rapid Rapid Non-rapid When the dissolution profiles are equivalent, they are judged as bioequivalent.

36 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

37 Bioequivalence Requirements in Japan: Background Concepts Hiroyasu Ogata, Ph.D. Thank you for your attention 37