Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union

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1 Clin Pharmacokinet (2017) 56: DOI /s REVIEW ARTICLE Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union Ryosuke Kuribayashi 1 Toru Yamaguchi 1 Hanaka Sako 1 Tomoko Takishita 1 Kazunori Takagi 1 Published online: 26 July 2016 Springer International Publishing Switzerland 2016 Abstract In Japan, the development of generic oral dry powder inhaler (DPI) drug products for marketing approval has recently increased. The Pharmaceuticals and Medical Devices Agency (PMDA) considers the required data for each drug product in the consultation meeting. However, guidelines for DPI drug products have been published by the US Food and Drug Administration and the European Medicines Agency. Recently, the basic principles of bioequivalence evaluations of generic DPI drug products were published in March 2016 by the Ministry of Health, Labour and Welfare. The document mainly outlines the current understanding regarding the bioequivalence evaluations of generic DPI drug products based on knowledge from PMDA consultation meetings. In this review, we compared the bioequivalence evaluations of DPI drug products among Japan, USA, and the European Union and discuss future development of generic DPI drug products in Japan. Key Points This article introduces the similarities and differences in the bioequivalence evaluations of generic dry powder inhaler drug products between Japan, USA, and the European Union. The Pharmaceuticals and Medical Devices Agency generally recommends a synthetically comprehensive approach judging bioequivalence on the basis of all data from in vitro, pharmacokinetic, and clinical studies. This is the first article to present and discuss the details of generic dry powder inhaler drug product regulations in Japan. 1 Introduction Disclaimer The views expressed in this article are those of the authors and do not necessarily reflect the official views of the Pharmaceuticals and Medical Devices Agency. Please note that in this article some proper nouns in English, such as titles of basic principles, were provisional translations from Japanese literature by the authors. & Ryosuke Kuribayashi kuribayashi-ryosuke@pmda.go.jp 1 Office of Generic Drugs, Pharmaceuticals and Medical Devices Agency, Kasumigaseki, Chiyoda-ku, Tokyo , Japan In Japan, development of generic oral dry powder inhaler (DPI) drug products for the treatment of asthma and/or chronic obstructive pulmonary disease (COPD) is conducted, and the Pharmaceuticals and Medical Devices Agency (PMDA) considers the required data for each drug product in the consultation meeting. Guidelines for DPI drug products have been published by the US Food and Drug Administration (FDA) [1 6] and the European Medicines Agency (EMA) [7], but the developmental approaches differ between the US FDA and the EMA. The US FDA adopts the weight of evidence approach, judging the therapeutic equivalence on the basis of all data from

2 226 R. Kuribayashi et al. in vitro, pharmacokinetic (PK), pharmacodynamic (PD), or clinical endpoint studies [8, 9]. However, the EMA adopts the stepwise approach, which uses in vitro studies, followed, if needed, by PK studies, and finally PD or clinical endpoint studies. If equivalence is not demonstrated at any of these major steps, subsequent studies are required. Recently, the basic principles for the bioequivalence evaluations of generic DPI drug products were published in March 2016 by the Ministry of Health, Labour and Welfare (MHLW) [10]. The document is the concept paper to clarify the required studies for bioequivalence evaluations of generic DPI drug products in Japan, but detailed acceptance criteria were not described. For the bioequivalence studies of DPI drug products, the PMDA generally requires a bioequivalence evaluation based on in vitro, PK, and clinical studies. In this review, we compared the bioequivalence evaluations of generic DPI drug products among Japan, USA, and the European Union (EU) and discuss future development of generic DPI drug products in Japan. 2 Methods The objective of this study was to clarify discussion points for the future development of Japanese guidelines for generic DPI drug products. First, we surveyed the pharmacological actions, brand names, active pharmaceutical ingredient (API) names, strengths or delivered dose (DD), indications, dates of approval, and the end of the reexamination period of innovator DPI drug products indicated for the treatment of asthma and/or COPD. This information was taken from package inserts and interview forms published on the PMDA homepage, which indicated the application time of each generic DPI drug product. In Japan, the generic drug applicants can apply for generic drugs after the reexamination period of innovator drug products. All information was collected in December 2015, and the innovator DPI drug products were approved from April 2004 through December Second, we compared similarities and differences in the bioequivalence evaluations of DPI drug products that were based on the published basic principles in Japan [10], FDA guidances (Product-Specific Recommendations for Generic Drug Development) [1 6], and the EMA guidelines [7], under the following topics: 1. In vitro studies. 2. PK studies. 3. PD or clinical studies. 3 Results 3.1 Application Time of Generic DPI Drug Products Table 1 shows the approved oral DPI drug products in Japan. Fourteen innovator DPI drug products have been approved, including four long-acting muscarinic antagonist (LAMA), and three inhaled glucocorticosteroid (ICS)/longacting b 2 adrenoceptor agonist (LABA) combination products. Ten products have been approved for COPD (two products have been approved for both asthma and COPD). Multiple strengths are available for Pulmicort (ICS), Asmanex (ICS), Adoair (ICS/LABA), and Relvar (ICS/ LABA) products, and the strengths of only the ICS products were different. We found that the reexamination periods of two ICS, two LABA, and two ICS/LABA drug products expired between 2014 and 2019, whereas those of three LAMA, one ICS/LABA, and two LABA/LAMA drug products expired between 2020 and In Vitro Studies Table 2 shows the similarities and differences of in vitro studies among Japan, USA, and the EU. The DD test is similar, but the aerodynamic particle size distribution (APSD) test differs among the three agencies. Both tests are recommended to be performed at all strengths at three flow rates [minimum, median, and maximum in the patient populations (e.g., 10th, 50th, and 90th percentiles)]. The single actuation content (SAC) test may be performed by using the dosage unit sampling apparatus [United States Pharmacopoeia (USP) \ 601 [ apparatus B], and the APSD test may be performed by using the Andersen cascade impactor (USP \ 601 [ apparatus 3) or the nextgeneration impactor (USP \ 601 [ apparatus 5), as specified in the US FDA guidances [11, 12]. However, in the EU guidelines, the DD and APSD tests may be performed by using the multistage impactor/impinger according to an accepted method of a pharmacopeia (e.g., USP, European Pharmacopeia [EP]) or a suitably validated alternative [13]. As per the MHLW basic principles, the use of dosage unit sampling apparatus for the DD test and the Andersen cascade impactor or the next-generation impactor for the APSD test is recommended. The US recommends the evaluation of impactor-sized mass (ISM), mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle mass (FPM), as well as of the individual stages. Population bioequivalence is recommended for data analysis of the SAC and ISM to determine equivalence, but the applicants are encouraged

3 Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products 227 Table 1 Approved oral dry powder inhaler drug products in Japan Classification Brand name Active ingredient name Strength or Delivered dose (lg) Indication Approval Reexamination period end ICS Pulmicort Turbuhaler Asmanex Twisthaler LABA Oxis Turbuhaler Formoterol Fumarate Hydrate Onbrez Inhalation Capsules LAMA ICS/LABA LABA/ LAMA SABA Spiriva Inhalation Capsules Seebri Inhalation Capsules Budesonide 100 and 200 Asthma (Adult) Asthma (Children) June 1999 July 2010 June 2005 July 2014 Mometasone Furoate 100 and 200 Asthma (Adult) July 2009 July (Formoterol Fumarate Hydrate) COPD June 2012 July 2016 Indacaterol Maleate 150 (Indacaterol) COPD July 2011 June 2019 Tiotropium Bromide Hydrate 18 (Tiotropium) COPD October 2004 Glycopyrronium Bromide 50 (Glycopyrronium) COPD September 2012 Encruse Ellipta Umeclidinium Bromide 62.5 (Umeclidinium) COPD March 2015 Eklira Genuair Aclidinium Bromide 400 (Aclidinium Bromide) Symbicort Turbuhaler Adoair Diskus Relvar Ellipta Ultibro Inhalation Capsules Anoro Ellipta Meptin Swinghaler Budesonide/Formoterol Fumarate Hydrate Fluticasone Propionate/ Salmeterol Xinafoate Fluticasone Furoate/ Vilanterol Trifenatate Indacaterol Maleate/ Glycopyrronium Bromide Vilanterol Trifenatate/ Umeclidinium Bromide Procaterol Hydrochloride Hydrate 160/4.5 (Budesonide/Formoterol Fumarate Hydrate) 100/50, 250/50, and 500/50 (Fluticasone Propionate/ Salmeterol) 100/25 and 200/25 (Fluticasone Furoate/ Vilanterol) 110/50 (Indacaterol/ Glycopyrronium) 25/62.5 (Vilanterol/ Umeclidinium) 10 (Procaterol Hydrochloride Hydrate) COPD Asthma (Adult) a Asthma (Adult) b COPD Asthma (Adult and Children) and COPD Asthma (Adult) COPD March 2015 October 2009 June 2012 August 2012 October 2012 September 2020 July 2022 March 2023 October 2015 June 2016 August 2016 April 2007 April 2017 September 2013 September 2013 September 2021 September 2020 COPD July 2014 July 2022 Asthma etc., February 2014 ICS inhaled glucocorticosteroid, LABA long-acting b 2 adrenoceptor agonist, LAMA long-acting muscarinic antagonist, SABA short-acting b 2 adrenoceptor agonist, COPD chronic obstructive pulmonary disease a Maintenance therapy b Maintenance and reliever therapy c The reexamination period expires in other formulations c to submit as supportive evidence for the MMAD, GSD, and FPM. Conversely, in Japan and the EU, the applicants should evaluate DD, FPM, and at least four groups of stages (or per impactor stages in the EMA guidelines). In addition, the EU guidelines adopt 90 % confidence intervals (CIs) within for the acceptance criteria [14, 15], whereas the MHLW basic principles do not clearly specify the acceptance criteria. As in other information, the US specifies the life stages at the beginning (B), middle (M), and end (E) for the SAC test, at B and E for the APSD test, and the mass balance assessment and volume of air drawn. 3.3 PK Studies Table 3 shows the comparison of PK studies among the three agencies. The study purposes are slightly different between the three agencies. Japan aims at systemic exposure, the USA aims at equivalent assessment of systemic exposure, and the EU aims at equivalent pulmonary deposition in addition to

4 228 R. Kuribayashi et al. Table 2 Comparison of in vitro studies among Japan, USA, and the EU Japan USA EU Type Criteria Design Type Criteria Design Type Criteria Design 1. DD 2. FPM 3. At least 4 groups of stages, etc. Not specified Strength: All strengths Flow rates: Minimum, medium, and maximum in the patient populations (e.g., 10th, 50th, and 90th percentiles). Apparatus DD: DUSA FPM and at least 4 groups of stages: ACI or NGI 1. SAC PBE Strength: All strengths Life stages: B, M, and E Flow rates: 30, 60, and 90 L/min, or 31.5, 63.0, and 94.5 L/min Apparatus: DUSA (USP \ 601 [ apparatus B) Volume of air drawn: 2 L 1. DD 2. FPM 3. Per impactor stage or at least four groups of stages 90% CIs within Strength: All strengths Flow rates: Minimum, medium, and maximum in the patient populations (e.g., 10th, 50th, and 90th percentiles) Apparatus: USP and EP Multistage impactor/ impinger 2.APSD ISM MMAD GSD FPM PBE Supportive Supportive Supportive Strength: All strengths Lifestages: B and E Flow rates: 28.3 or 30, 60, and 90 L/min or 28.3 or 31.5, 63.0, and 94.5 L/min Apparatus: ACI or NGI (USP \ 601 [ apparatus 3 or 5) Volume of air drawn: 4 L DD delivered dose, FPM fine particle mass, DUSA dosage unit sampling apparatus, ACI andersen cascade impactor, NGI next-generation impactor, SAC single actuation content, APSD aerodynamic particle size distribution, ISM impactor-sized mass, MMAD mass median aerodynamic diameter, GSD geometric standard deviation, B beginning, M middle, E end, USP United States Pharmacopeia, EP European Pharmacopoeia, PBE population bioequivalence, CI confidence interval systemic exposure. The EU guidelines recommend two studies: (1) for the purpose of pulmonary deposition, PK studies using charcoal blockade to exclude absorption of the API from the gastrointestinal tract and (2) for the purpose of systemic exposure, PK studies to assess absorption of the API, including from the lung and gastrointestinal tract. PK study designs are similar in Japan and USA, and are conducted with a single-dose two-way crossover for normal healthy volunteers under fasting conditions. However, the EU guidelines recommend a single dose with clinically relevant doses and strengths in the intended patient population to investigate total systemic exposure. In the draft guidances on fluticasone propionate/salmeterol xinafoate (FP/SX) and fluticasone furoate/vilanterol trifenatate (FF/VT), USA recommends performing PK studies at all strengths [1, 6]. The drug product is administered at the minimum number of inhalations sufficient to characterize a PK profile using a sensitive analytical method as specified in the US FDA guidances. Evaluation parameters common among Japan, USA, and the EU are area under the curve (AUC) and maximum plasma concentration (C max ), with the EU also comparing time to maximum concentration. For bioequivalence acceptance criteria, 90 % CIs for the ratios of the generic and innovator DPI drug products must be within % in USA and EU guidelines. In addition, the EU guidelines adopt a different bioequivalence range for narrow therapeutic index drug products (NTIDPs) and highly variable drug products (HVDPs) [7]. Thus, NTIDPs

5 Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products 229 Table 3 Comparison of PK studies among Japan, USA, and the EU Japan USA EU Purpose: Systemic exposure Purpose: Equivalent systemic exposure Purpose: Equivalent pulmonary deposition and systemic exposure Design Criteria Design Criteria Design Criteria Singledose, two-way crossover Fasting Strength: Not specified Subject: Normal healthy adult AUC and C max Equivalent with or less than exposure or below the permissible level Single-dose, two-way crossover Fasting Strength: All strengths Dose: Minimum number of inhalations that is sufficient to characterize a PK profile by using a sensitive analytical method. Subject: Normal healthy adult males and nonpregnant females. AUC and C max 90% CIs within 80.00% % Reference scaled approach can be considered for HVDP Single dose For purpose of pulmonary deposition: PK study using charcoal blockade. For purpose of systemic exposure: PK study not using charcoal blockade. Dose: With clinically relevant doses and strengths Subject: Intended patient population for purpose of systemic exposure. AUC and C max 90% CIs within 80.00% % NTIDP: Tighter limits HVDP: 75% 133% (C max only) T max should be compared AUC area under curve, CIs confidence intervals, C max maximum plasma concentration, PK pharmacokinetic, NTIDP narrow therapeutic index drug product, HVDP highly variable drug product, T max time to maximum plasma concentration with 90 % CIs for the ratios may have a narrower acceptance range. For HVDPs, the EU may widen the acceptance range of 90 % CI for C max only to % if certain conditions are satisfied. USA also accepts the use of the referencescaled average bioequivalence approach for HVDPs [9]. Japan adopts different objectives than those of USA and EU. In USA and EU, PK studies are required for bioequivalence, but Japan requires confirmation that the generic drug products show equivalence or non-superiority to innovator drug products in the total systemic exposure level. 3.4 PD or Clinical Studies Table 4 shows the comparison of PD or clinical studies among the three regulatory agencies. Six draft guidances on formoterol fumarate (FOF), indacaterol maleate (IM), fluticasone furoate (FF), aclidinium bromide (AB), FP/SX, and FF/VT for DPI drug products had been published by April 2016 by the US FDA. The EU primarily announces the guidelines for drugs with a specific pharmacological action, such as LABAs, short-acting b 2 adrenoceptor agonists (SABAs), anticholinergics, ICSs, and combination products, whereas Japan publishes the basic principles without specifying the API and pharmacological action USA Requirements USA recommends conducting the clinical PD studies that use a randomized, single-dose, placebo-controlled, crossover or parallel-group design at a minimum that consists of a run-in period (e.g., FOF draft guidance: 2 weeks), followed by a 1-day treatment period with the placebo, generic, or innovator product for DPI drug products of FOF, IM, and AB. In the draft guidances on FF, FP/SX, and FF/VT of combination products, USA recommends a randomized, multiple-dose, placebo-controlled, parallel-group design consisting of a 2-week run-in period followed by a 4-week treatment period of the placebo, generic or, innovator product. The use of placebo controls ensures adequate study sensitivity by demonstrating that both generic and innovator products should be statistically superior to placebo (p \ 0.05) with regard to the primary endpoint. The drug products addressed by the draft guidances on FOF, FF, FP/SX, and FF/VT are recommended for asthma patients, whereas the drug products addressed by the draft guidances on AB and IM are recommended for COPD patients. It is usually appropriate to study the lowest strength to enhance the sensitivity of the study. The primary endpoint is required to be the serial forced expiratory volume in 1 s (FEV 1 )-AUC 0 t change from the baseline in the FOF, IM, and AB draft guidances, whereas two primary endpoints of the serial FEV 1 -AUC 0 t on the first day and FEV 1 change on the last day of a 4-week treatment from the baseline are required in the draft guidance on FP/SX and FF/VT. In addition, the 90 % CI for the ratios of the generic and innovator drug products for the acceptance criteria is required to be within %.

6 230 R. Kuribayashi et al. Table 4 Comparison of pharmacodynamic or clinical endpoint studies among Japan, USA, and the EU Japan USA EU Classification Design and Criteria API name (Classification) Design and Criteria Classification Design and Criteria Not described Single-dose or multiple-dose crossover or parallel-group design Asthma or COPD patients Strength: Appropriate strength for assessing the therapeutic equivalence Assessment endpoint: Trough FEV 1 change from the baseline Morning PEF change from the baseline FEV1-AUC0 t change from the baseline, etc. Appropriate primary endpoint is chosen on the basis of the characteristics of each pharmaceutical product such as the subject, pharmacological action, treatment purpose, and duration of action. Criteria: Clinically acceptable range on the basis of the differences between the innovator product and an appropriate comparator in patients. Formoterol Fumarate (LABA) Indacaterol Maleate (LABA) Aclidinium Bromide (LAMA) Fluticasone Furoate (ICS) Randomized, single-dose, placebo-controlled, crossover or parallel-group design Asthma patients Dose: mg Criteria: FEV1-AUC0 12h change from the baseline, 90% CI within 80.00% % COPD patients Dose: mg Criteria: FEV1-AUC0 24h change from the baseline, 90% CI within 80.00% % Randomized, single-dose, placebo-controlled, crossover or parallel-group design COPD patients Dose: 375 lg Criteria: FEV 1 -AUC 0 6h change from the baseline, 90% CI within 80.00% % Randomized, multiple-dose, placebo-controlled, parallel group design Asthma patients Dose: 0.1 mg Criteria: Bronchodilators: LABA,SABA, and Anticholinergic ICS Bronchodilators: Single-dose, crossover design ICS: Multiple-dose, parallel group or crossover design Generally, a double-blind, double-dummy study design should almost always be possible. Asthma or COPD patients (Generally, asthma patients) Strength: One strength (Linearity) At least two strength (Nonlinearity) Bronchodilation study Bronchodilators: FEV 1 -AUC change from the baseline and the change in FEV1 from the baseline ICS: Change in FEV 1 or PEF from the baseline Bronchoprotection study. PC20FEV1 or PD20FEV1 change from the baseline. Criteria: The observed CIs comparing generic and innovator products should lie within the chosen equivalence margins to provide convincing evidence of equivalence. Relative potency 67% 150% There are special considerations for children. Fluticasone Propionate; Salmeterol Xinafoate (ICS/LABA) FEV1 change on the last day of a 4 week treatment from the baseline, 90% CI within 80.00% %. Randomized, multiple-dose, placebo-controlled, parallel group design Asthma patients Dose: 100/50 Criteria: FEV 1 -AUC 0 12 change from the baseline on the first day, Combination product Therapeutic equivalence should be demonstrated for each/all of the component active substances of a fixed-dose combination product and study design will depend on the specific active substances in the combination. Fluticasone Furoate; Vilanterol Trifenatate (ICS/LABA) FEV1 change on the last day of a 4 week treatment from the baseline, 90% CIs within 80.00% %. Asthma patients Dose: 100/25 Criteria: FEV 1 -AUC 0 24 change from the baseline on the first day, FEV 1 change on the last day of a 4 week treatment from the baseline, 90% CIs within 80.00% %. LABA long-acting b 2 adrenoceptor agonist, LAMA long-acting muscarinic antagonist, ICS inhaled glucocorticosteroid, SABA short-acting b 2 adrenoceptor agonist, COPD chronic obstructive pulmonary disease, FEV 1 forced expiratory volume in 1 s, CI confidence interval, PEF peak expiratory flow, PC provocative concentration, PD provocative dose

7 Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products EU Requirements The EU guidelines for bronchodilators (SABAs, LABAs, and anticholinergics) accept a single-dose, crossover design, while for those containing ICSs, a multiple-dose, parallel-group or crossover design is acceptable. Additionally, the EU recommends that a double-blind, doubledummy study design should almost always be possible. Asthma patients are generally recruited except the innovator products have only COPD as the authorized indication. The EU recommends one strength (usually the lowest strength) to assess the therapeutic equivalence if dose linearity is demonstrated between both generic and innovator products across all proposed strengths by in vitro studies. However, in contrast to USA, the doses are required to incorporate at least two dose levels if dose nonlinearity by in vitro studies is demonstrated for either of the generic or innovator drug products. In addition, the EU requires confirmation of the sensitivity for discrimination and the clinically relevant differences between the innovator and generic DPI drug products for the ICS, and the studies should incorporate at least two doses/strengths of the test and reference products. In the EU guidelines, two different types of bronchodilation and bronchoprotection studies for assessing therapeutic equivalence are suggested for PD studies. For bronchodilation studies, two primary endpoints are measured, including the FEV 1 -AUC (over at least 80 % of the duration of action after a single inhalation) change from the baseline and the change in FEV 1 from the baseline, whereas for ICS, only one primary endpoint is preferred, which is the change in FEV 1 from the baseline with daily measurements at home, if possible. If regular measurement of FEV 1 is not possible, morning peak expiratory flow (PEF) is measured and recorded daily at home and is an acceptable primary endpoint. For bronchoprotection studies, the primary outcome is adopted as the provocative concentration or dose of the provocation agent, which produces a 20 % decrease in FEV 1 (PC 20 FEV 1 or PD 20- FEV 1 ). The examples of direct provocation agents are methacholine, histamine, and acetylcholine, whereas those of indirect provocation are adenosine monophosphate, and mannitol. The EU guidelines specify the following two bioequivalence criteria. One approach is to calculate the relative potency, and another approach is to compare the results for the clinical endpoint for the generic and innovator products at each dose level studied. The results using both approaches should be provided. In both cases, the observed CI comparing generic and innovator products should lie within the chosen equivalence margins to provide convincing evidence of equivalence. For both approaches, the chosen equivalence margins should be prespecified and appropriately justified. The acceptance criteria for relative potency must be within %. For fixed combination products, therapeutic equivalence study design depends on the specific active substances in the combination. For example, in cases of fixed combinations of ICS and LABA, the study design should include two doses of each combination product to show a statistically significant dose response relationship. The endpoints should separate studies to assess each of the component active substances of a fixed-dose combination product. Therefore, ICS should be assessed by a multiple-dose study and LABA by a single-dose study Japanese Requirements As per the MHLW basic principles, clinical studies are conducted with a single- or multiple-dose, crossover or parallel-group design in patients with asthma or COPD. Japan recommends use of the appropriate strength for assessing the therapeutic equivalence. As candidates of assessment endpoints, Japan adopts the trough FEV 1 change from the baseline, morning PEF change from the baseline, and FEV 1 -AUC 0 t change from the baseline, and so on. Appropriate primary endpoints are chosen on the basis of the characteristics of each pharmaceutical product, such as the subject, pharmacological action, treatment purpose, and duration of action. For acceptance criteria, Japan recommends the clinically acceptable range on the basis of the differences between the innovator product and an appropriate comparator in patients. 4 Discussion In this article, we surveyed the fundamental information about innovator DPI drug products, such as the reexamination period end and published regulatory guidance, to clarify the discussion points for future development of the Japanese guidelines for generic DPI drug products. In Japan, because a generic drug applicant can apply for generic drug approval to the PMDA after the reexamination period of innovator drug products, the authors can predict approximate application timing by investigating the reexamination period end. The data suggest that generic DPI drug products containing ICS, LABA, and ICS/LABA will be applied for approval between 2015 and 2019, and products containing LAMA and LABA/LAMA will be applied for approval between 2020 and Interestingly, concerning the drug indication, innovator DPI drug products before 2019 will mainly be approved for asthma patients (some products also include COPD patients), but those after 2020 will be approved only for COPD patients. The number of COPD patients has been increasing around the world, and COPD is predicted to be the third leading cause of death worldwide by 2030 [16]. In Japan, it is

8 232 R. Kuribayashi et al. estimated that there are more than five million COPD patients, with more than 16,000 lives lost annually, which makes COPD the 10th leading cause of death [17]. Therefore, research and development of generic DPI drug products is expected to increase in the future. We also surveyed and compared the regulatory requirements among the three agencies on the basis of the latest publications. It has been previously reported that the developmental approach is different between USA and EU [8, 9]. Japan generally recommends a synthetically comprehensive approach judging bioequivalence on the basis of all data from in vitro, PK, and clinical studies, because the authors think that the correlations among the in vitro, PK, PD, and clinical endpoint studies for DPI drug products are not clear [18, 19]. The approaches differ in the details, but the authors believe that the approaches are largely similar in Japan and USA. By surveying and comparing the regulatory recommendations for bioequivalence evaluations of generic DPI drug products, the authors propose discussion of the following points in the future: Consideration of bioequivalence evaluations for multiple strengths; Consideration of device standards for generic DPI drug products; Consideration of PD endpoint studies. For multiple strengths, USA recommends bioequivalence evaluation of in vitro studies and PK studies between generic and innovator drug products of all strengths, whereas the EU recommends assessing the dose linearity of in vitro studies for both products across all proposed strengths [9]. The bioequivalence evaluation methods for multiple strengths are not specified in the basic principles of Japan. Therefore, the authors may consider the equivalence evaluation method including particularly the variability evaluation method of in vitro studies, for generic DPI drug products. USA recommends that generic and innovator DPI drug products be qualitatively and quantitatively the same with respect to device similarity and similar patient handling. For device similarity of DPI drug products, the AB draft guidance of USA recommends that generic products should have the following characteristics: passive (breath-actuated) device, device-metered multi-dose format, same number of doses as that of the innovator product, external operating procedures similar to those of the innovator product, size and shape similar to those of the innovator product, device resistance comparable to that of the innovator product, dose indicator/counter, and a patient feedback mechanism similar to that of the innovator product. In contrast, the EU recommends the following characteristics for generic products: similar inhaled volume through the device (within ±15 %), similar handling of the inhalation devices, and similar resistance to airflow (within ±15 %). Therefore, Japan should consider the requirements for device similarity between generic and innovator DPI drug products. Currently, clinical endpoints are primarily presented in the basic principles for the bioequivalence evaluations of generic DPI drug products in Japan. In the EU guidelines, the PD parameters are described as PC 20 FEV 1 or PD 20- FEV 1 in the bronchoprotection studies. USA also recommends the same endpoints in the draft guidance of metered dose inhalers containing albuterol sulfate [20]. Additionally, for the ICS, the EU may consider expired nitric oxide, sputum eosinophils, validated quality-of-life questionnaires, and validated patient reported outcome measures as other efficacy variables. In the EU, exhaled nitric oxide [21] and sputum eosinophils [22, 23] are accepted. Therefore, the authors may consider more sensitive endpoints as efficacy parameters for generic DPI drug products. 5 Conclusion In this article, we reviewed the similarities and differences in the bioequivalence studies of generic oral DPI drug products among Japan, USA, and the EU. Japan generally recommends a synthetically comprehensive approach by judging bioequivalence based on all data from in vitro, PK, and clinical studies. The basic principles have been presented in a concept paper to clarify the required studies for bioequivalence evaluations of generic DPI drug products in Japan, but detailed acceptance criteria were not described. Therefore, we think that a review of basic principles is the first step in creating new guidelines in the future. Additionally, we believe that the above points require more detailed consideration in the future to assess the bioequivalence of generic DPI drug products. We recommend that a detailed discussion and consultation with the PMDA be conducted to evaluate each generic DPI drug product comprehensively. This is the first article to present and discuss the details of generic DPI drug product regulation in Japan. We hope this article clarifies generic DPI drug product regulation in Japan. Compliance with Ethical Standards Funding No external funding was used in the preparation of this manuscript. Conflict of interest Ryosuke Kuribayashi, Toru Yamaguchi, Hanaka Sako, Tomoko Takishita, and Kazunori Takagi declare that they have no conflict of interest that might be relevant to the contents of this manuscript.

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