Revisions to the requirement of the Japanese clinical study data for biosimilar developments in Japan.

BACKGROUND: The 'Questions and Answers (Q&A)' document regarding Japanese biosimilar guideline elucidated that Japanese participant enrollment in at least one comparative clinical study was required for the marketing authorization application (MAA) of biosimilars in Japan. RESEARCH DESIGN AND METHODS: To discuss the requirement of Japanese clinical study data for biosimilar development, the trend in comparative clinical studies conducted for approved biosimilars of monoclonal antibodies and fusion proteins was analyzed, and the consistency of the results between the overall population and the Japanese population according to the publicly available information was reviewed. RESULTS: The number of comparative clinical studies enrolling Japanese participants was 25 cases, and the type and percentage were 13 (52%) and 12 (48%) cases of comparative pharmacokinetic study and comparative efficacy study, respectively. In all comparative clinical studies, consistent results between the overall population and the Japanese population were shown. CONCLUSIONS: Our study indicated that Japanese participant enrollment in comparative clinical studies may not always be necessary for biosimilar development when certain conditions are satisfied. This has been described in the revised Q&A document published by the Ministry of Health, Labour and Welfare in January 2024.

Survey of Data Package and Sample Size of Comparative Clinical Studies for Biosimilar Developments from PMDA Assessments.

BACKGROUND: The Japanese biosimilar guideline requires that the sponsors conduct clinical studies such as comparative pharmacokinetic (PK), pharmacodynamic (PD), or efficacy studies. In each biosimilar development, the sponsors consider the clinical data package, and thus clinical data packages vary among biosimilar developments. OBJECTIVES: The aim of this study was to elucidate the clinical data packages for the biosimilars approved in Japan. The details of clinical data packages and sample size for the regulatory approvals of biosimilars in Japan was reported. METHODS: We surveyed the clinical data packages and sample size based on the Pharmaceuticals and Medical Devices Agency (PMDA) website review reports between 2009 and 2023. RESULTS: Twenty-four biosimilars have been approved based on the comparative PK and efficacy studies, 10 biosimilars have been approved based on the comparative PK/PD study, and one biosimilar has been approved based on the comparative efficacy study. Regarding the sample size, comparative PK studies were conducted in healthy volunteers or patients for up to 300 cases, although the majority enrolled only 1-100 cases (68.1%, 32/47). Comparative PD studies enrolling 1-30, 31-60, and 61-90 cases totaled 4, 7, and 4 cases, respectively. Finally, comparative efficacy studies enrolling 1-300, 301-600, and 601-900 totaled 6, 10, and 11 cases, respectively. In particular, the oncology and rheumatology areas were the first and second disease areas recruiting 601-900 patients. CONCLUSION: Large numbers of patients were enrolled to conduct a comparative efficacy study. Efficient biosimilar development should be considered on the basis of the accumulation of scientific understanding of comparable features of biosimilars and their development.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Historical Overview of Regulatory Approvals and PMDA Assessments for Biosimilar Products in Japan During 2009-2022.

A biosimilar product is defined as "a biological product that is highly similar to an existing, approved biological product (known as originator or reference product) in terms of structure, function, quality, and clinical efficacy and safety". Recently, biosimilar products have been actively developed around the world, and part of the reason for this is to combat the rapid growth of medical expenses in many countries, including Japan, the United States (US), and Europe. The use of biosimilar products has been promoted as a measure to address this issue. The review of marketing authorization applications for biosimilar products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA), which reviews the comparability of the quality, efficacy, and safety based on the data submitted by the applicants. As of December 2022, 32 biosimilar products have been approved in Japan. Through this process, the PMDA has gained much experience and knowledge regarding the development and regulatory approval of biosimilar products; however, details of the regulatory approvals for biosimilar products in Japan have not been reported until now. Therefore, in this article, we present the details of regulatory history and revised guidelines for approval of biosimilar products in Japan, questions and answers, other relevant notifications, and consideration for comparability evaluations for analytical, non-clinical, and clinical studies. In addition, we provide details about the approval history, number, and types of biosimilar products that have been approved between 2009 and 2022 in Japan.

First Approval of Generic Mometasone Furoate Nasal Suspension Spray in Japan: Similarities and Differences Between Japan and the USA.

The Ministry of Health, Labour and Welfare (MHLW) in Japan approved the first generic version of Nasonex in February 2018. The Pharmaceuticals and Medical Devices Agency requires in vitro, pharmacokinetic, and pharmacodynamic or clinical endpoint data to approve generic nasal spray drug products. However, the MHLW has not published basic principle for approving nasal generic drug products. Therefore, this article summarizes the data used for the approval of the first generic Nasonex based on publicly available data. Additionally, we compare the bioequivalence evaluations regarding the human studies based on the generic version of Nasonex between Japan and the USA.

A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme.

The safety and efficacy of a generic product are partly based on demonstrating bioequivalence to the innovator product; however, when the innovator product is no longer available as a comparator product, a survey conducted within the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP) indicated that the criteria for selecting an alternative comparator product varies. For most members of the BEWGG, an existing marketed generic that was approved based on a comparison with the locally registered innovator product can be used, contingent on criteria that ranges from allowing any generic to be used, to allowing only specific criteria-defined generics to be used. Notwithstanding the acceptability of a generic as an alternative comparator, it is not always the preferred comparator for several jurisdictions. Some jurisdictions require the use of a locally sourced alternative innovator comparator (e.g., the same medicinal ingredient manufactured by a different company) or a foreign innovator comparator. Unlike the other members of the BEWGG, the European Union (EU) has no such options available, rather mechanisms are in place to allow manufacturers to develop a new comparator. The criteria described herein regarding the use of an alternative comparator product can also be applied to scenarios where a specific strength of a series of strengths or an innovative fixed dose combination are discontinued. The results of the survey demonstrate that while criteria for selecting alternative comparator products are not harmonized among the BEWGG participants, the common concern for all jurisdictions is to select a comparator product that meets the safety and efficacy standards of the original innovator product.

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

This article describes an overview of waivers of in vivo bioequivalence studies for additional strengths in the context of the registration of modified release generic products and is a follow-up to the recent publication for the immediate release solid oral dosage forms. The current paper is based on a survey among the participating members of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Program (IPRP) regarding this topic. Most jurisdictions consider the extrapolation of bioequivalence results obtained with one (most sensitive) strength of a product series as less straightforward for modified release products than for immediate release products. There is consensus that modified release products should demonstrate bioequivalence not only in the fasted state but also in the fed state, but differences exist regarding the necessity of additional multiple dose studies. Fundamental differences between jurisdictions are revealed regarding requirements on the quantitative composition of different strengths and the differentiation of single and multiple unit dosage forms. Differences in terms of in vitro dissolution requirements are obvious, though these are mostly related to possible additional comparative investigations rather than regarding the need for product-specific methods. As with the requirements for immediate release products, harmonization of the various regulations for modified release products is highly desirable to conduct the appropriate studies from a scientific point of view, thus ensuring therapeutic equivalence.

Generic Drug Product Development in Japan: Regulatory Updates During 2014-2019 and the Future.

The growth of healthcare cost is a serious issue in many countries. Generic drug products play an essential role in reducing healthcare costs because they are less costly than the innovator drug products. The regulatory review of generic drug products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). This report introduces the activities of the PMDA from fiscal years 2014-2019. The number of approvals of new generic drug products and partial changes was trending downward. Alternatively, the PMDA conducted six types of consultation meetings to advise on development and application; the number of consultation meetings was increasing. Moreover, during this period, the Ministry of Health, Labour and Welfare issued two basic principles for ophthalmic dosage forms and dry powder inhaler drug products and revised the guidelines for bioequivalence. Finally, the future of generic drug product development and considerations to improve their regulation were discussed. More efforts will continue to enable a more efficient and rational generic drug product development and shortening of the review period for partial change approval.

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme.

The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jurisdictions was a case-by-case approach given that most jurisdictions do not have well defined guidelines to support all possible scenarios. Even in the simplest case of intravenous solutions, the acceptability of qualitative changes in excipients differ between the IPRP members.  Notwithstanding the differences, the dissemination of the information is a first step towards regulatory convergence regarding biowaivers for certain dosage forms and should be useful for pharmaceutical companies currently developing generic medicinal products for IPRP jurisdictions.

Modernization and Strengthening of Bioequivalence Guidelines in Japan.

Until now, human bioequivalence (BE) studies were conducted based on the revised 'Guideline for Bioequivalence Studies of Generic Products' issued in 2012 by the Ministry of Health, Labour and Welfare (MHLW) in Japan. However, revisions of BE guidelines were required to account for the globalization of pharmaceutical development, new technology, and scientific rationales over the last 8 years. Therefore, the MHLW published the revised 'Guideline for Bioequivalence Studies of Generic Products' in 2020. In this article, we introduce the main revised contents, such as the addition of a fed-state BE study, reconsideration of the pilot study and add-on study, acceptance of foreign subjects in a BE study, and clarification of the requirement of a reference product. Furthermore, we compare the BE evaluations of generic oral solid dosage forms with those of the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA).

Current Regulation for Bioequivalence Evaluations of Generic Ophthalmic Dosage Forms in Japan.

In Japan, the revised version of bioequivalence (BE) evaluations for generic drug products was made available in 2012; however, the scope of this guideline is mainly oral solid dosage forms. Other dosage forms have to be discussed regarding how to evaluate BE by applicants and regulators during consultation meetings or the review process. Recently, there has been an increase in developing generic drug products in various dosage forms in Japan. Therefore, the Pharmaceuticals and Medical Devices Agency (PMDA) must strengthen their efforts to establish methodologies for BE evaluations for various dosage forms, including those of ophthalmic drugs. In 2016, the Japanese Ministry of Health, Labour and Welfare (MHLW) issued "The basic principles of bioequivalence evaluations of generic ophthalmic aqueous solutions." This document presents recommendations for clinical endpoint BE studies or biowaiver options to evaluate the BE of generic ophthalmic aqueous solutions. However, this document has brought other issues to the forefront, such as the lack of feasibility of human BE studies for certain indications. Therefore, the PMDA, Japan Ophthalmic Pharmaceutical Manufacturer's Association, and BE experts discussed these issues for 2 years, which led to an update by MHLW in 2018 entitled "The basic principles of bioequivalence evaluations of generic ophthalmic dosage forms." This document describes methodologies for evaluating the BE of ophthalmic dosage forms including suspensions. This article introduces recently approved generic products of ophthalmic dosage forms in Japan, the basic principle of which was issued in 2018, and compares the BE evaluations between the PMDA and U.S. Food and Drug Administration.

First approval of generic dry powder inhaler drug products in Japan.

The Japanese Ministry of Health, Labour and Welfare (MHLW) published the basic principles of bioequivalence evaluations for generic dry powder inhaler (DPI) drug products in March 2016. The basic principles were formulated to promote the development of effective and safe generic DPI drugs. Based on this document, the Pharmaceuticals and Medical Devices Agency (PMDA) advises generic companies on effective development through consultation meetings. The PMDA generally requires data from in vitro tests, pharmacokinetic studies, and pharmacodynamic or clinical endpoint studies for generic drug development. The MHLW approved the first generic version of the Symbicort Turbuhaler in 30- and 60-dose pack sizes in February 2019. This article presents the concrete data on the first approval of generic DPI drug products based on public information. Graphical abstract.

Current Understanding of the Equivalence Evaluations for In Vitro Tests on Generic Dry Powder Inhaler Drug Products in Japan.

The Japanese Ministry of Health, Labour and Welfare issued the basic principles for bioequivalence evaluations of generic dry powder inhaler (DPI) drug products in 2016. This document presents the recommendations of the methodology for the effective development of generic DPI drug products. Based on this document, the Pharmaceuticals and Medical Devices Agency (PMDA) advises the efficient development in the consultation meeting with generic companies. The PMDA generally requires the data of in vitro tests, pharmacokinetics studies, and clinical endpoint studies for generic development. In vitro tests play a critical role in the development of the generic versions because these tests are used to predict the efficacy and safety of other populations on whom clinical endpoint studies have not been conducted. We are aware that some points need further discussion, such as the recommendations for at least four groups of stages (group 1: the induction port and pre-separator, group 2: greater than 5 µm, group 3: ranging from 3 to 5 µm, group 4: ranging from 0.8 to 3 µm) for in vitro tests of the generic DPI products. This article shows the current understanding and recommendations with respect to in vitro tests, particularly for at least four groups of stages.

A Survey of the Regulatory Requirements for the Acceptance of Foreign Comparator Products by Participating Regulators and Organizations of the International Generic Drug Regulators Programme.

The acceptance of foreign comparator products is the most limiting factor for the development and regulatory assessment of generic medicines marketed globally. Bioequivalence studies have to be repeated with the local comparator products of each jurisdiction because it is unknown if the comparators of the different countries are the same product, with the consequent duplication of efforts by regulators and industry alike. The regulatory requirements on the acceptability of foreign comparator products of oral dosage forms differ between countries participating in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme. Brazil, Colombia, the European Union member States, Japan, Mexico, South Korea and the United States only accept bioequivalence studies with their local comparator. In contrast, Australia, Canada, New Zealand, Singapore, South Africa, Switzerland and Taiwan accept studies with foreign comparators under certain conditions. Canada limits its use to highly soluble drugs with a wide therapeutic range in immediate release products. Australia requires a comparison of the quantitative composition. In contrast, there are fewer restrictions on the acceptance of foreign comparators in New Zealand, Singapore, South Africa, Switzerland and Taiwan. For the WHO Prequalification of Medicines and for developing generics of the essential medicines the WHO lists comparators from different countries. In conclusion, there is currently no consensus amongst regulators on the acceptability of foreign comparator products.

The Requirements for Additional Strength Biowaivers for Immediate Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities.

In relation to the registration of generic products, waivers of in vivo bioequivalence studies (biowaivers) are considered in three main cases: certain dosage forms for which bioequivalence is self-evident (e.g. intravenous solutions), biowaivers based on the Biopharmaceutics Classification System and biowaivers for additional strengths with respect to the strength for which in vivo bioequivalence has been shown. The objective of this article is to describe the differences and commonalities in biowaivers for additional strengths of immediate release solid oral dosage forms between the participating members of the International Pharmaceutical Regulators Program (IPRP). The requirements are based on five main aspects; the pharmacokinetics of the drug substance, the manufacturing process, the qualitative and quantitative composition of the different strengths, and the comparative dissolution profiles. For the pharmacokinetic aspects, many regulators/agencies have the same requirements. All strengths must be manufactured with the same process, although a few regulators/agencies accept small differences. In relation to the formulation aspects, the data required breaks down into three major approaches based initially on one of those of the EU, the USA or Japan, but there are some differences in these three major approaches with some country specific interpretations. Most regulators/agencies also have the same requirements for the dissolution data, though there are some notable exceptions.

A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme.

PURPOSE: The Biopharmaceutics Classification System (BCS) based biowaiver is a scientific model which enables the substitution of in vivo bioequivalence studies with in vitro data as evidence of therapeutic equivalence subject to certain conditions. Despite being based on the same principles, BCS-based biowaivers are interpreted and regulated differently among international regulatory agencies. In this survey, the Bioequivalence Working Group (BEWG) of the International Generic Drug Regulators Programme (IGDRP) compared the criteria for BCS-based biowaivers applied by the participating regulators and organisations. METHODS: Differences and similarities regarding solubility, permeability, dissolution, excipients and fixed-dose combination products, were identified and compared in a detailed survey of each participant's criteria for BCS-based biowaivers. These criteria were determined based upon the participants' respective regulatory guidance documents, policies and practices. RESULTS: This review has, with the exception of two participants who do not accept BCS-based biowaivers, revealed that most IGDRP participants interpret the BCS principles and conditions similarly but notable differences exist in the application of these principles.  Conclusion: Although many similarities exist, this review identifies several opportunities for greater convergence of regulatory requirements amongst the surveyed jurisdictions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Current Japanese Regulatory Systems for Generics and Biosimilars.

Currently, biosimilar products are being actively developed around the world. One reason for this is the expiry of patents of original biopharmaceutical products with an extremely large market share because the biosimilar companies need to avoid infringing patents. A representative example of this is biosimilar versions of monoclonal antibodies. In Japan, the Ministry of Health, Labour and Welfare is promoting the use of biosimilar products because the market share of such products is currently extremely low compared with that of generic products. The Pharmaceuticals and Medical Devices Agency is responsible for reviewing generic and biosimilar products in Japan. However, no comparison of review systems for generics and biosimilars in Japan has been published. A more detailed understanding of review systems is important for using generic and biosimilar products. This article presents the current Japanese review systems for generic and biosimilar products and also the future challenges to facilitate the better regulation of both types of product.

Comparison of Generic Drug Reviews for Marketing Authorization between Japan and Canada.

PURPOSE: Generic drugs are assuming an increasingly important role in sustaining modern healthcare systems, as the cost of healthcare, including drug usage, is gradually expanding around the world. To date, published articles comparing generic drug reviews between different countries are scarce. OBJECTIVE: The objective of this study was to examine generic drug reviews in Japan and Canada. METHODS: We surveyed generic drug reviews from Japan and Canada and compared the following points: general matter (application types, type of partial change or Supplement to an Abbreviated New Drug Submission, application and approval numbers, review period, application format, review report, responsibility for review), bioequivalence studies for solid oral dosage forms, and bioequivalence guidelines, guidance, or basic principles regarding various dosage forms. RESULTS: This survey described the many similarities and differences in generic drug reviews between the two countries and points that should be improved to promote better generic drug reviews. In particular, regulations for the definition of the same or different active pharmaceutical ingredients (APIs) are similar for both authorities. CONCLUSIONS: The results clarified the future challenges of generic drug reviews, and the differences highlighted by this survey will be important considerations for the future. This is the first article to present and discuss the details of generic drug reviews between Japan and Canada.

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

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.

Similarities and Differences of International Practices and Procedures for the Regulation for Active Substance Master Files/Drug Master Files of Human Use: Moving Toward Regulatory Convergence.

PURPOSE: A gap analysis survey of international practices for Active Substance Master Files (ASMFs)/Drug Master Files (DMFs) of human use was conducted as a project of the ASMF/DMF working group of the International Generic Drug Regulators Pilot (IGDRP) to identify similarities and differences among ASMF/DMF procedures of 10 IGDRP members and 2 observers. METHODS: We conducted a questionnaire survey and compared the following aspects: overall ASMF/DMF procedures, submission requirements for ASMFs/DMFs, assessment processes for ASMFs/DMFs, the technical requirements for active pharmaceutical ingredients (APIs), generation of assessment reports for ASMFs/DMFs, procedures for changing ASMF/DMF details, and Good Manufacturing Practice (GMP) inspection/certification of API manufacturers. Twelve organizations participated in this project: the Brazilian Health Surveillance Agency (Anvisa), the European Union (EU), Health Canada (HC), the Singapore Health Sciences Authority (HSA), the South African Medicines Control Council (MCC), the South Korean Ministry of Food and Drug Safety (MFDS), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Swiss Agency for Therapeutic Products (Swissmedic), the Taiwan Food and Drug Administration (TFDA), the Australian Therapeutic Goods Administration (TGA), the European Directorate for the Quality of Medicines & HealthCare (EDQM) (Observer) and the Prequalification Team (PQT) of the World Health Organization (WHO), which includes the PQT-Medicines (Observer). RESULTS: Although there were many similarities among the participating agencies surveyed, there were also differences that should be discussed such as assessment processes of ASMFs/DMFs and Technical requirements for APIs. CONCLUSIONS: These differences revealed by this survey will be key considerations in order to facilitate the filing of ASMFs/DMFs globally and to establish a framework for sharing and utilizing information related to ASMFs/DMFs among IGDRP members in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.