- Email: [email protected]
New drug approval process in Japan
307
New drug approval
process in Japan
Takao Hayakawa Addresses National Institute Tokyo 158-8501,
of Health Sciences, l-1 8-1, Japan; e-mail: [email protected]
Current
in Biotechnology
IF,>Elsevier
Opinion
Science
Ltd
ISSN
0958-l
1999,
Kamiyoga, Setagaya-ku,
10307~311
669
Abbreviations ADR adverse drug reaction CPAC Central Pharmaceutical Affairs Council Good Clinical Practice GCP International Conference on Harmonization ICH Ministry of Health and Welfare MWH NDA New Drug Application National Institute of Health NIH National Institute of Health Sciences NIHS Natlonal Institute of lnfectlous Diseases NIID PA0
PAL PCD
PMDEC PMSB
Pharmaceutical Pharmaceutical Pharmaceuticals Pharmaceuticals Pharmaceutical
Affairs Bureau Affairs Law and Cosmetics Division and MedIcal Devices Evaluation and Medical Safety Bureau
Center
Introduction Recently, several new measures have been taken by Japan’s Ministry of Health and Welfare (MHW) to ensure that good quality, safe and effective pharmaceuticals are developed and registered in a more efficient and rational manner. ‘I’hese new measures include: amendments to the Pharmaceutical Affairs Law (the fundamental law regulating drugs) and other related laws: construction of a new system of drug review; and updating technical requiremcnts for new drug registration hased on the achievements of the International Conference on Harmonization (I(:H). ‘I’his paper will describe the current situation in Japan regarding the approval process for new drugs.
The legal basis of drug evaluation/registration and review system Pharmaceutical administration in Japan is conducted according to a number of laws. l;or the implementation and management of these laws, detailed regulations are prepared by government and ministerial ordinances and notices. and notifications are issued by the Director General of the Bureau of the MIHW or the directors of the Division in charge [ 1,2]. Among these laws and related regulatory documenrs, the Pharmac~cutical Affairs I,aw (PAL) is the supreme law. The purpose of the PAL is to regulate matters pertaining to drugs, including biotechnological/biological products. quasi-drugs, cosmetics, and medical devices, to ensure their quality, efficacy and safety. It also promotes the development of drugs for rare diseases. The principal legal basis of the drug evaluation/registration and review system is described in the PAL. The PAL
has been revised several times since it was enacted in 1960 in order to meet, firstly, scientific developments in the pharmaceutical field. secondly, public needs and demand for better quality, safe and effective pharmaceuticals, and finally, movement towards international harmonization on technical requirements for the registration of pharmaceuticals [3,4]. Some specific features of revisions of the PAL and ocher related laws, which have recently been made, are as follows 141: 1. ‘l’he amendments strengthened the regulations concerning clinical trials performed both for new drug applications (NDAs) and post-marketing surveillance (PMS). Manufacturers are legally required to adhere to Good (Yinical Practice (GCP) regulations, with legal repercussions if they do not. ‘I’he legal bases for GCP inspections have also been fortified. At the same time, the Organization for Drug Adverse Drug Reaction (ADR) Relief, Research and Development Promotion and Product Review (the I)rug Organization), a semi-governmental body authorized by MHW3 has been legally empowered to perform consultations on clinical trials with the sponsors: 7. Improvement
in the Nl)A/I’MS
review
system;
3. ‘I’he clinical and non-clinical NDA and post marketing data submitted have to meet the legally stipulated standards. ‘I‘his reflects an improvement in the data to meet recent advances in the related sciences that are embodied in the ICH guideline; 4. ‘I’he requirements concerning clinical trials and after marketing
AI)R reports both during have been documented.
Organizations involved in the new drug application review and restructuring of the review system Japan’s MHW is in charge of improving and promoting social welfare, social security and public health. The MHW consists of home offices and external bodies. The home offices comprise the Minister’s Secretariat, nine Bureaus, local branch offices and affiliated institutions. ITp to 1997, three different organizations were mainly involved in NDA review: firstly, the Pharmaceutical Affairs Bureau (PAR), one of the nine MHW Bureaus; secondly, affiliated institutions of MHW, namely the National Institute of Health Sciences (NIHS) and the National Institute of Health (NIH), which was renamed as the National Institute of Infectious Diseases (NIlD)in 1997; and finally, the Central Pharmaceutical Affairs Council (WAC), an advisory body to the Minister of Health and Welfare, which is composed of experts working in medical and pharmaceutical institutions and universities. ‘The CPAC: examines and reviews important pharmaceutical matters.
308
Regulatory
affairs
Among these organizations, the PAR - especially the Pharmaceuticals and Cosmetics Division (PCD) within the PAB, which was the regulatoF agency for drug approval played a central role in the administrative activities for evaluation and registration of new drugs. Although the PCD was engaged in the review of generic over the counter drugs, minor changes in new drug approval as well as in the preliminary review of NDAs, the scientific and medical aspects of the applicar-ions for approval of new prescription drugs were reviewed in essence by the members of the various CPAC committees. ‘I’he Minister of Health and Welfare makes the final decision on approval in accordance with the CPAC report. In this context, one of the activities of the PAB/PCLl was to act as a secretariat to organize and run the CPAC committees [5,6]. In the NDA review process, the NIHS and NIH/NIID have played roles as national control laboratories for pharmaceuticals by engaging in ‘Special Examinations’ in order to determine if the specifications and testing methods proposed for a new drug approval are appropriate. The NIHS deals with nearly all pharmaceuticals other than antibiocics, vaccines and some blood products, which are dealt with by the NIH/NIID. Furthermore, the experts from both institutions. especially at the NIHS in the drug clualit?; and safety fields, have positively supported the PAR acrivities in various ways throllgh their scientific research, testing and investigating to assess the quality. safety and efficacy of pharmaceutical products. Also, many NIHS experts have served as members of the (:PAC and have played a crucial role in their respective special fields. The CPAC functions to investiggte and discuss, as requested by the Minister of Health and \Velfare. important matters on drugs (including medical devices, quasi-drugs and cosmetics). Xlajor subjects of the CPA<: discussion are: revision of the Japanese Pharmacopoeia; eQ&lishment of standards for drugs and related products; judgement on manufacturing approval for new drugs; determination of the number of drugs designated for efficacy reevaluation and implementation of the efficacy reevaluation; judgement, in light of medic31 and pharmaceutical sciences. on granting the relief fund under the Law of the Organization for L>rug AI1K Relief, Research and Ijesign Promotion and Product Review. ‘I’he (:PA(: has one executive committee, 1.5 committees, and 6.1 subcommittees. Four crlmmittees and 14 sulxo~nmittees have been involved in the examination of NDAs. ‘I’he CPA(: subcommittees an(l committees are organized so as to enable the examinatiorl of new drugs according to category and intended clinical DISC.For example, the l;irst Subcommittee on New 1)rugs engages in the examination of hormonal drugs, as well as dri~gs for diseases of digestive organs, kidney, liver, and so on. ‘I‘hus, hormones, such as insulin. glucagon, growth hormone. somatomedin C or atrial natriuretic polypeptide. erychropoietines as drugs for renal anemia, intcrferons for viral hepatitis, and glucocerebrosidasc for Gaucher’s disease were reviewed by this
subcommittee. Plasminogen activators, such as t-PA, prourokinase and urokinase, were examined by the Second Subcommittee on New Drugs, which deals mainly with circulatory system drugs. When cytokines, such as interferons, colony-stimulating factors, interleukins, or tumor necrosis factor, were submitted for approval as new anticancer drugs, they were examined by the Subcommittee on Anticancer Drugs. If their intended clinical uses are other than as anticancer drugs, then their safety and efficabe reviewed by another appropriate CY would subcommittee. The results of the examination by these subcommittees are usually reconfirmed by the Committee on Drugs and then the Executive Committee. Vaccines, such as hepatitis B surface antigen, are examined by the Subcommittee and Committee on Biological Products and by the Executive Committee. The Committee on Blood Products deals with major components of blood, including blood coagulation factors, but excluding plasminogen activators, kallikreins, hormones, and cytokines. Committees on Biological Products and Blood Products also engage in the standardization of specifications and testing methods for vaccines, blood products, and interferons [S]. Lip to the end of 1998, SO biotechnology-derived prescription drugs have been approved in Japan and several biotechnology products are presently under review. Among these, 20 products originated and were developed in Japan. Very recently, recombinant glucocerebrosidase, 2nd recombinant blood coagulation factor VIII, 4th recombinant t-PA, a modified recombinant t-PA, interferon gamma from a continuous cell line ((XI,) and CCL-derived hepatitis B surface antigen have been approved as prescription drugs for marketing. The latter three products were discovered in Japan. In the framework of this Japanese drug approval process, the Japanese Government, to a large extent, has depended on the evaluation of NDAs to the over 500 members of the various CP,4(: committees. This means that the members of each subcommittee who examine, for example, a new biotechnology product according to its intended clinical use would decide on the type, extent, and methods of the preclinical and clinical studies required for the approval of the agent. ‘This might lead, however, to inconsistent regulatory and scientific policies between subcommittees of the CI-?4C because the subcommittee members are usually different depending on the committee. An important role of the PAB was to coordinate regulatory and scientific policies between the CPA(: subcommittees [7]. although this was sometimes time-consuming. In order to ensure better and more prompt NDA review within the MHW, or more broadly, to improve the regulatory system to ensure better quality, safety and efficacy of the drugs, and to avoid too much dependence on as well as make better use of the external advisory council (CPAC), the hlHW restructcd its organization in July 1997. These changes include: restructuring of one of the nine MHW Bureaus that has been responsible for the pharmaceutical
New
the PAB to the administration. that is, reform Pharmaceutical and Medical Safety Bureau (PMSB): establishment of the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) within the NIHS; and strengthening of the Drug Organization. This restructuring was especially intended to strengthen the government’s evaluation capacity for securing the safety of drugs and preventing ADRs. ‘T’he PMSB consists of six divisions, and for NDA review the Evaluation and L,icensing Division will supervise the overall process and handle polic~y-related matters. The newly established PMI)EC in the NIHS comprises three divisions initially, increasing to five divisions in April 1999. ‘I’he PMDEC houses more than 60 reviewers with expertise in pharmaceutical sciences, medicine, dentistry, veterinary science, bio-statistics and others, so it is capable of examining and evaluating NI)A dossiers in a more intensive and precise manner before consulting with the CI’.4C. ‘I’hc role of the Drug Organisatlon is to support the review by consulting with the sponsors and verifying the source data. ‘I’he latter activity including G(ZP as well as (;ood I,aboratory Practice inspections. and examining other raw data, is legally entrusted by MHW to the L>rug Organization.
The current new drug application review process With the rstahlishmcnt of the I’MDEC:, the NDA review process has boen improved. ‘I’he PMDK accepts, on behalf of the Minister of ITeallh and Welfare, the NDAs suhmittcd and leaves the dat‘l reliability survey to the I>rug Organization. A basic but intensive review is then conducted from the scientific point of view by an in-house evaluation team consisting of pharmacists, physicians, statisticians and other cxpcrts. alld an evaluation report is prepared. ‘I’he report is submitted to the WAC to consummate the review for appro\a1. ‘T’he aim is to prepare a report :IS complete as poss~hlc so that the WAC: Committee need only discuss critical issues, for example. key points to bc cl-aluated with respect to clinical safety and efficacy of the drug. Iyor th,tt purpose, whenever necessary during an in-house evaluation. the PhlDlK review team may consult with the experts from NIHS and other public institutions as well as the: I’hlSB staff. Indeed, the application of new I)iotcchnolog!-derived products will he evaluated jointly by I’MDEC’s review team and experts from the Division of Biological (Chemistry and Biologicals at NIHS before proceeding to the (X’AC. It should he noted that any person wishing to manufacture or import a new drug, f‘irst has to obtain a manufacturing/import approval followed by a manufacturer/importer’s license for each item from the hlinistrr of Hcaith and Welfare. ‘[‘he license is issued after the I-‘MSR/~~IHW ensures that the applicant is able to manufacture/import the approved drug, for example, whether
drug
approval
process
in Japan
Hayakawa
309
the manufacturing/business facilities of the applicant have sufficient structure/equipment, manufacturing and quality control methods and human resources to properly deal with the approved drug. Drug manufacturers cannot get a license unless they conform to Good Manufacturing Practice [ 1 ,Z].
Technical requirement biotechnological/biological
for products
Before the ICI-I, the official regulatory position of the Japanese government concerning biotechnology drugs could be found in two Notifications, PAB/Evaluation and Registration Division Notification no. 243 originally issued in March 1984 and revised in 1992, and PAB/First Evaluation and Registration Division Notification no. 10 issued in June 198X. ‘I’he former describes standard requirements for data to be submitted with applications for approval of recombinant DNA peptide or protein drugs derived from fi,‘:st;llrr~&icr roli or other microorganisms. ‘T-he latter covers recombinant DNA drugs derived from mammalian cells, monoclonal antibodies, and any other protein drugs produced by certain cell-culture systems [5,8]. ‘I’ogether with progress in the development of ICH-harmonizrd documents, the MHW, of course based on the achievements of the ICH, has been taking the necessary measures to update the technical requirements for new drug registration. As of March 1999, six internationally harmonized documents have been completed for biotechnological/ biological products. These include Cell Substrate, Genetic Stability. Viral Safety, Product Stability, Specifications and Preclinical Safety documents. ‘I’hc objective of the ‘Cell Substrate’ guideline is to provide broad guidance on appropriate standards for the derivation of human and animal cell lines and microbial cells to be used to prepare hiotechnological/bio~ogica) protein products defined in this document, and for the preparation and characterization of cell banks to be used for production. Some of the important components of the ‘Cell Substrate’ document include: firstly, source, history, and generation of the cell substrate: secondly. cell banking, and finally, characterization and testing of the cell bank. Biotcchnological/hiological product refers to any- product prepared from cells cultivated from cell banks with the exception of microbial metaholites. such as, for example, antibiotics, amino acids, carbohydrates and other low molecular weight substances. (:ell banks used to prepare gene therapy products or vaccines should follow the recommendations presented in this document. For some biological products, such as certain virul vaccines prepared in primary cell cultures derived directly from animal tissues or organs, considerations that may apply to primary cells are discussed further in the Appendix of the document.
310
Regulatory affairs
‘I’he objective of the ‘Genetic Stability’ guideline is to provide guidance regarding the characterization of the expression construct for the production of recombinant DNA protein products in eukaryotic and prokaryotic cells. The purpose of analyzing the expression construct is to establish that the correct coding sequence of the product has been incorpomted into the host cell and is maintained during culture to the end of production. ‘I‘he ‘Viral Safety’ document i$ concerned with testing and evaluation of the viral safet) of biotechnology products derived from characterized cell lines of human or animal origin (i.e. mammalian, avian, ,Insect) and outlines data that should be submitted in the marketing application/registration package. ‘I’he purpose of this document is to provide a general framework for virus testing. experiments for the assessment of viral clearance and a recommended approach for the design of viral tests and viral clearance studies. Major areas described in the viral safety document include: cell line qualification; testing for viruses in unprocessed bulk; a rational<. and action plan for viral cleamnce studies and virus tests on purified bulk; and evaluation and characterization of viral clearance from unprocessed bulk. ‘I‘he purpose of the ‘Product Stability’ document is to give guidance to applicants regarding the type of stability studies that should be provided in support of marketing applications for hiotechnolo~ical/biolo~ical products in which the active components are typically well-characterized proteins and/or polypeljtides. The specific areas described in the guideline inc,lude: selection of batches: stability-indicating profile that provides assurance that changes in the identity, purity and potency of the product will be detected; storage conditions; testing frequency; specifications: and labeling.
general areas considered in the guideline include: specification of the test materials that are utilized in safety assessment studies; considerations related to assessment of biological activity and pharmacodynamics; unique issues related to selection of animal species or models for pharmacology and toxicity studies; guidance related to the number/gender of animals; consideration related to designing the route, frequency and method of administration of test materials and dose selection; and specific considerations related to immunogenicity of a product. The guideline also describes areas of specific concern. It should be noted that the Cell Substrate and Genetic Stability documents are related to early stages in the manufacturing process, including banked cell substrates and cells at the limit. that is, production cells cultured up to the proposed limit of drug production runs. Viral Safety issues are related to all stages involved in the manufacturing process. including banked cell substrates, cells at the limit, unprocessed bulk, purified bulk or final product. Product Stability, Specifications and Preclinical Safety ‘I’esting documents are related to purified bulk and/or final products. ‘I’hus. fundamental issues related to technical requirements for the consistent production of biotechnology pharmaceuticals and for their assessment and control with respect to quality and preclinical safety have been mainly covered [9,10]. It is suggested that applicants should use these I(:H documents. whenever possible and appropriate. in place of the existing PAR Notifications. In addition, because of the nature of drug research and development, especially- in the biotechnology field and the specific features of each product, it will be necessary to adopt a science-based flexible approach upon reviewing an individual application. Also, updating any existing documents based on new and developing scientific data and development of new guidance for NDA concerning novel types of biopharmaceuticals, such as for gene therapy or cellular therapy or transgenic animal-derived products, will be necessary, though MHW has already issued guidance for clinical research for gene therapy. Scientific policies concerning new drug appro\,al will always need to be kept in the front line of research.
Bulk drug substance and final product specifications are key parts of the core documentation for world-wide product license applications. ‘l’he ‘Specification’ guideline provides general principles on the setting and justificarion, as far as is possible, of a uniform set of international specifications for biotechnological/bic,logical products to support new m.lrketing applications. The guideline identifies a number of general principles for consideration in setting specifications: first, characterization of a product; second, analytical considerations related to reference standards Jnd reference materials as well as validation of analytical procedures; third, process controls; fourth, pharmacopoeia] specifications: fifth, release limits versus shelf-life limits; and sixth. statistical concepts. The document also provides guidance for justification of the specification and drug substance specification and drug product specifications.
It is expected that developments in cooperative relationships among the PhlSR, PMDEC/NIHS, Drug Organization and CPAC will lead to ensuring smooth and rational processing throughout the administrative and scientific drug approval process. It is also expected that pharmaceutical administration will be conducted in an open and transparent manner.
The ‘Preclinical Safety’ guidelIne is intended to provide general principles for designing scientifically acceptable preclinical safety evaluation programs. The major
Of course the ultimate goal of this endeavor should be to allow patients increased accessibility to novel safe and effective medicines awaiting approval.
Conclusions
New
References 1.
Pharmaceutrcals and Cosmetics Division, Pharmaceutrcal Affarrs Bureau, Japanese Ministry of Health and Welfare (Eds): Japanese Technical Requirements for New Drug Registration 1997, with Relevant Japanese and ICH Guidelines Collected in an Appendix. Tokyo: Yakuji Nippo Ltd; 1997. Pharmaceutrcal Affairs Bureau, Japanese Minrstry of Health and Welfare (Eds): Pharmaceutical Administration in Japan fin Japanese and Eng/ish,J, edn 7. Tokyo: Yakuji Nippo Ltd; 1996.
3.
Doi 0: Opening addresses. In Proceedings of the Fourfh lnternafional Conference on /-/armonlzat/on: 1997; Brussels. Edited by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Ltd; 1998:21-24.
5.
6.
Tominaga T: The benefits of harmonization. In Proceedings of the Fourth biternational Conference on Harmonization: 1997; Brussels. Edited by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Ltd; 1998506-508. Hayakawa T: The Japanese perspective regarding regulatory concerns for biotechnology drugs and their scientific basis. Drug Biotechnology Regulation, Scientific Basis and Practices. Edtted by Chiu Y-YH, Gueriguian JL New York: Marcel Dekker 1991:468-498. Morrguchr process
H: Regulatory expectation for data on viral testing evaluation for phase 1 studies and product licensing
approval
process
in Japan
Hayakawa
311
Japan. In Viral Safety and Evaluation of viral Clearance from B/opharmaceutica/ Products. Developments in Biological Standardization, vol 88. Edited by Brown F, Lubiniecki A. Basel: Karger; 1996:143-l 47.
2.
4.
drug
7.
Hayakawa T: Current regulatory situation in Japan with respect to the preclinical safety testing for biotechnology products intended for human use. In Proceedings of the First fnternational Conference on Harmonization: 1991; Brussels. Edited by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Lid; 1992:295-301.
8.
Hayakawa T: Global perspective on specifications for biotechnology products. Perspective from Japan. In Development of Specifications for Biotechnology Products. Developments in Biological Standardization, vol91. Edited by Brown F, Fernandez Basel: Karger; 1997:15-23.
J.
9.
Hayakawa T: Technical workshop II: new medicines from biotechnology: workshop overview. In Proceedings of the Fourth fnternational Conference on Harmonization: 1997; Brussels. Edrted by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Ltd; 1998:153-156.
10
Hayakawa harmonization medicines Technology: by lkura K, Academrc
In Inc; and in
T: Overview of the international endeavor toward of technical requirements for the control of new from biotechnology. In Proceedings of Animal Cell Challenges for the 27s’ century (JAACUESACT). Edited Nagao M, Masuda S, Sasaki R. Netherlands: Kluwer Publishers; 1999:215-219.
New drug approval
process in Japan
Takao Hayakawa Addresses National Institute Tokyo 158-8501,
of Health Sciences, l-1 8-1, Japan; e-mail: [email protected]
Current
in Biotechnology
IF,>Elsevier
Opinion
Science
Ltd
ISSN
0958-l
1999,
Kamiyoga, Setagaya-ku,
10307~311
669
Abbreviations ADR adverse drug reaction CPAC Central Pharmaceutical Affairs Council Good Clinical Practice GCP International Conference on Harmonization ICH Ministry of Health and Welfare MWH NDA New Drug Application National Institute of Health NIH National Institute of Health Sciences NIHS Natlonal Institute of lnfectlous Diseases NIID PA0
PAL PCD
PMDEC PMSB
Pharmaceutical Pharmaceutical Pharmaceuticals Pharmaceuticals Pharmaceutical
Affairs Bureau Affairs Law and Cosmetics Division and MedIcal Devices Evaluation and Medical Safety Bureau
Center
Introduction Recently, several new measures have been taken by Japan’s Ministry of Health and Welfare (MHW) to ensure that good quality, safe and effective pharmaceuticals are developed and registered in a more efficient and rational manner. ‘I’hese new measures include: amendments to the Pharmaceutical Affairs Law (the fundamental law regulating drugs) and other related laws: construction of a new system of drug review; and updating technical requiremcnts for new drug registration hased on the achievements of the International Conference on Harmonization (I(:H). ‘I’his paper will describe the current situation in Japan regarding the approval process for new drugs.
The legal basis of drug evaluation/registration and review system Pharmaceutical administration in Japan is conducted according to a number of laws. l;or the implementation and management of these laws, detailed regulations are prepared by government and ministerial ordinances and notices. and notifications are issued by the Director General of the Bureau of the MIHW or the directors of the Division in charge [ 1,2]. Among these laws and related regulatory documenrs, the Pharmac~cutical Affairs I,aw (PAL) is the supreme law. The purpose of the PAL is to regulate matters pertaining to drugs, including biotechnological/biological products. quasi-drugs, cosmetics, and medical devices, to ensure their quality, efficacy and safety. It also promotes the development of drugs for rare diseases. The principal legal basis of the drug evaluation/registration and review system is described in the PAL. The PAL
has been revised several times since it was enacted in 1960 in order to meet, firstly, scientific developments in the pharmaceutical field. secondly, public needs and demand for better quality, safe and effective pharmaceuticals, and finally, movement towards international harmonization on technical requirements for the registration of pharmaceuticals [3,4]. Some specific features of revisions of the PAL and ocher related laws, which have recently been made, are as follows 141: 1. ‘l’he amendments strengthened the regulations concerning clinical trials performed both for new drug applications (NDAs) and post-marketing surveillance (PMS). Manufacturers are legally required to adhere to Good (Yinical Practice (GCP) regulations, with legal repercussions if they do not. ‘I’he legal bases for GCP inspections have also been fortified. At the same time, the Organization for Drug Adverse Drug Reaction (ADR) Relief, Research and Development Promotion and Product Review (the I)rug Organization), a semi-governmental body authorized by MHW3 has been legally empowered to perform consultations on clinical trials with the sponsors: 7. Improvement
in the Nl)A/I’MS
review
system;
3. ‘I’he clinical and non-clinical NDA and post marketing data submitted have to meet the legally stipulated standards. ‘I‘his reflects an improvement in the data to meet recent advances in the related sciences that are embodied in the ICH guideline; 4. ‘I’he requirements concerning clinical trials and after marketing
AI)R reports both during have been documented.
Organizations involved in the new drug application review and restructuring of the review system Japan’s MHW is in charge of improving and promoting social welfare, social security and public health. The MHW consists of home offices and external bodies. The home offices comprise the Minister’s Secretariat, nine Bureaus, local branch offices and affiliated institutions. ITp to 1997, three different organizations were mainly involved in NDA review: firstly, the Pharmaceutical Affairs Bureau (PAR), one of the nine MHW Bureaus; secondly, affiliated institutions of MHW, namely the National Institute of Health Sciences (NIHS) and the National Institute of Health (NIH), which was renamed as the National Institute of Infectious Diseases (NIlD)in 1997; and finally, the Central Pharmaceutical Affairs Council (WAC), an advisory body to the Minister of Health and Welfare, which is composed of experts working in medical and pharmaceutical institutions and universities. ‘The CPAC: examines and reviews important pharmaceutical matters.
308
Regulatory
affairs
Among these organizations, the PAR - especially the Pharmaceuticals and Cosmetics Division (PCD) within the PAB, which was the regulatoF agency for drug approval played a central role in the administrative activities for evaluation and registration of new drugs. Although the PCD was engaged in the review of generic over the counter drugs, minor changes in new drug approval as well as in the preliminary review of NDAs, the scientific and medical aspects of the applicar-ions for approval of new prescription drugs were reviewed in essence by the members of the various CPAC committees. ‘I’he Minister of Health and Welfare makes the final decision on approval in accordance with the CPAC report. In this context, one of the activities of the PAB/PCLl was to act as a secretariat to organize and run the CPAC committees [5,6]. In the NDA review process, the NIHS and NIH/NIID have played roles as national control laboratories for pharmaceuticals by engaging in ‘Special Examinations’ in order to determine if the specifications and testing methods proposed for a new drug approval are appropriate. The NIHS deals with nearly all pharmaceuticals other than antibiocics, vaccines and some blood products, which are dealt with by the NIH/NIID. Furthermore, the experts from both institutions. especially at the NIHS in the drug clualit?; and safety fields, have positively supported the PAR acrivities in various ways throllgh their scientific research, testing and investigating to assess the quality. safety and efficacy of pharmaceutical products. Also, many NIHS experts have served as members of the (:PAC and have played a crucial role in their respective special fields. The CPAC functions to investiggte and discuss, as requested by the Minister of Health and \Velfare. important matters on drugs (including medical devices, quasi-drugs and cosmetics). Xlajor subjects of the CPA<: discussion are: revision of the Japanese Pharmacopoeia; eQ&lishment of standards for drugs and related products; judgement on manufacturing approval for new drugs; determination of the number of drugs designated for efficacy reevaluation and implementation of the efficacy reevaluation; judgement, in light of medic31 and pharmaceutical sciences. on granting the relief fund under the Law of the Organization for L>rug AI1K Relief, Research and Ijesign Promotion and Product Review. ‘I’he (:PA(: has one executive committee, 1.5 committees, and 6.1 subcommittees. Four crlmmittees and 14 sulxo~nmittees have been involved in the examination of NDAs. ‘I’he CPA(: subcommittees an(l committees are organized so as to enable the examinatiorl of new drugs according to category and intended clinical DISC.For example, the l;irst Subcommittee on New 1)rugs engages in the examination of hormonal drugs, as well as dri~gs for diseases of digestive organs, kidney, liver, and so on. ‘I‘hus, hormones, such as insulin. glucagon, growth hormone. somatomedin C or atrial natriuretic polypeptide. erychropoietines as drugs for renal anemia, intcrferons for viral hepatitis, and glucocerebrosidasc for Gaucher’s disease were reviewed by this
subcommittee. Plasminogen activators, such as t-PA, prourokinase and urokinase, were examined by the Second Subcommittee on New Drugs, which deals mainly with circulatory system drugs. When cytokines, such as interferons, colony-stimulating factors, interleukins, or tumor necrosis factor, were submitted for approval as new anticancer drugs, they were examined by the Subcommittee on Anticancer Drugs. If their intended clinical uses are other than as anticancer drugs, then their safety and efficabe reviewed by another appropriate CY would subcommittee. The results of the examination by these subcommittees are usually reconfirmed by the Committee on Drugs and then the Executive Committee. Vaccines, such as hepatitis B surface antigen, are examined by the Subcommittee and Committee on Biological Products and by the Executive Committee. The Committee on Blood Products deals with major components of blood, including blood coagulation factors, but excluding plasminogen activators, kallikreins, hormones, and cytokines. Committees on Biological Products and Blood Products also engage in the standardization of specifications and testing methods for vaccines, blood products, and interferons [S]. Lip to the end of 1998, SO biotechnology-derived prescription drugs have been approved in Japan and several biotechnology products are presently under review. Among these, 20 products originated and were developed in Japan. Very recently, recombinant glucocerebrosidase, 2nd recombinant blood coagulation factor VIII, 4th recombinant t-PA, a modified recombinant t-PA, interferon gamma from a continuous cell line ((XI,) and CCL-derived hepatitis B surface antigen have been approved as prescription drugs for marketing. The latter three products were discovered in Japan. In the framework of this Japanese drug approval process, the Japanese Government, to a large extent, has depended on the evaluation of NDAs to the over 500 members of the various CP,4(: committees. This means that the members of each subcommittee who examine, for example, a new biotechnology product according to its intended clinical use would decide on the type, extent, and methods of the preclinical and clinical studies required for the approval of the agent. ‘This might lead, however, to inconsistent regulatory and scientific policies between subcommittees of the CI-?4C because the subcommittee members are usually different depending on the committee. An important role of the PAB was to coordinate regulatory and scientific policies between the CPA(: subcommittees [7]. although this was sometimes time-consuming. In order to ensure better and more prompt NDA review within the MHW, or more broadly, to improve the regulatory system to ensure better quality, safety and efficacy of the drugs, and to avoid too much dependence on as well as make better use of the external advisory council (CPAC), the hlHW restructcd its organization in July 1997. These changes include: restructuring of one of the nine MHW Bureaus that has been responsible for the pharmaceutical
New
the PAB to the administration. that is, reform Pharmaceutical and Medical Safety Bureau (PMSB): establishment of the Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) within the NIHS; and strengthening of the Drug Organization. This restructuring was especially intended to strengthen the government’s evaluation capacity for securing the safety of drugs and preventing ADRs. ‘T’he PMSB consists of six divisions, and for NDA review the Evaluation and L,icensing Division will supervise the overall process and handle polic~y-related matters. The newly established PMI)EC in the NIHS comprises three divisions initially, increasing to five divisions in April 1999. ‘I’he PMDEC houses more than 60 reviewers with expertise in pharmaceutical sciences, medicine, dentistry, veterinary science, bio-statistics and others, so it is capable of examining and evaluating NI)A dossiers in a more intensive and precise manner before consulting with the CI’.4C. ‘I’hc role of the Drug Organisatlon is to support the review by consulting with the sponsors and verifying the source data. ‘I’he latter activity including G(ZP as well as (;ood I,aboratory Practice inspections. and examining other raw data, is legally entrusted by MHW to the L>rug Organization.
The current new drug application review process With the rstahlishmcnt of the I’MDEC:, the NDA review process has boen improved. ‘I’he PMDK accepts, on behalf of the Minister of ITeallh and Welfare, the NDAs suhmittcd and leaves the dat‘l reliability survey to the I>rug Organization. A basic but intensive review is then conducted from the scientific point of view by an in-house evaluation team consisting of pharmacists, physicians, statisticians and other cxpcrts. alld an evaluation report is prepared. ‘I’he report is submitted to the WAC to consummate the review for appro\a1. ‘T’he aim is to prepare a report :IS complete as poss~hlc so that the WAC: Committee need only discuss critical issues, for example. key points to bc cl-aluated with respect to clinical safety and efficacy of the drug. Iyor th,tt purpose, whenever necessary during an in-house evaluation. the PhlDlK review team may consult with the experts from NIHS and other public institutions as well as the: I’hlSB staff. Indeed, the application of new I)iotcchnolog!-derived products will he evaluated jointly by I’MDEC’s review team and experts from the Division of Biological (Chemistry and Biologicals at NIHS before proceeding to the (X’AC. It should he noted that any person wishing to manufacture or import a new drug, f‘irst has to obtain a manufacturing/import approval followed by a manufacturer/importer’s license for each item from the hlinistrr of Hcaith and Welfare. ‘[‘he license is issued after the I-‘MSR/~~IHW ensures that the applicant is able to manufacture/import the approved drug, for example, whether
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the manufacturing/business facilities of the applicant have sufficient structure/equipment, manufacturing and quality control methods and human resources to properly deal with the approved drug. Drug manufacturers cannot get a license unless they conform to Good Manufacturing Practice [ 1 ,Z].
Technical requirement biotechnological/biological
for products
Before the ICI-I, the official regulatory position of the Japanese government concerning biotechnology drugs could be found in two Notifications, PAB/Evaluation and Registration Division Notification no. 243 originally issued in March 1984 and revised in 1992, and PAB/First Evaluation and Registration Division Notification no. 10 issued in June 198X. ‘I’he former describes standard requirements for data to be submitted with applications for approval of recombinant DNA peptide or protein drugs derived from fi,‘:st;llrr~&icr roli or other microorganisms. ‘T-he latter covers recombinant DNA drugs derived from mammalian cells, monoclonal antibodies, and any other protein drugs produced by certain cell-culture systems [5,8]. ‘I’ogether with progress in the development of ICH-harmonizrd documents, the MHW, of course based on the achievements of the ICH, has been taking the necessary measures to update the technical requirements for new drug registration. As of March 1999, six internationally harmonized documents have been completed for biotechnological/ biological products. These include Cell Substrate, Genetic Stability. Viral Safety, Product Stability, Specifications and Preclinical Safety documents. ‘I’hc objective of the ‘Cell Substrate’ guideline is to provide broad guidance on appropriate standards for the derivation of human and animal cell lines and microbial cells to be used to prepare hiotechnological/bio~ogica) protein products defined in this document, and for the preparation and characterization of cell banks to be used for production. Some of the important components of the ‘Cell Substrate’ document include: firstly, source, history, and generation of the cell substrate: secondly. cell banking, and finally, characterization and testing of the cell bank. Biotcchnological/hiological product refers to any- product prepared from cells cultivated from cell banks with the exception of microbial metaholites. such as, for example, antibiotics, amino acids, carbohydrates and other low molecular weight substances. (:ell banks used to prepare gene therapy products or vaccines should follow the recommendations presented in this document. For some biological products, such as certain virul vaccines prepared in primary cell cultures derived directly from animal tissues or organs, considerations that may apply to primary cells are discussed further in the Appendix of the document.
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‘I’he objective of the ‘Genetic Stability’ guideline is to provide guidance regarding the characterization of the expression construct for the production of recombinant DNA protein products in eukaryotic and prokaryotic cells. The purpose of analyzing the expression construct is to establish that the correct coding sequence of the product has been incorpomted into the host cell and is maintained during culture to the end of production. ‘I‘he ‘Viral Safety’ document i$ concerned with testing and evaluation of the viral safet) of biotechnology products derived from characterized cell lines of human or animal origin (i.e. mammalian, avian, ,Insect) and outlines data that should be submitted in the marketing application/registration package. ‘I’he purpose of this document is to provide a general framework for virus testing. experiments for the assessment of viral clearance and a recommended approach for the design of viral tests and viral clearance studies. Major areas described in the viral safety document include: cell line qualification; testing for viruses in unprocessed bulk; a rational<. and action plan for viral cleamnce studies and virus tests on purified bulk; and evaluation and characterization of viral clearance from unprocessed bulk. ‘I‘he purpose of the ‘Product Stability’ document is to give guidance to applicants regarding the type of stability studies that should be provided in support of marketing applications for hiotechnolo~ical/biolo~ical products in which the active components are typically well-characterized proteins and/or polypeljtides. The specific areas described in the guideline inc,lude: selection of batches: stability-indicating profile that provides assurance that changes in the identity, purity and potency of the product will be detected; storage conditions; testing frequency; specifications: and labeling.
general areas considered in the guideline include: specification of the test materials that are utilized in safety assessment studies; considerations related to assessment of biological activity and pharmacodynamics; unique issues related to selection of animal species or models for pharmacology and toxicity studies; guidance related to the number/gender of animals; consideration related to designing the route, frequency and method of administration of test materials and dose selection; and specific considerations related to immunogenicity of a product. The guideline also describes areas of specific concern. It should be noted that the Cell Substrate and Genetic Stability documents are related to early stages in the manufacturing process, including banked cell substrates and cells at the limit. that is, production cells cultured up to the proposed limit of drug production runs. Viral Safety issues are related to all stages involved in the manufacturing process. including banked cell substrates, cells at the limit, unprocessed bulk, purified bulk or final product. Product Stability, Specifications and Preclinical Safety ‘I’esting documents are related to purified bulk and/or final products. ‘I’hus. fundamental issues related to technical requirements for the consistent production of biotechnology pharmaceuticals and for their assessment and control with respect to quality and preclinical safety have been mainly covered [9,10]. It is suggested that applicants should use these I(:H documents. whenever possible and appropriate. in place of the existing PAR Notifications. In addition, because of the nature of drug research and development, especially- in the biotechnology field and the specific features of each product, it will be necessary to adopt a science-based flexible approach upon reviewing an individual application. Also, updating any existing documents based on new and developing scientific data and development of new guidance for NDA concerning novel types of biopharmaceuticals, such as for gene therapy or cellular therapy or transgenic animal-derived products, will be necessary, though MHW has already issued guidance for clinical research for gene therapy. Scientific policies concerning new drug appro\,al will always need to be kept in the front line of research.
Bulk drug substance and final product specifications are key parts of the core documentation for world-wide product license applications. ‘l’he ‘Specification’ guideline provides general principles on the setting and justificarion, as far as is possible, of a uniform set of international specifications for biotechnological/bic,logical products to support new m.lrketing applications. The guideline identifies a number of general principles for consideration in setting specifications: first, characterization of a product; second, analytical considerations related to reference standards Jnd reference materials as well as validation of analytical procedures; third, process controls; fourth, pharmacopoeia] specifications: fifth, release limits versus shelf-life limits; and sixth. statistical concepts. The document also provides guidance for justification of the specification and drug substance specification and drug product specifications.
It is expected that developments in cooperative relationships among the PhlSR, PMDEC/NIHS, Drug Organization and CPAC will lead to ensuring smooth and rational processing throughout the administrative and scientific drug approval process. It is also expected that pharmaceutical administration will be conducted in an open and transparent manner.
The ‘Preclinical Safety’ guidelIne is intended to provide general principles for designing scientifically acceptable preclinical safety evaluation programs. The major
Of course the ultimate goal of this endeavor should be to allow patients increased accessibility to novel safe and effective medicines awaiting approval.
Conclusions
New
References 1.
Pharmaceutrcals and Cosmetics Division, Pharmaceutrcal Affarrs Bureau, Japanese Ministry of Health and Welfare (Eds): Japanese Technical Requirements for New Drug Registration 1997, with Relevant Japanese and ICH Guidelines Collected in an Appendix. Tokyo: Yakuji Nippo Ltd; 1997. Pharmaceutrcal Affairs Bureau, Japanese Minrstry of Health and Welfare (Eds): Pharmaceutical Administration in Japan fin Japanese and Eng/ish,J, edn 7. Tokyo: Yakuji Nippo Ltd; 1996.
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Tominaga T: The benefits of harmonization. In Proceedings of the Fourth biternational Conference on Harmonization: 1997; Brussels. Edited by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Ltd; 1998506-508. Hayakawa T: The Japanese perspective regarding regulatory concerns for biotechnology drugs and their scientific basis. Drug Biotechnology Regulation, Scientific Basis and Practices. Edtted by Chiu Y-YH, Gueriguian JL New York: Marcel Dekker 1991:468-498. Morrguchr process
H: Regulatory expectation for data on viral testing evaluation for phase 1 studies and product licensing
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Japan. In Viral Safety and Evaluation of viral Clearance from B/opharmaceutica/ Products. Developments in Biological Standardization, vol 88. Edited by Brown F, Lubiniecki A. Basel: Karger; 1996:143-l 47.
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Hayakawa T: Current regulatory situation in Japan with respect to the preclinical safety testing for biotechnology products intended for human use. In Proceedings of the First fnternational Conference on Harmonization: 1991; Brussels. Edited by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Lid; 1992:295-301.
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Hayakawa T: Global perspective on specifications for biotechnology products. Perspective from Japan. In Development of Specifications for Biotechnology Products. Developments in Biological Standardization, vol91. Edited by Brown F, Fernandez Basel: Karger; 1997:15-23.
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Hayakawa T: Technical workshop II: new medicines from biotechnology: workshop overview. In Proceedings of the Fourth fnternational Conference on Harmonization: 1997; Brussels. Edrted by D’Arcy PF, Harron DWG. Northern Ireland: Greystone Books Ltd; 1998:153-156.
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T: Overview of the international endeavor toward of technical requirements for the control of new from biotechnology. In Proceedings of Animal Cell Challenges for the 27s’ century (JAACUESACT). Edited Nagao M, Masuda S, Sasaki R. Netherlands: Kluwer Publishers; 1999:215-219.