New drug approval process in Japan

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    New drug approval process in Japan Takao Hayakawa Addresses National Institute of Health Sciences, l-1 8-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; e-mail:

    Current Opinion in Biotechnology 1999, 10307~311

    IF,> Elsevier Science Ltd ISSN 0958-l 669

    Abbreviations ADR adverse drug reaction CPAC Central Pharmaceutical Affairs Council GCP Good Clinical Practice

    ICH International Conference on Harmonization

    MWH Ministry of Health and Welfare NDA New Drug Application NIH National Institute of Health

    NIHS National Institute of Health Sciences

    NIID Natlonal Institute of lnfectlous Diseases PA0 Pharmaceutical Affairs Bureau

    PAL Pharmaceutical Affairs Law

    PCD Pharmaceuticals and Cosmetics Division

    PMDEC Pharmaceuticals and MedIcal Devices Evaluation Center PMSB Pharmaceutical and Medical Safety Bureau

    Introduction Recently, several new measures have been taken by

    Japans 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. Ihese new measures include: amendments to the Pharmaceutical Affairs Law (the fundamental law regulat- ing drugs) and other related laws: construction of a new system of drug review; and updating technical require- mcnts for new drug registration hased on the achievements of the International Conference on Harmonization (I(:H). Ihis 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 pre- pared 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 reg- ulatory 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/registra- tion 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 pharmaceu- ticals, and finally, movement towards international harmonization on technical requirements for the registra- tion 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. lhe amendments strengthened the regulations concern- ing 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 repercus- sions if they do not. Ihe 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 consul- tations on clinical trials with the sponsors:

    7. Improvement in the Nl)A/IMS review system;

    3. Ihe clinical and non-clinical NDA and post marketing data submitted have to meet the legally stipulated stan- dards. Ihis reflects an improvement in the data to meet recent advances in the related sciences that are embodied in the ICH guideline;

    4. Ihe requirements concerning AI)R reports both during clinical trials and after marketing have been documented.

    Organizations involved in the new drug application review and restructuring of the review system Japans 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 Ministers 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.

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    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 pre- scription drugs were reviewed in essence by the members of the various CPAC committees. Ihe Minister of Health and Welfare makes the final decision on approval in accor- dance 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 phar- maceuticals by engaging in Special Examinations in order to determine if the specifications and testing methods pro- posed for a new drug approval are appropriate. The NIHS deals with nearly all pharmaceuticals other than antibi- ocics, 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 clual- it?; 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 cosmet- ics). Xlajor subjects of the CPArug AI1K Relief, Research and Ijesign Promotion and Product Review.

    Ihe (:PA(: has one executive committee, 1.5 committees, and 6.1 subcommittees. Four crlmmittees and 14 sulxo~n- mittees have been involved in the examination of NDAs. Ihe 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. Ihus, hormones, such as insulin. glucagon, growth hormone. somatomedin C or atri- al natriuretic polypeptide. erychropoietines as drugs for renal anemia, intcrferons for viral hepatitis, and glucocere- brosidasc for Gauchers 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 interfer- ons, colony-stimulating factors, interleukins, or tumor necrosis factor, were submitted for approval as new anti- cancer 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 effica-

    CY would be reviewed by another appropriate 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 acti- vators, 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 biotechnolo- gy 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 modi- fied 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 regu- latory and scientific policies between subcommittees of the CI-?4C because the subcommittee members are usual- ly 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 regula- tory 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 drug approval process in Japan Hayakawa 309

    administration. that is, reform the PAB to the

    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 restruc- turing was especially intended to strengthen the governments evaluation capacity for securing the safety of drugs and preventing ADRs.

    The 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. Ihe 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 inten- sive and precise manner before consulting with the CI.4C.

    Ihc role of the Drug Organisatlon is to support the review by consulting with the sponsors and verifying the source data. Ihe 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 IMDEC:, the NDA review process has boen improved. Ihe PMDK accepts, on behalf of the Minister of ITeallh and Welfare, the NDAs suhmittcd and leaves the datl 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, sta- tisticians and other cxpcrts. alld an evaluation report is prepared. Ihe report is submitted to the WAC to con- summate the review for appro\a1. The 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 nec- essary during an in-house evaluation. the PhlDlK review team may consult with the experts from NIHS and other public institutions as well as the: IhlSB staff. Indeed, the application of new I)iotcchnolog!-derived products will he evaluated jointly by IMDECs review team and experts from the Division of Biological (Chemistry and Biologicals at NIHS before proceeding to the (XAC.

    It should he noted that any person wishing to manufacture or import a new drug, first has to obtain a manufacturing/import approval followed by a manufactur- er/importers 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 manu- facture/import the approved drug, for example, whether

    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 for biotechnological/biological 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. Ihe 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 microorgan- isms. T-he latter covers recombinant DNA drugs derived from mammalian cells, monoclonal antibodies, and any other protein drugs produced by certain cell-culture sys- tems [5,8].

    Iogether with progress in the development of ICH-har- monizrd 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 docu- ments have been completed for biotechnological/ biological products. These include Cell Substrate, Genetic Stability. Viral Safety, Product Stability, Specifications and Preclinical Safety documents.

    Ihc objective of the Cell Substrate guideline is to pro- vide 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) pro- tein 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 mol- ecular weight substances. (:ell banks used to prepare gene therapy products or vaccines should follow the recommen- dations presented in this document. For some biological products, such as certain virul vaccines prepared in prima- ry 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

    Ihe objective of the Genetic Stability guideline is to pro- vide 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.

    Ihe 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/registra- tion package. Ihe 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

  • New drug approval process in Japan Hayakawa 311

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