Drug Approval System of Japan

Transcription

1 Drug Approval System of Japan December

2 Abbreviation MHLW: Ministry of Health, Labour, and Welfare PMDA: Pharmaceuticals and Medical Devices Agency PAFSC: Pharmaceutical Affairs and Food Sanitation Council PFSB: Pharmaceutical and Food Safety Bureau NIBIO: National Institute of Biomedical Innovation JPMA: Japan Pharmaceutical Manufacturers Association Notice 1. Due to the purpose of this document, most of the information was quoted directly from the website or related guidelines of each country s drug regulatory agencies and, reviewed by the agencies. 2. This document is limited only to pharmaceutical products, no applicable to biological and herbal products. 3. When referring to the contents of this document, check the up-to-date information including related laws and regulations, and revision of guidelines. 2

3 Table of Contents I. Drug Regulatory Agency 7 1. Ministry of Health, Labour and Welfare (MHLW) Organization Task of Pharmaceutical and Food Safety Bureau and its related Organization Website Pharmaceuticals and Medical Devices Agency (PMDA) Organization Tasks Website 14 II. Related Laws Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics Brief overview of revision of PAL Related regulations Guidance and guidelines 15 III. Classification of Pharmaceutical Products New drug Generic drug Orphan drug Number of patients Medial needs Possibility of development 18 IV. Drug Approval System Clinical trial (IND) notification 19 3

4 1.1 Overview Interview advice meeting Review period Required documents New drug approval (NDA) application Procedure PMDA evaluation process PAFSC consultation Review period Required documents Generic drug approval application Procedure Review period Required documents Patent-approval linkage system Orphan drug Organization that designates orphan drugs Orphan drug designation procedure Required documents for designation Review period Incentives Priority review Pharmaceutical products for priority review Procedure Priority review meeting Review period 38 V. Others Good Manufacturing Practice (GMP) 39 4

5 1.1 GMP compliance inspection concerning pharmaceuticals (including APIs) of foreign manufacturers Drug Master File (DMF) Overview Items targeted for Drug Master File registration Labeling and package inserts Overview Headings and their sequence in package inserts that are required in the labeling Requirements for Certificate of a Pharmaceutical Product (CPP) Approval of manufacturing/marketing of medicinal products Manufacturing/marketing business license Efficacy and Safety of medicinal products Accreditation of foreign manufacturers Fees for regulatory approval 51 VI. References 52 5

6 List of Figures Figure 1 Organization of Ministry of Health, Labour and Welfare (MHLW) Figure 2 Organization of Pharmaceuticals and Medical Devices Agency (PMDA) Figure 3 Procedure of Interview Advice Meeting Figure 4 New Drug Marketing Approval Process Figure 5 Flowchart of New Drug Development and Approval Figure 6 Organizations that Designate Orphan Drug/Medical Device Figure 7. Flow Chart for Orphan Drug/Medical Device Designation Figure 8 Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (1) Figure 9 Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (2) Figure 10 Layout of a Package Insert for a Prescription Drug (with "Warning") Figure 11 Flow of Drug Manufacturing/Marketing Approvals List of Appendices Appendix 1. Instructions for Filling Out the IND Application Form 6

7 I. Drug Regulatory Agency 1. Ministry of Health, Labour and Welfare (MHLW) The Ministry of Health, Labour, and Welfare (MHLW) is responsible for medical care, long-term care, pensions, labour, childcare, and public assistance of Japanese. It has its mission to enable people to live fulfilling lives with a greater sense of security. 1 Therefore, the MHLW is also in charge of pharmaceutical regulatory affairs in Japan (except veterinary drugs which are under the jurisdiction of the Ministry of Agriculture, Forestry and Fisheries). 1.1 Organization The MHLW consists of headquarters, affiliated institutions, councils, regional bureaus, and external bureaus. The headquarters includes the Minister's Secretariat, 11 bureaus including Pharmaceutical and Food Safety Bureau, 6 departments and the Director-General for Policy Planning and Evaluation. Affiliated institutions include quarantine stations, National Hansen s Disease Sanatoriums, research institutions including National Institute of Health Sciences, and social welfare facilities. There are 14 Councils, including the Social Security Council and Pharmaceutical Affairs and Food Sanitation Council (PAFSC). Moreover, there are regional bureaus such as Regional Bureaus of Health and Welfare and Prefectural Labor Bureaus; and external bureaus including the Central Labor Relations Commission. The detailed organization is shown in Figure 1 as below: 1 Ministry of Health, Labour and Welfare Service Guide 2014, For people, for life, for the future (pamphlet of MHLW) 7

8 Figure 1. Organization of Ministry of Health, Labour and Welfare (MHLW) 8

9 1.2 Task of Pharmaceutical and Food Safety Bureau and its related organization 2 The Pharmaceutical and Food Safety Bureau (PFSB) undertakes main duties and functions to ensure the quality, efficacy, and safety of drugs, medical devices, and food. It handles clinical studies, approval and post-marketing safety measures, i.e., approvals and licensing. The PFSB consists of Secretary-General, Councilor in charge of drugs, five divisions (General Affairs Division, Evaluation and Licensing Division, Safety Division, Compliance and Narcotics Division, and Blood and Blood Products Division), and one office. Especially, tasks of the Evaluation and Licensing Division are as follows: - Technical guidance and supervision concerning the production of drugs, quasi-drugs, cosmetics, and medical devices ( drugs, etc. ) - Manufacturing/marketing business licenses and approvals to manufacture and market drugs, etc. - Re-examination and re-evaluation of drugs and medical devices - Business license and approvals to market, rental, or repair medical devices (excluding areas under the control of the Health Policy Bureau) - Issues related to the Japanese Pharmacopoeia (JP) - Standards and specific precautions concerning drugs, etc. - Designation of orphan drugs and orphan medical devices - Enforcement of laws pertaining to poisonous and deleterious substances (excluding areas under the control of the Compliance and Narcotics Division) 2 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 9

10 - Regulations related to evaluation of chemicals that might cause damage to the health of humans, animals, and plants in living environment from the standpoint of the environment and public health, as well as regulations concerning the manufacture, import, use, and other handling of such chemicals - Control of household products containing harmful substances - Establishment of tolerable daily intake (TDI) of dioxins and related compounds - Work related to the PMDA (limited to approval and license to manufacture and market drugs, medical devices, etc.) - Control and dissemination of industrial standards for medical devices and other hygiene products and other industrial standards The Pharmaceutical Affairs and Food Sanitation Council (PAFSC) is an advisory body to the MHLW, the PAFSC reviews and discusses important pharmaceutical and food sanitationrelated matters. 1.3 Website 2 Pharmaceuticals and Medical Devices Agency (PMDA) The PMDA was established in April 2004 in order to serve in areas of review of drugs and medical devices, post-marketing safety measures, relief services for adverse health effects. 2.1 Organization Under the Chief Executive, the PMDA consists of 27 offices, including Office of Regulatory Science, Office of Review Administration, Office of Review Management, Office of Standards and Guidelines Development, Office of International Programs, Office of New Drug I, Office of New Drug II, Office of New Drug III, Office of New Drug IV, Office of New Drug V, Office of Cellular and Tissue-based Products, Office of Vaccines and Blood Products, Office of OTC/Quasi-drugs, Office of Generic Drugs, Office of Non-clinical and Clinical Compliance, Office of Safety I, Office of Safety II, Office of Medical Informatics and Epidemiology, Office of Manufacturing/Quality and Compliance, Office of Relief Funds, Office of General Affairs, Office of Financial Management, and Office of Planning and Coordination. The organization structure is shown in Figure 2 as below: 10

11 Figure 2. Organization of Pharmaceuticals and Medical Devices Agency (PMDA) 3 3 About PMDA>Organization ( 11

12 2.2 Tasks 4 The service of the PMDA is divided into three main categories: 1) Relief service for adverse health effects, 2) review, and 3) post-marketing safety measures. The role of each office related to drug approval is as follows: - Office of Review Administration: This office handles tasks related to the receipt and processing of license and other applications, drug master file (MF) registrations and modifications, clinical trial notifications, simple consultation applications on generic drugs and the issuance of manufacturing/marketing authorization letters, etc. - Office of Review Management: This office handles tasks related to the publication (disclosure) of approval review results, receipt and processing of clinical trial consultations on new drugs, and receipt of processing of reports including basic protocols for post-marketing surveillance, and periodic safety update reports (PMS, reevaluation, GVP). The office also handles pharmaceutical affairs consultation on R&D strategy on drugs and medical devices mainly for universities, research institutes, and venture companies. - Office of Standards and Guidelines Development: This office handles tasks related to the preparation of draft Japanese Pharmacopoeia, standards on medical devices, standards on drugs, master file systems, and generic names (JAN). - Office of International Programs: This office represents PMDA at bilateral talks with foreign regulatory agencies and plays a central role in international communication such as the sharing of public and non-public information with foreign regulatory agencies and organizations. The main services rendered are the promotion of international harmonization of regulatory standards/practices, planning of international activities, foreign public relations campaign, and expansion of human exchange. - Office of New Drug I: This office confirms clinical trial notifications and adverse drug reactions and conducts reviews required for approval, re-examinations, and reevaluation of gastrointestinal drugs, dermatologic drugs, hormone preparations, and metabolic disease drugs (e.g., anti-diabetic, osteoporosis, gout, and congenital metabolic disorder drugs) - Office of New Drug II: This office confirms clinical trial notifications and adverse drug reactions and conducts reviews required for approval, re-examinations and re-evaluation of new cardiovascular drugs, drugs to treat Parkinson s disease, drugs to treat Alzheimer s disease, urogenital and anal drugs, combination drugs, radiopharmaceuticals, and contrast media. 4 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, July, ( 12

13 - Office of New Drug III: This office confirms clinical trial notifications and adverse drug reactions and conducts reviews required for approval, re-examinations, and reevaluation of new central nervous system drugs, peripheral nervous system drugs, anesthetic agents, sensory organ drugs (other than drugs for inflammatory diseases), and narcotics. - Office of New Drug IV: This office confirms clinical trial notifications and adverse drug reactions and conducts reviews required for approval, reexaminations, and reevaluation of antibacterial drugs, antiviral agents (except for anti-hiv/aids agents), new respiratory tract drugs, anti-allergy drugs, sensory organ drugs (limited to drugs for inflammatory diseases), and anti-hiv/aids agents. - Office of New Drug V: This office confirms clinical trial notifications and adverse drug reactions and conducts reviews required for approval, re-examinations, and reevaluations of antineoplastic drugs. - Office of Cellular and Tissue-based Products: This office confirms clinical trial notifications and adverse drug reactions and conducts reviews required for approval, reexaminations, and reevaluations of regenerative medical products (cellular and tissuebased products and gene therapy products), preliminary reviews for approval or verification based on the Cartagena Protocol, and quality review of antibody preparations. - Office of Vaccines and Blood Products: This office confirms clinical trial notifications and adverse drug reactions of globulins, blood coagulation-factor products, vaccines, and antidotes and performs the reviews required for approval, reexamination, or reevaluation. - Office of OTC/Quasi-Drugs: This office conducts reviews required for the approval, export certification, and quality reevaluations of guidance-mandatory drugs nonprescription drugs, quasi-drugs, and cosmetics. - Office of Generics: This office conducts reviews required for the approval, export certification, and quality reevaluations of generic drugs, etc. (ethical drugs excluding new drugs and extracorporeal diagnostic medicines). - Office of Compliance and Standards: This office reviews the documentation included with applications for approval, reexamination, or reevaluation of drugs, medical devices, and regenerative medicine products to assure that the studies on which the data is based comply with GLP, GCP, GPSP, study protocol, etc. both ethically and scientifically to determine if the documents have been prepared appropriately and accurately based on the study results in accordance with the Criteria for Reliability of Application Data (Article 43 of the Enforcement Regulations, Pharmaceutical Affairs Law) (hereinafter 13

14 Reliability Criteria ) and examined on site and on paper. Compliance of facilities performing GLP-based studies is also examined and certified. - Office of Safety I: This office undertakes centralized collection and compilation of information related to the quality, efficacy, and safety of drugs and medical devices, conducts surveys and guidance on the application of such information in medical institutions, and conducts scientific analysis and evaluation of such safety information using pharmaceutical and epidemiological procedures. It also undertakes consultations and information dissemination work. - Office of Safety II: This office undertakes analysis and evaluation of adverse reactions of drugs and medical devices. 2.3 Website 14

15 II. Related Laws 5 1. Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics 6 The name of the Pharmaceutical Affairs Law (PAL) was be revised to the Act on Securing Quality Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy products, Gene Therapy Products, and Cosmetics. Revision of the Pharmaceutical Affairs Law (PAL) was adopted by the Diet and announced on 27 November, The amendment was enforced on November 27, The Brief overview of revision of PAL 7 Points of the amendment of the law are to: - Strengthen safety measures regarding drugs and medical devices - Revise medical device regulations based on its characteristics - Introduce Regenerative and Cellular Therapy Products (RCTP) & Gene Therapy Products (GTP) regulations based on their characteristics 1.2. Related regulations - Enforcement Ordinance on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics ( 医薬品 医療機器等の品質 有効性及び安全性の確保等に関する 法律施行令 ): Jan. 9, 2015 (No. 2 of Japan government ordinance) - Enforcement Regulation on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics ( 医薬品 医療機器等の品質 有効性及び安全性の確保等に関する法律施行規則 ): Jun. 16, 2015 (No. 82 of MHLW) 8 2. Guidance and guidelines Guidelines on drug approval are available at the PMDA website (few English versions are available):

16 III. Classification of Pharmaceutical Products 1. New drug New drugs are defined as drugs with ingredients, dosage, administration route, or indications, which are clearly different from those of drugs, which have already been approved for manufacture and marketing or those listed in the JP. 9 Classification of a new prescription drug (1) Prescription drugs with new active ingredients (2) New combination prescription drugs (3) Prescription drugs with new administration routes (4) Prescription drugs with new indications (5) Prescription drugs with new dosage forms (6) Prescription drugs with new doses (7) Biosimilar products (8) Prescription drugs with additional dosage forms (9) Combination prescription drugs with similar formulations 2. Generic drug According to the Guideline for bioequivalence studies of generic products, Generic product means the products of which active ingredients, strengths, dosage forms, and dosage regimens are the same as those of innovator s products. 9 薬事法医薬品 医療機器等の品質 有効性及び安全性の確保等に関する法律, No 14-4 (JPMA) 16

17 3. Orphan drug In Japan, drugs and medical devices can be designated as orphan drugs or medical devices based on the Article 77-2* of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics. The Minister of Health, Labour and Welfare (MHLW) may designate drugs and medical devices satisfying the following criteria as orphan drugs/medical devices after receiving applications for orphan designation from the applicants. *Article 77-2 (1) When an application has been made by a person who engages in marketing a drug or medical device which fall under any and all of the following items (including those engaging in manufacturing, etc. in foreign countries of those which are intended to be exported to Japan), the Minister of Health, Labour and Welfare may designate the drug or medical device in the application as an orphan drug or medical device, after hearing the opinion of the Pharmaceutical Affairs and Food Sanitation Council. (i) The number of subjects for whom the drug or medical device used does not satisfy the requirement of number laid down by the Ordinance of the Ministry of Health, Labour and Welfare in Japan; (ii) The drug or medical device in the application, if approved for manufacturing and sales, is expected to prove especially valuable when applied in medical practice in terms of the usage. 3.1 Number of patients In order to be designated as orphan drug, the number of patients who may use the drug or medical device should be less than 50,000 in Japan. The number of patients could be estimated based on the report of the Health and Labour Science Research or the data published by reliable scientific societies. The number of patients with a difficult-to-treat disease is sometimes difficult to estimate accurately due to lack of research on the patient population. Therefore, estimates from a variety of statistical data are generally used to indicate that the number of those patients is less than 50,000 in Japan. Submission of an estimate based on multiple statistical methods is recommended. Since financial year 2006, applicants may apply for orphan drug designation with the following new drugs if the estimated number of patients who may use the drug at the time of application is less than 50,000 in Japan. - A vaccine to prevent an infectious disease rarely reported in Japan or that only reported overseas and the use of which is limited to a specific population, such as people who have visited the endemic area. - A vaccine to prevent an emerging or re-emerging infectious disease associated with genetic mutation, of which an outbreak has not been reported at the time of designation but which may significantly affect the lives and health of Japanese people, and of which the time and size of epidemic are unpredictable. 17

18 3.2 Medical needs The drugs or medical devices should be indicated for the treatment of serious diseases, including difficult-to-treat diseases. In addition, they must be drugs or medical devices for which there are high un-met medical needs satisfying one of the following criteria: - There is no appropriate alternative drug/medical device or treatment option. - Better efficacy or safety is expected compared with existing products. 3.3 Possibility of development There should be a theoretical rationale for the use of the product for the target disease, and the development plan should be appropriate. For example, in the case of application of an orphan drug, the possibility of development should be explained based on existing nonclinical and clinical data in the late stage of the phase I study or in the early stage of the phase II study except when the product has already been approved overseas or sufficient clinical study data are available. 18

19 IV. Drug Approval System 1. Clinical trial notification for new drug development 1.1 Overview 10 In order to conduct clinical studies to collect data to be submitted with approval applications for new drug manufacturing and marketing, the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics and the GCP require that the MHLW be notified of the study protocol beforehand and provide various requirements to be met by the sponsor when requesting medical institutions to perform clinical studies. From April 1st, 2011, attachments to the clinical trial notification are required to be submitted in electronic format as well as in paper format. The range of the GCP covers not only clinical studies on patients, but also Phase I studies in healthy volunteers, bioequivalence studies on humans, studies for additional indications for an approved drug and post-marketing clinical trials after marketing. At the time of the clinical trial protocol notification, a system by which the PMDA reviews the contents of the initial notification at the request of the MHLW is now specified by law, and a "clinical trial consultation system" in which the PMDA gives guidance and advice concerning study protocols has also been established Type of clinical trial notification Industry Sponsored Clinical Trial - Investigator Initiated Clinical Trial: The term "sponsor-investigator" as used in the Ministerial Ordinance on Good Clinical Practice for Drugs means an investigator who has submitted a clinical trial notification pursuant to the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics, (the Act) in order to conduct a clinical trial at the medical institution etc. to which the investigator belongs (including a coordinating investigator who has submitted a clinical trial notification pursuant to the Act, on behalf of all participating investigators, for a clinical trial conducted according to a single protocol but at more than one medical institution). 10 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 11 治験の依頼をしようとする者による薬物に係る治験の計画の届出等に関する取扱いについて, 平成 25 年 5 月 31 日, 薬食審査発 0531 第 8 号,(Notification for clinical trial plan, Notification 0531 No. 8 of PFSB) 12 自ら治験を実施しようとする者による薬物に係る治験の計画の届出等に関する取扱いについて, 平成 25 年 5 月 31 日, 薬食審査発 0531 第 4 号, (Notification for clinical trial plan by investigator sponsor, Notification 0531 No. 4 of PFSB) 19

20 1.1.2 Products required for clinical trial notification 13 The following products are required to submit clinical trial (protocol) notifications: 1) Drugs with new active ingredients 2) Drugs with new administration routes(excluding bioequivalence studies) 3) New combination drugs, drugs with new indications or new dosage and administration (excluding bioequivalence studies) 4) Drugs containing the same active ingredients with the drugs with new active ingredients, for which the reexamination period has not been completed yet (excluding bioequivalence studies) 5) Drugs considered to be biological products [excluding 1) to 4)] (excluding bioequivalence studies) 6) Drugs manufactured using gene recombinant technology [excluding 1) to 5)] (excluding bioequivalence studies) 1.2 Interview advice meeting 14 The PMDA has established a consultation system for clinical study protocols to improve and reinforce the quality of clinical studies. The procedure of interview advice meeting is as below: Figure 3 Procedure of Interview Advice Meeting 13 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, July, ( 14 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, July, ( 20

21 Key consultation items and fees are as table below 15 : Contents Fee ( ) 1. consultations on procedure 143, consultations on bioequivalence studies 571, consultations on safety 1,833, consultations on quality 1,520, consultations before start of Phase I studies 6. consultations before start of early phase II studies 7. consultations before start of late phase II studies 8. consultations after completion of phase II studies 9. consultations before application Non-orphan 4,360,500 Orphan 3,277,200 Non-orphan 1,669,400 Orphan 1,257,400 Non-orphan 3,114,900 Orphan 2,339,200 Non-orphan 6,183,300 Orphan 4,644,800 Non-orphan 6,183,200 Orphan 4,642, Consultations when planning clinical studies for reevaluation and reexamination 11. Consultations on completion of clinical studies for reevaluation and reexamination re-evaluation and re-examination reviewing the approval condition (evaluate the propriety quickly) 1,664,800 1,664, , Additional consultations on drugs Non-orphan 2,752,100 Orphan 2,067, Review period According to the new GCP, when a clinical study is requested, a contract for clinical trials can be concluded only when 30 days have passed from the initial notification of the study protocol received by the PMDA (at least 2 weeks have passed for subsequent notifications, as a rule). For drugs required in emergencies to prevent diseases that have a major effect on the life or health of the patient or to prevent other damage to the health, clinical study protocols may be submitted within 30 days after the start of the study (MHLW Ordinance No. 89, dated May 2003) 15 Clinical trial consultations, etc. (new drugs) ( consultations/0007.html) 21

22 1.4 Required documents Form of clinical trial notification (Attachment Form 2) ID: Type of documents: Clinical trial notification and attached documents Clinical trial ingredient code: Clinical trial notification date: Reporter: Document title: Number of notification: Number of amendment: Generic name (Japanese): Generic name (English): Dosage form (Japanese): Drug classification (Japanese): Expected dose and dosage: Route of administration (Japanese): Notes (1) Please complete Attachment Form 2 in the format of Text or MS-Word. (2) Please complete each section consistent with the clinical trial protocol notification. (3) Rather than the first notification date, clinical trial notification date indicates the submission date of the clinical trial notification. Keep the first notification date in case of suspension of the notification. (4) Please write the number of revision for every clinical trial protocol revision notification and leave blank in other cases. (5) Please leave [ID] and [Document title] sections blank. (6) If the generic name is not determined, please leave the section blank. For instructions for filling out the application form, refer to Appendix Documents to be attached for the first notification - Documents that give the reason why the request for the clinical study was judged to be scientifically appropriate - Clinical study protocol - Explanatory materials and consent form used for obtaining informed consent 16 治験の依頼をしようとする者による薬物に係る治験の計画の届出等に関する取扱いについて, 平成 25 年 5 月 31 日, 薬食審査発 0531 第 8 号, (Notification for clinical trial plan, Notification 0531 No. 8 of PFSB 17 自ら治験を実施しようとする者による薬物に係る治験の計画の届出等に関する取扱いについて平 成 25 年 5 月 31 日, 薬食審査発 0531 第 4 号 (Notification for clinical trial plan by sponsor investigator, Notification 0531 No. 4 of PFSB) 18 Clinical trial plan notification system of pharmaceutical (drug) ( 22

23 - Sample of the case report form (CRF) (The sample is not required if information to be contained in the CRF is explicitly stated in protocol.) - Latest Investigator s Brochure Documents to be attached from the second notification - Documents that give the reason why the request for the clinical study was judged to be scientifically appropriate (including a description of the results of new clinical studies since the previous notification and a summary of information) - Clinical study protocol - Explanatory materials and consent form used for obtaining informed consent - Sample of the case report form (CRF) (The sample is not required if information to be contained in the CRF is explicitly stated in protocol.) - Latest Investigator s Brochure Format of documents submission Effective on 1 Apr 2011, all attachments to be submitted along with the notification on clinical study plan should be submitted in electronic format in addition to paper format. For the paper format; stamp the printed papers with the company seal; and submit written report. For the details of the notification, electronic files, such as electronic medical entry forms and structure definition of XML documents are available from the website ( In principle, follow the below for the number of notification copies depending on the type of notification. - For the applicable clinical study plan notification: two original copies and three copies of the notification - Five copies of the document to be attached to the notification; 1 electronic media for XML file; and 1 PDF file for data management - Report on clinical study plan other than the report under 30-day investigation - One original copy and one copy of the notification; two documents to be attached to the notification - One copy of electronic media for XML file and 1 copy of PDF file for information management. 23

24 2. New drug approval (NDA) application 2.1 Procedure 1920 The entire process of approval review from review-related inspections and clinical trial consultation to review works is undertaken by the PMDA (Figure 4, Figure 5). Application forms for drug marketing authorization are submitted to the PMDA. When application forms for new drugs marketing authorization are received by the PMDA, a compliance review of the application data (certification from source data), GCP on-site inspection, and detailed review are undertaken by review teams of the PMDA and the team prepares a review report. The approval review process consists of expert meetings of review team members and experts to discuss important problems. A general review conference attended by team members, experts and representatives of the applicant is held after the expert meeting. It is necessary to submit a list of persons involved in compilation of attached data and a list of competitive products and companies in relation to persons who participated in clinical studies submitted as application data immediately after application submission, prior to the expert meeting, and prior to meeting of the Committee on Drugs. Figure 4. New Drug Marketing Approval Process 19 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 20 新医薬品の承認審査の進捗状況の確認について, 薬機発第 号, 平成 22 年 12 月 27 日 (Procedure for new drug review, Notification No of PMDA) ( 24

25 Figure 5. Flowchart of New Drug Development and Approval Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 25

26 2.2 PMDA review process The evaluation process followed by the PMDA is as follows: 1) Interview (presentation, inquiries, and replies) 2) Team review 3) Inquiries and replies 4) Application for GMP inspection (about 6 months before the meeting of the Committee on Drugs) 5) Review report (1) 6) Expert meeting () 9) Review report (2) 10) Report to MHLW for consultation to PAFSC 2.3 PAFSC consultation After the PMDA review, the PAFSC is then consulted for discussions by the related committees and the Pharmaceutical Affairs Committee as required on the basis of the review report. After the PAFSC report is obtained and it is confirmed that the standards are met in a separate GMP compliance review, the Minister grants the new drug manufacturing/marketing approval. 2.4 Review period 2223 In addition to the 1 year standard approval review time of the MHLW for approval of new drugs from April 1, 2000 (dated March 28, 2000) (excluding the time taken by applicants to prepare responses, etc.), the time allotted to the applicant is also 1 year so that the time from the application to marketing approval is a maximum of 2 years. The applicant is requested by the MHLW to withdraw the application in case a longer time is required for responding to inquiries or conducting additional studies. In June 2010, Points to consider in applications for shortening the PMDA review period for new drugs 24 was issued. This document includes points to consider from the applicant s side to achieve the target PMDA review periods of 12 months for ordinary reviews and 9 months for priority reviews by Further, the standard review timeline for new drug applications has been shown by the Ministry to achieve a median total review time of 12 months for new drugs (It is shown by 22 標準的事務処理期間の設定等について, 昭和六〇年一〇月一日, 薬発第九六〇号 (Standard review time, Notification No. 60 of PSB, 1985) 23 新医薬品等の承認申請に係る取下げ依頼について薬食審査発第 号平成 16 年 6 月 4 日 (New drug application, Notification No of the Evaluation and Licensing Division, PFSB dated June 4, 2004) 24 日本の薬事行政省医薬食品局審査管理課 監視指導 麻薬対策課事務連絡 2010 年 6 月 9 日付厚生労働 Office Communication of the Evaluation and Licensing Division and Compliance and Narcotics Division, PFSB dated June 9,

27 the Minister in 2012 that the median standard review timeline for new drug approval is 12 months). 25 The median review time for new drugs is found in the website of PMDA. 2.5 Required documents Form of documentation With the agreement reached on the Common Technical Document (CTD) guidelines of the International Conference on Harmonization (ICH), new guidelines for preparation of approval application data were issued. Applications using the CTD became obligatory for new products in applications filed on or after July 1, In Japan, submission of e-ctd is not obligatory, but recommended. It is no longer necessary to submit paper data for approval applications if an e-ctd is submitted as the original. 25 新医薬品に係る承認審査の標準的プロセスにおけるタイムラインについて事務連絡平成 24 年 3 月 30 日 (Standard process for new drug review, Administrative Notice of the Evaluation and Licensing Division, PFSB dated March 30,

28 2.5.2 Details for documents required to the regulatory agency 26 - Prescription drugs a. Origin or background of discovery, conditions of use in foreign countries b. Manufacturing methods, standards and test methods 1. Origin or background of discovery 2. Conditions of use in foreign countries 3. Special characteristics, comparisons with other drugs, etc. 1. Chemical structure and physicochemical properties, etc. 2. Manufacturing methods 3. Standards and test methods c. Stability 1. Long-term storage tests 2. Tests under severe conditions (stress tests) 3. Accelerated tests d. Pharmacological action 1. Tests to support efficacy 2. Secondary pharmacology, Safety pharmacology 3. Other pharmacology e. Absorption, distribution, 1. Absorption 2. Distribution 3. Metabolism metabolism, and excretion f. Acute, subacute, and chronic toxicity, teratogenicity, and other types of toxicity g. Clinical studies Clinical trial results 4. Excretion 5. Bioequivalence 6. Other Pharmacokinetics 1. Single dose toxicity 2. Repeated dose toxicity 3. Genotoxicity 4. Carcinogenicity 5. Reproductive toxicity 6. Local irritation 7. Other toxicity 26 医薬品の承認申請について, 平成 17 年 3 月 31 日, 薬食発第 号, (Application for drug, Notification No of the PFSB dated March 31, 2005) 28

29 29

30 2.5.3 Use of foreign clinical data 27 Japan has taken various measures in keeping with this change in the international environment, and data from nonclinical studies such as physicochemical studies, stability studies and animal studies performed in foreign countries are accepted, in principle, if their study designs comply with the Japanese guidelines. Two notifications were issued in relation to the acceptance of foreign clinical data: - Handling of Data on Clinical trials on Drugs Performed in Foreign Countries 28 - Ethnic Factors to be Considered in the Acceptance of Foreign Clinical Trial Data and its Q & A 29 According to these notifications, when data from clinical studies performed in foreign countries are used for new drug application in Japan, the data is firstly checked to assure that it complies with legal requirements in Japan. Whether or not the drug is apt to be affected by ethnic factors (intrinsic or extrinsic factors) is then evaluated. When necessary, a bridging study is performed, and when it is concluded that the clinical study outcome in a foreign population can be extrapolated to the Japanese population, the foreign data can be accepted. Since the possibility of acceptance is actually left up to the authorities concerned, it is recommended that the requirements for bridging studies are confirmed as acceptable for the regulatory agencies through consultations with PMDA. It is mandatory to conduct pharmacokinetic studies in Japanese people as the bridging study. With the intent to promote global clinical trials to achieve more efficient and rapid development of new drugs and to eliminate drug lag in which the approval timing of new drugs is several years behind that in other countries, basic concepts related to global clinical trials have been compiled. 30 In addition, the notice Basic Principles on Global Clinical Trials (Reference Cases) was issued based on achievements of mutual cooperation and latest knowledge obtained relating to multinational clinical trials among Japanese, Chinese, and South Korean regulatory authorities with an objective of a smooth and appropriate conduct of global clinical trials, especially in East Asia. 3. Generic drug approval application 27 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 28 外国で実施された医薬品の臨床試験データの取扱いについて平成 10 年 08 月 11 日医薬発第 739 号 (Handling for foreign clinical trial, Notification No.739 of the PMSB dated August 11, 1998) 29 データを受け入れる際に考慮すべき民族的要因について, 平成 10 年 08 月 11 日医薬審第 672 号 (Ethnic difference on foreign clinical trial, Notification No. 672 of the Evaluation and Licensing Division, Pharmaceutical and Medical Safety Bureau dated August 11, 1998 and partial revision by Office Communication dated January 4, 1999) 30 国際共同治験に関する基本的考え方について, 平成 19 年 09 月 28 日薬食審査発第 号, (Multinational clinical study, Notification No of the Evaluation and Licensing Division, PFSB dated September 28,

31 3.1 Procedure 31 Applications for generic drugs cannot be filed until completion of the reexamination. Branded products are protected from patent and reexamination period during this period. The PMDA reviews submitted data such as 1) specification and test methods, 2) stability tests, 3) and bioequivalence study and determines the equivalence (quality, efficacy, and safety) of generic drugs to the original drugs. The MHLW then approves manufacturing/marketing business of the applied drugs. Integrity of the submitted data including raw data must be checked. 3.2 Review period 32 There was no difference between new drugs and generic drugs. (Drugs for prescription: 1 year, drugs for non-prescription: 10 months) 3.3 Required documents 33 Specification and test methods, stability data, and bioequivalence data are required to determine whether they are the same to the originator Specification and test methods Section Raw material Preparation 1. Name 2. Structural formula and rational formula 3. Molecular formula and molecular weight 4. Origin 5. Strength 6. Appearance 7. Identity test 8. Property value (physical and chemical properties, etc.) 31 ジェネリック医薬品 ( 後発医薬品 ) の使用促進について ( 医療用医薬品の承認申請の際に添付すべき資料の取扱いについて薬食審査発第 号, 平成 20 年 1 月 9 日 (Documentation for drug approval, Notification No of PMDA dated January 9, 2008) 32 標準的事務処理期間の設定等について, 昭和六〇年一〇月一日, 薬発第九六〇号 (Standard review time, Notification No. 60 of PSB, 1985) 33 ジェネリック医薬品 ( 後発医薬品 ) の使用促進について (Promotion on use of generic drugs) ( 31

32 9. Purity test 10. Moisture content (moisture and loss on dry) 11. Ignition residue, ash and acid-insoluble ash 12. Formulation test 13. Special test 14. Other test items (including microbial limit test and particle diameter of bulk) 15. Assay 16. Reference substance 17. Reagent and test solution Dosage form powder, granule tablet, compressed pill, capsule, troche injection aerosol (requiring quantitativeness) elixirs, spirits, tincture, fluid extract ophthalmic ointment percutaneous absorption, such as PLASTERS suppository eye drop Details of 12 preparation test preparation uniformity test, particle size test, elution Test and collapse test preparation uniformity test, elution Test and collapse test insoluble foreign substance test, collected dose test, agent uniformity test, endotoxin test and pyogen Test, emission test, and particle diameter test relation between the spray time and amount of spray, particle diameter test (if for suspension type) measurement of alcohol number metallic foreign substance test, sterility test, emission test, particle diameter test, and plasticity test adhesion test, emission test melting temperature test, emission test, softening point insoluble foreign material test, sterility test, emission test, particle diameter test Stability data For generic drugs, accelerated test data (at 40 (±1) degree, RH 75% (±5%), 3 lots, for 6 months) should be conducted and submitted for review Bioequivalence study 32

33 For bioequivalence study, refer to following guidelines for bioequivalence studies of generic products that are published in Japanese 34 and English Guideline for Bioequivalence Studies of Generic Products - Guideline for Bioequivalence Studies of Generic Products for Different Strengths of Oral Solid Dosage Forms - Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage Forms - Guideline for Bioequivalence Studies for Different Oral Solid Dosage Forms - Guidelines for the Design and Evaluation of Oral Prolonged Release Dosage Forms 3.4 Patent-approval linkage system Patent system 36 The patent term is 20 years from the time of application as a rule. However, if the patent cannot be implemented because of laws and regulations to ensure safety of drugs, etc. the patent term can be extended for a maximum of 5 years. The extension is for the period that the patented invention cannot be utilized, such as the period from the date of the start of clinical trials or date of patent registration, whichever is later, until one day prior to the date on which the patentee receives approval for the drug. Patentees who want an extension of the patent term must submit an application to the Patent Office for extension of registration including the required items such as the requested extension period before the patent rights become invalid within 3 months from the date of receipt of drug approval. In cases where it is anticipated that it will not be possible to obtain approval as specified by government ordinance by the day before 6 months prior to the date on which the patent expires, a document showing necessary information including the patent number must be submitted. If an application for an extension is submitted, it can be considered that the patent term has been extended until it is finally rejected or the extension is registered Manufacturing/marketing authorization on generic drugs and patent Generic drugs will not be approved until the substance (application) patent has expired. Branded products are protected from generics entry during this period. However, in the past if some of the indications or dosage and administration of branded products were patented, partial approvals were not granted because of patent protection, but with Notification, partial approvals of indications or dosage and administration not covered by the patent are permitted. 4. Orphan drug 後発医薬品の生物学的同等性試験ガイドライン等の一部改正について平成 24 年 2 月 29 日, 薬食審査発 0229 第 10 号 (Partial amendment of bioequivalence study for generic drugs) English translation of Attachment 1 of Division-Notification 0229 No. 10 of the Pharmaceutical and Food Safety Bureau, dated February 29, 2012, page 5 ( 35 Division of Drugs ( 36 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 33

34 4.1 Organization that designates orphan drugs The responsibilities of major regulatory authorities involved in the designation system are described as below: MHLW - Review and designation of orphan drugs/medical devices - Review and approval of orphan drugs/medical devices - Pre-designation consultation for orphan drugs/medical devices - Payment for the operational cost of the National Institute of Biomedical Innovation (NIBIO) PMDA - Priority scientific consultation for clinical trials and dossiers for marketing authorization of orphan drugs/medical devices National Institute of Biomedical Innovation (NIBIO) - Subsidy payment to the applicant - Accreditation for research expenses to be used by the applicant - Provision of guidance and consultation to the applicant Figure 6 Organizations that Designate Orphan Drug/Medical Device 37 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 38 Overview of Orphan drug/medical device designation system ( 34

35 4.2 Orphan drug designation procedure After the consultation, the applicant should submit an original and a copy of the application for designation to the Evaluation and Licensing Division under the Pharmaceutical and Food Safety Bureau (PFSB) of MHLW. The application of orphan designation should be submitted in Japanese. The submitted application will be reviewed by the Evaluation and Licensing Division, and if a designation can be determined, PAFSC will be consulted. A designation will be granted in principle if the First or Second Committee on New Drugs of PAFSC (or the Committee on Medical Devices and In-vitro Diagnostics for orphan medical devices) approves of the designation. The designation notice will be sent to the applicant after all the procedures are completed. The designation [the name of drug (ingredient), expected indication(s), name and address of applicant and date of designation] will be published in a government gazette as a MHLW Ministerial Notification. Figure 7. Flow Chart for Orphan Drug/Medical Device Designation 4.3 Required documents for designation 39 The following documents are required for the orphan drug designation: 1) Data on the number of patients 2) Objective statistical data on the number of patients in Japan for whom the drug or medical device will be indicated 3) Data on medical needs - Data on the diseases such as etiology and symptoms - Data on the current status such as availability of similar drugs/medical devices and treatment 4) Data on the theoretical rationale for the use of the drugs/medical devices 39 薬事法及び医薬品副作用被害救済 研究振興基金法の一部を改正する法律の施行について, 平成五年八月二五日, 薬発第七二五号 (Partial amendment on compensation for adverse drug reaction and research support fund, Notification No. 72 of PSB, dated August 25, 1993) 35

36 5) Related data in a draft dossier of application for marketing authorization, which is available at the time of application for orphan drug/medical device 6) Development plan (data on the possibility of development) 7) Data on the outline of the development plan, including the current development status, expected test items, duration of the study and necessary expenses 8) Preparation of Summary of the Orphan Drug/Medical Device: the Summary of the Orphan Drug/Medical Device should be prepared for Committee meetings and publication. 4.4 Review period Orphan drug is subject to the priority review and the review period takes about 9 months. 4.5 Incentives 40 For designated orphan drugs and medical devices, measures to support the research and development activities described below are taken: - Subsidy payment: Orphan drug/medical device applicants can receive subsidies through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development. (The total budget for financial year 2010 was 650 million yen.) - Guidance and consultation: Orphan drug/medical device applicants can receive guidance and consultation from the Ministry of Health, Labour and Welfare (MHLW), the Pharmaceuticals and Medical Devices Agency (PMDA), and NIBIO on research and development activities. The PMDA provides a priority consultation system for designated orphan drug/medical device. Lower user fee categories for PMDA s consultation are applicable to designated orphan drugs. - Preferential tax treatment: Twelve percent of study expenses for orphan drug/medical device incurred during the NIBIO subsidy payment period (not including subsidies granted by NIBIO) can be reported as a tax credit. - Priority review: Designated orphan drugs and medical devices will be subject to priority review for marketing authorization to ensure that they are supplied to clinical settings at the earliest possible opportunity. Categories of lower user fees are applicable to review for marketing authorization of designated orphan drugs. - Extension of re-examination period: After orphan drug/medical device designation and approval, the re-examination period for the concerned products will be extended up to 10 years for drugs and up to 7 years for medical devices. 40 Overview of the designation system of orphan drugs and rare diseases for medical devices ( 36

37 5. Priority review Pharmaceutical products for priority review Drug approval reviews are normally processed in the order that the application forms are received. However, for drugs designated as orphan drugs, and other drugs considered to be especially important from a medical standpoint such as new drugs to treat serious diseases, a decision must be made whether or not to specify an overall evaluation of (1) the seriousness of the targeted disease and (2) the clinical effetiveness With this system, applications for specified drugs of the following criteria are reviewed on a priority basis: 43 Priority review criteria 1) Seriousness of indicated diseases Diseases with important effects on patient s survival (fatal diseases) Progressive and irreversible diseases with marked effects on daily life Others 2) Overall assessment of therapeutic usefulness There is no existing method of treatment, prophylaxis, or diagnosis. Therapeutic usefulness with respect to existing treatment - Standpoint of efficacy - Standpoint of safety - Reduction of physical and psychological burden on the patient 5.2 Procedure When drugs are designated for priority reviews, opinions of experts on such designations are compiled by the PMDA immediately after the application and reported to the MHLW. Based on this report, the Evaluation and Licensing Division decides whether or not to apply the priority review. The Evaluation and Licensing Division notifies this decision to the applicant and the PMDA. The Evaluation and Licensing Division reports this application to the next meeting of the review committee concerned of the PAFSC and obtains their approval. Products for priority review are given priority at each stage of the review process as much as possible. When products subject to priority review are approved as new drugs, this fact is made public. 5.3 Priority review consultation 41 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 42 the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics 43 優先審査等の取扱いについ平成 23 年 9 月 1 日, 薬食審査発 0901 第 1 号 (Handling of Priority Review, Notification No (1) of the Evaluation and Licensing Division, PFSB dated February 27, 2004) 37

38 When a product has been designated for priority review at the development stage, it is possible to obtain priority interview advice on indications and other items concerning the designated product. Products are designated on the basis of an overall evaluation of the seriousness of indicated disease and clinical usefulness using the propriety review selection criteria. Applicants are requested to submit results of clinical studies up to late Phase II as a rule as data for estimating the clinical usefulness assessment. Hearings and inquiries are undertaken for the applicant as required and the designation is decided after hearing opinions of experts in the field. The results, including reasons, are notified to the applicant in writing. Orphan drugs are all handled as products for priority interview advice and an application is not required. 5.4 Review period Period for the priority review is about 9 months. 38

39 V. Others 1. Good Manufacturing Practice (GMP) GMP compliance inspection concerning pharmaceuticals (including APIs) of foreign manufacturers General GMP compliance inspections include the following: 1) Inspections that are conducted at the point of application for new marketing approval or of application for partial changes of approved information, and 2) inspections that are conducted every five years following the obtainment of marketing approval. In the case of ethical drugs, packaging, labeling and storage facilities and external testing laboratories are included in the scope of GMP Inspection, in addition to the manufacturing sites of drug products, APIs (Active Pharmaceutical Ingredients) and intermediates. In the case of application for partial change approval, GMP Compliance Inspection is not required if the partial change is addition, change, or deletion etc. of dosage and administration, or indication that will not affect the methods for manufacturing control or quality control. While drug products for over-the-counter drugs are included in the scope of GMP compliance inspection, APIs for over-the-counter drugs are excluded from the inspection (however APIs of over-the-counter for new marketing approval are in the scope of GMP compliance inspection). A marketing authorization holder that applies for the marketing approval of pharmaceutical, or an appointed marketing authorization holder designated by a manufacturer that seeks to obtain foreign restrictive approval, shall file an application with the PMDA for GMP compliance inspection of foreign manufacturing sites. Following the application for GMP compliance inspection, the applicant shall submit documents pertaining to manufacturing control and quality control of product(s) concerning the compliance inspection and documents pertaining to manufacturing control and quality control of manufacturing sites concerning the compliance inspection, at request of the PMDA. Even applications and attached documents are concerning foreign manufacturing sites, it should be prepared in Japanese. If the attachment includes a large volume of documents written in a foreign language, it is acceptable to prepare only an overview of such documents in Japanese. 44 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 45 治験薬の製造管理 品質管理等に関する基準 ( 治験薬 GMP) について, 平成 20 年 07 月 09 日薬食発第 号, (GMP for investigational drug for clinical trial, Notification No of the PFSB) 治験薬の製造管理 品質管理等に関する基準 ( 治験薬 GMP) に関するQ&Aについて, 平成 21 年 0 7 月 02 日事務連絡 (Q&A on GMP for investigational drug for clinical trial) 46 GMP Compliance Inspection Concerning Pharmaceuticals (including APIs) of Foreign Manufacturers (Overview Guideance for Foreign Manufacturers), Sep.1, 2008, tentative translation (as of Oct. 7, 2008) ( 39

40 1.1.2 Scope of the drugs subject to GMP compliance inspection The scope of the drugs subject to GMP compliance inspection are drugs and APIs. The products shown as below from a. through g. and APIs for over-the-counter drugs do not require GMP compliance inspection a. Drugs that are intended to be used for the extermination or prevention of rats, flies, mosquitoes, fleas and other similar creatures, which are not used directly on human bodies. b. Drugs that are intended to be used mainly for disinfection and sanitization, which are not used directly on human bodies. c. Drugs that are, APIs, intended to be mainly used for the manufacturing of drugs indicated in a. or b. d. Drugs that are manufactured at manufacturing sites that only conduct processes of powdering and/or cutting crude drugs. e. Drugs that are manufactured and/or marketed by pharmacies. f. Of gases used for medical purposes, 1) nitrous oxide, 2) oxygen, 3) nitrogen, 4) carbon dioxide, 5) compound of nitrous oxide and oxygen. g. In addition to a. through f., drugs included in the Japanese Pharmacopoeia, which are designated by the Minister of Health, Labour and Welfare as causing mild action to human bodies (107 items including gum arabic) Facilities subject to inspection All manufacturing sites (including external testing laboratories) listed in the marketing approval application or authorization Flow of GMP compliance inspection A marketing authorization holder that is applying for the marketing approval, or a marketing authorization holder that has obtained marketing approval, shall file an application with the PMDA for GMP compliance inspection of foreign manufacturing sites. The PMDA shall conduct the inspection. In principle, GMP compliance inspection shall be onsite inspection by the PMDA. However, inspection may be conducted on documents only (hereinafter document inspection ), by the PMDA s judgment on GMP compliance etc. based on the product s risk, the country s GMP standards and their operation, and documents submitted for the inspection. The PMDA shall report the inspection results to the Ministry of Health, Labour and Welfare, using the form of GMP Compliance Inspection Result Notification. The PMDA shall issue a copy of the GMP Compliance Inspection Result Notification to the marketing approval holder that applied for the inspection, and a copy of the GMP Compliance Inspection Result Report to the foreign manufacturer on which the onsite inspection was conducted. In the case of document inspection only, a copy of the GMP Compliance Inspection Result Report is not issued. 40

41 Figure 8. Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (1) 47 Figure 9. Flowchart of GMP Onsite Inspection of Foreign Manufacturers by the PMDA (2) Attached documents for an inspection application 47 GMP compliance inspection concerning pharmaceuticals (including APIS) of foreign manufacturers (Overview guidance for foreign manufacturers), Sep.1,2008, Office of Compliance and Standards, Pharmaceuticals and Medical Devices Agency 41

42 Below are the attached documents for an application for manufacturing/marketing approval and an application for some amendment approval. - Copy of compliance inspection result notification or report conducted for the past two years from the application date of the applicable compliance inspection (including the inspection conducted by other inspectors ) - For manufacturing sites in countries where MOU has been executed for the inspection on overseas manufacturing sites, a copy of compliance certificate of other countries based upon the applicable MRA, or a copy of GMP inspection report; for manufacturing sites in the countries having executed an MOU etc., a copy of the other country s certificate or a copy of GMP inspection report based upon the applicable MOU; and for manufacturing sites in other countries, WHO certificate and Compliance Certificate of the applicable government agency. - A copy of an application for manufacturing/marketing approval for the product under application - Data requiring other compliance inspection The following documents are required for the compliance inspection conducted every five years after manufacturing/marketing approval - Copy of compliance inspection result notification or report according to GMP inspection conducted for the past two years from the application date of the applicable compliance inspection (the inspection conducted by other inspectors ) - For manufacturing sites in countries where MRA has been executed for the inspection into overseas manufactories, a copy of compliance certificate of other countries based upon the applicable MRA, or a copy of GMP inspection report; for manufacturing sites in the countries having executed an MOU etc., a copy of the other country s certificate or a copy of GMP inspection report based upon the applicable MOU; and for manufacturing sites in other countries, WHO certificate and compliance certificate of the applicable government agency. - Copy of manufacturing/sales approval letter - Copy of some amendment approval letter for the last five years - Copy of minor amendment report for the last five years - When submitting an application for two or more products, a workplace, a workroom, an area, and facilities are categorized and then a representative product is selected from each category. The data indicating the rationale for categorization and selection should be submitted. - Presence or absence of recall of the product for the last five years from application (if yes, provide the summary) - Written pledge (prepared by an applicant) - Other documents that compliance inspection need Costs for inspection The costs shall be paid by the manufacturer/marketing business who submitted an application for manufacturing/marketing approval or obtained the approval. If the same manufacturing site had GMP compliance inspection for the same product by other manufacturer/marketing business; and provided a copy of compliance inspection result notification to the applicable manufacturer/marketing business (within the past two years of 42

43 the dispensing date, in principle), the applicable manufacturer/marketing business does not need to get GMP compliance inspection for the applicable manufacturing site Applicable laws - Article 14, Paragraph 1 of Pharmaceutical Affairs Law (Approval for Manufacturing and Approval for Drugs) - Article 14, Paragraph 6 of Pharmaceutical Affairs Law - Article 14-2, Paragraph 1 of Pharmaceutical Affairs Law (PMDA inspection conduct) - Article 21 of Enforcement Ordinance of Pharmaceutical Affairs Law (Inspection period according to manufacturing management or quality control method) - Article 50, Paragraph 1 of Enforcement Regulation of Pharmaceutical Affairs Law (Application for Compliance Inspection): #25 PDF format template (PDF format): Template for Compliance Survey Application - Article 50, Paragraph 2 of Enforcement Regulation of Pharmaceutical Affairs Law - Article 50, Paragraph 3 of Enforcement Regulation of Pharmaceutical Affairs Law - Article 51 of Enforcement Regulation of Pharmaceutical Affairs Law (Notification for Compliance inspection Result): PDF format template #26 (PDF format): Notification for Compliance inspection Result Others Japan has been registered as PIC/S GMP member on 1 July, Drug Master File (DMF) 2.1 Overview 48 With the amendment of the Pharmaceutical Affairs Act (now the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics) enforced in April 2005, approvals for drug substances that had been necessary in the past were no longer required. Instead of that, the information of quality and manufacturing method of drug substance are required to be included in the application document of finished product. The DMF system aims at protecting intellectual property of relevant information at the time of license application and facilitating review work by allowing a registrant (master file registrant) of drug substances other than an applicant of finished product to separately submit information on quality and the manufacturing method of drug substances to be used in drug products Items targeted for Drug Master File registration 48 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 49 原薬等登録原簿の利用に関する指針について, 平成 17 年 02 月 10 日薬食審査発第 号 (Drug master file, Notification No of the Evaluation and Licensing Division, PFSB dated February 10, 2005) 43

44 - Drug substances, intermediates - Pharmaceutical product materials (materials of pharmaceutical products with special dosage form, etc.) - Excipients (new excipients, new pre-mix excipients) - Materials for medical devices - Containers, packaging materials When an overseas drug substance manufacturer submits a DMF registration application, it is necessary to appoint an in-country caretaker to handle the activities of the MF registrant in Japan. When the registered contents of the DMF are changed, an application to change the DMF or a minor DMF modification notification must be submitted. Detailed information is found in the PMDA website. 3. Labeling and package inserts 3.1 Overview 5051 Specified items must be entered on the immediate container of drugs. The package inserts must contain indications, dosage/administration, precautions, and precautions for handling. In addition, all ingredients used as excipients must be included in the package inserts of products. According to the Pharmaceutical Affairs Act (now the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics) amended on April 1, 2005, a new regulatory category for prescription drug labeling Caution: Use only with a prescription from a physician and a labeling item for manufacturer/marketing business instead of manufacturer or importer were added. The Law for Partial Amendment of the Pharmaceutical Affairs Act (now the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics) issued on June 14, 2006 requires the manufacturer of non-prescription drugs to prescribe labeling contents specified in the Law according to the level of potential risks. To prevent medical accidents due to misunderstandings, assure traceability, and improve the efficiency in prescription drug distribution, the implementation of barcode labeling for prescription drugs (excluding in vitro diagnostics) 52 and preparation of medication guides for patients are being promoted so that the patient understands the prescription drug correctly and serious adverse drug reactions can be discovered at an early stage 医薬品 医療機器等の品質 有効性及び安全性の確保等に関する法律 No Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 52 医療用医薬品へのバーコード表示の実施要項の一部改正について平成 24 年 06 月 29 日医政経発第 号 (Bar code for pharmaceutical products, Notification No. 1 of the Economic Affairs Division, HPB and No. 1 of the Safety Division, PFSB both dated June 29, 2012) 53 患者向医薬品ガイドの運用について平成 18 年 2 月 28 日付け薬食安発第 号 薬食監麻発第 号, (Medication guides for patients, Notification No of the Safety Division, PFSB and No of the Compliance and Narcotics Division, PFSB both dated February 28, 2006) 44

45 The Agency posted information on revisions to package inserts of prescription drugs, etc., on its website within two days after receiving such information. To improve the supply of information on generic drugs, the Agency is asking for revisions to include bioequivalence test and other results (in accordance with improving the supply of Information on Generic Drugs, Notification No of the Safety Division, issued by PFSB, March 24, 2006). 54 This notification specifies to include the bioequivalence study data in the Pharmacokinetics section of the package insert. In accordance with the issue of the Law for Partial Amendment of the Pharmaceutical Affairs Act (now the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics), a new package insert notification system was introduced to strengthen measures for safety assurance. The manufacturing/marketing authorization holder is required to prepare package insert based on latest scientific knowledge and information and notify the contents of the package insert to the PMDA prior to marketing and upon every amendment. 3.2 Headings and their sequence in package inserts that are required in the labeling 1) Date of preparation and/or revision(s) of the package insert 2) Standard Commodity Classification No. of Japan, etc. - Standard Commodity Classification No. of Japan (SCCJ) - Approval number - Date of listing in the National Health Insurance (NHI) Reimbursement Price List - Date of initial marketing in Japan - Date(s) of latest reexamination - Date(s) of latest reevaluation - Date(s) of latest approval of additional indication(s) - International birth date - Storage conditions, etc. (storage, expiration date, shelf-life, etc.) 3) Therapeutic category 4) Regulatory classification (specified biological product, biological product, poisonous substance, deleterious substance, habit-forming drug, prescription drug, etc.) 5) Name(s) [brand name, non-proprietary name, Japanese Accepted Name (JAN), etc.] * At the beginning of the package insert Precautions concerning specified biological products (encased in black) 6) Warning(s) (in red letters encased in red) 7) Contraindications (in black letters encased in red) - Contraindications - Relative contraindications 8) Compositions and description - Compositions - Product description 9) Indication(s) - Indication(s) 54 後発医薬品に係る情報提供の充実について, 平成 18 年 3 月 24 日, 薬食安発第 号, (Information on generic drugs, Notification No of the Safety Division, PFSB dated March 24, 2006) 45

46 - Precautions related to Indications 10) Dosage and administration - Dosage and administration - Precautions related to dosage and administration 11) Precautions: Refer to the following box. 55 Headings used with precautions 1 "Warning" (in red letters and encased in red at beginning of "Precautions") 2 "Contraindications" (in black letters and encased in red following "Warning" in principle. However, at the beginning of Precautions when there is no "Warning") - Contraindications ("This product is contraindicated in the following patients.") - Relative contraindications ("As a general rule, this product is contraindicated in the following patients. If the use of this product is considered essential, it should be administered with care.") 3 Precaution related to indications (In the event of such precautions, they are indicated as "Indications" under the heading "Precautions" in the package insert) 4 Precaution related to dosage and administration (In the event of such precautions, they are indicated as "Dosage and Administration" under the heading "Precautions" in the package insert.) 5 Careful administration ("This product should be administered with care to the following patients ) 6 Important precautions 7 Drug interactions - Contraindications for co-administration ("This product should not be coadministered with the following drugs") (in black letters and encased in red, with simple explanation provided under "Contraindications" above) - Precautions for co-administration: The MHLW issued an office communication stressing that the Drug Interaction section must be based on the latest scientific findings. 8 Adverse drug reaction (incidence indicated in numerical values whenever possible) * A key to the frequency of adverse reactions should be provided at the beginning. 55 医療用医薬品添付文書の記載要領について平成九年四月二五日, 薬発第六〇六号, 医療用医薬品添付文書の記載要領について平成九年四月二五日, 薬安第五九号医療用医薬品の使用上の注意記載要領について, 平成九年四月二五日, 薬発第六〇七号生物由来製品の添付文書の記載要領について, 平成 15 年 05 月 20 日医薬安発第 号生物由来製品の添付文書に記載すべき事項について, 平成 15 年 05 月 15 日医薬発第 号 (Preparation on insert paper, Notifications No. 606 of PAB, No. 59 of the Safety Division, PAB, No. 607 of PAB, No of PFSB, and No of the Safety Division, PMSB) 46

47 - Clinical significant adverse drug reactions - Other adverse drug reactions 9 Use in the elderly 10 Use during pregnancy, delivery, or lactation 11 Pediatric use (low-birth weight infants, newborns, infants, small children, children) Reference: Age classification for pediatric use (basic standards) Children: under 15 years of age Small children: under 7 years of age Infants: under 1 year of age Newborns (neonates): under 4 weeks of age Low birth weight infants (premature infants): body weight of less than 2500g (according to the WHO recommendation) 12 Effects on the laboratory test 13 Overdosage 14 Precaution concerning use 15 Other precautions (Toxicity obtained in animal studies requiring particular caution, etc.) 12) Pharmacokinetics 13) Clinical studies 14) Clinical pharmacology 15) Physicochemistry (active ingredient) 16) Precautions for handling 17) Conditions for approval 18) Packaging 19) References and reference requests * Information of drugs with limited administration periods 20) Manufactured and/or marketed by: (name and address) 47

48 Figure 10. Layout of a Package Insert for a Prescription Drug (with "Warning") Requirements for Certificate of a Pharmaceutical Product (CPP) CPP is not required in the approval application. 56 Pharmaceutical Administration and Regulations in Japan, Japan Pharmaceutical Manufacturers Association, March, ( 48

49 5. Approval of manufacturing/marketing of medicinal products 5758 To get the manufacture/marketing approval on drugs, the following three reviews by regulatory agency were required. - Qualification of company: Licensing for Manufacturing/Marketing Businesses - Efficacy and safety of medicinal products: Licensing for Manufacturing/Marketing on drugs - Qualification on manufacturing system and management: Licensing for Manufacturing Businesses (domestic manufacturing), Accreditation of manufacturing business of overseas manufacturers Figure 11. Flow of Drug Manufacturing/Marketing Approvals 57 医薬品の製造販売手順について (Procedure for manufacturing and marketing for pharmaceutical products) ( Accreditation of Foreign Manufacturers ( 49