TABLE OF CONTENTS Spring 2004 . Spring 2005 18th New Drug Evaluation Division Information Meeting 19th New Drug Evaluation Division Information Meeting 20th New Drug Evaluation Division Information Meeting 21st New Drug Evaluation Division Information Meeting Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) 18th New Drug Evaluation Division Information Meeting Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) 18th New Drug Evaluation Division Regular Meeting Date: February. 19, 2004 Time: 10:30 . 15:00 Venue: Melpark Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: . Japan Federation of Pharmaceutical Manufacturers�EAssociations (JFPMA) . Japan Pharmaceutical Manufacturer Association (JPMA) . The Pharmaceutical Manufacturers�E Association of Tokyo (PMAT) (Incorporated Association) . Osaka Pharmaceutical Manufacturers Association (OPMA) . Japan Medical Association (JMA) (Incorporated Association) February 2004 February 2004 PROGRAM 10:30-1040 Opening Address from the Organizer Mr. Uchiyama (SJP) 10:40-11:00 Current Status of the Pharmaceutical Administration MHLW, PFSB, Evaluation and Licensing Division Division Head Dr. Shuichi Kishida 1 11:00-11:50 New Drug Approval Review MHLW, PFSB, Evaluation and Licensing Division Assistant Division Head Dr. Hidehito Sekino Lunch Break 13:00-13-50 Biostatistics in the New Drug Approval Review NIHS, PMDEC, Evaluation Division I Evaluation Manager Dr. Daisuke Shibata Break 13:50-14:10 GCP Compliance Investigation and Initial Clinical Trial Review OPSR, Clinical Trials Guidance Department Head of Clinical Trials Investigation Division Dr. Junichi Ohnishi Disclaimer 1 Due to absence the presentation was made by Mr. Hidehito Sekino. February 2004 Title No. New Drug Evaluation Division Information Meetings 18 Periodic ICH Information Meetings 9 Problems with Safety of Drugs 6 Problems with QA of Drugs 4 14th Japanese Pharmacopoeia 1 Total as of February 2004 38 Opening Address from the Organizer: Mr. Uchiyama (SJP) (Gist) The progress in the research and development of medicinal products in our country is remarkable; however a number of difficulties have appeared recently. In this foundation (The Society of Japanese Pharmacopoeia) we selected some recent topics affecting the development of medicinal products, and with guidance and support we organized this information meeting and hope even small this would be helpful for all of you in the audience. We also would like to thank to our sponsors and to all participants. Note: The first of the series of information meetings was carried out on January 29, 1999 in Tokyo with the purpose to provide direct clarification for a number of current topics (organizational changes, acceptance of ICH Guidelines, GCP and the conduct of clinical trials). The title “New Drug Evaluation Division Meeting�Ereflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 38 meetings have been held as follow: February 2004 Current Status of the Pharmaceutical Administration MHLW, PFSB, Evaluation and Licensing Division Division Head Dr. Shuichi Kishida 2 Key points of the presentation: .. For new drug applications, current average period for clerical procedure is 12 months. .. The Pharmaceuticals and Food Safety Bureau (PFSB) will continue its effort to collect and make announcements on data on new drug approvals. .. As of April 1, 2004, three major organizations for evaluation of medicinal products3 - National Institutes of health Sciences (NIHS), Pharmaceutical and Medical Device Evaluation Center (PMDEC), Organization for Pharmaceutical Safety and Research (OPSR) - will merge into one organization, the Pharmaceuticals and Medical Devices Organization (PMDO) 4 (Independent Administrative Organization). Basic functions of MHLW and the new organization will be as follows: - MHLW : Planning and drafting of basic policies; take administrative measures for approvals, orders, judgments, etc. - PMDO: Conduct evaluation, review, handling of data, etc. that do not require administrative decisions .. Other tasks of the MHLW - Priority reviews 2 Due to absence the presentation was made by Mr. Hidehito Sekino. 3 Including pharmaceuticals, medical devices, quasi-drugs and cosmetics. 4 The English name of the PMDO will be officially unveiled on April 1, 2004. February 2004 - New scheme on wider application of anti-cancer agents for parallel treatment, expanded access program - Off-label use - ICH - The government will continue its basic policy to comply with ICH, and observe its movements on tasks such as: biotechnology and other new technologies, cooperation with non-ICH regions, etc. February 2004 New Drug Approval Review MHLW, PMSB, Evaluation and Licensing Division Assistant Division Head Dr. Hidehito Sekino Key points of the presentation: A. About the Pharmaceuticals and Medical Devices Organization (Independent Administrative Organization) Name5: Pharmaceuticals and Medical Devices Organization (Independent Administrative Organization6) Employees: non-civil servants Establishment: April 1, 2004 Description: . Operations: . Provide benefits to the sufferers of health damages due to Adverse Drug Reactions . Conduct investigation and evaluation based on Pharmaceutical Affairs Law . Provide consultation on initial clinical trial . Accumulate data on efficacy and safety of drugs, further investigate, analyse and evaluate. . Promote research and development . Tasks: . Reinforce the evaluation system .. new organization .. priority review . Provide safe and effective new drugs to the nation .. revision of law .. re-evaluation system 5 At the presentation only the name in Japanese was given: Iyakuhin Iryoukiki Sogo Kiko 6 Denotes the legal status. February 2004 . Aims: . For the benefit of both the industry and nation, the organization will make effort to shorten time period of new drug approvals. .. For the initial 5 years: approve 50 to 80% of the applications within 12 months (for priority approvals to accomplish 50% in 6 months) . Collaborative approval and post-marketing safety .. survey on all cases .. post-marketing clinical study .. compilation and announcement of ADR cases . Promote “Creation�E(R&D) and “Fosterage�E (post-marketing) .. encouragement for proper use .. post-marketing safety measures .. prevention of health damages . Drug safety .. collection and supervision of drug safety information at one place .. conduct survey, analysis and consultation in accordance with the characteristics of the product .. improve communication with medical workers, companies and patients .. consultation and education of medical related people and the nation . Expected requirements .. swift and efficient approval .. collaboration of clinical study consultation and evaluation .. first-track system and priority approval .. improvement of evaluator skill and knowledge .. effectiveness and clarity of the process .. communication with industry/nation .. complaint management February 2004 B. On the domestic clinical trials . Current status .. numbers of clinical trials have decreased after revision of Pharmaceutical Affairs Law .. physicians are now able to conduct clinical studies . Tasks .. provide satisfactory information to the patients after completing clinical study .. report as much as possible on the status of the trial .. companies to obtain as much data for trial to prompt the approval procedure C. Miscellaneous An appeal was made to the physical and legal persons with a request to refrain from submitting application for approvals from March 1 to April 9, 2004, in order to prevent disorders at the kick-off period of the Pharmaceuticals and Medical Devices Organization. February 2004 Biostatistics in the New Drug Approval Review NIHS, PMDEC, First Evaluation Division Evaluation Manager Dr. Daisuke Shibata Key points of the presentation: A. Current Status Environmental changes . Social need for scientific review of drugs is rising . Break away from “authority vs. company�Estructure . Change in flow of information Time period . There is no significant difference between USA and Japan whereas there is a big difference in the system, structure and role of the reviewing organization 7 Basic attitude . Appropriate (scientific, rational, realistic) judgement . Prompt judgement . Follow-up of judgement B. Future Tasks . Collaboration with clinical trial consultation . scientific report, analysis and consideration on the status quo . critical and constructive evaluation . Speed-up the review procedure . speed-up the clerical procedure of the reviewer . speed-up the clerical procedure of the applicant . shorten the waiting line 7 http://www.pharmasys.gr.jp http://www.fda.gov/cder/rdmt/NMEapps93-02.htm http://www.fda.gov/cder/Offices/Biostatistics/default.htm February 2004 .. reviewer: priority system .. applicant: submit scientifically adequate application data . Post-marketing safety measures and means for providing information . Adequate evaluation of the study conducted by those in charge of biostatistics will create additional value . Enable smooth flow of project from study design, development plan, to post-marketing policies . Enhance decision-making . Expansion of role of those in charge of biostatistics Accurate and swift analysis enhance the application procedure Avoid trouble caused by misuse of statistics . Participation in Project Management . Participation in Risk Communication/Risk Management . Participation in Lifecycle Management C. Further issues to tackle . Consider the measures for tailor-made treatment; seeking possibilities in how to scheme the clinical studies to enable that . Seeking what is necessary for smooth collaboration of development evaluation, post-marketing safety . How to collect and accumulate necessary data at the stage of development . How to utilize the accumulated data, how to utilize the daily data and reflect on the accumulated data . How to solve the communication defects February 2004 Summary Involvement of those in charge of biostatistics in companies has started to contribute to the improvement of application data quality. For further improvement, it is considered to become more important for them to be involved in even more parts of the drug development. February 2004 GCP Compliance Investigation and Initial Clinical Trial Review OPSR, Clinical Trials Guidance Department Head of Clinical Trials Investigation Division Dr. Junichi Ohnishi Key points of the presentation: A. Status quo of GCP compliance review Numbers of items reviewed and sponsors/institutions have not changed in the recent 5 years, however, the numbers of national medical institutions have decreased whereas private clinics have increased for one of the basic policies to select the institutions to review is to conduct on institutions that have not been reviewed in the recent years (or never have been). B. Violation of GCP by medical institutions Violation of GCP has decreased from fiscal year 2000 to 2001, however, boosted in 2002, which is believed to be because the survey was conducted for the first time at 49% of the institutions. The most prominent violation is against the protocol. The increase in the number of coordinators (CRC) has contributed in keeping good records. C. Violation of GCP8 by sponsors The revised GCP enforced the role of sponsors to take more responsibility on clinical trials. Sponsors�Eviolations of GCP concentrate on Article 20 Paragraph 1 and 2 9 (in case 8 PAB Notification No. 430 dated March 27, 1997 on Enforcement of Good Clinical Practice for Trials on Drugs (GCP) 9 MHW Ordinance No. 28 dated March 27, 1997 on Good Clinical Practice (GCP) February 2004 of ADR, sponsors are responsible to report, as soon as possible, to the investigator and the head of institution), and Article 22 Paragraph 2 10 (monitors should submit monitoring report to sponsors). D. Important factors in monitoring The essential condition for IRB is to be able to conduct the review sufficiently. Those that are not specialized in the related area and those who do not have any interest with institutions should be included in the board members. Also, procedure manual, board member name list and minutes should be composed (Article 28)11. Additionally, those who have not attended the review do not have the right to vote (Article 29). The study directors should sufficiently consider the patient’s condition, symptom, age and ability to consent, etc., in accordance to the purpose of the study (Article 44)12. The investigator has the responsibility to keep a record and report to the sponsor and the head of study institution whenever compliance of protocol is not kept as of Article 46 13 and Article 6-2-8-214. E. Initial Trial Review Inquiry from OPSR to the sponsor should be replied in 30 days. Dissatisfactory data on investigators brochure, reasons of extrapolation, protocol, and written informed consent are the major inquiries. 10 MHW Ordinance No. 28 dated March 27, 1997 on Good Clinical Practice (GCP) 11 MHW Ordinance No. 28 dated March 27, 1997 on Good Clinical Practice (GCP) 12 MHW Ordinance No. 28 dated March 27, 1997 on Good Clinical Practice (GCP) 13 MHW Ordinance No. 28 dated March 27, 1997 on Good Clinical Practice (GCP) 14 "CPAC-GCP Advised to MHW from CPAC" - CPAC Notification No. 40 dated March 13, 1997 19th New Drug Evaluation Division Information Meeting Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) 19th New Drug Evaluation Division Regular Meeting Date: May 20, 2004 Time: 10:30 . 15:00 Venue: Kosei-Nenkin Kaikan Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: . Japan Federation of Pharmaceutical Manufacturers�EAssociations (JFPMA) . Japan Pharmaceutical Manufacturer Association (JPMA) . The Pharmaceutical Manufacturers�E Association of Tokyo (PMAT) (Incorporated Association) . Osaka Pharmaceutical Manufacturers Association (OPMA) . Japan Medical Association (JMA) (Incorporated Association) May 2004 May 2004 PROGRAM 10:30-10:40 Opening Address from the Organizer Mr. M. Uchiyama (SJP) 10:40-11:10 Current Trends in the Approval Examination MHLW, PFSB, Evaluation and Licensing Division Division Head Dr. Shuichi Kishida 11:10-11:55 Clinical Trial Consultations in PMDA Pharmaceuticals and Medical Devices Agency Priority Review, Coordinator Dr. Takeyuki Sato Lunch Break 13:00-13-50 Drug Safety Measures of PMDA Pharmaceuticals and Medical Devices Agency Safety Control, Supervisor Dr. Tatsuo Kurokawa Break 13:50-14:10 New Approval Review System of PMDA Pharmaceuticals and Medical Devices Agency Director (concurrently, Head of Evaluation Centre) Dr. Satoshi Toyoshima Disclaimer May 2004 Key illustrations Table 1. New categories of consultations Table 2. Present Consultation Categories (for new medicinal products) Table 3. Fees for new drug clinical trial consultations Flowchart 1. Procedure for consultation in PMDA Flowchart 2. Flow-chart of the review work by PMDA Table 4. Department in charge of clinical trial consultation May 2004 Opening Address from the Organizer: Mr. M. Uchiyama (SJP) (Gist) The progress in the research and development of medicinal products in our country is remarkable; however a number of difficulties have appeared recently. In this foundation (The Society of Japanese Pharmacopoeia) we selected some recent topics affecting the development of medicinal products, and with guidance and support we organized this information meeting and hope even small this would be helpful for all of you in the audience. We also would like to thank to our sponsors and to all participants. Note: The first of the series of information meetings was carried out on January 29, 1999 in Tokyo with the purpose to provide direct clarification for a number of current topics (organizational changes, acceptance of ICH Guidelines, GCP and the conduct of clinical trials). The title “New Drug Evaluation Division Meeting�Ereflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 38 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 19 Periodic ICH Information Meetings 9 Problems with Safety of Drugs 6 Problems with QA of Drugs 4 14th Japanese Pharmacopoeia 1 Total as of February 2004 39 May 2004 Current Trends in the Approval Examination MHLW, PFSB, Evaluation and Licensing Division Division Head Dr. Shuichi Kishida Key points of the presentation: .. Outline of Pharmaceuticals and Medical Devices Agency (PMDA) .. Flow of new drug approval .. Importance of the applicant to respond to the requirements of the reviewing authority in order to achieve approval as fast as possible .. Priority review .. Clinical trial priority consultation .. Regulations to be framed on partial modification during approval application - Partial modification during partial modification of drugs and quasi-drugs - Additional application during new drug application .. Off-label use .. Expanded access program of anti-cancer multiple drug treatment - Conduct a rapid review (4 months) May 2004 .. Improvement in pediatric use of medicines - Protocol, post-marketing drug safety, gathering of data .. Announcement by authority of the approval data - Outline of approval shall be made public after 3 months of approval .. Promote countermeasures on misuse of drugs - Label dosage regiment with trade name, etc. .. Re-evaluation of drugs - Approximately 30% of total results are dissatisfactory (leading to disapproval) .. Schedule on re-evaluation of antibacterial products - Deliberate by June and notify in September 2004 .. ICH, CTD issues .. GCP compliance - Performance is greatly influenced by the degree of contribution of the monitors May 2004 Clinical Trial Consultations in PMDA Pharmaceuticals and Medical Devices Agency Priority Review, Coordinator Dr. Takeyuki Sato Key points of the presentation: A. Basic view of clinical trial consultations Description: . Basic view: - Clinical trial consultation in PMDA will have designated consulting team for each case. In this way, the applicant and the consulting team will have closer communication, which will lead to an effective consultation result - In order to provide more effective drugs to the medical scene, PMDA is determined to offer apt consultation in a swift manner . Is Consultation an advantage for the approval? - Consultation will often shorten the total time for approval if applicants observe the consultation results - Judgment of PMDA is subject to change according to new scientific discoveries and progress May 2004 . Changes in handling fee: . Consultation fees 1 have been revised . Timing for payment is to be reconsidered . Cancellation fee will be charged B. New categories of consultations . Changes in the categories of consultations: . Consultation categories have been changed during 3 periods (Table 1): a) Before July 13, 2003 . prior to the introduction of CTD b) Between July 14, 2003 and March 31, 2004 . transition period prior to the establishment of PMDA c) After April 1, 2004 . present period after the establishment of PMDA . Present consultation categories are listed in details on Table 2 below. 1 See Table 3 (page 15) May 2004 Table 1. New categories of consultations Before July 13, 2003 From July 14, 2003 to March 31, 2004 After April 1, 2004 Initial clinical trial consultation for: “Clinical trial consultation�E “Safety consultation�E “Quality consultation�E Post-phase II consultation Pre-application consultation Specific consultation Re-evaluation/re-examination: Protocol consultation Post clinical test consultation Procedure consultation Pre-phase I consultation Safety consultation Quality consultation Pre-phase II consultation Additional consultation Earlier pre-phase II consultation Latter pre-phase II consultation Bioequivalence study consultation May 2004 Early pre-phase II consultation . Restricted to consultation on protocol of earlier phase II clinical trial. Guidance and advice will be provided based on the results and data of the phase I trial . For example, adequacy of parameter applied to the pharmacokinetics of patients. Late pre-phase II consultation . For the first time, the organization will consult on those cases that arise after completing phase I trial until settlement of clinical dosage, that is, for example, on phase II protocols . Consultation will be based on the result of phase I trial, overseas clinical data in human, approvals of other countries and information on similar drugs . When even before the earlier phase II trial is launched, if the consultation should include matters on latter phase II protocols, the case will be categorized here . That is, validity of dosage of the investigational drug in phase II trial, written informed consent for patients, and so on May 2004 Consultation on pharmaceutical bioequivalence study . Guidance and advice on those cases that do not categorize under phase I ~ III trials nor under quality / safety consultation, but require data evaluation are categorized here. Such cases as consultation on the categorization, bioequivalence study reviews will be allocated here. Consultation prior to application for new nonprescription drugs (planned) . Guidance and advice on those non-prescription drugs classified (2) 2 and (3) 3 in the approval application classification and have more new aspects to the drug. Consultations will be on the necessity of clinical trial, adequacy of protocol, non-clinical study data, and on . Before applying for this consultation, it is highly recommended to receive a good advice through the prior interview service. 2 Class 2 - “New Proprietary Ingredient�Enon-prescription medicines 3 Class 3 - “New Compound Ingredients�Enon-prescription medicines May 2004 Consultation prior to clinical trial and application of medical devices / in-vitro diagnostics products (planned) . Guidance and advice on those that require data evaluation, such as non-clinical study plan and adequacy of trial method. May 2004 Table 2. Present Consultation Categories (for new medicinal products) [1] Consultations available during the new drug development (1) Pre-phase I consultation (2) Earlier pre-phase II consultation (3) Latter pre-phase II consultation (4) Post-phase II consultation (5) Pre-application consultation [2] Consultations on clinical trials for reevaluation / re-examination (1) Re-evaluation/re-examination Protocol consultation (2) Re-evaluation/re-examination Post clinical test consultation [3] Consultations that supplement the above (1) Procedure consultation (2) Bioequivalence study consultation (3) Quality consultation (4) Safety consultation (5) Additional consultation May 2004 Table 3. Fees for new drug clinical trial consultations Consultation category Fee per consultation(Yen) Procedure consultation 172,100 Bioequivalence study consultation 566,100 Early pre-phase II consultation 2,349,900 Quality consultation 1,483,500 Safety consultation 1,637,200 Early pre-phase II consultation 865,200 Late pre-phase II consultation 1,678,700 Post-phase II consultation 3,331,900 Pre-application consultation 3,333,000 Re-evaluation/reexamination Protocol consultation 3,331,900 Re-evaluation/ re-examination 3,333,000 Post clinical trial consultation 3,333,000 Additional consultation 1,483,500 May 2004 C. Procedure of face-to-face advice Flowchart 1. Procedure for consultation in PMDA Temporary application for consultation schedule adjustment notification of the consultation date contract (payment) prior research face-to-face advice close consultation report conveyance of the record Work-flow in PMDA The review work carried by PMDA is summarized in Flowchart 2. (next page) May 2004 Flowchart 2. Flow-chart of the review work by PMDA テキスト ボックス: Convey recordsテキスト ボックス: Scheduling, consultation reception/informationテキスト ボックス: Recordテキスト ボックス: Schedule adjustmentテキスト ボックス: Designated person in chargeテキスト ボックス: Clinical trial coordinatorテキスト ボックス: Evaluation and Licensing Divisionテキスト ボックス: Answerテキスト ボックス: Face-to-face adviceテキスト ボックス: Evaluation Sectionテキスト ボックス: Evaluator in chargeテキスト ボックス: Person in chargeテキスト ボックス: Advisorテキスト ボックス: Applicantテキスト ボックス: PMDAテキスト ボックス: Question May 2004 Table 4. Department in charge of clinical trial consultation Department in charge Medicinal products First New drug evaluation Department Anti-malignancy, anti-bacterial, anti-HIV-viral related drugs Second New drug evaluation Department Cardio-vascular drugs, urinary and recto-anal drugs, reproductive organ drugs, metabolic disease drugs (limited to combined ingredients), internal diagnosis drugs, radioactive drugs Third New drug evaluation Department Gastrointestinal drugs, metabolic disease (other than combined ingredients), hormonal drugs, dermatological drugs, central nervous system drugs, peripheral nervous system drugs, respiratory organs drugs, allergy drugs, narcotics Biological evaluation Department Biological, cell and tissue drugs, blood products May 2004 D. For more effective consultations .. Consultation is available in morning and afternoon from Monday to Friday .. Write at least 3 possible days for consultation when applying for consultation .. Make good use of the prior interview system for deliberation of the consultation category and data preparation .. Contact the evaluation department when payment is to be delayed .. Cancellation procedure will be necessary if the applicant request to cancel or change the date of face-to-face interview due to the applicants reason, and in that case, 50% of consultation fee will be reimbursed .. When cancellation by PMDA reasons, 100% of the fee will be reimbursed .. For more information visit the web site of the PMDA at http://www.pmda.go.jp May 2004 E. Priority face-to-face interview on designated items . Criteria and necessary documents - Drug items that are considered important for treatment of serious disease will be designated as priority face-to-face interview items - In order to achieve this priority, submission of data that prove the importance of the item in medical treatment is necessary, for example, outline of investigation drug, etc. . Procedure of priority face-to-face interview proprietary steps - Inquiry and hearing will be conducted to the applicant - PMDA internal deliberation (with opinions from specialists) - Notification of the result to the applicant - Report to the relevant sections of MHLW and Health Science Council May 2004 . Procedure after designated as priority face-to-face item - Those items, compounds or effects of drug that is designated as priority item through the above procedure is prioritized in face-to-face interview (clinical trial consultation) - The case is also applicable to consultation on the reliability standard conformation - Designation is subject to withdrawal in specific cases such as violation of pharmacopoeia . Prior to applying for the designation - Thorough deliberation should be made at prior interview, which can be applied in the same procedure with the regular new drug prior interview application. May 2004 Drug Safety Measures of PMDA Pharmaceuticals and Medical Devices Agency Safety Control, Supervisor Dr. Tatsuo Kurokawa Key points of the presentation: . Inauguration of PMDA was a good opportunity to improve and reinforce human resource and organization in drug safety administration. Expanded capacity of specialized personnel will handle drugs for disease such as cancer, dementia and acute infectious disease, which require drugs of new mechanism and technology . Drug Safety operation in PMDA will take-over routine operations of MHLW therefore giving leeway to the total drug safety of the country . MHLW will be in charge of decision making while PMDA will implement the established projects . MHLW and PMDA will share information and promote the safety measures together, will cooperate with other medical institutes in a friendly manner, and will improve in operational transparency May 2004 . Continue to work on the post-marketing drug safety issues of new drugs. Post-marketing adverse drug reactions (ADR) are constantly reported, due to the fact that ADR information at the pre-marketing stage is likely to be held back owing to expectations of patients, families, concerned medical workers and companies�Edesire to develop the new drug as a block buster. May 2004 New Approval Review System of PMDA Pharmaceuticals and Medical Devices Agency Director (concurrently, Head of Evaluation Centre) Dr. Satoshi Toyoshima Key points of the presentation: . Provide better medicinal products to the medical scene in a swift manner . Organization of PMDA . improvement . Clinical trial evaluation procedure 20th New Drug Evaluation Division Information Meeting Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) 20th New Drug Evaluation Division Regular Meeting Date: October 22, 2004 Time: 10:30 . 15:00 Venue: Melparque Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: . Japan Federation of Pharmaceutical Manufacturers�EAssociations (JFPMA) . Japan Pharmaceutical Manufacturer Association (JPMA) . The Pharmaceutical Manufacturers�E Association of Tokyo (PMAT) (Incorporated Association) . Osaka Pharmaceutical Manufacturers Association (OPMA) . Japan Medical Association (JMA) (Incorporated Association) October 2004 October 2004 PROGRAM 10:20-10:30 Opening Address from the Organizer Mr. M. Uchiyama (SJP) 10:30-11:00 Current Trends in the Approval Examination MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara 11:00-11:45 CTD and eCTD Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masakatsu Imoto Lunch Break 13:00-13:45 Directions for Pediatric Pharmacotherapy National Center for Child Health and Development Chief of Clinical Trial Management Office Dr. Hidefumi Nakamura Break 13:45-14:00 New Drug Application Risk Communication Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masayuki Ikeda Disclaimer October 2004 Key illustrations Figure 1. Current system of manufacturing and sales, licensing and approval Figure 2. Overview of the Master File system Figure 3. Flowchart of the Evaluation system after April 2005 Figure 4. Outline of the CTD structure Table 1. Changes in the format for submission October 2004 Opening Address from the Organizer: Mr. M. Uchiyama (SJP) (Gist) The progress in the research and development of medicinal products in our country is remarkable; however a number of difficulties have appeared recently. In this foundation (The Society of Japanese Pharmacopoeia) we selected some recent topics affecting the development of medicinal products, and with guidance and support we organized this information meeting and hope even small this would be helpful for all of you in the audience. We also would like to thank to our sponsors and to all participants. Note: The first of the series of information meetings was carried out on January 29, 1999 in Tokyo with the purpose to provide direct clarification for a number of current topics (organizational changes, acceptance of ICH Guidelines, GCP and the conduct of clinical trials). The title “New Drug Evaluation Division Meeting�Ereflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 38 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 20 Periodic ICH Information Meetings 10 Problems with Safety of Drugs 7 Problems with QA of Drugs 4 14th Japanese Pharmacopoeia 1 Total as of October 2004 42 October 2004 Current Trends in the Approval Examination MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara Key points of the presentation: 1. Implementation of the revised Pharmaceutical Affairs Law According to the revised Pharmaceutical Affairs Law, in 2003, a revision in the regulations of biological products and clinical tests were implemented, and in 2004, PMDA was established. In 2005, revisions on the followings are planed: .. Manufacturing and sales, licensing and approval .. Foreign manufacturers .. Master file system .. Classification of drugs .. Labeling .. Others 1) Manufacturing and sales, licensing and approval In the present approval/licensing system, significance is placed on the manufacturing part of the drug and it is on the premises that all pharmaceutical companies own the manufacturing facility. However, in accordance to business diversification and globalization of the industry, it is necessary to allow flexibility in the system, maintain international conformation and secure further safety. See Figure 1 (next page) October 2004 Figure 1. Current system of manufacturing and sales, licensing and approval Japan US EU Approval System Manufacturing approval Sales approval Sales approval テキスト ボックス: Factors to be improved角丸四角形吹き出し: From manufacturing to post marketing safety measuresテキスト ボックス: ? Are post marketing safety measures enough? ? Is the present system eligible to cope with diversification of business such as branch offices and consignments? ? Should the system not conform to that of EU and US where more significance is placed on approval on sales? テキスト ボックス: Issues to solveテキスト ボックス: ? On the premises that the developer has the manufacturing facility ? Manufacturing approval by each items and manufacturing license are necessary 角丸四角形吹き出し: Manufacturingテキスト ボックス: Present Systemテキスト ボックス: Applicationテキスト ボックス: Salesテキスト ボックス: Manufacturing (Licensing of manufacturing) テキスト ボックス: Quality, efficacy and safety evaluation (Manufacturing approval by items) テキスト ボックス: R&Dテキスト ボックス: ? Clarify market responsibility of companies ? Enforce post marketing measures and clarify its regulations on consignments ? Enable complete liberalization of manufacture outsourcing by “original sales license�E“original sales approval�Esystem October 2004 2) Outline of Master File system Figure 2. Overview of the Master File system テキスト ボックス: Both EU and US carry out the Master File system: global conformation角丸四角形吹き出し: It is necessary to avoid trouble between original drug manufacturer and pharmaceutical company for the approval procedure will go into details of manufacturing details.テキスト ボックス: The registered data will be available also for other manufactures to utilize.テキスト ボックス: The system will allow data that is submitted separately by manufacturers other than the applicant of the drug. テキスト ボックス: Quality, manufacturing data registrationテキスト ボックス: Application form円形吹き出し: Information concealed (except for cases when disclosure is necessary for safety reasonsテキスト ボックス: Allow other companies to useテキスト ボックス: Evaluate as a complete dataテキスト ボックス: MF Registrationテキスト ボックス: Evaluation authorityテキスト ボックス: Quality, manufacturing method and dataテキスト ボックス: Original drug manufacturer テキスト ボックス: Efficacy, Safety Quality (partial) テキスト ボックス: Pharmaceutical company (applicant) October 2004 2. Evaluation system in PMDA 1) Evaluation Flow (2005~) Figure 3. Flowchart of the Evaluation system after April 2005 テキスト ボックス: Overseas GMP Surveyテキスト ボックス: Evaluation Reportテキスト ボックス: Approvalテキスト ボックス: Clinical Trial Consultationテキスト ボックス: Applicationテキスト ボックス: GMP Survey (excluding new drug, biological, radiation products)テキスト ボックス: PMDAテキスト ボックス: MHLWテキスト ボックス: Equivalence Review (incl. GMP) Compliance Review テキスト ボックス: Prefectureテキスト ボックス: Manufacturing Companyテキスト ボックス: Manufacturing and Sales Companyテキスト ボックス: Foreign Manufacturing Companyテキスト ボックス: Approvalテキスト ボックス: GMPテキスト ボックス: GMP Survey (new drug, biological, radiation products)テキスト ボックス: Excluding prefecture approvalテキスト ボックス: Report October 2004 2) Establishing a system that provides stable total evaluation time 3) Priority evaluation Consider the seriousness of the disease and medical benefit 4) Priority consultation on clinical trial 5) Work flow of approval evaluation results etc. 6) Collaboration of approval evaluation and postmarketing safety measures 7) Developing and fostering Promoting development of new drug, enhanced prompt approval, and enforcing the post-marketing safety 8) Promotion of re-evaluation Efficacy re-evaluation, quality re-evaluation 9) Evaluate clinical value of the drug on the basis of latest medical standard 10) New scheme for expanded access program of anti-cancer multiple drug treatment Establish anti-cancer multiple drug treatment committee Speed up approval procedure October 2004 11) Promoting medical malpractice prevention Add supply type and amount on trade name Trade name of prescription drugs 12) Prompt action against prevention of malpractice 13) Prevent delay of evaluation process 14) Others under consideration Part of OTC drugs to be shifted to quasi drugs Labeling of generics ICH Lectures for manufacturing control Clinical trial promotion committee OTC sales improvement Risk triage study group October 2004 CTD and eCTD Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masakatsu Imoto Key points of the presentation: New Drug Approval Application Documents Dossier .. Name (generic name, trade name) .. Ingredients, composition .. Manufacturing procedure .. Dosage .. Effect and efficacy .. Storage and validity .. Standard and method of trial .. Others October 2004 Data a. Data on origin, details of discovery, use in foreign countries, etc. b. Data on physical and chemical properties, specifications, testing methods, etc. c. Data on stability d. Data on acute toxicity, subacute toxicity, chronic toxicity, teratogenicity and other toxicity e. Data on pharmacological action f. Data on absorption, distribution, metabolism and excretion g. Data on results of clinical trials Outline of data October 2004 Common Technical Document (CTD) . Japan, US, and EU Common document for drug application . Agreed at ICH (International Conference on Harmonization) . Developed by 3 specialists committee, Quality, Safety and Efficacy . When applying for approval in Japan, US, and EU, the common documentation style will save time and will enhance speed in providing drug to patients and market . However, the approval/licensing system is different between countries, therefore, it will comply with the order of the document, the contents will accord to ICH guideline, and the details will be decided by each local authority . Drugs that CTD is to be applied Drugs with new active ingredients New combination prescription drugs Drugs with new routes of administration Drugs with new indication Drugs with new dosage forms October 2004 Drugs with new doses (Additional dosage forms, generics are acceptable in the previous form) . CTD Guidelines do not indicate what kinds of trials are required but shows the appropriate format to apply to submit the obtained data See also Figure 4 (next page) October 2004 Figure 4. Outline of the CTD structure テキスト ボックス: Part 5 Clinical Test Report テキスト ボックス: Part 4 Laboratory Test Report テキスト ボックス: Part 3 Quality テキスト ボックス: Part 2 Quality Laboratory Clinical Outline Outline Outline テキスト ボックス: Part 1 Local authority テキスト ボックス: USubmitted Dataテキスト ボックス: UOutline of data submitted Origin, etc Properties, stability Toxicity Pharmacology Pharmacokinetics Clinical trial テキスト ボックス: CTD October 2004 From CTD to eCTD CTD: Common Technical Document eCTD: Electronic Common Technical Document Table 1. Changes in the format for submission Period Original copy Duplicate June 1, 2004~ Paper Paper (eCTD) April 1, 2005 ~ Paper or eCTD Under consideration .. Signature and Statement of the documents To guarantee that the eCTD is correctly duplicated from the paper materials or electronic materials, for example, correctly scanned, correctly transferred to PDF .. Electronic documentation is expected for attached data within one year from now .. The Japanese authority request to submit a list of symptoms (basically in PDF) and a list of attached data (in both PDF and Excel) October 2004 .. The applicant is responsible to confirm the accessibility of submitted application data at the PMDA computer. If not, the time clock will be returned to the applicant .. PMDA plan to organize a reception number for each case .. The submitted data should be renewed, replaced or deleted according to the evaluation process and results. (Life cycle management) .. Cover letter A cover letter should be attached as PDF and paper October 2004 Directions for Pediatric Pharmacotherapy National Center for Child Health and Development Chief of Clinical Trial Management Office Dr. Hidefumi Nakamura Key points of the presentation: Present status and issue of off-label use for pediatric pharmacotherapy Among drugs commonly administered for pediatric use, almost 70% of package inserts lack sufficient information on dose and dosage, efficacy and safety. These include those drugs that indicate, “safety not established in certain age range�E(40% of total) and “contraindicated�Eor “conform to contraindication�E(2~3% of total). Dosage form is another issue for pediatric usage. Solid dosage form drugs and oral administration drugs (p.o.) that are prepared by hospitals for pediatric use (taking off capsules, grinding pills, transferring i.v. to p.o.) should be standardized officially. Additionally, for those drugs that are not yet approved in Japan, there are cases that drugs obtained personally from October 2004 overseas doctors or compounds for clinical trials are administered. Present status of pediatric clinical trial “Guidance on Pharmaceuticals for Pediatric Use�EICH E-11: Pharma No.1334) has been implemented since April 2001. This guidance advises, “When the drug is presumed to be pediatrically administered, the pediatric use should be merged in the new drug development plan.�EThis guidance, however, has no enforcement to pharmaceutical companies and there is little incentive for companies to develop such drugs (profit do not increase by pediatric use drugs), therefore, there is little impression that pediatric use drug has increased by the guidance. Promotion of pediatric clinical trial in Europe and US In the US such laws as Pediatric Research Equity Act of 2003 and Best Pharmaceuticals for Children Act are established, FDA has the right to request necessary pediatric clinical trial, and drug patent will be legally extended if pediatric clinical trial is conducted. These measures result in rapid increase of pediatric clinical trials. Such law is also being prepared in the EU and is considered to put into practice shortly. Under such October 2004 movements, it is necessary for Japan to take prompt action to enact such policies. Update on administrational policies By the “Handling of prescription drugs and off-label use�E February 1, 1999, drugs from overseas can be approved with only partial or totally no clinical trials conducted in Japan, when the medical society request, the medical necessity is clear, and the efficacy and safety of the drug is publicly apparent. Under present regulation, however, it is reportedly said to have given negative impressions to the companies on the development of pediatric drugs for such reasons as delay in insurance administration for difficulties in settling the NHI drug price, and cooperation to pediatric R&D is economically unprofitable. “Revision on post-marketing sales survey and reevaluation�E December 27, 2000, promote special survey on pediatric use and post-marketing clinical tests for pediatric dose regimen. When implementing clinical tests for pediatric dose during re-evaluation period, extension of re-evaluation period (not over 10 years) is granted. The notice has been applied, however, for only 2 items as October 2004 of February 2004. The incentive for pharmaceutical companies is extremely limited. Policies of Medical Societies Japan Pediatric Society (JPS) Pharmaceutical Committee, other sub-committees of JPS, and Japan Developmental Pharmacology and Therapeutics are actively working on the off-label use issues. Drugs considered necessary to promptly enact the approval were listed with collaboration of the various activities. In addition, “Action plan for pediatric off-label use and clinical trial promotion�Ewas assigned at the JPS Pharmaceutical Committee meeting in July 2004, which clarified the policy and indicated concrete measures to undertake. 1. Pediatric off-label use and clinical trial promotion are one of the most important missions of the JPS and it will continue its active and positive efforts to tackle the issue. 2. Enhance synthetic categorization of the entire offlabel use drugs and pursue concrete measures to solve each off-label use issues. 3. Outline the problems on reagents, chemically October 2004 synthesized or reformed drugs and named patient program. 4. Implement active measures on improving the systems on pediatric clinical trials. 5. Take movements to legalize incentives of pharmaceutical companies, or right to request pediatric clinical trial. 6. Frame a system to collect data on pediatric treatment through post-marketing survey / drug use survey. 7. Improve safety information on pharmacotherapy during pregnancy and lactation. Full-scale measures to be implemented in 2005 According to the newspapers, MHWL will appropriate pediatric drug problems fee in the fiscal 2005 budget, and kick-off a study group to tackle the above-mentioned problems including such regulations seen in the US and others. In order to gain success in the project, cooperation of various organizations, society and companies are required. For the fair pediatric pharmacotherapy In order to cover all the off-label use issues, it is necessary that the pharmaceutical companies, government, October 2004 and society cooperate to satisfactorily study measures on each issue, and create a new regulation on all category of drugs, from those that need new clinical trials to those that is considered enough if existing evidence or postmarketing survey and safety information is reflected in the package insert. On the reagent and named patient program, measures to promote development and solve problems are essential. Fundamental solution of off-label use is unachievable without environmental improvement in pediatric drug development of pharmaceutical companies. In order to gain this target, effective and strong incentives for the companies such as free PMDA consultation, extension of patent, or advantage in NHI drug price are necessary and as well as to exchange frank opinions with companies on the matter. National Center for Child Health and Development desire to settle measures on pediatric clinical trial within few years in collaboration with companies and authorities since solving the problems of off-label use and promotion of clinical trial are crucial for the fair pediatric pharmacotherapy. October 2004 New Drug Application Risk Communication Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masayuki Ikeda Key points of the presentation: Application dossier Application dossier is a vital tool to maintain communication between the applicant and evaluation team and clarify various matters on risk and benefit of the drug. In order to keep away from trouble, companies are likely to avoid referring on negative factors, however, bad news travel fast and therefore it is important to consider the way to break the bad news and take prompt necessary actions in a calm manner. Adverse event or adverse drug reaction (ADR) Those ‘possible�E‘probable�E‘definite�Eadverse events in causal relationship criteria are considered as ADR in US, whereas in Japan ‘unlikely�Eadverse events are also included. Application data should be compiled on the basis of all adverse event data with medical judgment and should try to avoid being suspected of any scheme to conceal negative data. PMDA hold a weekly meeting with clinical October 2004 specialists and provide such suggestions as, to submit comprehensible CIOMS report, provide adequate translation for overseas report, select correct MedDRA words, write down ADR name when symptoms are listed, write down the consideration of the company and react promptly to questions. Risk and benefit It is important to balance the risk and benefit of the drug, which every drug is different. Companies should make effort to minimize the risk, provide enough information to doctors so that patients receive satisfactory explanation, and continue to gather information on risk/benefit. Common Technical Document (CTD) All adverse events should be analyzed and reported in the CTD Module 2. Parameters should be indicated in 3 steps, central tendency, example, and the group mean and median values. Caution should be paid to confusing symptoms. October 2004 Summary Application dossier is the history book of the drug, the communication basis and the key to release risk information. Media Establish good media and public relations and promote understanding by the nation. Future tasks Compile ADR data (publicize clinical trial data: ICJME, structure pharmacovigilance system and harmonization on safety. Improve mass-media relationship and enact risk communication. 21st New Drug Evaluation Division Information Meeting Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) 21st New Drug Evaluation Division Regular Meeting Date: May 26, 2005 Time: 10:20 . 15:00 Venue: Melparque Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: . Japan Federation of Pharmaceutical Manufacturers�EAssociations (JFPMA) . Japan Pharmaceutical Manufacturer Association (JPMA) . The Pharmaceutical Manufacturers�E Association of Tokyo (PMAT) (Incorporated Association) . Osaka Pharmaceutical Manufacturers Association (OPMA) . Japan Pharmaceutical Association (JPA) (Incorporated Association) May 2005 May 2005 PROGRAM 10:20-10:30 Opening Address from the Organizer Mr. M. Uchiyama (SJP) 10:30-11:00 Present environment of research and development / approval of new medicinal products MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara 11:00-11:45 Guidance on pharmacogenomics MHLW, PFSB, Evaluation and Licensing Division Deputy Division Head Mr. Kazuhiko Chikazawa Lunch Break 13:15-14:00 Evaluation and consultation for clinical trials in the newly integrated system Pharmaceuticals and Medical Devices Agency Priority Evaluation Coordinator Mr. Takeyuki Sato Break 14:00-15:00 Approach to unapproved drugs in Japan and how the clinical trials should be in the future MHLW, PFSB, Evaluation and Licensing Division Deputy Division Head Mr. Yoshikazu Hayashi Further readings Disclaimer May 2005 Key illustrations Figure 1. Manufacturing and Marketing License Figure 2. Master File System of Active Drug Substances Figure 3. Prescription medicinal products Figure 4. GPMSP, GPSP and GVP Figure 5. Responsibilities under the GPSP/GVP system Figure 6. Evaluation of the clinical efficacy of the medicinal products Figure. 7. Logistic model analysis of blood concentration of HbAlc & reptin before administration of pioglitazone Figure 8. New review system Figure 9. Internal flow of PMDA Figure 10. Use of unapproved medicinal products in Japan Figure 11. Additional Trial and Safety Confirmatory Test Figure 12. Examples of the examined unapproved medicinal products May 2005 Opening Address from the Organizer: Mr. M. Uchiyama (SJP) (Gist) The progress in the research and development of medicinal products in our country is remarkable; however a number of difficulties have appeared recently. In this foundation (The Society of Japanese Pharmacopoeia) we selected some recent topics affecting the development of medicinal products, and with guidance and support we organized this information meeting and hope even small this would be helpful for all of you in the audience. We also would like to thank to our sponsors and to all participants. Note: The main organizer of the series of periodic information meetings held by the regulatory authorities is the Society of Japanese Pharmacopoeia (SJP). Although, named a society, the SJP is an organization of the Japanese regulatory authorities and until the administrative reforms of 2001 was fully subordinated to the National Institutes of Health Sciences (HIHS). Presently, the SJP is an incorporated foundation and works closely with the governmental bodies, independent administrative institutions (such as PMDA) and private industry and professional associations. May 2005 About the Periodic Information Meetings Held by the Regulatory Authorities The first of the series of periodic information meetings held by the regulatory authorities was carried out on January 29, 1999 in Tokyo with the purpose to provide direct clarification for a number of current topics (organizational changes, acceptance of ICH Guidelines, GCP and the conduct of clinical trials). The title “New Drug Evaluation Division Meeting�E reflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 45 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 21 ICH Immediate Briefings 11 Drugs and Medical Devices Safety Update Seminars 7 Current Issues in QA of Medicinal Products 5 14th Japanese Pharmacopoeia 1 Total as of May 2005 45 May 2005 Present environment of research and development / approval of new medicinal products 1 MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara 2 Key points of the presentation: The opening presentation gave an overview of the key administrative, regulatory and international problems currently faced by the Japanese pharmaceuticals authorities during the continuous process of deregulation, international harmonization and trade. 1 The regulated medicinal products in Japan are classified according to the Pharmaceutical Affairs Law as drugs, quasi-drugs, medical devices and cosmetics. 2 At the meeting in Tokyo, on May 26, 2005 the scheduled presenter Mr. A. Kawahara was substituted by another representative of the MHLW, PFSB, Evaluation and Licensing Division . the Deputy Division Head Mr. Yoshikazu Hayashi, who also made the last presentation that day. May 2005 Enforcement of the revised the Pharmaceutical Affairs Law (PAL) and recent administrative problems About the system for Marketing Authorization License Maintenance of approval records / Master Files Prescription medicinal products GPSP Improvement of consultation on clinical trials of new medicinal products Measures for adjustment of the external interactions / influence Grappling with the problem of domestically unapproved medicines and their clinical trials Measures for revaluation of medicinal products May 2005 Figure 1. Manufacturing and Marketing License 3 Notes: 1. For license authorization, appropriate post-marketing vigilance system is required (GMP compliance) 2. Outsourcing of the whole manufacturing process will be liberalized 3. License holders bear the entire responsibility in the market. 4. Minor partial modifications of the authorized information → only notifications are required. (Applicants should determine by themselves whether the relevant modification should be qualified as minor or “not minor�E - Minor modification: Refer to the Article 47 of Enforcement 3 More details in the reports “Current Issues in QA of Medicinal Products�Eavailable in the JKS Document Store (http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=PROD&Product_Code=JM_I_0015&Cat egory_Code=JMI) May 2005 Regulations of PAL - “Not minor�Emodification: the addition/modification/deletion of effect-efficacy, etc Deemed authorization/license and transition period .. Authorization/license at the date of enforcement is deemed as Manufacturing and Marketing Authorization/Manufacturing License until the renewal date of the current license. (For manufacturing and marketing, the location of principal office of the applicant should be filed.) .. By the date of the renewal of the license under the old system, the license should be switched to the license under the new system. Applied information should be reorganized based upon the new system. (E.g. manufacturing process, manufacturer identification.) .. When the same company holds multiple manufacturing/import and marketing licenses, the followings are applied: .. Renewal procedure for all the licenses at one time to be deemed as manufacturing/manufacturing and marketing under the new system is granted. .. It is also granted to do the renewal procedure by each or sequentially. .. It is also possible to do the renewal procedure of the deemed manufacturing/marketing to be authorized under the new system, at the latest renewal date among all the licenses. .. In-advance application can be accepted for manufacturing and marketing/manufacturing licenses. May 2005 Figure 2. Master File System of Active Drug Substances 4 MF Ethical Drugs テキスト ボックス: Registration of Quality and Formula テキスト ボックス: MF Registrationテキスト ボックス: Product quality Data of manufacturing process 角丸四角形吹き出し: Available for other manufacturers of pharmaceutical preparationsテキスト ボックス: Non-disclosed Data (Formula, etc.)テキスト ボックス: Attached Dataテキスト ボックス: MF Registration Number角丸四角形吹き出し: Reviewed as the completed data角丸四角形: Reviewing Authority メモ: Application form 角丸四角形: Drug Substance Manufacturer (No need for Manufacturing and Marketing Authorization) 角丸四角形: Manufacturer (Applicant of Manufacturing and Marketing Authorization) テキスト ボックス: Efficacy, safety, quality (partial) 4 Further information regarding the Drug Master File implementation in Japan could be found in the Report of the 20th New Drug Evaluation Division Information Meeting available in the JKS Document Store at the following address http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=PROD&Product_Code=JM_I_009&Category_Code=JMI May 2005 Prescription medicinal products Designated standards of prescription medicinal products 1. Prescription medicinal products should be used only on the basis of the diagnosis of the doctors, and the examination of the treatment policy as they can not be used safely and effectively if not selected appropriately according to the condition and constitution etc. of the patient because of complications such a inducing resistant bacteria, etc. Example: Antibiotic formulations, hormone drugs, all injections, narcotic formulations 2. Prescription medicinal products may be associated with serious side effects what requires a in-depth examination and periodic check of patient’s conditions. Example: Blood glucose lowering agents, anti-tumor agents, human-blood-based manufactured blood products 3. Prescription medicinal products may cause excitement or dependency, thus posing a risk of being used for purposes other their original designation. Example: CNS agents May 2005 Based of the designated standards of prescription medicinal products . New standards for prescription medicinal products were enforced . With the results: - Existing, ethical medicinal products 5 are redesignated - Narcotics, psychotropic drugs, stimulants, stimulant raw materials, living organism originated products 6 are newly designated - Others, clearly falling into the designation standards See also Figure 3 (next page) 5 The name in Japanese of the “ethical medicinal products�Ecould be translated as “products requiring instructions for use�E. thus including not only prescription products (dispensed only on written prescription by a physician or dentist), but some other types of products, including prescription drugs for veterinarian use. 6 See the titles in JKS Documents Store related to use of materials originating from living organisms at http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=CTGY&Category_Code=7M : May 2005 Figure 3. Prescription medicinal products Categorization of Medicinal Products For Medical Use For General Purpose ..Products provided for the use of doctors, etc. ..Authorized professionals comprehend effectiveness and efficiency, dosage and administration, and the patients should follow their advice. ..Products provided for the use of general public. ..Effectiveness and efficiency, dosage and administration are easily described so that general public can comprehend, and they will apply the products at one's own discretion. Prescription Drug Nonprescription Drug Supply Perspective Usage Perspective Safety Perspective Sale without prescription, such as over the counter, is prohibited under any circumstances.To any violation, the penal regulations is applied. Applied with prescription, but adequate sale is required under administrative guidance. Sale without prescription, such as over the counter, is allowed. License requirement is; 1. Establishment of Overall Safety Control Department. 2. Safety Control Manager is required for 3 years working experience. 3. Development of Procedure Manual Type I Manufacturing and Marketing License requirement is; 1. Establishment of Overall Safety Control Department is not required. 2. Safety Control Manager is required but with no quality requirement. 3. Development of Procedure Manual Type II Manufacturing and Marketing Categorization of Medicinal Products For Medical Use For General Purpose ..Products provided for the use of doctors, etc. ..Authorized professionals comprehend effectiveness and efficiency, dosage and administration, and the patients should follow their advice. ..Products provided for the use of general public. ..Effectiveness and efficiency, dosage and administration are easily described so that general public can comprehend, and they will apply the products at one's own discretion. Prescription Drug Nonprescription Drug Supply Perspective Usage Perspective Safety Perspective Sale without prescription, such as over the counter, is prohibited under any circumstances.To any violation, the penal regulations is applied. Applied with prescription, but adequate sale is required under administrative guidance. Sale without prescription, such as over the counter, is allowed. License requirement is; 1. Establishment of Overall Safety Control Department. 2. Safety Control Manager is required for 3 years working experience. 3. Development of Procedure Manual Type I Manufacturing and Marketing License requirement is; 1. Establishment of Overall Safety Control Department is not required. 2. Safety Control Manager is required but with no quality requirement. 3. Development of Procedure Manual Type II Manufacturing and Marketing May 2005 About the designated prescription medicinal products All designated medicinal products should adhere to the following 3 requirements: . From hygienic point, the use should be limited only to what is instructed by a physician, etc. . Under no circumstances, the sale of ethical products should be allowed in the pharmacies without a written prescription . Penalties under the law 7 shall be applied for the violations of the rules About the non-designated prescription medicinal products The prescription medicinal products other than designated prescription medicinal products . Generally, all products medicinal products for medicinal use 8 should be used only with prescription from a physician, etc. . On the administrative base is necessary to balance the regulations for a reasonable use of the medicinal products for medicinal use and the excessive penal regulations . There is no such term as “non-prescription medicinal products�E 7 Such as Chapter 11. Punitive Provisions of the PAL, entered into force on April 1, 2005. 8 The term “medicinal products for medicinal use�Eis common although not official . used mainly to distinguish from other products in the category of medicinal products h\not intended for “medical use�E. such as quasi-drugs or cosmetics. May 2005 GPSP Figure 4. GPMSP, GPSP and GVP Current GPMSP GPSP (Surveillance) GVP (Vigilance)* 1. Requirement for License In more details the assignment of responsibilities under the new system is shown at Figure 5. below. Figure 5. Responsibilities under the GPSP/GVP system Joint production distribution Production distributor Medical sites (facilities) GPSP Pharmacy/Ward/DI Dept. Investigation/Clinical Trials Dept. QA Manager Safety Manager Representative responsible for after-sales research Person responsible for over-all sales GVP May 2005 Other activities . Elimination of off-label use (e.g. the combination therapy of antitumor drugs) 9 .. To encourage the partial modification application for the items requested by the relevant societies, based on the approvals in other countries, track records in the medical field, and article publications on reliable source journals . Improvement of pediatric medication 9 The off-label use of various approved medicinal products and or the use for individual patients of drugs not yet approved in Japan (such as thalidomide) became so wide-spread that prompted the authorities to review the situation and to plan respective measures as detailed in the last part of this report. May 2005 . Improvement of the clinical trial consultations Improvement of clinical trial consultations affecting new medicinal products 1. Improvement of waiting time 10 of clinical trial consultations . Meeting the demand for possible timeframes for clinical trial consultations . Review of the methods for clinical trial consultations application . Reinforcement of the functions of those responsible for the clinical trial consultations 2. Improvement of duties to affect clinical trial consultations . Efforts to resolve unapproved drugs problems in Japan (Detailed in the last part of this report ) . Measures for revaluation of medicinal product See also Figure 6. (next page) 10 Due to excessive demands for clinical consultations, the requesting parties had been forced to wait for prolonged periods of time, and in 2004 the consultations were temporarily discontinued. The overall impact of that crisis was a delay in the development in a number of products. May 2005 Figure 6. Evaluation of the clinical efficacy of the medicinal products MHLW Request for Data Submission Request for Data Submission evaluation evaluation - Or Designation of Re Or Designation of Re �E Trove of Information Trove of Information �E Provision of Provision of Clinical Trial Clinical Trial Implementation of Implementation of �E Trove of Information Trove of Information �E Compilation of Compilation of Marketing Surveillance Data, etc. Marketing Surveillance Data, etc. - Post Post When Approved When Approved Data of the Clinical Trial Data of the Clinical Trial Internal Data Reduction Internal Data Reduction Notification of the Result Notification of the Result Internal Data Submission Internal Data Submission Food Sanitation Council Food Sanitation Council Pharmaceutical Affairs and Pharmaceutical Affairs and Compiled Result of the study Compiled Result of the study Business Organization Business Organization Collected Information Collected Information Technical Evaluation of Technical Evaluation of EBM Guidelines, etc. EBM Guidelines, etc. based on the recent medical standard based on the recent medical standard Evaluation of the clinical efficacy of the medicinal product Evaluation of the clinical efficacy of the medicinal products May 2005 Guidance on pharmacogenomics MHLW, PFSB, Evaluation and Licensing Division Deputy Division Head Mr. Kazuhiko Chikazawa Key points of the presentation 11 Pharmacogenetics and Drug Review . What are the technical hurdles in scientific drug review? . What are the hurdles in clinical development? . How to facilitate a sound drug development? Basic Needs for PGt/PGx 12 . Using Drug in the optimal condition, most effective and safest regime is ultimate goal of appropriate use . A personalized or tailored medication to the patient with expected efficacy & safety would be ideal . Scientific approach toward individual difference will be a key issue 11 Presentation was done by using English-language screen slides and delivered in Japanese. The style and language of the presentation are largely preserved here. 12 PGt, pharmacogenetics; PGx, pharmacogenomics May 2005 Background guidance of PGt/PGx in PK/PD 13 . Guidance on clinical pharmacokinetics / pharmacodynamics (ELD Notification No. 796) . 1 June 2001 14 2. In case genetic polymorphism is likely to affect individual difference in pharmacokinetics, a sponsor is recommended to select subjects with or without specific genetic factor, based on objective criteria such as genotyping tests. . Guidance on drug-drug interaction study (ELD Notification No. 813) . 4 June 2001 15 3. In case a metabolic enzyme reflecting genetic polymorphism significantly affects metabolism of the investigated drug in individual subjects, a sponsor is recommended to study drug interactions, considering phenotypes and/or genotypes of individual subjects. 13 PK/PD, pharmacokinetics/pharmacodynamics 14 PMSB/ELD Notification No. 796 (dated June 1, 2001) 15 PMSB/ELD Notification No. 813 (dated June 4, 2001) May 2005 Areas in progress for PGx/PGt (for personalized medicines) . Cancer therapy seems to be most in progress and accepted 4. Example 1: “trastuzumab�Eallows insurance coverage for HER2 DNA tests 5. Example 2: A post-marketing PGx study on interstitial pneumonia associated with “Iressa�E are being studied by the sponsor company and the institute of Tokyo University. . CYP geno-typing to determine PM/EM metabolizes (Japanese CYP2CI9 subtype) . These cases require less mental/social obstacles for patients Approval of Trastuzumab . Indications 6. For treatment of patients with metastatic breast cancer whose tumors overexpressed the HER2 protein . Precautions related to the indications 7. Assessment for HER2 overexpression should be performed by pathologists or laboratories with demonstrated proficiency Tests under national health insurance .. Biochemistry: HER2 protein in plasma (EIA) .. Pathology: HER2 protein (EIA), HER2 DNA (FISH) May 2005 Regulatory Implications of PGx Questions: . Is genotyping valuable for enrichment in clinical trials? . Is a PGx targeted drug of therapeutic value? . Does PGx CT become mandatory for genotyping requirement in the labeling? . Is value of PGx in terms of pharmacoeconomics clear? Which direction are we going? May 2005 Use of PGx for products approval Should doses, indications or warnings related to genotyping in the product labeling be addressed mandatory? . Scientific benefit of using PGx and genotyping for personalizing medicine? . Clinical benefit overweighs the cost for genotyping? So far�E . Can efficacy and safety be highly expected, compared to the currently available medicines? . Can safety be only assured with genotyping? . Can efficacy be only expected for particular patients with specific gene or genotype? . Can we ethically eliminate patients who do not come under the criteria of genotyping (precision)? Still the implication of PGx/PGt to approval process is not clear, but may be too far from the NDA with non-PGx enrichment clinical data. May 2005 Expected values of PGx/PGt . At least: - To secure pipeline of developing a drug with narrow range of safety margin for specific patient subpopulation (a drug with wide safety margin and with wide applicability to whole patient population is ideal) - To add values for recommending more appropriate patient sub-population and/or appropriately tailored drug dosing May 2005 How is PGx being applied for Drug Development? PGx “Enrichment�Emethod in drug evaluation . Efficacy / Safety consideration: - The more targeted the drug is, needs the less number of patients for clinical study (Sales vs. R&D costs) - It is a potential fear that preclusion of subjects might lead to overlook low ratio but serious ADRs) - Confirmatory study on the correlation (gene identification/ effect) should be needed . Quality of test and other drug response mechanism: - Specificity and precision of the test used (and economical availability) - Uncertainty: Are other individuals�Efactors than genetic polymorphism well specified? (Human physiological mechanism is so complex) - Can genetic test results only be a determinant to rule out the patients with lower expectancy of drug response? May 2005 Is prediction of responder/non-responder using biomarkers “easy�E . Example: MHLW sponsored a prospective exploratory clinical study to find potential biochemical parameters to be associated with responder/non-responder (non- PGx/PGt) of pioglitazone (2000-2003) showed: Figure. 7. Logistic model analysis of blood concentration of HbAlc & reptin before administration of pioglitazone 16 Expected Responder Expected Nonresponder PGx/PGt might be, to some extent, analogous to this non-PGx parameter analysis A single biomarker (even genomic biomarker) may not necessarily predict everything? Real responder 39 34 Real nonresponder 23 73 precision 63% 68% 16 As shown at http://www.mhlw.go.jp/shingi/2003/10/s1022-3.html (in Japanese) May 2005 Is PGx necessarily shifting the efficacy/safety value of a product? . From the viewpoint of conventional drug evaluation, therapeutic superiority / non- inferiority to the existing comparator drugs is evaluated in any controlled trials . Do you evaluate the following types of drugs? .. Not superior to the existing drug for a given therapeutic population .. Reasonably superior to the existing drug for the particular sub-population For the future . Using Drug in the optimal condition, most effective and safest regime is ultimate goal of appropriate use . A personalized or tailored medication to the patient with expected efficacy & safety would be ideal. . If GYP genotyping is mandatory when clinical data is generated to resolve a specific well-established (in the future) safety issue? . If PM/EM diagnosis is to be performed by genotyping before administration (more effectively than TDM)? . If there is an increase in number of gene targeted drugs, following trastuzumab? May 2005 Ethical Consideration 1. Public acceptance of genotyping itself 2. Securing privacy and protecting patient Information 3. Type of the anonymization 4. Use of specimens collected at clinical trial in the past (retrospective use of genomic information and banking) Ref. Japan’s “Ethical Guideline on Clinical Human Genomic Study�E17 (Inter-ministerial common guideline, independent of GCP for drug clinical trials) - Prior informed consent to subjects - Ethics Committee - Handling anonymized data of individual patients and security of personal genomic information 17 Human genomic studies are distinct from human cloning and related procedures (see more in the JKS Document Store: http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=PROD&Product_Code=1_D_B00 2&Category_Code=1D ) May 2005 Approaches to regulatory guidance . Regulatory guidance development is usually retrospective process based on the experiences of approved data; however, PGx studies are still under development. . For an emerging innovative technology, is prospective guidance development needed? Why? . Regulatory guidance does not necessarily suppress R&D, but would provide efficient/acceptable ways for collecting/evaluating data, based on scientifically sound consensus. Current Policy . Fact finding activity initiated for technical guidance . Sharing experiences should be crucial and internationally coordinated approach to PGx/PGt matters should be anticipated (toward ICH informal discussion) . Proper Information treatment will be promoted in conjunction with GCP . Transparent regulatory guidance will give: .. Public acceptance and confidence on new technologies .. Support for development policy May 2005 Guidance of Information Submission for developing PGx Clinical Trial Guidelines . On 18 March 2005, the guidance was issued 18 . Manufacturers are recommended voluntarily to submit; - List of PGx studies (planning, being conducted, or conducted in the past) - Tandem development of IVDs or medical devices 19 . Submission period: 30 September 2005 . Regulatory authorities will grasp the overall PGx situations and may request further relevant information for guidance/guideline development . Information submitted must be disclosed . Results to support “indication�Eand/or “dosage�Ein the approval will be subject to submission for new drug application (e.g. in case that co-relation of CYP genotyping and clinical safety were confirmed) 18 PFSB/ELD Notification No. 0318001 dated March 18, 2005 . the scope of the Notification is to solicit a feedback from the public (manufacturers, physicians, patients, etc.) in order to more effectively develop the future guidelines. 19 Development of in vitro diagnostic products or medical devices for pharmacogenomics diagnosing, in parallel with the new drugs themselves. May 2005 US FDA’s policy Guidance for Industry: Pharmacogenomics Data Submissions . FDA published the guidance for industry on pharmacogenomics data submission on 22 March 2005 . FDA is collecting PGx data to develop guidance for drug development using PGx . This addresses the basic rules to deal with genomic data within FDA, depending on the purposes of data submission. Voluntary data submission is not subject to regulatory decision making EMEA (European Agency for the Evaluation of Medicinal Products) Position Paper on Terminology in Pharmacogenetics . EMEA published the Position Paper on 21 November 2002 (Leaflet on 29 July 2004) . “Pharmacogenetics�Eand “Pharmacogenomics�E . Definitions applicable to DNA samples and data in clinical trials including pharmacogenetic testing . Sample coding procedure (to) be documented according to GCP ICH Work Plan . Brussels, Belgium, on May 9-12, 2005 Steering Committee (SC) / Expert Working Groups (EWGs) . Chicago, USA, on November 7-11, 2005 SC / EWGs May 2005 QECD Workshop An International Perspective on Pharmacogenetics: The Intersections between Innovation, Regulation and Health Delivery Rome, ITALY, 17-19 October, 2005 Session 1: New paradigms in biomedical research and drug discovery Session 2: Pharmacogenetics today: What do we know? Session 3: Social and public policy Issues in pharmacogenetic data, sample collection and storage Policy Forum: Managing regulatory uncertainty in rapidly emerging areas such as pharmacogenomics 20 Session 4: Pharmacogenetic testing: What’s different, what’s not? Session 5: Impacts on human health and health care systems To be continued PMDA’s study and building expertise Open dialogues and forums with industry and academia Fact finding ICH discussions Guideline development 20 A presentation “Japan-MHLW/PMDA Perspectives and Strategies�Eis scheduled May 2005 Evaluation and consultation for clinical trials in the newly integrated system Pharmaceuticals and Medical Devices Agency Priority Evaluation Coordinator Mr. Takeyuki Sato Key points of the presentation: Appropriate and speedy evaluation of medicinal products . Improvement of the evaluation system . Introduction of the process control system of the evaluation . Clearance of the delayed evaluation . Others Improvement of the consultations on clinical trials of new drugs . Clearance of the delay of the consultation . Reorganization of the consultation system to respond to more requests for consultation May 2005 Figure 8. New review system (Reference) New Review System (Consistency of Review Team and Counseling/Review) Applicant Expert Member MHW Pharmaceutical Affairs and Food Sanitation Council Pharmaceuticals and Medical Devices Agency Counseling/Review of Clinical Trial (Review Team Approval Report Advisory Surveillance of Conformance, etc. Counseling of Clinical Trial Guidance Application for Approval Notification of the Result Inquiries /Replies Technical Conference (Reference) New Review System (Consistency of Review Team and Counseling/Review) Applicant Expert Member MHW Pharmaceutical Affairs and Food Sanitation Council Pharmaceuticals and Medical Devices Agency Counseling/Review of Clinical Trial (Review Team Approval Report Advisory Surveillance of Conformance, etc. Counseling of Clinical Trial Guidance Application for Approval Notification of the Result Inquiries /Replies Technical Conference May 2005 Priority Review System . Criteria for priority: Determined comprehensively based on the severity of the applied disease and the clinical efficacy of the drug . Necessary requirement: Study results and data suggesting the clinical efficacy .. Summary of the investigational drugs .. Explanatory materials for clinical efficacy .. Summary of the study results . Given priorities: Priorities in counseling on the clinical tests, and on the reliability compliance . Current situation: 8 items designated by May 1, 2005: .. Antitumor agents: 4 items .. CNS drugs: 1 item .. Cerebral circulation and metabolism improvers: 1 item .. Therapeutic products for severe infection: 1 item .. Antiviral drugs: 1 item May 2005 Figure 9. Internal flow of PMDA Review Management Division Scheduling/Application for Counseling/Background Data Internal Flow of Pharmaceuticals and Medical Devices Agency Inquiries Person in Charge Consultor Review Officer in Charge Adviser Face-to-face Advisory Review Division Consulting Advisory Scheduling, etc. Record Notification Replies Record Designation of the Division Generalization of Counseling Agency Review Management Division Scheduling/Application for Counseling/Background Data Internal Flow of Pharmaceuticals and Medical Devices Agency Inquiries Person in Charge Consultor Review Officer in Charge Adviser Face-to-face Advisory Review Division Consulting Advisory Scheduling, etc. Record Notification Replies Record Designation of the Division Generalization of Counseling Agency May 2005 Approach to unapproved drugs in Japan and how the clinical trials should be in the future MHLW, PFSB, Evaluation and Licensing Division Deputy Division Head Mr. Yoshikazu Hayashi Key points of the presentation: Basic Agreement of December 15, 2004 between the Minister of Health, Labor and Welfare and the Minister of State in charge concerning so-called “Mixed payment for medical examination and treatment�E21 Use of medicinal products not approved domestically The use of medicinal products not approved domestically is tied with conducting certain clinical trials and the establishment of system for covering the health insurance Concrete targets 1. Steady implementation of the clinical trials 2. Support system of investigator-initiated clinical trials 3. Introduction of additional clinical trials 4. Health insurance coverage for whole treatment even after the clinical trial 21 Also known as “mixed insurance�Eand “mixed co-payment�E May 2005 Use of medicinal products not approved domestically 8. Steady implementation of the clinical trials . Establishment of the Committee for the Examination of the Use of Unapproved Medicinal Products . Periodic comprehension and scientific evaluation of the academic societies / patient demands and requests . Sorting into either company-initiated (MHLW requests the manufacturers when the review results show that the clinical trials should be conducted on the relevant drugs) or investigator-initiated clinical trials (such as orphan drugs) . Regular meeting of Committee to be carried periodically four times a year; Review of results within three months . New medicinal products already approved in US, UK, Germany and France (and other countries approved by the review meeting to have the equivalent quality in regulations to Japan) are automatically considered for approval in Japan 9. Support system of investigator-initiated clinical trials . Substantial information services to the investigator, simplification of various procedure, etc. . Clarification of the doctors�Eright to charge patients for medication and expansion of the scope of the prescription benefits . Expansion of a large-scale clinical trials network May 2005 3. Introduction of additional clinical trials . Additional clinical trials for the patients who want to participate in the trials after the relevant trials were already closed (limited for the patients not covered by (4) below and other relevant studies) 10. Health insurance coverage for whole treatment even after the clinical trial . Introduction of safety confirmatory test into clinical trial phase to cover the whole treatment with the current insurance system 22 22 When the treatment is approved as a part of “clinical trial�E then it is covered by insurance system as Special Healthcare Expenditure. However, after the termination of the clinical trial, it is not covered by insurance system until listed on NHI price list. This can be regarded as a front-loaded post-marketing surveillance study (of long-term administration test, corresponding to Phase IIIb in EU and the US) to relief the patients from bearing the full expenses. May 2005 Figure 10. Use of unapproved medicinal products in Japan テキスト ボックス: Working Groupsテキスト ボックス: Requestテキスト ボックス: Surveillance Result角丸四角形: Additional Trial角丸四角形: Unapproved Drugs in Japan角丸四角形: Clinical Trial (Requested by MHW)角丸四角形: Additional Trial角丸四角形: Clinical Trial (Investigator-initiated)テキスト ボックス: Clinical Trialテキスト ボックス: Combined with Insurance Treatment 角丸四角形: Safety Confirmatory Test Conducted as a part of clinical trial (Front-loaded Post-marketing Surveillance Study)テキスト ボックス: Seamless Coverage by insurance systemテキスト ボックス: Clinical Trial (New)テキスト ボックス: Review テキスト ボックス: NHI Price Listingテキスト ボックス: Insurance Coverage テキスト ボックス: (1) Steady implementation of the clinical trialsテキスト ボックス: (3) Introduction of additional clinical trialsテキスト ボックス: (2) Support system of investigator-initiated clinical trialsテキスト ボックス: Review Meetingテキスト ボックス: 60 daysテキスト ボックス: (4) Health insurance coverage for whole treatment even after the clinical trial May 2005 The Committee for the Examination of the Use of Unapproved Medicinal Products . Consists of 13 members . Four meeting were held in the period January- April 2005, as the meetings re carried regularly and whenever necessary . General Rules / open to the public . Minutes of the meetings and Committee documents are made public (refer to the web sites 23) . Special working parties could called out if necessary Consideration of review session . Regular grasp of licensing status in the four courtiers in Europe and America . Periodic comprehension and scientific evaluation of the academic societies / patient demands . Scientific verification concerning validity of necessity for the use and the clinical trials of unapproved medicinal products . Further dissemination of company-requested and a turn to the investigator-initiated clinical trials . Execution of certain of safety confirmation examinations (tentative name) etc. 23 At present the information about the Committee, its meetings and documents are posted at two web sites of the Japanese Government . the mail site of the MHLW (www.mhlw.go.jp) and the Welfare and Medical Services site - WAMNET (www.wam.go.jp) May 2005 Unapproved drugs regarded as subjects for clinical trials Determined comprehensively based on the severity of the applied disease and the clinical efficacy of the drugs . Severity of the applied disease (fatal disease: irreversible disease seriously affecting the daily life of the patient, etc.) . Clinical efficacy (no other treatment or prevention methods in existence: superiority in efficacy and safety to the existing methods are proved in the clinical trials in Europe or in the US: Established as a standard therapy in Europe or in the US) Unapproved drugs to be reviewed under the new system 1. Drugs approved in the four countries (US, UK, Germany and France) after April of 2005 2. Drugs approved in the four countries (US, UK, Germany and France) before March of 2005, for which reviews have been requested by academic societies or by patient groups within the past five years 3. Drugs approved in the four countries (US, UK, Germany and France) within the past two years, for which reviews have not been requested by societies or by patient groups but still are regarded as highly effective in medical use. May 2005 Additional Trial and Safety Confirmatory Test Figure 11. Additional Trial and Safety Confirmatory Test . Additional clinical trials for the patients who want to participate in the trials after the relevant trials were already closed (limited for the patients not covered and other relevant studies) . Introduction of safety confirmatory test into clinical trial phase to cover the whole treatment with the current insurance system . After the termination of the clinical trial, it is not covered by insurance system until listed on NHI price list. This can be regarded as a front-loaded post-marketing surveillance study (of long-term administration test, corresponding to Phase IIIb in EU and the US) to relief the patients from bearing the full expenses Notes: .. These two tests are also the subjects to the evaluation for approval by MHLW .. GCP compliance is required テキスト ボックス: Clinical trial for application for approval 角丸四角形: Additional Trialテキスト ボックス: Safety Confirmatory Test テキスト ボックス: Post-marketing Surveillance Study テキスト ボックス: Long-term Administration Testテキスト ボックス: Approvalテキスト ボックス: Application May 2005 Examples of the examined unapproved medicinal products at the 4th review session Unapproved medicinal products in which using with health insurance treatment with frame of clinical trial together is demanded from academic society and self-help patient group Figure 12. Examples of the examined unapproved medicinal products 1st review session (January 24, 2005) .. Oxiliplatin (colon and rectum cancer) 24 .. Pemetrexed (malignant mesothelioma) .. Thalidomide (multiple myeloma) 4th review session (April 27, 2005) .. Bortezomib (multiple myeloma) .. Laronidase (type I mucohyperglycemia) .. Diazoxide(high insulin blood symptom-related low blood sugar symptom) 24 Oxaliplatin (Elplat from Yakult Honsha KK) was approved in March 2005. For more details see the Japan Approval Database (JAD) at http://www.jouhoukoukai.com/disclosed/jad_intro.htm May 2005 Study committee on ideal way for clinical trials Background 4. The situation to date . Implementation on “Three-year Clinical Trial Revitalization Plan�E . Promotion of the institutionalization of the doctor-initiated clinical trials by revision of the pharmaceutical legislation, etc. 2. Improvement in the environment of clinical trial execution and necessity such as reduction of burden on the businesses 5. Considerations for environment of the clinical trial execution are indispensable to promote smoothly the use of the domestically unapproved medicinal products. Study committee on ideal way for clinical trials Considerations Examination of the strategy to execute smoothly the clinical trials and securing the reliability of the clinical trials and the safety of the patients . Deliberation on environmental to execute clinical trial smoothly . Enforcement of practical reduction of the burdens on the businesses in executing clinical trials Committee composition etc. May 2005 The committee has membership of 13 people, General Rules / open to the public; and special working parties Study committee on ideal way for clinical trials Meeting holding schedule . March 29, 2005 . Inauguration meeting . April 20, 2005 . 2nd Meeting . May 26, 2005 . 3rd Meeting 25 . June 30, 2005 . 4th Meeting (scheduled) Outlook for the future It is expected to proceed to a discussion dividing problems into short-term and mid/long-term problems 25 Proceedings available at http://www.mhlw.go.jp/shingi/2005/05/s0526-2.html (in Japanese) May 2005 References System for specific medical expenses in relation to the medicinal products (enforced on April 1, 2005) . To reduce the economical load of the clinical trial for doctors and the medical institutions, so the clinical trials are executed smoothly when the use chance of the unapproved medicinal product is offered to the patient in the doctor-initiated clinical trial, and the range of the insurance supply is expanded about the clinical trials of the doctor-initiated clinical trials. . To be clarified though that the clinical trial investigator (physician) is not especially prohibited from requesting the defrayal of the medicine fee etc. from the patient in the doctorinitiated clinical trials. At the same time the necessary measures to be taken so the charge should not rise unjustifiably when the defrayal of the medicine fee etc. is also requested from the patients in the clinical trials. RELATED TITLES Drugs and Medical Devices Safety Update Seminar September 17, 2004, Tokyo Available in the JKS Document Store Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) Current Issues in QA of Medicinal Products February 18, 2005, Tokyo Available in the JKS Document Store Spring 2004 . Spring 2005 (No. 18, 19, 20 and 21) 12th ICH Immediate Briefing June 21, 2005, Tokyo Available in the JKS Document Store May 2005 . Disclaimer This publication is based on information obtained through inhouse research and from sources available to public and it is not a complete analysis of every material fact. Statements of fact have been obtained from sources considered reliable but no representation is made as to their completeness or accuracy. Whilst the utmost care has been taken in the preparation of Jouhou Koukai Services and Jouhou Koukai Publishing (JKS) publications and documents and JKS Store database, they are provided "as is" without warranty of any kind, either expressed or implied, including, but not limited to, the implied warranties of merchantability, accuracy, fitness for a particular purpose, or noninfringement. Any reliance on the information provided herein is solely at the user's discretion and risk and neither JKS nor any third party source would be liable for the contents of the JKS publications and documents and JKS Store database. In certain circumstances, works which have been sourced from a third party and incorporated into the JKS publications and documents and JKS Store database and any interpretations and commentaries relating thereto, may not be considered to be official versions of such works. JKS are committed to use utmost efforts to include accurate, actualized and reliably translated information, but JKS make no warranties or representations as to its accuracy. The Japanese Government does not provide authorized (officially sanctioned) translations of its documents. In case of legal dispute, the original texts in Japanese will prevail. Neither JKS, nor any party involved in creating, producing or delivering JKS publications and documents shall be liable for any direct, incidental, consequential, indirect or punitive damages arising out of access to, use of or inability to use publications and documents, or any errors or omissions in the content thereof. Jouhou Koukai Services LLC and its business Jouhou Koukai Publishing provide information and intelligence on the Japanese pharmaceutical market in the fields of medicine, pharmaceuticals, patents, licensing, copyrights and data protection, business and corporate development, information technology, including ehealth, and medical communication, however, this information does not constitute for nor can it be used as such for a substitute of medical, legal or investment advice. . . Worldwide.Copyright.c.2001‐2005.by.JKS.LLC.. Reproduction.in.whole.or.part.without.permission.is.forbidden. .. www.jouhoukoukai.com..