Enterprise-wide Use License - 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' Associations (JFPMA) * Japan Pharmaceutical Manufacturer Association (JPMA) * The Pharmaceutical Manufacturers' Association of Tokyo (PMAT) (Incorporated Association) * Osaka Pharmaceutical Manufacturers Association (OPMA) * Japan Medical Association (JMA) (Incorporated Association) 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 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 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" reflects 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 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) ? 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 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 * Changes in handling fee: ? Consultation fees 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. 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" "Safety consultation" "Quality consultation" 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 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 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 non- prescription drugs (planned) * Guidance and advice on those non-prescription drugs classified (2) and (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. 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. 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 re- evaluation / 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 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/re- examination Protocol consultation 3,331,900 Re-evaluation/ re-examination 3,333,000 Post clinical trial consultation 3,333,000 Additional consultation 1,483,500 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) Flowchart 2. Flow-chart of the review work by PMDA 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 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 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 * 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. 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 * 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' desire to develop the new drug as a block buster. 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 Disclaimer This publication is based on information obtained through in-house 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. 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Worldwide Copyright (c) 2001-2004 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com See Table 3 (page 15) Class 2 - "New Proprietary Ingredient" non-prescription medicines Class 3 - "New Compound Ingredients" non-prescription medicines 19th New Drug Evaluation Division Information Meeting May 2004 JM_I_004 - 3 - 19th New Drug Evaluation Division Information Meeting May 2004 JM_I_004 - 11 - 19th New Drug Evaluation Division Information Meeting May 2004 JM_I_004 - 17 - 19th New Drug Evaluation Division Information Meeting May 2004 JM_I_004 - 18 - 19th New Drug Evaluation Division Information Meeting May 2004 JM_I_004 - 26 -