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' Associations (JFPMA) * Japan Pharmaceutical Manufacturer Association (JPMA) * The Pharmaceutical Manufacturers' Association of Tokyo (PMAT) (Incorporated Association) * Osaka Pharmaceutical Manufacturers Association (OPMA) * Japan Pharmaceutical Association (JPA) (Incorporated Association) 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 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 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. 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" 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 Present environment of research and development / approval of new medicinal products MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara 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. 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 Figure 1. Manufacturing and Marketing License 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") - Minor modification: Refer to the Article 47 of Enforcement Regulations of PAL - "Not minor" modification: 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. Figure 2. Master File System of Active Drug Substances MF Ethical Drugs 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 Based of the designated standards of prescription medicinal products * New standards for prescription medicinal products were enforced * With the results: - Existing, ethical medicinal products are re- designated - Narcotics, psychotropic drugs, stimulants, stimulant raw materials, living organism originated products are newly designated - Others, clearly falling into the designation standards See also Figure 3 (next page) Figure 3. Prescription medicinal products 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 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 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" 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) Other activities * Elimination of off-label use (e.g. the combination therapy of antitumor drugs) > 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 * Improvement of the clinical trial consultations Improvement of clinical trial consultations affecting new medicinal products 1. Improvement of waiting time 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) Figure 6. Evaluation of the clinical efficacy of the medicinal products Guidance on pharmacogenomics MHLW, PFSB, Evaluation and Licensing Division Deputy Division Head Mr. Kazuhiko Chikazawa Key points of the presentation 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 * 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 Background guidance of PGt/PGx in PK/PD * Guidance on clinical pharmacokinetics / pharmacodynamics (ELD Notification No. 796) - 1 June 2001 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 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. Areas in progress for PGx/PGt (for personalized medicines) * Cancer therapy seems to be most in progress and accepted 4. Example 1: "trastuzumab" allows insurance coverage for HER2 DNA tests 5. Example 2: A post-marketing PGx study on interstitial pneumonia associated with "Iressa" 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) 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 pharmaco- economics clear? Which direction are we going? 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... * 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. 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 How is PGx being applied for Drug Development? PGx "Enrichment" method 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' factors 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? Is prediction of responder/non-responder using biomarkers "easy"? * 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 Expected Responder Expected Non- responder 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 non- responder 23 73 precision 63% 68% 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? 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" (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 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 Guidance of Information Submission for developing PGx Clinical Trial Guidelines * On 18 March 2005, the guidance was issued * 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 * 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" and/or "dosage" in 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) 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" and "Pharmacogenomics" * 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 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 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 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 Figure 8. New review system 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 Figure 9. Internal flow of PMDA 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" 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 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' right to charge patients for medication and expansion of the scope of the prescription benefits * Expansion of a large-scale clinical trials network 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 Figure 10. Use of unapproved medicinal products in Japan 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 ) * 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. 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. 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 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) ? Pemetrexed (malignant mesothelioma) ? Thalidomide (multiple myeloma) 4th review session (April 27, 2005) ? Bortezomib (multiple myeloma) ? Laronidase (type I muco- hyperglycemia) ? Diazoxide(high insulin blood symptom-related low blood sugar symptom) Study committee on ideal way for clinical trials Background 4. The situation to date * Implementation on "Three-year Clinical Trial Revitalization Plan" * 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. 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 * 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 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 doctor- initiated 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. Further readings Reports of the meetings held in 2004-2005 * 18th New Drug Evaluation Division Regular Meeting, held on February 19, 2004 Available in the JKS Document Store * 19th New Drug Evaluation Division Regular Meeting, held on May 20, 2004 Available in the JKS Document Store * Drugs and Medical Devices Safety Update Seminar, held on September 17, 2004 Available in the JKS Document Store * 20th New Drug Evaluation Division Regular Meeting, held on October 22, 2004 Available in the JKS Document Store Cont. * * Current Issues in QA of Medicinal Products, a meeting held on February 18, 2005 Available in the JKS Document Store * 21st New Drug Evaluation Division Regular Meeting, held on May 26, 2005 Available in the JKS Document Store * 12th ICH Immediate Briefing, held on June 21, 2005 Available in the JKS Document Store 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. 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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 e- health, 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 The regulated medicinal products in Japan are classified according to the Pharmaceutical Affairs Law as drugs, quasi-drugs, medical devices and cosmetics. 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. More details in the reports "Current Issues in QA of Medicinal Products" available in the JKS Document Store (http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=PROD&Product_Code=JM_I_0015&C ategory_Code=JMI) 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 The name in Japanese of the "ethical medicinal products" could be translated as "products requiring instructions for use" - 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. 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 : Such as Chapter 11. Punitive Provisions of the PAL, entered into force on April 1, 2005. The term "medicinal products for medicinal use" is common although not official - used mainly to distinguish from other products in the category of medicinal products h\not intended for "medical use" - such as quasi-drugs or cosmetics. 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. 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. Presentation was done by using English-language screen slides and delivered in Japanese. The style and language of the presentation are largely preserved here. PGt, pharmacogenetics; PGx, pharmacogenomics PK/PD, pharmacokinetics/pharmacodynamics PMSB/ELD Notification No. 796 (dated June 1, 2001) PMSB/ELD Notification No. 813 (dated June 4, 2001) As shown at http://www.mhlw.go.jp/shingi/2003/10/s1022-3.html (in Japanese) 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_ B002&Category_Code=1D ) 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. Development of in vitro diagnostic products or medical devices for pharmacogenomics diagnosing, in parallel with the new drugs themselves. A presentation "Japan-MHLW/PMDA Perspectives and Strategies" is scheduled Also known as "mixed insurance" and "mixed co-payment" When the treatment is approved as a part of "clinical trial", 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. 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) 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 Proceedings available at http://www.mhlw.go.jp/shingi/2005/05/s0526-2.html (in Japanese) The above schedule reflects the meetings held in Tokyo. The following meetings held in Osaka - within days of the Tokyo meetings, are organized under the identical program, as only presenters may vary at each venue. 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 3 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 12 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 14 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 15 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 19 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 20 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 35 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 36 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 37 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 38 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 41 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 42 - 21st New Drug Evaluation Division Information Meeting May 2005 JM_I_017 - 52 -