Enterprise-wide Use License 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 泥rugs and Medical Devices Safety Update Seminars・reflects the aim of the organizers to summarize once a year (in September) the recent changes in the relevant regulations concerning the safety issues. Since the beginning of the series totally 47 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 21 ICH Immediate Briefings 12 Drugs and Medical Devices Safety Update Seminars 8 Current Issues in QA of Medicinal Products 5 14th Japanese Pharmacopoeia 1 Total as of September 2005 47 Drugs and Medical Devices Safety Update Seminar Date: September 16, 2005 Time: 10:30 ・15:30 Venue: Kudan 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 (SJP) 10:40-11:00 Recent Safety Measures on Medicinal Products MHLW, Pharmaceutical and Food Safety Bureau Safety Division Head Mr. Toshiro Nakagaka 11:00-11:50 Code Designation of Medicinal Products in Relation to the Use of IT / Safety of the Medical Treatment Professor of Tokyo Medical and Dental University and Center for Medical Science Information Head Mr. Hiroshi Tanaka Lunch Break 13:00-13:40 Implementation of Safety Measures for Medicinal Products MHLW, Pharmaceutical and Food Safety Bureau Safety Division GVP Specialist Mr. Takahiro Inoue 13:40-14:30 Guidelines for Evaluation and Treatment of Drug-Induced Lung Disorders Professor of Department of Medicine at Shinshu University Mr. Keitsugu Kubo 14:50-15:30 Efforts for Safety Precautions by the Pharmaceutical and Medical Devices Agency (PMDA) PMDA, Safety Department Drug Safety Division Acting Director Mr. Tatsuya Kashi KEY ILLUSTRATIONS Relations within the GPSP/GVP system Summary of Drug-induced Lung Disorders (DILDs) Differential diagnosis of DILDs (flowchart) Basic medical institutions network (diagram) Related reports Disclaimer Opening Address from the Organizer: (SJP) (Gist) The keen interest toward the safety of medicinal products is increasing and securing the safety of the medicine is noteworthy. In our society (Society of Japanese Pharmacopoeia), meetings on the major problem concerning the safety of the medicine have already been held several times and also training has been held. This time, various specialists active in the field of the post marketing surveillance are invited as the lecturers, so we hope it would be helpful for everybody participating in this seminar. 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. Recent Safety Measures on Medicinal Products MHLW, Pharmaceutical and Food Safety Bureau Safety Division Head Mr. Toshiro Nakagaka Key points of the presentation: The presenter ・in his capacity as the Head (Division Manager) of the SD to the PFSB, made a short introduction to the topic of the present seminar and pointed to some of the recent actions undertaken by the regulatory authorities toward an increased safety for the medicinal products 1 approved in Japan. ➢ Safety measures focused on the post-marketing period: on October 3, 2005 a new 撤regnancy and Drugs Information Center・started ➢ Measures to limit the cases of malpractice ・especially, medical errors involving drugs (mistakenly administered drugs ・e.g. with similar names, or incorrect doses, etc.) Code Designation of Medicinal Products in Relation to the Use of IT / Safety of the Medical Treatment Professor of Tokyo Medical and Dental University and Center for Medical Science Information Head Mr. Hiroshi Tanaka Key points of the presentation: Concerning the use of IT in the medical treatment IT, the number of the countries that have accepted the risk and started to promote it as a kernel of the medical policy - including nations of Europe and America, has increased rapidly as a strategy that solves various problems because the medical treatment becomes more complicated. The application of IT aims at the prevention of the medical malpractice and to support the circulation and the management and related activities in the physical distribution of the medicines. On the other hand, the application and making electronic tags and enabling mobile forms, the further use in the medical treatment centers of care card (EHR) as a part of the computerization of the public health medical treatment record through life, are now being promoted. However, not only the computerization of the medium but also the standardization of the code of the medicines and the medical treatment materials become important problems in the use of IT in the medical treatment process. The establishment of a new, united code system capable to achieve measures for safety was related to the creation of the MHLW痴 Code Display Standardization Study Committee in 2004 fiscal year in a purport with "The code standardization from the viewpoint of securing traceability, malpractice prevention and secure supply of medicinal products", as the uniform drug code to be used in manufacturing, distribution, hospital in-house examination, etc. As a result, the discussions are focused astringently on several code systems: 1) The boxes outside the drugs that becoming an object of distribution, should bear along with the conventional Japan Article Number (JAN), additional 14-digit package indicator, in compliance to GTIN. 2) For safe use in the hospitals, the internal (in-house) code should be replaced with a new code. To put a separate code on same medicines, according to each sheet. Even packages of 500 tablets and 100 tablets should keep separate code. 3) As a matter of basic policy, the codes used in distribution should be clear and also the use of transparent wrapping (packing) in the sales. Code standardization of medicinal products for medical security is the problem that you should approached as a fundamental element primarily of the ubiquitous medical care in the future, while satisfying the issues of distribution. Implementation of Safety Measures for Medicinal Products MHLW, Pharmaceutical and Food Safety Bureau Safety Division GVP Specialist Mr. Takahiro Inoue Key points of the presentation: The Japanese regulatory authorities have implemented the system for Good Vigilance Practice (GVP) 2 along with the requirements of the international harmonization and the demand for improved safety of medicinal products marketed domestically. 1. About the GVP system and the side effect report system ・About the GVP system ・the GVP system implemented in Japan has evolved from the system of Good PMS Practice (GPMSP) and recently is considered as critical for assuring the safety of marketed medicinal products. Relations within the new GPSP / GVP system Relations within the new GPSP / GVP system Joint production distribution Production distributor Medical sites (facilities) Note: DI (Drug Information), source: PFSB (adapted) Cont. ・About the adverse events (AEs) reporting system: the system in place in Japan is designed to be compliant to both the domestic regulations and to the requirements under the International Conference of Harmonization (ICH). It was pointed that while in 2003 the number of AEs reported stood at 2,800, for the period of 2005 (until this seminar) the number is approaching 23,000. 2. Safety measures in the post-marketing period in the future: ・Establishment of the "Pregnancy and Drug Information Center・3 ・Activities for analyzing of the serious AEs 3. Promotion of measures for safety immediately after marketing (budget request for the 2006 fiscal year) ・defining the fixed points for observation after the marketing Guidelines for Evaluation and Treatment of Drug-Induced Lung Disorders Professor of Department of Medicine at Shinshu University Mr. Keitsugu Kubo Key points of the presentation: This presentation was made by Dr. K. Kubo, who is a member of the Committee for Generating Guidelines for Evaluation and Treatment of Drug-Induced Lung Disorders, which committee is controlled under the Japanese Respiratory Society and a part of a research commissioned by Japanese Ministry of Health, Labor and Welfare. * Recently, drug-induced lung disorders (DILDs) have attracted much attention along with growing recognition for safety of medicines, increasing number of DILDs cases, and their direct life-threatening impact. It is predicted that the number of patients with DILD will continue to grow. * From the epidemiological standpoint, cases with DILDs are increasing, especially after the year 2000. A variety of drugs can cause DILDs. Causative agents include anti-cancer drugs, anti-pathogenic microorganism agents, anti-rheumatics, biological products, Chinese herbal medicines (Kampo preparations) and anti-inflammatory analgesics. * In order to diagnose DILDs, it is always important to bear in mind that any drug can cause DILDs, even after completion of pharmacological treatment. Of course, we have to discriminate DILDs from exacerbation of the primary and/or opportunistic lung diseases. To diagnose a certain lung disorder as a DILD, it is essential to obtain information on the patient痴 clinical presentation, blood testing results, CXR / CT / HRCT images, respiratory function testing results, bronchoalveolar lavage fluid (BALF), lung histopathological manifestations, and the presence of risk factors. * Clinical manifestations of DILDs include interstitial pneumonia, bronchial contraction/asthma, bronchiolitis obliterans, pulmonary edema, pleurisy, mediastinal lymph node hyperplasia, pulmonary vascular disorder. Pathogenesis of these disorders could be cytotoxic or non-cytotoxic, i.e. allergic. With blood testing, markers for inflammatory reactions and/or tissue injuries (elevated erythrocyte sedimentation rate, high serum CRP, elevated lactate dehydrogenase (LDH), peripheral eosinophilia, elevated serum IgE), and those for interstitial pneumonia (serum KL-6 and SP-D) can be measured. Drug lymphocytes stimulation test (DLST) can also be performed. Although BAL is obtained non-invasively and its testing result cannot be definitive, it can provide beneficial information to diagnose not only DILDs but also other pulmonary injuries. Histopathological manifestations of DILDs will vary with patients・primary diseases and drug(s) used. Even with the same drug, those manifestations differ depending on individuals, dosages, route of administration and concomitant drug(s). * Risk factors for DILDs include age of 60 or older, existing pulmonary lesion (especially fibroid lung), reduced respiratory functions, oxygen inhalation therapy, irradiation to lung, polypharmacy of anti-tumor agents, and the presence of renal disorder(s). For amiodarone, bleomycin and busulfan, amount of drug administered and the duration of treatment should be taken into care, although for almost of other drugs those factors are not related to DILDs. As an example, gefitinib (Iressaョ) can causes lung disorder in two to five percents of patients, mostly within one month from dosing. In some lung cancer patients, Iressa could reduce the number and size of nodes in lung, while in others develop pathological changes, one of which was diffuse alveolar disorders (DAD). The findings from lung imaging vary among the cases of Iressa-induces lung disorders (IILDs), as those findings histopathological diffuse alveolar disorders. As morbidity and mortality from IILDs in Japan are about 6-times higher than those of the Western countries, genetic differences are proposed as a cause of IILDs. * DILDs should be differentiated from primary or opportunistic diseases based on these information and drugs (sometimes including supplements) used. Patients should be evaluated on symptoms, results of clinical laboratory tests, chest imaging and other specified tests, and also broncho-alveolar lavage fluid (BALF) to discriminate DILDs from exacerbation of primary diseases. Also infectious complication should be paid attention to. * To treat DILDs, the application of the suspected agent(s) should be stopped immediately, then the diagnosis confirmed. Corticosteroids should be given to treat DILDs. Disorders for which corticosteroids may be effective are: 1) those with allergic pathogenesis; 2) those diagnosed as eosinophilic pneumonia, bronchiolitis obliterans organizing pneumonia (BOOP), or hypersensitivity pneumonia from their clinical presentations and/or imaging findings; 3) those DLST positive; and 4) those with normal serum KL-6. For DILDs with cytotoxic pathogenesis or those with clinical presentations of DAD, non-cardiac pulmonary edema, or acute lung injuries (ALI)/acute respiratory distress syndrome (ARDS), pulse therapy of corticosteroid will be effective. * With recognizing that any drug can cause DILDs, attention should be paid to detect them as earlier as possible to prevent them from causing an exacerbation. Summary of DILDs Differential diagnosis of DILDs (flowchart) DIAGNOSIS AND TREATMENT OF DILDs Summary ・The surge in the concerns about the safety of medicinal products, ・the development of medicines acting directly on immunity system and molecular mechanisms, ・the improvement of the diagnosis of infectious diseases and interstitial pneumonia, and other factors provide a ground to predict a significant increase in the incidence of DILDs in the future. The possibility for inducing DILDs should be taken very seriously by all drug developers and the any DILDs capacity to reveal at earliest stage. Efforts for Safety Precautions by the Pharmaceutical and Medical Devices Agency (PMDA) PMDA, Safety Department Drug Safety Division Acting Director Mr. Tatsuya Kashi Key points of the presentation: Pharmaceutical and Medical Devices Agency (PMDA) is an independent administrative institution which cooperates with pharmaceutical companies and the Japanese Ministry of Health, Labor and Welfare (MHLW). Efforts for safety precautions by PMDA and some of their current status are now summarized: * PMDA receives information from pharmaceutical companies on quality, efficacy and safety of pharmaceuticals and conducts hearings with the companies. It also receives information from MHLW, and independently obtains information in scientific articles and regulations overseas. Moreover, it offers counseling on drugs to consumers. After hearings and analysis and evaluation of information gathered, PMDA reports the results to MHLW, and issues safety information for medical institutions and consumers, independently of MHLW. * For PMDA痴 activity during the fiscal year of Heisei 16 (From 2004 April to 2005 March; referred to as 滴16・, there were a total of 87,218 reports on side effects of pharmaceuticals, approximately 30 % of which were domestic 4reports on side effects and infections and case reports from abroad (reported via pharmaceutical companies) were about 65%. The domestic reports on side effects are constantly increasing for more than a decade and about 20 % of them originate from pharmaceutical companies. During H16 fiscal year, PMDA had 513 hearings with pharmaceutical companies and almost 70% of them were about revision of package insert in relation with reported adverse effects. * PMDA issued 133 of safety precautions for pharmaceuticals to MHLW in H16. Although those warnings include a variety of drugs, reports on drugs for central nervous system, neoplasm, and antibiotics are more frequent. Over 90% of the proposals were about serious adverse effects and the pharmaceuticals linked to those effects were widely varied. * PMDA also received more than 15,000 consultations regarding pharmaceuticals from consumers in the fiscal year H16, the number being similar for these several years. * PMDA also studies introduction of data mining procedure to its safety precaution services. In the mid-term plan for the introduction, it was planed to start investigation on data mining procedure in H16. Currently, in the safety analysis, the line list analysis and the case analysis are used with extracting the side effect data from their database and both are utilized as a basis for hearing to pharmaceutical companies and experts. Data mining procedures, i.e. signals detection, is to be used as one of information when extracting side effects and associated pharmaceuticals for case analysis. Combined with conventional procedures and voluntary reports database, data mining procedure, would bring about additional advanced data other than basic signals. Cont. * PMDA is also, in its mid-term plan, to organize medical institutions by pharmaceuticals・categories, particular products and a group of diseases in order to construct networks for information centers of medical institutions, with cooperation from MHLW. With data mining procedure, important items are to be extracted, and among the extracted items, those with unknown occurrence mechanism or causal relationship, or those for which gathering safety information (outcome) is necessary from the policy standpoint, shall be the candidates to be considered for networks・surveillances. In these networks, PMDA is to request cooperation from the centers, and upon agreement, centers shall provide required data, and finally then PMDA will disclose information including safety precautions. Basic medical institutions network (diagram) * As planned for the fiscal year of Heisei 17 (from April 2005 to March 2006, hereafter as 滴17・, PMDA aims at building such networks for combined anti-cancer therapies and pediatric pharmacotherapeutics. For the former, PMDA has surveyed the present status of combined anti-cancer therapies in May 2005 and will finish the surveillance for outcome/results of combined anti-cancer therapies within H17. The surveys are conducted for 21 therapies of pharmaceuticals reviewed at MHLW. Participating centers are 175 medical institutions including advanced treatment hospitals, local cancer center hospitals, and institutions of the Japanese Association of Clinical Cancer Centers, 114 of which already had declared their participation. These surveys continue for one year (nine months for patients registration and three months for follow-up) since a survey had started at a given institution. The participating centers are expected to provide the patients information and to report adverse events to PMDA. PMDA is to monitor the frequency of side effects and to analyze the collected data and after then to feed information obtained back to centers. Separately results have to be reported to MHLW, which is to take appropriate action for safety use of pharmaceuticals. When the centers are having patients whom should be applied a certain combined therapy, the investigator is required to report the case to the record manager, and the manager to update/save the patients・data and to send the date to PMDA. When adverse events (grade four and more) are observed in patient(s), the record manager has to report it the incident immediately to PMDA. PMDA is, in turn, should report it to the representative company of the relevant companies group 5 by therapy. The companies group is to investigate the case thoroughly. These results are published in the 鉄urveillance for outcome/results of anti-cancer combination therapy (tentative title)・in PMDA website to provide information accordingly. Related reports Drugs and Medical Devices Safety Update Seminar 2004 ・Report on the 泥rugs and Medical Devices Safety Update Seminar・held in Tokyo on September 17, 2004 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. 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 ゥ 2001-2005 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com 1 The Pharmaceutical Affairs Law (PAL) defines four categories of regulated medicinal products in Japan: medicines or drugs (including pharmaceuticals and products originating from living organisms), quasi-drugs, cosmetics and medical devices. 2 The GVP system in Japan is described in greater details in the report on the ・1st New Drug Evaluation Division Information Meeting・available online in the JKS Document Store: http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=PROD&Product_Code=JM_I_017&Category_Code=JMI 3 Started activities on October 3, 2005 4 In this case 電omestic・ means reported domestically (to the Japanese authorities) and include both reports from Japanese pharma companies and Japanese office of foreign companies. 5 Manufacturers are grouped by the type of product and one member company is acting as a contact (intermediary) with the PMDA, as the information is shared among the group痴 members. ?? ?? ?? ?? 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