Enterprise-wide Use License - Drugs and Medical Devices Safety Update Seminar Date: September 17, 2004 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 Mr. M. Uchiyama (SJP) 10:40-11:10 Prospective Post-Marketing Safety Measures MHLW, Pharmaceutical and Food Safety Bureau Safety Division Head Dr. Yoshinobu Hirayama 11:10-11:50 Drug Safety Measures of PMDA Pharmaceuticals and Medical Devices Agency Safety Division, Drug Safety Section Acting Head Dr. Hideyoshi Katsura Lunch Break 13:00-13:40 Drug Information for the Public The Japan Pharmacists Education Center (JPEC) Pharmaceutical Manufacturing Division Manager Ms. Reiko Kubo 13:50-14:20 Drug Safety Information on Pharmacotherapy during Pregnancy Toranomon Hospital, Pharmacy Division Head Mr. Masahiro Hayashi Break 14:40-15:20 Drugs and Medical Devices Safety Measures MHLW, Pharmaceutical and Food Safety Bureau Safety Division Safety Usage Promotion Office Malpractice Information Specialist Mr. Takashi Goto KEY ILLUSTRATIONS Figure 1. Basic concept Figure 2. Basic concept of safety measures Figure 3. Objectives of PMDA Figure 4. Structures involved in Safety Measures in PMDA Figure 5. Content of the drug information for the public Table 1. Reference books on drug administration in pregnant women Table 2. Risk Evaluation Points of the Drugs Table 3. Dosage Phase Drug Risk Evaluation Points Table ４. List of high teratogenesis risk drugs ATTACHMENTS Attachment 1. Specification working group Attachment 2. Name analogy working group and Injection agent analogy working group Attachment 3. Transfusion working group Attachment 4. Ophthalmic agent working group Attachment 5. MHLW, Health Policy Bureau Notification No. 0602012/ Pharmaceutical and Food Safety Bureau Notification No. 0602007 Attachment 6. MHLW, Pharmaceutical and Food Safety Bureau Notification No. 0602009 Attachment 7. Pharmaceutical and Medical Devices Safety Information No. 202 Note of the Publisher -Regulatory information inquiries Disclaimer 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 41 meetings have been held as follow: Topics No. New Drug Evaluation Division Information Meetings 19 Periodic ICH Information Meetings 10 Problems with Safety of Drugs 7 Problems with QA of Drugs 4 14th Japanese Pharmacopoeia 1 Total as of September 2004 41 Prospective Post-Marketing Safety Measures MHLW, Pharmaceutical and Food Safety Bureau Safety Division Head Dr. Yoshinobu Hirayama Key points of the presentation: Figure 1. Basic Concept Ideal improvement Post-event action (action after ADR) 　 Predictive action (target on drugs with possible ADR) Preventive action (patients with high risk of ADR) Aspects of ADR to overcome ? liable to occur on organs that the doctor in charge is not specialized in ? frequency of ADR is not often, therefore, doctors are not experienced ? in many cases, its cause and symptoms are yet to be clarified Therefore, in order to prevent ADR, it is crucial to collect factual data and to identify the risk factors, causes and symptoms, and to provide information in a broad manner. Figure 2. Basic concept of safety measures Note: The tasks in red - delineate the uncompleted / in progress tasks Measures to be taken General In order to identify risk factors, causes and symptoms, organizational and systematic approach is necessary: * accumulation of data and clinical test results * comparison of data * interdisciplinary research * patient cooperation Improvement in post-marketing research is vital to collect sufficient ADR data: * create research system corresponding to each possible ADR * research system that enables flow of information in multiple directions Improvement at medical site is also essential. * create system to increase opportunity to detect ADR * improve quality of information Pharmacies are important contact to patients * provide information to customers * measures against ADR Specific projects ? Combined usage of anti-cancer drugs Collect information on combined usage of anti-cancer drugs after the ease of restriction. It will require cooperation of multiple pharmaceutical companies and academic societies. ? Pediatric pharmacotherapy Compile and evaluate data on pediatric pharmacotherapy by overcoming difficulties of clinical trials in pediatric cases. ? "Pregnant women's drug information center (temporary)" plan Substantiate the plan in order to enable to deal with pregnancy and pharmacotherapy. ? Prescribing information Today, patients are more likely to make their own decisions on what kind of treatments to undergo, thus, it is significant to improve information provided to patients who are the end-users of drugs as well as the detectors of ADR. ? Comprehensive countermeasure project for severe ADR cases In the next 4 years, a manual for 120 specific severe ADR cases will be completed which covers the diagnosis, treatment, initial symptoms, typical symptoms, prescribing information for patients, risk factors, etc. Further research will be carried out based on the information collected systematically by practice of the manual. ? Code control Project to code control drugs is progressing. This will help to prevent mistakes and provide traceability of drugs. Drug Safety Measures of PMDA Pharmaceuticals and Medical Devices Agency Safety Division, Drug Safety Section Acting Head Dr. Hideyoshi Katsura Key points of the presentation: Outline of PMDA Following the 2001 Cabinet decision on "Special Service Agency Restructuring Plan" and in accordance with the "Law for the Incorporated Administrative Agency - Pharmaceuticals and Medical Devices Agency", the Pharmaceuticals and Medical Devices Agency (PMDA) was established and began operations on April 1, 2004. PMDA is dedicated to improving the health of the nation and providing information pertaining of post-marketing safety (Safety Measures) is one of the many significant functions of the organization. Figure 3. Objectives of PMDA Improving the public health * Adverse health effect relief * Approval review * Safety measures * R & D promotion Safety Operations of PMDA Standards, such as those for Japanese Pharmacopoeia set forth in the Pharmaceutical Affairs Law, form one of the cornerstones of safety measures for pharmaceuticals. PMDA collect and compile information regarding the safety of pharmaceuticals, after which the results are submitted to MHLW. Figure 4. Structures involved in Safety Measures in PMDA Note: Safety Information Division Tel: 03-3506-9003; Fax: 03-3506-9441) Miscellaneous The licensed pharmaceutical and medical device companies are requested by the Law of PMDA to participate in the annual donation per quantity of product in order to maintain the operational cost for the safety measures. Drug Information for the Public The Japan Pharmacists Education Center (JPEC) Pharmaceutical Manufacturing Division Manager Dr. Reiko Kubo Key points of the presentation: In order to provide reliable and comprehensible pharmaceutical information to the patients and the public, and to realize patient-participating medical environment, the round-table group on the "Providing of pharmaceutical information - construction of synthetic network" announced a Guideline in its final report in September 2001. Recent trend of health consciousness has boosted the amount of health relating information among the patients and the public. Amongst the abundant information, including the one provided by medical professionals, a survey revealed that patients are likely to accept only the information favorable to the patients. One of the possible reasons for this phenomenon is lack of thorough comprehension on the prescribed drug, thus leading to devaluation of its necessity. Or distrust may prevail because of the abundant ADR information. Patients may not feel comfortable to talk with doctors; as a result they may be compelled to self-diagnosis. In order to solve such situation, reliable information should be provided to patients, and on the basis of it, better communication between patient /public and medical professionals should be developed. Since 2001, the speaker (JPEC) was involved in the research program of MHLW to study the provision of pharmaceutical information to patients and public. The study was conducted on the basis that for the safety of patients and public both medical professionals and patients/public have their important role. The study group compiled a glossary for patients which collaborates ADR terms and subjective symptom terms, a manual for early detection of ADR based on the actual experience of patients, and made a research on the improvement in prescribing information. Overseas status of prescribing information for patients In USA the FDA provides information on drugs that may cause severe ADR and other drugs. EU provides information on all drugs, and Australia (Consumer Medicine Info, CMI) not only provides information on all prescribed drugs but on some OTC drugs that require explanation by pharmacists. In all three regions, it is obligatory to provide specialized information in comprehensible terms. In Australia, more than 90% of the nation is able to access the necessary information provided by CMI, and of which 90% can conform to its direction. "Web edition" of prescribing information (Japan) Survey revealed that patients demand information in detail and that they comprehend 90% of the content of a medical article in general newspapers in spite of some specialized terms that they don't understand. In consideration with such demand, the study group designed a new style of providing prescribing information, the web edition of prescribing information, carefully made to be precise, informative, and easy to understand. Continue on next page Figure 5. Content of the drug information for the public Required parts A) Name B) Efficacy C) Cautions prior to dosing D) Dosage regime E) Cautions during dosing F) ADR G) Storage H) Outline of the drug I) Others Note: The speaker presented an actual example with Panaldine tablets. Drug Safety Information on Pharmacotherapy during Pregnancy Toranomon Hospital, Pharmacy Division Head Mr. Masahiro Hayashi Key points of the presentation: Pharmacotherapy during pregnancy requires cautious administration with due consideration on the influence of pregnancy itself, pharmacokinetics, and influence to fetus. On the other hand, maternal disadvantage from anxieties of mal-influence to the fetus should be avoided. Therefore, it is essential to evaluate the teratogenic information of drugs in an adequate manner allowing necessary maternal treatment with least teratogenesis risk. Thalidomide incident in the 1960's has preached not only medical professionals but also the common pregnant women on the teratogenic risk of drugs, which tend to lead to an excess anticipation. Consequently, it is necessary to prepare an environment to guide pregnant women on the benefit and safety of drugs in order to achieve pharmacotherapy in a positive attitude. The Toranomon Hospital has opened a "Pregnancy and Drug Consultation Ambulatory" with joint operation of O&G (uterology) and Pharmacy Departments and as of end June, 2004, has consulted on 7,544 cases and researched on the teratogenesis on 3,470 drug components. Drug risk information in pregnancy In our country, official evaluation of drug risk during pregnancy, delivery or lactation is indicated in precautions of package insert. During pregnancy, it is a principle not to prescribe those drugs indicated "contraindicated in pregnancy" or "desired to not to administer". On the other hand, when having had such drugs prescribed unaware of pregnancy, teratogenic risk or propriety of carriage do not necessarily comply with package insert. Rationale for "contraindication" range form "cases suspected of teratogenesis reported" to "not established safety on dosage during pregnancy". Therefore not all drugs stated as "contraindicated in pregnancy" cause teratogenesis. In such cases, counseling based on detailed research and evaluation should be held (Table 1). Table 1. Reference books on drug administration in pregnant women Author Title Publisher Year T. Sato, H. Kano (Pregnancy and Drug) Jiho 1992 Y. Amenomori (Administration during Pregnancy and the Risk) Pharmaceuticals and Treatment Laboratory 1993 J.L. Schardein Chemically Induced Birth Defects, 2nd Marcel Dekker 1993 G.G. Briggs Drugs in Pregnancy and Lactation, 5th Williams & Wilkins 1998 Yanaginuma (Pregnancy, Lactation and Drug Handbook) Medical Science International 2000 In the United States, FDA indicates the standardized category for drug risk on fetus in 5 categories (Pregnancy Category). Based on animal reproduction test and human teratogenesis information it shows substantial criteria for categorizing the drug risk level, which is also valuable for clinical pharmacotherapy. Toranomon Hospital "Pregnancy and Drug Consultation Ambulatory" organized drug teratogenic risk evaluation points (Table 2) to evaluate the risk by standardizing it based on epidemiological research, case report and reproduction test. Continue on next page Table 2. Risk Evaluation Points of the Drugs Evaluation Items 5 points ? firmly considered to have the risk of teratogenesis based on epidemiological research ? or, as result of reproduction test, firmly considered to have teratogenesis in human 4 points ? reported cases of suspected teratogenesis by epidemiological research, or both negative and positive results reported with more significance on positive results ? or, no epidemiological research been conducted, and more than one trustful case report on teratogenesis 3 points ? epidemiological research resulting in suspected teratogenesis and negative of teratogenesis, with more significance on negative results ? or, no epidemiological research been conducted, but reports on teratogenesis case in reproduction test, or both positive and negative case reports with equal significance 2 points ? no epidemiological research conducted, no positive reports on human teratogenesis. But reports of teratogenesis in reproduction test, or both positive and negative reports with equal significance 1 point ? no epidemiological research conducted, no positive reports on teratogenesis and reproduction test not conducted or teratogenesis not found. Or topical usage and Chinese Kampo 0 point ? no tendency of teratogenesis by epidemiological research and no positive case reports and reproduction test not conducted or no teratogenesis. Or those used as food Cautions for evaluation of teratogenesis information １) Cautions for evaluating epidemiological research Cohort study is considered reliable in teratogenesis epidemiological research, however, for rare cases, case- control study is more realistic. Therefore, it is important to pay attention to the design and scale of the study: i Bias In interviews, mothers of children with teratogenesis may have biased memory than other mothers because of various forms of suffering ii Confounding For example, when comparing 2 groups, mothers who had codeine, an antitussive, and mothers who had not, the study will be confounding for a virus infection and the dosage of codeine Evaluation of risk in pregnancy by dosage phase １) Evaluating points by dosage phase of pregnancy In addition to the above, influence of drug to fetus depends largely to its dosage phase. The Toranomon Hospital categorizes this in 5 levels (Table 3): Table 3. Dosage Phase Drug Risk Evaluation Points Numbers of days from the 1st day of final menstruation Description Evaluation Points 0 days to 27 days No influence 0 points 28 days to 50 days Absolutely sensitive 5 points 51 days to 84 days Relatively sensitive 3 points 85 days to 112 days Comparatively sensitive 2 points 113 days to birth Potentially sensitive 1 points 2) Correction of dosage phase risk points Danazol for endometriosis may produce an androgenic reaction, if dosed during pregnancy, report reveals to cause defemination of female child. Human androgen receptor sensibility, however, is considered to be activated after the 8th weeks of pregnancy; therefore, during the general absolute sensitivity period (beginning of 4th week to end of 7th), the risk is small. Consequently, absolute sensitivity period is corrected to after 8th week. Sensitive period of tetracycline antibiotics are also during the latter period of pregnancy, therefore requires a correction. Synthetic evaluation of fetus risk during pregnancy Influence to fetus caused by drug dosed during pregnancy is affected by the risk of the drug itself and the phase of pregnancy the drug was dosed. At Toranomon Hospital, the synthetic risk is calculated as bellow and is categorized in 4 levels. Figure 6. Synthetic evaluation of fetus risk Formula Fetus Risk Degree = Risk Evaluation Point of the Drug × Dosage Phase Drug Risk Evaluation Point Points Action 0 to 6 points no influence 7 to 11 points caution 12 to 19 points warning 20 to 25 points risk Specificity and importance of guidance on pharmacotherapy in pregnancy Explain the risk by first enlightening on the natural teratogenesis rate, then from viewpoint of whether the drug will increase the rate or not in an objective and clear manner. Continue on next page Drugs of high teratogenic risk The actual risk should be gained synthetically based on risk of the drug itself and dosage phase risk with corrections according to dosage, route, duration, and combination. Table ４. List of high teratogenic risk drugs Points Generic name Brand name 5 points etretinate warfarin phenytoin sodium valproate trimetazidine methotrexate (omitted) 5 to 4 points vitamin A (over 10,000 units) (omitted) 4 points aminoglycoside antibiotics carbamazepine clonazepam colchicines diazepam danazol HMG-CoA reductase inhibitors lithium carbonate phenobarbital primidone misoprostol ovarian follicle hormone mixture ACE inhibitors (omitted) 4 points at latter pregnancy ARB tetracycline lithium carbonate (omitted) Homology of package inserts and drug epidemiology As one of the 2003 governmental research, the Toranomon Hospital conducted a study against cases that require continued pharmacotherapy in pregnancy and lactation on homology of the package inserts information and epidemiological research results information. As a result, it was made clear that information on maternal pharmacotherapy and influence to fetus, such as teratogenesis, completely lacked in the package insert. It was considered necessary to establish measures to improve the situation involving pharmaceutical companies. Tasks ? Organize multi institutional cooperation to collect safety information on drug administration to pregnant women. ? MHLW plans to establish "Pregnancy and Drug Information Center" in 2005 which will cooperate with "Mother Risk Program" of Canada, the largest teratogenesis counseling system in North America. ? Cooperation between Toranomon Hospital and other hospitals, pharmaceutical companies and medical institutes continue to be important. Drugs and Medical Devices Safety Measures MHLW, Pharmaceutical and Food Safety Bureau, Safety Division Malpractice Information Specialist Safety Usage Promotion Office Mr. Takashi Goto Key points of the presentation: 1. Outline of medical safety measures * Outline * Measures in Japan (from March 2000) * Synthetic measures of medical safety (April 17, 2002) * Emergency appeal by Minister of MHLW on medical malpractice (errors) (December 24, 2003) 2. Analogy study of pharmaceuticals A) 2003 Working group reports * Specification working group * Name analogy working group * Injection agents analogy working group * Transfusion working group * Ophthalmic agents working group B) Safety measures based on the working group reports * MHLW, Health Policy Bureau Notification No. 0602012/ Pharmaceutical and Food Safety Bureau Notification No. 0602007, of the Director-General of Health Policy Bureau / Director-General of Pharmaceutical and Food Safety Bureau * MHLW, Pharmaceutical and Food Safety Bureau Notification No. 0602009, of the Director-General of Pharmaceutical and Food Safety Bureau C) Tasks of working group, fiscal 2004 * Establish evaluation flow chart (decision criteria) of name analogy database. * Review medical information exemption rules for small space * Others 3. Development of name analogy database A) Name analogy database B) Utilization of name analogy database * Medical institutions * Pharmaceutical companies C) Schedule 4. Pharmaceutical codes A) Outline and purpose for introducing pharmaceutical codes B) Projects of our country * 2003 MHLW science research special project "Study on traceability of medicals (drugs/medical materials)" * Institution of code standardization study group C) Schedule ATTACHMENTS Attachment 1. Specification working group 1. Objective Mistakes of drugs repeatedly reported to have been caused by analogy in the specifications. The working group will research and study on the means that should be carried out at medical institutions and pharmaceutical companies. 2. Members 3. Results (1) Trade names Since 2000, MHLW has guided the basic rules on the trade names; however, there still remain drugs that do not follow the rules. For example, for those drugs that have several different types of supplies under one trade name, there are cases that the revision according to the new rules is partially still not applied. (2) Information on package Necessary contents of information are different among doctors, pharmacists and nurses. For doctors, effective component is important, but for pharmacists and nurses, it is important to know the dosage. For this reason, calculation for dosage is being conducted frequently at medical sites and this is one of the elements for mistakes. Therefore, necessary information for all should be added to supplies and packages of drugs. (3) Ways to indicate existence of other supply types under the trade name. It was concluded, for various reasons, inadequate to indicate information on all supply types on each product. At pharmacies and hospital wards, such means as putting up stickers that draw attention to the existence of other supplies could prevent mishandling of supply types. Doctors should not omit drug name and unit when writing down or orally instructing the prescription. For stereotype drugs, visual effect is being tested. (4) Concrete suggestions for high risk drugs ? Phenobarbital: The pharmaceutical company is under procedure to unify the color of the drug. At medical institutes, prescriptions should indicate 10% or else following the drug name. ? Drug for diabetes and anti-malignant tumor, digitalis and warfarin. Mistakes could lead to severe or fatal ADR. Such measures as stickers, tags for attention should be taken. (5) Other measures Attachment 2. Name analogy working group and Injection agent analogy working group 1. Objectives (1) Name analogy Many cases of malpractice (errors) are being reported caused by analogy of names. The working group will wrap up countermeasures and make a suggestion (2) Injection agent analogy There are malpractices (errors) caused by analogy of injection agents in vials or ampules. The working group will consider on the countermeasure and make a suggestion. 2. Members 3. Results (1) Establishment of an evaluating system for name analogy and concrete procedure to avoid name analogy before new drug application A study is being carried out by MHLW science research program. A prototype system of 7000 brand name database is under pilot study at Japan Pharmaceutical Information Center (JAPIC) and pharmaceutical companies. It is not easy to make post-marketing changes; therefore it is important to confirm the analogy before new drug application. (2) Basic regulations for changing names For those new drugs to be approved, the above-mentioned analogy evaluation system should be applied. The working group made a research on the change of names of drugs already in market. It is considered that change of the name of already existing drugs will cause confusion and past data show that the name is not the only cause of malpractice. Therefore, the working group will analyse the past data and study the expected risk caused by name change to come up with countermeasures. Those drugs used at emergency rescue, where prescription is made orally, change of name should be carried out in a positive manner when severe ADR case is reported. (3) Drugs of high risk when mistaken The working group conducted an extended study on 5 cases of high risk when mistaken. Each of the related companies has already taken certain measures against mistakes, but further custom-made countermeasures should be taken. Drug safety improvement has been conducted with emphasis on the safety of the drug itself. The facts on the safety in clinical usage, however, are yet to be clarified. In order to achieve "usage safety" a continuous and detailed exchange of information between the user and provider is essential. (4) Database for analogy of injection agents Picture image database prototype system is proposed. (5) Information on injection agent labels Addition of information on injection label, literal clarity and other factors are necessary to be studied. (6) Promotion of Check system for drug name and prevention of mistakes at medical institutions and pharmacies Mistakes of drugs are considered to being caused not only of name/package analogy but also with various different elements in each case. Therefore, it is important to take measures not only to change the names and packages but also to implement such improvements by revising procedures, organizations and environment at medical sites. Attachment 3. Transfusion working group 1. Objective Analogy in codes and bags, name and package of transfusion is causing malpractice. Therefore, the working group researched and discussed on countermeasures thus allowing suggestions to medical institutes, pharmaceutical companies and administration. 2. Members 3. Results (1) Transfusion mistake analysis based on human engineering technology Analysis of reported malpractice cases revealed that many cases were either a mistake of transfusion series for single-bag transfusions or a forgetting to release for double-bag transfusions. From human engineering standpoint, backgrounds of the two are different. Therefore, the working group decided to study the case from two aspects, "mistake" and "forgetting". (2) Prevention measures on single-bag transfusion products Labels of single bag transfusion sequence products often simply indicate the brand name of electrolyte and sequence numbers and this is considered one of the big reasons for mistakes. It is recommended to indicate not just the numbers but also words that reveal each treatment objective. (3) Measures against forgetting to release double-bag transfusions Print an alert sign "confirm release" on the bag, draw red bold line between the separations, and promote attention by posters. (4) Education by promoting tools "Discussion tool for improvement of handling transfusion" (5) Others Attachment 4. Ophthalmic agent working group Suggestions on measures to prevent mistakes of ophthalmic agents and those for athlete's foot were made. Attachment 5. (omitted) MHLW, Health Policy Bureau Notification No. 0602012 Director-General of Health Policy Bureau MHLW, Pharmaceutical and Food Safety Bureau Notification No. 0602007 Director-General of Pharmaceutical and Food Safety Bureau Issued June 2, 2004 "Reinforcement and thoroughness of the measures for prevention of drugs and medical devices related accidents in the medical institutions" Attachment 6. (omitted) MHLW, Pharmaceutical and Food Safety Bureau Notification No. 0602009 Director-General of Pharmaceutical and Food Safety Bureau Issued June 3, 2004 "Reinforcement and thoroughness of the measures for prevention of drugs and medical devices related accidents" Attachment 7. (omitted) Pharmaceutical and Medical Devices Safety Information Bulletin No. 202 Note: The Bulletin is released monthly by the MHLW / PFSB to promote the safety of the drugs and medical devices by collecting and summarizing to all concerned the most recent information. The Pharmaceutical and Medical Devices Safety Information Bulletin No. 202 is issued in June 2004. By September 2004, the latest release is No. 2005. For further information, see next page. Note of the Publisher - Regulatory information inquiries The translation of the Attachments 5 and 6 into Japanese is not included here since those were provided as supplementary materials. Titles, bibliographic details are given here for the clarity. Further details on the issues for drugs and medical devices safety are contained in the Office Communication dated September 1, 2004 of the Safety Division of the Pharmaceutical and Food Safety Bureau entitled: Q & A on the "Reinforcement and thoroughness of the measures for prevention of drugs and medical devices related accidents". Further information and details regarding the Attachment 5 and Attachment 6 are available from the Regulatory Group of the JK Services LLC at the contacts given below. Email: regulatory@jouhoukoukai.com International Tel: +81-367-174-195 International Fax: +81-367-174-141 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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