Single User 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 “Drugs and Medical Devices Safety Update Seminars�Ereflects 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 48 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 22 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 48 22nd New Drug Evaluation Division Regular Meeting Date: October 19, 2005 Time: 10:30 �E15:00 Venue: Melparque Hall, Tokyo Organizer: The Society of Japanese Pharmacopoeia (SJP) (Incorporated Foundation) Sponsors: �EJapan Federation of Pharmaceutical Manufacturers�EAssociations (JFPMA) �EJapan Pharmaceutical Manufacturer Association (JPMA) �EThe Pharmaceutical Manufacturers�EAssociation of Tokyo (PMAT) (Incorporated Association) �EOsaka Pharmaceutical Manufacturers Association (OPMA) �EJapan Medical Association (JMA) (Incorporated Association) PROGRAM 10:30-10:40 Opening Address from the Organizer (SJP) 10:40-11:10 Present environment of research and development / approval of new medicinal products MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Head Mr. Akira Kawahara 11:00-12:00 Study Committee on Ideal Way for Clinical Trials (Working Group for Practice of Clinical Trials) MHLW, Pharmaceuticals and Food Safety Bureau Evaluation and Licensing Division Deputy Manager Mr. Tsuyoshi Shimizu Lunch Break 13:15-14:05 Consultations (including face-to-face advisory meetings) on new drug approvals Pharmaceuticals and Medical Devices Agency Priority Evaluation Coordinator Mr. Shunsuke Ono 14:05-14:20 Break 14:20-15:00 The Project “Promotion of Pediatric Pharmaceutical Treatment Based on EBM�E MHLW, Pharmaceuticals and Food Safety Bureau Evaluation and Licensing Division Deputy Manager Mr. Takeyuki Satou KEY ILLUSTRATIONS * Diagram: Evaluation of clinical use of drugs adequately to the latest level of the medical treatment * Diagram: Use of medicines unapproved domestically * Flowchart: Sequence of the consultations * Diagram: Consultation comprehensive mechanism flow * Diagram: Project “Promotion of Pediatric Pharmaceutical Treatment Based on EBM�E 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. Present environment of research and development / approval of new medicinal products MHLW, Pharmaceutical and Food Safety Bureau Evaluation and Licensing Division Head Mr. Akira Kawahara Key points of the presentation: This introductory presentation was made by Mr. Kawahara, the Division Head of the Evaluation and Licensing Division (ELD) 1 �Ea key unit of the Pharmaceutical and Food Safety Bureau (PFSB), directly responsible for evaluation of new medicinal products. Six topics related to the implementation of the revised Pharmaceutical Affairs Law and recent administrative issues were presented: ➢ Revision of the Pharmaceutical Affairs Law and measures taken thereafter - Recently the Pharmaceutical Affairs Law (PAL) was revised and the revisions have been implemented in series from the year of 2003. These revisions include fundamental review of safety measures for medical devices, enhancement of safety measures for biological products, enhancement of post-marketing safety measures and review of the approval system. Upon the implementation, the subordinated regulations, ordinances and notifications shall be revised or prepared accordingly and notified effectively, and actions have taken (and are going to be taken) to inform them to those whom the regulations / notifications may concern so that they are smoothly implemented. ➢ GPMSP (Good Post-Marketing Surveillance Practice) - The existing Good Post-Marketing Surveillance Practice (GPMSP), has been divided into two provisions: one part consists of provisions for the post-marketing safety measures, surveillances immediately after launch, and collection of information on appropriate usage; the other part includes provisions on the standards for collection of materials/documents which should be submitted for the reevaluation. Post-marketing surveillance and study include usage results surveillance (including special usage results surveillance) and post-marketing clinical trial. These surveillances should be achieved upon the collaboration between manufacturers and medical facilities. ➢ Reinforcement of the systems for approval and clinical trial consultation - For the purposes above, main points to be addressed preferentially in the year of 2005 shall as follows: 1) appropriate and swift approval of drugs; 2) improvements of clinical trial consultation system for new drugs; and 3) reinforcement of GMP surveillance system. For the appropriate and swift approval, Pharmaceutical and Medical Devices Agency (PMDA) was founded in 2004 and now it works to develop new drug approval systems (mainly by increasing the necessary staff), to realize the approval management system, and to reduce accumulated backlog of applications, etc. ➢ Addressing the non-indicated (off-label) usage - Today, there are many drugs used to treat diseases/conditions which are not approved as their indications. For those so called “non-indicated uses" 2, a notification was published to encourage pharmaceutical companies to submit applications partially revising their domestic submissions �Eon the basis on their submissions overseas, substantial clinical usage, and scientific articles, published in reliable international journals and used on the basis of scientific research results. Examples of these drugs include anticancer drugs used for combination therapy. In order to apply the Special Healthcare Expenditure 3 earlier and to expand the indications of anticancer drugs for combination therapy, a working group has been founded 4 which collects information enough to review efficacy and safety of anticancer drugs in such a use. The duration to the approval is to be reduced by advisory board pre-evaluation. In addition, a revision of the Guideline for Clinical Evaluation of Anticancer Drugs 5 is now ongoing. ➢ Issues of drugs unapproved domestically and their clinical trial in Japan - There are also many drugs unapproved domestically, 6 despite being already approved abroad (in U.S. or Europe). If used in Japan, expenses for them cannot be covered by the public health insurance system 7 in Japan, which may cause patients to pay whole the cost, even if it contains costs usually covered by the insurance. Therefore, it is necessary to develop the system which leads those unapproved drugs to reliable clinical trials and allow combination use with insurance-covered medical care. For the purposes, a working group (The Committee for the Examination of the Use of Unapproved Medicinal Products) was founded to discuss drugs unapproved domestically, and which is to further assemble special task forces if necessary. A working group 8 also has been founded for discussion on measures to facilitate clinical trials. Reevaluation 9 of existing drugs is also now under way, such as reevaluation for efficacy and safety, developments of Evidence-based Medicine (EBM) guidelines, and reevaluation of quality. Drugs�Eclinical efficacy should be evaluated based on the state-of-the-art medical care standard, by means of MHLW and pharmaceutical companies�Ecooperation. ➢ Nomenclature of ethical generic drugs - As the prescribed generic drugs have become much more known and recently their use increased considerably, a notification was made in September 2005 to prevent medical accidents resulting from the similarity of drug names. The prescription generic drugs 10 launched from now on should have a name of “generic name + formulation + content + company name�E while newly approved drugs when launched should have one of “brand name + formulation + content�E Diagram: Evaluation of clinical use of drugs adequately to the latest level of the medical treatment Diagram: Evaluation of clinical use of drugs adequately to the latest level of the medical treatment Source: MHLW (adapted) Study Committee on Ideal Way for Clinical Trials (Working Group for Practice of Clinical Trials) MHLW, Pharmaceuticals and Food Safety Bureau Evaluation and Licensing Division Deputy Manager Mr. Tsuyoshi Shimizu Key points of the presentation: In the practice of clinical trials, there are two main challenges to be solved. The first is to improve the environment of clinical trial and to reduce the actual workload on staff involved in clinical trials (such as the cumbersome procedures to start trials, limited time and financial resources). The second is to establish a system allowing the combination use of drugs unapproved domestically with medical care covered by the public health insurance system, while utilizing the clinical trials. To investigate the necessary measures for conducting clinical trials smoothly while ensuring their reliability to contribute in solving the above problems, a working group for practice of clinical trials was established in March 2005 and had meetings monthly. Below is the tentative outline of an interim report (from the Working Group for Practice of Clinical Trials) on the practical improvement measures for conducting physician-initiated clinical trials: �ENotify that study drugs already approved abroad (in U.S. or Europe) can be obtained internationally if given criteria are satisfied (another option for obtaining a study drug) �ENotify that in the Summary, necessary for the Notification of Clinical Trial of study drugs already approved abroad, others than main parts need not to be translated (translation workload reduction) �ENotify that the package insert 11 for study drugs already approved abroad can be used to maintain study drugs (reduction of workload to newly create the package insert for study drugs) �ENotify that for Case Report on adverse vents and infectious diseases in multi-center trials, it is possible to submit a complied report containing the reports from each center if given criteria are satisfied (reduction of desk work in each center) �ENotify that for reporting adverse events and infectious diseases in case of clinical trials for addition of efficacy, only the cases of which death was or could be caused by unknown side effect(s) unexpected when dosing, and the Adverse Events (AEs) with unknown severe symptom(s) occurred inside the center should be reported to the regulatory authority, omitting adverse event cases abroad (workload reduction for adverse event case reporting) �ENotify that monitoring and audit for the trial can be performed by the personnel in the same medical facility if given criteria are satisfied (workload reduction) �ENotify that production of the clinical study report can be outsourced under the direction of a person who oneself participates the trial (deskwork reduction). These and other issues, related to conducting clinical trials and also encompassing system of approval, will be identified and discussed by the working group. For establishment of platforms for clinical research, a special task force will be established. Also the nature of the approval committee will be preferentially discussed. Diagram: Use of medicines unapproved domestically Source: MHLW (adapted) Diagram: Use of medicines unapproved domestically Consultations (including face-to-face advisory meetings) on new drug approvals Pharmaceuticals and Medical Devices Agency Priority Evaluation Coordinator Mr. Shunsuke Ono Key points of the presentation: PMDA provides consultations and advices related to the clinical trials of new drugs. These consultations are classified, depending on their character into the following groups and sub-groups: 1) Five types of consultations on new drug clinical trial according to relevant step of the product development: �Epre-Phase I �Epre-early Phase II �Epre-late Phase II �Eafter Phase II �Epre-application 2) Two consultations on clinical trials for drug reevaluation / reapplication: �Eplanning clinical trials for reevaluation / reapplication �Eafter clinical trials for reevaluation / reapplication 3) Other five types of consultations complementing the above consultations and focused on: �Econsultations on procedures �Ebioequivalence trials �Equality �Esafety �Eadditional studies Flowchart: Sequence of the consultations tentative application -> notification of determined schedule -> application (fee payment) 　-> pre-investigation -> face-to-face meeting for advice 　　-> generation of consultation record -> providing the consultation record According to the field of the objective drug, consulting department of PMDA shall be different. In the year 2004, there were 334 applications for scheduling, 193 face-to-face advisory meetings and 23 cancellations. The reasons for the increase of application for scheduling include the growth of the demand for consultations resulted from the raised expectations (from the side of the applicants) �Emostly due to the integration with the approval process, and from the other hand �Ethe two months suspension of the consultation during the business transition to PMDA. Facing an increase of the applications for consultation, several improvements have been suggested and some have already implemented - such as the specialization of the staff for consultations, alteration of scheduling measures, and enforcement of consultation management function. Other measures are now under preparation, including the preliminary investigation of a demand for face-to-face advisory meetings for new drug development, additional forms of consultation for clinical trial, and simplification of the face-to-face advisory records. There is in place a system to designate drugs for preferential face-to-face advisory meetings. To be indicated as a “preferential�Edrug, materials and documents which indicate the drug’s clinical usefulness are necessary, and a decision will be made based on the materials, seriousness of the indications and medical usefulness of the drug. Once designated, it is possible to have preferentially face-to-face advisory meetings and to apply to reliability standard suitability consultation. However, if there is any legal violation or newly obtained results which show the drug cannot apply to the indication criteria, the designation shall be suspended. When applying for the designation of the preferential drug, it is recommended to have an interview and a thorough discussion before the application, as the potential applicants are also suggested to look for related information provided on the web site of PMDA. Diagram: Consultation comprehensive mechanism Flow Source: MHLW (adapted) Diagram: Consultation comprehensive mechanism flow The Project “Promotion of Pediatric Pharmaceutical Treatment Based on EBM�E MHLW, Pharmaceuticals and Food Safety Bureau Evaluation and Licensing Division Deputy Manager Mr. Takeyuki Satou Key points of the presentation: In Japan, there is a big concern about pediatric medications, where from 70% to 80% of all are off label treatment and those have not been properly applied in the clinical environment for pediatric patients. The main reason for this issue in Japan is the lack of information concerning the proper use of the pediatric pharmaceuticals. Under these circumstances, in order to improve safety and efficacy of pharmaceutical application in children, it is critical to establish an environment whereas to urge their proper use according to the EBM (Evidence-Based Medicine) and to support pediatric patients to take safe medications and physicians to prescribe pharmaceuticals appropriately for children. In EU and in the US, this environment for pediatric medications is far better than in Japan. In US, the Best Pharmaceuticals for Children Act was enacted in 2002, mandating to gather clinical data based on prescriptions for pediatric pharmaceuticals, especially those lacking information about accurate method of use. Under this law, the Food and Drug Administration (FDA) makes an annual priority list for pediatric pharmaceuticals with coordination by the National Institute of Health (NIH), and requests pharmaceutical companies to conduct clinical trials for the drugs in the list. If companies deny conducting clinical studies, NIH has the right to directly contract hospitals or institutions to conduct public clinical studies. Supported by the results obtained from the public clinical studies, FDA directly requests companies which are approved application holders to amend the drug labels in order to be valid in term of efficacy and safety for children. In EU, new regulations of pediatric pharmaceuticals were adopted in September 2004. Based on the regulations, the following decisions have been made; 1) to provide 6 months extension for market exclusivity period, if new drugs are approved for pediatric contingents; 2) to admit law enforcement right to promote clinical research development for pediatric Pharmaceuticals; 3) to establish centralized database to gather evidence of pharmaceuticals for clinical use in children; 4) to obtain funds from within and outside of EU to encourage clinical studies for pediatric pharmaceuticals. Owning to the decrease in children population in Japan, private sectors, who seek economic profit, are generally reluctant to promote pediatric medicines and therefore it is much more necessary for the Japanese Government to establish a good environment for children medical care. Under these circumstances, the Ministry of Health, Labor and Welfare (MHLW) in Japan started a project of “Promotion of Pediatric Pharmaceutical Treatment Based on EBM�Ein 2005 and the project is now continuing. Under this project, the MHLW has set a goal to complete within five years guidelines for adequate methods of use of one hundred different pharmaceutical products. The first steps of this project are: 1) to establish an expert panel for evaluation of pediatric pharmaceutical methods of use and to establish a priority list for pediatric pharmaceuticals; 2) to collect safety and efficacy data from actual clinical application and prescription for children; 3) to gather evidences about efficacy and safety from academic papers and to prepare and publish reports. The next steps should be: 1) to send the collected data to the National Center for Child Health and Development (NCCHD) for evaluation and analyzing the methods of use and dosages for children; 2) the expert panel to evaluate and analyze scientifically the results obtained from NCCHD and to summarize is findings in reports which will be sent to the private companies requesting them to apply and obtain approvals for the pediatric drugs. Diagram: Project “Promotion of Pediatric Pharmaceutical Treatment Based on EBM�E Source: MHLW (adapted) Diagram: Project “Promotion of Pediatric Pharmaceutical Treatment Based on EBM�E Types of pharmaceuticals included in the priority list The criteria for pharmaceuticals eligible for inclusion in the priority list are: 1) Approved drugs with active ingredients but having no adequate formulations for children. This type are currently used mostly off-label in modes such as breaking capsules, grinding tablets, oral administration of intravenous formulation, etc. 2) Approved drugs with active ingredients and appropriate formulations but having no adequate method of use for children or populations of specific age; 3) Approved drugs with active ingredients and appropriate formulations but lacking adequate of use information for children; 4) Pharmaceuticals without any safety information for children or with insufficient or excessive safety information approved for pediatric population. Priority standards for pharmaceuticals to be listed Priority for pharmaceuticals is to be determined by: 1. Level of evidence �EPharmaceuticals with sufficient efficacy data, recognized method of use and dosage, and already approved in any of the following countries - US, UK, Germany and France. �EPharmaceuticals completed several III phase trials abroad and demonstrating proven efficacy and safety. �EPharmaceuticals already known as common treatment standard abroad and prescribed widely. 2. Level of importance or urgency �EIf the types of diseases, which given drugs are intended to treat are very severe, irreversible or very affective to Quality of Life (QOL) of patients. 3. Clinical importance of the drugs �EPharmaceuticals with proven efficacy and safety in clinical studies abroad intended for treatment of diseases with no existing treatment or preventive methods �EPharmaceuticals with clinical importance for the pediatric population Other pediatric projects now undertaken by the MHWL A. Committee for Evaluation of Unapproved Drugs In Japan, physicians often can not apply useful pharmaceuticals approved abroad for the reason they are not yet approved in Japan. And generally, it will take a long period for them to be approved. Currently these drugs are not covered by health insurance and patients must pay full price for them, representing a big financial burden. In order for those unapproved drugs to be covered by health insurance and to facilitate the safe clinical studies in Japan, a new system needed to be established urgently. Under the circumstances, the MHLW established a Committee for Evaluation of Unapproved Drugs. This panel consists of 13 members and its meetings were held every month from January to April in 2005, as later it was decided to be held quarterly from July 2005 onward (providing that additional meetings could be organized anytime when a new need emerges). The aim of this panel is to update the current needs from academic societies or from patients and to clarify the situation with new drugs approved in US, UK, Germany or France. Based on the data and from scientific point, the Committee evaluates the clinical validity and necessity for any unapproved drugs to be approved also in Japan. After the completion of evaluation by the panel, if is determined that a drug further requires clinical studies in Japan, the MHWL request pharmaceutical companies to undertake clinical development. Also there might be cases when the MHWL requesting physicians in hospitals or medical facilities to initiate clinical studies. The requested clinical studies are classified into three categories: 1) studies necessary for approval; 2) supplemental studies; and 3) safety confirmation studies. In the cases of drugs with pediatric application, the aims for the studies are in giving chances to the pediatric patients to use new and unapproved drugs in Japan, while providing a safer environment. Targeted pharmaceuticals for the Committee to evaluate are in the following categories: 1) pharmaceuticals approved in one of four countries (US, UK, Germany and France) after April 2005; 2) Drugs requested by Japanese academic societies, patients�Egroups or others in past five years and have been approved in one of above four countries before March 2005; 3) Drugs not requested by academic associations or patients, but considered to be important due to their efficacy, and which have been approved in one of above four countries for past two years. In order for the pharmaceuticals to be included in clinical studies in Japan, above mentioned standards shall be applied to the established priority list. Up to the fifth Committee meeting, which have been held in 2005, unapproved pharmaceuticals in Japan such as oxaliplatin, pemetrexed、 thalidomide (at the 1st meeting), bortezomib, laronidase, diazoxide (4th meeting), bevacizumab、cetuximab, erlotinib, temozolomid, streptozotocin (5th meeting) have been evaluated based on requests from academic associations and patient groups, who hope these drugs to be approved soon and covered by health insurance. B. MHWL-funded studies From the year 2002, the MHWL have provided research funds to researches in pediatric fields, aiming to undertake large scale clinical studies and to collect clinical evidences. In 2005, the MHWL funded researches, evaluating and establishing safety, efficacy, dosages and method of use for pharmaceuticals which have not been adequately used in Japan. Most specific element is the coordination within the project for promotion of pediatric pharmaceutical treatment based on EBM, as if the data gathered through the project were determined to be insufficient, the MHWL may urge the academic societies to engage in additional clinical studies and to find additional information about efficacy, safety, pharmacokinetics, dosage and method of use. The data gathered shall be sent to the National Center for Child Health and Development for further analyses and evaluation. Related reports New Drug Evaluation Division Regular Meetings �EIndividual reports on the New Drug Evaluation Division Regular Meetings �E18th, 19th and 20th (held in 2004), and 21st (previous in 2005): Available in the JKS Document Store �EReport on the “Drugs and Medical Devices Safety Update Seminar�Eheld in Tokyo on September 16, 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. 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 © 2001-2005 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com 1 The previous name of the ELD is actually used for the title of the most numerous meetings organized by the Japanese pharmaceutical regulatory authorities: New Drug Evaluation Division Information Meetings �Ethe present 22nd of the series. 2 Equivalent to the term “off-label�E 3A fee paid to designated “Technologically Advanced Hospitals�E which have over 200 beds and provide cutting-edge medical care. 4The Committee for the Examination of the Use of Unapproved Medicinal Products 5Guideline for Clinical Evaluation of Anticancer Drugs (PAB/NDD Notification No. 9 dated February 4, 1991) 6 For complete description, refer to the Report on the 21st New Drug Evaluation Division Regular Meeting available at the JKS Document Store (click or copy the web address below): (http://www.jouhoukoukai.com/Merchant2/merchant.mvc?Screen=PROD&Product_Code=JM_I_017&Category_Code=JMI1) 7 For details of the so called “mixed insurance�Erefer to the information in footnote 6. 8 Also called “Study Committee on Ideal Way for Clinical Trials�E(Working Group for Practice of Clinical Trials) �Esee also next presentation 9 The equivalent of re-evaluation in Japanese refers to whole therapeutic groups or classes under scrutiny 10 The practice to state the generic manufacturer’s name with the name of the product existed before but more like a style of the individual makers, however from January 1, 2006 become mandatory. 11 Or product profile ?? ?? ?? ?? 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 3 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 14 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 17 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 18 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 22 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 23 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 27 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 28 - 22nd New Drug Evaluation Division Regular Meeting October 2005 JM_I_025 - 36 -