Enterprise-wide Use License - 20th New Drug Evaluation Division Regular Meeting Date: October 22, 2004 Time: 10:30 - 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 Medical Association (JMA) (Incorporated Association) PROGRAM 10:20-10:30 Opening Address from the Organizer Mr. M. Uchiyama (SJP) 10:30-11:00 Current Trends in the Approval Examination MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara 11:00-11:45 CTD and eCTD Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masakatsu Imoto Lunch Break 13:00-13:45 Directions for Pediatric Pharmacotherapy National Center for Child Health and Development Chief of Clinical Trial Management Office Dr. Hidefumi Nakamura Break 13:45-14:00 New Drug Application Risk Communication Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masayuki Ikeda Disclaimer Key illustrations Figure 1. Current system of manufacturing and sales, licensing and approval Figure 2. Overview of the Master File system Figure 3. Flowchart of the Evaluation system after April 2005 Figure 4. Outline of the CTD structure Table 1. Changes in the format for submission Opening Address from the Organizer: Mr. M. Uchiyama (SJP) (Gist) The progress in the research and development of medicinal products in our country is remarkable; however a number of difficulties have appeared recently. In this foundation (The Society of Japanese Pharmacopoeia) we selected some recent topics affecting the development of medicinal products, and with guidance and support we organized this information meeting and hope even small this would be helpful for all of you in the audience. We also would like to thank to our sponsors and to all participants. Note: The first of the series of information meetings was carried out on January 29, 1999 in Tokyo with the purpose to provide direct clarification for a number of current topics (organizational changes, acceptance of ICH Guidelines, GCP and the conduct of clinical trials). The title "New Drug Evaluation Division Meeting" reflects the name of the current Evaluation and Licensing Division (ELD) back in 1999. Since then totally 38 meetings have been held as follow: Title No. New Drug Evaluation Division Information Meetings 20 Periodic ICH Information Meetings 10 Problems with Safety of Drugs 7 Problems with QA of Drugs 4 14th Japanese Pharmacopoeia 1 Total as of October 2004 42 Current Trends in the Approval Examination MHLW, PFSB, Evaluation and Licensing Division Division Head Mr. Akira Kawahara Key points of the presentation: 1. Implementation of the revised Pharmaceutical Affairs Law According to the revised Pharmaceutical Affairs Law, in 2003, a revision in the regulations of biological products and clinical tests were implemented, and in 2004, PMDA was established. In 2005, revisions on the followings are planed: ? Manufacturing and sales, licensing and approval ? Foreign manufacturers ? Master file system ? Classification of drugs ? Labeling ? Others 1) Manufacturing and sales, licensing and approval In the present approval/licensing system, significance is placed on the manufacturing part of the drug and it is on the premises that all pharmaceutical companies own the manufacturing facility. However, in accordance to business diversification and globalization of the industry, it is necessary to allow flexibility in the system, maintain international conformation and secure further safety. See Figure 1 (next page) Figure 1. Current system of manufacturing and sales, licensing and approval Japan US EU Approval System Manufacturing approval Sales approval Sales approval 2) Outline of Master File system Figure 2. Overview of the Master File system 2. Evaluation system in PMDA 1) Evaluation Flow (2005~) Figure 3. Flowchart of the Evaluation system after April 2005 2) Establishing a system that provides stable total evaluation time 3) Priority evaluation Consider the seriousness of the disease and medical benefit 4) Priority consultation on clinical trial 5) Work flow of approval evaluation results etc. 6) Collaboration of approval evaluation and post- marketing safety measures 7) Developing and fostering Promoting development of new drug, enhanced prompt approval, and enforcing the post-marketing safety 8) Promotion of re-evaluation Efficacy re-evaluation, quality re-evaluation 9) Evaluate clinical value of the drug on the basis of latest medical standard 10) New scheme for expanded access program of anti-cancer multiple drug treatment Establish anti-cancer multiple drug treatment committee Speed up approval procedure 11) Promoting medical malpractice prevention Add supply type and amount on trade name Trade name of prescription drugs 12) Prompt action against prevention of malpractice 13) Prevent delay of evaluation process 14) Others under consideration Part of OTC drugs to be shifted to quasi drugs Labeling of generics ICH Lectures for manufacturing control Clinical trial promotion committee OTC sales improvement Risk triage study group CTD and eCTD Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masakatsu Imoto Key points of the presentation: New Drug Approval Application Documents Dossier > Name (generic name, trade name) > Ingredients, composition > Manufacturing procedure > Dosage > Effect and efficacy > Storage and validity > Standard and method of trial > Others Data a. Data on origin, details of discovery, use in foreign countries, etc. b. Data on physical and chemical properties, specifications, testing methods, etc. c. Data on stability d. Data on acute toxicity, subacute toxicity, chronic toxicity, teratogenicity and other toxicity e. Data on pharmacological action f. Data on absorption, distribution, metabolism and excretion g. Data on results of clinical trials Outline of data Common Technical Document (CTD) * Japan, US, and EU Common document for drug application * Agreed at ICH (International Conference on Harmonization) * Developed by 3 specialists committee, Quality, Safety and Efficacy * When applying for approval in Japan, US, and EU, the common documentation style will save time and will enhance speed in providing drug to patients and market * However, the approval/licensing system is different between countries, therefore, it will comply with the order of the document, the contents will accord to ICH guideline, and the details will be decided by each local authority * Drugs that CTD is to be applied Drugs with new active ingredients New combination prescription drugs Drugs with new routes of administration Drugs with new indication Drugs with new dosage forms Drugs with new doses (Additional dosage forms, generics are acceptable in the previous form) * CTD Guidelines do not indicate what kinds of trials are required but shows the appropriate format to apply to submit the obtained data See also Figure 4 (next page) Figure 4. Outline of the CTD structure From CTD to eCTD CTD: Common Technical Document eCTD: Electronic Common Technical Document Table 1. Changes in the format for submission Period Original copy Duplicate June 1, 2004~ Paper Paper (eCTD) April 1, 2005 ~ Paper or eCTD Under consideration ? Signature and Statement of the documents To guarantee that the eCTD is correctly duplicated from the paper materials or electronic materials, for example, correctly scanned, correctly transferred to PDF ? Electronic documentation is expected for attached data within one year from now ? The Japanese authority request to submit a list of symptoms (basically in PDF) and a list of attached data (in both PDF and Excel) ? The applicant is responsible to confirm the accessibility of submitted application data at the PMDA computer. If not, the time clock will be returned to the applicant ? PMDA plan to organize a reception number for each case ? The submitted data should be renewed, replaced or deleted according to the evaluation process and results. (Life cycle management) ? Cover letter A cover letter should be attached as PDF and paper Directions for Pediatric Pharmacotherapy National Center for Child Health and Development Chief of Clinical Trial Management Office Dr. Hidefumi Nakamura Key points of the presentation: Present status and issue of off-label use for pediatric pharmacotherapy Among drugs commonly administered for pediatric use, almost 70% of package inserts lack sufficient information on dose and dosage, efficacy and safety. These include those drugs that indicate, "safety not established in certain age range" (40% of total) and "contraindicated" or "conform to contraindication" (2~3% of total). Dosage form is another issue for pediatric usage. Solid dosage form drugs and oral administration drugs (p.o.) that are prepared by hospitals for pediatric use (taking off capsules, grinding pills, transferring i.v. to p.o.) should be standardized officially. Additionally, for those drugs that are not yet approved in Japan, there are cases that drugs obtained personally from overseas doctors or compounds for clinical trials are administered. Present status of pediatric clinical trial "Guidance on Pharmaceuticals for Pediatric Use" ICH E-11: Pharma No.1334) has been implemented since April 2001. This guidance advises, "When the drug is presumed to be pediatrically administered, the pediatric use should be merged in the new drug development plan." This guidance, however, has no enforcement to pharmaceutical companies and there is little incentive for companies to develop such drugs (profit do not increase by pediatric use drugs), therefore, there is little impression that pediatric use drug has increased by the guidance. Promotion of pediatric clinical trial in Europe and US In the US such laws as Pediatric Research Equity Act of 2003 and Best Pharmaceuticals for Children Act are established, FDA has the right to request necessary pediatric clinical trial, and drug patent will be legally extended if pediatric clinical trial is conducted. These measures result in rapid increase of pediatric clinical trials. Such law is also being prepared in the EU and is considered to put into practice shortly. Under such movements, it is necessary for Japan to take prompt action to enact such policies. Update on administrational policies By the "Handling of prescription drugs and off-label use" February 1, 1999, drugs from overseas can be approved with only partial or totally no clinical trials conducted in Japan, when the medical society request, the medical necessity is clear, and the efficacy and safety of the drug is publicly apparent. Under present regulation, however, it is reportedly said to have given negative impressions to the companies on the development of pediatric drugs for such reasons as delay in insurance administration for difficulties in settling the NHI drug price, and cooperation to pediatric R&D is economically unprofitable. "Revision on post-marketing sales survey and re- evaluation" December 27, 2000, promote special survey on pediatric use and post-marketing clinical tests for pediatric dose regimen. When implementing clinical tests for pediatric dose during re-evaluation period, extension of re-evaluation period (not over 10 years) is granted. The notice has been applied, however, for only 2 items as of February 2004. The incentive for pharmaceutical companies is extremely limited. Policies of Medical Societies Japan Pediatric Society (JPS) Pharmaceutical Committee, other sub-committees of JPS, and Japan Developmental Pharmacology and Therapeutics are actively working on the off-label use issues. Drugs considered necessary to promptly enact the approval were listed with collaboration of the various activities. In addition, "Action plan for pediatric off-label use and clinical trial promotion" was assigned at the JPS Pharmaceutical Committee meeting in July 2004, which clarified the policy and indicated concrete measures to undertake. 1. Pediatric off-label use and clinical trial promotion are one of the most important missions of the JPS and it will continue its active and positive efforts to tackle the issue. 2. Enhance synthetic categorization of the entire off- label use drugs and pursue concrete measures to solve each off-label use issues. 3. Outline the problems on reagents, chemically synthesized or reformed drugs and named patient program. 4. Implement active measures on improving the systems on pediatric clinical trials. 5. Take movements to legalize incentives of pharmaceutical companies, or right to request pediatric clinical trial. 6. Frame a system to collect data on pediatric treatment through post-marketing survey / drug use survey. 7. Improve safety information on pharmacotherapy during pregnancy and lactation. Full-scale measures to be implemented in 2005 According to the newspapers, MHWL will appropriate pediatric drug problems fee in the fiscal 2005 budget, and kick-off a study group to tackle the above-mentioned problems including such regulations seen in the US and others. In order to gain success in the project, cooperation of various organizations, society and companies are required. For the fair pediatric pharmacotherapy In order to cover all the off-label use issues, it is necessary that the pharmaceutical companies, government, and society cooperate to satisfactorily study measures on each issue, and create a new regulation on all category of drugs, from those that need new clinical trials to those that is considered enough if existing evidence or post- marketing survey and safety information is reflected in the package insert. On the reagent and named patient program, measures to promote development and solve problems are essential. Fundamental solution of off-label use is unachievable without environmental improvement in pediatric drug development of pharmaceutical companies. In order to gain this target, effective and strong incentives for the companies such as free PMDA consultation, extension of patent, or advantage in NHI drug price are necessary and as well as to exchange frank opinions with companies on the matter. National Center for Child Health and Development desire to settle measures on pediatric clinical trial within few years in collaboration with companies and authorities since solving the problems of off-label use and promotion of clinical trial are crucial for the fair pediatric pharmacotherapy. New Drug Application Risk Communication Pharmaceuticals and Medical Devices Agency New Drugs Division III, Chief Specialist Mr. Masayuki Ikeda Key points of the presentation: Application dossier Application dossier is a vital tool to maintain communication between the applicant and evaluation team and clarify various matters on risk and benefit of the drug. In order to keep away from trouble, companies are likely to avoid referring on negative factors, however, bad news travel fast and therefore it is important to consider the way to break the bad news and take prompt necessary actions in a calm manner. Adverse event or adverse drug reaction (ADR) Those 'possible' 'probable' 'definite' adverse events in causal relationship criteria are considered as ADR in US, whereas in Japan 'unlikely' adverse events are also included. Application data should be compiled on the basis of all adverse event data with medical judgment and should try to avoid being suspected of any scheme to conceal negative data. PMDA hold a weekly meeting with clinical specialists and provide such suggestions as, to submit comprehensible CIOMS report, provide adequate translation for overseas report, select correct MedDRA words, write down ADR name when symptoms are listed, write down the consideration of the company and react promptly to questions. Risk and benefit It is important to balance the risk and benefit of the drug, which every drug is different. Companies should make effort to minimize the risk, provide enough information to doctors so that patients receive satisfactory explanation, and continue to gather information on risk/benefit. Common Technical Document (CTD) All adverse events should be analyzed and reported in the CTD Module 2. Parameters should be indicated in 3 steps, central tendency, example, and the group mean and median values. Caution should be paid to confusing symptoms. Summary Application dossier is the history book of the drug, the communication basis and the key to release risk information. Media Establish good media and public relations and promote understanding by the nation. Future tasks Compile ADR data (publicize clinical trial data: ICJME, structure pharmacovigilance system and harmonization on safety. Improve mass-media relationship and enact risk communication. New Drug Evaluation Division Regular Meetings 2004 In 2004 the following meetings were held: * 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 * * Cumulative edition of the 18th, 19th and 20th New Drug Evaluation Division Regular Meetings 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. Whilst the utmost care has been taken in the preparation of Jouhou Koukai Services and Jouhou Koukai Publishing (JKS) publications and documents and JKS Store database, they are provided "as is" without warranty of any kind, either expressed or implied, including, but not limited to, the implied warranties of merchantability, accuracy, fitness for a particular purpose, or non-infringement. Any reliance on the information provided herein is solely at the user's discretion and risk and neither JKS nor any third party source would be liable for the contents of the JKS publications and documents and JKS Store database. In certain circumstances, works which have been sourced from a third party and incorporated into the JKS publications and documents and JKS Store database and any interpretations and commentaries relating thereto, may not be considered to be official versions of such works. JKS are committed to use utmost efforts to include accurate, actualized and reliably translated information, but JKS make no warranties or representations as to its accuracy. The Japanese Government does not provide authorized (officially sanctioned) translations of its documents. In case of legal dispute, the original texts in Japanese will prevail. Neither JKS, nor any party involved in creating, producing or delivering JKS publications and documents shall be liable for any direct, incidental, consequential, indirect or punitive damages arising out of access to, use of or inability to use publications and documents, or any errors or omissions in the content thereof. 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) 2001-2004 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com 20th New Drug Evaluation Division Information Meeting October 2004 JM_I_009 - 3 - 20th New Drug Evaluation Division Information Meeting October 2004 JM_I_009 - 30 -