Nonclinical Guideline

Transcription

1 Development ansd Evaluation of Medicinal Products Master Degree, Nonclinical Guideline Tuesday 23 October 2012 Claude Bernard University, Lyon France Laennec, Room 106 Rolf Bass, FFPM (Hon) Apl. Prof. Pharmacol. and Toxicol., Charité, Univ. Hospital Berlin Visiting Prof. Pharmaceutical Medicine, Univ. Basel

2 NONCLINICAL GUIDELINE (S) R. Baß

3 Drug Regulation in the EU Directive Addressed to whom? EU-Member States Effect? to be transposed into national law Regulation Decision Guidelines all persons of the EU single person(s) (MAH, EU-MS,.. ) interested persons (MAH,...) directly binding - breaks national law directly binding - case by case - breaks national law provision of guidance ( soft-law ) MAH: Marketing Authorisation Holder R. Baß

4 Pharmaceutical Legislation The testing Council Directive 75/318/EEC ( as amended) (now: moved to Dir 2001/83/EC: Annex) Introduction of Standards and protocols for the performance of tests and trials: protection of public health and facilitation of Free movement of goods within the EU Adoption of Uniform rules applicable to tests and trials and their assessment will provide same chances for all companies R. Baß

5 Pharmaceutical Legislation Nota bene: The relevant EU Legislation is now set out in Directive 2001/83/EC as amended by Commission Directive 2003/63/EC, thus incorporating the updated ANNEX I (previously Annex I to Directive 75/318/EC) on the Testing of medicinal products (as set forth in Art. 8( )(i) of this Directive): Q, S, E Standards and Protocols in respect of the testing of medicinal products for humans R. Baß

6 Pharmaceutical Legislation Nota bene: Commission Dir 2003/63/EC sets the requirements (among others) for the CTD, GLP, and the Non-clinical Details according to the agreed CTD Standards and Formats: Summaries (ex-expert Reports): Non-clinical Overview Summaries of studies/data: Tabulated Study Reports Reports: slot your study here the test on xyz must show, the xyz test means R. Baß

7 Regulatory Procedures All current Regulatory Procedures evolved from national procedures and rely on involvement of National Competent Authorities and their (internal and/or external) Experts Regulatory handling, scientific assessment and regulatory decisions may be performed or handled by the same or different (legal) entities (Authorities) All Procedures remain under the responsibility of the sponsor / company, and under the control of the Competent Authority R. Baß

8 Regulatory Procedures Competent Authorities are: EMA (reg/scientific) plus Eur. Com. (reg decisions) Competent Authorities of the Member States (scientific/reg) Each Member State has one or more such Authority Decisions may need to be taken by the relevant Ministry of that Member State e.g. BfArM and PEI for human medicines in Germany They are competent to assess and decide R. Baß

9 Regulatory Procedures EMA National Competent Authorities EU - Network of European Experts For the authorisation of medicinal products For pharmacovigilance European Risk Management Strategy For GXP and other quality related inspections and surveillance R. Baß

10 Federal Institute for Drugs and Medical Devices (BfArM) Kurt-Georg-Kiesinger-Allee 3 D Bonn Tel.: +49 (0) Competent Authorities in Germany Paul-Ehrlich-Strasse D Langen Tel: +49-(0) Paul-Ehrlich-Institut (PEI) R. Baß

11 Regulatory Procedures Centralised Procedure Mutual Recognition Procedure, and Decentralised Procedure National procedure One Pan- European MA MA in more than one EU- Member State MA in just one EU- Member State Marketing Authorisation (MA) in the EU R. Baß

12 Regulatory Procedures Applicant submits Dossier Day 1 Questions Responses Day 120 Clock stop Answers Day 121 Clock start Day 210 Commission triggers Decision Making Process for EU-MA EU / National Approval in 210 days National approval by Member States Marketing Authorisation Time Table R. Baß

13 Regulatory Procedures: Scope Centralised Procedure: Mandatory biotechnological medicinal products, orphan medicinal products new active substances for which the therapeutic indication is the treatment of: diabetes cancer acquired immune deficiency syndrome (HIV) neurodegenerative disorder (Alzheimer, ) auto-immune diseases and other immune dysfunctions viral diseases other extensions to be approved by the Council upon proposal from the EC R. Baß

14 Regulatory Procedures: Scope Centralised Procedure: Optional (any) new active substance innovative medicinal products Products in the interest of patients at Community level Pandemic Generic medicinal products of nationally authorised reference medicinal products OTC medicinal products generic medicinal products of reference medicinal products authorised by the CP Any other product / substance Decentralised, Mutual Recognition, National, Herbal R. Baß

15 Scheme of Centralised Procedure Mandatory Scope? Optional Scope? Scientific Assessment by Rapporteur and Co-Rapporteur - Discussion with CHMP Pre Submission Phase 1 Clock Phase 2 Stop Clock Stop Hearing Opinion Decision making phase Decision Post Authorisation Scientific Advice Pre-Submission queries and meetings Submission of the application Appointment of Rappoprteurs Validation of the Dossier CHMP Peer Review Accelerated assessment procedure? Conditional marketing authorisation? Compassionate use? Cooperation with WHO? PIP? GXP I n s p ec t i o s to be p e r f o r m e d? Overview (and Conclusions on Benefit/Risk Issues to be addressed) Quality Non-Clinical Clinical Marketing Authorisation valid throughout the EU/EEA : DAY Fulfillment of Obligations and PhV RMS R. Baß

16 Regulatory Procedures: Scope MRP/DCP: National Marketing Authorisation new active substances (unless mandatory for the centralised procedure) generic medicinal products to national (and centrally?) authorised Reference Medicinal Products (not applicable for biotechnological medicinal products) Informed consent Well established use (WEU) (bibliographic applications) Line extensions to national authorisations Known substances in new combination Homeopathics Traditional herbal medicinal products R. Baß

17 Regulatory Procedures Mutual Recognition Procedure (MRP) and Decentralised Procedure (DCP) are methods of work sharing between the MS They constitute mandatory Procedures to obtain national MAs in MS s of the EEA for the same medicinal product: If and and Same qualitative and quantitative active ingredient There may be the differences in excipients provided that there is no impact on safety and efficacy Same pharmaceutical form, but Link between companies all license holders all legal entities (Commission Communication July 1998) R. Baß

18 Regulatory Procedures: Applicability 1. Mutual Recognition Procedure (MRP) where the medicinal product has already received in a MS a MA at the time of application and/or 2. Decentralised Procedure (DCP) where the medicinal product has not received in a MS a MA at the time of application R. Baß

19 MA RMS Regulatory Procedures 1. MRP 2. DCP RMS AR, SPC, PL, label 90 days Dossier CMSs Applicant Dossier Proposal for changes (CMSs) Dossier RMS CMSs Draft AR, SPC, PL, label 120 days Discussion between all MS 90 days Final AR + Final SPC, PL, label Final AR, SPC, PL, label MA RMS MA CMS MA CMS MA MA MA MA MA CMS CMS CMS RMS CMS R. Baß

20 Regulatory Procedures: Guidelines European Union basic legislation in the pharmaceutical sector: Rules Governing Medicinal Products in the EU : EUDRALEX Volume 1 Volume 2 Community legislation The Notice to Applicants NTA Volume 2A Procedures for Marketing Authorisation Volume 2B Presentation & content of the application dossier Volume 2C Regulatory Guidelines (see EMA-website) Volume 3 Volume 4 Guidelines Quality, Safety, Efficacy (see EMA-website) Guide to Good Manufacturing Practice for Medicinal Products Volume 5-8 Veterinary issues (mirror image of human medicines) Volume 9 Pharmacovigilance (9A-human; 9B-veterinary) - NOW REPLACED Volume 10 Good Clinical Practice R. Baß

21 EMA website: Human medicines Human guidelines Guidelines General guidance: Guideline Procedure, Regulatory Affairs Guidelines CHMP Guidelines: Position Papers, scientific Guidelines, e.g. Safety Q, S, E Guidelines are valid for all Procedures R. Baß

22 CHMP Working Parties To provide recommendations to the CHMP in the form of : Guidelines / Notes for Guidance Points to consider Position statements Public statements Guidelines on specific matters related to the quality, efficacy and safety, etc. of medicinal products To be adopted by the CHMP R. Baß

23 Guidelines CHMP Working Party: SWP Problem and /or topic arises: task attributed to SWP Problem Statement: provided to CHMP Position Paper: adopted by CHMP (published) Draft guideline: Rapporteur system: SWP Provisional adoption: CHMP (published for comments) Hearing with Interested Parties: SWP Revision of draft Guideline: SWP Adoption of Guideline: CHMP Publication: EMA: announcing implementation date, e.g.: CHMP/SWP/1042/99: Repeated dose toxicity ICH Guidelines may enter at any stage, e.g.: CHMP/ICH/174/95: Genotoxicity: Standard battery for testing R. Baß

24 Work plan for the Safety Working Party Product related issues Expected contribution in scientific advice Expected contribution in protocol assistance Expected contribution in product assessment Expected contribution in post-authorisation issues Requests from other working parties, and committees such as CHMP, CAT and HMPC on product related issues. R. Baß

25 CHMP guidelines and related documents Note for guidance on photosafety testing (CPMP/SWP/398/01) Action: The guideline will be developed as ICH topic S10 Comments: Concept Paper for the revision of the guideline adopted by the CHMP in 2Q Q&A adopted by CHMP in June 2010 Reflection paper on the impact of 3Rs on pharmaceutical testing Action: To be considered in 2011 Reflection/Position paper on available validated biomarkers Action: To be considered in 2011 Comments: Intended to be updated regularly to provide a comprehensive list of validated bimarkers R. Baß

26 CHMP guidelines and related documents The Safety Working Party shall contribute to multidisciplinary guidelines under development, at the request of the CHMP or other working parties, which are identified after adoption of this work plan. Guideline on the quality, preclinical and clinical aspects of medicinal products containing genetically modified cells (EMEA/GTWP/58311/2007) Revision of the note for guidance on quality, preclinical and clinical aspects of gene transfer medicinal products (CPMP/BWP/3088/99) Guideline on quality, non-clinical and clinical aspects of live recombinant viral vectored vaccines (EMEA/CHMP/VWP/141697/2009) Guideline on DNA vaccines Guideline on the application of the risk-based approach for advanced therapy medicinal products R. Baß

27 CHMP guidelines and related documents Reflection paper on the non-clinical and clinical aspects of cellbased products containing stem cells Reflection paper on quality, nonclinical and clinical aspects specific to autologous chondrocyte medicinal products Guideline on similar biological medicinal products containing monoclonal antibodies Guideline on similar biological product containing recombinant interferon beta Guideline on similar biological medicinal products containing recombinant follicle stimulation hormone Evaluation of pandemic lesson learnt R. Baß

28 CHMP SWP guidelines for revision Points to consider on the non-clinical assessment of the carcinogenic potential of insulin analogues (CPMP/372/01) Action: Possible revision in 2011 Comments: The guideline will be updated when ICH S6 is finalised Note for guidance on non-clinical tolerance testing of medicinal products (CPMP/SWP/2145/00) Environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00) R. Baß

29 CHMP SWP guidelines for revision Replacement of animal studies by in vitro models (CPMP/SWP/ 728/95) Guideline on excipients in the label and package leaflet of medicinal products for human use (CPMP/463/00) Note for guidance on pre-clinical pharmacological and toxicological testing of vaccines (CPMP/SWP/465/95) Guideline on the investigation of drug interactions (CPMP/EWP/ 560/95/Rev. 1) R. Baß

30 CHMP/ICH Guidelines and activities The Safety Working Party shall contribute to applicable ICH guidelines under development that are identified after adoption of this work plan. ICH S2 R1: Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use ICH S6: Preclinical safety evaluation of biotechnology-derived pharmaceuticals ICH M3R2: Guidance on the non-clinical safety studies for the conduct of human clinical trials and marketing authorisation for pharmaceuticals ICH S10: Guidance on photosafety testing R. Baß

31 CHMP/ICH Guidelines and activities ICH Q3D: Guidance on heavy metal impurities ICH M7: Guidance on genotoxic impurities ICH Topic M6: General principles to address viral shedding of gene therapy vector ICH E14: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs ICH SX: Non-clinical testing of vaccines ICH Brainstorm session on reproduction toxicity R. Baß

32 EU Regulatory Activities Requests from other scientific committees and working parties and the HMPC on guidelinerelated issues. Medical devices and ancillary medicinal products: data requirements for Notified body consultations Requests from the European Commission, EDQM and Member States on pharmacotoxicological issues Animal Welfare EU initiatives in the 3Rs (EPAA, ECVAM) Assessor s training (tbc) Workshop (tbc) R. Baß

33 Activities with external parties Drug regulatory authorities outside the EU - Liaison with FDA and other agencies. Meeting with interested parties e.g. learned societies, public health stake holders (public health professionals, patients organisations), pharmaceutical industry representatives upon request. - Meetings with the EFPIA Safety Ad Hoc Group. - ILSI HESI - Expansion of the collaboration on the following topics: hepatotoxicity, toxicogenomics, carcinogenicity studies, developmental toxicity (juvenile), cardiac safety, in vitro genotoxicity, environmental risk assessment and association of adjuvants and autoimmunity. Critical Path Initiative (US) Innovative Medicines Initiative (imi) (Europe) R. Baß

34 ICH? INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE R. Baß

35 History (1) 1960, 1970 >> Rapid increase in laws, regulation and guidelines for reporting and evaluation the data on quality, safety and efficacy of new medicinal products. R. Baß

36 History (2) The detailed technical requirements had diverged over time to such extent that industry found it necessary to duplicate many time-consuming and expensive test procedures, in order to be able to market new products internationally. R. Baß

37 History (3) Harmonisation of regulatory requirements was pioneered by the European Community in the 1980ies Europe demonstrated that harmonisation was feasible. R. Baß

38 History (4) Birthday April 1990, at a meeting hosted by EFPIA in Brussels Representatives of the regulatory agencies and industry associations of Europe, Japan and the USA met and agreed ICH Steering Committee was established R. Baß

39 Animal exposure (months) INTERNATIONAL GUIDELINES FOR THE DURATION OF ANIMAL TOXICITY STUDIES week to month Up to 3 months 3 months and longer Proposed human exposure EC Japan Canada USA From: R. Walker, DIA Symposium, Tokyo, October 1990 R. Baß

40 Early meetings Topics selected for harmonisation would be divided into Quality, Safety and Efficacy Six-party Expert Working Groups (EWGs) for each topic EWGs meet in the same week as the Steering Committee and report on their progress R. Baß

41 International Conference on Harmonisation INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH 1 - Brussels, November 1991 ICH 2 - Orlando, October 1993 ICH 3 - Yokohama, November 1995 ICH 4 - Brussels, July 1997 ICH 5 - San Diego, November 2000 ICH 6 - Osaka, November 2003 R. Baß

42 International Conference on Harmonisation Improving Regulatory Success of the nonclinical parts of the CTD CTD as facilitator or setting the stage and requirements? CTD setting straight your mind or compiling the Dossier? CTD compilation as a last-minute exercise or slotting in reports as they come (and continuously assessing the new situation )? R. Baß

43 Targets of harmonisation Remove the need to duplicate studies Avoid repetition of clinical studies Reduce animal usage Make research more economical Harmonise application of requirements Definitions Presentation of documentation Bring new medicines to the market sooner R. Baß

44 Proposals for harmonisation (1) New types of medicinal product Proposals for guidelines to cover new products resulting from advances in technology and techniques for producing medicines (e.g., products arising from gene therapy and other developments in biotechnological and genomic research); Lack of harmonisation in current technical requirements Proposals for further harmonsisation of existing requirements (e.g., as a result of work on the Common Technical Document); Transition to technically improved testing procedures Proposals for action to facilitate the replacement of currently established testing procedures to more efficient and economical methods where these provide equal or better assurance to the safety and/or quality of new drug products. R. Baß

45 Proposals for harmonisation (2) Review of an existing ICH Guideline Proposals for significant changes to the technical aspects of an ICH Guideline or proposals for a major addition to the guideline. Maintenance of an existing ICH Guideline Proposals for relatively minor modification, updating clarification or review of ICH agreements to take account of either problems with implementation, new information or new scientific knowledge. R. Baß

46 Organisation: Parties to ICH Trade Associations EFPIA European Federation of Pharmaceutical Industries and Associations JPMA Japanese Pharmaceutical Manufacturers Association PhRMA Pharmaceutical Research and Manufacturers Association (USA) Regulatory Authorities European Union: Commission and appropriate 'Parties' (CHMP, QWP, BQWP, EWP, SWP, PhVWP) Japan Ministry of Health and Welfare and appropriate expert support (MHLW, NIHS, Universities) USA Food and Drug Administration and appropriate expert support (regulatory communication, efficacy, safety, quality - review staff, expert leads - CDER/CBER chief officers) Oberservers Canada, EFTA, WHO Umbrella Organisation, ICH Secretariat IFPMA: International Federation of Pharmaceutical Manufacturers Associations R. Baß

47 STEP 1: DEVELOPMENT OF CONSENSUS 1 Technical Discussions in EWG EWP = Expert Working Group R. Baß

48 STEP 2: CONSENSUS TEXT RELEASED FOR CONSULTATION 2 Consensus Achieved 1 Technical Discussions in EWG R. Baß

49 STEP 3: CONSULTATION OUTSIDE ICH 3 Formal Consultation 2 Consensus Achieved 1 Technical Discussions in EWG R. Baß

50 STEP 4: ICH GUIDELINE FINALIZED 4 Finalized Text 3 Formal Consultation 2 Consensus Achieved 1 Technical Discussions in EWG R. Baß

51 THE FIVE ICH STEPS 5 Implementation 4 Finalized Text 3 Formal Consultation 2 Consensus Achieved 1 Technical Discussions in EWG R. Baß

52 Guidelines - Safety ICH No. Title CPMP Doc. No. Step S1A S1B S1C (R2) The Need for Carcinogenicity Studies of Pharmaceuticals Carcinogenicity: Testing for Carcinogenicity of Pharmaceuticals Carcinogenicity: Dose selection for carcinogenicity studies of pharmaceuticals CPMP/ICH/140/95 Step 5 CPMP/ICH/299/95 Step 5 EMEA/CHMP/ICH/ 383/95 Step 5 R. Baß

53 Guidelines - Safety (cont.) ICH No. S2A S2B S2 (R1) Title Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use CPMP Doc. No. Step CPMP/ICH/141/95 Step 5 CPMP/ICH/174/95 Step 5 CHMP/ICH/126642/ 08 Step 5 R. Baß

54 Guidelines - Safety (cont.) ICH No. Title CPMP Doc. No. Step S3A S3B Toxicokinetics: A Guidance for Assessing Systemic Exposure in Toxicology Studies Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies S4A Duration of Chronic Toxicity Testing in Animals (Rodent and non Rodent Toxicity Testing) S5 (R2) Reproductive Toxicology: Detection of Toxicity to Reproduction for Medicinal Products + Male Fertility S6 (R1) Preclinical Safety Evaluation of Biotechnology-Derived Products CPMP/ICH/384/95 Step 5 CPMP/ICH/385/95 Step 5 CPMP/ICH/300/95 Step 5 CPMP/ICH/386/95 Step 5 CPMP/ICH/302/95 Step 5 R. Baß

55 Guidelines - Safety (cont.) ICH No. Title CPMP Doc. No. Step S7A S7B Safety Pharmacology Studies for Human Pharmaceuticals Non-Clinical Studies for Assessing Risk of Repolarisation Associated Ventricular Tachyarrhythmia for Human Pharmaceuticals S8 Immunotoxicology Studies EMEA/CHMP/ S9 Nonclinical Development of Oncology Pharmaceuticals CPMP/ICH/539/00 Step 5 CPMP/ICH/423/02 Step /2004-ICH CHMP/ICH/646197/ 08 Step 5 Step 5 S 10 Photosafety Step 0 R. Baß

56 Guidelines - Multidisciplinary ICH No. Title M3 (M) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (Modification) M3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals CPMP Doc. No. Step CPMP/ICH/286/95 Step 5 Step 5 M7 Genotoxic Impurities Step 0 R. Baß

57 Other Guidelines - Safety CPMP/QWP/1719/00 rec on safety requirements added 2008 CHMP/SWP/28367/07 first in-human trials CPMP/SWP/91850/06 Environmental risk assessment CPMP/SWP/799/95 mixed applications CHMP/SWP/258498/05 Fixed combinations CPMP/SWP/1094/04 Evaluation of control samples CPMP/3097/02 Comparability biotech proteins CPMP/QWP/159/01 Use of ethylene oxide CPMP/465/95 Vaccines 3CC29A Chiral active substances CHMP/SWP/199726/04 Antisense oligodeoxynucleotide CPMP/818/97 Phenolphthalein ca. potential CPMP/SWP/2592/02 Rev 1 genetically modified animal models for ca. testing CPMP/SWP/372/01 Human insulin analogues ca. testing CHMP/203927/08 RA Repro/Lactation: from data to labelling CHMP/SWP/169215/05 Juvenile animals paed. indications CHMP/SWP/2600/01 Human insulin analogues repro. Testing CPMP/SWP/2145/00 Local tolerance CHMP/SWP/150115/06 Drug-nduced hepatotxicity CHMP/SWP/94227/04 Dependence potential CPMP/SWP/398/01 Photosafety testing CPMP/2278/00 Addicition/dependence/withdrawal SSRIs R. Baß

58 Advantages (1) Improved Regulatory Cooperation atmosphere of mutual confidence and trust Globalisation of EU standards GCP Periodic Safety Updates Reports Genotoxicity Impurities Scientific perspective ICH Guidelines are robust greater scientific value R. Baß

59 Advantages (2) Trade effects Increase of market penetration of EU companies in other regions Potential trade conflicts have been avoided because of enhanced co-operation Political perspectives Active participation of the EU Investment in the EU, such as pharmaceutical research and development Reduction of duplication and resources Reduced duplication of testing Reduced number of animals R. Baß

60 Animal Use for Toxicological Studies Advantages (3) Single dose toxicity (2 routes) Repeated-dose sub-chronic Repeated-dose chronic Reproduction 2 Rodent 1 Non-rodent From: C. E. Lumley and H. van Cauteren, st duration ( eg 1 month) Rodent Non-rodent 2nd duration ( eg 3 months) Rodent Non-rodent Recovery Rodent Non-rodent 1 st duration ( eg 6 or 9 months) Rodent Non-rodent 2nd duration ( eg 12 months) Rodent Non-rodent Segment I rat eg Japanese style eg US/EU style Segment II rat eg Japanese style eg US/EU style Segment II rabbit Segment III rat Before ICH After ICH Carcinogenicity 1st species ( eg rat) nd species ( eg mouse) Medium or short-term study TOTAL * *Excludes offspring and dose-range finding studies R. Baß

61 Disadvantages(1) Non-ICH Countries Legitimacy of ICH ICH representing countries: 15% of the world population, and 90% of the pharmaceutical worldwide sale Legitimacy of WHO To establish global standards has been embodied in WHO s constitution adopted in 1946 R. Baß

62 Disadvantages (2) Resources ~ 20 European regulatory experts to be out of their offices (for two periods of one week every year) > 20 European regulatory experts involved in background preparatory and consulting work (for many periods, every year) R. Baß

63 Disadvantages (3) Relative US dominance FDA tends to play a dominant role Language advantage Approach taken by Japanese Some topics with little EU interest Implementation problems Delay in the other regions, in some cases for legal reasons additional explanations, e.g. repeated dose testing in non-rodents in US R. Baß

64 Future (1) Global co-operation Co-operation between regulators Topics which can be legally implemented Continuation of maintenance process New technologies Implementation and monitoring of the CTD R. Baß

65 Future (2) New technologies / Topics Pharmacovigilance Gene therapy Cell therapy Pharmacogenomics Need of additional experts? Need of brainstorming meetings? Need of other documents, like 'points to consider'? R. Baß

66 Internet ICH guidelines IFPMA EMEA EU FDA MHLW EFPIA JPMA PhRMA R. Baß

67 Place and Value of the CTD Arriving at relevant statements Administrative Non-scientific Highest level of abstraction: SmPC, PIL, Labelling Readability, interpretation Problems within and beyond Non-clinical Non-clinical narrative, summaries, tables and interpretation Reports created and presented according to Guidelines and GLP Data as reported R. Baß

68 ICH Common Technical Document Module 1 Regional Administrative Information 1.0 Not part of CTD Module 2 Quality Overall Summary 2.3 CTD Table of Contents 2.1 CTD Introduction 2.2 Nonclinical Overview 2.4 Nonclinical Summary 2.6 Clinical Overview 2.5 Clinical Summary 2.7 CTD Module 3 Quality 3.0 Module 4 Nonclinical Study Reports 4.0 Module 5 Clinical Study Reports 5.0 R. Baß

69 THANK YOU R. Baß