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Evaluation and Regulation of Medicines & Health Products

Evaluation and Regulation of Medicines & Health Products. Implementation of the CTD in Europe & EMEA Experiences. FFUL Lisbon Hilde Boone 29 May 2003 EMEA . 1. Why CTD. Industry initiative/request  discussed at ICH level

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Evaluation and Regulation of Medicines & Health Products

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  1. Evaluation and Regulation of Medicines & Health Products Implementation of the CTD in Europe&EMEA Experiences FFUL Lisbon Hilde Boone 29 May 2003 EMEA 1

  2. Why CTD Industry initiative/request  discussed at ICH level To provide for a common format/template for the submission of information to the regulatory authorities in the 3 ICH regions “Common Technical Document” signed-off by ICH in November 2000 2

  3. Why CTD Advantages / Objectives: Resource saving for industry Facilitate simultaneous submission in 3 regions Facilitate exchange of regulatory information Harmonised format to be further supported by e-CTD More efficient assessment; use of hyperlinks etc… Faster availability of new medicines 3

  4. Why CTD However, CTD is only a FORMAT ! It’s not a “single” dossier, with a “single” content since Legal requirements differ in the 3 regions ICH guidelines have not yet harmonised all requirements Pharmacopoeias are not harmonised Applicant may have regional preferences 4

  5. Modular structure of CTD Part IIPart III Part IV Quality Non-clinical Clinical    Module 3 Module 4Module 5 Module 2: written + tabular formats ( replaces expert reports) Module 1: administrative, regional info(not as such part of the ICH CTD) 5

  6. Modular structure of CTD Module 2: Quality Overall Summary Non-clinical Overview Clinical Overview Non-clinical Summaries (tables) Clinical Summaries (tables) To provide a summary of the development plan and of the Q, S and E data To integrate the most important information To facilitate the task of the assessor 6

  7. Modular structure of CTD Module 2 should provide (a.o.): Integrated & critical analysis of the key-parameters of the product Summary and analysis of the main tox/clin data Justifications for deviations from requirements and guidelines Non-clinical and clinical strategy used by company Comment on GLP, GCP status of data submitted Benefit/risk conclusions Clear tabulated summaries of the tests/trials 7

  8. Modular structure of CTD Module 3-4-5: Body of data / Study Reports + references Module 3  2 main parts: 3.2.S Drug Substance 3.2.P Drug Product Module 4-5: similar structure to current format 8

  9. Module 1: Not Part of the CTD Content to be determined by EU, US, JP authorities Module 1 Regional Information 1.0 CTD Table of Contents 2.1 CTD Introduction 2.2 Module 2 Nonclinical Overview 2.4 Clinical Overview 2.5 Quality Overall Summary 2.3 Module 2-5 CTD Nonclinical Summaries 2.6 Clinical Summary 2.7 Module 3 Quality 3.0 Module 5 Clinical Study Reports 5.0 Module 4 Nonclinical Study Reports 4.0 9

  10. Implementation of CTD Each region (US, EU, Japan) to introduce CTD into legislation or guidance As of July 2003 :Mandatory use of CTD for EU, Japan (MHLW) Highly recommended for US (FDA) In EU: CTD reflected in Notice To Applicants (NTA) and in Legislation 10

  11. Why CTD implemented in NTA ? ‘old’ Annex I to Directive 2001/83/EC: « …. Application …. shall be presented in 4 parts…taking account of guidance published by EC in Notice To Applicants ….. » European Commission Publication (9 volumes):“Rules governing medicinal products in the EU”http://pharmacos.eudra.org/F2/eudralex/index.htm Volume 1 = Community legislation Volume 2= Notice To Applicants…… 11

  12. 2C 2A What is NTA ? Volume 2 = NTA * Volume 2A: Info on Procedures for MA(guidance, interpretation) *Volume 2B: Presentation and content of a MA dossier (format template) * Volume 2C: Regulatory guidelines First published in 1986 - Regularly updated http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm 2B 12

  13. NTA - Volume 2BPresentation & Content 2B 2C 2A “CTD” 5 Modules Current EU format for submission of applications4 parts Replace by newformat based on CTD - 5 Modules«4 parts may be presented as 5 modules» Volume 2B 2C 2A “NTA” Revised NTA incorporating CTD: published 29 June 2001 13

  14. Module 1: Not Part of the CTD Content to be determined by EU, US, JP authorities Module 1 Regional Information 1.0 CTD Table of Contents 2.1 CTD Introduction 2.2 Module 2 Nonclinical Overview 2.4 Clinical Overview 2.5 Quality Overall Summary 2.3 Module 2-5 CTD Nonclinical Summaries 2.6 Clinical Summary 2.7 Module 3 Quality 3.0 Module 5 Clinical Study Reports 5.0 Module 4 Nonclinical Study Reports 4.0 14

  15. NTA CTD implementation Topics to be addressed in EU Give EU specific guidance in the Introduction Defining scope & application types AgreeonTime frame for implementation Defining Region-Specific items Content of Module 1 Prepare FAQs document Prepare amendment of Directive 2001/83/EC to legally reflect CTD structure by July 2003 15

  16. NTA CTD implementation Time-Frames NTA (CTD) Volume 2 published June 2001 July 2001 – July 2003 :TRANSITIONAL PERIODDossier can be presented using the * 1998 NTA Vol. 2 B edition, or* 2001 NTA Vol. 2 B editionMixtures of both formats between modules could be accepted, but not within parts/modulese.g. Q module 3 + S & E Parts III + IV 16

  17. Mixed format applications See EC WebSite 17

  18. NTA CTD implementation Time-Frames As of July 2003 :Mandatory for EU, Japan (MHLW) Hihgly recommended for US (FDA) Commission to amend Relevant EU legislation to fully reflect CTD (Annex I to Dir. 2001/83/EC) New Annex I to be published SOON ! 18

  19. NTA CTD implementation Scope Applicable to all types of EU procedures:- Centralised procedure- Decentralised (MR) procedure- National procedures Applicable to all types of products:- NCEs- Biologicals, biotech- Herbal medicinal products specific guidance will be provided- OTC products 19

  20. NTA CTD implementation Scope Applicable to all types of applications:- Full, new applications- Bibliographical applications- Abridged, Generic applications- Line-extensions & Variations 20

  21. Regional (EU) specific Information – Module 1 Requirements for content of EU application: * Directive 2001/83/EC – Art. 8-12* Directive 2001/83/EC– Annex I Administrative and Scientific information * required by EU legislation provide in * but not reflected in CTD Module 1 21

  22. Module 1 of Volume 2B (NTA) 1.1Overall Table of Contents(complete application; modules 1-5) 1.2 Application Form = current IA-form 1.3 SPC, Labelling & Package Leaflet 1.4 Experts 1.5 Specific Requirements Annex Environmental Risk Assessment 22

  23. Module 1.2Application Form Complete revisionby NTA group, to reflect Principles agreed in Chapter 1 (Vol. 2A) * Legal basis * Annex II / Line-extension Latest MS/EMEA requirements NEW developments: Orphan Drugs, TSE, Scientific Advice, GMOs To be used in current & new dossier format 23

  24. Module 1.3SPC/Labelling/PL * Based on EMEA/QRD Templates* National templates may apply(for MR or national procedures) In line with SPC and Readability guideline Standard headings and sentences Available in 13 languages (EMEA Web) * Mock-ups or Specimen of sales presentation 24

  25. Module 1.4Experts Art. 12 of Directive 2001/83/EC * experts must provide detailed reportson the Q, S & E data * duties of experts Annex I to Directive 2001/83/ECSIGNED expert reports « critical » evaluation 25

  26. Module 1.4Experts Expert Reports Module 2 Overviews & Summaries Signatures Module 1.4 Info on experts Module 1.4(education, experience) 26

  27. Module 1.5Specific Requirements 1.5 Specific requirements for different types of applications1.Information for bibliographical applications summary document on justification for “well-established use” claim 2.Information for generics applications summary document on evidence for “essential similarity” claim 27

  28. Well-established use(bibliographical applications) • Intended for “Old” products; no Essential Similarity • Explain grounds for using publications •  Literature to be included in Module 4 and/or 5 •  Discussion in Module 2 (overviews and summaries; incl. WEU claims) •  Summary of WEU demonstration in Module 1.5 • addressing each indent of of Part 3I/4I of Annex I to Dir. 2001/83/EC 28

  29. Essential Similarity(generic applications) • Module 1.5: to contain summary document on: • Active substance (« same ») • Overall S/E profile • Bio-availability , Bio-equivalence • Demonstrate « Essential Similarity » as defined by the NTA (chapter 1) • Case-by-case validation decision by authorities 29

  30. Module 1Annex ANNEX: Environmental Risk Assessment (Separate binder) Incl. Risk Assessment Overview * Non GMO containing medicinal products* Medicinal product containing/consisting of GMOs There is no ANNEX II ! (orphan drugs) 30

  31. Questions & Answers General CTD questions & Module 3-5 : IFPMAhttp://www.ich.org ctd-related.question@ifpma.org EU-specific Regulatory / Administrative questions Questions on Module 1 : EC http://pharmacos.eudra.org/F2/eudralex/vol-2/B/ctdqa_032003.pdf Aim to maintain harmonised approach Shared, common interpretation Refinement of guidance ? 31

  32. EU Questions & Answers Q1: Guidance on Mixed format applications Q2: Need to reformat ‘old’ dossiers? Q3: Reformatting = variation? Fee? Q4: Format of Variation applications? Q5: Mixed formats allowed after July 2003? Q6: Format of Line Extensions? Q7: Format of Generic applications? Q8: Module 2 for Generic applications? Q9: Format of Herbal Medicinal Product applicat.? 32

  33. EU Questions & Answers Q10: Format of Mutual Recognition Applications? Q11: Reformatting of MRP dossiers ? Q12: Location of Certificate of Suitability? Q13: Format of bibliographical applications? Q14: Format of EDMFs in CTD applications? Q15: Use of ‘old format’ EDMFs in CTD applications? Q16: Format of variations to EDMFs? 33

  34. EU Questions & Answers Q2: Need to reformat ‘old’ dossiers?NOClinical, non-clinical = not usefulQuality = recommended, encouraged -> complete Quality part (incl.DMF if applicable) - > signed declaration from the MAH - > no need for Quality Summary 34

  35. EU Questions & Answers Q4: Format of Variation Application?NO requirement to reformat ‘old’ dossier - New Variation data = mandatory in CTD- Cross-reference to ‘old’ data allowed- Copies of approved docs to be provided:  take first variation opportunity to reformat the doc / section concerned. 35

  36. EU Questions & Answers Q6: Format of Line Extensions?NO requirement to reformat ‘old’ dossier - New data = mandatory in CTD- Always Module 1 + 2- Cross-reference to ‘old’ data allowed - Follow guidance on ‘mixed’ applications- MAHs are encouraged to reformat ‘old’ quality data (may not always be feasible) 36

  37. EU Questions & Answers Q10: Format of Mutual Recognition Applications? If MRP starts after 1 July 2003 CMS will accept the submission of dossiers in the ‘old EU’ -format until 31 December 2004 MAH to submit reformatted dossier to RMS first. -> no update of the RMS AR necessary-> simple acknowledgement 37

  38. Other EU initiatives Training for EU EU and CADREAC Assessors (~200): June – July 2001  Quality, Safety, Efficacy workshops Update of CPMP Assessment Report Templates(available on EMEA Website since March 2002) Included list of CPMP/ICH guidelines as an Annex to Modules 3-5 38

  39. Other EU initiatives EC: Revision of Legislation Update of Annex I to Dir 2001/83/EC to reflect CTD format & terminology  implement by July 03Will be published soon  check EC’s Website ! Update of Directive 2001/83/EC as part of the Review proposals: ‘expert reports’   ’detailed summaries’ 39

  40. CTD Applications receivedJuly 01 – May 03 EMEA (Centralised Procedure): 16 new applications in full CTD format 6 new applications in mixed CTD+’old’ format Of those, 5 concerned ‘Part A’ products 21 concerned ‘Part B’ products 9 line extensions (Q only; Q + C) 40

  41. EMEA ExperienceGeneral issues Experience so far is positive Most questions & issues handled during Pre-Submission contacts with Applicants or during validation of the application. So far, no feedback from assessors on any difficulties encountered during assessment. Issues encountered now clarified via Q&A on Web 41

  42. EMEA ExperienceGeneral issues No deviations from headings & numbering  leave CTD headings & numbering unchanged  OK to introduce further sub-headings under existing CTD headings x other deviations refused NO additions NO deletions NO re-numbering 42

  43. EMEA ExperienceGeneral issues Sections “not applicable” or cross-referring to “old” data  to be maintained in dossier structure + commented in Overviews No new Appendices or Annexes:All information to be included in the relevant sections of Modules 3-5 and not at the end of the Module as new appendices not foreseen in CTD (e.g. stability protocols, validation data). 43

  44. Advice to Applicants Follow CTD guidance; do not invent or adapt Consult Q&A on ICH and Commission’s Website In case of doubt: consult relevant Authority or send questions to ICH / EC mailbox EMEA provides assistance to applicants in the pre-submission stage 44

  45. Conclusion - Overall Benefit • Common format for applications, to be used in the 3 Regions • Requires commitment & (re-)organisation • Resource saving for industry  Single dossier and • Possible simultaneous submissions in the 3 regions • Implementation of electronic CTD (e-CTD) • More consistent assessment • Accelerate availability of new medicines ? 45

  46. Useful Websites ICH – CTD Guidelines + Q&A + e-CTD: http://www.ich.org/ich5c.html EU – NTA incorporating the CTD + Q&A: http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm#2b FDA - Guidance on CTD http://www.fda.gov/cder/guidance/4539O.htm#top 46

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