-Evolving ectd Technology Transforming Global Regulatory Submission Strategy. PART TWO 30-Mar ectd MASTERCLASS 1

Transcription

1 ectd MASTERCLASS -Evolving ectd Technology Transforming Global Regulatory Submission Strategy PART TWO 30-Mar-2016 ectd MASTERCLASS 1

2 Session Chair Handsome Ji Senior Publishing Team Manager, Worldwide Regulatory Operations, Pfizer Handsome Ji started in the Pharmaceutical industry in 2006 as a Clinical Study Report Coordinator/Publisher at Pfizer. After 3 years working experience in Clinical Operations, Handsome moved to Regulatory Operations team as a Regulatory Submission Specialist. In 2012, Handsome was appointed as the team leader directing a team which is responsible for publishing both Clinical Study Reports and Regulatory Submissions, this team works on the Clinical Study Reports from Phase I to IV and regulatory submissions across all regions during all stage of a product lifecycle. Handsome has considerable project and operations experience, has developed and implemented strategies resulting in operational excellence and process efficiencies. He is highly driven and experienced, with 10+ years operational, project and change management experience within multi-cultured global environments. Handsome was invited as guest speaker in DIA China 7th Annual Meeting and served as host for CMWC (China Medical Writing Community) forum in Handsome holds bachelor degree in Computer Science from Fudan University. ectd MASTERCLASS 2

3 Agenda (Part II) Mar 30 th Xiaofu Luo, Sr. Clinical Publisher, Novo Nordisk (China) Pharmaceutical Co., Ltd Meg Wang, Publishing Manager, Pfizer Kane Song, Publishing Manager, Pfizer ectd MASTERCLASS 3

4 Speaker Bio Xiaofu Luo Sr. Clinical Publisher Novo Nordisk Xiaofu Luo holds a MBA degree from Graduate School of Chinese Academy of Social Science (CASS) and a bachelor degree from Peking University Health Science Center. He joined Novo Nordisk in 2011 supporting publishing activities of clinical study reports (CSR) and clinical trial transparency issue across China market. Clinical Publishing: five years experience on clinical publishing of regulatory documents including CSR, clinical overview etc. to secure conformity to ectd requirements. Clinical Trial Transparency: three years experience on clinical trial registry and disclosure within Region China. System Training: Super User and trainer of regulatory systems like FirstDoc, Liquent InSight etc. and tools like Acrobat, EndNote, Illustrator etc. ectd MASTERCLASS 4

5 ectd Specifications requirements to realize ectd Xiaofu LUO Sr. Clinical Publisher Novo Nordisk 30 th March, 2016 ectd MASTERCLASS ectd MASTERCLASS 5

6 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to IBC Asia, its directors, officers, employees, volunteers, members, chapters, councils, communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. All other trademarks are the property of their respective owners. ectd MASTERCLASS 6

7 1 Naming Convention Folder Architecture File Naming Standard 2 File Format Requirement Table of Contents Regional File Format PDF Standards Linking/Bookmark 3 Life Cycle Management Lifecycle Operation Attributes Sequence/Cumulative/Current View 4 Metadata Envelop/admin ICH v3.2.2 Metadata 5 Node Extension/STF ectd MASTERCLASS 7

8 Specification The ectd specification lists the criteria that will make an electronic submission technically valid. The specification provides the ability to transfer the registration application electronically from industry to authority. ectd MASTERCLASS 8

9 ICH Europe Union United States ICH ectd Specification EU Module 1 ectd Specification Version Version 2.0 Version 2.3 The ectd Backbone Files Specification for Module 1 July 2008 September 2013 February module1/index.htm ntapprovalprocess/formssubmission Requirements/ElectronicSubmissions/ ucm htm ectd MASTERCLASS 9

10 Specifications ICH FDA Name Version Date ectd Specifications STF Specification PDF Specifications Transmission Specifications File Format Specifications M1 Specifications Specifications for ectd Validation Criteria ectd CTOC Addendum to M1 Specifications Addendum 2 to M1 Specifications Refer to FDA ectd Submission Standards v7 ectd MASTERCLASS 10

11 1 Naming Convention Folder Architecture File Naming Standard 2 File Format Requirement Table of Contents Regional File Format PDF Standards Linking/Bookmark 3 Life Cycle Management Lifecycle Operation Attributes Sequence/Cumulative/Current View 4 Metadata Envelop/admin ICH v3.2.2 Metadata 5 Node Extension/STF ectd MASTERCLASS 11

12 ectd Folders and Names Documents in modules should be formatted as defined by the ICH Common Technical Document (CTD) Folder and file names given in ICH specification are recommended Folder Structure: EU Module 1 National/Regional data Module 2 5 form the ICH CTD Module 2 Summary Documents Module 3 Quality Module 4 Non-Clinical Data Module 5 Clinical Data Folder Naming Convention: letters a to z, digits 0 to 9 and - Lower case only no Space Maximum length of a single folder is 64 characters ectd MASTERCLASS 12

13 Folder Hierarchy (Module 1) US EU JP Module 1 contains administrative information that is unique for each region. ectd MASTERCLASS 13

14 Folder Hierarchy (Module 2) General rules for module 2 5 Full folder hierarchy is provided by ICH, recommended to use Empty directories can be omitted Folder Name can be reduced or omitted to minimize path length Section in CTD Description Folder Name 2.2 Introduction 22-intro 2.3 Quality overall summary 23-qos Module Nonclinical Overview 24-nonclin-over 2.5 Clinical Overview 25-clin-over 2.6 Nonclinical Written and Tabulated Summaries 26-nonclin-sum 2.7 Clinical summary 27-clin-sum ICH Module 2 ectd MASTERCLASS 14

15 Folder Hierarchy (Module 3 5) ICH Module 3 ICH Module 4 ICH Module 5 Recommended names by ICH, can be changed according to regional guidance ectd MASTERCLASS 15

16 File Naming Convention (cc-)fixed-var.ext (Country code) Defined component of filename based on CTD Additional optional variable component File extension ICH requirements Letters a to z, digits 0 to 9 and - Lower case only No Space Maximum length of file is 64 characters Maximum length of path is 230 characters EU: No more than 180 characters 0000/m1/eu/12-form/CC/CC-form-VAR.EXT ectd MASTERCLASS 16

17 1 Naming Convention Folder Architecture File Naming Standard 2 File Format Requirement Table of Contents Regional File Format PDF Standards Linking/Bookmark 3 Life Cycle Management Lifecycle Operation Attributes Sequence/Cumulative/Current View 4 Metadata Envelop/admin ICH v3.2.2 Metadata 5 Node Extension/STF ectd MASTERCLASS 17

18 Regional File Format Module 1 Module 2-5 EU In addition to PDF (as defined by ICH ectd), XML and image formats are also accepted on an ad hoc basis. No additional file formats are defined for M2-5 other than those mentioned in ICH ectd. US General Rule: Documents should be provided in PDF searchable format. Image (e.g., BPM, JPG, GIF, PNG) should be rendered into PDF format and retain searchable text whenever possible. Text Layer Image Layer ectd MASTERCLASS 18

19 Backup slide: Accepted file formats for Module 1 (EU) Document Format Remark Cover Letter PDF PDF preferably generated from electronic source. Administrative forms: Application form and its annexes Variation application form incl. background for the variation Renewal form and its annexes PDF PDF PDF For business related information on submission requirement refer to ex.htm and Product Information: Product information text Packaging mock-ups Reference to specimens Other PDF PDF PDF PDF preferably generated from electronic source. If a higher resolution is necessary for the mock-ups, use JPEG, GIF, PNG or SVG on a case-by-case basis PDF preferably generated from electronic source. * Regulatory authorities and applicants could agree on the use of other formats for Module 1 content provided outside of the ectd in the working-document folder ectd MASTERCLASS 19

20 Backup slide: Accepted file formats (US) Format Module 1 Module 2-5 ectd Module/Section DOC, DOCX x m1-14 sub-sections XML x x m1\us\[labeling\spl], m4, m5 (CDISC metadata) GIF, JPG, JPEG, PNG x x m1-14 and m1-15 sub-sections, m1-15 sub-sections, m2-m5 AU, MP2, MP3, MP4, WAV, WMA x m1-15 sub-sections AVI, FLV, MPEG, SWF, WMV x m1-15 sub-sections BPM x m1-15 sub-sections HTM, HTML x m1-15 sub-sections Flash and Shockwave (.f4v,.fla,.flv,.swf) x m1-15 sub-sections CSS x m4, m5 (CDISC metadata) DAT x m4, m5 (data) SVG x M2-m5 TXT x m3 - m5 (data) XPT x m3 - m5 (data) XSD x m4, m5 (CDISC metadata) XSL x m4, m5 (CDISC metadata) * Source: Specifications for File Format Types Using ectd Specifications v1.0 delivered on 2013-Apr-11 ectd MASTERCLASS 20

21 EU centralized procedure, working document ectd MASTERCLASS 21

22 PDF Requirements Version PDF versions 1.4 is acceptable to all ICH Regional Health Authorities Security No security settings or password protection Fonts Font Size/Color Page Size and Margins A4 and Letter, sufficient margins (at least 2.5 cm) Page Numbering No larger than 100MB and for Fast Web View Navigation Table of contents (TOC), hypertext links and bookmarks ectd MASTERCLASS 22

23 PDF Properties ectd MASTERCLASS 23

24 Hyperlink Intra-Document Links Linking to a location in the same document Related sections, references, appendices, tables and figures in the same document Inter-Document Links Inter-document links, linking to a location (sections, references, appendices, tables/figures) in another document Intra-Document Inter-Document Target Inter-Document 1 Target 1 Intra-Document Inter-Document 2 Target 2 ectd MASTERCLASS 24

25 Intra-Document Links Inter-Document Links ectd MASTERCLASS 25

26 Bookmarks Bookmarks should follow hierarchical level and order of table of contents. The use of no more than 4 levels in the hierarchy is recommended. ectd MASTERCLASS 26

27 1 Naming Convention Folder Architecture File Naming Standard 2 File Format Requirement Table of Contents Regional File Format PDF Standards Linking/Bookmark 3 Life Cycle Management Lifecycle Operation Attributes Sequence/Cumulative/Current View 4 Metadata Envelop/admin ICH v3.2.2 Metadata 5 Node Extension/STF ectd MASTERCLASS 27

28 ectd Life Cycle Attributes Subsequent submissions with incremental updates Every Document has a life cycle operation attribute It is these lifecycle operation attribute which allows the reviewer to see which documents are relevant to the review at any given time. Operation attribute Value New Append Replace Delete Meaning The file has no relationship with files submitted previously. This means there is an existing file in a previous submission to which this file should be associated. Replace This means there is an existing file in a previous submission that this new file replaces. There is no new file submitted in this case. Instead, the leaf has the operation of delete and the modified file attribute identifies the file in a previous submission that is to be considered no longer relevant to the review ectd MASTERCLASS 28

29 Sequence view (Individual Dossiers) Initial MAA M1 M2 M3 M4 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 29

30 Sequence view (Individual Dossiers) Initial MAA Variation M1 M1 M2 M2 M3 M3 M4 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 30

31 Sequence view (Individual Dossiers) Initial MAA Variation Variation Variation M1 M1 M1 M1 M2 M2 M2 M3 M3 M3 M4 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 31

32 Cumulative view (All Dossiers) Initial MAA Cumulative View M1 M1 M2 M2 M3 M3 M4 M4 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 32

33 Cumulative view (All Dossiers) Initial MAA Variation Cumulative View M1 M1 M1 M2 M2 M2 M3 M3 M3 M4 M4 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 33

34 Cumulative view (All Dossiers) Initial MAA Variation Variation Cumulative View M1 M1 M1 M1 M2 M2 M2 M2 M3 M3 M3 M4 M4 M5 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 34

35 Cumulative view (All Dossiers) Initial MAA Variation Variation Variation Cumulative View M1 M1 M1 M1 M1 M2 M2 M2 M2 M3 M3 M3 M3 M4 M4 M5 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 35

36 Current View (Most Recent Documents) Initial MAA Current View M1 M1 M2 M2 M3 M3 M4 M4 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 36

37 Current View (Most Recent Documents) Initial MAA Variation Current View M1 Replaces M1 M1 M2 Replaces M2 M2 M3 Replaces M3 M3 M4 M4 M5 M5 MAA=Marketing Authorisation Application ectd MASTERCLASS 37

38 Current View (Most Recent Documents) Initial MAA Variation Variation Current View M1 Replaces M1 Replaces M1 M1 M2 M2 M2 M2 Replaces Replaces M3 M3 M3 Replaces M4 M4 M5 M5 M5 Appends MAA=Marketing Authorisation Application ectd MASTERCLASS 38

39 Current View (Most Recent Documents) Initial MAA Variation Variation Variation Current View M1 Replaces M1 M1 M1 Replaces New Data M1 M2 M2 M2 M2 Replaces Replaces M3 M3 M3 M3 Replaces Replaces M4 M4 M5 M5 M5 Appends MAA=Marketing Authorisation Application ectd MASTERCLASS 39

40 ectd Life Cycle Management To establish relationships between documents and submissions To reduce redundancy To track product history ectd MASTERCLASS 40

41 1 Naming Convention Folder Architecture File Naming Standard 2 File Format Requirement Table of Contents Regional File Format PDF Standards Linking/Bookmark 3 Life Cycle Management Lifecycle Operation Attributes Sequence/Cumulative/Current View 4 Metadata Envelop/admin ICH v3.2.2 Metadata 5 Node Extension/STF ectd MASTERCLASS 41

42 ectd Metadata Information used to define the contents of submission sections. E.g. indication, substance, manufacturer Module 1: Envelope/admin, information in the XML that describes the submission Module 2 to 5: Substance, Manufacturer Product, Dosage Form, Dosage Strength, Manufacturer, Excipient 3.2.A Appendix Metadata Indication and Novel Excipient (Optional) ectd MASTERCLASS 42

43 Envelop (eu-regional.xml) envelop For all types of submission Submission Type Tracking Number Applicant Agency Procedure Invented Name INN (International Nonproprietary Name) Sequence Related Sequence Submission description m1-regional Based on ICH ectd DTD It provides an XML catalogue including pointers to the location of files in a directory structure ectd MASTERCLASS 43

44 admin (us-regional.xml) admin Applicant-info ID Company-name Submission-description Applicant-contacts Application-set Application-information Submission-information m1-regional ectd MASTERCLASS 44

45 ICH Metadata (index.xml) CMC (M 2.3 QOS and M 3.2.S/ 3.2.P) Drug Substance: (Substance/Manufacturer) Drug Product: (Product/Dosage Form/Dosage Strength/Manufacturer) Clinical (M 2.7 and M 5.3.5) Indication ectd MASTERCLASS 45

46 1 Naming Convention Folder Architecture File Naming Standard 2 File Format Requirement Table of Contents Regional File Format PDF Standards Linking/Bookmark 3 Life Cycle Management Lifecycle Operation Attributes Sequence/Cumulative/Current View 4 Metadata Envelop/admin ICH v3.2.2 Metadata 5 Node Extension/STF ectd MASTERCLASS 46

47 Study Tagging Files An STF should be provided with the submission of any file, or group of files belonging to a study in Modules 4 and 5. Uses file tags to describe the content of individual files Provides for additional heading elements and heading attributes not currently provided by the ectd DTD. Required by US, not required in EU, not allowed in Japan ectd MASTERCLASS 47

48 Node Extension Node extensions are a way of providing extra organisational information to the ectd. It should be visualised as an extra heading in the CTD structure and should be displayed as such when the XML backbone is viewed. used in EU, Canada, Australia as an alternative to STF Without node extension With node extension lowest level of the ectd structure ectd MASTERCLASS 48

49 Summary Specification information for ectd v3.2.2 Folder/Naming Convention File Format/PDF Life Cycle Management Metadata Node extension/stf ectd specification lists the technical criteria to realize electronic submission Different in all regions/countries Under development ICH ectd v4.0 EU v3.0 ectd MASTERCLASS 49

50 ectd MASTERCLASS 50

51 Speaker Bio Meg Wang Publishing Manager, Submission publishing team, Publishing and Product License Support, Pfizer Meg Wang holds both master and bachelor degrees in China Pharmaceutical University, majored in Society and Management Pharmacy. Have an extensive interest in regulatory affair. She has been in Pfizer as Publishing Manager since Working on various countries and regional ectd submissions: for example, U.S.,Australia, Canada, Swiss and EU CP/MRP/DCP ectd. Have a deep insight on both regional and ICH specifications; Very rich experience gained from publishing work about ectd validation criteria. Extensive knowledge and enriched skills in other publishing format: NeEs for EU, Australia, New Zealand and GCC (Gulf Cooperation Council) countries; Dummy ectd for South Korea; Also electronic and paper submissions for AfME(Africa and the Middle East),Asia, EU and Swiss; Prior to Pfizer, One-year working as a drug registration specialist for preparing new drugs along with generic drugs submissions submitted to CFDA in China. ectd MASTERCLASS 51

52 ectd Technical Deep Diving Meg Wang, Publisher Manager 30 th March, 2016 ectd MASTERCLASS ectd MASTERCLASS 52

53 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to IBC Asia, its directors, officers, employees, volunteers, members, chapters, councils, communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. All other trademarks are the property of their respective owners. ectd MASTERCLASS 53

54 Agenda ectd technology for ectd v3.2.2 XML DTD/Schema XSL MD5 Checksums ICH ectd v4.0: Brief Introduction Background RPS/eCTD v4.0 Basic Concepts/Terminology Benefits ectd MASTERCLASS 54

55 ectd submission:folder view ectd XML File Checksum file for index.xml 2 XMLs xx Regional XML File 2 DTDs/Schema 2 Stylesheet 3 places for MD5 checksums xx DTD for Module 1 ICH DTD for Modules 2 to 5 ICH style sheet for Modules 2 to 5 Style sheet for xx regional backbone ectd MASTERCLASS 55

56 ectd technology for ectd v3.2.2 XML DTD/Schema Stylesheet MD5 Checksum Backbone/table of contents Regional/ICH Outline module structure Regional/ICH Display one seq. in a browser Optional Integrity Stored in XMLs ectd MASTERCLASS 56

57 XML instance: take EU for example Backbone structure, sever as comprehensive table of content Hyperlinks to regional.xml and files ectd MASTERCLASS 57

58 Regional XML instance: take EU for example Envelope information Module 1 Table of Content ectd MASTERCLASS 58

59 XML Basics Syntax XML stands for extensible Markup Language Tag<> Open tag <> Close tag </> Tags <> :used to define a data element. Each element must have an opening Tag and a closing Tag Data is placed between the Opening and Closing Tag; <> and </> Attribute value Elements can also have attributes applied to them: The attribute value must be between quote marks. Tags must be nested correctly ectd MASTERCLASS 59

60 DTD/Schema: DTD Example DTD stands for Document Type Definition ICH dtd: define the structure and the legal elements and attributes of the XML for module 2-5; Regional dtd: define the structure and the legal elements and attributes of the XML for module 1 XSD stands for XML Schema Definition Schema is newer solution than DTD Regional schema: define the structure and the legal elements and attributes of the XML for module 1 No ICH schema, only regional schema: e.g: regional Schema for JP/AU/TH ectd; With a DTD/Schema: Independent groups of people can agree on a standard DTD for interchanging data; An application can use a DTD/Schema to verify that XML data is valid ectd MASTERCLASS Pfizer Confidential 60 60

61 DTD basics Syntax The first line is always declaration Comments <!-- --> are ignored in the DTD <!-- This is a comment --> Declaring Entities: used to define shortcuts to special characters 1) % att: entity-name 2) " ID ID #IMPLIED xml:lang CDATA #IMPLIED : entity-value Declaring Elements: 1) Element name: ectd:ectd 2) Children elements: m1-..;m2-..;m3- ; 3)?: Declaring Zero or One Occurrences of an Element Declaring Attributes: 1)element name: ectd:ectd 2)attribute name: xmlns:ectd;xmls:xlink. 3)attribute type: CDATA 4)value: FIXED or Implied ectd MASTERCLASS 61

62 Stylesheet XSL stands for extensible Stylesheet Language, a style sheet language for XML documents Stylesheet enables XML information to be displayed in a user friendly manner in a browser Enable displaying one ectd sequence, but cannot display neither cumulative sequences, nor the document lifecycle (new, replace, delete or append) Stylesheets are optional, not mandatory by HA. However, we always include them in the ectd to make viewing of an individual sequence easier ectd MASTERCLASS 62

63 MD5 Checksums: examples used to ensure a document has not been damaged during transit between the sender and recipient A checksum: calculated by the sender and provided alongside the document being sent No two files should produce the same checksum) The recipient can then calculate the checksum for the document and ensure that it matches the checksum provided by the sender ectd MASTERCLASS 63

64 MD5 Checksums: location Xx-regional.xml: checksums of documents in module 1; indexl.xml: checksums of documents in module 2-5; checksums of xx-regional.xml Index-md5.txt: checksum of index.xml Where are checksums of dtd and stylesheet? ectd MASTERCLASS 64

65 Agenda ectd technology for ectd v3.2.2 XML DTD/Schema XSL MD5 Checksums ICH ectd v4.0: Brief Introduction Background RPS/eCTD v4.0 Basic Concepts/Terminology Benefits ectd MASTERCLASS 65

66 Background Experience gained in using ectd v3.2.2 and ICH M8 Identified improved functionality to assist both agencies and applicants One way Communication Documents can not be re-used from different application. Metadata edit is inflexible ICH Steering Committee endorsed working with HL7 using RPS to develop Next Major Version(NMV) ectd --- ectd v4.0 ectd MASTERCLASS 66

67 Background Regulated Product Submissions (RPS) Developed by Health Level Seven International (HL7) Standards Development Organisation (SDO) Open forum with membership from health authorities, applicants and solution vendors/consultants ectd V4.0 RPS HL7 Goal: Create a single message exchange standard that can be used for the submission of any regulated product. Covers drugs, Vet Med, Medical Devices, Food supplements, etc ectd v4.0 is a subset of RPS ectd MASTERCLASS 67

68 RPS/eCTD v4.0 Basic Concepts/Terminology Application Submission (Regulatory Activity) Submission Unit (Sequence) Keyword Context of Use Source: Regulated Product Submission Standard Release 2 Implementation Guide, ectd MASTERCLASS 68

69 RPS/eCTD v4.0 Basic Concepts/Terminology Documents not physically placed into a specific Section Tables of Contents defined by each RPS implementation Controlled Vocabularies (CVs) define the TOC A Context of Use (CoU) is used to define where a Document is applicable by Document ID: what is the document COU code from CVs: where a document is applicable A priority number: display the order of the Context of Use if they are the same Any mandatory or optional CoU keywords: provide further definition e.g. substance-manufacturer Context of Use CoU Code: Study Reports Keyword: Indication = Migraine Document: ID123 Source: ICH_eCTDv4_0_Step2_Packagev2_0 ectd MASTERCLASS 69 ICH ectd v4.0,nov, 2015 Leigh Sandwell, Pfizer

70 Benefit: Flexible Structure and Document Re-use EU Grouping/Worksharing v4.0 v3.2.2 Structure is independent of application format There is no Table of Contents stored within Regulated Product Submission (RPS) standard Changes to the ICH and regional structure no longer required in DTD/schema Just a change to the Controlled Vocabulary Terms One ectd submission Many ectd submissions Enables Re-Use:Unique identifier approach means documents can be referenced/reused more effectively Across a Submission Unit (Sequence) Across an application Across different applications Source: ICH ectd v4.0,nov, 2015 Leigh Sandwell, Pfizer ICH_eCTDv4_0_Step2_Packagev2_0 ectd MASTERCLASS 70

71 Benefit: More Stable and Flexible Folder Structure Removes Append operation that caused lifecycle issues in the past; There are only new, replace, delete in ectd v4.0; Flattened, Flexible Folder Structure Benefits: Significantly reduces issues with long file paths. Flexibility of folder structure ectd v3.2.2 ectd v4.0 Source: ICH ectd v4.0,nov, 2015 Leigh Sandwell, Pfizer ICH_eCTDv4_0_Step2_Packagev2_0 ectd MASTERCLASS 71

72 Benefit: Potential for Two-Way Communication Receive questions and other communications back from the Health Authority as ectd v4.0 Ability to keep track of status of the application through metadata provided back by the Health Authority Implementation across regions may be limited Further discussion required in the EU Source: ICH ectd v4.0,nov, 2015 Leigh Sandwell, Pfizer ectd MASTERCLASS 72

73 Where is ectd v4.0 in the ICH process? ectd v4.0 current Status: ICH Formal Process - Five Steps Implementation package being finalised Schema Controlled Vocabularies/Codelists Implementation Guides ICH (Global) ectd v4.0 Implementation Guide Regional Implementation Guides Submission Format Guide Source: ICH ectd v4.0,nov, 2015 Leigh Sandwell, Pfizer ICH website ICH Step 4 for Adoption: Have signed off at ICH meeting in Jacksonville, US in December 2015 ectd MASTERCLASS 73

74 Closing Advancing Harmonisation for Better Global Health Achieving greater harmonisation in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration, thereby reducing or obviating duplication of testing carried out during the research and development of new human medicines. Registered in the most resource-efficient manner ectd MASTERCLASS 74

75 Q & A ectd MASTERCLASS 75

76 Speaker Bio Kane Song Publishing Manager, Publishing and Product License Support, World Regulatory Operation, Worldwide Safety and Regulatory, Pfizer Kane Song holds a Master degree of Material Science from State University of New York, Stony Brook. He joined Pfizer from 2013 supporting publishing activities of Global Submissions and US Investigational New Drug (IND) safety submission Working on a variety of Pfizer global submissions including: EU ectd/nees, Swiss ectd/paper, Africa and Middle East (AfME) NeeS/Paper, Emerging Market Europe, Russia, India & Turkey Paper/Electronic submission. Working on US pharmacovigilance submission: Monitor Serious Adverse Event (SAE) Safety Report System; Delivering IND safety report submission package. ectd MASTERCLASS 76

77 ectd Technical Issues Case Study Kai Song, Publishing Manager 30 th March,2016 ectd MASTERCLASS ectd MASTERCLASS 77

78 Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to IBC Asia, its directors, officers, employees, volunteers, members, chapters, councils, communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. All other trademarks are the property of their respective owners. ectd MASTERCLASS 78

79 Topic ectd Technical Rejections Case Study ectd Technical Issues Case Study ectd MASTERCLASS 79

80 ectd Submission Publishing Workflow Plan Receive documents and task comments Build File Naming Placement of documents Fit & Finish Pagination Bookmark &link Compile Integrate whole files to a package Validate Testing file with a variety of validation tools Dispatch Create Media Submit through gateway ectd MASTERCLASS 80

81 Agenda ectd Lifecycle Operation Case #1 ectd Node Extension Case #2 ectd PDF documents content Case #3 Document Type Definition (DTD) Update Case #4 ectd MASTERCLASS 81

82 Case #1 - Background ectd Lifecycle Operation Attributes New Replace Append Delete Every Document within an ectd submission has a lifecycle operation attribute. It is these lifecycle operation attribute which allows the reviewer to see which documents are relevant to the review at any given time. ectd MASTERCLASS 82

83 New Operation Initial MAA Seq Variation Seq Current View New The file has no relationship with M1 New M1 New Data M1 files submitted previously. M2 M2 M3 M3 M4 M4 M5 M5 ectd MASTERCLASS 83

84 Replace Operation Initial MAA Seq Variation Seq Current View Replace There is an existing file in a previous M1 M1 submission that this new file M2 M2 M2 replaces. Replaces M3 M3 M4 M4 M5 M5 ectd MASTERCLASS 84

85 Append Operation Initial MAA Seq Variation Seq Current View Append This means there is an existing file in a M1 M1 previous submission to which this file M2 M2 should be associated. M3 M4 Append M3 M3 M4 M5 M5 ectd MASTERCLASS 85

86 Quiz Is it a correct Delete operation? Initial MAA Seq M1 M2 M3 M4 M5 Variation Seq M4 Current View ectd MASTERCLASS 86 M1 M2 M3 M4 M5 Delete There is no new file submitted in this case. Instead, the leaf has the operation of delete and the modified file attribute identifies the file in a previous submission that is to be considered no longer relevant to the review

87 Correct Delete Operation Initial MAA Seq Variation Seq Current View M1 M1 M2 M2 M3 M3 M4 M5 Delete M4 M4 M5 ectd MASTERCLASS 87

88 Quiz what files are revealed in Current View? Initial MAA Seq Variation Seq Variation Seq Variation Seq Current View M1 M1 M1 M1 M1 Replaces Replaces New Data M2 M2 M2 M2 Replaces Replaces M3 M3 M3 M3 Replaces Replaces M4 Delete M4 M4 M5 M5 M5 Appends ectd MASTERCLASS 88

89 Case #1 Initial MAA Seq M1 M2 M3 What if file was mistakenly removed in previous submitted sequence, is it good to recover it and built it back to this old sequence? M4 M5 ectd MASTERCLASS 89

90 Case #1 - Leaf Property Initial MAA Seq M1 M2 M3 Leaf Title Xlink: Href: Leaf Property Characterization of XXXX m4/42-stud-rep/421-pharmacol/4211- prim-pd/xxxx.pdf Leaf ID Pfi Checksum 9adc3a76b1358ee675e3a116b868b5 M4 M5 Checksum: a small-size datum from a block of digital data for the purpose of detecting errors which may have been introduced during its transmission or storage. Delete document mistakenly and rebuild will cause the checksum change and inconsistent with previous submitted. ectd MASTERCLASS 90

91 Case #1 Solution & Lessons 0000 Lessons: Extract Replace Any action in a file will cause the checksum changed. Delete document VS lifecycle operation Delete. NEVER do any operation in the previous ectd sequences. Establish a well-organized archive mechanism, once previous files were compromised, backup sources should still be utilized. Communicate with submission management and technical support constantly. ectd MASTERCLASS 91

92 ectd Lifecycle Operation Case #1 ectd Node Extension Case #2 ectd PDF documents content Case #3 Document Type Definition (DTD) Case #4 ectd MASTERCLASS 92

93 Case #2 - Background Node Extension To created additional navigation in the XML backbone In Module 5, allow multiple files for a single study to be grouped together and separated distinctly from other studies. ectd MASTERCLASS 93

94 Case #2 Seq M1 M2 M3 M4 m5-3-5-reports-of-efficacy-andsafety-studies m study-reports-ofcontrolled-clinical A SAP A Signature Investigators B Preliminary Synopsis B Report Body M5 ectd MASTERCLASS 94

95 Case #2 Seq M1 M2 M3 M4 m5-3-5-reports-of-efficacy-and-safety-studies m study-reports-of-controlled-clinical Phase 3, Randomized, Open-Label Study of A A Synopsis A Report Body Phase 3, Randomized, Open-Label Study of B B Preliminary Synopsis B Report Body M5 ectd MASTERCLASS 95

96 Case #2 Sequece 0011 without node extension m5-3-5-reports-of-efficacy-and-safety-studies m study-reports-of-controlled-clinical A SAP A Signature Investigators B Preliminary Synopsis B Report Body Replaces Replaces Documents of Seq 0020 a sap a invest-signature Sequece 0016 with node extension m5-3-5-reports-of-efficacy-and-safety-studies m study-reports-of-controlled-clinical Phase 3, Randomized, Open-Label Study of A A Synopsis A Report Body Phase 3, Randomized, Open-Label Study of B B Synopsis B Report Body Replaces Replaces a synopsis a report-body ectd MASTERCLASS 96

97 Case #2 - Solution Sequece 0011 without node extension m5-3-5-reports-of-efficacy-and-safety-studies m study-reports-of-controlled-clinical A SAP A Signature Investigators B Preliminary Synopsis B Report Body Delete Delete Documents of Seq 0020 Delete Delete Sequece 0016 with node extension m5-3-5-reports-of-efficacy-and-safety-studies m study-reports-of-controlled-clinical Phase 3, Randomized, Open-Label Study of A A Synopsis A Report Body Phase 3, Randomized, Open-Label Study of B B Synopsis B Report Body Replaces Replaces a sap a invest-signature a synopsis a report-body ectd MASTERCLASS 97 New New

98 Agenda ectd Lifecycle Operation Case #1 ectd Node Extension Case #2 ectd PDF documents content Case #3 Document Type Definition (DTD) Case #4 ectd MASTERCLASS 98

99 Imaging you are a reviewer ectd MASTERCLASS 99

100 Case #3 ectd MASTERCLASS 100

101 Case #3 - Hypertext Link Issues Insufficient hyperlinks (none or not enough) Hypertext links go to incorrect destination or don t work (destination set to same page) References aren t descriptive enough for a Reviewer to find the information if the link doesn t work or doesn t exist The Table of Contents (TOC) isn t linked For inter-document links, it s preferred that the link opens the other document in a new window Reviewers appreciate links instead of searching for a reference (table, figure, document, section, etc.) ectd MASTERCLASS 101

102 Case #3 Bookmark Issues Not providing bookmarks Providing a few bookmarks when more are needed for navigating the document Providing bookmarks that don t have meaningful names (e.g., appendix 1, page 1, etc.) ectd MASTERCLASS 102

103 Case #3 - Examples of Bad Bookmarks ectd MASTERCLASS 103

104 Case #3 - Examples of Good Bookmarks ectd MASTERCLASS 104

105 ectd Lifecycle Operation Case #1 ectd Node Extension Case #2 ectd PDF documents content Case #3 Document Type Definition (DTD) Case #4 ectd MASTERCLASS 105

106 Background Case #4 Concept - DTD/Schema DTD - Document Type Definition XSD - XML Schema Definition A Document Type Definition (DTD) defines the legal building blocks of an XML document. It defines the document structure with a list of legal elements and attributes. ectd MASTERCLASS 106

107 Background Case #4 FDA began to accept ectd submissions using the new Module 1 specifications (DTD 3.3) from Jun 15,2015. The retirement date for the current DTD 2.3 has not been set. Once an application is converted to the new M1 specifications, you cannot return to an older version. Metadata in this new Module 1 is more robust, including regulatory and technical contacts, regulatory activity and so on. ectd MASTERCLASS 107

108 Case #4 - A Company begin to use DTD 3.3 from Jan 01,2016 Dec 27 Dec 28 Dec 29 Dec 30 Jan 1 Jan 2 Jan 3 Jan 4 Jan 5 Jan 6 Jan 7 Jan 8 Sequence 0010 Rejection Rejection Sequence 0011 Sequence 0012 Build as per old DTD Build as per new DTD Dispatch Sequence 0010: Build on Dec 28 using old DTD, Planning Dispatch on Jan 5 Sequence 0011: Build on Dec 29 using old DTD, Planning Dispatch on Jan 7 Sequence 0012: Build on Jan 1 using new DTD, Planning Dispatch on Jan 3 ectd MASTERCLASS 108

109 Case #4 - A Company begin to use DTD 3.3 from Jan 01,2016 Dec 27 Dec 28 Dec 29 Dec 30 Jan 1 Jan 2 Jan 3 Jan 4 Jan 5 Jan 6 Jan 7 Jan 8 Sequence 0010 Sequence 0011 Sequence 0012 Build as per old DTD Build as per new DTD Dispatch Has ongoing sequence in old DTD Has subsequent sequences in new DTD already been submitted Approach for new sequence No / New DTD Yes Yes New DTD Yes No Old DTD ectd MASTERCLASS 109

110 Closing Validation would be the premise for the following content reviewing. Submission package without issues is the first step for THE Approval. As application of ectd widely spreading, issues occur inevitably. Issue trouble-shooting process would render us a comprehensive understanding of ectd technology and minimize similar issues in the furture. ectd MASTERCLASS 110

111 Q&A ectd MASTERCLASS 111