Welcome to: eCTD Hands-on Workshop Creating your first eCTD Submission (Session 2) 1

Agenda (Session 2) Steps involved in creating an eCTD Submission Create Submission Map Create Submission Documents Compile the Documents in eCTD format Publish the eCTD Assembly 2

Create Submission Map Overview Sample Submission Map Template Submission Metadata Document to Module Mapping 3

Submission Map A successful submission begins with creating a roadmap for the entire submission 4

Submission Metadata(1) EU-Envelope   Country EMEA Application Number cp-123-457 Applicant Take Pharma Agency Name European Medicines Agency ATC L01DB03 Submission Type Initial Marketing Authorisation Procedure Type Centralised Procedure Invented Name Medicinal Product INN Active Ingredients Sequence OOOO Related Sequence NA Submission Description This is a MAA for Drug product for belgium under national procedure 5

Submission Metadata (2) Application Number (EU) Application number is Alpha Numeric EU/1/00/150/001 Application number is key – ties all submissions together as an application 6

Submission Metadata (3) Sequence Number (EU) Sequence number values must be four digits - No alpha characters No “-”, “,” or other punctuation No spaces Sequence number is key and relates all submission components together Sequence numbers need not be received/submitted in sequence 7

Submission Metadata (4) Procedure Type Centralised procedure National procedure Mutual recognition procedure Decentralised procedure 8

Submission Metadata (5) Application Types (EU) New Active Substance (Same as NDA) Abridged Applications ( Same as ANDA) Biological and Biotechnological Products (Same as BLA) Active Substance Master File (ASMF) 9

Submission Metadata (6) Submission Types (EU) Initial marketing authorisation application Supplemental information after questions Follow-up measure Specific obligation Variation type 1a Variation type 1b Variation type 2 10

Submission Metadata (7) Submission Types (EU) Periodic Safety Update Report Renewal Drug master file Arbitration under article 29, 30 or 31 Specific obligation following conditional approval Safety restriction 11

Submission Map Template 12

Create Submission Documents Overview Image-Based Docs Document Scanning Page Numbering Navigation Aids 13

Submission Docs (1) Avoid Image based docs Agency strongly urges sponsors to provide text-based documents rather than scanned image-based documents because: Occupies more storage space Electronically unsearchable Longer time to print them Can be difficult to read 14

Submission Docs (2) Image-based docs Scanned image-based documents can be considered in the following situations: Hand-written and signed documents Documents generated outside the company Documents that are available only in paper 15

Submission Docs (3) Scanned documents at a resolution of 300 dpi balances Legibility (computer screen/printouts) and the file size Use of Gray Scale and Color Increases the file size Should be used only to improve the reviewability of the material Post Scanning Avoid re-sampling to lower resolution (sizing) 16

Submission Docs (4) Scanning Resolution Document Types Resolution 1 Handwritten Notes 300 dpi (black ink) 2 Plotter output graphics 300 dpi 3 Photographs – Black & White 600 dpi (8-bit gray scale) 4 Photographs – Color 600 dpi (24-bit RGB) 5 Gels and Karyotypes 600 dpi (8-bit grayscale depth) 6 High pressure liquid chromatography 17

Submission Docs (5) Page Numbering Across documents paging is not required Easy navigation If page numbers of the document and PDF numbering are in synch Page numbers are Arabic numerals, numbered consecutively, starting with page 1 including appendices and attachments Avoid Roman numerals (e.g. Title page, TOC) Avoid unnumbered pages (e.g. Title page) 18

Navigation Aids – Bookmarks Submission Docs (6) Navigation Aids – Bookmarks Provide Bookmarks with intuitive names 19

Submission Docs (7) Bookmarks arranged hierarchically enhance reviewability 20

Submission Docs (8) When to provide hyperlinks? Anytime the text refers to a reference (table, figure, etc.) that is not on the same page Validate all hyperlinks and bookmarks Broken hyperlinks and bookmarks diminish reviewer confidence in the submission Include TOCs in almost all PDF documents 21

Submission Docs (9) Documents should conform to eCTD granularity Avoid combining documents at higher parent leaf level Tempting – small initial savings in combining Large cost in lifecycle complexity 22

Compile in eCTD Format Overview eCTD Triangle Leaf Title & Leaf Operations Lifecycle Management Files, Folder naming conventions Assembling M1-M5 Study Tagging File Document Re-Use 23

Nonclinical Study Reports Clinical Study Reports eCTD Triangle Module 1 Regional Admin Module 2 Summaries Japanese Language 2.3.R ISS/ISE 3.2.R Node Extensions Case Report Forms Module 3 Quality Module 4 Nonclinical Study Reports Module 5 Clinical Study Reports Tab List Trial Subj STF Dataset Folders 24

Leaf Metadata Leaf Title Leaf Operation Should be informative and succinct Should not include the eCTD numbering Should immediately reveal to the reviewer what’s inside Leaf Operation 25

Leaf Title Example Note: Reviewers would not be able to view the entire title if it is too long 26

Leaf Operation Attribute It is a key to managing each individual file in a submission Applicant uses this attribute to inform the reviewer how he intends the files in the submission to be used It describes the relation between files in subsequent submissions during the lifecycle of a medicinal product 27

Accepted Leaf Operations New: The file has no relationship with files submitted previously. Append: There is an existing file with which this file should be associated (e.g., providing missing or new information to that file). Append should not be used to associate two files in the same submission (e.g., splitting a file due to size restrictions). 28

Accepted Leaf Operations Replace: This means there is an existing file that this file replaces. Delete: This operation identifies the file in a previous submission that is to be considered no longer relevant to the review. There is no file submitted in this case. 29

Accepted leaf Operations In the very first submission all the files will have operation “New” In subsequent submissions for an application, files can have different values depending on their relation with previous submitted files 30

Document (leaf) Lifecycle App# 0000 Sequence 0001 Net View index.xml index.xml M2.2 M2.2 M2.3.P Introduction.pdf Introduction.pdf Desc_comp- prod.pdf M2.3.P M3.2.P.1 Desc_comp- prod.pdf M3.2.P.1 Desc_comp- prod.pdf X Delete operation Folders Files XML Legend 31

Lifecycle Sample 32

Lifecycle Sample 33

File Names Rules File Extensions Naming Conventions Only one file extension File extensions indicate the format of the file Naming Conventions Lowercase No spaces Alphanumeric, hyphen and minus are allowed Maximum characters allowed is 64, including the extension File name and extension are separated by a period 34

Folder & Path Names Rules Folder names cannot exceed 64 characters Path cannot exceed 230 characters including the file name and extension Folder and file names need to be abbreviated in situations exceeding 230 characters 35

Files, Folders & File Path File names, folders and file paths are not displayed explicitly to reviewers A good eCTD builder tool would check for all the file, folder and file path validations and intuitively enable the user to conform 36

Application / Submission Identity Assembling Module 1 Application / Submission Identity Module 1 is the only place where application administrative/identification information is provided in “machine readable” form Include Module 1 in all your eCTD Submissions Forms and cover letters should be considered “new” documents submitted to an application 37

Assembling Module 1 What if there’s no available heading? Special programs Accelerated approval Priority Review Cover Subpart E General Investigational Plan (outside of an annual Report Make Use of the Cover Letter 38

Assembling Module 1 39

Assembling Module 2 40

Assembling Module 2 Things to Do Summarize Modules 3, 4 & 5 Make your points in sum and refer to (don’t repeat) details in other sections Use leaf titles for differentiation of documents at the same level Ensure your Module 2 meets the definition of a summary 41

Assembling Module 2 Things Not to Do Don’t include 10,000 pages of detailed patient profiles and other data Patient Data  Module 5 ISS and ISE  Module 5 Don’t use Node extensions Don’t combine documents together at too high a granularity level 42

Assembling Module 3 Multiple drug substances (e.g. Augmentin) <m3-2-s-drug-substance substance=“amoxicillin” manufacturer =“ABC, Inc; Ringaskiddy, IE; CFN 9999999”> Substance 2 <m3-2-s-drug-substance substance=“clavulanic acid” manufacturer =“XYZ, Inc; Mumbai, IN; CFN 6666666”> 43

Assembling Module 3 One drug substance Two Manufacturers Case 1 Case 2 <m3-2-s-drug-substance substance=“amoxicillin” manufacturer =“ABC, Inc; Ringaskiddy, IE; CFN 9999999”> manufacturer =“XYZ, Inc; Mumbai, IN; CFN 6666666”> Case 2 manufacturer =“ABC, Inc; Ringaskiddy, IE; CFN 9999999 and XYZ, Inc; Mumbai, IN; CFN 6666666”> 44

Assembling Modules 4 & 5 Modules 4 & 5 are very similar Both contain study results, data and related information Module 4 – Pre-clinical (Safety) Module 5 – Clinical (Efficacy) Approach for building M4 and M5 is very similar 45

Similarities and Differences Assembling Modules 4 & 5 Similarities and Differences 46

Study Example 47

Document Re-Use A document can be associated with more than one heading. However, the actual electronic file would only be provided once. The eCTD specifications provide details on how to refer to an electronic file. 48

eCTD Specifications EU Module 1 Specification http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm ICH Modules 2 to 5 Specification 49

Publishing in eCTD format Overview Publishing in eCTD format Published Package Testing the Published Package 50

Publishing in eCTD format Follow your internal SOP before publishing the dossier in eCTD format Validate the XML backbone against the schema Preview and Review the pre-published package Get the concerned Approvals and record the Publishing act through an electronic signature or system audit trails 51

Published Package (1) 52

Published Package (2) Published package must contain the following standard components Util folder 3 standard DTDs 3 standard style sheets in util folder Custom components create issues in Agency’s environment Checksum file One or more Module folders Avoid GIFs, custom CSS, custom DTDs, custom elements with standard DTDs 53

Test the Published package Test the Published package before you submit Open the eCTD XML backbone in a browser Validate all the file references from the XML backbone Check for the Util folder and the checksum files Write the Package to a CD/DVD and send it to the Agency 54

Session 2 Review… How many repeatable sections (such as drug substance) are there in Module 3? If a document has to be reused in two different sections within a single submission, is it necessary to send two copies of the document with the submission? 55

Questions END OF SESSION 2 Any Questions? 56