eCTD Submissions

Saikat Chakraborty

WHAT IS COMMON TECHNICAL DOCUMENT?

CTD is an ICH standard that FDA adopted in a consensus process,

as a member of ICH, together with other member regions, Europe

and Japan

Currently global format for regulatory submissions

Consistent data organization

Method to electronically transfer product information and data

Collection of electronic files organized according to guidelines

defining file format, folder/files naming convention, document

specifications etc.

Applies to all NDAs, ANDAs, BLAs, INDs and master files

In the US, eCTD-only NDAs, BLAs and INDs are accepted – no

paper necessary

eCTD plus paper still needed for Medical authorities in EU

Paper is still the official archival copy of the EU MA

EU wants eCTD as preferred format for all Marketing

Authorization Applications(MAAs) and variations

Only eCTD for MA for all EU members states by 1 Jan 2010

Health Canada wants eCTD format on CD/DVD plus paper

The eCTD challenge

100.000 pages represent ~ 250 volumes

250 volumes represent ~ 80 boxes

80 boxes represent approx. 3 –4 palettes

3 – 4 palettes require a truck for transportation

Accepting an Initial Marketing Authorization at the

agency

The technology and the legislation of today can change this!

NEED FOR ELECTRONIC SUBMISSIONS

Designed with consideration that facilitate

Creation

Review

Assists project management and information management

Lifecycle management

(the history of a product application)

Archiving

Drug development planning

Current Status of US eCTD Submissions

FDA Office of Chief Information Officer

Quarterly briefing, 12 Dec 2008

During the period 2005 to 2008, eCTD submission volume grew at a

compounded annual growth rate of approximately 300%.

Costs (initial capital: $200K- $300K and annual expense: $100

- $200K) of building, validating and operating an electronic

publishing system.

Effort and time to learn and understand the regulatory

requirements and to develop the organizational competency to

efficiently produce compliant eCTD submissions.

Growth of eCTD as a fraction of total submissions.

In 2007, eCTDs represented 10% of total submissions to CDER.

By February 2009, eCTDs were 20% of the total received.

It is expected that by the end of 2012, eCTD submissions may

represent 40 or 50% of total submissions to CDER.

Barriers to adoption typically include:

The ICH M4 Expert Working Group (EWG) has defined the

Common Technical Document (CTD).

The ICH M2 EWG has defined, in the current document, the

specification for the Electronic Common Technical Document

(eCTD).

There are 5 modules in the submission report.

A hierarchical cabinet/folder structure containing the electronic

documents (PDF).

An XML backbone that provides a structure to display the PDF

documents in the eCTD format (eCTD viewer)

Basics of eCTD

CTD STRUCTURE

Module 1

Regional

Admin

Information

Module 3

Quality

Module 4

Nonclinical

Study Reports

Module 5

Clinical

Study Reports

Quality

Overall

SummaryNonclinical

Summary

Nonclinical

Overview

Clinical

Summary

Clinical

Overview

Module 2

NOT Part of the

CTD

The CTD

Comparing paper CTD and eCTD

eCTD File Structure

Example of XML backbone

XML Mapping to Folder

All eCTD Submissions Include Module 1

Module 1 Identifies important information

Company Name

Drug Name

Submission Type

Submission Date

Application Number

Sequence Number

Document Granularity

Module 2 – Summaries

Module 3 consists of highly granular Quality documents that can

be individually updated

ICH eCTD specification and CTD guidance provides level of

granularity

Module 3 contains hundreds of granules in MA

Document granularity – Module 3

Document Granularity – Module 3

Study report formats

– Legacy report

• Report components published and submitted as a single

PDF with maximum size 100 MB

– Granular report – US eCTD

• Study documents submitted as separate PDF files as originally

published

Document granularity – Modules 4 and 5

Module 4 contains the Preclinical data

Module 5 contains Clinical Study Data

Use tools based on Adobe Acrobat 5.0 or higher

(PDF version 1.4)

Publishing greatly facilitated by use of Word templates

Automate extraction of bookmarks and hyperlinks from Word files

Create PDFs from intelligent source- MS Office—Word, Excel,

PowerPoint or Other word processors, spreadsheets, ASCII text etc.

PDF should be text searchable, however some legacy document

may only be available in scanned form

Document Publishing

Compare file names with document contents

In PDF

Check page size and orientation

US accepts edocuments as A4 in eCTD

EU MS require A4 paper dossier but you can submit letter- size PDF in an

eCTD

Document Processing

Avoid scanning unless no other choice

If You Must Scan

Scanned Documents

Document Type Resolution

Handwritten notes 300 dpi (black ink)

Plotter output graphics 300 dpi

Photographs—b&w 600 dpi (8 bit gray scale)

Photographs—color 600 dpi (24 bit RGB)

Gels and karotypes 600 dpi (8 bit grayscale depth)

High pressure liquid chromatography 300 dpi

Navigation improved for PDF documents

Hypertext links for:

„ Annotations

„ Related sections

„ References

„ Appendices

„ Tables or figures

„ For anything not located on same page

Hypertext Linking

Hyperlinks designated by blue text or rectangles with thin lines

„Blue text for PDFs from intelligent source

„ Thin rectangles only option for scanned documents

„ Tables of Contents

„ Hyperlinked

„ Invisible rectangles and blue text preferred

Table of contents and hyperlinks

Bookmarks

– Match the document TOC

– Bookmarks – Up to level 4, e.g. 1.1.1.1

– For documents with multiple granules, each granule

has its own bookmarks

Provide Bookmarks with Intuitive Names

Bookmarks and Hyperlink

Incorrect Correct

One of the important aspect in eCTD reports is to maintain ‘inherit

zoom’ throughout the document.

eCTD publishing system should generate automatically.

It can also be done manually with arcobat.

Bookmarks and Hyperlink

Page Numbering

Document Page = PDF Page

Bookmarks Hierarchy Initial View = Bookmarks & Page

Use lower cases letters

Avoid special characters

except hyphens

File/folder path:

„230 characters for full

folder/file path

„64 characters for folder names

File Naming & Folder/File Path

eCTD publishing system should generate/truncate automatically

Font size

„ 12 point font for text

„ 10 point for tables (9.5 pt)

Font Style:

Arial, Times New Roman, Courier

Optimize for Fast Web View

Verbally Communicated Requirements

Precompilation

QC interdocument links

100% QC that all bookmarks and hyperlinks are live

100% QC that all bookmarks and hyperlinks point to the correct targets

Check all all documents for presence and location

Check document titles in eCTD viewer

Postcompilation

Validate eCTD

Recheck for broken links

QC of eCTD

Cover letter (From the ICH eCTD spec, v. 3.2.2) as paper copy

with any non-electronic portions and as cover.pdf

A description of the submission including appropriate regulatory

information.

A listing of the sections of the submission filed as paper,

electronic, or both paper and electronic.

A description of the electronic submission including type and

number of electronic media,

Approximate size of the submission, and, if appropriate,

characteristics concerning the media (e.g. Format used for DLT

tapes) based on regional guidance.

Submitting the eCTD

A statement that the submission is virus free with a description of

the software used to check the files for viruses.

The regulatory and information technology points of contact for

the submission.

Copy eCTD to CD-ROM, DVD or DLT master

Reload eCTD from CD, DVD or DLT master and revalidate

Create eCTD copies from master

Number of copies determined by each EU MS

Submitting an eCTD

1. Files Referenced in the XML Backbone(s)

2. eCTD Submissions Include Module 1

3. Application Numbers are 6 Digits

4. Sequence Numbers are 4 Digits

5. Ensure we receive what you intended

6. Do not send in one submission to be applied to

multiple applications

7. XML must be Standard Components

8. PDF contains Recognizable Text

9. PDF Hyperlinks/Bookmarks are Correct

10.PDF Documents include TOCs

Points to Remember

The end is near for the traditional paper base era for

managing, reviewing, and submitting regulatory submissions.

Successful transtition to eCTD provides competitive advantages:

Increased review efficiency

Decreased risk of refusal to file

Faster time to market

„Happier stockholders

„Greater employee & management satisfaction

„ Lower cost of production

„ Simultaneous global submissions

„ Healthier patients

Closing Remarks

CDER Contact for information on eCTD submissions

esub@fda.hhs.gov

CDER Contact for information on SDTM submission

cder-edata@fda.hhs.gov

Electronic Regulatory Submissions and Review

website

http://www.fda.gov/cder/regulatory/ersr/default.htm

• International Conference on Harmonization

http://www.ich.org

• All FDA Guidances on Electronic Submissions

http://www.fda.gov/cder/guidance/index.htm#electronic_submissions

References