A Filing Reviewers Perspective on Electronically Submitted Documents

Regulatory Support Branch Division of Labeling and Program Support (FDACDEROGD)

Julia Lee, Pharm.D.

Agenda
Regulations Why is this significant? Guidance for Industry Specifications Other issues at Filing

Recent Regulations
Approved by the 112th U.S. Congress in 2012 Amended the Federal Food, Drug and Cosmetic Act (FD&C Act) to establish user-fee programs for generic drugs and for other purposes. Section 745A(a) was added by Section 1136 of the Food and Drug Administration Safety and Innovation Act (FDASIA)

Sec. 745A FD&C Act (21 U.S.C. 379k-1)

ELECTRONIC FORMAT FOR SUBMISSIONS. (a) DRUGS AND BIOLOGICS. (1) IN GENERAL.Beginning no earlier than 24 months after the issuance of a final guidance issued after public notice and opportunity for comment, submissions under subsection (b), (i), or (j) of section 505 of this Act or subsection (a) or (k) of section 351 of the Public Health Service Act shall be submitted in such electronic format as specified by the Secretary in such guidance. (2) GUIDANCE CONTENTS.In the guidance under paragraph (1), the Secretary may (A) provide a timetable for establishment by the Secretary of further standards for electronic submission as required by such paragraph; and (B) set forth criteria for waivers of and exemptions from the requirements of this subsection. (3) EXCEPTION.This subsection shall not apply to submissions described in section 561.

Current Regulation: 21 CFR 314.94(d)(iii) and 21 CFR 601.14(a) Electronic format submissions. Electronic format submissions must be in a form that FDA can process, review, and archive. FDA will periodically issue guidance on how to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and organization of files).

GDUFA Commitment Letter

Jointly proposed by the Agency and industry Review metric goals only apply to submissions made electronically following the Electronic Common Technical Document (eCTD) format in effect at the date of submission

Why is this Significant?

Per Section 745A(a) of the FD&C Act, applications will have to be submitted electronically. The format has to be in the standard requested by the Agency. May be considered as an easily correctable deficiency in the near future and may also lead to a refusal There are guidance documents and specifications available on the FDA site to ensure documents are submitted correctly.

Useful Documents and Sites

ANDA Filing Checklist for Completeness and Acceptability of an Application

(updated October 2013)
http://www.fda.gov/downloads/Drugs/Devel opmentApprovalProcess/HowDrugsareDev elopedandApproved/ApprovalApplications/ AbbreviatedNewDrugApplicationANDAGen erics/UCM151259.pdf

Electronic Common Technical Document

(eCTD)

eCTD Documentation and Resources

2, dated June 2008)

Providing Regulatory Submissions in Electronic Format Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision

***NOTE: There is a 3rd Revision (dated January 2013) available on the Agencys guidance site. It is currently in Draft form, but after finalization will supersede the document shown.***
Revision 2: http://www.fda.gov/downloads/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/UCM072349.pdf Revision 3: http://www.fda.gov/downloads/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/UCM333969.pdf

The Comprehensive Table of Contents Headings and Hierarchy

(Version 2.3, revised February 2014)
http://www.fda.gov/downloads/Drugs/Devel opmentApprovalProcess/FormsSubmission Requirements/ElectronicSubmissions/UCM 163175.pdf

FDA Portable Document Format (PDF) Specifications

(Version 3.1, revised January 2012)
http://www.fda.gov/downloads/Drugs/Devel opmentApprovalProcess/FormsSubmission Requirements/ElectronicSubmissions/UCM 163565.pdf

Specifications

Checking Document Properties

Or Pressing CTRL + D will bring up the Document Properties.

Document Properties

SECURITY

Reviewers should be able to print, select text and graphics, and make changes to text, notes and form fields With this error, the applicant should resubmit the document with no security settings or password protections

SECURITY-INCORRECT

SECURITY-CORRECT

FONTS
Font sizes ranging from 9 to 12 point font Recommended Font Sizes:
Narrative Text: 12-point font Times New Roman Tables: 9-10 point
A balance between providing sufficient information on a single page for data comparison and legibility

Footnotes: 10 point

Color:
Black for narrative text Blue for hypertext links

FONTS Standard

PAGE SETUP
ORIENTATION
All pages of the document should be submitted in the correct orientation.

Print area for pages to fit on a page 8.5 inches by 11 inches with a margin of at least of an inch on the left side and 3/8 of an inch on the other sides Oversized documents and promotional materials submitted in PDF format should be created according to their actual page size
If in landscape orientation, a margin of of an inch at the top

SOURCE OF ELECTRONIC DOCUMENTS

PDF documents produced from electronic source documents (i.e., word processing files) are preferred If documents are scanned, the text and diagrams should be legible on the screen and if the document is printed.

SCANNED DOCUMENTS
Should be made text searchable where possible Standard Resolutions for Scanned documents:

Document was scanned, so the text is not as clear as a PDF document converted from the source. Firm wanted to add their own header and footer so they shrink an 8.5x11 document smaller. The text is now, < 9 point font AND legibility is affected. All documents submitted should be easily legible. These include Certificates of Analysis from outside suppliers as well as chromatograms and spectra data.

HYPERTEXT AND BOOKMARKS

Hypertext
Can be designated by rectangles using thin lines or by blue text

Bookmarks
Identical to the TOC Recommended for documents 5 pages or longer Up to 4 levels deep in the hierarchy

HYPERTEXT AND BOOKMARKS

For documents with a table of contents
Bookmarks and hypertext links for each item listed in the TOC including all tables, figures, publications, other references, and appendices that are essential for navigation through documents
The use of invisible rectangles and blue text in the TOC avoids obscuring text

Bookmark and Hyperlink Magnification set to INHERIT ZOOM

BOOKMARKS AND HYPERLINKS Why does INHERIT ZOOM matter?

Lets say youre reviewing a document

You decide to select a bookmark/hyperlink and

the entire document zooms in

OR the entire document zooms out

HYPERLINKS and BOOKMARKS

This method creates an additional task for reviewers. It is time wasted. Each individual reviewer has to take the time and effort to zoom in or out of the document each time they utilize a hyperlink or bookmark.

Right Click on bookmark and select Properties

BOOKMARK PROPERTIES

BOOKMARKS INHERIT ZOOM

Initial Window

BOOKMARKS BAD NAMES

Example 1: Bad Bookmarks Example 2: More Bad Bookmarks

BOOKMARKS GOOD NAMES

Bioequivalence Summary Tables in m2-7 Protocol Case Report Form (CRF)

INITIAL VIEW SETTINGS

Navigation-Bookmarks Panel and Page

DEFAULT Page Layout-Default

DEFAULT Magnification-Default

LEAF TITLES

LEAF TITLES
Poor or Bad Leaf Titles
E.g.:
Appendix 1, Appendix 2, etc Attachment 1, Attachment 2, etc 356h, 356h, 356h, etc

Should include sequence number or submission date in the leaf title to help differentiate between documents
For non-PDF documents, a file extension or type of application (e.g., MS Word) should be identified

BAD LEAF TITLES

GOOD LEAF TITLES

VS.

Drug Substance Separated by drug substance, if more than 1 is present in the drug product Drug Product One Section encompassing all strengths. If the quality information is the same between all strengths, the data should only appear once

Sections and Subsections

Good Section Bad Section

Other questions or issues?

CONTACT ESUB
ESUB@FDA.HHS.GOV

They can help you fix your submission.

References
GDUFA Commitment Letter Generic Drug User Fee Amendments of 2012; Pub. L. 112-144, Title III Electronic Common Technical Document Site (eCTD)
http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissi ons/ucm153574.htm

Guidance for Industry Providing Regulatory Submissions in Electronic Format-Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Final June 2008)*** Comprehensive Table of Contents Headings and Hierarchy Portable Document Format Specifications (Version 3.1)

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissi ons/ucm153574.htm

Guidance for Industry M4: The CTD Quality Questions and Answers/Locations Issues (June 2004)

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electron icSubmissions/UCM163565.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073285.pd f