Day1.3 - Lee - A Filing Reviewer's Perspective

Julia Lee, Pharm.D. Regulatory Support Branch

Division of Labeling and Program Support (FDACDEROGD)

A Filing Reviewers Perspective on Electronically Submitted Documents

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/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM151259.pdf

Electronic Common Technical Document (eCTD)

eCTD Documentation and Resources

Providing Regulatory Submissions in Electronic Format Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 2, dated June 2008) ***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/GuidanceComplianceRegulatoryInformation/Guidances/UCM072349.pdf Revision 3: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM333969.pdf

The Comprehensive Table of Contents Headings and Hierarchy (Version 2.3, revised February 2014)

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM163175.pdf

FDA Portable Document Format (PDF) Specifications (Version 3.1, revised January 2012)


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 If in landscape orientation, a margin of of an inch at the

top Oversized documents and promotional materials

submitted in PDF format should be created according to their actual page size

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.

BOOKMARK PROPERTIES Right Click on bookmark and select 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

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

LEAF TITLES

VS.

BAD LEAF TITLES GOOD LEAF TITLES

Sections and Subsections 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

Bad Section

Good Section

Other questions or issues?

CONTACT ESUB [email protected]

They can help you fix your submission.

References GDUFA Commitment Letter

http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf Generic Drug User Fee Amendments of 2012; Pub. L. 112-144, Title III

http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf Electronic Common Technical Document Site (eCTD)

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/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)***

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

Comprehensive Table of Contents Headings and Hierarchy Portable Document Format Specifications (Version 3.1)


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

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073285.pdf

Slide Number 1AgendaRecent RegulationsSec. 745A FD&C Act (21 U.S.C. 379k-1)Current Regulation:21 CFR 314.94(d)(iii) and 21 CFR 601.14(a)GDUFA Commitment LetterWhy is this Significant?Useful Documents and SitesSlide Number 9Electronic Common Technical Document (eCTD)eCTD Documentation and ResourcesSlide Number 13Slide Number 14SpecificationsChecking Document PropertiesDocument PropertiesSECURITYSECURITY-INCORRECTSECURITY-CORRECTFONTSFONTSStandard PAGE SETUPSlide Number 24SCANNED DOCUMENTSSlide Number 26HYPERTEXT AND BOOKMARKSHYPERTEXT AND BOOKMARKSBOOKMARKS AND HYPERLINKSWhy does INHERIT ZOOM matter?Lets say youre reviewing a documentSlide Number 31Slide Number 32HYPERLINKS and BOOKMARKSSlide Number 34Slide Number 35Slide Number 36Slide Number 37INITIAL VIEW SETTINGSNavigation-Bookmarks Panel and PageDEFAULTPage Layout-DefaultDEFAULTMagnification-DefaultLEAF TITLESSlide Number 43Slide Number 44Sections and SubsectionsSlide Number 46Other questions or issues?ReferencesSlide Number 49