GDUFA’s Impact on eCTDs / Case Study: Implementing PDF ... · GDUFA’S Impact on eCTDs| GPhA 2015 Fall Technical Conference 1 GDUFA’s Impact on eCTDs / Case Study: Implementing

GDUFA’S Impact on eCTDs| GPhA 2015 Fall Technical Conference 1

GDUFA’s Impact on eCTDs / Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference

Introductions

Kevin Tompkins Director, Head of North America, Regulatory Submissions Management

Meghan Hughes Associate Director, Submission Ready Standards Program Lead


Global Regulatory Operations

Regulatory Submissions Management

Regulatory Information

Management

Planning, Metrics and Reporting

Procedures, Learning and

Centralized Services

Submission Standards Program

Agenda

• Regulations/Guidances • eCTD Filing Review Comments • Case Study on Implementing PDF Standards at Teva • Submission Standards Program


What, Why, & How

• Section 745A(a) of the FD&C Act states that applications will have to be submitted electronically

• “Electronic format submissions must be in a form that FDA can process, review, and archive.” 21 CFR 314.94(d)(iii)

• GDUFA Review Metrics began in October 2014 • FDA is now enforcing their submission standards • FDA has communicated to industry for the past few years that

these standards will be enforced


Regulations


Generic Drug User Fee Act Program Performance Goals and Procedures

ANDA Submissions – Refuse-to-Receive Standards

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

Guidances


Providing Regulatory Submissions in Electronic Format —Certain Human Pharmaceutical Product Applications and Related

Submissions Using the eCTD Specifications

Table of Contents

Headings and Hierarchy Providing

Regulatory Submissions in Electronic

Format — Standardized

Study Data

Transmitting Electronic

Submissions using eCTD

Specifications

PDF Specification

ANDA Filing Checklist

ICH Guidances

eCTD Technical

Conformance Guide

Specifications for eCTD

Validation Criteria

RTR and Filing Review Comments “Documents submitted electronically should follow all published eCTD specifications and guidances including those on the CDER eCTD web page, which is located at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmission Requirements/ElectronicSubmissions/ucm153574.htm. There are documents within your submission that do not conform to the standards outlined in the specifications which affect the display/reviewability of the ANDA. The following issues regarding eCTD specifications and guidances were found:” RTR Standards Guidance: In 2012, of the 100 ANDAs that FDA refused-to-receive, 40 were refused because of serious bioequivalence (BE) deficiencies; 36 because of serious chemistry deficiencies; 13 because of format or organizational flaws; 6 because of clinical deficiencies; 4 because of inadequate microbiology (sterility assurance) information; and 1 was refused because an incorrect reference listed drug (RLD) was cited as the basis of submission.


Top 10 Common eCTD Filing Review Comments


“There are issues where documents do not contain adequate, descriptive bookmarks and/or hypertext links.” • Document Navigation

• Table of Contents • Mandatory for 5 pages or longer • Include sections, tables, figures, and appendices • Add Hypertext Links

• Bookmarks • Identical to the Table of Contents • Build a four level deep hierarchy structure • Meaningful bookmark names

• Hypertext Links • Links to supporting information not on the same page • Blue text links or blue box links • Links should open to a new window

• Initial View Settings • Inherit Zoom for all Bookmarks and Hypertext Links



“There are pages that were not easily legible and/or text searchable.” • Avoid image-based PDF documents whenever possible • Standardized image resolution for scanned documents

• Ensure your technology meets the standards • The “Eye Test”



“There are pages that were not easily legible and/or text searchable.”

• Text-based documents • No issues

• Scanned documents • Optical character recognition (OCR) Software

• Allow the reviewer to search or copy/paste text for editing


“There are issues with the font size.” • 12 point font for narrative text • 9-10 point font for tables • Use FDA standard fonts to avoid font embedding issues • Black for narrative text; blue for hypertext links • Header and Footer Overlays may shrink document content • Inserting Scanned Images into Word Document


“There are pages that are not oriented correctly.” • Portrait vs Landscape • Page Size (8.5 in by 11 in) • Recommended margins


“There are issues with the format.” • PDF versions 1.4 through 1.7, PDF/A-1 and PDF/A-2 • Readable by Adobe Acrobat X • Ensure plug-ins are not needed for review • No security settings or password protection (exception FDA forms)



“There are issues with the study tagging files.” • STFs are necessary for every study • Applying the appropriate file tag to every

document/file in the study • Documents not tagged will fall into an

“Unassigned” folder


“There are issues with the naming of files.” • Leaf title is the display name to a reviewer • Concise and descriptive for each document • Use variables to differentiate between documents • Does not have to match file output name • File extension in Leaf Title for non-PDF documents


“There are issues where documents were placed in the wrong sections.” • ANDA Checklist • eCTD Table of Contents Headings and Hierarchy • Module best practices M3 and M5

• BE Study Tables in 2.7 • Datasets belong with study in M5 with the study



“There are issues where there are duplicate sections and/or duplicate documents.” • “Replace” lifecycle operator when replacing a previously submitted

document • “Delete” lifecycle operator when you remove a file from the dossier


Cumulative View:

Current View:

Current View:

Lessons Learned

• Typically not just “one” issue • Technical • Lack of training • Lack of understanding requirements • Business practices

• Good Authoring Practices


Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference

Meghan Hughes, Submission Ready Standards Program Lead

Overview of Teva

43,000 employees

Operations in 60 countries

64 billion capsules and tablets produced each year

Case Study: Implementing PDF Standards| GPhA 2015 Fall Technical Conference 25

United States

Europe

ROW

Why?

Receiving comments from FDA - documents are non-compliant with eCTD specifications and guidances

Creates a single company “look and feel” for documents and facilitates the re-use of content globally

Most requirements are easily implemented during document creation process Functions now responsible for submission ready compliance


Project Charter

Objectives Ensure that submission documentation supplied by sites meet Health

Authority requirements for electronic navigation and formatting Develop local SMEs

Key Issue Quality of some documentation does not meet Agency requirements including

the follows items: Scanned documents making searching and copying and pasting text not possible Inadequate or broken electronic navigation (bookmarks/hyperlinks, lack of TOCs)

Scope All sites that produce components included in a Health Authority submission


Approach


Communication – Regulatory Affairs • Minimum Standards • Health Authority expectations – Why now? Why so stringent? • Additional internal benefits of PDF Standards

Education – Regulatory Operations • Macro-enabled Templates • PDF Standards checklists • Authoring Style Guide • Training to authors/contributors on how to make compliant PDFs

Modification – Site, QA, Reg Ops and IT • Review and modify business processes (i.e., scanning documents etc) • Review of system and system enhancements needed • Implement new practices at the regional/site level

High Level Plan


Identify sites Collect baseline metrics Set KPIs around metric improvement Prioritize sites Train identified sites Develop site specific corrective action plans Collect end of year metrics

Program Structure


Steering Committee

Core Implementation Team

Site Team

Site Team

Site Team

Training Team SME Team

Communication Team

Regulatory Affairs Staffed Site Staffed

Program Structure


Steering Committee

Core Implementation Team

Site Team

Site Team

Site Team

Training Team SME Team

Communication Team

Responsibilities • Validates approach • Answers/decides

policy questions • Gives direction • Gains buy-in from

others, eg, QA/Operations

Responsibilities • Project Manages the Site Teams • Gives direction • Harmonizes items across sites • Manages the support website • Metrics analysis and reporting

Responsibilities • Identify changes to achieve

submission ready documents

• Facilitate business process changes

• Explain technology enhancement requirements

• Become the Champions at the site

Responsibilities • Experts in PDF standards • Ensures continued

compliance with standards • Resides within functional

area creating documentation

Metrics Review documents for compliance Report deficiencies back to sites Used as basis for corrective action plan


Training

Requirements Good authoring practices MS Word source files

macro-enabled templates

PDF source files PDF plug-in tool for bookmarks, hyperlinks, TOCs, etc


Training Materials

Created “How To” guides and videos

Developed a communication package for third party vendors

Distilled FDA PDF specifications to a checklist


Training Method Face-to-face

Presentation (why and what) Hands-on (how to use software)


File

Sta

ndar

ds

•No password protection

•No

annotations • File size </=

400MB Page

Sta

ndar

ds

•Page Size: US Letter (8.5 X 11), A4 (8.27x11.69)

•Margins

•Page

orientation •No blank

Pages •Paginated

Font

s • Standard Black text

• Standard

Fonts (e.g. Times New Roman, Arial, Courier)

•Narrative Font

size 9-12 •Table font size

9-10

Tabl

e of

Con

tent

s •TOC for doc with 5 pages or more

•Hyperlinked

TOC •Appendices

included in TOC

Scan

ned

imag

es

• Images legible •Text

Searchable

Over two weeks Developed site corrective

action plan during this time

Conclusion

Have patience – it takes time to make changes Continual follow-up with sites regarding corrective action plans Work closely with sites on upcoming submissions

Ensure sustainability Create a governance plan Develop a communication plan


Thank You!


Questions?