GDUFA s Impact on ectds / Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 1
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 2
Agenda Regulations/Guidances ectd Filing Review Comments Case Study on Implementing PDF Standards at Teva Submission Standards Program GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 3
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 4
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 5
Guidances Specifications for ectd Validation Criteria Table of Contents Headings and Hierarchy Providing Regulatory Submissions in Electronic Format Standardized Study Data ectd Technical Conformance Guide Providing Regulatory Submissions in Electronic Format Certain Human Pharmaceutical Product Applications and Related Submissions Using the ectd Specifications Transmitting Electronic Submissions using ectd Specifications ICH Guidances PDF Specification ANDA Filing Checklist GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 6
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. GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 7
Top 10 Common ectd Filing Review Comments GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 8
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 9
GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 10
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 11
GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 12
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 13
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 14
There are pages that are not oriented correctly. Portrait vs Landscape Page Size (8.5 in by 11 in) Recommended margins GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 15
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) GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 16
GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 17
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 18
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 19
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 GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 20
GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 21
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 Current View: Cumulative View: Current View: GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 22
Lessons Learned Typically not just one issue Technical Lack of training Lack of understanding requirements Business practices Good Authoring Practices GDUFA S Impact on ectds GPhA 2015 Fall Technical Conference 23
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 United States Europe ROW Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 25
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 Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 26
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 Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 27
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 Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 28
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 Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 29
Program Structure Site Team Core Implementation Team Site Team Steering Committee Site Team Training Team SME Team Communication Team Regulatory Affairs Staffed Site Staffed Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 30
Program Structure Steering Committee Responsibilities Validates approach Answers/decides policy questions Gives direction Gains buy-in from others, eg, QA/Operations Core Implementation Team Responsibilities Project Manages the Site Teams Gives direction Harmonizes items across sites Manages the support website Metrics analysis and reporting Training Team Communication Team Site Team Site Team Site Team SME Team 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 Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 31
Metrics Review documents for compliance Report deficiencies back to sites Used as basis for corrective action plan Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 32
Training Requirements Good authoring practices MS Word source files macro-enabled templates PDF source files PDF plug-in tool for bookmarks, hyperlinks, TOCs, etc Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 33
Training Materials Created How To guides and videos Developed a communication package for third party vendors Distilled FDA PDF specifications to a checklist Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 34
Training Method Face-to-face Presentation (why and what) Hands-on (how to use software) Over two weeks Developed site corrective action plan during this time File Standards No password protection No annotations File size </= 400MB Page Standards Page Size: US Letter (8.5 X 11), A4 (8.27x11.69) Margins Page orientation No blank Pages Paginated Fonts Standard Black text Standard Fonts (e.g. Times New Roman, Arial, Courier) Narrative Font size 9-12 Table font size 9-10 Table of Contents TOC for doc with 5 pages or more Hyperlinked TOC Appendices included in TOC Scanned images Images legible Text Searchable Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 35
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 Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 36
Thank You! Questions? Case Study: Implementing PDF Standards GPhA 2015 Fall Technical Conference 37