1. FDASIA, GDUFA and eCTD Mandate
Antoinette Azevedo
President, e-SubmissionsSolutions.com
22 October 2012

2. Agenda FDASIA* 2012 eCTD overview Discussion & conclusion GDUFA*
New Module 1
New validation criteria
New FDA forms
Discussion & conclusion
*definition to follow

3. Signed by President Obama 9 July 2012
Food and Drug Administration Safety and Innovation Amendment of 2012 (FDASIA*)
Effective 1 October 2012
Signed by President Obama 9 July 2012
Near unanimous approval by both houses of Congress June 2012
Result of nearly 2 years negotiations
FDA
Regulated industry (trade associations)
Stakeholders
* S3817; also known as the “UFAs” – PDUFA V, MDUFA III, GDUFA, BsUFA

4. User fees contribute 2/3 of FDA CDER annual budget
Definitions
Generic Drug User Fee Amendments (GDUFA)
Prescription Drug User Fee Amendment (PDUFA V)
Medical Device User Fee Amendment (MDUFA III)
Biosimilars User Fee Amendment (BsUFA)
FDA User Fees web page
User fees contribute 2/3 of FDA CDER annual budget

5. GDUFA Resources Website: https://www.fda.gov/gdufa
Call: (866)

6. Key Provisions of FDASIA
New user fees
ANDAs
DMF-IIs (drug substance + drug product)
Collected on unapproved ANDAs & open DMFS
30+ month backlog of unapproved ANDAs/unreviewed DMFs
Collected on newly-submitted ANDAs and DMF-IIs (referenced by ANDA) starting 1 October 2012
No commitment to meet GDUFA timeline if not in electronic format
Biosimilars (generic biologics)
May cause companies to withdraw ANDAs and DMFs due to cost of doing business

7. Key Provisions of FDASIA
New electronic submission mandates
NDA, BLA, ANDA, DMF – 24 months after final guidance
INDs – 36 months after final guidance
Section 561 exception (single-patient compassionate use investigator-initiated)
Unclear about academic-initiated INDs
CDRH – after issuance of final guidance presubmissions and submissions (IDE, PMA, 510K, Master Access File [MAF])
Exceptions will not be granted

8. GDUFA Value to Consumers & Industry
Timely access to generic drugs
Safe, high quality generic drugs
Maintains affordability of generic drugs
Increases transparency
Addresses globalization
Advances regulatory science
Puts FDA’s generic drug program on stable financial footing

9. GDUFA Addresses Challenges
User fees $299 million per year
Ten-month review cycle for 90% in year 5
Effectively eliminate backlog within 5 years
Risk-based, biennial inspections
Parity of foreign and domestic frequency in year 5
Efficiency enhancements, starting day one, are a critical component of GDUFA
4 types of fees: backlog; DMF; ANDA/PAS, Facility
70% of program revenue from facilities; 30% from applications
80% of program revenue from FDF; 20% from API

10. FDA Commitments on DMFs
Initial completeness assessment
“Available for reference” list on the web
DMF completeness letter
Inspections
Release inspection classification and date
Third-party foreign regulator inspection program

11. GDUFA Effect of failure to pay fees Other provisions
Appropriations and spending triggers
Streamlined hiring authority
Exception for positron emission tomography (PET) drugs
Reauthorization built into process

12. GDUFA eCTD Mandate Timeline*
31December2012 Issue draft guidelines
31December2013 Issue final guidance
31December2015 Binding on sponsors, applicants, manufacturers submitting NDAs, BLAs, ANDAs, and DMFs
31December2016 All original commercial INDs and amendments (except section 561 submissions)
*FDA speakers at meetings 9/18/2012 and 9/20/2012

13. GDUFA Implication for Sponsors
Obtain budget for EDMS & eCTD
Select vendors
Implement & validate EDMS
Implement & validate eCTD system
Participate in FDA pilots: eCTD, CDISC, ESG
Go-live 6 to 12 months ahead of deadline
What if multiple
budget cycles
required?
What if one or
more vendors
fail?
What if one
or more
pilots fail?
What if
FDA
validation
fails?
4Q2015
Mandate
(est.)
3Q2012
Business process redesign/reengineering
Training, coaching, content remediation

14. Source: John K. Jenkins, MD, Director, Office of New Drugs, CDER
Review Timeline
Source: John K. Jenkins, MD, Director, Office of New Drugs, CDER
Current PDUFA IV timeline
New PDUFA V timeline
ANDAs
NMEs & NCEs

15. GDUFA Process Meetings between FDA and stakeholder groups
Minutes posted on FDA web site
Stakeholders – health care industry, patient/disease advocates, consumer groups
Regulated Industry – individual company members of GpHA, SOCMA, EFG
FDA not able to get representation from Asia

16. GDUFA Commitment Letter
GDUFA commitment letter (draft)
Public health benefit from generic drugs
Transparency of the review process
Equal emphasis on FDF and API
Moving to equal emphasis on US and foreign inspections

17. GDUFA User fees effective 1 October 2012 to:
Clear up backlog of pending ANDAs & DMFs
DMF referenced after this date; one-time fee per DMF
ANDAs & Prior Approval Supplements (PAS)
Generic drug facility & API facility

18. DMF-II Electronic Mandate
Beginning to have an impact on companies submitting other types of DMF
API manufacturer ability to submit DMF in eCTD format emerging as a selection criteria for initiating/retaining business relationship
Be aware of technical challenges faced by API manufacturers using non-English UIs

19. FDASIA Conclusions
MS Word & Adobe Acrobat competencies are critical for all “UFA” submissions
Waiting for mandates is very dangerous
Building a repository of noncompliant documents which will require remediation
Delay initiating the learning curve
Deferring the inevitable reengineering
ANDA & DMFs – user fees must be paid whether eCTD format used or not

20. eCTD Overview

21. 2.3 Quality Overall Summary
What is eCTD?
Module 1 Not part of CTD
Module 1
Regional Info
2.1 Table of Contents
2.2 Introduction
Module
Module 2
Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.3 Quality Overall Summary
2.6 Nonclinical
Summary
2.7 Clinical Summary
Module 3
Quality
Module 4
Safety
Module 5
Efficacy

22. Characteristics of eCTD
Pre-defined Folder & File Structure
Organized by technical discipline
Quality = Chemistry, Manufacturing & Controls
Safety = Non-clinical (animal studies)
Efficacy = Clinical (human studies)
US requires additional documentation
Case Report Forms (CRFs)
Case Report Tabulations (CRTs)
Integrated Analyses of Safety & Efficacy (IAS & IAE)
Each geography has specific regional requirements confined to Module 1 (mostly)

23. What is eCTD? Submission “900603” Sequence “0000” with 5 modules

24. File Formats eXtensible Markup Language (XML)
Adobe Portable Document Format (PDF)
Bookmarks & hyperlinks:
Navigate through a file
Easily access related files & referenced content
Document TOCs to navigate content of a file
Labeling in XML
US: Structured Product Labeling (SPL)
US: SAS Transport for datasets
US: XML evolving datasets interchange standard

25. XML Backbone – Internet Explorer

26. Life Cycle – eCTD Browser
History of submissions
Modify content submitted in prior sequences
View PDF file content
Filtered views

27. Purpose of File Formats
PDF: facsimile of a paper document
Hyperlinks/bookmarks to navigate within the content of a file
Hyperlinks/bookmarks to navigate to other file/folders in the electronic submission
SAS Transport (.XPT)
Industry standard to transfer statistical content between eCTD & reviewers’ statistical analysis software packages

28. FDA Workflow for eCTD Dependencies
Fillable forms
Electronic signatures
Submission via Electronic Submission Gateway (ESG)
Receipts & acknowledgments returned to sponsor
Programmatic validation with error reports returned to sponsor

29. FDA Electronic Submission Gateway
ASR

30. ASR Process FDA Automated Submission Receipt (ASR)
Receipt via Electronic Submission Gateway (ESG)
ASR process
Processes eCTD
Performs initial validation
Activates eCTD validation
Loads the submission into CDER’s tracking system (need for fillable forms)
Notifies the Regulatory Project Manager

31. FDA Use of eCTD FDA CDER & CBER Replace paper submissions
For use in office
For use at home
For use at sponsor sites during investigations
Navigate content more quickly
Cut & paste from PDF file into reviewers’ reports
Copy SAS Transport files into reviewers’ statistical analysis environment
Reduce cost of handling/managing/retrieving paper submissions – miles of paper!
Increased velocity of review

32. Sponsor Workflow for Paper Submissions
Compilation
Submission
Traditional
of paper
1. Collect
documents
copies
Volumes & create TOCs
2. Manually
break into
~350pp
3. Photocopy,
create & insert
tabs
Prepare & label boxes, Prepare & label binders, Box, seal, palletize, shrink-wrap, ship

33. Sponsor Workflow for eCTD
2. Convert to PDF, confirm bookmarks &
hyperlinks, insert in eCTD folder structure
3. Add intra- document
hyperlinks, compile XML backbone, transmit
Author & maintain content in electronic format
eCTD Compilation

34. Options for eCTD
Produce in-house
Outsource
Combination

35. Steps to Prepare for eCTD
Purchase/develop MS Word templates
Train authors
Acquire digital certificates*
Acquire eCTD publishing capability (purchase software or arrange outsource service)
Qualify secure account with FDA
Qualify ESG production account*
Complete FDA pilots to (ESG, eCTD*, CDISC, etc.)
*more detail to follow

36. FDA eCTD Pilot
Recommended even if outsource vendor has history of successful submissions
Verify your own internal processes for finalizing documents for submission lifecycle
Develop communication process with outsource vendor
Develop internal QA/QC processes for source documents and submission sequences

37. FDA eCTD Pilot
Purpose
Validates the XML content of your pilot submission
Also looks at validity of folder/file structure
Turnaround time for feedback ~4 weeks weeks
Validation failure will require correction & resubmission
CDER does not look at PDF files*
CBER will look at all files and comment on their submission-readiness
*this will change with implementation of upgraded eCTD validation software

38. FDA eCTD Pilot
Additional details:

39. eCTD Quality Processes
Submit sample eCTD to FDA
Build quality into your process for success
Plan and prepare early
Build knowledge base: MS Word, Acrobat, eCTD
Require CROs & CMOs to supply searchable PDF reports compliant with eCTD Granularity & FDA PDF specs
Utilize a process & checklists to verify that submission is complete and accurate
Don’t rush (wrong digit in application number; duplicate submissions)
Validate and view submissions prior to submitting
Can’t trust outsource vendor – quality of submission is Sponsor’s responsibility

40. FDA Electronic Submission Gateway (ESG) Pilot
Additional details:
No paper required if eCTD submitted via ESG
Maximum submission size 45GB
FDA Forms require a signature:
Scanned – not recommended – fillable forms required by ASR process
Flattened digital signature
Digital

41. Flattened Digital Signature

42. Digital Certificate

43. FDA ESG Qualification & Costs
Obtain digital certificate: $0 - $100/person/year
Register for pilot
request for test account
Hardcopy letters of nonrepudiation
Prepare technical infrastructure – Webtrader $0 cost
Java software
Firewall configuration
Receive test account:
Submit small (20KB) text file for connectivity & load testing
Send 7.5GB non FDA-compliant load test submission
Receive acknowledgement and send FDA-compliant submission
Receive production account!

44. eCTD Near-Term Enhancements
FDA eCTD Validation Criteria V2.0
Draft guidance
58 total new errors
4 new High
38 new Medium
16 new Low
14 total removed
7 High
2 Medium
5 Low
New validation criteria for PDF file compliance*
*Noncompliant PDFs will be discovered earlier in the review process

45. FDA Validation Severity Levels
High – The error is a serious technical error which prevents the processing of the submission and will require resubmission. The submission is considered not received by FDA.
Medium – The error may impact the reviewability of the submission but cannot be determined without further inspection by the review staff. The submission might be considered received by FDA.
Low – The error is a technical error which may or may not impact the reviewability or the integrity of the submission. The submission will likely be considered received by FDA.

46. eCTD validation errors upon receipt
eCTD Points of Failure
PDUFA V timeline
Medium severity PDF errors that impede navigation
Bookmark/hyperlinks deficiencies
Content deficiencies
Incomplete submission
Incompatible datasets formats
eCTD validation errors upon receipt

47. PDF File Validation Errors
Description
Severity
Corrective Action
3102
Failed to process PDF contents
Medium
Resubmit corrected leaf in future submission
5005
Non standard font (not embedded)
See above
5020
PDF security used
5035
PDF version of document is incorrect
Low
No action necessary; modify SOPs to ensure future conformance
5040
PDF does not have “Fast Web Access” active
Ensure future documents have this feature
5045
PDF open settings not optimal
Ensure settings correct for all future submissions
5050
Document has password protection
Resubmit in a later submission

48. PDF File Validation Errors
Description
Severity
Corrective Action
5055
Document has annotations
Medium
Ensure documents in future submissions do not have this feature
5057
Document contains no text
Ensure documents in future submissions have searchable text
5100
Broken bookmark
You will be contacted if corrective action necessary; avoid in future submissions
5101
Corrupt bookmark
See above
5102
Bookmark has non-existent named destination or page
5103
Multiple action bookmark

49. PDF File Validation Errors
Description
Severity
Corrective Action
5105
External bookmark
Medium
Ensure future submissions do not contain bookmarks with this error
5110
Inactive bookmark
You will be contacted if corrective action necessary; avoid in future submissions
5115
Non-relative bookmark
See above
5117
Bookmark does not “Inherit Zoom”
Ensure all bookmarks are set to this property
5200
Broken hyperlink

50. PDF File Validation Errors
Description
Severity
Corrective Action
5201
Corrupt link
Medium
You will be contacted if corrective action necessary; avoid in future submissions
5202
Link has non-existent named destination or page
See above
5203
Multiple action hyperlink
5205
External hyperlink (e.g., web link, link)
Ensure documents in future submissions do not have external hyperlinks
5210
Inactive hyperlink

51. PDF File Validation Errors
Description
Severity
Corrective Action
5215
Non-relative hyperlink
Medium
You will be contacted if corrective action necessary; avoid in future submissions
5217
Link does not “Inherit Zoom”
Ensure all links in future submissions are set to this property

52. PDF Error Corrective Actions
Resubmit corrected leaf in future submission
You will be contacted if corrective action necessary; avoid in future submissions
No action necessary; modify SOPs to ensure future conformance
Ensure settings correct for all future submissions
Ensure future documents have this feature

53. Implementation of FDA Validation Criteria
FDA will give industry 30 days’ notice
Software has been installed and tested at FDA for over 1 year
Expected to be 1Q2013

54. Cost of eCTD Compliance
22% of FDA validation errors can be eliminated at the document formatting level* 70% of time, cost, effort of eCTD spent in remediation**
*FDA case study
**e-SubmissionsSolutions.com case study

55. US Module 1 Update Final guidance published in Federal Register
Implementation September 2013
New forms
New submission metadata
Future change add more headings for REMS
New 1.15 section & metadata for advertising and promotional materials

56. Conclusion & Action Items
If you haven’t already
Implement MS Word templates
Begin implementing your mandatory electronic submission compliance strategy today
Embrace the FDA PDF specifications
Engineer paper out of your content preparation processes
Become familiar with all the other provisions of FDASIA not covered today

57. Questions & Discussion
Antoinette Azevedo, President & CEO
e-SubmissionsSolutions.com
Telephone (619)
Fax (619)
Questions & Discussion