FDASIA, GDUFA and eCTD
Mandate
Antoinette Azevedo
President, e-SubmissionsSolutions.com
22 October 2012
1
Agenda

FDASIA* 2012


GDUFA*
eCTD overview
New Module 1
 New validation criteria
 New FDA forms


Discussion & conclusion
*definition to follow
2
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
3
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
http://www.fda.gov/ForIndustry/UserFees/default.htm
User fees contribute 2/3
of FDA CDER annual budget
4
GDUFA Resources
Website: https://www.fda.gov/gdufa
 Email: AskGDUFA@fda.hhs.gov
 Call: (866) 405-5367

5
Key Provisions of FDASIA

New user fees


ANDAs
DMF-IIs (drug substance + drug product)

Collected on unapproved ANDAs & open DMFS


Collected on newly-submitted ANDAs and DMF-IIs (referenced
by ANDA) starting 1 October 2012



30+ month backlog of unapproved ANDAs/unreviewed DMFs
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
6
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
7
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
8
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


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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
9
FDA Commitments on DMFs

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

10
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

11
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
12
GDUFA Implication for Sponsors
What if multiple
budget cycles
required?
Obtain
budget for
EDMS &
eCTD
3Q2012
What if one or
more vendors
fail?
Select
vendors
Implement &
validate
EDMS
What if one
or more
pilots fail?
Implement &
validate
eCTD
system
Participate
in FDA
pilots:
eCTD,
CDISC,
ESG
Business process redesign/reengineering
Training, coaching, content remediation
What if
FDA
validation
fails?
Go-live 6 to
12 months
ahead of
deadline
4Q2015
Mandate
(est.)
13
Review Timeline

Source: John K. Jenkins, MD,
Director, Office of New Drugs, CDER
Current PDUFA IV timeline
ANDAs

New PDUFA V timeline
NMEs &
NCEs
14
GDUFA Process



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Meetings between FDA and stakeholder groups
Minutes posted on FDA web site
http://www.fda.gov/ForIndustry/UserFees/GenericD
rugUserFees/ucm256662.htm
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
15
GDUFA Commitment Letter





GDUFA commitment letter (draft)
http://www.fda.gov/downloads/ForIndustry/UserFe
es/GenericDrugUserFees/UCM282505.pdf
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
16
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
17
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
18
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

19
eCTD OVERVIEW
20
What is eCTD?
Module 1
Not part of CTD
Module 1
Regional Info
2.1 Table of Contents
2.2 Introduction
2.3
Quality
Overall
Summary
Module 3
Quality
2.4
Nonclinical
Overview
2.6 Nonclinical
Summary
Module 4
Safety
2.5 Clinical
Overview
Module 2
Summary
2.7 Clinical
Summary
Module 5
Efficacy
21
Characteristics of eCTD

Pre-defined Folder & File Structure

Organized by technical discipline

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US requires additional documentation



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Quality = Chemistry, Manufacturing & Controls
Safety = Non-clinical (animal studies)
Efficacy = Clinical (human studies)
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)
22
What is eCTD?



Submission “900603”
Sequence “0000” with 5
modules
Sequence “0001” with 2
modules
23
File Formats


eXtensible Markup Language (XML)
Adobe Portable Document Format (PDF)

Bookmarks & hyperlinks:




Labeling in XML



Navigate through a file
Easily access related files & referenced content
Document TOCs to navigate content of a file
US: Structured Product Labeling (SPL)
US: SAS Transport for datasets
US: XML evolving datasets interchange standard
24
XML Backbone – Internet Explorer
25
Life Cycle – eCTD Browser
History of
submissions
Modify content
submitted in
prior
sequences
Filtered
views
View PDF file
content
26
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
27
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
28
FDA Electronic Submission Gateway
ASR
29
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
30
FDA Use of eCTD

FDA CDER & CBER

Replace paper submissions

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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
31
Sponsor Workflow for Paper Submissions
1. Collect
copies
of paper
documents
Prepare & label
boxes, Prepare
& label binders,
Box, seal,
palletize, shrinkwrap, ship
Traditional
Submission
Compilation
2. Manually
break into
~350pp
Volumes &
create TOCs
3. Photocopy,
create & insert
tabs
32
Sponsor Workflow for eCTD
1. Author &
maintain
content in
electronic
format
2. Convert to
PDF, confirm
bookmarks &
hyperlinks,
insert in eCTD
eCTD
Compilation folder structure
3. Add intradocument
hyperlinks,
compile
XML backbone,
transmit
33
Options for eCTD
Produce in-house
 Outsource
 Combination

34
Steps to Prepare for eCTD


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Purchase/develop MS Word templates
Train authors
Acquire digital certificates*
Acquire eCTD publishing capability (purchase
software or arrange outsource service)
Qualify secure email account with FDA
Qualify ESG production account*
Complete FDA pilots to (ESG, eCTD*, CDISC,
etc.)
*more detail to follow
35
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

36
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
37
FDA eCTD Pilot

Additional details:
http://www.fda.gov/Drugs/DevelopmentAppr
ovalProcess/FormsSubmissionRequirement
s/ElectronicSubmissions/ucm153574.htm
38
eCTD Quality Processes


Submit sample eCTD to FDA
Build quality into your process for success



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
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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
39
FDA Electronic Submission
Gateway (ESG) Pilot




Additional details: http://www.fda.gov/esg/
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
40
Flattened Digital Signature
41
Digital Certificate
42
FDA ESG Qualification & Costs


Obtain digital certificate: $0 - $100/person/year
Register for pilot



Prepare technical infrastructure – Webtrader $0 cost



Java software
Firewall configuration
Receive test account:




Email request for test account
Hardcopy letters of nonrepudiation
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!
43
eCTD Near-Term Enhancements

FDA eCTD Validation Criteria V2.0

Draft guidance http://tinyurl.com/4mh7p8l/

58 total new errors




14 total removed




4 new High
38 new Medium
16 new Low
7 High
2 Medium
5 Low
New validation criteria for PDF file compliance*
*Noncompliant PDFs will be discovered earlier in the review process
44
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.
45
eCTD Points of Failure

PDUFA V timeline
eCTD
validation
errors upon
receipt
•
•
•
•
•
Medium severity PDF errors that impede navigation
Bookmark/hyperlinks deficiencies
Content deficiencies
Incomplete submission
Incompatible datasets formats
46
PDF File Validation Errors
Error# Description
Severity Corrective Action
3102
Failed to process PDF contents
Medium
Resubmit corrected leaf in
future submission
5005
Non standard font (not embedded)
Medium
See above
5020
PDF security used
Medium
See above
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
Medium
Ensure future documents
have this feature
5045
PDF open settings not optimal
Medium
Ensure settings correct for
all future submissions
5050
Document has password protection Medium
Resubmit in a later
submission
47
PDF File Validation Errors
Error#
Description
Severity
Corrective Action
5055
Document has
annotations
Medium
Ensure documents in future
submissions do not have this feature
5057
Document contains
no text
Medium
Ensure documents in future
submissions have searchable text
5100
Broken bookmark
Medium
You will be contacted if corrective
action necessary; avoid in future
submissions
5101
Corrupt bookmark
Medium
See above
5102
Bookmark has nonexistent named
destination or page
Medium
See above
5103
Multiple action
bookmark
Medium
See above
48
PDF File Validation Errors
Error# Description
Severity
Corrective Action
5105
External bookmark
Medium
Ensure future submissions do
not contain bookmarks with this
error
5110
Inactive bookmark
Medium
You will be contacted if
corrective action necessary;
avoid in future submissions
5115
Non-relative
bookmark
Medium
See above
5117
Bookmark does
not “Inherit Zoom”
Medium
Ensure all bookmarks are set to
this property
5200
Broken hyperlink
Medium
You will be contacted if
corrective action necessary;
avoid in future submissions
49
PDF File Validation Errors
Error#
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
Medium
See above
5203
Multiple action hyperlink
Medium
See above
5205
External hyperlink (e.g.,
web link, email link)
Medium
Ensure documents in
future submissions do
not have external
hyperlinks
5210
Inactive hyperlink
Medium
You will be contacted if
corrective action
necessary; avoid in
future submissions
50
PDF File Validation Errors
Error#
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”
Medium
Ensure all links in future
submissions are set to
this property
51
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
52
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

53
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
54
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

55
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

56
Antoinette Azevedo, President & CEO
e-SubmissionsSolutions.com
AAzevedo@e-SubmissionsSolutions.com
http://www.e-SubmissionsSolutions.com/
Telephone (619) 220-7081
Fax (619) 220-0831
Questions & Discussion
57