1

2 Presenter

Nancy SmerkanichVice President, Regulatory Affairs

Octagon Research SolutionsNsmerkanich@octagonresearch.com

610.265.8300

3 The Evolution of Electronic Submissions

• History of Electronic Submissions (eSubs)• Review of FDA Guidance Documents• Review of Structured Product Labeling• eCTD Impact• eSub Definitions: “Hybrid” vs. eCTD

4 US vs. Global

• US has been the global leader in Electronic submissions– Electronic review aids in EU– Archive requirements in EU

• US focus on the data • EU focus on the summaries

5 Paper Submissions

• “Volumes” of information– 350-400 pages per volume– New Drug Applications may be hundreds or

thousands of volumes– Typically delivered to Regulatory Authority in

trucks• Cross References located by tabs or manual

searching• Pagination and Tables of Contents at very end

6 US - CANDAs

• Computer Assisted New Drug Application (CANDA)• Given priority status over paper submissions• Gave reviewers access to reports and data• No standard – each sponsor chose hardware and software

and delivered to FDA• Required new training for each new submission• Reduced review time by 6 months on average (from 24.6 to

18.4 months)

7 Need for Electronic Submissions in the US

• PDUFA deadlines• Medical reviewer questions

– Written request sent to sponsor for questions about documents and data

– Agency relies on Sponsor for all analyses• Reworking of statistical data

– Might take weeks• Reviews created “from scratch”

8 Technical Foundations of Electronic Submissions

• Portable Document Format (PDF)– Format for reports and other documentation– Preserves format of source documents– Can be viewed using Acrobat Reader or other software

• Statistical Analysis System (SAS) Transport Files (.xpt)– Format for clinical data– Similar to spreadsheet– Platform independent

• Extensible Markup Language – XML– Provides context and organization for submission content– Flexible, vendor-neutral technology

9 Trends

• It’s not just an electronic copy of the paper– Value added features– Navigation

• More work for sponsor initially• Critical importance of QA/QC• Submission development is a cross functional activity• Need for document and data standards• High impact on authoring/review and approval/process• Quicker reviews – internal and external• Drug Product Lifecycle Management – IND to NDA and

beyond

10 1997 Guidance

• September of 1997• Agency sought to define the structure and

technology used to submit Case Report Forms (CRFs) and Patient Data Listings (CRTs) electronically

• Consistent format would prevent reviewers from needing to be trained on multiple systems

• Accomplished through Guidance documents

11 1999 Guidances

• Guidance for Industry: Providing Regulatory Submissions in Electronic Format – General Considerations

• Providing Regulatory Submissions in Electronic Format – New Drug Applications– Allows for entire application (archival

and reviewer copies) to be submitted electronically

12 2001 Draft Guidance

• Guidance for Industry: Submitting Marketing Applications According to the ICH/CTD Format: General Considerations – Common Technical Document content in

eNDA folder structure– Considered an Interim Solution or Hybrid

13 Common Technical Document

What the CTD is NOT:• It is not a content tool

What the CTD IS:

• It is a formatting tool

• It is a logical ordering and organization of information

• It is a way of managing information at the document/page level

What the eCTD is:

• It is a delivery mechanism

14 Common Technical Document

• Module 1: Regional information (Not part of the CTD)

• Module 2:– Quality Overall Summary – Nonclinical Overview and Summary – Clinical Overview and Summary

• Module 3: Quality

• Module 4: Nonclinical Study Reports

• Module 5: Clinical Study Reports 3 4 5

1

2

15 “Hybrid” eSub

NDA/BLA Sections1. Index2. Labeling3. Summary4. Chemistry5. Nonclinical Pharm/Tox6. Human PK and Bio7. Clinical Microbiology8. Clinical Data9. Safety Update Report10. Statistical Section11. Case Report Tabulations12. Case Report Forms13. Patent Information14. Patent Certification15. Establishment Description16. Debarment Certification17. Field Copy Certification18. User Fee Cover Sheet19. Financial Disclosure20. Other

CTD Modules

Module 1 – Regional Admin

Module 2 – Summaries

Module 3 – Quality

Module 4 – Nonclinical

Module 5 - Clinical

16 2003 Draft Guidance

• Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions– Addresses IND/NDA, Annual Reports and other

submissions– Refer to Comprehensive Table of Contents;

Headings and Hierarchy and electronic Common Technical Document (eCTD) specifications

17 Electronic Common Technical Document

When is the eCTD being implemented?

• EU – Pilot viewing tool selected & implemented; EU Member states will accept eCTD as archive dependent on change in legislation (ie Denmark, Netherlands and Austria can archive electronic application)

• Observers such as Canada will be accepting eCTD for Modules 3,4 & 5 in June 05

• US – Pilot to eSUB office NOW; Review Divisions have access and training with new EVS tool; CDER evaluating viewing tools

• Japan – will be accepting eCTD for all modules beginning Apr 05

18 eCTD US Implementation

• FDA recommends starting with original applications (IND, NDA, sNDA, ANDA), as opposed to pending applications

• Once eCTD, always eCTD

19 Differences

eCTD• Applies to all types of

applications• For submissions to

multiple HAs• Documents are more

granular• Structure is rigid – not

flexible• Uses an XML backbone

for the table of contents

eNDA/eBLA/eIND• Applies to each

type of application• For FDA

submissions• Documents have

low level of granularity

• Structure is flexible• Uses PDF tables of

contents

20 Structured Product Labeling

• Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Content of Labeling (Draft Guidance Feb 2004)– Final Rule 11 Dec 2003 requiring submission of the

content of labeling in electronic format for marketing applications

– Effective 8 June 2004– Can be sent as pdf file– FDA Goal to transition to SPL format (XML) in 2005

21 Structured Product Labeling:XML Sample

22 Transitions to Electronic Submissions

• All companies will need to develop processes for electronic components– Labeling (SPL)– Data (CDISC)– Applications (eCTD)

• XML enabled tools• Assessment on organization and resources will be

critical

23 FDA eCTD Metrics

• Samples/pilots 38• IND application 1 (with 3 submissions)• ANDA applications 4 (with 7 submissions)• NDA applications 9 (with 94 submissions)• DMF applications 2 (with 2 submissions)• Total applications 16 (with 106 submissions)

• Per Ken Edmunds email 9/30/2004

24 eCTD Primer

ICH Vendors Contains XML &

File/folder structure

(ingredients)

+ TOOL+

(mixer/oven)

= eCTD submission

Sponsor

(recipe)

DTD

25 eCTD Primer

• Business implications of creating an eCTD– DTD dictates “heading” and “leaf” element metadata

• e.g., “operation” for leafs – new, append, replace or delete

• e.g., substance and manufacturer for <m2-3-s-drug-substance>

– Picking a starting point in a product submission lifecycle• Agency recommending original applications

• Submitting previously-submitted documents

– Study Tagging File

– Data Standards coming from CDISC

– Electronic signatures will be the subject of separate guidance

26 Pre eCTD: Input = Output

Assembly Formatting Clean Up

HyperlinksBookmarksReport page numbering

PublishingHeaders/Footers

TOCsHyperlinksBookmarks

Volume page numbering

Section/Piece Report Volume/Submission

PROCESS

PROCESS

27 eCTD: Input = Output

Section/Piece eCTD

3.2.P.1 3.2.P.1

28 CSRs/STF: Input = Output

29 eCTD Impact: Document Creation

• New mindset: Responsibility shifts to the author• Functional areas are the major contributors and directly

impacts the e-submission process• Authors can make the big difference in submission timing by

creating e-submission-ready pieces• Review and Approval of small pieces means content will be

reviewed out of context• Format in addition to content is important• Quality Assurance/ Quality Control• Consistency is the key

30 Summary

Issues for Transition to eCTD• Emphasis on developing/evaluating granular templates

• Guidance interpretation/organizational standards

• Maintaining document and data standards

• Authoring/review and approval impacts

• New processes required

• New tools for XML – effects all functions

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31 Summary

• Phased Transition approach– Guidance Interpretation– Process Definition– Implementation Plan

• Develop/document organizational standards

• Train staff on process, technology & NEW deliverables!

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32 Resources

Useful Links:

ICH – CTD: http://www.ich.org

FDA – CTD: http://www.fda.gov/cder/guidance/index.htm

FDA – eCTD: http://www.fda.gov/cder/m2/eCTD.htm

33 Questions

34

Thank You

Octagon Research Solutionswww.octagonresearch.com

610.265.8300