the evolution of electronic submissions by Pharma Student

Presenter

Nancy Smerkanich Vice President, Regulatory Affairs Octagon Research Solutions Nsmerkanich@octagonresearch.com 610.265.8300

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

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

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

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)

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”

Technical Foundations of Electronic Submissions

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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

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

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

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

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

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

Common Technical Document

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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

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Module 5: Clinical Study Reports

CTD Modules Module 1 – Regional Admin

Module 2 – Summaries

Module 3 – Quality

Module 4 – Nonclinical

Module 5 - Clinical

“Hybrid” eSub

NDA/BLA Sections 1. Index 2. Labeling 3. Summary 4. Chemistry 5. Nonclinical Pharm/Tox 6. Human PK and Bio 7. Clinical Microbiology 8. Clinical Data 9. Safety Update Report 10. Statistical Section 11. Case Report Tabulations 12. Case Report Forms 13. Patent Information 14. Patent Certification 15. Establishment Description 16. Debarment Certification 17. Field Copy Certification 18. User Fee Cover Sheet 19. Financial Disclosure 20. Other

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

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)

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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

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

eCTD US Implementation

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

Differences

eNDA/eBLA/eIND

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

• • • •

Applies to each type of application For FDA submissions Documents have low level of granularity Structure is flexible Uses PDF tables of contents

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

Structured Product Labeling: XML Sample

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

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

(recipe)

eCTD Primer

(ingredients)

DTD +

ICH

Sponsor

(mixer/oven)

TOOL

Vendors

= eCTD submission

Contains XML & File/folder structure

•

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

Pre eCTD: Input = Output

Section/Piece

Report

Volume/Submission

P R O C E S S

Assembly Formatting Clean Up Hyperlinks Bookmarks Report page numbering

Publishing Headers/Footers TOCs Hyperlinks Bookmarks Volume page numbering

eCTD: Input = Output

Section/Piece

3.2.P.1

eCTD

3.2.P.1

CSRs/STF: Input = Output

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

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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•

Summary

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

• •

Develop/document organizational standards Train staff on process, technology & NEW deliverables!

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

Questions

Thank You

Octagon Research Solutions www.octagonresearch.com 610.265.8300