Preparing Compliant eCTD Submissions


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Presented by Antoinette Azevedo, at Documentation and Training Life Sciences, June 23-26, 2008 in Indianapolis.

Life sciences regulatory authorities in North America, Europe and Japan have been developing standards for drug and biologic registration submissions in electronic format for over ten years. The current version of the format—electronic Common Technical Document (eCTD)—has been the recommended format since 2005 and is on the way to becoming mandatory. This presentation will provide an overview of best practices to enable a sponsor to prepare a compliant eCTD for regulatory authority review.

A California biotech submitted an eCTD to the US FDA in summer 2005. This company used commercial-off-the-shelf publishing software, experienced consultants, and in-house staff to compile this eCTD. This drug was the biotechs first candidate for commercialization. The biotech was partnered with big Pharma to assist with sales and marketing after the FDA authorized the drug for marketing. The biotech hired a sales force of nearly 200 in anticipation of FDA approval.

The FDA issued a refuse-to-file on this eCTD in fall 2005, due to problems with the PDF files and navigability of the content of the submission. The company’s market capitalization dropped 50% overnight. The company had to recompile the submission, by reworking the source files and rebuilding the XML backbone. The new version of the eCTD was resubmitted in early 2006. The FDA accepted the resubmission for review.

However, in May 2006 the FDA issued an approvable letter, that meant the drug could be approved in the future if certain conditions were met (meaning yet another delay in being able to market the product, plus additional expense to conduct further clinical studies). In June, 2006, the big pharma company terminated the partnership with the biotech. In July 2006, the biotech laid off their sales force. In August, 2006, the biotech laid off 100 more employees. In September 2006, the biotech had a meeting with FDA to discuss what additional studies and analysis was needed. Finally, in January 2007, the biotech announced plans to resubmit its NDA by end of second quarter 2007.

This presentation will describe:

* Regulatory and business drivers behind the eCTD format
* Technical components of an eCTD
* Practical implications of collecting documents and data over the discovery, development, application review, and post-marketing lifecycle phases of a drug or biological product
* Global picture for adoption of the eCTD format
* Future direction for the eCTD format
* Role of electronic document management in the eCTD lifecycle
* Top 12 Issues FDA Has with eCTD and how to avoid them
* Preparing submission-ready source documents and data for submission in eCTD
* Whether to purchase an eCTD publishing system or to outsource.
* How to prepare for the technical challenges of eCTD

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Preparing Compliant eCTD Submissions

  1. 1. Preparing Compliant eCTD Submissions Antoinette Azevedo, President DocTrain Life Sciences, Indianapolis, IN 24 June 2008 Copyright 2008 1
  2. 2. Agenda RTF Case Study What Can Go Wrong? How to Assure Compliance of Source Files? eCTD Workflow Questions & Discussion Copyright 2008 2
  3. 3. Four Keys to eCTD Success Content Process Standards Technology Copyright 2008 3
  4. 4. Refuse-to-File (RTF) Case Study Copyright 2008 4
  5. 5. The Guidance on RTF . . . July 2006, US FDA, “Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications,” Revision 1, 7087rev.pdf. Copyright 2008 5
  6. 6. A Picture through Stock Price Copyright 2008 6
  7. 7. Summer 2005 Small California Biotech-- Submits NDA in eCTD format to FDA CDER eCTD publishing system PDF toolkit Electronic document management systems Documentum OpenText LiveLink Consultants PDF preparation eCTD publishing & QC Copyright 2008 7
  8. 8. The Business Overview NDA is company’s first candidate for commercialization Company is partnered with big pharma who will assist with international sales and marketing post-approval Company hires 200 person sales force in anticipation of approval Copyright 2008 8
  9. 9. Fall 2005 FDA issues Refuse to File (RTF) under PDUFA timeline Inadequacy of individual PDF files Navigability of content of submission Market capitalization drops 50% overnight Analyst conference call Copyright 2008 9
  10. 10. Early 2006 Small biotech prepares resubmission Rework source files Rework CTD folder/file structure Rebuild XML backbone FDA accepts resubmission for review under PDUFA timeline Copyright 2008 10
  11. 11. May 2006 FDA issues “approvable” letter under PDUFA: Drug could be approved in future if certain conditions could be met “Conditions” to be determined in future meeting with FDA Copyright 2008 11
  12. 12. June 2006 Big pharma company withdraws from partnership Copyright 2008 12
  13. 13. July 2006 Small biotech lays off sales force Copyright 2008 13
  14. 14. August 2006 Small biotech lays off more than 100 additional employees Copyright 2008 14
  15. 15. September 2006 Small biotech has meeting with FDA concerning “approvable” conditions Additional studies required Additional analysis required Copyright 2008 15
  16. 16. January 2007 Biotech announces plans to resubmit NDA by 2Q2007 Copyright 2008 16
  17. 17. August 2007 FDA accepts NDA for review FDA sets PDUFA action date of 12 December 2007 Copyright 2008 17
  18. 18. December 2007 Company Announces Sale and Leaseback of Real Estate Assets Deal valued at $109M Net $61M after fees, expenses, etc. Leases back corporate headquarters Copyright 2008 18
  19. 19. December 2007 FDA issues “approvable” letter under PDUFA deadline: Objective/subjective trial in elderly Comparator safety study Preclinical evaluation during 3rd trimester of pregnancy Company cuts half its workforce Company prepares meeting request to FDA Ceases all clinical development and pre- commercialization activities for candidate drug Copyright 2008 19
  20. 20. January 2008 Founder-President-CEO resigns after 14 years of service Granted a formal meeting with FDA during 1Q08 to discuss 2007 Approvable Letter Copyright 2008 20
  21. 21. February 2008 Hope springs eternal . . . $20.0 million upfront license fee paid for drug candidate rights for Japan Balance sheet assets of $276.7 million 10 indications Three programs in Phase 1-2 for 7 indications Three research programs Copyright 2008 21
  22. 22. What Can Go Wrong with an eCTD? Copyright 2008 22
  23. 23. FDA’s Top 12 Issues for eCTD Success* 12. SPL must be in “SPL” folder 11. Use elements and leaf titles correctly 10. Always reference all files in the XML backbone(s) 9. Include Module 1 in All eCTD Submissions 8. Make sure all application numbers are 6 digits 7. Make sure all sequence numbers are 4 digits 6. Do not use node extensions 5. Verify that all MD5 checksums are correct 4. All documents should conform to eCTD granularity 3. All XML must use standard components *Source: Virginia Ventura, FDA CDERPDF hyperlinks & bookmarks 2. Be sure all Office of Business Process Support are correct Copyright 2008 23 1. Include TOCs in all PDF documents
  24. 24. Technical Issues with eCTD* 12. SPL must be in “SPL” folder 11. Use elements and leaf titles correctly 10. Always reference all files in the XML backbone(s) 9. Include Module 1 in All eCTD Submissions 8. Make sure all application numbers are 6 digits 7. Make sure all sequence numbers are 4 digits 6. Do not use node extensions 5. Verify that all MD5 checksums are correct 3. All XML must use standard components *Source: Virginia Ventura, FDA CDER Office of Business Process Support Copyright 2008 24
  25. 25. Technical Issues with Source Files* 4. All documents should conform to eCTD granularity 2. Be sure all PDF hyperlinks & bookmarks are correct 1. Include TOCs in all PDF documents *Source: Virginia Ventura, FDA CDER Office of Business Process Support Copyright 2008 25
  26. 26. What is CTD/eCTD? Module 1 Not part of CTD Module 1 Regional Info 2.1 Table of Contents 2.2 Introduction Module 2 2.3 2.4 Nonclinical 2.5 Clinical Summary Overview Overview Quality Overall 2.6 Nonclinical 2.7 Clinical Summary Summary Summary Module 3 Module 4 Module 5 Quality Safety Efficacy Copyright 2008 26
  27. 27. What is CTD/eCTD? Submission “nda121212” Sequence “0000” with 5 modules Sequence “0002” with 4 modules Copyright 2008 27
  28. 28. Where is XML Required? “XML backbone” Copyright 2008 28
  29. 29. As the FDA Sees an eCTD Copyright 2008 29
  30. 30. Where is XML Required? Module 1 Regional Copyright 2008 30
  31. 31. Where is XML required? Structured Product Labeling (SPL) Copyright 2008 31
  32. 32. Where is XML required? Module 4 Study Tagging File (STF) Copyright 2008 32
  33. 33. STF for Module 4 Copyright 2008 33
  34. 34. Where is XML required? Module 5 Study Tagging File (STF) Copyright 2008 34
  35. 35. STF for Module 5 Copyright 2008 35
  36. 36. Potential Problems with XML Sponsor’s hand coding of XML eCTD publishing vendor misinterpretation of XML document type definition (DTD) Sponsor’s usage of eCTD publishing system eCTD publishing vendor not providing enough guidance and control of user actions Copyright 2008 36
  37. 37. What is XML? Document/data interchange standard Originated from SGML/HTML Replaces traditional submission table of contents Rules for individual instances contained in Document Type Definitions (DTD) or Schemas Copyright 2008 37
  38. 38. What is XML? Copyright 2008 38
  39. 39. Challenges of eCTD: The Numbers According to FDA CDER: NDAs will have multiple submissions over their life- cycle Of 10 most active eNDAs: 6 had 111 to 139 submissions 1 had 185 submissions 1 had 202 submissions Of eSubmissions: One initial submission had 5478 files One eCTD supplement had over 15,000 files Copyright 2008 39
  40. 40. Challenges of eCTD Document Authoring -- Creation of PDFs highly dependent on use of word processor Templates Styles Cross references – how & to what Within document Outside document Copyright 2008 40
  41. 41. Challenges of eCTD Granularity of content organization Module 2: Quality, Nonclinical, Clinical summaries Module 3: Quality Module 4: Nonclinical study reports Module 5: Clinical study reports Regional differences US Integrated Analysis of Safety (IAS—formerly ISS) Integrated Analysis of Efficacy (IAE—formerly ISE) EU Expert reports CRFs – in or out CRTs – in or out Copyright 2008 41
  42. 42. Challenges of eCTD Collecting documents/data from study sites Case Report Forms Cost/time to convert to compliant electronic format Consistency of organization Changes of study protocol Different CROs involved in different study phases Electronic Data Capture (EDC) Location of queries & data correction forms (DCFs) Does my drug’s indication imply need to review CRFs? Which CRFs will I need to submit? Deaths/Drops/Serious AEs All Other Copyright 2008 42
  43. 43. Challenges of eCTD Documents/data from study sites Data Can all the data be delivered in electronically-reviewable format? Can I convert from proprietary formats into SAS XPT compliant formats? Excel Access Other Will the agency review my electronic datasets? Stability Nonclinical Clinical Copyright 2008 43
  44. 44. Challenges of eCTD Electronic Document Management Systems (EDMS) vs. Shared File System How do I know I have the final, approved document? What if the final, approved document changes? What is the effective version for a submission sequence? Do I have the time/budget/resources to implement EDMS? Will the EDMS meet the needs of my entire enterprise? Will the EDMS integrate with my e-Submission publishing process and tools? How do I assure the EDMS is 21 CRF 11 compliant? Copyright 2008 44
  45. 45. eCTD Challenge: The Granularity FDA CDER Study Tagging Files Scope – nonclinical & clinical study reports Lifecycle – from initial IND to product end-of- life Small unit of document granularity Hyperlinking between files Hyperlinking between submission serial numbers A cultural change for most CROs and authors Copyright 2008 45
  46. 46. Granularity – Quality Overall Summary Copyright 2008 46
  47. 47. Granularity – CMC/Quality Drug Product Copyright 2008 47
  48. 48. Study Report Granularity Copyright 2008 48
  49. 49. US, EU, Japan Experience To Date Problems with PDF Files Lacking navigation aids: Bookmarks Hyperlinks Document tables of contents Absolute paths on hyperlinks Security File format Incorrect granularity Referencing proprietary style sheets Copyright 2008 49
  50. 50. Conclusion from Experience to Date System is needed to produce XML backbone Source documents and data need to be submission-ready & compliant with requirements Sponsors need intimate knowledge of the XML output of their commercial-off-the-shelf (COTS) systems Sponsors must understand how agencies use the components of an eCTD for review Copyright 2008 50
  51. 51. Four Keys to eCTD Success Content Process Standards Technology Copyright 2008 51
  52. 52. How to Assure Compliance of Source Files? Copyright 2008 52
  53. 53. Credits & Disclaimers MS Word templates courtesy Sage Submissions LLC MS Office version 2000 Professional Adobe Acrobat 2007 Professional MS Windows XP Professional 5.1 (SP2) ISIToolbox Pharma Edition 5.5.1 Copyright 2008 53
  54. 54. Credits & Disclaimers Enfocus PitStop Professional 7.01 eCTD sample courtesy GlobalSubmit Parsing/validating samples courtesy GlobalSubmit & ING America Copyright 2008 54
  55. 55. FDA Portable Document Format Specifications PDF_specification_v11.pdf Examples follow . . . Copyright 2008 55
  56. 56. PDF Version 1.4 Options: “Reduce file size” Output by EDMS or eCTD publishing system Copyright 2008 56
  57. 57. Embed Fonts Not needed for standard font sets Options Converting from MS Word Setting in Acrobat Distiller Copyright 2008 57
  58. 58. Embed Fonts Options Embed from within Acrobat Standard or Professional Done on a text blocks Not recommended unless no other option Copyright 2008 58
  59. 59. Embed Fonts Options Enfocus PitStop Professional Done a line at a time Not recommended unless no other option Copyright 2008 59
  60. 60. Page Orientation Copyright 2008 60
  61. 61. Page Size & Margins Copyright 2008 61
  62. 62. Source of Electronic Document Avoid scanning unless no other choice Create PDFs from intelligent source MS Office—Word, Excel, PowerPoint Other word processors, spreadsheets, etc. ASCII text PDFs should be: Searchable Copy & paste to edit in other documents Copyright 2008 62
  63. 63. If You Must Scan Document Type Resolution Handwritten notes 300 dpi (black ink) Plotter output graphics 300 dpi Photographs—b&w 600 dpi (8 bit gray scale) Photographs—color 600 dpi (24 bit RGB) Gels and karotypes 600 dpi (8 bit grayscale depth) High pressure liquid chromatography 300 dpi Copyright 2008 63
  64. 64. Lossless Image Compression for Scanned Documents Black & White Image Color & Grayscale CCITT Group 4 Fax Zip/Flate Reduce file size No loss of data Copyright 2008 64
  65. 65. Copyright 2008 65
  66. 66. Image Color Matching CMYK for display Pantone for printing aspx Calibrated lookup tables for printers Printer application support files Adobe Illustrator, Photoshop, Indesign Macromedia Freehand CorelDraw Quark Xpress Copyright 2008 66
  67. 67. Copyright 2008 67
  68. 68. Hypertext Linking Navigation improved for PDF documents Hypertext links for: Annotations Related sections References Appendices Tables or figures For anything not located on same page Copyright 2008 68
  69. 69. Table of Contents & Hyperlinks Hyperlinks designated by blue text or rectangles with thin lines Blue text for PDFs from intelligent source Thin rectangles only option for scanned documents Tables of Contents Hyperlinked Invisible rectangles and blue text preferred eCTD publishing system can automate some Copyright 2008 69
  70. 70. Copyright 2008 70
  71. 71. Use Relative Paths for Hyperlinks eCTD publishing system should generate automatically Copyright 2008 71
  72. 72. Use Relative Path for Hyperlinks However! Acrobat still shows relative path Link report courtesy Image Solutions, Inc. ISIToolbox Pharma Edition Bookmark & Link Auditor, Export Bookmarks and Links Copyright 2008 72
  73. 73. Bookmarks Hierarchy = TOC Up to 4 Levels eCTD publishing system should generate automatically Copyright 2008 73
  74. 74. Bookmarks & Hyperlinks Magnification = Inherit Zoom eCTD publishing system should generate automatically Link/Bookmark report courtesy Image Solutions, Inc. ISIToolbox Pharma Edition Export Bookmarks and Links Copyright 2008 74
  75. 75. Page Numbering Document Page = PDF Page Copyright 2008 75
  76. 76. Initial View = Bookmarks & Page eCTD publishing system should generate automatically Copyright 2008 76
  77. 77. File Naming & Folder/File Path Use lower cases letters Avoid special characters except hyphens File/folder path: 230 characters for full folder/file path 64 characters for folder names eCTD publishing system should generate/truncate automatically Copyright 2008 77
  78. 78. Verbally Communicated Requirements Open to TOC Optimize for Fast Web View Font size 12 point font for text 10 point for tables (9.5 pt) Copyright 2008 78
  79. 79. Open to TOC Page Copyright 2008 79
  80. 80. Open to TOC Copyright 2008 80
  81. 81. Optimize for Fast Web View Copyright 2008 81
  82. 82. Institute Standards for Data Inside and outside suppliers Datasets – must have complete documentation Datasets table of contents Variable definition file—complete Datasets in SAS transport Annotated CRF (for human studies) Copyright 2008 82
  83. 83. Complete Datasets Documentation Copyright 2008 83
  84. 84. Bookmarking of CRFs Copyright 2008 84
  85. 85. Four Keys to eCTD Success Content Process Standards Technology Copyright 2008 85
  86. 86. eCTD Workflow Copyright 2008 86
  87. 87. eCTD Single “Document” Workflow Compile to Collect Source Verify Single Files or Release for Documents Completeness Study Tagging Files Publishing & Data (STF) If incomplete, Incorrect, or PDF Deliverables – Individual Files Content revised Bookmarks & hyperlinks Tables of contents Pagination 1 through n Optimized for fast web viewing File Format 1.4 Copyright 2008 87
  88. 88. eCTD Submission Workflow Prepare Repository Insert Content in Insert Cross- Output for Handoff eCTD Outline Document Hyperlinks for QC Set Submission Adjust Submission & Document & Document Issues? Attributes Attributes • Invalid XML • Source document changed • Dead or missing bookmarks or hyperlinks Copyright 2008 88
  89. 89. Components of an EDMS Authoring Client Scanner EDMS Server Rendition Server RDBMS for PDF Renditions & File Store Copyright 2008 89
  90. 90. Components of Submission Publishing System e-Submission Publishing Client File Server FDA ESG EDMS Server, Publishing Server, RDBMS & RDBMS p-Submission & File Store Web Server Copyright 2008 90
  91. 91. TimeLine for Implementation Implementation Steps 1Q 2Q 3Q 4Q 5Q 6Q Gather EDMS & eCTD system requirements; determine validation requirements Identify potential vendors; select short list Prepare & issue RFP, reduce vendor list, start negotiations Order & install hardware; install EDMS software, perform IQ/OQ validation Train users, help desk, administrators; perform EDMS UAT & PQ validation Install & validate eCTD software. Produce small submissions – INDs, Annual Reports, Amendments, Supplements, Safety Updates Produce marketing application & submit Copyright 2008 91
  92. 92. Consistency of eCTD across ICH Vendors’ ability to offer Sponsors’ systems inexpensive solutions ability to manage for multiple eCTD lifecycle metadata markets’ requirements over drug’s lifetime eCTD Critical Success Factors Copyright 2008 92
  93. 93. eCTD: Challenges to Sponsors Return on Investment (ROI) Cost of systems, training, process redesign Cost of noncompliance Speed, efficiency Submission compilation Agency review process Lead time to application submission On-going compliance Copyright 2008 93
  94. 94. eCTD: Benefits to Sponsors: Electronic content for sponsor’s internal access (Potentially) faster agency review Higher quality agency review Demonstrated lower cost of production compared with paper Faster time from database lock to submission Copyright 2008 94
  95. 95. Status of eCTD Requirements FDA CDER eCTD mandated January 1, 2008+ for electronic submissions CBER Accepting both eCTD and eBLA Sometimes e-submission mandatory (fast-track, rolling submissions) FDA CDRH Guidances required Informal pilots underway Turbo 510K Global Harmonization Task Force (GHTF) and STED Copyright 2008 95
  96. 96. Status of FDA ESG e-Sub May 2006 May 2007 Feb 2008 Total AERS 9,109 12,917 247,925 CDER 20 1,009 15,931 CBER 6 101 2,146 CDRH 153 75 3,364 CVM 414 Totals 9,228 14,201 269,780 Copyright 2008 96
  97. 97. Business Case for ESG 1500 submissions (non-AERS) Manual submission of electronic media & supporting paper = $111,183 ESG startup (training, security certificates, hardware) = $30,999 . . . $20.00+ Time/resource efficiency for Sponsor & Agency Copyright 2008 97
  98. 98. Business Case Against Paper 10 copies, 100 volume submission $163,290 Total $147,000 = printing $5,790.00 = binder materials $10,500.00 = shipping Does not include labor to assemble, page stamp, manual TOCs, binding, QC, labeling, packing Copyright 2008 98
  99. 99. Four Keys to eCTD Success Content Process Standards Technology Copyright 2008 99
  100. 100. Status of eCTD Requirements EU/Japan/Canada PDF reviewers’ aids accepted along with paper volumes eCTD dependent on each country’s information technology infrastructure Needs early & frequent communication to determine ability to accept & review Rest of World Highly dependent on information technology infrastructure to review e-submissions Copyright 2008 100
  101. 101. EMEA eCTD Statement of Intent 1 July 2008 – accept eCTD or non-eCTD electronic-only 1 January 2009 – strongly recommend eCTD or non-eCTD; paper an exception 1 July 2009 – strongly recommend eCTD; paper and other formats an exception All applications (new and existing) All submission types for Centralised Procedure Rapporteurs & CHMP members receive no paper or other electronic formats beyond this date Copyright 2008 101
  102. 102. Japan eCTD Experience MHLW statistics as of December 2007: Original Applications = 6 (13 sequences) Reference Applications = 52 (70 sequences) Total = 58 (83 sequences) Free eCTD Validator Integrating eClinical Trial and eSubmission throughout drug development lifecycle CDISC standars for clinical trial data Copyright 2008 102
  103. 103. Health Canada eCTD Transition Phase 1 – Co-submission Original Submission: eCTD Format on CD and DVD along with full paper-based submission in CTD format Subsequent Submissions: Continue use of both formats Phase 2 - Hybrid submission Original Submission: eCTD format on CD and DVD along with Module 1 and 2 only in paper-based CTD format Subsequent submissions: Submit Modules 1 & 2 in both formats Original & Subsequent Submissions: Modules 3 to 5 may be subject to print-on-demand requests Electronic-only Original Submission: eCTD format with no accompanying paper Subsequent submissions: Do not revert to paper-based CTD Copyright 2008 103
  104. 104. Health Canada: Criteria for Participation in the Hybrid Filing Format Pilot Guidance January 25, 2006 December 31, 2007 Comparison (for pilot beginning on June 30, (effective immediately) 2006) Candidate Submission has priority review status New Drug Submissions (NDSs), submission Submission qualifies under the Abbreviated New Drug Submission types Notice of Compliance with conditions (ANDS), Supplement to a New Drug (NOC/c) policy Submission (SNDS), Supplement to a Health Canada does not have Abbreviated New Drug Submission capacity or ability to perform (SANDS) electronic review NDS labeling only if the original Submission to be assigned to a submission was filed in the co-submission reviewer on contract or a teleworker or hybrid filing formats Notifiable Change submissions and annual updates of Notices of Change related to a previously filed eCTD submission that was filed in the hybrid filing format Copyright 2008 104
  105. 105. Health Canada: Criteria for Participation in the Hybrid Filing Format Pilot Guidance January 25, 2006 December 31, 2007 Comparison (for pilot beginning on June 30, (effective immediately) 2006) Conditions Submission has Priority Review Health Canada does not have the where status capacity and ability to perform an candidate will Submission qualifies under the Notice electronic review not be of Compliance with conditions Submission to be assigned to a considered (NOC/c) policy reviewer on contract Health Canada does not have the capacity and ability to perform an electronic review Submission to be assigned to a reviewer on contract or a teleworker Copyright 2008 105
  106. 106. Health Canada: Implementation Considerations Issue Co-Submission Hybrid Submission Electronic-only Submission (Guidance Section 6.1) (Guidance Section 6.2) (Guidance Section 6.3) Paper content Complete paper-based Modules 1 & 2 in paper No paper CTD format Legal record Paper-based submission eCTD submission eCTD submission Signature Wet ink signature Digitized or scanned copy Electronic signature required of signed document Letter of Stating that material in Stating Modules 1 & 2 in Not applicable Attestation eCTD format exactly eCTD format exactly matches material in CTD matches material in CTD Technical pre- Recommended Required To be determined submission consultation Print on Not applicable <500 pages – done by To be determined demand Health Canada >500 pages – done by sponsor on request Copyright 2008 106
  107. 107. FDA Status--Part 15 Hearing Request for public input to influence development of new policy/regulation What do you think about an all-electronic submission environment? What do you think about implementing an electronic platform to promote electronic sharing and exchange of research and regulatory information? Public rule being written to mandate electronic submissions across all Centers of FDA—”years” to reach final rule RFI issued for public-private partnership to implement all- electronic submission environment Copyright 2008 107
  108. 108. FDA Datasets Status -- Study Data Tabulation Model (SDTM) FDA Public Meeting February 1, 2005 Steps being taken by FDA to require submission in electronic format: Stability datasets – HL7 Animal datasets – tabulation & analysis-ready Human datasets – tabulation & analysis-ready Profound change from business as usual Agency Sponsors CROs Vendors Additional resources: Copyright 2008 108
  109. 109. FDA Status—Electronic Submission Gateway (ESG) May 2006 – implemented Electronic Submission Gateway to enable fully-electronic bidirectional communication If sponsor has electronic signature policy & technology in place, no paper is required with submissions Forms (1571, 356h) and documents which require original wet signature on hardcopy Acceptable formats Scanned signatures Digital signatures Flattened digital signatures Copyright 2008 109
  110. 110. FDA Status--RPS Regulated Product Submission (RPS) under development Create one model for submission of regulated product information Framework for sponsors to send regulatory information Reviewers able to consistently locate requisite content Animal and human products—human therapeutics, medical devices, food additives, veterinary Worldwide use Copyright 2008 110
  111. 111. FDA Status--RPS Development under HL7 Randy Levin of FDA CDER one of three Co-Chairs HL7 being recognized as standards body by ICH Status June 2005 RPS Project initiated Sept. 2006 first test submission to FDA 2010+ implemented as extension to eCTD Copyright 2008 111
  112. 112. RPS--More Information RCRIM’s TC: RPS Information Page Product%20Submission&id=234&type=g HL7 tools model/V3Tooling/toolsIndex.htm Copyright 2008 112
  113. 113. FDA—SPL Resources Providing Regulatory Submissions in Electronic Format – Content of Labeling SPL Standard for Content of Labeling Q&As FDA proposes to perform Indexing of SPL: Copyright 2008 113
  114. 114. FDA Data Standards Council Structured Product Labeling Drug Registration Drug Listing Regulated Product Submission CDISC Data Standards Stability Data Standards Copyright 2008 114
  115. 115. FDA Resources for CTD Regulatory Submissions in Electronic Format – General Considerations eCTD Backbone Files Specification for Module 1 eCTD Backbone Files Specification for Modules 2 through 5 Copyright 2008 115
  116. 116. FDA Resources for CTD eCTD Backbone Files Specification for Study Tagging Files (STF)--Module 4 & Module 5 n%20of%20STFv2-6.pdf Comprehensive Table of Contents Headings and Hierarchy TOC-v1.2.pdf Copyright 2008 116
  117. 117. FDA Resources for CTD Study Data Specifications--Datasets ata-v1.3.pdf Portable Document Format Specifications Copyright 2008 117
  118. 118. Summary EU & Japan & Canada – eCTD preferred format for electronic; CTD required format for paper US – CTD preferred format for paper Rest of World-- ability to accept & review varies widely eCTD preferred format for e-Submissions eCTD remains optional except FDA CDER Paper submissions required by most countries Agency cannot legally accept electronic-only Agency IT infrastructure inadequate to perform electronic review Copyright 2008 118
  119. 119. eCTD Success! Critical Success Factors: Faster time to market Happier stockholders Greater employee & management satisfaction Lower cost of production Simultaneous global submissions Healthier patients Copyright 2008 119
  120. 120. Questions & Discussion Antoinette Azevedo, President & CEO Telephone (619) 220-7081 Fax (619) 220-0831 Copyright 2008 120