Preparing Compliant eCTD Submissions

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 e-SubmissionsSolutions.com 5

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 e-SubmissionsSolutions.com 7

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 e-SubmissionsSolutions.com 8

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 e-SubmissionsSolutions.com 9

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 e-SubmissionsSolutions.com 10

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 e-SubmissionsSolutions.com 11

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 e-SubmissionsSolutions.com 18

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 e-SubmissionsSolutions.com 19

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 e-SubmissionsSolutions.com 21

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 e-SubmissionsSolutions.com 23 1. Include TOCs in all PDF documents

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 e-SubmissionsSolutions.com 24

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 e-SubmissionsSolutions.com 25

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 e-SubmissionsSolutions.com 26

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 e-SubmissionsSolutions.com 36

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 e-SubmissionsSolutions.com 37

Challenges of eCTD: The Numbers According to FDA CDER: NDAs will have multiple submissions over their lifecycle 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 e-SubmissionsSolutions.com 39

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 e-SubmissionsSolutions.com 40

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 e-SubmissionsSolutions.com 41

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 e-SubmissionsSolutions.com 42

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 e-SubmissionsSolutions.com 43

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 e-SubmissionsSolutions.com 44

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 e-SubmissionsSolutions.com 45

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 e-SubmissionsSolutions.com 49

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 e-SubmissionsSolutions.com 50

Credits & Disclaimers MS Word templates courtesy Sage Submissions LLC http://www.sagesubmissions.com/ MS Office version 2000 Professional Adobe Acrobat 2007 Professional http://www.adobe.com/products/acrobat/index.html MS Windows XP Professional 5.1 (SP2) ISIToolbox Pharma Edition 5.5.1 http://www.imagesolutions.com/Default.aspx?alias=www. imagesolutions.com/isitoolbox Copyright 2008 e-SubmissionsSolutions.com 53

Credits & Disclaimers Enfocus PitStop Professional 7.01 http://www.enfocus.com/product.php?id=855 eCTD sample courtesy GlobalSubmit http://www.globalsubmit.org/ Parsing/validating samples courtesy GlobalSubmit & ING America http://www.ingamerica.com/ Copyright 2008 e-SubmissionsSolutions.com 54

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 e-SubmissionsSolutions.com 62

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 e-SubmissionsSolutions.com 63

Image Color Matching CMYK for display Pantone for printing http://www.pantone.com/pages/pantone/index. aspx Calibrated lookup tables for printers Printer application support files Adobe Illustrator, Photoshop, Indesign Macromedia Freehand CorelDraw Quark Xpress Copyright 2008 e-SubmissionsSolutions.com 66

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 e-SubmissionsSolutions.com 68

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 e-SubmissionsSolutions.com 69

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 e-SubmissionsSolutions.com 72

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 e-SubmissionsSolutions.com 74

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 e-SubmissionsSolutions.com 77

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 e-SubmissionsSolutions.com 82

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 e-SubmissionsSolutions.com 87

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 e-SubmissionsSolutions.com 88

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 e-SubmissionsSolutions.com 90

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 e-SubmissionsSolutions.com 91

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 e-SubmissionsSolutions.com 92

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 e-SubmissionsSolutions.com 93

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 e-SubmissionsSolutions.com 94

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 http://www.fda.gov/cdrh/cesub/index.html Global Harmonization Task Force (GHTF) and STED Copyright 2008 e-SubmissionsSolutions.com 95

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 e-SubmissionsSolutions.com 96

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 e-SubmissionsSolutions.com 97

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 e-SubmissionsSolutions.com 98

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 e-SubmissionsSolutions.com 100

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 e-SubmissionsSolutions.com 101

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 e-SubmissionsSolutions.com 102

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 e-SubmissionsSolutions.com 103

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 e-SubmissionsSolutions.com 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) 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 e-SubmissionsSolutions.com 105

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 e-SubmissionsSolutions.com 106

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 http://www.fbo.gov/spg/HHS/FDA/DCASC/e-Platform-RFI/listing.html Copyright 2008 e-SubmissionsSolutions.com 107

FDA Datasets Status -- Study Data Tabulation Model (SDTM) FDA Public Meeting February 1, 2005 http://www.fda.gov/oc/datacouncil/presentations.html 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: http://www.cdisc.org/ http://www.hl7.org/ Copyright 2008 e-SubmissionsSolutions.com 108

FDA Status—Electronic Submission Gateway (ESG) May 2006 – implemented Electronic Submission Gateway to enable fully-electronic bidirectional communication http://www.fda.gov/esg/ 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 e-SubmissionsSolutions.com 109

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 e-SubmissionsSolutions.com 110

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 e-SubmissionsSolutions.com 111

RPS--More Information RCRIM’s TC: https://www.hl7.org/Special/committees/rcrim/index.cfm RPS Information Page https://gforge.nci.nih.gov/plugins/wiki/index.php?Regulated%20 Product%20Submission&id=234&type=g HL7 tools https://www.hl7.org/Library/data- model/V3Tooling/toolsIndex.htm Copyright 2008 e-SubmissionsSolutions.com 112

FDA—SPL Resources Providing Regulatory Submissions in Electronic Format – Content of Labeling http://www.fda.gov/cder/guidance/6719fnl.pdf SPL Standard for Content of Labeling Q&As http://www.fda.gov/cder/guidance/7074fnl.pdf FDA proposes to perform Indexing of SPL: http://www.fda.gov/cder/guidance/7662dft.pdf Copyright 2008 e-SubmissionsSolutions.com 113

FDA Data Standards Council http://www.fda.gov/oc/datacouncil/ Structured Product Labeling Drug Registration Drug Listing Regulated Product Submission CDISC Data Standards Stability Data Standards Copyright 2008 e-SubmissionsSolutions.com 114

FDA Resources for CTD Regulatory Submissions in Electronic Format – General Considerations http://www.fda.gov/cder/guidance/4156dft.pdf eCTD Backbone Files Specification for Module 1 http://www.fda.gov/cder/regulatory/ersr/Module1Spec.pdf eCTD Backbone Files Specification for Modules 2 through 5 http://www.fda.gov/cder/regulatory/ersr/module2-5spec.pdf Copyright 2008 e-SubmissionsSolutions.com 115

FDA Resources for CTD eCTD Backbone Files Specification for Study Tagging Files (STF)--Module 4 & Module 5 http://www.fda.gov/cder/regulatory/ersr/FDA%20implementatio n%20of%20STFv2-6.pdf Comprehensive Table of Contents Headings and Hierarchy http://www.fda.gov/cder/regulatory/ersr/5640C TOC-v1.2.pdf Copyright 2008 e-SubmissionsSolutions.com 116

FDA Resources for CTD Study Data Specifications--Datasets http://www.fda.gov/cder/regulatory/ersr/Studyd ata-v1.3.pdf Portable Document Format Specifications http://www.fda.gov/cder/regulatory/ersr/PDF_specification_v11.pdf Copyright 2008 e-SubmissionsSolutions.com 117

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 e-SubmissionsSolutions.com 118

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 e-SubmissionsSolutions.com 119

Questions & Discussion Antoinette Azevedo, President & CEO e-SubmissionsSolutions.com AAzevedo@e-SubmissionsSolutions.com http://www.e-SubmissionsSolutions.com/ Telephone (619) 220-7081 Fax (619) 220-0831 Copyright 2008 e-SubmissionsSolutions.com 120