Guidance for Industry: Preparation of Drug Submissions in the Electronic Common Technical Document (eCTD) Format

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Contact: eReview

Notice

November 4, 2009

Our file number: 08-132465-142

Release of Revised Health Canada Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document (eCTD) Format

Health Canada is pleased to announce finalization of the document Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document (eCTD) Format. This guidance document will assist sponsors in the preparation of drug submissions in Electronic Common Technical Document (eCTD) format developed by the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use.

A Health Canada Questions and Answers document has also been developed to further clarify issues that have been raised in the course of consultations. This document, which can be found on the Health Canada Web site, will address future questions as they are submitted.

The guidance document defines the electronic format requirements, and provides additional guidance on the structure, content, and format of information to be included in submissions in eCTD format. It includes extensive discussion of the life cycle management of submissions. It defines three types of filing formats for drug submissions in eCTD format, co-submission, hybrid submission, and electronic-only submission, and contains information on the pilot implementation of the hybrid filing format. Health Canada's Guidance for Industry: Creation of the Canadian Module 1 eCTD Backbone File defines the specifications for the regional administrative module (Module 1) of the eCTD standard.

Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document (eCTD) Format is meant to be read in conjunction with the Electronic Common Technical Document Specification (Version 3.2), developed by the ICH M2 Expert Working Group, and the corresponding Questions and Answers document on the International Conference on Harmonisation Web site. Sponsors should also consult the other Health Canada guidance documents and notices on the Health Canada Web site, as listed in Appendix A of the guidance document.

The revised guidance document reflects comments received from stakeholders, including industry representatives. Those comments are collected in an issues analysis document, which includes the changes made to the document in response to the comments. The implementation and use of the eCTD format is a work in progress. Future refinements to the guidance document will continue to be necessary as a result of experience gained during implementation and subsequent iterations of the document will be released.

Health Canada has planned the transition from the acceptance of solely paper-based submissions and other electronic submission formats to the acceptance of stand-alone submissions in eCTD format that are filed in compliance with the ICH eCTD specification. Since September 1, 2004, Health Canada has accepted submissions in eCTD format accompanied with full paper-based submissions in CTD format (known as the co-submission filing format). On June 30, 2006, Health Canada began a pilot project for submissions in the hybrid format, which combines submission of all modules in eCTD format with submission of Modules 1 and 2 in the paper-based CTD format. The pilot project will be assessed once a sufficient number of submissions in hybrid format have been reviewed.

Health Canada's goal is to implement acceptance of submissions in eCTD format without any negative impacts on the review process, particularly with regards to performance targets. Health Canada is continuing through the following stages to implement its plan to enable acceptance of stand-alone submissions in eCTD format:

1. Acceptance of submissions in eCTD format on compact disks (CDs) and digital video disks (DVDs) along with full paper-based submissions in CTD format (ongoing).
2. Acceptance of submissions in eCTD format on CDs and DVDs along with partial paper-based submissions in CTD format (pilot project for hybrid submission ongoing).
3. Acceptance of submissions in eCTD format (electronic-only submission).

Any updates to eCTD filing requirements will only be introduced following advance consultation and notice, and will not be applied retroactively to submissions pending review. Furthermore, sponsors may continue to follow the Health Canada guidance documents in effect prior to the date of release of this notice for submissions currently in preparation. Subsequent submissions, however, should be compiled using the most recent guidance documents.

Contact

Questions or comments on Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document Format should be directed to the following contact:

Submission and Information Policy Division (SIPD)
Therapeutic Products Directorate
Health Canada
101 Tunney's Pasture Driveway
Address Locator: 0201A1
Ottawa, Ontario
K1A 0K9
E-mail: eReview@hc-sc.gc.ca

Date Adopted: 2005/05/16
Revised Date: 2008/09/17
Effective Date: 2009/11/04

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

Revision History

May 17, 2004: Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format (co-submission filing format only).

May 16, 2005: Guidance for Industry: Preparation of Drug Submissions in the eCTD Format (co-submission filing format only); final.

January 20,2006: Draft Guidance for Industry: Preparation of Drug Submissions in eCTD Format (co-submission and hybrid filing formats).

September 17, 2008: Guidance for Industry: Preparation of Drug Submissions in eCTD Format (co-submission and hybrid filing formats); final.

Table of Contents

• 1 Introduction
• 2 Purpose and Scope
  • 2.1 Structure and Content of this Guidance Document
  • 2.2 Drug Submission Information
  • 2.3 Additional Information and Subsequent Submissions
  • 2.4 Filing Formats of Submissions in eCTD Format
• 3 Structure and Content of Submissions in eCTD Format
  • 3.1 Cover Letter
  • 3.2 Folder Structure and File Naming Convention
  • 3.3 eCTD Structure and Leaf Title
• 4 Technical Requirements for Submissions in eCTD Format
  • 4.1 File Formats
  • 4.2 Media for Submitting Electronic Data in eCTD Format
  • 4.3 Life Cycle Management
  • 4.4 Bookmarks in PDF Files
• 5 Filing Process for Submissions in eCTD Format
  • 5.1 Hold Technical Pre-submission Consultation
  • 5.2 File eCTD Sample
  • 5.3 Verify eCTD Sample
  • 5.4 Correct Errors and File Corrected Sample
  • 5.5 Obtain eCTD Identifier
  • 5.6 File Submission in eCTD Format
  • 5.7 Verify Submission in eCTD Format
  • 5.8 Correct Errors and File Corrected Submission in eCTD Format
  • 5.9 Upload Submission in eCTD Format to Server
• 6 Filing Formats of Submissions in eCTD Format
  • 6.1 Co-submission
  • 6.2 Hybrid Submission
  • 6.3 Electronic-only Submission
• 7 Appendices
  • Appendix A: References
  • Appendix B: Contacts
  • Appendix C: List of Abbreviations
  • Appendix D: Sample Letters of Attestation
  • Appendix E: Print on Demand
  • Appendix F: Pilot Implementation of the Hybrid Filing Format
  • Appendix G: Example Life Cycle Management Table
  • Appendix H: Life Cycle Management Scenarios for Operation Attributes

1 Introduction

This guidance document is to be used in the preparation and filing of drug submissions to Health Canada in Electronic Common Technical Document (eCTD) format established by the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. This guidance document reflects decisions made by the ICH working groups and steering committee, incorporates suggestions made by stakeholders, and describes both new and revised filing requirements.

The preparation and filing of submissions as well as additional information in eCTD format is encouraged but remains optional. Sponsors who choose to file a submission in eCTD format must comply with the specifications for such submissions included in this guidance document, in Health Canada's Guidance for Industry: Creation of the Canadian Module 1 eCTD Backbone File, and in the Electronic Common Technical Document Specification (Version 3.2, February 4, 2004), developed by the ICH M2 Expert Working Group (EWG). Submissions and additional information in eCTD format that do not comply with these requirements will not be accepted.

It is important to note that the implementation and use of eCTD format represents a work in progress. Future refinements to this guidance document will continue to be necessary as a result of experience gained during implementation.

This guidance document is meant to be read in conjunction with the ICH Electronic Common Technical Document Specification and the corresponding Questions and Answers document on the International Conference on Harmonisation Web site. Sponsors should also consult the following documents:

• Health Canada's Notice and Questions and Answers for this guidance document for supplementary or interim guidance on regional issues; and
• Related Health Canada guidance documents and notices on the Health Canada Web site, as listed in Appendix A.

2 Purpose and Scope

The purpose of this guidance document is to integrate the eCTD format within the Canadian drug registration framework by describing the electronic format requirements for new drug submissions filed pursuant to Part C, Division 8, New Drugs, of the Food and Drug Regulations. This guidance document also applies to submissions for radiopharmaceuticals, covered in Part C, Division 3, Schedule C Drugs, and drugs of biological origin, covered in Part C, Division 4, Schedule D Drugs. Sponsors of drug submissions should read all of this guidance document, as well as the reference documents listed in Appendix A.

2.1 Structure and Content of this Guidance Document

This guidance document covers the preparation and filing requirements for submissions and additional information in eCTD format, including all filing formats of submissions in eCTD format. See Section 2.4 for a definition and description of the filing formats.

Sections 3 through 5 provide detailed guidance, specific to Health Canada's requirements, on all aspects of submissions in eCTD format. These sections of the guidance document apply to all submissions in eCTD format, regardless of the filing format of the submission.

Section 6 describes specific details pertaining to the three filing formats of submissions in eCTD format. These filing formats are co-submission, hybrid submission, and electronic-only submission in eCTD format. To prepare a submission in one of the filing formats, sponsors should have read all of the sections preceding Section 6.

Section 7 contains appendices providing background information. The appendices include references to other documents, contact information, a list of abbreviations, sample Letters of Attestation, the parameters for dealing with requests for printed copies, and information on the pilot implementation of the hybrid filing format.

2.2 Drug Submission Information

The following drug submission information is eligible for filing in eCTD format:

• New Drug Submission (NDS);
• Abbreviated New Drug Submission (ANDS);
• Supplement to a New Drug Submission (SNDS)
• Supplement to an Abbreviated New Drug Submission (SANDS);
• Notifiable Change (NC) only when related to previously filed submissions in eCTD format;
• Forms summarizing the Changes to Marketed Human New Drug Products: Notices of Change (Level III), only when related to previously filed submissions in eCTD format;¹ and
• Periodic Safety Update Reports (PSURs) requested during the pre-market review process by Therapeutic Products Directorate (TPD) and Biologics and Genetic Therapies Directorate (BGTD).

Once a sponsor has filed a submission type under scope in eCTD format, NCs, and forms summarizing the changes to Changes to Marketed Human New Drug Products: Notices of Change (Level III) associated with the submission in eCTD format should be filed in eCTD format.

A sponsor may file submissions in the paper-based CTD format, have the information approved, and then file subsequent submissions in the eCTD format. In such cases, the sponsor is not expected to refile the previously approved paper-based submissions in electronic format. The submissions in eCTD format must be among those listed above as eligible.

The eCTD format is also encouraged for the drug component of drug and device combinations, where the primary mechanism of action is drug-related. Where the combination product is classified as a device, the use of eCTD format for the drug component is optional.

This guidance document does not currently apply to Clinical Trial Applications or Amendments (CTAs or CTA-As), Drug Identification Number Applications (DINAs), Natural Health Products (NHP) applications, Drug Master Files (DMFs), Site Reference Files (SRFs), Licence Applications or Amendments (LAps or LAms), lot release documentation and Yearly Biologic Product Reports (YBPRs), PSURs submitted to the Marketed Health Products Directorate (MHPD), or NCs for which submissions in eCTD format have not already been filed. Health Canada will publish a Notice alerting sponsors when additional types may be filed in eCTD format.

¹ Forms summarizing the Changes to Marketed Human New Drug Products: Notices of Change (Level III) are to be submitted with the annual drug notification. Supporting data should not be submitted with the form, but the data must be available on the manufacturer's premises. For more information, see "Level 3 - Notice of Change" in the Health Canada policy document, "Changes to Marketed New Drug Products."

2.3 Additional Information and Subsequent Submissions

Once a sponsor files a submission in eCTD format, all additional information and subsequent submissions for the same drug product should be filed in eCTD format. Sponsors should not revert to paper-based CTD format for additional information and subsequent submissions for the same drug product. However, for submissions in the co-submission filing format, subsequent submissions should be filed in both eCTD and CTD formats, and for submissions in the hybrid filing format, where information related to Modules 1 and 2 is required, that information should continue to be filed in both formats (see Section 2.4, "Filing Formats of Submissions in eCTD Format").

Providing additional information and subsequent submissions in eCTD format will enable life cycle management of drug submissions (see Section 4.3, "Life Cycle Management"), facilitate the review process, and maintain the incremental numbering convention applied to the submission (see Section 3.2.1, "Top Level Folder and eCTD Identifier"). The recommendation to continue submitting in eCTD format does not apply to CTAs submitted after the Notice of Compliance has been issued.

Additional information includes solicited and unsolicited information. Throughout this guidance document, when additional information is generally referred to, solicited and unsolicited information should be understood. Solicited information includes responses to Screening Deficiency Notices (SDNs), to clarification requests (Clarifaxes), to Notices of Non-compliance (NONs), and to Notices of Deficiency (NODs). Throughout this document, when solicited information is specifically referred to, these types of responses should be understood. Unsolicited information includes safety information and changes in the name of the sponsor. For more details about solicited and unsolicited information, see Section 5.5, "Evaluation of Submissions," in Health Canada's Guidance for Industry: Management of Drug Submissions.

To accommodate responses to Clarifaxes in a timely manner, both a paper and an electronic response to a Clarifax should be filed at the same time. A sponsor who is unable to file the electronic response to a Clarifax at the same time as the paper response should provide with the paper response a time frame within which the electronic response will be filed. This commitment should be provided in the accompanying cover letter. Multiple paper Clarifax responses can be bundled in one compact disk (CD) or digital video disk (DVD) and submitted together in the electronic format. However, each of the electronic responses should be filed using a separate sequence number.

The consequences for delays in the delivery of the electronic response to a Clarifax vary depending on the filing format of the submission in eCTD format. For the co-submission filing format, see Section 6.1.7, "Additional Information for Co-submissions"; for the hybrid submission filing format, see 6.2.7, "Additional Information for Hybrid Submissions."

The paper response to a Clarifax should be sent directly to the Health Canada official who requested the information. The response in eCTD format should be sent to the Submission and Information Policy Division (SIPD). Responses to Clarifaxes should otherwise conform to procedures described in Health Canada's Guidance for Industry: Management of Drug Submissions, Section 5.2.6, "Responses to Clarification Requests."

2.4 Filing Formats of Submissions in eCTD Format

Health Canada is taking a structured approach to the adoption of eCTD format for drug submissions. This approach will allow sponsors and Health Canada to gradually gain experience with the preparation, processing, and review of submissions in eCTD format. Health Canada has set three stages for the adoption of eCTD format and these stages correspond to three filing formats of submission in eCTD format:

Co-submission

A submission in eCTD format that accompanies a complete paper-based submission in CTD format. See Section 6.1 for further information.

Hybrid submission

A submission in eCTD format that is accompanied by Modules 1 and 2 in the paper-based CTD format. See Section 6.2 for further information.

Electronic-only submission

A submission in eCTD format that is not accompanied by any portion of a paper-based submission in CTD format. See Section 6.3 for further information.

For an overview of the three filing formats, see Table 2 at the beginning of Section 6. The table cross-references the full details of the filing formats provided in the remainder of Section 6. To successfully produce a submission in eCTD format, sponsors should also read sections 3 to 5.

3 Structure and Content of Submissions in eCTD Format

Health Canada's information requirements for submissions in eCTD format are the same as they are for paper-based submissions in CTD format. However, the location of certain files in the submission in eCTD format may differ from the location of the paper documents in the submission in CTD format. Health Canada's Guidance for Industry: Preparation of New Drug Submissions in the CTD Format and corresponding ICH guidance documents on the CTD format outline the modular structure and content of paper-based submissions in CTD format. The CTD structure and content has been carried over to the eCTD standard.

It is necessary to understand the distinction between the eCTD structure and the folder structure. A folder is the organizing unit for a computer operating system and the unit in which electronic files are stored and accessed on a computer.

Windows Explorer®, for example, provides the means for storing, saving, viewing, and accessing files in folders on a computer using the Windows operating system. Figure 1 illustrates a portion of the folder structure for storing files in a submission in eCTD format, as seen using Windows Explorer.

Figure 1: Folder Structure

The eCTD structure is the rendering of the submission through its organization in an eXtensible Markup Language (XML) backbone. The rendered XML backbone is equivalent to the table of contents of a hard-copy document. The eCTD structure is presented through an XML viewing tool. Figure 2 illustrates a portion of the eCTD structure, as seen using an XML viewing tool. While Figure 2 shows a submission with one sequence, Figure 3 illustrates a portion of the eCTD structure of a submission with multiple sequences.

Figure 2: Electronic Common Technical Document (eCTD) Structure with One Sequence

Figure 3: Electronic Common Technical Document (eCTD) Structure showing Multiple Sequences

3.1 Cover Letter

Submissions as well as additional information in eCTD format should be accompanied by an administrative cover letter in both paper and portable document format (PDF). The cover letter should always state whether the information provided is a drug submission, such as an NDS, an ANDS, an SNDS, an SANDS, or an NC, or additional information concerning a drug submission. For the filing location of the cover letter in the submission in eCTD format, see Section 3.3.1, "Module 1: Administrative Information and Prescribing Information."

In addition to the content recommended by ICH, Health Canada suggests that the paper and PDF cover letters include, as Appendix I, the Life Cycle Management Table, discussed in Section 4.3, "Life Cycle Management." This Appendix should be submitted as a separate file.

The paper and PDF cover letters should have the same content, with the following exception. The paper cover letter accompanying the DVD or CD should include, as Appendix II, the printed content of the checksum file (index-md5.txt).

3.2 Folder Structure and File Naming Convention

For an illustration of the folder structure, see Figure 1.

3.2.1 Top Level Folder and eCTD Identifier (Product Identifier)

The top level folder of a submission in eCTD format contains all other folders and their contents. The name for the top level folder of the submission in eCTD format is the eCTD Identifier number obtained from Health Canada (for example(e.g.), e123456 in Figure 1). This number is the unique identifier for the drug product. Subsequent submissions as well as additional information in eCTD format for the same drug product should retain the same eCTD Identifier. The eCTD Identifier is created by Health Canada (see Section 5.5, "Obtain eCTD Identifier").

3.2.2 Sequence Number Folder

All files and folders in a submission in eCTD format are to be placed under the sequence number folder, as described in the ICH Electronic Common Technical Document Specification (Version 3.2), "File Names and Directory Structure," pages 6-1 and 6-2. The sequence number folder should be named using a four-digit number. The sequence number for the first submission for a drug product should be 0000. Each time a sponsor submits new information for that product, the sponsor should provide an incremental number, unique within the same product, for the sequence number folder in which the new information is placed.

When building an information package, the sequence number should be kept the same when the submission is refiled subsequent to failing verification because of a technical error. When building a response to Screening Deficiency Notices (SDNs) or Clarifaxes, the sequence number should be incremented.

The sequence number folder includes an m1 subfolder, m2-m5 subfolders (optional), and a util subfolder (see Figure 1). The eCTD backbone file (index.xml) and the checksum file (index-md5.txt) should be in the sequence number folder.

3.2.3 Module 1 Subfolder

The structure and content of the Module 1 subfolder (m1) is defined in Health Canada's Guidance for Industry: Creation of the Canadian Module 1 eCTD Backbone File. Sponsors should use the Canadian document type definition (DTD) for Module 1. The most recent version of the Canadian DTD has been posted on Health Canada's E-Review Web site. The m1 subfolder contains a ca subfolder. The ca subfolder contains the Canadian Module 1 eCTD backbone file (ca-regional.xml) and should not contain any subfolders.

3.2.4 Modules 2 to 5 Subfolders

The structure and content of the Modules 2 to 5 subfolders (m2-m5) are defined in the ICH Electronic Common Technical Document Specification, Health Canada's Guidance for Industry: Preparation of New Drug Submissions in the CTD Format, and other relevant guidance documents listed in Appendix A.

3.2.5 util and dtd Subfolders

The util subfolder contains a dtd subfolder. The dtd subfolder should contain Health Canada's Canadian DTD for Module 1 (e.g. ca-regional-1-0.dtd), used to define the regional Module 1 backbone file. The dtd subfolder should also contain the ICH eCTD DTD (ich-ectd-3-2.dtd) used to define the eCTD backbone file (index.xml).

3.2.6 Leaf File Naming Convention

Choice of file naming convention is up to the sponsor. To assist sponsors, this subsection presents an example naming convention for leaf files for Module 1. Health Canada suggests that file names begin with the sequence number, followed by "ca," followed by the module and, if applicable, the section number, and then a phrase describing the contents of the file. All components of the file name can be divided by hyphens.

The following are examples of file naming conventions for Module 1:

• 0000-ca-m1-cover-letter.pdf
• 0000-ca-m1-note-to-reviewer.pdf²
• 0000-ca-m131-annotated-pm.pdf
• 0001-ca-m122-hc-sc-3011-en.pdf
• 0001-ca-m131-pristine-pm.doc
• 0001-ca-m131-note-to-reviewer-pm.pdf

ICH requires that the file names be limited to a maximum of 64 characters, including the file extension. See the ICH Electronic Common Technical Document Specification (Version 3.2), "Name," page 2-5. Meaningful abbreviations, such as PM for Product Monograph, can be used to shorten file names.

² For information about notes to reviewers, see Section 3.3.1, "Module 1: Administrative Information and Prescribing Information."

3.3 eCTD Structure and Leaf Title

For an illustration of the eCTD structure, see Figure 2.

3.3.1 Module 1: Administrative Information and Prescribing Information

The following documents when required should be filed as leaf elements under the m1-administrative-information-and-prescribing-information heading:

• The cover letter.
• Appendix I, Life Cycle Management Table, which should be filed as a separate leaf element that points to a separate file. The filing of the table as a file separate from the cover letter will allow for proper life cycle management. See Figures 1 and 2 for examples.
• The copy of the original request and the summary responses in a Question and Answer format to SDNs, Clarifaxes, Notices of Non-Compliance (NONs), and Notice of Deficiencies (NODs), which should be filed as a separate leaf element that points to a separate file. The responses should not be included in the cover letter.

The following documents when required should be filed as leaf elements under the m1-2-3-submission-certification subheading (Section 1.2.3 of the CTD structure):

• The Product Monograph (PM) certification form
• The Letter of Attestation (also see sections 6.1.5 and 6.2.5 of this guidance document).

The following documents when required should be filed as leaf elements under the m1-2-8-other-application-information subheading (Section 1.2.8 of the CTD structure):

• Bioequivalence (BE) data sets (see Section 4.1, "File Formats," of this guidance document).
• Forms summarizing the Changes to Marketed Human New Drug Products: Notices of Change (Level III).

Notes to reviewers are not a requirement, but since sponsors occasionally include them, the following guidelines are provided to promote a consistent approach to placing them in submissions and naming them:

• A Note to Reviewer that addresses the submission as a whole should be filed as a leaf element under the m1-administrative-information-and-prescribing-information heading. The title of the leaf should be "Note to Reviewer."
• A Note to Reviewer that is specific to a section should be filed as the first leaf element in that section. For example, a Note to Reviewer that addresses the PM should be filed as a leaf element under the m1-3-1-product-monograph subheading. The title of the leaf should be "Note to Reviewer PM."

3.3.2 Modules 2 to 5

If new or updated information is required in response to SDNs, Clarifaxes, NONs, NODs, or other solicited information, then that information should be filed in the same location within Modules 2 to 5 as the information it replaces, and the modified-file attribute used to associate it with the information to which it relates. For further information about the modified-file attribute, see the ICH Electronic Common Technical Document Specification (Version 3.2), "Operation Attribute," page 6-3 ff.

The PSUR requested during the pre-market review process by TPD and BGTD should be filed as a leaf element under the m5-3-6-report-of-postmarketing-experience subheading.

Case Report Forms (CRFs) and individual patient data listings should be filed as leaf elements under the m5-3-7-case-report-forms-and-individual-patient-listings subheading. According to the ICH eCTD IWG Question and Answer and Specification Change Request Document, Question 42, the filing of CRFs within a submission should be decided on a regional basis. Health Canada prefers that CRFs be organized according to the following principles:

• They should be filed under Section 5.3.7;
• They should be organized by study name within Section 5.3.7 using node extensions; and
• Any further breakdown in the organization of CRFs should be developed during discussion with reviewers at the regulatory pre-submission meeting.

The Literature Reference related to the PM should be filed as a leaf element under the m5-4-literature-reference heading.

The use of Study Tagging Files (STFs) is currently not encouraged by Health Canada and is not treated by this guidance document. STFs will, however, be accepted in a submission in eCTD format, if they pass validation.

3.3.3 Leaf Titles

The leaf title is an attribute of the file that will appear in the viewing tool. Health Canada's eCTD viewing tool displays icons that differentiate between PDF and Microsoft Word documents, therefore sponsors should not specify the format of a document in the title of the leaf.

Incorrect: Pristine Product Monograph.MS Word
Correct: Pristine Product Monograph
Incorrect: Cover Letter.PDF
Correct: Cover Letter

Sponsors should not include the numbering of the heading in the title of the leaf, because this is redundant and confusing for the reviewer.

Incorrect: 1.3.1 Annotated Product Monograph
Correct: Annotated Product Monograph

See Figure 2 for an example.

4 Technical Requirements for Submissions in eCTD Format

4.1 File Formats

The ICH Electronic Common Technical Document Specification (Version 3.2) requires the provision of components of the submission in eCTD format as PDF files.

Health Canada recommends that sponsors also provide versions of specific components in their original word-processed format.³ The required hyperlinks to related information should be included in the PDF version of files, not the word-processed versions. The following components should be provided in both PDF (Adobe Acrobat, version 5.0, 6.0, or 7.0) and word-processed format:

• PM;
• Quality Overall Summary (QOS);
• Certified Product Information Document (CPID);
• Comprehensive Summary: Bioequivalence (CS:BE); and
• Responses to SDNs, Clarifaxes, NONs, and NODs.

Note: Annotated PMs should only be submitted in PDF and Non-annotated and Pristine PMs should only be submitted in word-processed format.

Any time that a sponsor provides both PDF and word-processed files, the leaf elements pointing to these files should be included under the same heading. See Figure 2 for an illustration.

The BE data sets must be provided in ASCII format. See Health Canada's Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format, Appendix B, "Computer Format for the Submission of Data for Comparative Bioavailability Studies."

PDF versions of documents should be generated from electronic source documents and not from scanned material, except where the source electronic files are not available or where a signature is required. See the ICH Electronic Common Technical Document Specification (Version 3.2), "Source of Electronic Document," page 7-2, and "Methods for Creating PDF Documents and Images," page 7-3.

³ Sponsors are requested to submit original files in Microsoft Word 2000, 2002, and 2003, or in Corel WordPerfect versions 6, 7, 8, 9, or 10. Sponsors should use the appropriate template for the original word processing format of their choice or for XML, as the templates become available.

4.2 Media for Submitting Electronic Data in eCTD Format

The only formats accepted at this time are Compact Disc-Recordable (CD-R) conforming to the Joliet specification, and Digital Versatile Disc-Random-access memory (DVD-RAM) and Digital Versatile Disc-Recordable (DVD+R/-R) recorded in the Universal Disk Format (UDF) standard. These are the formats that are currently supported. Contact SIPD for other formats that may be acceptable at the time of submission. See Appendix B for full contact information.

Sponsors should fit all documents in as few CDs or DVDs as possible. Duplicate copies of the CDs or DVDs are not required. The discs should be submitted in individual slim jewel cases.

Only the discs should be labelled. The labels on the disc should contain the following information:

• Sponsor name and brand name;
• eCTD Identifier and sequence number;
• Control number, if known;
• "Protected B";⁴
• Virus-free certification, the software used for the virus check, and the date of the virus definition file or files;
• Month and year of the submission; and
• Disc number and total number of discs (e.g., Disc 1 of 5).

Note: CD or DVD cases do not need to be labelled since Health Canada will place its own label on the front covers of the cases.

Subsequent to burning the CD or DVD, sponsors should ensure that all files can be opened and that no files are corrupt.

⁴ "Protected" status identifies information the unauthorized disclosure of which could reasonably be expected to cause injury to private interests. "Protected B" indicates a medium degree of potential injury. See Government Security Policy (February 2002), Section 10.6, " Identification of Assets."

4.3 Life Cycle Management

Sponsors should include as Appendix I to the cover letter a Life Cycle Management Table describing all sequence numbers and how they relate to each other. It should contain the information indicated by the column titles in Table 1, "Example Life Cycle Management Table." The most recent entries should be listed last. A completed example of a Life Cycle Management table can be found in Appendix G.

Table 1: Example Life Cycle Management Table

Sponsor Name:

Brand Name:

eCTD Identifier:

Sequence Number

Date Submitted

Control Number

Related Sequence

Sequence Number Description

For further information on life cycle management, see the ICH Electronic Common Technical Document Specification (Version 3.2), "Life Cycle Management," pages 6-2 and 6-3.

4.3.1 Life Cycle Management at the Drug Product Layer

The eCTD Identifier links all subsequent submissions to the original submission for a drug product. See Figure 4 for an illustration of how various types of submissions are linked by the eCTD Identifier.

Figure 4: Subsequent Submissions Linked to an Original Submission by Electronic Common Technical Document (eCTD) Identifier

The eCTD Identifier links all subsequent submissions to the original submission for a drug product. See Figure 4 for an illustration of how various types of submissions are linked by the eCTD Identifier.

4.3.2 Life Cycle Management at the Submission Layer

The related-sequence-number sub-element describes the relationship of additional information to the original submission or subsequent submissions. For life cycle management at the submission layer, the related-sequence-number sub-element should be treated as described:

• For all drug submissions types (NDS, SNDS, ANDS, SANDS, and NC) in eCTD format, the related-sequence-number sub-element should not be used.
• For all additional information, the related-sequence-number sub-element should be the sequence number of the submission to which the additional information applies. The related-sequence-number sub-element should only be one sequence number.

See Figure 5 for an illustration of how the related-sequence-number is used to describe the relationship of additional information to the original and subsequent submissions.

Figure 5: Additional Information Linked to Submissions by Related Sequence Number

4.3.3 Life Cycle Management at the Document Layer

Granularity of the document goes hand in hand with life cycle management. Adequate life cycle management is difficult without proper granularity at the document level.

The operation attribute describes the relationship of leaf files within the submission. See Figure 6 for an illustration of how the operation attribute is used to describe the relationship between leaf files in submissions subsequent to the original submission and in additional information related to those submissions.

The operation attributes used to manage the life cycle of Word and WordPerfect documents should be the same as the attributes used to describe their counterparts in PDF.

4.3.4 General Rules for Use of Operation Attributes

In general, how the operation attributes "append" and "replace" should be used is related to how the content of a document is managed. The operation attribute "replace" should be used when the additional information and the previously submitted information are provided as a consolidated document. The operation attribute "append" should be used when the additional information submitted is used to build upon previously submitted information, without resubmitting it.

For example, in Section 3.2.P.8.3, Stability Data, if in sequence 0000, stability data for one year are provided in one document, then when sequence 0001 is submitted to update the stability data, two options are possible. The first option is to create a new document that includes the first year of data plus the additional year of data. In this instance, the operation attribute should be "replace." The second option is to create a new document that includes only the additional year of data. In this instance, the operation attribute should be "append."

Health Canada does not recommend using the operation attribute to modify a document twice in the same sequence such as is shown in Scenario 13 in Appendix H. Health Canada instead recommends proper document management, which would be the consolidation or modification of the document itself.

For figures illustrating the general rules, see Appendix H.

4.3.5 Rules for Use of Operation Attributes for Specific Documents

For life cycle management at the document layer, the operation attribute should be treated as described below for specific documents. For further information, see the ICH Electronic Common Technical Document Specification (Version 3.2), "Operation Attribute," page 6-3.

• For all leaf files provided as part of the first submission to Health Canada and given the sequence number 0000, the operation attribute in the leaf element should be "new."
• The "append" operation attribute should not be used to link files that are split because they would otherwise exceed the 100 megabyte limit. Instead, proper file management using an adequate level of granularity will ensure that no file exceeds the limit.
• For the cover letter, Letter of Attestation and notes to reviewers leaf elements provided with all sequence numbers, the operation attribute should always be "new."
• For the Appendix I, Life Cycle Management Table leaf element provided with sequence number 0000, the operation attribute should be "new." For the leaf element provided with all other sequence numbers, the operation attribute should be "replace."
• For the copy of the original request and the summary responses in a Question and Answer format leaf elements provided with all sequence numbers, the operation attribute should always be "new."
• For the Drug Submission Application Form (3011 form) leaf element,
  • when provided with all submission types (NDS, SNDS, ANDS, SANDS, and NC), the operation attribute should be "new"; and
  • when provided as additional information for a correction of an error in the 3011 form in response to Health Canada requests, such as SIPD queries, screening Clarifaxes, and SDNs, the operation attribute should be "replace."
• For the PM leaf element (see Figure 6 for a graphic representation),
  • when a non-annotated or annotated PM is provided as part of an NDS, SNDS, SANDS, ANDS, or NC, the operation attribute should be "new";
  • when a non-annotated or annotated PM is provided in response to an SDN, NOD, NON, or Clarifax, the operation attribute should be "replace";
  • when a pristine PM is provided for the first time, the operation attribute should be "new" and the most recent non-annotated and annotated PMs provided as part of that submission should be assigned the operation attribute of "delete"; and
  • when a pristine PM is provided to replace a previously approved pristine PM, the operation attribute should be "replace" and the most recent non-annotated and annotated PMs provided as part of that submission should be assigned the operation attribute of "delete."
• For the Certified Product Information Document (CPID) leaf element (see Figure 7, for a graphic representation),
  • when an annotated CPID is provided with an SNDS, ANDS, SANDS, or NC, the operation attribute should be "new" (a CPID does not have to be provided at time of filing with an NDS);
  • when an annotated CPID is provided as additional information in response to an SDN, NOD, NON, or Clarifax, the operation attribute should be "replace";
  • when a clean CPID is provided for the first time, the operation attribute should be "new" and the most recent annotated CPID provided as part of that submission should be assigned the operation attribute of "delete"; and
  • when a clean CPID is provided to replace a previously approved clean CPID, the operation attribute should be "replace" and the most recent annotated CPID provided as part of that submission should be assigned the operation attribute of "delete."
• For the leaf element provided for forms summarizing the Changes to Marketed Human New Drug Product: Notices of Change (Level III), for the first form the operation attribute should be "new." For the leaf element provided with all subsequent forms, the operation attribute should be "append" to the initial leaf (parallel "append"; see Scenario 3 in Appendix H). "Append" to "append" (chain "append") is not recommended. (See Scenario 4 in Appendix H for more details.) Parallel "appends" enable the replacement or deletion of an appended document at a later time, whereas serial "appends" do not allow this possibility.

Figure 6: Life Cycle Management Product Monograph (PM) Scenario

Product Monograph Scenario

Figure 7:Life Cycle Management Certified Product Information Document (CPID) Scenario

Certified Product Information Document (CPID)

4.4 Bookmarks in PDF Files

It is important that PDF files be properly bookmarked. Rules of thumb for good bookmarking include:

• Documents of ten pages or more should be bookmarked.
• Bookmarks are equivalent to and should be organized like a document table of contents, and should not include the submission level.
• Sections, subsections, tables, figures, and appendices should all be bookmarked.
• Too many levels of bookmarks are inefficient; in most instances, three levels of bookmarks should be sufficient:
  
  1 Heading
  1.1 Subheading
  1.1.1 Sub-subheading
• Health Canada recognizes that bookmarks are generated automatically from document headings, but nevertheless recommends they be kept concise.

5 Filing Process for Submissions in eCTD Format

Figure 8 illustrates the process for preparing and filing submissions in eCTD format. The steps discussed in the following subsections correspond to the process diagram.

Figure 8: Filing Process for Submissions in Electronic Common Technical Document (eCTD) Format

5.1 Hold Technical Pre-submission Consultation

Sponsors filing a submission in eCTD format for the first time are recommended to request a technical pre-submission consultation with Health Canada. This consultation is held to clarify needs, responsibilities, and expectations, and to provide Health Canada the opportunity to offer assistance and guidance for the eCTD filing process. The meeting will not necessarily take place at the same time as the regulatory pre-submission meeting. To request a technical pre-submission consultation, contact SIPD. See Appendix B for full contact information.

Sponsors should include the following information in their requests:

• The purpose of the meeting;
• A brief description of the product to be discussed at the meeting;
• Three proposed dates for the meeting, including whether an afternoon or morning meeting is being requested;
• Type of meeting requested, in person or teleconference; and
• An agenda for the meeting including the number of sponsor representatives attending the meeting.

5.2 File eCTD Sample

Sponsors filing a submission using the eCTD format for the first time are recommended to file an eCTD sample at least four weeks in advance of filing their formal submission in eCTD format with Health Canada. This period is not part of and will not delay the review process. Analysis of the sample may serve to identify potential issues before the actual submission is filed. The filing of an eCTD sample as a preliminary step for subsequent submissions will depend on various factors, including changes in ICH specifications, changes in the Health Canada DTD Module 1 specifications, and changes in technology (e.g., file formats, submission media).

The eCTD Identifier for an eCTD sample does not have to be obtained from Health Canada since the eCTD sample is not considered for review. The Identifier for the sample should be an "s" followed by the date the sample was created, in the format yymmdd (e.g., s080721).

The eCTD sample can be a partial submission but should contain, at a minimum, the following files:

• eCTD backbone file (index.xml);
• eCTD backbone MD5 checksum file (index-md5.txt);
• Canadian Module 1 eCTD backbone file (ca-regional.xml);
• Canadian Module 1 DTD, Version 1.0 (ca-regional-1-0.dtd);
• ICH eCTD DTD (ich-ectd-3-2.dtd); and
• Leaf files containing sample data.

If a sponsor intends to include them in the submission, style sheets and Study Tagging Files should be included in the sample.

The sample should be sent to SIPD. See Appendix B for full contact information.

5.3 Verify eCTD Sample

Upon receipt, Health Canada tests the eCTD sample to ensure that it conforms to the requirements outlined in this guidance document, Health Canada's Guidance for Industry: Creation of the Canadian Module 1 eCTD Backbone File, and the ICH Electronic Common Technical Document Specification. The verification process has two stages, the first of which is manual and includes ensuring that the eCTD Identifier is appropriately used. The second stage of the verification process includes tests conducted to validate the DTD against validation rules published by Health Canada.

During the verification process, the content of the eCTD sample is not reviewed according to the Health Canada submission evaluation process. Within two weeks of receipt of the sample submission, Health Canada provides the sponsor with a written eCTD Submission Validation Report outlining the degree of compliance with eCTD requirements. Deficiencies identified during the testing will be included in the report.

5.4 Correct Errors and File Corrected Sample

When Health Canada identifies errors in the eCTD sample, the sponsor corrects the errors and files the corrected eCTD sample with SIPD. If the sponsor wishes to discuss the eCTD Submission Validation Report, the sponsor should contact SIPD. Health Canada verifies the corrected sample and sends a written eCTD Submission Validation Report to notify the sponsor of any required technical changes prior to the sponsor filing the submission in eCTD format. This process is iterative; Health Canada will work with the sponsor to increase the probability of an error-free submission in eCTD format. See Appendix B for full contact information.

5.5 Obtain eCTD Identifier

Before a sponsor files a submission in eCTD format, the sponsor should obtain an eCTD Identifier (see Section 3.2.1, "Top Level Folder and eCTD Identifier"). The sponsor should submit a written request for an eCTD Identifier by contacting SIPD prior to sending the submission in eCTD format to Health Canada. (See Appendix B for full contact information.) The request should include the control number of the regulatory pre-submission meeting or a draft 3011 form on which the sponsor has completed Part 1, boxes 8 and 9, and all of Part 1, Section A.

Note that the requirement to obtain an eCTD Identifier from Health Canada does not apply to eCTD samples (see Section 5.2, "File eCTD Sample").

5.6 File Submission in eCTD Format

The submission in eCTD format should be sent to SIPD. See Appendix B for full contact information.

5.7 Verify Submission in eCTD Format

Upon receipt, Health Canada tests the submission in eCTD format to ensure that it conforms to the requirements outlined in this guidance document, Health Canada's Guidance for Industry: Creation of the Canadian Module 1 eCTD Backbone File, and the ICH Electronic Common Technical Document Specification. The verification process has two stages, the first of which is manual and includes ensuring that the eCTD Identifier is correct. The second stage of the verification process includes tests conducted to validate the DTD, to verify file checksums, and to identify missing files. During the verification process, the content of the submission in eCTD format is not reviewed according to the Health Canada submission evaluation process.

Within seven calendar days of receipt of the submission in eCTD format, Health Canada will provide the sponsor with a written eCTD Submission Validation Report describing the degree of compliance with eCTD requirements. Deficiencies identified during the testing will be included in the report. The eCTD version of a Response to Clarifax will be validated by Health Canada within two calendar days. The exception is for a Response to Clarifax received after noon on the last working day of the week, for which the validation response period will begin on the next working day.

5.8 Correct Errors and File Corrected Submission in eCTD Format

When Health Canada identifies errors in the submission in eCTD format, the sponsor corrects the errors and files the corrected submission in eCTD format with SIPD. If the sponsor wishes to discuss the written eCTD Submission Validation Report, the sponsor should contact SIPD. Health Canada verifies the corrected submission in eCTD format and notifies the sponsor of any required technical changes. This process is iterative. See Appendix B for full contact information.

If a submission fails verification due to a technical error, the sequence number does not change when the submission is filed again. If the submission passes verification, but has screening deficiencies, then responses to SDNs or Clarifaxes require an increment to the sequence number.

5.9 Upload Submission in eCTD Format to Server

When the submission in eCTD format has passed the verification process, the submission is uploaded to the Health Canada secure server.

6 Filing Formats of Submissions in eCTD Format

Health Canada's structured approach to the implementation of eCTD format for drug submissions specifies three filing formats for submissions in eCTD format, each characterized by whether and to what extent the submission is accompanied by a paper-based submission in CTD format.

Table 2 provides an overview of the three filing formats of submissions in eCTD format, particularly as aspects of the filing formats bear on implementation considerations. Items in the table are cross-referenced to sections of this guidance document that discuss the items in greater detail.

Table 2: Implementation Considerations for the Three Filing Formats

Issue	Co-submission Section 6.1	Hybrid Submission Section 6.2	Electronic-only Submission Section 6.3
Portion of submission in paper-based CTD format	Complete submission in eCTD format with complete submission in paper-based CTD format (see Section 6.1.3).	Complete submission in eCTD format with partial submission in paper-based CTD format of Modules 1 and 2 (see Section 6.2.3).	Complete submission in eCTD format without any submission in paper-based CTD format (see Section 6.3).
Legal record	The paper-based submission in CTD format remains the legal document (see Section 6.1.1).	The electronic submission in eCTD format is the legal document (see Section 6.2.1).	The electronic submission in eCTD format is the legal document (see Section 6.3).
Signature	Wet ink signature is required (see Section 6.1.1).	Scanned copy of signed document is required (see Section 6.2.1).	Scanned copy of signed document is required (see Section 6.3).
Letter of Attestation for submission and additional information	Letter of Attestation stating that material in the submission or additional information in eCTD format exactly matches material in CTD format (see Section 6.1.2).	Letter of Attestation stating that Modules 1 and 2 in partial submission in CTD format exactly match Modules 1 and 2 in eCTD format (see Section 6.2.2).	Not Applicable
Technical pre-submission consultation	Technical pre-submission consultation recommended (see Section 6.1.6).	Technical pre-submission consultation required (see Section 6.2.6).	To be determined
Print on Demand	Not Applicable	See Appendix E.	To be determined
Calendar	Accepted as of September 1, 2004.	Accepted as of June 30, 2006.	To be determined

6.1 Co-submission

A co-submission is a submission in eCTD format that is accompanied by a complete paper-based submission in CTD format. For a co-submission in paper-based CTD and eCTD formats, both submissions must be complete and comply with all of the specifications applicable to either format.

6.1.1 Legal Document for Co-submissions

The paper-based submission in CTD format remains the legal document and must be filed.

6.1.2 Congruence of Content of Co-submissions

According to Health Canada's Guidance for Industry: Preparation of New Drug Submissions in the CTD Format, the paper-based submission in CTD format should be complete, including all files in electronic format that support the paper-based submission in CTD format. The content of the paper-based submission in CTD format and the content of the submission in eCTD format should be identical. Cross-references in the paper-based submission in CTD format should be compliant with Section 5.2 of the Guidance for Industry: Preparation of New Drug Submissions in the CTD Format.

All processes related to paper-based submissions in CTD format remain the same. Sponsors are, for example, to submit the same number of copies of coloured binders. CDs used to provide files in electronic format for paper-based submissions in CTD format are not required in Section 1.6 of the CTD structure. The CDs and DVDs used for the submission in eCTD format will be used as replacements for the files in electronic format in the paper-based submission in CTD format.

6.1.3 Congruence of Structure of Co-submissions

Index headings, and headers and footers in the submission in eCTD format are to match the paper-based submission in CTD format for ease of reference between the two types of submissions. The BE data sets are an exception. The BE data sets are included in paper-based submissions in CTD format in Section 1.6, which is a placeholder section for files in electronic format that supplement the submission. Because submissions in eCTD format do not have a Section 1.6, the BE data sets are to be included in Section 1.2.8, "Other Application Information" (m1-2-8-other-application-information leaf element).

6.1.4 Hyperlinks and Cross-References for Co-submissions

Page content is to be identical in co-submissions in the eCTD and CTD formats, with the exception of navigational aids and metadata. In a submission in eCTD format, hyperlinks should be used wherever cross-references are used in the submission in CTD format (e.g., annotations of PMs). Health Canada prefers that the paper-based cross-references converted to electronic hyperlinks also be spelled out as cross-references in the electronic files, with explicit citation of module, and section, as appropriate.

In submissions in eCTD format, sponsors may want to add hyperlinks in studies that would not be cross-referenced in submissions in CTD format. The ICH Electronic Common Technical Document Specification requires other hyperlinks and these should also be added. Hyperlinks are not expected for word-processed documents. Hyperlinks, with the exception of tables of contents, should be indicated typographically with blue text or a blue box.

6.1.5 Letters of Attestation for Co-submissions

A Letter of Attestation should be included in the submission in eCTD format confirming that the content contained in the submission in eCTD format is identical to the content contained in the paper-based submission in CTD format. A Letter of Attestation is required for every sequence number. The Letter of Attestation should be filed under the m1-2-3-submission-certification heading of the submission in eCTD format and in Section 1.2.3 of the paper-based submission in CTD format. The Letter of Attestation should be signed by the senior officer in charge of Regulatory Affairs or the official delegate. See Appendix D, "Sample Letters of Attestation," of this guidance document.

6.1.6 Filing Process for Co-submissions

Sponsors filing a submission in eCTD format in the co-submission filing format for the first time are recommended to arrange for a pre-submission consultation (see Section 5.1, "Hold Technical Pre-submission Consultation"). Such sponsors should also file an eCTD sample prior to filing a complete co-submission in eCTD format (see Section 5.2, "File eCTD Sample"). The sponsor should file one copy of the submission in eCTD format at the same time as the paper-based submission in CTD format. The submissions in both formats should be sent to SIPD.

The CD or DVD containing the submission in eCTD format should not be inserted in Module 1.6 of the paper-based submission in CTD format. The CD or DVD containing the submission in eCTD format should be provided separately from the paper-based submission in CTD format.

If the co-submission in eCTD format fails eCTD verification (see Section 5.7, "Verify Submission in eCTD Format"), Health Canada will initiate screening of the paper-based submission in CTD format. The screening and review process will proceed on the paper-based submission in CTD format, as described in Health Canada's Guidance for Industry: Management of Drug Submissions. The sponsor can resubmit the submission in eCTD format as soon as the sponsor corrects the technical deficiency highlighted in the eCTD Submission Validation Report. Any additional information filed in paper prior to refiling the submission in eCTD format should also be included in the appropriate sequence numbers. If corrected before the start of the review of the submission, the submission in eCTD format will be used in the remainder of the review process.

6.1.7 Additional Information for Co-submissions

In the case of submissions in the co-submission filing format, should the time frame for delivery of the Response to Clarifax in eCTD format exceed the time to completion of the review, Health Canada will proceed with the paper-based submission in order to process the letter of decision. The life cycle of the electronic submission in eCTD format will be incomplete and no further eCTD sequences will be accepted until the Response to Clarifax in eCTD format is submitted.

6.2 Hybrid Submission

A hybrid submission is a submission in eCTD format that is accompanied by Modules 1 and 2 in the paper-based CTD format. For a hybrid submission in eCTD and CTD formats, only the submission in eCTD format must be complete.

The paper-based submission in CTD format only contains Modules 1 and 2. Modules 3 to 5 are submitted only in eCTD format, although they may be subject to print-on-demand requests (see Section 6.2.8, "Print on Demand for Hybrid Submissions," and Appendix E, "Print on Demand").

6.2.1 Legal Document for Hybrid Submissions

The electronic submission in eCTD format is the legal document for submissions in the hybrid filing format.

The page or pages of those documents that legally require a signature should be printed, signed, scanned, and saved as PDF files. The PDF file containing the image of the signed page or pages should be included in the submission in eCTD format.

If only one page of a multi-page document contains a signature, the sponsor should scan the page and then include the scanned page at the same location in the PDF file of the document. Each document should have only one PDF file.

6.2.2 Congruence of Content of Hybrid Submissions

The content of Modules 1 and 2 of the submission in eCTD format and the content of Modules 1 and 2 of the partial paper-based submission in CTD format should be identical. All processes related to partial paper-based submissions in CTD format of Modules 1 and 2 remain the same. The one exception is that sponsors are not required to submit the CD containing electronic files included in Section 1.6 of the submission in CTD format. Cross-references in the paper-based submission in CTD format should be compliant with Section 5.2 of the Guidance for Industry: Preparation of New Drug Submissions in the CTD Format.

6.2.3 Congruence of Structure of Hybrid Submissions

Index headings, headers and footers, and all other structural elements in Modules 1 and 2 of the partial paper-based submission in CTD format are to match Modules 1 and 2 of the electronic submission in eCTD format for ease of reference between the two filing formats. The BE data sets are an exception. The BE data sets are included in partial paper-based submissions in CTD format in Section 1.6, which is a placeholder section for files in electronic format that supplement the submission. Because submissions in eCTD format do not have a Section 1.6, the BE data sets are to be included in Section 1.2.8, "Other Application Information" (m1-2-8-other-application-information leaf element).

6.2.4 Hyperlinks and Cross-References for Hybrid Submissions

Page content is to be identical in Modules 1 and 2 of the partial paper-based submission in CTD format and Modules 1 and 2 of the electronic submission in eCTD format, with the exception of navigational aids and metadata. In the submission in eCTD format, hyperlinks should be used wherever cross-references are used in the submission in CTD format (e.g., annotations of PMs). Health Canada prefers that the paper-based cross-references converted to electronic hyperlinks also be spelled out as cross-references in the electronic files with explicit citations of module, and section, as appropriate.

In submissions in eCTD format, sponsors may want to add hyperlinks in studies that would not be cross-referenced in submissions in CTD format. The ICH Electronic Common Technical Document Specification requires other hyperlinks and these should also be added. Hyperlinks, with the exception of tables of contents, should be indicated typographically with blue text or a blue box.

6.2.5 Letter of Attestation for Hybrid Submissions

A Letter of Attestation should be included confirming that the content contained in Modules 1 and 2 of the partial paper-based submission in CTD format is identical to the content contained in Modules 1 and 2 of the electronic submission in eCTD format. A Letter of Attestation is required for every sequence number for which a paper equivalent is submitted. The Letter of Attestation should be filed under the m1-2-3-submission-certification heading of the submission in eCTD format and in Section 1.2.3 of the paper-based submission in CTD format. See Appendix D, "Sample Letters of Attestation," of this guidance document.

6.2.6 Filing Process for Hybrid Submissions

Sponsors filing a submission in eCTD format in the hybrid filing format for the first time are required to arrange for a pre-submission consultation (see Section 5.1, "Hold Technical Pre-submission Consultation"). Such sponsors should also file an eCTD sample prior to filing a complete hybrid submission in eCTD format (see Section 5.2, "File eCTD Sample").

The sponsor is required to file Modules 1 and 2 of the partial paper-based submission in CTD format at the same time as the complete submission in eCTD format. The submissions in both formats should be sent to SIPD.

6.2.7 Additional Information for Hybrid Submissions

In the case of submissions in the hybrid filing format, if the review of the submission is completed before the electronic response to a Clarifax is filed, the issuance of the Notice of Compliance (NOC) may be delayed because the electronic response is required to complete the legal document.

6.2.8 Print on Demand for Hybrid Submissions

Health Canada may request that a drug submission sponsor supply portions of Modules 3 to 5 in paper in CTD format. For the details about Print on Demand requests, see Appendix E, "Print on Demand."

6.3 Electronic-only Submission

An electronic-only submission is a submission in eCTD format that is not accompanied by any portion of a paper-based submission in CTD format. For an electronic-only submission in eCTD format, the submission in eCTD format must be complete.

Note: Electronic-only submissions in eCTD format are currently not being accepted by Health Canada. Later versions of this guidance document will contain more information about this filing format.

7 Appendices

Appendix A: References

Health Canada Reference Documents:

The latest versions of Health Canada's guidance documents are available under the Drug and Health Products subject of Health Canada's Web site.

• Guidance for Industry: Management of Drug Submissions

This guidance document can be found by selecting the following topics located on the left-hand navigation panel. Drug Products; Applications & Submissions and Guidance Documents.

• Guidance for Industry: Preparation of Drug Submissions in eCTD Format, "Questions and Answers"
• Canadian DTD for ICH Module 1, Version 1.0
• Guidance for Industry: Creation of the Canadian Module 1 eCTD Backbone File

These guidance documents can be found by selecting the following topics located on the left-hand navigation panel. Drug Products; Applications & Submissions; Guidance Documents; Common Technical Document (CTD) and eCTD.

• Guidance for Industry: Preparation of New Drug Submissions in the CTD Format
• Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format

These guidance documents can be found by selecting the following topics located on the left-hand navigation panel. Drug Products; Applications & Submissions; Guidance Documents and Common Technical Document (CTD).

• "Notice: New Draft Quality Guidances on the Implementation of the Common Technical Document for Biological Products"
• Guidance for Industry: Preparation of the Quality Information for Drug Submissions in the CTD Format: Biotechnological/Biological (Biotech) Products
• Guidance for Industry: Preparation of the Quality Information for Drug Submissions in the CTD Format: Blood Products
• Guidance for Industry: Preparation of the Quality Information for Drug Submissions in the CTD Format: Conventional Biotherapeutic Products
• Guidance for Industry: Preparation of the Quality Information for Drug Submissions in the CTD Format: Vaccines
• "Certified Product Information Document (Schedule D Drugs) (CPID (Schedule D Drugs)) Template in the CTD Format"

These Schedule C and Schedule D products guidance documents can be found by selecting the following topics located on the left-hand navigation panel. Biologics, Radiopharmaceuticals & Generic Therapies; Applications & Submissions; Guidance Docuements; Quality; Blood Products, Vaccines, Genetic Therapies & Diagnositics and Notice: New Draft Quality Guidances on the Implementation of the Common Technical Document for Biological Products.

ICH Reference Documents:

• Electronic Common Technical Document Specification (Version 3.2 )
• Guidance for Industry M4: The CTD-General Questions and Answers
• Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use
• eCTD IWG Question and Answer and Specification Change Request Document

These documents and related specification documents, information, and questions and answers on CTD and eCTD implementation issues are available on the International Conference on Harmonisation Web site.

Appendix B: Contacts

Submission and Information Policy Division (SIPD)
Therapeutic Products Directorate
Health Canada
101 Tunney's Pasture Driveway
Address Locator: 0201A1
Ottawa, Ontario
K1A 0K9
E-mail: eReview@hc-sc.gc.ca

Appendix C: List of Abbreviations

3011 form:

Drug Submission Application Form

ANDS:

Abbreviated New Drug Submission

BE:

Bioequivalence

BGTD:

Biologics and Genetic Therapies Directorate

CBE:

Centre for Biologics Evaluation

CERB:

Centre for the Evaluation of Radiopharmaceuticals and Biotherapeutics

Clarifax:

A fax requesting clarification

CPID:

Certified Product Information Document

CRF:

Case Report Form

CS:BE:

Comprehensive Summary: Bioequivalence

CTA:

Clinical Trial Application

CTA-A:

Clinical Trial Application Amendment

CTD:

Common Technical Document

DINA:

Drug Identification Number Application

DMF:

Drug Master File

DTD:

Document Type Definition

eCTA:

eCTD-formatted Clinical Trial Application

eCTA-A:

eCTD-formatted Clinical Trial Application Amendment

eCTD:

Electronic Common Technical Document

EWG:

Expert Working Group

ICH:

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

LAp and LAm:

Licence Application and Licence Amendment

NC:

Notifiable Change

NDS:

New Drug Submission

NHP:

Natural Health Product

NOC:

Notice of Compliance

NOC/c:

Notice of Compliance with Conditions

NOD:

Notice of Deficiency

NOD-W:

Notice of Deficiency-Withdrawal

NON:

Notice of Non-Compliance

NON-W:

Notice of Non-Compliance-Withdrawal

PDF:

Portable Document Format

PSUR:

Periodic Safety Update Report

PM:

Product Monograph

SANDS:

Supplement to an Abbreviated New Drug Submission

SDN:

Screening Deficiency Notice

SIPD:

Submission and Information Policy Division

SNDS:

Supplement to a New Drug Submission

SRF:

Site Reference File

STF:

Study Tagging File

UDF:

Universal Disk Format

TPD:

Therapeutic Products Directorate

XML:

eXtensible Markup Language

YBPR:

Yearly Biologic Product Report

Appendix D: Sample Letters of Attestation

Sample Letter of Attestation for Co-submissions

We certify that, to the best of our knowledge and belief, with reference to the submission pertaining to

submitted by

All information and material included in the submission in Electronic Common Technical Document (eCTD) format exactly matches the information and material included in the submission on paper in the Common Technical Document (CTD) format. No information has been added, removed, or changed.

Signed

Sample Letter of Attestation for Hybrid Submissions

We certify that, to the best of our knowledge and belief, with reference to the submission pertaining to

submitted by

All information and material included in Modules 1 and 2 of the partial submission on paper in Common Technical Document (CTD) format exactly matches the information and material included in Modules 1 and 2 of the electronic submission in Electronic Common Technical Document (eCTD) format. No information has been added, removed, or changed.

This letter also certifies that all information that may be provided in response to Print on Demand requests from Health Canada will exactly match the information in eCTD format. No information will be added, removed, or changed.

Signed

Appendix E: Print on Demand

It is assumed that submissions in eCTD format in the hybrid filing format will be screened and reviewed electronically. However, Health Canada may want to review portions of Modules 3 to 5 on a transitory paper copy. Print on Demand is meant to be a transitional activity and requests are expected to drop in frequency as Health Canada gains experience in working electronically. A paper copy of portions of a submission might be required if

• a review is being performed by an employee who has not yet acquired the ability to perform electronic review;
• a reviewer has started using the submission in eCTD format, but for ergonomic reasons wants to revert to a paper copy; or
• the information technology environment is unstable and could affect performance targets.

The paper copy provided in response to a Print on Demand request is a review aid and not a permanent record. It is a transient document and will be securely disposed of after use. In case of discrepancy between the transitory paper copy and the submission in eCTD format, the submission in eCTD format is the legal record.

Based on the size or complexity of the requested copy, the printing will be completed either by Health Canada or the sponsor, at the expense of the respective party. The sponsor should provide the copy to Health Canada within a negotiated time to ensure that the performance target is met.

Health Canada will contact the sponsor as soon as the need for a transitory paper copy is identified. This may be when the work is scheduled or during the review process. The earlier the need is assessed, the more flexibility there will be in negotiating a time frame for delivery.

The following parameters for Print on Demand requests are proposed:

• Health Canada will print 500 pages or less in total for each submission. Health Canada may give the sponsor the option of providing the printed copy.
• For requests of 500 pages or more, the sponsor will provide the transitory paper copy within a negotiated time frame.

The format of the transitory paper copy should comply with the CTD specification. The copy should be accompanied by a cover letter that includes the following information: the submission number, sequence number, and the name of the requester. The sponsor should send the copy to SIPD at the address provided in Appendix B.

Appendix F: Pilot Implementation of the Hybrid Filing Format

Health Canada has decided to adopt a controlled implementation for submissions in eCTD format in the hybrid filing format, beginning with a pilot starting June 30, 2006. Health Canada will select a limited number of submissions in eCTD format for which it has the capacity to perform electronic review, while respecting performance targets and minimizing Print on Demand requests (see Appendix E, "Print on Demand").

Criteria for Participation in the Hybrid Filing Format Pilot

The following drug submission types may be candidates for the pilot implementation of the hybrid filing format:

• NDS, ANDS, SNDS, and SANDS;
• NDS labelling, only if the original submission was filed in the co-submission or hybrid filing formats; and
• NC submissions and forms summarizing Changes to Marketed Human New Drug Products Notices of Change (Level III), related to a previously filed eCTD submission that was filed in the hybrid filing format.

At this time, a submission will not be considered a candidate for the pilot of the hybrid filing format if any of the following conditions apply:

• Health Canada does not have the capacity or ability to perform an electronic review of a submission.
• A submission is to be assigned to a reviewer on contract.

Submissions outside of the scope outlined above may be considered on a case-by-case basis.

Request for Participation in the Hybrid Filing Format Pilot

Sponsors wishing to file a submission in eCTD format in the hybrid filing format as part of the pilot project should submit a written request to SIPD as soon as possible. Within two weeks of receiving the request, SIPD will inform the sponsor as to whether the submission can be accepted for the pilot project.

The following information should be included in the written request:

• Anticipated date of filing;
• Sponsor name and address;
• Contact information;
• Type of submission;
• Brand or common name;
• Therapeutic or pharmacological classification;
• Dosage form;
• Route of administration;
• Indication(s) or type of changes;
• For SNDS or SANDS, the reason for the supplement; and
• If applicable, the rationale for requesting to include in the pilot a submission outside of the scope of the criteria outlined above.

With the request to participate in the pilot, the sponsor should make a written commitment to provide the following material to Health Canada:

• Upon request, a partial or full printed copy of one or more of Modules 3, 4, or 5 in CTD format within a negotiated time frame. See Appendix E for further information.
• A full printed copy of an NC in CTD format at the same time that the eCTD is provided. (Health Canada currently has no experience with submissions that have a short review time frame.)

Assessment of the Pilot

The pilot will be monitored. All information gathered will be assessed after the following number of submissions have been completed up to the issuance of an NOC or Notice of Non-Compliance-Withdrawal (NON-W):

• For BGTD, five NDSs, preferably one type for each review division (three in the Centre for the Evaluation of Radiopharmaceuticals and Biotherapeutics [CERB] and two in the Centre for Biologics Evaluation [CBE]), or sufficient SNDSs providing the same amount of exposure (essentially those with 300-day targets); and
• For TPD, five NDSs and ten ANDSs.

During the assessment, Health Canada will continue to accept submissions as part of the pilot. The outcome of the assessment will be used for evaluating Health Canada's readiness to move toward full implementation of the hybrid filing format.

Appendix G: Example Life Cycle Management Table

Table G-1: Example Life Cycle Management Table

Sponsor Name: pharmacompany

Brand Name: Drug X

eCTD Identifier: e123456

Sequence Number (most recent first)	Date Submitted	Control Number	Related Sequence	Sequence Number Description
0000	Jul. 05, 2004	123456	0000	Initial
0001	Sep. 15, 2004	123456	0000	Response to Screening Clarifax dated Sep. 01, 2004 (requester)
0002	Nov. 03, 2004	123456	0000	Response to NOD dated Oct. 01, 2004 (requester)
0003	Feb. 22, 2005	123456	0000	Response to Safety and Efficacy Clarifax dated Feb. 10, 2005 (requester)
0004	Apr. 11 , 2005	123456	0000	Response to e-mail request dated Mar. 28, 2005 (requester)
0005	Jun. 22, 2005	123456	0000	Response to Labelling Clarifax dated Jun. 10, 2005 (requester)
0006	Jan. 09, 2006	123555	----	Post NOC Change
0007	Mar. 15, 2006	123555	0007	Response to NON dated Mar. 03, 2006 (requester)
0008	Jul. 04, 2006	123555	0007	Response to Quality Clarifax dated Jun. 22, 2006 (requester)
0009	Oct. 18, 2006	123666	----	Post NOC Change
0010	Nov. 23, 2006	123666	0010	Response to Labelling Clarifax dated Nov. 10, 2006 (requester)
0011	Dec. 20, 2006	123666	0010	Response to telephone request dated Dec. 8, 2006 (requester)
0012	Jan. 23, 2007	123666	0010	Pristine PM

Appendix H: Life Cycle Management Scenarios for Operation Attributes

The scenarios provided in this appendix describe rules applicable to the general use of the operation attribute for life cycle management. They are examples from a broad range of possibilities. They are not intended to be a comprehensive set and merely address some common situations that sponsors are likely to encounter.

Table H-1: Valid Append Scenarios

Scenario Number and Description			Attributes
	Seq. #	Leaf ID	File Ref.	Operation	Mod. File	Comment
1. Append to a New leaf (EDMS 10)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
2. Append to a Replace leaf (EDMS 21)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
	0002	B2	B2.pdf	append	A1	Valid append to replace
3. Parallel Appends to a New leaf (EDMS 28)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
	0002	C2	C2.pdf	append	A0	Valid append

Figure H-1: Valid Append Scenarios

Table H-2: Invalid Append Scenario

It is not a valid operation to append to a leaf that has already been appended to a new leaf.

Scenario Number and Description			Attributes
	Seq. #	Leaf ID	File Ref.	Operation	Mod. File	Comment
4. Append to an Append leaf (EDMS 29)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
	0002	C2	C2.pdf	append	B1	Invalid append

Figure H-2: Invalid Append Scenario

Table H-3: Valid Replace Scenarios

Scenario Number and Description			Attributes
	Seq. #	Leaf ID	File Ref.	Operation	Mod. File	Comment
5. Replace a New leaf (EDMS 8)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
6. Replace a Replace leaf (EDMS 19)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
	0002	A2	A2.pdf	replace	A1	Valid chain replace
7. Replace an Append leaf (ETICS 3, EDMS 27)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
	0002	C2	C2.pdf	replace	B1	Valid replace
8. Replace a New leaf that has an Append leaf, with a leaf that consolidates the content of both (ETICS 2, EDMS 26)*	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
	0002	C2	C2.pdf	replace	A0	Valid replace
		B2	Empty	delete	B1	Mandatory delete

*When replacing the original document, any appended document must be deleted. Therefore the content of A0.pdf and B1.pdf should be consolidated.

Figure H-3: Valid Replace Scenarios

Table H-4: Valid Delete Scenarios

Scenario Number and Description			Attributes
	Seq. #	Leaf ID	File Ref.	Operation	Mod. File	Comment
9. Delete a New leaf (EDMS 9)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	Empty	delete	A0	Valid delete
10. Delete a Replace leaf (EDMS 20)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
	0002	A2	Empty	delete	A1	Valid delete replace
11. Delete an Append leaf (EDMS 30)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
	0002	A2	Empty	delete	B1	Valid delete
12 Delete a New leaf that has an Append leaf (ETICS 1, EDMS 25)*	0000	A0	A0.pdf	new	Empty	Valid new
	0001	B1	B1.pdf	append	A0	Valid append
	0002	C2	Empty	delete	A0	Valid delete
		D2	Empty	delete	B1	Mandatory delete

*When the original document is deleted, any appended documents must be deleted.

Figure H-4: Valid Delete Scenarios

Table H-5: Invalid Operations on Non-current Leaves

As a general principle, an operation should not be applied to a leaf that is no longer active, that is, that has already been replaced or deleted.

Scenario Number and Description			Attributes
	Seq. #	Leaf ID	File Ref.	Operation	Mod. File	Comment
13. Attempt to Replace a New leaf that has been Deleted (EDMS 31)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	Empty	delete	A0	Valid delete
	0002	A2	A2.pdf	replace	A0	Cannot undelete leaf
14. Attempt to Delete a New leaf that has been Replaced (EDMS 32)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
	0002	A2	Empty	delete	A0	Must act on current leaf
15. Attempt to Delete a New leaf that has already been Deleted (EDMS 33)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	Empty	delete	A0	Valid delete
	0002	A2	Empty	delete	A0	Cannot re-delete leaf
16. Attempt to Append to a New leaf that has already been Replaced (EDMS 34)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
	0002	B2	B2.pdf	append	A0	Must act on current leaf
17. Attempt to Append to a New leaf that has already been Deleted (EDMS 35)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	Empty	delete	A0	Valid delete
	0002	B2	B2.pdf	append	A0	Cannot undelete leaf
18. Attempt to Replace a New leaf that has already been Replaced (EDMS 36)	0000	A0	A0.pdf	new	Empty	Valid new
	0001	A1	A1.pdf	replace	A0	Valid replace
	0002	A2	A2.pdf	replace	A0	Undefined replace

*When the original document is deleted, any appended documents must be deleted.

Figure H-5: Invalid Operations on Non-current Leaves