Health Canada has posted a final version of Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document (eCTD) Format on their web site.  This version, dated November 4, 2009, replaces the draft version dated January 25, 2006.

On the whole, the changes are more evolutionary than revolutionary.  Throughout the document, the previous terminology of “Annual update forms summarizing the Notices of Change” has been updated to refer to “Forms summarizing the Changes to Marketed Human New Drug Products”.  Some of the more significant changes are described below.

Guidance on placement of leaf elements

In the section “3.3.1 Module 1: Administrative Information and Prescribing Information”, considerably more detail is provided for the organization and content of Module 1.  New items in this section include:

·         Granularity and placement of Appendix I, Life Cycle Management Table

·         Construction of summary responses and placement in Module 1, along corresponding original requests

·         Placement of the Product Monograph (PM) certification form

·         Handling of notes to reviewers

In the section “3.3.2 Modules 2 to 5”, additional information includes placement of PSURs requested during the pre-market review process by TPD and BGTD as well as placement of Case Report Forms.

Changes to Recommended Module 1 File Naming Conventions

Module 1 recommended file naming conventions have changes.

Choice of file naming convention is up to the sponsor… 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.

For more details and examples, see “3.2.6 Leaf File Naming Convention”.

More Help with eCTD Operations

Section 4.3 and its subsections have been enhanced to provide additional guidance on and examples for operation attributes.  Some useful advice includes:

·         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.

·         Health Canada does not recommend using the operation attribute to modify a document twice in the same sequence.

·         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.

·         Notes to Reviewers, the Lifecycle Management Table, and Q&A Leaf Elements should always be new (along with letters of attestation).

·         Detailed guidance on how to handle the PM leaf element and forms summarizing the Changes to Marketed Human New Drug Product is provided. 

·         Figures are provided to illustrate life cycle management scenarios for the Product Monograph (PM) and Certified Product Information Document (CPID).

Bookmarking Guidance

Section 4.4, Bookmarks in PDF Files, provides guidance for the first time on bookmarking. This guidance differs in some places from that provided by FDA.

·         Documents of ten pages or more should be bookmarked. (FDA says three pages or more.)

·         Too many levels of bookmarks are inefficient; in most instances, three levels of bookmarks should be sufficient.  (FDA says four levels.)

·         Health Canada recognizes that bookmarks are generated automatically from document headings, but nevertheless recommends they be kept concise. (This is a point I have often thought about but never seen discussed – if you are following good authoring practices most bookmarking should be automatic.)

Clarifications

Some other noteworthy clarifications include:

·         Periodic Safety Update Reports (PSURs) requested during the pre-market review process by Therapeutic Products Directorate (TPD) and Biologics and Genetic Therapies Directorate (BGTD may be filed in eCTD format. PSURs submitted to the Marketed Health Products Directorate (MHPD) may not be filed in eCTD format.

·         SNDS and SANDS are not longer limited to being filed when the original NDS or ANDS was in eCTD format.  Apparently, Health Canada will now allow a sponsor to switch to eCTD format for any major submission (like the FDA and EMEA).

·         Lot release documentation and Yearly Biologic Product Reports (YBPRs) may not be filed in eCTD format.

·         When a sponsor initially files in the paper-based CTD format and subsequently moves to the eCTD format, the sponsor is not expected to refile the previously approved paper-based submissions in electronic format.

·         Leaf titles should not include a file format (e.g., “Pristine Product Monograph.MS Word” should not include the .MS Word portion)

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

·         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.

·         Sponsors should only label discs.  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. Requested label information is slightly updated.

·         For all drug submission types (NDS, SNDS, ANDS, SANDS, and NC) when they are first filed, the related-sequence-number sub-element should be empty.  (Formerly, guidance said it should not be used.)

·         All mention of digital or electronic signatures has been dropped.

Additional Background Material

A significant amount of additional background material has been added, including:

·         A figure illustrating an eCTD Structure showing multiple sequences

·         An Example Life Cycle Management Table

·         A series of tables illustrating valid and invalid scenarios for Life Cycle Management Scenarios for Operation Attributes

Note: The Guidance document is a 59 page document with no bookmarks or hyperlinks.  I have thoroughly bookmarked and hyperlinked my copy.  If you work for a sponsor organization, send me an email (kathleen.clark@globalsubmit.com) from your company email account and I’ll send you a copy.   No CROs, consultants or vendors please – I’m not quite that nice J.