Issue Analysis Summary - Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document (eCTD) Format

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Table of Contents

• 1 Issue
• 2 Objective
• 3 Background
• 4 Options Analysis
• 5 Consultations
• 6 Recommendations
• 7 Implementation and Evaluation Plans
• Appendix
  • Appendix A: Summarised Comments and Recommendations from External Consultations

1 Issue

The purpose of this document is to provide a summary analysis of issues raised by comments from industry stakeholders in response to the Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format. The guidance document is intended to ensure that sponsors of drug submissions are provided the information they need to prepare their submissions in the Electronic Common Technical Document (eCTD) format developed by the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use. The guidance document is to be used in conjunction with other documents produced by Health Canada and the ICH, which are referenced in the guidance document.

2 Objective

The objective of this issue analysis is to introduce the issues raised by industry stakeholders in their comments on the Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format and explain how the current version of that document addresses those issues.

3 Background

The implementation and use of the eCTD format by Health Canada represents a work in progress. The format has been developed by the ICH; Health Canada has implemented the technologies necessary to process submissions in the format. The Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format was released in January 2006 for consultation with industry and internal stakeholders. During the first phase of implementation, Health Canada began accepting submissions in eCTD format along with full paper-based submissions in Common Technical Document (CTD) format. Health Canada began a pilot in June 2006, during which it accepted hybrid submissions, for which a full submission in eCTD format is accompanied by Modules 1 and 2 in the paper-based CTD format.

4 Options Analysis

The main issue associated with the Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format is its value in providing guidance to the pharmaceutical industry in their preparation of drug submissions in eCTD format. The submissions must conform to a rigid and detailed set of technical standards established by the ICH and adapted by participating countries to the particulars of their regulatory regime. Drug sponsors need assistance in interpreting the ICH standards and in understanding the local variations of those standards.

The industry consensus is that the Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format provides invaluable assistance to them in developing their drug submissions to conform to the Canadian version of the eCTD standard. However, industry comments identified numerous instances where the document could be clarified. Clarification could be a matter of simple rewording to remove ambiguity or it could be a matter of expanding explanations and providing examples to illustrate the explanations. Other comments pinpointed areas where the implications of Health Canada's interpretation of the ICH standard required further elaboration. In these cases, Health Canada staff in charge of administering, processing and reviewing submissions in eCTD format were referred to for their contributions.

5 Consultations

The draft guidance document was posted on the Health Canada Web site for internal and external consultation. The E-Review working group revised the draft to address all internal and industry comments. This interim draft was distributed to members of the Working Group on Electronic Submissions (WGES), composed of representatives from drug manufacturers and Health Canada. WGES met with the E-Review working group to discuss the guidance document and to provide detailed comments. All industry comments received through the consultations are in Appendix A, "Summarised Comments and Recommendations from External Consultations."

6 Recommendations

The E-Review working group has addressed all comments received from internal and external stakeholders. Appendix A, "Summarised Comments and Recommendations from External Consultations," describes how industry comments have been addressed, usually by editing the text of the guidance document. In addressing all comments, the E-Review working group has also identified other areas in the document that could be expanded or clarified. This work has resulted in the production of a completely revised Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format.

This report recommends that the revised draft guidance should be published on the Health Canada Web site and be released to industry as the final guidance for submission in eCTD format.

7 Implementation and Evaluation Plans

The version of the Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format that has been produced as a result of consultations and editing is currently being translated into French. Once the translation has been completed, both language versions will be posted on the Health Canada Web site as the final version.

Appendix

Appendix A: Summarised Comments and Recommendations from External Consultations

The draft guidance document entitled Draft Guidance for Industry: Preparation of Drug Submissions in the eCTD Format was generated by the E-Review working group in Health Products and Food Branch (HPFB), in consultation with the industry representatives through Working Group on Electronic Submissions (WGES).

The draft guidance document was published on the Health Canada Web site for a 60 day consultation period on January 25, 2006. The following is a summary of the comments received, together with discussions and recommendations for revisions.

The comments are excerpts from the original responses. Issues in the "Comments Received" column are discussed when the comment first appears or, in some cases, where the issues are most applicable. The comment is not repeated when it or a similar comment appears later in the document.

Note that suggestions for editorial changes to the document have not been included in the summary below, although some editorial changes were made.

General Comments

Comments Received

Health Canada Discussion and Recommendation

We believe this guidance provides valuable direction on Health Canada's plan for adoption of the Electronic Technical Document (eCTD) as well as instructions to sponsors who wish to submit electronically. We would encourage Health Canada to adopt a timeline and tools which are consistent with other major regulatory bodies. Also, in order for Health Canada to obtain greater experience with the eCTD, sponsors choosing to file them, should not be at a disadvantage. The guidance acknowledges potential delays associated with e-review, without any assurance about overall review times for these submission. The FDA has indicated that their performance will not be negatively impacted by any sponsor filing their applications electronically. We believe if Health Canada adopted a similar stance, it would encourage more sponsors to submit eCTDs.

This comment is addressed in the notice that will accompany the document.

1.0 Introduction

Comment Received	Health Canada Discussion and Recommendation
The draft guidance makes reference on various pages to the Electronic Common Technical Document Specification (Versions 3.0 and 3.2). It is our understanding that Version 3.2 superseded Version 3.0 and therefore we recommend that Version 3.0 be removed from the draft guidance document. We were not able to locate Version 3.0 anywhere on the International Conference on Harmonisation (ICH) Web site.	This comment has been addressed by changing references to the Electronic Common Technical Document Specification throughout.

2.2 Drug Submission Types

Comments Received	Health Canada Discussion and Recommendation
Regarding the drug submission types, as listed in section 2.2 of the document, it is stated that a Supplement to a New Drug Submission (SNDS) is eligible for filing in Electronic Common Technical Document (eCTD) format. From the guideline it is not clear if the first submission to be filed in eCTD format is for a SNDS - labelling update only (Product Monograph, or additional indication) without any update in the Module 3 information, how would a subsequent submissions be related to it for life cycle management? For example, if the subsequent submission is a Notifiable Change (NC) for an additional manufacturing site, would it be acceptable to submit only the new information as related to the NC, or all previous submission information has to be provided in eCTD format, since there are no previous Module 3 documents filed in eCTD format? We propose that this should be clarified in the updated Guidance.	The first part of this comment has been addressed by revisions to the text of Section 4.3, Life Cycle Management. The second part has been addressed by the third paragraph in Section 2.2, Drug Submission Types.
In addition, regarding the drug submission types in section 2.2 - annual update forms summarizing the Notices of Changes as relating to previously filed Electronic Common Technical Document (eCTD) submission will have to be filed in eCTD format as well. The draft guidance document does not provide further information on the requirement for filing annual updates. Do the sponsors have to provide at the same time the updated documentation as well (for example the updated Testing specification and updated Certified Product Information Document (CPID)) in order to maintain the life cycle of the documents? We propose that further details should be provided in the updated Guidance.	This comment has been addressed by the development of a new footnote to the text.
In this section the Electronic Common Technical Document (eCTD) scope is outlined, however, details regarding how a Level 3 or 4 (such as (i.e.,) Non-Notable Change) is handled for eCTD is not specified. For example, it is not clear when and how the "information not submitted Level 3 Notice of Change" (refer to page 13 of the guidance, Figure 4, Sequence #0010) would be submitted to Health Canada. We believe additional detail should be added to the guidance to clarify the process for how the sequence containing the Non-Notifiable Change details is provided to Health Canada. We recommend that this new sequence (i.e. Non-Notifable Change) be provided to Health Canada with the subsequent filable submission (i.e. Supplement to a New Drug Submission (SNDS), Notifiable Change (NC)) for that product.	This comment is to be addressed by a new Q&A.
The same section 2.2 indicates additional types of submissions, which are excluded from the current draft guideline (Clinical Trial Application (CTA), Clinical Trial Application - Amendment (CTA-A), DINA, etc.). The list includes “Periodic Safety Update Reports (PSURs) submitted to the Marketed Health Products Directorate (MHPD)”. In section 2.3 Additional information and subsequent submissions, includes the expectations that all additional information on an Electronic Common Technical Document (eCTD) submission should be filed in eCTD format. Our question is if the PSUR is requested as additional information during the review of a eCTD submission, is the expectation that the document be provided in eCTD format as well? Clarification should be provided in the updated Guidance.	This comment has been addressed by revisions to the text.

4.1 File Formats

Comments Received	Health Canada Discussion and Recommendation
In Section 4.1 File Formats (page 10) and/or in Section 6.2.1 Legal Document for Hybrid Submissions (page 23) we recommend that a reference be added to the International Conference on Harmonisation (ICH) guidelines Version 3.2 February 04, 2004 to Source of Electronic Document (page 7-2) and Methods for Creating Portable Document Format (PDF) Documents and Images (page 7-3). These references provide more details about scanning requirements.	To the extent possible, this comment has been addressed by revisions to the text. The comment also applies to 6.2.1. Some details in this comment the level of technicality of this guidance document.
Section 4.1 File Formats (page 10) addresses the Adobe Acrobat, version 4.0, 5.0 and 6.0). Version 7.0 is available and therefore our recommendation is to include this as well.	We have added Acrobat 7.0 because it has been adopted as the standard by Health Canada.
Section 4.1 refers to documents that are required to be submitted in word-processed format as well as Portable Document Format (PDF). Occasionally, Clarifax's are sent to request documents other than those listed in word-processed format. Will it be correct to provide them within the Electronic Common Technical Document (eCTD) in the relevant module?	This comment has been addressed by revisions to the text.
There is a possibility that electronic data in the form of Compact disks (CDs) and Digital Video disks (DVDs) may be misplaced using couriers. When will Health Products and Food Branch (HPFB) establish a "technical transfer" between HPFB and the industry for Electronic Common Technical Document (eCTD) submissions? Will this "technical transfer" be implemented before the pilot period for the eCTD concludes?	Secure electronic two-way communication between Health Canada and our sponsors will not be implemented before the pilot for submissions in Electronic Common Technical Document (eCTD) format in the hybrid filing format concludes. Further information about secure two-way communication will be provided on the Health Canada Web site.
Section 4.3 refers to the Life Cycle Management Table that should include all sequences and how they relate to each other. Is there a preference as to whether the newest sequence is listed first or last on the table? Also, will there be any kind of size limitation, for instance for drugs that have multiple indications and span several years, this table could grow quite large. Will there be a "cut-off" where older information is removed to keep the file size manageable?	The preferred order is for the newest sequence to be listed last on the table. This information has been added to text. The length of the table is irrelevant. There are no current plans to have a "cut-off" for older information.

Table 1: Example Life Cycle Management Table

Comments Received

Health Canada Discussion and Recommendation

In addition, we would like to clarify our understanding of Table 1 (page 12) and Figure 4 (page 13). It appears that for the original submission, the Electronic Common Technical Document (eCTD) Identifier would be the letter "e" plus the Control Number for that submission. For each subsequent submission, since the eCTD Identifier doesn't change, it would not match the new control number issued for that submission. Is our understanding of this process correct? If so, please clarify in the guidance.

This understanding of the relationship between the Electronic Common Technical Document (eCTD) Identifier and Control Number is correct.

4.3.2 Life Cycle Management at the Submission Layer

Comments Received	Health Canada Discussion and Recommendation
The guideline is not clear on the life cycle management of documents and submissions. Our suggestion is to include some examples or different scenarios in an Appendix or Frequently Asked Questions (FAQ) document, specifically on using the operations (append, replace and delete) and on document life cycle for Product Monographs and Certified Product Information Documents (CPIDs), including cases of "in-house submissions" such as Level 3 & 4 and the way documents need to be treated in order to preserve the life cycle?	This and the following section have been revised to address this comment.
Section 4.3.2 notes that the relate-sequence-number sub-element should not be used for Supplement to a New Drug Submission (SNDS) and Notifiable Change (NC) submission types. There is Electronic Common Technical Document (eCTD) publishing software on the market right now that requires all subsequent submissions after the original application to have at least one related sequence number or it will not validate. Since this is a technical limitation with software, will you ignore it in your validation reports, or provide a work-around suggestion (relate to 0000 if you have no other choice) in your guidance?	A general guidance document cannot deal with exceptions caused by software used by a limited number of companies. This comment cannot be dealt with in a general Guidance Document. If problems arise they will be dealt with on a case-by-case basis.

5.8 Correct Errors and File Corrected Submission in Electronic Common Technical Document (eCTD) Format

Comments Received

Health Canada Discussion and Recommendation

The guidance should provide clarification regarding situations when screening deficiencies are found that would necessitate the altering of documents in an Electronic Common Technical Document (eCTD). Technically, if new information is added or replaced, a new sequence should be created with the new or replacement documents. However, this may be an issue for the reviewer because with the current specification and review tools, there is no ability to create a cumulative submission from two sequences [i.e. initial submission (sequence 0000) plus the revised sequence due to screening deficiencies (sequence 0001)]. We believe that a replacement sequence (with same sequence number i.e. sequence 0000) should be provided under these circumstances. Therefore, the incorrect document (the document that was replaced) would not be included in the updated sequence. We also suggest that more guidance be provided in section 5.8 concerning resubmission of an eCTD, when errors are identified during validation. We believe the corrected submission should retain the same sequence number.

Sponsors should understand the content of their submission and how to manage the submission life cycle of the document accordingly. There is no ability to create a "cumulative submission;" the comment means "current submission." The corrected submission should not retain the same submission number. As soon as a sequence is loaded and validated in the viewing tool, the sequence number cannot be removed or edited.

6.1.3 Congruence of Structure of Co-submissions

Comments Received	Health Canada Discussion and Recommendation
Technically it is difficult to comply with the requirement on matching headers and footers. Volume based pagination are (for example (e.g.), not meaningful to include in an Electronic Common Technical Document (eCTD) structure with individual files.	This comment is not accurate because volume-based pagination is not required in either the Common Technical Document (CTD) or Electronic Common Technical Document (eCTD).

6.1.6 Filing Process for Co-submissions

Comments Received	Health Canada Discussion and Recommendation
Please clarify whether co-submissions will only be screened electronically.	Screening is done using the paper or electronic copy based on the submission in Electronic Common Technical Document (eCTD) format having been submitted at the same time as the paper-based submission and the screener’s readiness to use the eCTD format.
In addition, we would like to make a recommendation concerning the requirement to submit both a hard copy and Electronic Common Technical Document (eCTD) simultaneously. Considerable additional work is required to prepare an eCTD submission for a co-submission. A significant portion of this work occurs once the last document is received, as only now can the eCTD be completed (such as (i.e.), hyperlinking, validation in eCTD and viewing tool, Quality Assurance (QA) check). We suggest that rather than have sponsors delay filing the paper submission until the eCTD can be prepared, allowances could be made in the guidance for the receipt of the eCTD up to 20 days post receipt of the paper submission.	Health Canada would recommend that the sponsor consider submitting in hybrid filing format to offset the burden of preparing both paper and electronic copies.

6.2.1 Legal Document for Hybrid Submissions

Comments Received	Health Canada Discussion and Recommendation
From a Good Practice viewpoint it is not a good practise to manipulate with approved documents. If "empty signature lines" in the master Portable Document Format (PDF) documents cannot be accepted then scanned signature pages could either be "available upon request" or provided as separate documents.	This comment has been addressed by revisions to the text.

6.2.8 Print on Demand for Hybrid Submissions

Comments Received

Health Canada Discussion and Recommendation

The current Electronic Common Technical Document (eCTD) tools do not have printing capabilities and therefore, in order to produce hard copies, significant resource is needed (printing, compiling, preparing tabs to comply with Common Technical Document (CTD) specifications). Since the guideline does not limit to the amount, or how often paper copies of information can be requested during the review process, we are concerned that the review would be halted during such requests and this would ultimately have a negative impact on overall review times. We recommend that such requests be identified well in advance and a limit as to the amount of information requested be added to the guideline so that there is no impact to the review timelines.

So far, there have been few requests for Print on Demand; therefore, it does not appear to be necessary to address this comment.

6.3 Electronic-only Submission

Comment Received	Health Canada Discussion and Recommendation
What is Health Products Food Branches (HPFB's) timeline for the eventual acceptance of electronic-only submissions? What are the requirements regarding a technical pre-submission consultation and Print on Demand for electronic-only submissions (see Table 2)?	Information regarding electronic-only submissions is unavailable at this time.

Appendix E: Print on Demand

Comments Received	Health Canada Discussion and Recommendation
There is a concern about the potential impact to performance targets due to Print on Demand requests. We recommend that there be an option for Health Canada to print the transitory paper copy for requests of 500 pages or more, and invoice the sponsor for the printing costs.	Health Canada does not have resources that are needed for printing, compiling, and preparing tabs to comply with Common Technical Document (CTD) specifications.

Appendix F: Pilot Implementation of the Hybrid Filing Format, Request for Participation in the Hybrid Filing Format Pilot

Comments Received	Health Canada Discussion and Recommendation
We recommend to add the date when referring to the Electronic Common Technical Document Specification (Version 3.2 - February 04, 2004).	This comment has been addressed by additions to the text.