Release of New and Revised Health Canada Draft Guidances and Templates for Use in the Preparation of Submissions in the CTD Format

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Notice

Date: 2003-06-25

Our file number: 03-111720-509

The Biologics and Genetic Therapies Directorate (BGTD) and the Therapeutic Products Directorate (TPD) are pleased to announce the release of the following guidance documents and summary template, meant to assist applicants in the preparation of drug submissions in the Common Technical Document (CTD) format developed by the International Conference on Harmonisation (ICH):

Draft Guidances for Industry:

• Preparation of New Drug Submissions in the CTD Format (updated)
• Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format¹ (updated)
• Preparation of the Quality Information for Drug Submissions in the CTD Format: Biotechnological/ Biological (Biotech) Products² (updated)
• Preparation of the Quality Information for Drug Submissions in the CTD Format: Blood Products (new)
• Preparation of the Quality Information for Drug Submissions in the CTD Format: Conventional Biotherapeutic Products (new)
• Preparation of the Quality Information for Drug Submissions in the CTD Format: Vaccines (new)

¹ Replaces Guidance for Industry: Preparation of Bioequivalence Information for Drug Submissions in the CTD Format

² Replaces previous draft (dated September 12, 2001) entitled Preparation of the Quality Information for Drug Submissions in the CTD Format.

Guidance for Clinical Trial Sponsors:

• Clinical Trial Applications (new)

Draft Summary Template:

• Certified Product Information Document (Schedule D Drugs)³ (new)

A Health Canada Questions and Answers document is also being developed to further clarify certain regional issues.

Related, unchanged Health Canada publications include:

• Quality Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)
• Quality Overall Summary - Chemical Entities (New Drug Submissions and Abbreviated New Drug Submissions) (QOS-CE (NDS))
• QOS-CE Analytical Procedures and Validation Information Summaries
• Certified Product Information Document - Chemical Entities (CPID-CE)

Together, these guidances and templates serve to integrate the CTD within the Canadian drug regulatory framework by describing regional administrative (Module 1) and general filing requirements, and by providing additional guidance on the location, level and suggested format of information to be included within CTD-formatted submissions. Furthermore, the newly released draft guidances enables the use of the CTD format to be extended to most biological (Schedule D) products.

These guidances are meant to be read in conjunction with the most recent version of the CTD guidances and the corresponding Questions and Answers documents on the ICH website⁴. It is also necessary for drug submission applicants to consult relevant Health Canada and ICH-adopted guidances regarding content (data) requirements.

The Guidance for Industry: Preparation of New Drug Submissions in the CTD Format has been amended to reflect decisions taken by the ICH CTD implementation working groups and steering committee since the previous release of this document. It has also been amended to clarify certain issues, incorporate a number of suggestions made by stakeholders and describe some new filing requirements. A summary of principal revisions is provided in the Attachment. For a description of changes to the other referenced Health Canada guidances and templates, please consult the associated notice to the guidance(s).

³ Replaces previous draft Certified Product Information Document (Biotech) in the CTD Format (dated September 12, 2001) and its application now expands to all Schedule D drugs.

⁴ At www.ich.org. See also the companion Notice on the formal Health Canada adoption of the CTD M4 guidances and Appendix A of the draft Preparation of New Drug Submissions in the CTD Format guidance for relevant Health Canada websites.

Implementation Dates and Scope of Application

As previously noted, as of July 1, 2003 the Common Technical Document and appropriate adaptations of the CTD officially replace previous formats in Canada for all drug submissions filed pursuant to Divisions 5 and 8, Part C of the Food and Drug Regulations, as specified below. As of this date the use of the CTD is expected for original filings and subsequent filings, regardless of the format of the original submission. It is also expected to be used for the drug component of drug/device combinations where the primary mechanism of action is drug-related.⁵ Submission types affected:

• New Drug Submissions (NDSs)
• Abbreviated New Drug Submissions (ANDSs)
• Supplements and Notifiable Changes (NCs)
• Clinical Trial Applications (CTAs) and Amendments (CTA-As)

Requirements on the filing of CTD-formatted Clinical Trial Applications (CTAs) and their amendments are described in the new Guidance for Clinical Trial Sponsors - Clinical Trial Applications.

Note: An applicant is not expected to reformat a previously-related submission into the CTD format for cross-referencing purposes. However, the cross-referencing should be specific and clear enough for the evaluator to easily locate the information.

Health Canada is currently developing guidance documents to extend the application to other submission and product types other than those identified above, specifically Drug Identification Number submissions (DINs), Drug Master Files (DMFs) and Radiopharmaceuticals (Schedule C drugs).

Until such time that these guidance documents become available, applicants may voluntarily file these types of submissions in a CTD format provided that current filing expectations are respected (e.g., as in the case with a Type 1 DMF (Drug Substance), "Open" and "Closed" portions are provided). Applicants are advised to consult the relevant Bureau/Centre for additional information regarding the use of the CTD format for these and any other submission/product types for which specific guidance is not currently available.

⁵ Where the combination product is classified as a device the use of the CTD format for the drug component is optional.

Draft documents are expected to undergo further changes pending their consultation period, based upon comments received, efforts to further harmonize internationally and/or with the introduction of the electronic or eCTD.⁶ Nonetheless, all draft documents referred to within this notice may now be used to prepare drug submissions in the CTD format.

Any updates to CTD-related filing requirements will only be introduced following advance notice and will not be applied retroactively to submissions pending review. Furthermore, for submissions currently in preparation applicants may continue to follow the Health Canada guidances/templates in effect prior to the date of release of this notice. Subsequent submissions, however, should be compiled using the most recent guidances.

Regional Summaries

As noted in the previous Consultation Document dated April 17, 2001, the use of the Quality Overall Summary - Chemical Entities (QOS-CE) is encouraged but not mandatory. The QOS-CE is considered an acceptable replacement for the Quality Overall Summary defined by the CTD-Q guidance as its use promotes review efficiencies by serving as the basis for the Quality assessment report. For similar reasons, the Comprehensive Summary: Bioequivalence (CS-BE) may be filed in lieu of the CTD Clinical Overview/Summaries for submissions that rely solely on pivotal comparative bioavailability studies to establish safety and efficacy. The completion of the CS-BE is also encouraged as a supplement to the Module 2 summaries when, for example, such studies serve to link the product used in pivotal clinical trials with the proposed commercial product.

In response to proposals by submission applicants, Health Canada recently considered allowing, on an interim basis, the QOS-CE and CS-BE to be submitted within a specified period after the initial filing but prior to the review of the submission. This would have required that the corresponding ICH CTD summaries form part of the initial submission package and that applicants certify that the regional summaries contain no new information as compared to the initial submission filing. However, in light of administrative and other considerations the Department has decided that it would be more appropriate to accelerate the development of simplified versions of the regional summary templates and the migration from the currently specified electronic file format for these summaries.

Note: The former Pre-clinical and Clinical Evaluation Template (PCERT) should not be prepared for CTD-formatted New Drug Submissions and Supplements, with the exception of the distinct CS:BE module. Please also note, however, that the counterpart 'PCERT' for CTAs and CTAAs for Pharmaceuticals (only) should be completed and filed in conjunction with these latter submission types.

⁶ It is also expected that, for the reasons cited above, previously released Quality guidances and templates for 'Pharmaceuticals' (Chemical Entities) will also be amended.

Electronic Review Documents and the eCTD

Health Canada is in the process of developing a phased migration plan from paper-based submissions and proprietary software standards to the ICH eCTD specification. In this regard, a new Advisory Committee on Electronic Submissions (ACES) has been established to provide advice on a wide range of issues associated with e-submissions, similar to but more focussed in mandate than the former Advisory Panel on Electronic Transmission Interchange (APETI).

The multi-year plan foresees the implementation of full e-review capability within affected Health Canada directorates as a result of the investment of necessary funds under the 'Smart Regulation' commitment in the September 30, 2002 Speech from the Throne. An immediate priority will be the resolution of difficulties experienced by applicants with the QOS-CE and CS-BE as a result of the current electronic file format specification. Details of the plan and ACES activities will be made publicly available.

Contacts and Comment Period

September 2003 is the anticipated target for finalization of the newly released draft guidances/template and the soon to be released counterpart documents for Radiopharmaceuticals (Schedule C drugs).

Questions or comments relating to these documents should be submitted no later than July 25, 2003. For Quality and Comparative Bioavailability documents, refer to the contacts identified in the accompanying notice. Comments on the updated draft Preparation of New Drug Submissions in the CTD Format guidance should be directed to:

Ms. Christine Guirguis
International Programs Division
Policy Bureau
Therapeutic Products Directorate
Fax: (613) 941-9672
christine_guirguis@hc-sc.gc.ca

Questions concerning general filing requirements for CTD formatted submissions and the possible need for a pre-submission meeting should be directed to:

For BGTD submissions:

Regulatory Affairs Division
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Fax: (613) 957-0364
BGTD_RAD_Enquiries@hc-sc.gc.ca

For TPD Submissions:

Regulatory Project Management Division
Office of Business Transformation
Therapeutic Products Directorate
Fax: (613) 957-1483
RPM_Division-GPR_Division@hc-sc.gc.ca

Attachment

Summary of Revisions to Draft Preparation of New Drug Submissions in the CTD Format Guidance

• Amendments have been introduced to reflect recent decisions made at the ICH level concerning the definition of a 'document', Table of Contents formatting, cross-referencing within the CTD and on document pagination, segregation and section numbering. Applicants are now advised to consult the revised ICH Organisation of the Common Technical Document and Questions and Answers documents for guidance on these topics
• Interim guidance on the filing of 'mixed' format submissions during the July 2001 - July 2003 transition period has been deleted
• Further guidance has been provided on the filing of Supplements and Notifiable Changes, while additional sections of the CTD have been identified for use in the preparation of ANDSs. More comprehensive guidance on the filing of ANDSs is provided in the cross-referenced Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format
• Clarification is provided concerning the use of the CTD format for drug/device combinations
• Filing requirements for electronic documents (Table 2) have been amended in terms of the number of copies, segregation of files on distinct CDs, file format version and reference to *.pkv files for bioequivalence data sets
• The status of the PCERT has been further clarified (see also the Health Canada Questions and Answers document)
• Rewording of text to clarify what information is expected under section 5.3.7 - Case Report Forms and Individual Patient Listings
• The requirement to include the day of filing as an identifier on submissions binders has been abolished. (Date of filing should appear in the covering letter.)
• Module 1 changes include:
  • the extension of the concept of a 'document' to components of Module 1
  • the addition of three new placeholders: International Registration Status, Other Application Information and Environmental Assessment Statement
  • removal of options for the ToC in section 1.1, which should now cover the entire submission (i.e. Modules 1 - 5, consistent with current ICH guidance)
  • a statement on covering letters
  • rewording of guidance on section 1.2.5 - GMP and Establishment Information - to clarify actual filing requirements
• Relevant website addresses have been updated (Appendix A)
• To facilitate the compilation of submissions to be filed with Health Canada a new table has been included entitled Regional Information for Canada (new Appendix B)