Draft Guidance for Industry: Preparation of New Drug Submissions in the CTD Format

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact

Draft Guidance for Industry:

Preparation of New Drug Submissions in the CTD Format

Published by authority of the Minister of Health

Draft Date: 2003/06/25

Available in Canada through
Health Canada - Publications
Brooke Claxton Building, A.L. #0913A
Tunney's Pasture
Ottawa, Ontario
K1A 0K9
Tel: (613) 954-5995
Fax: (613) 941-5366

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.

Table Of Contents

1. Introduction
2. Scope
3. Implementation Considerations
4. Structure And Content Of Drug Submissions In CTD Format
   • 4.1 Module 1: Administrative Information and Prescribing Information
   • 4.2 Module 2: Common Technical Document Summaries
   • 4.3 Module 3: Quality
   • 4.4 Module 4: Nonclinical Study Reports
   • 4.5 Module 5: Clinical Study Reports
5. Presentation Of The Submission
   • 5.1 Organization and Identification of Submission Volumes
   • 5.2 Organization, Presentation and Identification of Information within the Submission
   • 5.3 Language
   • 5.4 Legibility and Font Size
6. Appendices
   • Appendix A: References
   • Appendix B: Regional Information for Canada
   • Appendix C: Correlation of CTD versus 1991 Canadian Formats
   • Appendix D: Terminology

1. Introduction

This guidance is to be used in the preparation of drug submissions in the Common Technical Document (CTD) format, for presentation to Health Canada.

The focus of the CTD is to provide a common format for the preparation of a well-structured submission according to the modular framework described in the ICH guidances on the Common Technical Document for Registration of Pharmaceuticals for Human Use (ICH Topic M4)¹.

The CTD guidances indicate where and how available information is to be presented. The CTD is not intended to indicate what studies are actually required. Accordingly, when preparing a submission, it is necessary to consult Health Canada guidances (including adopted ICH guidances) on technical (data) requirements. Drug submission applicants are advised to consult the Health Canada website for the latest updates on guidance documents (see Appendix A for relevant website addresses).

This guidance 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 and revised filing requirements. A summary of revisions to the previous guidance is provided as an attachment to the accompanying Notice to this document.

It is important to note that the implementation and use of the CTD represents a work in progress. As such, it is expected that future refinements to this guidance will continue to be necessary as a result of experience gained. Amendments will also be necessary as a result of the migration to and implementation of the eCTD.

This guidance is meant to be read in conjunction with the most recent version of the ICH CTD guidances and the corresponding Questions and Answers documents on the ICH website². Applicants should also consult:

• the accompanying Health Canada Notice and Questions and Answers documents for supplementary and/or interim guidance on regional issues
• related Health Canada guidances and notices on Quality and comparative bioavailability information².

¹ The ICH CTD guidances are divided into four component documents:

M4 Organisation: Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use
M4 Quality
M4 Safety (Nonclinical)
M4 Efficacy (Clinical)

² See Appendix A.

2. Scope

This guidance serves to integrate the CTD format within the Canadian drug registration framework by defining regional administrative (Module 1) and general filing requirements.

This guidance covers the preparation and filing of CTD-formatted drug submissions for human use, filed pursuant to Division 8, Part C of the Food and Drug Regulations; including:

• New Drug Submissions (NDSs)
• Abbreviated New Drug Submissions (ANDSs)
• Supplemental New Drug Submissions (SNDSs) and Supplemental Abbreviated New Drug Submissions (SANDSs)
• Notifiable Changes (NCs)

The scope includes the range of Schedule C and D drugs excluded from the scope of the ICH guidance Q6B.

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

3. Implementation Considerations

Division 8, Part C of the Food and Drug Regulations provides governance on the sale of new drugs in Canada and prohibits the sale of new drugs unless the manufacturer has filed a submission that is satisfactory to the Minister. The Regulations do not define format requirements. Wording affords the Minister the flexibility to accept submissions in various formats, provided they are deemed acceptable (as set out in guidance) and the information contained in these submissions complies with Division 8, Part C.

This and related Health Canada guidances, in conjunction with the ICH CTD guidances and Questions and Answers, provide placeholders for all registration (content) information prescribed by Division 8, Part C. In terms of structural components, the combined clinical/nonclinical overviews and written/tabulated summaries of Module 2 of the CTD are considered to satisfy the requirement to file a comprehensive summary (C.08.005.1(1)©)), while study reports equate directly with sectional reports C.08.005.1(1)(b)). Module 1 is designed for placement of product labelling and regional administrative information (including the submission certificate - C.08.005.1(1)(d)).

While the scope of the CTD guidance as developed by ICH is limited to the range of products covered by ICH guidances Q6A and Q6B, that is, new chemical entities and well characterized biotech products³, there was clear recognition by the ICH parties of its potential applicability to other submission and product types.

As of July 1, 2003 the Common Technical Document and appropriate adaptations of the CTD officially replace previous formats in Canada for those drug submissions specified under Scope. 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. The CTD format is also expected to be used for the drug component of drug/device combinations where the primary mechanism of action is drug-related. Where the combination product is classified as a device the use of the CTD format for the drug component is optional.

³ Consult the scope of the draft Guidance for Industry entitled Preparation of the Quality Information for Drug Submissions in the CTD Format: Biotechnological/ Biological (Biotech) Products for a more precise description of biotech products.

4. Structure And Content Of Drug Submissions In CTD Format

This section outlines filing considerations for paper based New Drug Submissions in the CTD format. Table 1 below provides an overview of the presentation of the drug submission, including modular structure and main headings.

For original filings, if no information is available or required under a specific heading, that section or subsection of the submission should be marked "not applicable" or "not relevant" while retaining the section title and numbering, and, if necessary, a justification for the absence of information should be provided ⁴.

In using the CTD format for ANDSs, Supplements and NCs, the submissions should be organised similarly to NDSs, although only certain sections or modules may be necessary depending on the submission and/or changes. For example, in the case of an ANDS, applicants would normally provide the relevant components of Module 1, Modules 2.1 (CTD Table of Contents), 2.2 (Introduction), 2.3 (Quality Overall Summary⁵), Module 3 (Quality data), Modules 5.1 (Table of Contents for Module 5), 5.2 (Tabular Listing of all Clinical Studies), 5.3.1.2 (Comparative Bioavailability (BA) and Bioequivalence (BE) Study Reports), 5.4 (Literature References) and possibly 5.3.1.4 (Reports of Bioanalytical and Analytical Methods for Human Studies). For specific guidance on the filing of ANDSs applicants should refer to the Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format.

In the case of Supplements and NCs, applicants would normally provide only the relevant modules affected by the change. For example, if the Supplement was for a new indication, with no change to Quality information, Modules 2.3 and 3 would not need to be submitted. Similarly, if an NC was filed for the addition of a new container closure system there would be no need to submit Modules 4, 5 and the corresponding Module 2 Overviews / Summaries.

This principle may also be applied to sections and subsections within a module which would otherwise principally reference unchanged information from a previous submission(s), as for example in Modules 2.3 and 3 for the NC described above. In these situations a general note should be included in the covering letter regarding the contents of the submission and the rationale for omissions. In all other situations headings should be retained, together with the designation "not applicable", "not relevant" or "not changed", as appropriate. Within the covering letter and/or submission it should be clear as to which previously filed submission reference is being made when information is unchanged. The crossreference should include the submission type, control number, brand name, manufacturer / applicant's name, HC file number and the date the submission was approved.

For additional guidance, the applicant should consult the appropriate review Bureau or Centre.

⁴ It is not necessary, however, to include subsection headings when an entire section is designated "not applicable".

⁵ Throughout this guidance the term Quality Overall Summary (QOS) is used generically to encompass Quality summaries prepared according to the ICH M4 guidance or the more detailed ('granular') Quality templates or guidances referenced in this document.

Table 1: Presentation of Information in a CTD-formatted NDS

CTD Module No.	Title and Main Section Headings	Cross-Reference to Modules	Binder/Label colour	No. of Paper Copies
1	Administrative Information and Prescribing Information		Red	2*
1.1	Table of Contents (Modules 1 to 5)
1.2	Application Information
1.2.1	Drug Submission Application Form (HC/SC 3011)
1.2.2	Drug Submission Fee Application Form
1.2.3	Submission Certification Form
1.2.4	Patent Information
1.2.5	GMP and Establishment Licensing (EL) Information
1.2.6	Letters of Access
1.2.7	International Registration Status
1.2.8	Other Application Information
1.3	Product Labelling
1.3.1	Product Monograph	2**
1.3.2	Inner and Outer Labels
1.3.3	Non-Canadian Package Inserts
1.4	Health Canada Summaries
1.4.1	Certified Product Information Document
1.4.2	Comprehensive Summary: Bioequivalence	3 and 5
1.5	Environmental Assessment Statement+	Module 1 Annex
1.6	Electronic Review Documents++
2	CTD Summaries		Yellow	2*
2.1	CTD Table of Contents (Modules 2 to 5)	2 to 5
2.2	Introduction
2.3	Quality Overall Summary	3, 4 and 5
2.4	Nonclinical Overview	3, 4 and 5
2.5	Clinical Overview	3, 4 and 5
2.6	Nonclinical Written and Tabulated Summaries	4
2.7	Clinical Summary	5
3	Quality		Blue	BGTD: 2* TPD: 1*
3.1	Table of Contents of Module 3
3.2	Body of Data
3.3	Literature References
4	Nonclinical Study Reports		Green	1
4.1	Table of Contents of Module 4
4.2	Study Reports
4.3	Literature References
5	Clinical Study Reports		Black	1
5.1	Table of Contents of Module 5
5.2	Tabular Listing of All Clinical Studies
5.3	Clinical Study Reports
5.4	Literature References

* Drugs with devices require an additional copy of Modules 1, 2, and 3.
** Applicants may also choose to include references to related information in Modules 3 to 5, as appropriate. When submitted, the Comprehensive Summary: Bioequivalence (Module 1.4.2), should also be referenced (e.g. in the case of most ANDSs).
+ When provided, an environmental assessment data package is to be included in a separate volume(s) as an Annex to Module 1.
++ Electronic review documents should be provided in a separate volume as section 1.6 of Module 1 (see Table 2).

4.1 Module 1: Administrative Information and Prescribing Information

This region-specific module defines administrative information, proposed labelling and summaries for inclusion in New Drug Submissions. The information to be provided in Module 1 is identified below and includes documents previously specified in Part 1, Master Volume of the guidance Preparation for Human New Drug Submissions 1991, and in the 1992 Supplement. For convenience, a listing of Module 1 elements and those Module 2 - 5 NDS elements either unique to Canada or not common to all ICH regions is provided in Appendix B.

In accordance with the principle that the CTD (i.e. Modules 2-5) is composed of a series of structured documents (as defined in the Annex to the ICH Organisation of the Common Technical Document guidance), Module 1 should also be viewed as a series of documents defined by the numerical items listed in the Module 1 Table of Contents (ToC), for example, 1.2.4 - Patent Information or 1.5 - Environmental Assessment Statement (see Table 1). While the ToC for Module 1 should go down to the third level only, each of the Module 1.1-1.6 subsections may contain a single or multiple document(s). Consult the annex of the M4 guidance Organisation of the Common Technical Document and ICH General Questions and Answers for further guidance on ToC formatting, cross-referencing within the submission and on document pagination, segregation and section numbering.

Note: it is not necessary to include a header or footer on Module 1 documents (except where already an integral part of the document, e.g. CPID template), nor to paginate Module 1 forms or labels.

Covering Letter

If an applicant chooses to include a cover letter with the submission it should be placed at the beginning of Module 1. The submission filing date should be specified in the cover letter.

1.1 Table of Contents

Module 1.1 is the placeholder for the ToC for the entire submission. This ToC should list all documents included in Module 1 and the contents of Modules 2-5 to the level of detail or 'granularity' defined in the Organisation of the Common Technical Document guidance.

1.2 Application Information

1.2.1 Drug Submission Application Form

The completed and signed Drug Submission Application Form (HC/SC 3011) should be presented in this section.

1.2.2 Drug Submission Fee Application Form

The completed Drug Submission Fee Application Form should be presented in this section.

1.2.3 Submission Certification Form

The Submission Certification must be provided according to section C.08.005.1 of the Food and Drug Regulations. It is preferred that companies use their letterhead for the submission certification.

The submission certification is to be signed and dated by the senior executive officer of the manufacturer in Canada and the medical or scientific director of the manufacturer. If the submission certification or any significant part of the certification was prepared by an agent authorized by the manufacturer, the submission certification must also be signed by that agent.

Responses to Screening Deficiency Notices, Notices of Noncompliance and Notices of Deficiency should include a revised submission certificate signed and dated as described above.

1.2.4 Patent Information

When filing a submission, patent holders should submit a list of products for which they own a patent or have a license or obtained the consent of the owner for the inclusion of the patent (Form IV: Patent List - Pertaining to Patented Medicines). Following the issuance of a Notice of Compliance (NOC), the information contained on the list is placed on a Patent Register.

Pursuant to Section 5 of the Patented Medicines (Notice of Compliance) Regulations a second person applicant is required to address all first person patent(s) listed on the Patent Register (Form V: Declaration Re: Patent List). Documents relating to Allegations are also to be placed in this section.

1.2.5 Good Manufacturing Practices (GMP) and Establishment Licensing (EL) Information

Establishment Licensing and GMP compliance information should be provided for each establishment involved in the manufacture of the drug product or dosage form and, additionally for biologics and radiopharmaceuticals, the bulk process intermediate and drug substance. This would include sites involved in the activities of fabricating, packaging or labelling, testing, importing, storage, distributing, and wholesaling. This information should include the date of the last GMP inspection, the current GMP compliance rating, the Establishment Licence number and, if relevant, the date of the last on-site evaluation. Where applicable, other information should include the HPFBassigned Site Reference File (SRF) number and cross-reference to any Letter(s) of Access (provided under Module 1.2.6). The applicant should refer to the Health Canada guidances on Good Manufacturing Practices, Site Reference Files, Good Manufacturing Practices (GMP), and the Establishment Licensing Enforcement Directive.

1.2.6 Letters of Access

Letters authorizing the TPD or the BGTD to share information in the submission with other regulatory authorities (or vice versa) and/or to access other (third party) drug submissions, Drug Master Files and Site Reference Files should be provided in this section.

1.2.7 International Registration Status

Information on the product application and marketing status in other countries/regions should be provided in this section. Depending upon the status this would include confirmation of filing or the date(s) of approval and/or withdrawal.

1.2.8 Other Application Information

This section serves as a placeholder for other administrative information that may be filed by the applicant in relation to the submission. Examples include:

• confirmation that a Canadian reference product was used in a comparative bioavailability study for a subsequent market entry (generic) product⁶
• waiver requests in relation to conducting a comparative bioavailability study
• Certificates of Analyses for test and reference products used in a comparative bioavailability study.

⁶ Refer to the Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format for further information on filing requirements for reference product confirmation, waiver requests and certificates of analyses.

1.3 Product Labelling

1.3.1 Product Monograph

Non-annotated Product Monograph

A copy of the "Clean" or "Non-annotated" Product Monograph, is to be provided first in this section.

The Guidance for Industry Product Monograph describes the format and content of an acceptable Product Monograph. The section intended to provide Consumer Information should include the complete text of the information that is to be made available to patients at the time of dispensing. This section is to provide adequate information about the product to support informed use by the patient and/or their care givers.

Annotated Product Monograph

An additional copy of the Product Monograph is to be provided in an annotated format. The text of the annotated copy should be cross-referenced to supporting information and study findings reported in Module 2 documents and, when submitted, the Bioequivalence Summary (Module 1.4.2). Applicants may also choose to include references to related information in Modules 3 to 5, as appropriate.

Within the sections of the annotated Product Monograph the text should also be crossreferenced by number to the References or Selected Bibliography section at the end of the Product Monograph.

Articles from publications listed in the References section should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journals Editors (ICMJE). If reference is made to publication(s) not provided in the CTD (i.e. Modules 2 - 5), copies of the reference material should be provided in this subsection.

1.3.2 Inner and Outer Labels

Copies of all inner and outer labels should be provided. This should include the labels for all strengths, dosage forms and reconstitution diluents. Typewritten or other draft label copy is acceptable for review purposes. Labels and inserts should be prepared in accordance with the appropriate Food and Drug Regulations. See the guidance entitled Labelling of Drugs for Human Use.

1.3.3 Non-Canadian Package Inserts

If the drug product has been marketed outside Canada, the applicant is encouraged to supply the monograph or package inserts used in other jurisdictions, identified by country/region.

1.4 Health Canada Summaries

1.4.1 Certified Product Information Document

At the time of drug submission, a paper copy of the completed Certified Product Information Document (CPID) should be provided in this subsection for Supplements and NCs only. For NDSs and ANDSs, the CPID is requested towards the end of the review cycle. The applicant should refer to the appropriate Health Canada Quality guidance(s) regarding the preparation of the CPID.

1.4.2 Comprehensive Summary: Bioequivalence

The paper copy of the completed Comprehensive Summary: Bioequivalence (CS:BE) for pivotal comparative bioavailability (bioequivalence) studies should be included in this subsection.

Note: With the exception of the distinct CS:BE module, the former Pre-clinical and Clinical Evaluation Template (PCERT) should not be completed and submitted in conjunction with CTD-formatted submissions.

1.5 Environmental Assessment Statement

Note: Placeholder for statement regarding the inclusion, or not, of an environmental assessment package as an annex to Module 1⁷.

1.6 Electronic Review Documents

Health Canada is developing a phased migration plan from the current paper-based and proprietary standards to the ICH eCTD specification. Applicants should consult CTD/eCTD update notices for further information.

Refer to Table 2 for current filing specifications. Electronic documents listed in Table 2, and an attestation that the electronic and hardcopy documents are identical in content and format, should be provided in a separate volume as section 1.6 of Module 1. It is preferable that applicants use their own letterhead for the attestation letter.

⁷ New substances in products regulated under the F & DA are subject to an environmental assessment under the New Substances Notification Regulations (NSN) of the Canadian Environmental Protection Act (CEPA). Under CEPA, notification regarding the environmental assessment is required prior to importing into or manufacturing a new substance in Canada.

Health Canada is now developing new environmental assessment regulations specific for products regulated under the Food and Drugs Act. These regulations are expected to be published in Canada Gazette Part I in the Spring of 2005.

For any questions regarding the NSN environmental assessment submission contact the Environmental Assessment Unit at 1-613-941-0144. For general inquires contact 1-888-492-1104 or 613-941-8322 or consult the Health Canada website at: http://www.hc-sc.gc.ca/ear-ree/.

Table 2: Electronic Review Documents Filed in Conjunction with the CTD-Formatted, Paper ND

CD Series No.	Document or Data File	File Format	Number of Copies	Remarks
1	Product Monograph	WordPerfect®	BGTD: 2	Provide "annotated" and "non - annotated" (or "clean") versions of PM, labelled "Original" on one CD, "Working" on a second CD File at time of submission
			TPD: 1	Provide " annotated" and "non - annotated" versions of PM File at time of submission
2	Quality Overall Summary	WordPerfect®	1	File at time of submission
	CPID	WordPerfect®	BGTD: 1	For NDSs: File upon request during review process For SNDSs/NCs: File "annotated" and "clean"copies at time of submission
			TPD: 1	For NDSs/ANDSs: File upon request during review process For Supplements/NCs: File at time of submission
3	Comprehensive Summary: BE	WordPerfect®	TPD: 1	File at time of submission
	BE Data Sets	ASCII	TPD: 1	*.inf and *.dat files should be in ASCII format. File at time of submission

Notes:

• Acceptable WordPerfect® versions (having same file format): 6/7/8/9/10.
• CD ROMs should be used as the transport standard, in accordance with the eCTD specification.
• Files should be provided on three separate CDs, as indicated in the table above. Each CD should be placed in a separate sleeve.
• CDs should be labelled as to series number (1-3), contents, name of the applicant and the proprietary or brand name of the drug. Electronic files provided subsequent to the original filing of a given submission should also include the submission control number.
• The applicant should include an attestation at the beginning of Module 1.6 to the effect that electronic and hard copy versions of documents are identical.

4.2 Module 2: Common Technical Document Summaries

The ToC for Module 2 is provided in the M4 guidances, Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use. Additional guidance is provided in the first part of each of the associated guidances: M4Q Module 2: Quality Overall Summary (QOS); M4S Safety Nonclinical Summaries and M4E Efficacy Module 2: Clinical Overview and Clinical Summary. The summary documents for this module should be provided in the manner described below.

2.1 Common Technical Document Table of Contents

This document provides an overall ToC for Modules 2, 3, 4 and 5.

2.2 Introduction

2.3 Quality Overall Summary

In order to help maintain review efficiencies afforded by Health Canada's Quality summaries, applicants are encouraged to complete the Quality Overall Summary - Chemical Entities (New Drug Submissions and Abbreviated New Drug Submissions) (QOS-CE (NDS)). Consult the accompanying Notice and Health Canada Questions and Answers document for further information.

For Schedule C and D drugs, the applicant should consult the appropriate productspecific guidance(s) Health Canada Quality guidances.

2.4 Nonclinical Overview

2.5 Clinical Overview

2.6 Nonclinical Written and Tabulated Summaries

2.7 Clinical Summary

4.3 Module 3: Quality

The applicant should refer to both Module 3: Quality of the M4Q guidance, as well as the appropriate Health Canada Quality guidance(s) listed below on how to complete this module.

For products containing drugs of synthetic or semi-synthetic origin (excluding Schedule C and D drugs) consult: Quality Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) for Chemical Entities.⁸

For Schedule C and Schedule D drugs consult: Preparation of the Quality Information for Drug Submissions in the CTD Format.⁸ Refer to the version(s) pertaining to the appropriate product line(s), e.g. Biotechnological/ Biological (Biotech) Products, Blood Products, Conventional Biotherapeutic Products, Vaccines, and/or Radiopharmaceutical (Schedule C) Products.

⁸ Note: These guidances will be updated as necessary to reflect the ICH CTD Quality Questions and Answers document.

4.4 Module 4: Nonclinical Study Reports

The ToC for Module 4 is provided in M4S guidance under the heading The Organisation of Module 4: Nonclinical Study Reports and lists the order in which documents are to be presented.

4.5 Module 5: Clinical Study Reports.

Guidance on how to complete this module is provided in the M4E guidance under Module 5: Clinical Study Reports. The ICH E3 guidance, Structure and Content of Clinical Study Reports, provides information on the structure and content of clinical study reports. In addition, the applicant should note the following in relation to cited modules of the CTD:

5.3.1.2 Comparative Bioavailability (BA) and Bioequivalence (BE) Study Reports and 5.3.1.4: Reports of Bioanalytical and Analytical Methods for Human Studies

Additional notes concerning the technical requirements for pivotal comparative bioavailability (bioequivalence) studies are provided in the Health Canada Guidance for Industry: Preparation of Comparative Bioavailability Information for Drug Submissions in the CTD Format.

5.3.5.3 Reports of Analyses of Data from More than One Study, Including Any Formal Integrated Analyses, Meta-analyses, and Bridging Analyses

The CTD guidance states that when the details of formal meta-analyses and integrated analyses from more than one study are too extensive to be reported in a summary document, they should be reported here. Although not generally mandatory, applicants are encouraged to provide such reports when available.

Applicants are also advised to consult the ICH Questions and Answers for information on the appropriate placement of the U.S. integrated summary of safety and effectiveness (ISS/ISE).

5.3.7 Case Report Forms and Individual Patient Listings

Case report forms that are described as appendix 16.3.1 in the ICH clinical study report guideline (E3) should be placed in this section at the time of filing, in the same order as the clinical study reports and indexed by study. Appendices 16.3.2 (Other Case Report Forms (CRFs)) and 16.4 (Individual Patient Data Listings), are to be sent only upon request. If requested, appendices should be delivered promptly (normally within two working days).

When all CRFs (i.e., including 16.3.2) are available in PDF file format on CD ROM, applicants are encouraged to provide one copy at the time of filing in Module 1.6 - Electronic Review Documents. In such instances, applicants are not required to provide the paper copy of CRFs.

5. Presentation Of The Submission

This section describes the physical specifications for submitting paper submissions in CTD format. The paper submission is to serve as the official Central Registry copy until such time that Health Canada is ready to accept submissions in electronic (eCTD) format only.

5.1 Organization and Identification of Submission Volumes

The paper copies of the submission should be bound for easy access of information. Three-ring binders meet this criterion and should be used for all modules. Binders should be colour-coded as specified in Table 1. Alternatively, labels on the spines as well as on the cover are to be colourcoded as indicated. Use of the coloured binders easily identifies the module number.

Each binder should be identified with the trade (brand) name of the drug product, the name of the manufacturer, and where applicable, the proper or common and code names. Each binder should be sequentially numbered, starting at Volume 1 for each module. The volume number for that binder, out of the total number of volumes for that module, the section(s) contained within each volume, and the date of submission (month and year), should also be specified on the label. It is not necessary to specify the module number since the CTD numbering scheme begins with the module number. For example, the label on a blue-coloured binder (Volume 1 of Module 3: Quality), would read as follows:

Drug Product "ABC"
Applicant/manufacturer "XYZ"
Volume 1 of 63
3.1-3.2.S.2.3
Month/year

This information should appear on the spine as well as on the front cover of the binder.

Note: In the case of NCs containing small amounts of information it is recommended, where possible, that all modules of the submission be provided in one (black) binder.

For administrative submissions (such as, a change in the name of the product or manufacturer), it is anticipated that only Module 1 would be required.

5.2 Organization, Presentation and Identification of Information within the Submission

Information within the CTD is organized into a series of structured documents which are in turn organized into modules. Consult the M4 guidance Organisation of the Common Technical Document and ICH General Questions and Answers for the definition of a document and guidance on ToC formatting, cross-referencing within the CTD and on document pagination, segregation and section numbering.

Throughout the Common Technical Document, the display of information should be unambiguous and transparent, in order to facilitate the review of the basic data and to help a reviewer become quickly oriented to the application contents.

Literature references should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journals Editors (ICMJE).

Acronyms and abbreviations should be defined the first time they are used in each module.

5.3 Language

Information in the submission should be recorded in either English or French. Material in a different language should be accompanied by an English or French translation with the possible exception of Case Report Forms (consult the appropriate Bureau/Centre first).

5.4 Legibility and Font Size

Text and tables should be prepared using margins that allow the document to be printed on 8.5 x 11 inch paper. The left-hand margin should be sufficiently large that information is not obscured by the method of binding. Font sizes for text and tables should be of a style and size that are large enough to be easily legible, even after photocopying. Times New Roman, 12-point font is recommended for narrative text.

6. Appendices

Appendix A: References

ICH guidances and information, including Questions and Answers on CTD implementation issues, are available from the  official ICH website.

The latest versions of Health Canada guidances, policies, templates and forms can be obtained from the TPD and BGTD websites at:

Appendix B: Regional Information for Canada⁹

Module	Chemical Entity (CE) Products	Biological and Radiopharmaceutical Products
1	Administrative Information and Prescribing Information
1.1	Table of Contents (Modules 1-5)
1.2	Application Information
1.2.1	Drug Submission Application Form (HC/SC 3011)
1.2.2	Drug Submission Fee Application Form
1.2.3	Submission Certification Form
1.2.4	Patent Information
1.2.5	Good Manufacturing Practices (GMP) and Establishment Licensing (EL) Information
1.2.6	Letters of Access
1.2.7	International Registration Status
1.2.8	Other Application Information
1.3	Product Labelling
1.3.1	Product Monograph
1.3.2	Inner and Outer Labels
1.3.3	Non-Canadian Package Inserts
1.4	Health Canada Summaries
1.4.1	Certified Product Information Document
1.4.2	Comprehensive Summary: Bioequivalence
1.5	Environmental Assessment Statement10
1.6	Electronic Review Documents
2	Common Technical Document Summaries
2.311	Quality Overall Summary - Chemical Entities (QOS-CE) and Analytical Procedures and Validation Information Summaries
3	Quality
3.2.R.1	Production Documentation
3.2.R.1.1	Executed Production Documents	Executed Batch Records (not applicable to Positron-Emitting Radiopharmaceuticals (PERs))
3.2.R.1.2	Master Production Documents	(applicable to PERs only)
3.2.R.2	Medical Devices
3.2.R.3		Lot Release Documentation

⁹ Submission elements either unique to Canada or not common to all ICH regions

¹⁰ When provided, the accompanying environmental assessment data package is to be included in a separate volume(s) as an Annex to Module 1.

¹¹ Refer to the appropriate Health Canada Quality guidance(s) for additional, specific information on the Quality Overall Summaries.

Appendix C: Correlation of CTD versus 1991 Canadian Formats¹²

CTD Format Module#	CTD Format Section Headings	1991 Canadian Format Part#	1991 Canadian Format Section Headings
1	Administrative Information and Prescribing Information (for Canada)	1	Master Volume
1.1	Table of Contents (Modules 1-5)	1.3	Table of Contents of Complete Submission
1.2	Application Information	1.2	Application Form
1.2.1	Drug Submission Application Form (HC/SC 3011)	1.1	Submission Certification
1.2.2	Submission Fee Application Form		Drug Submission Application Form
1.2.3	Submission Certification Form		Submission Fee Application Form
1.2.4	Patent Information		Declaration of Patent Status
1.2.5	Good Manufacturing Practices (GMP) and Establishment Licensing (EL) Information
1.2.6	Letters of Access
1.2.7	International Registration Status
1.2.8	Other Application Information
		1.7	List of Prior Related Submissions
1.3	Product Labelling
1.3.1	Product Monograph	1.5	Product Monograph
1.3.2	Inner and Outer Labels	1.6	Draft of Every Label...
1.3.3	Non - Canadian Package Inserts	1.8	Non-Canadian Package Inserts
1.4	Health Canada Summaries
	Partially covered in HPFB 3011 Form and Module 2.2	1.4	Brief Summary
1.4.1	Certified Product Information Document (CPID)	(In case of Supplements and NCs)	Certified Product Information Document (CPID)
1.4.2	Comprehensive Summary: Bioequivalence (CS:BE)	3.2.2.1	Pivotal Trials
1.5	Environmental Assessment Statement
1.6	Electronic Review Documents	1 (for BGTD) TPD: to be filed with paper copies13

¹² Refer to Health Canada guidelines, Preparation of Human New Drug Submissions (1991) and Supplement to Preparation of Human New Drug Submissions (1992)

¹³ i.e., with Parts 2 and 3, respectively, for Quality summaries and the Comprehensive Summary: Bioequivalence in WordPerfect® file format, and with Part 4 for bioequivalence study datasets.

CTD Format Module#	CTD Format Section Headings	1991 Canadian Format Part#	1991 Canadian Format Section Headings
2	Common Technical Document Summaries	2 and 3	Comprehensive Summaries
2.1	Common Technical Document Table of Contents (Modules 2-5)	1.3	Table of Contents - Complete Submission
2.2	Introduction	1.4	Brief Summary
2.3	Quality Overall Summary	2	Version of a Quality Summary (QIS, CS(CM))
2.4	Nonclinical Overview	3.1	Investigational Studies
2.5	Clinical Overview	3.2	Clinical Studies
2.6	Nonclinical Summary and Tabulated Summaries	3.1	Investigational Studies and NDS Supplement (table)
2.7	Clinical Summary	3.2	Clinical Studies
3	Quality	2	Chemistry and Manufacturing
3.1	Table of Contents of Module 3	2	Table of Contents
3.2	Body of Data	2	Chemistry and Manufacturing
3.2.S	Drug Substance	2.1	Drug Substance
3.2.S.1	General Information
3.2.S.1.1	Nomenclature	2.1.1	Names
3.2.S.1.2	Structure	2.1.4	Structure Elucidation and Confirmation
3.2.S.1.3	General Properties	2.1.5	Physicochemical Properties
3.2.S.2	Manufacture
3.2.S.2.1	Manufacturer(s)	2.1.2	Source
3.2.S.2.2	Description of Manufacturing Process and Process Controls	2.1.3	Method of Manufacture
3.2.S.2.3	Control of Materials	2.1.3	Method of Manufacture
3.2.S.2.4	Controls of Critical Steps and Intermediates	2.1.3	Method of Manufacture
3.2.S.2.5	Process Validation and/or Evaluation	2.1.3	Method of Manufacture
3.2.S.2.6	Manufacturing Process Development
3.2.S.3	Characterisation	2.1.4 and 2.1.5	Structure Elucidation and Confirmation/ Physicochemical Properties
3.2.S.3.1	Elucidation of Structure and other Characteristics	2.1.4	Structure Elucidation and Confirmation
3.2.S.3.2	Impurities	2.1.6	Impurities
3.2.S.4	Control of Drug Substance
3.2.S.4.1	Specification	2.1.8	Specifications and Test Methods
3.2.S.4.2	Analytical Procedures	2.1.8	Specifications and Test Methods
3.2.S.4.3	Validation of Analytical Procedures	2.1.8	Specifications and Test Methods
3.2.S.4.4	Batch Analyses	2.1.9	Batch Analyses
3.2.S.4.5	Justification of Specification	2.1.8	Specifications and Test Methods
3.2.S.5	Reference Standards or Materials	2.1.7	Reference Standard
3.2.S.6	Container Closure System	2.1.3	Method of Manufacture
3.2.S.7	Stability	2.1.10	Stability
3.2.S.7.1	Stability Summary and Conclusions	2.1.10	Stability
3.2.S.7.2	Post-approval Stability Protocol and Stability Commitment	2.1.10	Stability
3.2.S.7.3	Stability Data	2.1.10	Stability
3.2.P	Drug Product	2.2	Dosage Forms
3.2.P.1	Description and Composition of the Drug Product	2.2.1	Names
3.2.P.2	Pharmaceutical Development	2.2.3	Developmental Pharmaceutics
3.2.P.3	Manufacture	2.2.4	Formulation and Method of Manufacture
3.2.P.3.1	Manufacturer(s)	2.2.2	Source
3.2.P.3.2	Batch Formula	2.2.4	Formulation and Method of Manufacture
3.2.P.3.3	Description of Manufacturing Process and Process Controls	2.2.4	Formulation and Method of Manufacture
3.2.P.3.4	Controls of Critical Steps and Intermediates	2.2.4	Formulation and Method of Manufacture
3.2.P.3.5	Process Validation and/or Evaluation	2.2.4	Formulation and Method of Manufacture
3.2.P.4	Control of Excipients
3.2.P.4.1	Specifications	2.2.5	Specifications of Excipients
3.2.P.4.2	Analytical Procedures	2.2.5	Specifications of Excipients
3.2.P.4.3	Validation of Analytical Procedures	2.2.5	Specifications of Excipients
3.2.P.4.4	Justification of Specifications	2.2.5	Specifications of Excipients
3.2.P.4.5	Excipients of Human or Animal Origin	2.2.5	Specifications of Excipients
3.2.P.4.6	Novel Excipients	2.2.5	Specifications of Excipients
3.2.P.5	Control of Drug Product
3.2.P.5.1	Specification(s)	2.2.6	Specifications and Test Methods
3.2.P.5.2	Analytical Procedures	2.2.6	Specifications and Test Methods
3.2.P.5.3	Validation of Analytical Procedures	2.2.6	Specifications and Test Methods
3.2.P.5.4	Batch Analyses (For BGTD): Batch Analyses (For TPD):	2.3.4 2.2.6	Evidence Establishing Ability to Produce a Consistent Product Omission from 1991 guidance - label as 'Batch Analyses'
3.2.P.5.5	Characterisation of Impurities	2.2.6	Specifications and Test Methods
3.2.P.5.6	Justification of Specification(s)	2.2.6	Specifications and Test Methods
3.2.P.6	Reference Standards or Materials	2.1.7	Reference Standard
3.2.P.7	Container Closure System	2.2.7	Packaging
3.2.P.8	Stability	2.2.8	Stability
3.2.P.8.1	Stability Summary and Conclusions	2.2.8	Stability
3.2.P.8.2	Post-approval Stability Protocol and Stability Commitment	2.2.8	Stability
3.2.P.8.3	Stability Data	2.2.8	Stability
3.2.A	Appendices
3.2A.1	Facilities and Equipment	For BGTD: 2.3.1, 2.3.2, and 2.3.3	Addendum for Biologics: Description of Manufacturing Facilities, Work Flow/ Other Drugs Prepared in the Same and Adjacent Areas
3.2.A.2	Adventitious Agents Safety Evaluation	2.1.3 and 2.2.4	Method of Manufacture and Formulation and Method of Manufacture
3.2.A.3	Excipients	2.2.5	Specifications for Excipients
3.2.R	Regional Information
3.2.R.1	Production Documentation
3.2.R.1.1	Executed Batch Records (for BGTD; except for PERs): Executed Production Documents (for TPD)	2.3.4 2.2.6	Evidence Establishing Ability to Produce a Consistent Product Omission from 1991 guidance - label as 'Batch Analyses'
3.2.R.1.2	Master Production Documents (for TPD; for BGTD, Positron-Emitting Radiopharmaceuticals (PERs) only)	2.4	Formulation and Method of Manufacture
3.2.R.2	Medical Devices	2.2.7	Packaging
3.2.R.3	Lot Release Documentation (for BGTD)	2.3.5 and 2.3.6	Proposed Format of a Protocol for Lot Release of Product Characteristics of the Product
	3.2.S.3.1 Elucidation of Structure and other Characteristics 3.2.P.2 Pharmaceutical Development (3.2.P.2.1.1 Drug Substance 3.2.P.2.2.3 Physicochemical and Biological Properties)	For BGTD: 2.3.7	Active and Passive Immunization Studies
3.3	Literature References	End of related section or end of Part 2
4	Nonclinical Study Reports	4	Sectional Reports
4.1	Table of Contents of Module 4
4.2	Study Reports	4.1	Investigational Studies
4.2.1	Pharmacology	4.1.1	Pharmacology
4.2.1.1	Primary Pharmacodynamics	4.1.1.1	Primary Actions
4.2.1.2	Secondary Pharmacodynamics	4.1.1.2	Secondary Actions
4.2.1.3	Safety Pharmacology	4.1.1.4	Other Studies
4.2.1.4	Pharmacodynamic Drug Interactions
4.2.2	Pharmacokinetics
4.2.2.1	Analytical Methods and Validation Reports (if separate reports are available)
4.2.2.2	Absorption	4.1.1.3	Absorption,
4.2.2.3	Distribution	4.1.1.3	Distribution
4.2.2.4	Metabolism	4.1.1.3	Metabolism
4.2.2.5	Excretion	4.1.1.3	Elimination
4.2.2.6	Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7	Other Pharmacokinetic Studies
4.2.3	Toxicology	4.1.2	Toxicology
4.2.3.1	Single-Dose Toxicity (in order by species, by route)	4.1.2.1	Acute Toxicity
4.2.3.2	Repeat-Dose Toxicity	4.1.2.2	Long-term Toxicity
4.2.3.3	Genotoxicity	4.1.2.4	Mutagenicity
4.2.3.3.1	In vitro		a) In Vitro Tests
4.2.3.3.2	In vivo (supportive toxicokinetics evaluations)		b) Animal Studies
4.2.3.4	Carcinogenicity (including toxicokinetics)	4.1.2.3	Carcinogenicity
4.2.3.4.1	Long-term studies (not included in repeat-dose toxicity or pharmacokinetics)
4.2.3.4.2	Short- or medium-term studies (not included under repeat-dose toxicity or pharmacokinetics
4.2.3.4.3	Other studies
4.2.3.5	Reproductive and Developmental Toxicity	4.1.2.5	Reproduction and Teratology
4.2.3.5.1	Fertility and early embryonic development
4.2.3.5.2	Embryo-fetal development
4.2.3.5.3	Prenatal and postnatal development, including maternal function
4.2.3.5.4	Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
4.2.3.6	Local Tolerance	4.1.2.7	Other Studies
4.2.3.7	Other Toxicity Studies (if available)	4.1.2.7	Other Studies
4.2.3.7.1	Antigenicity
4.2.3.7.2	Immunotoxicity
4.2.3.7.3	Mechanistic studies (if not included elsewhere)
4.2.3.7.4	Dependence	4.1.2.6	Dependence Liability
4.2.3.7.5	Metabolites
4.2.3.7.6	Impurities
4.2.3.7.7	Other
4.3	Literature References	4.1.4	Published and Unpublished Investigational Reports
5	Clinical Study Reports	4	Sectional Reports
5.1	Table of Contents of Module 5
5.2	Tabular Listing of Clinical Studies
5.3	Clinical Study Reports	4.2	Clinical Studies
5.3.1	Reports of Biopharmaceutic Studies	4.2.1	Clinical Pharmacology
5.3.1.1	Bioavailability (BA) Study Reports	4.2.1.3	Bioavailability Studies
5.3.1.2	Comparative Bioavailability (BA)and Bioequivalence (BE) Study Reports	4.2.1.3	Bioavailability Studies
5.3.1.3	In vitro-In vivo Correlation Study Reports
5.3.1.4	Reports of Bioanalytical and Analytical Methods for Human Studies
5.3.2	Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.2.1	Plasma Protein Binding Study Reports
5.3.2.2	Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3	Reports of Studies Using Other Human Biomaterials
5.3.3	Reports of Human Pharmacokinetic(PK) Studies	4.2.1.2	Pharmacokinetic Studies
5.3.3.1	Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2	Patient PK and Initial Tolerability Study Reports
5.3.3.3	Intrinsic Factor PK Study Reports
5.3.3.4	Extrinsic Factor PK Study Reports
5.3.3.5	Population PK Study Reports
5.3.4	Reports of Human Pharmacodynamic (PD) Studies	4.2.1.1	Pharmacodynamic Studies
5.3.4.1	Healthy Subject PD and PK/PD Study Reports
5.3.4.2	Patient PD and PK/PD Study Reports
5.3.5	Reports of Efficacy and Safety Studies	4.2.2	Clinical Trials
5.3.5.1	Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication	4.2.2.1	Pivotal Trials
5.3.5.2	Study Reports of Uncontrolled Clinical Studies	4.2.2.2 4.2.2.3 4.2.2.4	Non-Pivotal Trials Special Clinical Trials Uncompleted Clinical Trials
5.3.5.3	Reports of Analyses of Data from more than one study, including any formal integrated analyses, meta-analyses, and bridging analyses	3.2.4.1 3.2.4.2	Effectiveness Safety
5.3.5.4	Other Clinical Study Reports	4.2.2.5	Other Clinical Trials
5.3.6	Reports of Postmarketing Experience
5.3.7	Case Report Forms and Individual Patient Listings (when submitted)	5.2	Raw Data: Clinical Studies
5.4	Literature References	4.2.3	Published and Unpublished Clinical Reports

Appendix D: Terminology

In order to avoid possible ambiguity in terminology in this and related guidances on the preparation of drug submissions in the CTD format, explanations are provided below for a number of terms. This glossary may be expanded within the Canadian context, if required.

Pharmaceutical: A pharmaceutical (product), in ICH usage, covers both chemical entities and biotech/biological products. Historically, the term 'pharmaceutical' has been used by Health Canada to mean products that are not of biotech/biological origin (Schedule D).

In general, the terms 'Safety' and 'Nonclinical' may be considered synonymous terms. The same holds true for the terms 'Efficacy' and 'Clinical'.