Clinical Trial Applications (CTAs)

The following section provides the requirements for a CTA involving the use of pharmaceutical, biological, and radiopharmaceutical drugs. The requirements are the same for these drug products with a few exceptions.

Please consult the Clinical Trial Applications for Biologics and Radiopharmaceuticals page for more information related to these types of products.

Pre-Clinical Trial Application Consultation Meeting

Health Canada invites sponsors to request a pre- CTA consultation meeting. Such consultations may be particularly useful for new active substances or applications that will include complex issues that may be new to Health Canada. For further information, consult the Pre- CTA Consultation Meeting page.

Clinical Trial Application ( CTA )

• Module 1 - contains administrative and clinical information about the proposed trial
• Module 2 - contains Quality (Chemistry and Manufacturing) information about the drug product(s) to be used in the proposed trial
• Module 3 - contains additional supporting Quality information

The modules are organized and numbered consistently in an internationally adopted format - the Common Technical Document ( CTD ). Adhering to the CTD format facilitates evaluation by Health Canada and ensures consistency of documents in subsequent stages of the drug authorization process. Additional information about the CTD format is available on the web site of the International Conference on Harmonisation ( ICH )

The following guidance documents may be useful in the preparation of the application:

• Guidance for Clinical Trial Sponsors: Clinical Trial Applications
• Guidance for Sponsors of Clinical Trial Applications: Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications
• Health Canada / ICH Guidance Document E6 : Good Clinical Practice: Consolidated Guideline
• Quality guidance documents for Biologics (refer to the Relevant Links page for a list of the documents)

How to organize your application

Health Canada encourages the submission of applications in Common Technical Document ( CTD ) format. This format, as applied to a CTA , is shown below.

• Module 1: Administrative / Clinical Information
  • Cover Letter
  • [1.1] Table of Contents
  • [1.2] Application Information
    • [1.2.1] Drug Submission Application Form ( HC/SC 3011)
    • [1.2.2] Information on Prior-related Applications
    • [1.2.3] Investigator's Brochure
    • [1.2.4] Protocol Synopsis ( PSEAT-CTA ) or Submission Rationale / Brief Summary of the Drug Product
    • [1.2.5] Study Protocol(s)
    • [1.2.6] Informed Consent Document(s)
    • [1.2.7] Clinical Trial Site Information
    • [1.2.8] Canadian Research Ethics Board(s) Refusals
    • [1.2.9] Foreign Refusals
    • [1.2.10] Letters of Access
    • [1.2.11] Other Information
    • [2.1] Common Technical Document Table of Contents
    • [2.2] Introduction - Not applicable to Clinical Trials
    • [2.3] Quality Overall Summary ( QOS )
    • [3.1] Table of Contents
    • [3.2] Body of data
    • [3.3] Literature references

    Each Module should be submitted in a separate binder.

    For Biologics and Radiopharmaceuticals:

    if the CTA contains both Clinical and Quality (Chemistry and Manufacturing) information, Module 1 (Administrative / Clinical Information) should be submitted in duplicate.

    For clinical trials involving a PHARMACEUTICAL and a BIOLOGICAL / RADIOPHARMACEUTICAL drug, refer to Question 8 of the Frequently Asked Questions - Filing of Clinical Trials page.

    For clinical trials involving INVESTIGATIONAL MEDICAL DEVICES and a DRUG (PHARMACEUTICAL OR BIOLOGICAL / RADIOPHARMACEUTICAL), refer to Questions 9-10 of the Frequently Asked Questions - Filing of Clinical Trials page.

    Module 1: Administrative / Clinical Information

    [1.2.1] Drug Submission Application Form ( HC/SC 3011)

    A completed Drug Submission Application Form (including Appendix 3), must be signed by the Senior Medical or Scientific Officer in Canada AND the Senior Executive Officer. In the case of investigator initiated trials (see Institution/Investigator Initiated Clinical Trials), Appendix 3 may be signed by the appropriate Department Head in lieu of the Senior Executive Officer, and the Qualified Investigator may sign in lieu of the Senior Medical or Scientific Officer in Canada. Appendix 1 ("Authorization for a third party to import. ") and Appendix 2 ("Authorization for a third party to sign/file. ") should be submitted only if applicable.

    [1.2.2] Information on Prior-related Applications (if applicable)

    This is a list of the sponsor's ongoing clinical trials in Canada, previously authorized by Health Canada.

    [1.2.3] Investigator's Brochure

    A copy of the current Investigator's Brochure, supplemented with up-to-date safety, pre-clinical and clinical data, must be submitted.

    The Investigator's Brochure containing all information regarding the product should be prepared in accordance with the Health Canada / ICH Guidance Document E6 : Good Clinical Practice: Consolidated Guideline, and updated annually. Sectional reports should not be submitted, but may be requested during the CTA review.

    For products marketed in Canada, a copy of the Product Monograph may be submitted in lieu of the Investigator's Brochure.

    For Biologics and Radiopharmaceuticals:

    if the Investigator's Brochure has been updated relative to a version contained within a previously authorized CTA/CTA-A , a summary of the changes should be provided.

    The Investigator's Brochure must be submitted in both hard copy and electronic format. Note that electronic copies must be submitted on CD-ROM or diskette, in either editable PDF , MS Word, or WordPerfect format.

    [1.2.4] Protocol Synopsis ( PSEAT-CTA ) or Submission Rationale / Brief Summary of the Drug Product

    For Pharmaceutical Drugs

    A protocol synopsis in the format of the Protocol Safety and Efficacy Assessment Template - Clinical Trial Application ( PSEAT-CTA ) should be submitted. A submission rationale and a brief summary are included in the PSEAT-CTA .

    The PSEAT-CTA should be submitted in both hard copy and electronic format. Note that electronic copies must be submitted on CD-ROM or diskette, in either editable PDF , MS Word, or WordPerfect format.

    For Biologics and Radiopharmaceuticals

    A Submission Rationale and a Brief Summary of the Drug Product being proposed for use in the clinical trial must be submitted.

    The Submission Rationale / Brief Summary of the Drug Product must be submitted in both hard copy and electronic format. Note that electronic copies must be submitted on CD-ROM or diskette, in either editable PDF , MS Word, or WordPerfect format.

    [1.2.5] Study Protocol(s)

    A copy of the final study protocol should be submitted. The information in the protocol must follow the Health Canada / ICH Guidance Document E6 : Good Clinical Practice: Consolidated Guideline.

    The study protocol must be submitted in both hard copy and electronic format. Note that electronic copies must be submitted on CD-ROM or diskette, in either editable PDF , MS Word, or WordPerfect format.

    [1.2.6] Informed Consent Document(s)

    A copy of the Informed Consent document(s) to be used in conjunction with the clinical trial must be submitted. The Informed Consent document(s) must include a statement regarding the risks and anticipated benefits to the clinical trial subjects as a result of their participation in the clinical trial(s).

    [1.2.7] Clinical Trial Site Information ( CTSI )

    A completed Clinical Trial Site Information Form ( CTSI Form) for each proposed clinical trial site, if known at the time of the application, is to be submitted. Please do not provide forms until all fields are completed. Dates for sections 35 and 47 of the CTSI Form must be provided. In addition, the sponsor may also utilize their cover page to provide additional and relevant information related to specific sections of the form when submitting it to the relevant Directorate, if applicable.

    For clinical trial site information which becomes available after the time of application, a completed CTSI Form must be provided to the appropriate Directorate before the trial is initiated at that site.

    In the event that an amendment must be implemented prior to the approval due to safety reasons, the commencement date of the amendment should reflect the date the amendment was implemented at the site. To avoid any confusion during the data entry, a supplemental document should also be attached to the CTSI form justifying the situation. Please refer to the section C.05.008 (4) of the Food and Drug Regulations for additional information." The word 'safety' can also be inserted in brackets next to the date [eg: January 15th, 2008 (safety)].

    If any changes are made to the CTSI Form (e.g., change of qualified investigator) a revised form should be submitted. Receipt of the CTSI Form will not be subject to an acknowledgment letter.

    [1.2.8] Canadian Research Ethics Board(s) Refusals (if applicable)

    If known at the time of submitting the application, the following information must be provided: the name, address and telephone number and, if applicable, the fax number and electronic mail address of any Research Ethics Board ( REB ) in Canada that has previously refused to approve the clinical trial protocol, its reasons for doing so, and the date on which the refusal was given.

    [1.2.9] Foreign Refusals (if applicable)

    Information regarding refusals by regulatory authorities outside Canada must be included.

    [1.2.10] Letters of Access (if applicable)

    If applicable, letters authorizing Health Canada to access related files (e.g., Drug Master Files, Site Reference Files) must be submitted.

    A letter of access may be required to satisfy regulatory requirements for a CTA .

    For example: A sponsor is utilizing a drug in a clinical trial that has not received a Notice of Compliance ( NOC ) and/or a Drug Identification Number ( DIN ). Furthermore, the manufacturer of the drug does not wish to disclose confidential information about the drug to the clinical trial sponsor. In such an instance, a letter authorizing Health Canada to access related files may be used to satisfy regulatory requirements for a CTA .

    For Pharmaceutical Drugs

    • Reference to a Drug Master File ( DMF ):
      • A letter written by the holder of the DMF permitting Health Canada to reference information in the DMF in support of the sponsor 's CTA must be submitted.
      • The CTA sponsor should ensure that the supporting Drug Master File (including submission of the letter of access and payment of related fees) has been submitted to and accepted by Health Canada prior to filing a CTA .
      • Reference to an application previously submitted to and authorized by Health Canada:
        • A letter written by the sponsor/manufacturer of the referenced application authorizing Health Canada to access the information in support of the sponsor's CTA must be submitted;
        • The referenced information must meet the regulatory requirements for CTA s;
        • The letter of access must include the file number and control number(s) of the referenced submission(s).

        Note: Where chemistry and manufacturing information is referenced, the appropriate Quality Overall Summary ( QOS ) template (Module 2 , [2.3]) must be submitted with the CTA . The INTRODUCTION section of the QOS must be completed as well as any other sections containing information not covered by the letter of access.

        For Biologics and Radiopharmaceuticals

        Any supporting Master File information should be submitted or resubmitted simultaneously to the Biologic and Genetic Therapies Directorate with the related CTA .

        [1.2.11] Other Information (if applicable)

        Any additional information that may be relevant to the application (e.g. pre- CTA meeting minutes) should be submitted, if applicable.

        [1.3] Electronic Review Documents

        Module 1 electronic files should be placed under this section. The following documents must be submitted in electronic format:

        • Investigator's Brochure or Product Monograph
        • PSEAT-CTA or Submission Rationale / Brief Summary
        • Study Protocol(s)

        Electronic documents must be identical to the hard copies provided in the CTA .

        Electronic review documents must be submitted on CD-ROM or diskette, in either editable PDF , MS Word, or WordPerfect format.

        Module 2: Common Technical Document Summaries - Quality (Chemistry and Manufacturing) Information

        This section does not apply if the drug product to be used in the clinical trial has received a Notice of Compliance ( NOC ) and/or a Drug Identification Number ( DIN ) Footnote 1 .

        For a CTA , this module reflects Quality (Chemistry and Manufacturing) information only. The Common Technical Document Summaries Module should include:

        [2.1] Common Technical Document Table of Contents

        A listing of the contents of Modules 2 and 3.

        [2.2] CTD Introduction

        Not applicable to CTA s. This section has been reserved for use during the preparation of drug submissions at later stages of development (e.g., New Drug Submissions) and maintained to ensure consistent numbering of subsequent sections (e.g., Section 2.3).

        [2.3] Quality Overall Summary ( QOS )

        This document must be submitted in both hard copy and electronic format. Note that electronic copies must be submitted on CD-ROM or diskette, in either MS Word or WordPerfect format ( PDF format of the QOS is not acceptable) . Module 2 electronic files should be placed at the beginning of Module 2.

        For Pharmaceutical Drugs

        Depending on the phase of the clinical trial, the applicable Quality Overall Summary - Chemical Entities ( QOS-CE ) template as well as additional Quality information as outlined in the template, should be completed and submitted.

        • Quality Overall Summary - Chemical Entities (Clinical Trial Applications Phase I) ( QOS-CE ( CTA - Phase I))
        • Quality Overall Summary - Chemical Entities (Clinical Trial Applications - Phase II ) ( QOS-CE ( CTA - Phase II ))
        • Quality Overall Summary - Chemical Entities (Clinical Trial Applications - Phase III ) ( QOS-CE ( CTA - Phase III ))

        For detailed instructions on completing the Quality Overall Summary - Chemical Entities templates, see Guidance for Sponsors of Clinical Trial Applications, Quality (Chemistry and Manufacturing)

        If the Quality information was previously submitted to and authorized by Health Canada and has not changed, re-submission of the applicable Quality Overall Summary is not required. However, the relevant application control number(s) should be stated on the cover letter of the current CTA .

        For placebo-controlled studies, a qualitative list of the ingredients in the placebo should be submitted.

        • Quality information for Phase II trials cannot be cross-referenced to the Quality information submitted with Phase I trials
        • Quality information for Phase III trials cannot be cross-referenced to the Quality information submitted with Phase II trials.

        For Biologics and Radiopharmaceuticals:

        If the Quality information was previously submitted to and authorized by Health Canada and has not changed, re-submission of the applicable Quality Summary is not required. Sponsors should, however, refer to the control number of the prior related application.

        The completed Quality Summary (i.e., check marked sections of an acceptable and appropriate version available, based upon the product type), should be provided. Sponsors should also refer to the applicable Health Canada Quality guidances and updated notices for additional information.

        For placebo-controlled studies, a qualitative list of the ingredients in the placebo should be submitted.

        Module 3 - Quality - Additional Supporting Quality Information

        The Quality Module should include:

        [3.1] Table of Contents of Module 3

        A listing of the contents of Module 3 (Quality).

        [3.2] Body of Data

        Where there is additional supporting Quality information to that provided in Module 2.3, this information should be provided separately in the appropriate Module 3 section and cross-referenced under Module 2.3. The extent of available supporting information may vary depending upon the stage of drug development (e.g., Phase I-III studies). Sponsors should also refer to the applicable Health Canada Quality guidances for additional information.

        For Biologics and Radiopharmaceuticals only:

        [3.2.R.1] Production Documentation

        • [3.2.R.1.1] Executed Batch Records: Executed Batch Records should be provided if available, depending upon the stage of drug development (e.g., Phase I - III studies).

        [3.3] Literature References

        For Biologics and Radiopharmaceuticals only:

        Literature references related to Quality information should be provided here, if applicable.

        Filing a CTA

        The CTA should be sent directly to the appropriate Directorate. The outer label should be clearly state "Clinical Trial Application".

        Note: Where a sponsor wishes to make changes to the CTA under review, the sponsor should withdraw the active CTA and submit a new CTA .

        Records Related to Clinical Trials

        Records of clinical trials should be maintained by the sponsor for 25 years, as required in Part C, Division 5 of the Food and Drug Regulations. (C.05.012 - Sponsor's Obligations - Records).

        A Qualified Investigator Undertaking and a Research Ethics Board Attestation must be completed for each clinical trial site.

        • Qualified Investigator Undertaking ( QIU ) Form
        • Research Ethics Board Attestation ( REBA ) Form

        Records must be made available to Health Canada within 2 days if there is a concern regarding the use of a clinical trial drug and/or a risk to the health of the clinical trial subject. In any other case, records must be provided within 7 days of request. ( C.05.013 - Sponsors' Obligations - Submission of Information and Samples).

        Post-Authorization Changes

        For proposed Clinical and/or Quality (Chemistry and Manufacturing) changes to a previously authorized application, see Clinical Trial Application - Amendments ( CTA-A s) or Notifications for requirements.

        Footnotes

        Footnote 1

        For placebo-controlled studies, a qualitative list of the ingredients in the placebo must be provided.