Clinical Trial Application - Amendments (CTA-As)

CTA-A s are applications in which a sponsor proposes information to support changes to a previously authorized application [C.05.008]. Where a sponsor wishes to make changes to a CTA under review, the sponsor should withdraw the active CTA and submit a new CTA .

CTA-A s may involve changes to an authorized protocol (Clinical Amendments), changes to clinical trial drug supplies (Quality Amendments), or both.

Note: If the sponsor is required to immediately make one or more of the amendments referred to in subsection (2) of C.05.008 because the clinical trial or the use of the drug for the purposes of the clinical trial endangers the health of a clinical trial subject or other person, the sponsor may immediately make the amendment without prior review by Health Canada. A corresponding CTA-A which provides the information required below, and which clearly identifies the change and the rationale for immediate implementation of the change must be filed within 15 days after the date of implementation of the amendment [C.05.008(4)]. This is subject to a 30 day review period.

• affect the selection, the criteria for selection, monitoring, or dismissal of a clinical trial subject
• affect the evaluation of the clinical efficacy of the drug
• alter the risk to health of a clinical trial subject
• affect the safety evaluation of the drug
• extend the duration of the clinical trial

Sponsors must file a Quality CTA-A for chemistry and manufacturing changes that may affect the quality or safety of the clinical trial drug supplies. Changes include, but are not limited to:

For Pharmaceutical drugs

• MANUFACTURE (Drug Substance), where new ingredients are used, including ingredients which do not appear in the final drug substance;
• IMPURITIES, where a new impurity or degradation product has been identified;
• CONTROL OF DRUG SUBSTANCE, where a test is removed from the specification and/or the test methods or limits are relaxed
• MANUFACTURE (Drug Product), where new ingredients are used, including ingredients which do not appear in the final product
• DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS, for sterile products only where the sterilization process is changed
• CONTROL OF DRUG PRODUCT where a test is removed from the specification and/or the test methods or limits are relaxed

For Biologics and Radiopharmaceuticals

• MANUFACTURE, regarding raw materials, where a new medicinal or non-medicinal ingredient is used, including ingredients not appearing in the final formulation
• CONTROL OF DRUG SUBSTANCE, where a test method is altered and/or the test limits are relaxed
• MANUFACTURE, where minor changes to the formulation process are proposed
• CONTROL OF DRUG PRODUCT, where a test method is changed and/or test limits are relaxed
• STABILITY, where an extension of the shelf life for drug product is proposed, and the original expiry date granted was < 18 months; and
• FACILITIES AND EQUIPMENT, where modifications to an existing facility are proposed

It should be noted that for Biologics and Radiopharmaceuticals, certain changes relating to the production of a given drug may be considered beyond the scope of an authorized CTA . If such changes are submitted as CTA-A s they will be subject to reclassification as a CTA ..

These changes include, but are not limited to:

• use of a new or alternate facility for any stage of production except those used for packaging
• changes in biological source material
• changes to genetic expression systems
• changes to the purification process
• changes in drug substance and/or final product dosage form (e.g., liquid to lyophilized formulation)
• significant changes to product release specifications
• changes in drug substance and/or final product strength

How to organize your Clinical Amendment

The main components of clinical amendments include a copy of the amended Protocol, a copy of the most recently authorized protocol, a clear description of the proposed changes (i.e., original wording vs. revised wording), and a rationale for each proposed change. If the purpose of the amendment is to extend the duration of the study, a copy of the amended Investigator's Brochure or an addendum to the Investigator's Brochure must be provided [C.05.008 3b].

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

The cover letter should indicate the file number and control number(s) of the original CTA (s).

• 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)
    • [1.2.3] Investigator's Brochure
    • [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

    How to organize your Quality Amendment

    Quality amendments include applicable components of Module 1 (e.g. Drug Submission Application Form ( HC/SC 3011) and revised sections of Modules 2 and 3.

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

    The cover letter should indicate the file number and control number(s) of the original CTA (s).

    • 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)
        • [1.2.3] Investigator's Brochure (for biologics and radiopharmaceuticals only)
        • [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
        • Body of data
        • Literature references

        Module 1 : Administrative / Clinical Information

        [1.2] Application Information

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

        A completed Drug Submission Application Form (including a completed 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.

        [1.2.3] Investigator's Brochure (if applicable)

        Clinical amendment:

        As per C.05.008 3b, Part C, Division 5 of the Food and Drug Regulations, in respect of an amendment to the protocol that extends the duration of the clinical trial, a copy of the amended Investigator's Brochure or an addendum to the Investigator's Brochure that indicates the new information, including supporting toxicological studies and clinical trial safety data must be submitted.

        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.

        Quality amendment:

        For Biologics and Radiopharmaceuticals only:

        a revised Investigator's Brochure or an Addendum to the Investigator's Brochure describing any new Quality (Chemistry and Manufacturing) information, including supporting data as required, if applicable.

        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.

        [1.2.5] Study Protocol(s)

        The following information must be submitted in both hard copy and electronic format:

        • Copy of the amended protocol(s)
        • Copy of the most recently authorized protocol(s)
        • A clear description of the proposed changes (i.e., original wording vs. revised wording)
        • A rationale for each proposed change

        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) (if applicable)

        If changes to the study protocol(s) or any other supporting documentation affect the information contained in the Informed Consent Document (s), the revised Informed Consent Document(s) must be submitted.

        [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.

        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 the application.

        [1.2.11] Other Information (if applicable)

        Any additional information that may be relevant to the application 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 and/or addendum (if applicable)
        • Amended Protocol
        • Most recently authorized protocol
        • Description of the proposed changes (i.e., original wording vs. revised wording)
        • A rationale for each proposed change.

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

        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

        [2.1] Common Technical Document Table of Contents

        A listing of the contents of Modules 2 and 3.

        [2.3] Quality Overall Summary ( QOS )

        The applicable updated Quality Summary must be submitted in both hard copy and electronic format. Revised information should be clearly identified.

        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

        The relevant components of the QOS-CE template should be completed. Those sections not affected by the change should be deleted.

        Module 3: Quality - Additional Supporting Quality Information

        The Quality Module should include: