Post-Authorization Requirements
Once an application has received regulatory authorization, the sponsor is required to inform Health Canada of the following:
- If clinical trial site information was not available at the time of application, a completed Clinical Trial Site Information (CTSI) form must be provided to the appropriate Directorate before the trial is initiated or prior to implementation of an amendment at that site.
- After a CTA has been authorized, any changes to the protocol and/or clinical trial drug supplies must be submitted to Health Canada either as an Amendment or a Notification .
- In the event of the premature discontinuation of a trial in its entirety or at a clinical trial site for which a CTA or CTA-A has been filed in Canada, the responsible Directorate must be notified as soon as possible, but no later than 15 calendar days after the date of discontinuance [REGULATIONS, C.05.015] ).
- For drugs used in clinical trials in Canada, only those ADRs that are both serious and unexpected are subject to expedited reporting to Health Canada, regardless whether the ADR occurred inside or outside of Canada. Expedited reporting of reactions which are serious but expected is not required. Expedited reporting is also inappropriate for serious events from clinical investigations that are considered unrelated to the study product, whether or not the event is expected.
Research Ethics Board Refusals
- Following regulatory autorization of a CTA or a CTA-A, information regarding refusals by other regulatory authorities or Research Ethics Board(s), should be submitted as a notification. This information will be added to the file, but will not be subject to an acknowledgement letter.
- With the exception of vaccines, in lieu of routine lot testing, the Biologics and Genetic Therapies Directorate (BGTD) will require that the CTA sponsor/manufacturer provide the Directorate, before its use in the trial, with the following information on the final product and bulk product of their material:
- Lot numbers of materials being used during the trial and any Batch Identification Numbers that are assigned to lots received from elsewhere (i.e. all numbers associated with a particular lot), and
- The lot number(s) and manufacturing source of any associated human-derived excipient (e.g. human albumin).
- An updated Investigator's Brochure, including all safety information and global status should be submitted annually.
NOTE: Health Canada may suspend or cancel a trial in instances such as, but not limited to:
- A sponsor has contravened the Act or Regulations relating to the drug
- Any information submitted in respect of the drug or clinical trial is false or misleading
- A sponsor failed to comply with good clinical practices
- A sponsor has failed to provide Health Canada with certain requested information
Please refer to [REGULATIONS, C.05.016] and [REGULATIONS, C.05.017] for further information.
Clinical Trial Site Information
If a completed Clinical Trial Site Information (CTSI) Form (including dates for sections 35 and 47 of the form) for each proposed clinical trial site was not provided at the time of application (CTA or CTAs -A), the CTSI form must be submitted to the appropriate Directorate prior to commencement of the trial or implementation of the amendment 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)].
All fields must be fully completed, including the:
- dates for sections 35 and 47;
- Control Number assigned by Health Canada in section 3;
- CR File Number assigned by Health Canada in section 4.
If any changes are made to the Clinical Trial Site Information form (e.g., change of qualified investigator) a revised form should be submitted. Receipt of the Clinical Trial Site Information form will not be subject to an acknowledgment letter.
Changes to a Previously Authorized CTA
Amendments
Amendments are applications in which a sponsor proposes changes to a previously authorized application [REGULATIONS, C.05.008] . Amendments may involve changes to clinical trial drug supplies (e.g., the manufacturing process for the drug has changed), changes to an authorized protocol (e.g., a revised dosing regimen), or both.
Amendments must be authorized by Health Canada prior to implementation of the changes and are subject to the 30-day review period.
If the sponsor is required to immediately make one or more of the amendments because the clinical trial or the drug for the purpose 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 amendment to the CTA which provides the required information 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. This is subject to a 30-day default review period.
For further information, consult the Clinical Trial Application - Amendments page.
Notifications
Notifications, as described below, must be provided for changes to CTAs and CTAs -As. The changes may be implemented immediately, but Health Canada must be informed in writing, within 15 calendar days after the day of the change [REGULATIONS, C.05.007] . Notifications include the following changes to CTAs and CTAs -As.
- Changes to the protocol that do not affect the safety of the trial participants and which would not be considered an Amendment
- Information on site closure or completion of the clinical trial
- When the clinical trial has been discontinued in its entirety or at any clinical trial site for reasons not related to the safety of clinical trial participants (e.g., for administrative purposes, lack of recruitment, etc).
- Updated Investigator's Brochure
- Changes to Quality (Chemistry and Manufacturing) information that do not affect the quality or safety of the drug, for example:
- for Pharmaceuticals: production scale-ups with no changes in the process
- tightening of existing test specifications
- changes in contract testing laboratories
- changes in packaging material
- for Pharmaceuticals: extension of shelf life
- for Pharmaceuticals: which would not be considered and Amendment.
Updated information regarding the change should be submitted in the form of a cover letter and any supporting documentation. The cover letter should indicate the file number, control number(s), and protocol number(s) of the original CTAs (s).
The Notification will be reviewed and added to the file.
Premature Discontinuation of a Clinical Trial
In the event of the premature discontinuation of a trial in its entirety or at a clinical trial site for which a CTA or a CTAs -A has been filed in Canada, the responsible Directorate must be notified within 15 calendar days of the date of discontinuance. This notification should include:
- detailed rationale for this action
- description of the impact on the proposed or ongoing trials, in respect of the drug, conducted in Canada
- confirmation that all qualified investigators involved in the clinical trial, have been notified of the discontinuation and the reasons for the discontinuance and have been advised in writing of any potential risks to the health of clinical trial subjects or other persons
- confirmation that the sale or importation of the drug to all sites involved has been stopped
- confirmation that reasonable measures to ensure the return of all unused quantities of the drug will be taken
Note: Notification of a premature discontinuation of a clinical trial outside Canada, for which there are ongoing trials in Canada, should also be submitted to the appropriate Directorate.
In order to resume a suspended trial, the sponsor must submit a CTAs -A. Sponsors may only resume a trial when a No Objection Letter (NOL) has been issued from the appropriate Directorate within 30 days of the submission of information. The CTAs -A must include:
- the information submitted as a notification at the time of trial suspension
- the name, address and telephone number, and if applicable, the fax number and electronic mail address of the qualified investigator for each site and of the REB that approved the re-initiation of the trial at each site
- the name, address and telephone number and, if applicable, the fax number and electronic mail address of any REB that has previously refused to approve the re-initiation of the trial, if applicable
- the proposed date of re-initiation of the clinical trial at each clinical trial site
Adverse Drug Reactions (ADR) Reporting
For drugs used in clinical trials in Canada, only adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting to Health Canada. Expedited reporting of reactions which are serious but expected is not required. Expedited reporting is not required for serious events from clinical investigations that are considered unrelated to the study product, whether or not the event is expected.
During a clinical trial the sponsor is required to inform Health Canada of any serious, unexpected adverse drug reaction that has occurred inside or outside Canada. ADR report must be filed in the cases:
- where the ADR is neither fatal nor life-threatening, within 15 days after becoming aware of the information
- where it is fatal or life-threatening, immediately where possible and, in any event, within 7 days after becoming aware of the information
- within 8 days after having informed Health Canada of the ADR, submit as complete as possible, a report which includes an assessment of the importance and implication of any findings
Each ADR which is subject to expedited reporting should be reported individually in accordance with the Health Canada / ICH Guidance Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
Ongoing safety information respecting a drug should be conveyed to Investigator(s) and their Research Ethics Board(s). For further information refer to the Health Canada / ICH Guidance Documents E6: Guideline for Good Clinical Practice and E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
How to file an ADR report to Health Canada:
A completed ADR Expedited Reporting Summary Form should be attached to the front of the completed ADR report (suggested ADR report format: Suspect Adverse Reaction Report - CIOMS form of the Council for International Organizations of Medical Sciences (CIOMS)).
The report should be submitted by fax to the appropriate Directorate.
Lot Release Information (for Biologics and Radiopharmaceuticals)
With the exception of vaccines, in lieu of routine lot testing, the Biologics and Genetic Therapies Directorate will require that the CTA sponsor/manufacturer provide the Directorate, before its use in the trial, with the following information on the final product and bulk product of their material:
- Lot numbers of materials being used during the trial and any Batch Identification Numbers that are assigned to lots received from elsewhere (i.e. all numbers associated with a particular lot), and
- The lot number(s) and manufacturing source of any associated human-derived excipient (e.g. human albumin).
The sponsor/manufacturer is required to sign a certification stating that all testing, on the drug substance as well as any human-derived excipients, is complete and within specification. A completed "Fax-Back" form, including the required certification, should be sent to the BGTD. This will be faxed back to the sponsor/manufacturer within 48 hours, providing the CTA has received prior BGTD authorization. If the CTA has not been cleared by the BGTD, the Fax-Back will be held until such time as authorization for the CTA has been given. Upon receipt of the faxed-back form, the sponsor/manufacturer may implement the use of the particular lot(s).
If the sponsor/manufacturer wishes to use a lot that has failed one or more specifications, they must provide the testing protocol, an explanation, and the rationale for its use along with the completed Fax-Back form. The lot must not be used until such time as it has been released by the BGTD.
In cases where a previously authorized biological is being used in a clinical trial, for a new indication, a Fax-Back will still be required.
In the case of vaccines, the BGTD will continue to require samples and testing protocols respecting Clinical Trial Application ( CTA ) submissions.
Updated Investigator's Brochure
Updated Investigator's Brochures, including all safety information and global status should be submitted annually. Additional information and any changes that have been incorporated in the updated Investigator's Brochure should be highlighted for ease of review and evaluation. If an Investigator's Brochure is updated more frequently, it should be submitted as required.
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