Notice: Release of New Guidance for Clinical Trial Sponsors: Clinical Trial Applications

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The Biologics and Genetic Therapies Directorate (BGTD) and the Therapeutic Products Directorate (TPD) are pleased to announce the release of the new guidance document for Clinical Trial Applications. This guidance document supercedes the Clinical Trials Review and Approval Policy (1997), the Preparation of Investigational New Drug Submissions (1991) and the Conduct of Clinical Investigations (1989).

This guidance is intended for the administration of the amendment under Part C, Division 5 of the Food and Drug Regulations (Schedule No. 1024) Clinical Trial Framework [SOR/2001-203] (also referred to as the Regulations). The updated Regulations are consistent with the principles, definitions and standards for designing, conducting, performing, monitoring, auditing, recording, analyzing, and reporting clinical trials, as described in the Health Canada / ICH Guidance Documents: E6: Good Clinical Practice- Consolidated Guideline; E8: General Considerations for Clinical Trials; and E2A: Clinical Safety Data Management- Definitions and Standards for Expedited Reporting.

Outlined in the guidance are the Clinical Trial Application (CTA) and Clinical Trial Application- Amendment (CTA-A) requirements for the sale and importation of drugs for use in human clinical trials in Canada [C.05.006(1) and C.05.008]. Prior to the initiation of a clinical trial conducted with drugs in humans in Canada, sponsors must file a CTA or CTA-A to Health Canada and receive a No Objection Letter (NOL) or not be issued a Notice in respect of the drug, which indicates that the sponsor may not sell or import the drug. These requirements apply to clinical trials in Phases I through III of drug development, and comparative bioavailability trials, as well as, clinical trials involving marketed products, where the proposed use of the product is outside the parameters of the approved Notice of Compliance (NOC) or Drug Identification Number (DIN) application. Sponsors conducting clinical trials in Canada with products that have received a Notice of Compliance with Conditions (NOC/C) are also required to file a CTA. However, Phase IV clinical trials are not subject to CTA filing requirements with Health Canada. Sponsors must conduct all clinical trials, including Phase IV trials, in accordance with the principles of Good Clinical Practices [C.05.010].

Health Canada must review a CTA or CTA-A and notify the sponsor within 30 days, if the application is found to be deficient [C.05.006(1)]. For comparative bioavailability trials and Phase I trials in healthy adult volunteers, a review completion date of 7 days is targeted, with the exception of Phase I trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies.

The format outlined in this guidance for Clinical Trial Applications (CTAs) and Clinical Trial Application- Amendments (CTA-As) is consistent with that used for other types of drug submissions filed in Canada, based upon the format of the International Conference on Harmonization (ICH) Common Technical Document (CTD). Although the scope of ICH's CTD does not include applications at the clinical research stage of development, the modular format of the CTD is being extended to CTAs and CTA-As that are filed with Health Canada, as part of the initiative to integrate the CTD format within the Canadian drug regulatory framework. This approach is intended to facilitate the preparation of drug submission information throughout the lifecycle of a drug (e.g., from Clinical Trial Application to the New Drug Submission stage).

Implementation Dates and Scope of Application

The general principles of this guidance document and the updated Regulations for clinical trials are effective immediately. As of July 1, 2003, the Common Technical Document format and appropriate adaptations of the CTD, such as for CTAs and CTA-As, will officially replace previous formats in Canada for all drug submissions filed pursuant to Divisions 5 and 8, Part C of the Food and Drug Regulations. The use of this format will be expected for original filings and subsequent filings, regardless of the format of the original submission. Furthermore, amendments filed to Investigational New Drug Submission(s) submitted prior to September 1^st, 2001 should be filed in accordance with the requirements of Part C, Division 5 of the Regulations. 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-related¹.

Note: Further changes respective of the CTD format may be necessary, based upon practical experience gained through the use of the CTD, with efforts to further harmonize internationally, and/or with the introduction of the electronic or eCTD. As a matter of good guidance practices, any updates to CTD-related filing requirements will only be introduced following advance notice and will not be applied retroactively to submissions pending review. During the transition period of implementing the CTD format, a certain level of discretionary flexibility may be exercised by Health Canada with respect to format changes.

Electronic Review Documents and the eCTD

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

The multi-year plan foresees the implementation of full e-review capability within affected Health Canada directorates as a result of the investment of necessary funds under the 'Smart Regulation' commitment in the
September 30, 2002 Speech from the Throne. An immediate priority will be the resolution of difficulties experienced by applicants with the Quality Summary and Protocol Synopsis (Preclinical and Clinical Evaluation Report Template (PCERT)) templates, as a result of the current electronic file format specification. Details of the plan and ACES activities will be made publicly available.

Contacts

Questions concerning general filing requirements for CTAs or CTA-As and the possible need for a pre-submission meeting should be directed to:

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

For TPD:
Senior Medical Advisor Bureau
Therapeutic Products Directorate
Fax: (613) 954-4474
smab_enquiries@hc-sc.gc.ca

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¹ Where the combination product is classified as a device, the use of the CTD format for the drug component is optional.