Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications

Health Canada is consulting on the draft guidance on expanded access clinical trials. Find out how you can participate.

Notice

Health Canada is pleased to announce the release of the finalized Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications which provides guidance to all sponsors [for example (e.g.) industry, academic, contract research organization] seeking authorization to sell or import a drug for the purpose of a clinical trial in Canada. The Guidance was revised based on stakeholder consultation processes and as part of Health Canada's statutory review of Part C, Division 5 of the Food and Drug Regulations (Drugs for Clinical Trials Involving Human Subjects).

The Guidance for Clinical Trial Applications (CTAs) is consistent with the new Common Technical Document (CTD) format and is clear on application requirements. This Guidance document supersedes the previous Guidance for Clinical Trial Sponsors: Clinical Trial Applications (June 25, 2003). The revised guidance includes application requirements for comparative bioavailability trials and filing requirements for the importation of clinical trial supplies. It includes clarifications to amendment and notification requirements, study termination and closure criteria, application and review processes, and adverse drug reaction reporting criteria as well as format requirements. All stakeholder comments were considered in the finalization of this guidance document. A table of comments from industry stakeholders in response to the draft CTA Guidance is available upon request.

As a reminder, Health Canada is advising sponsors of the new electronic adverse drug reactions (ADR) reporting that is currently in pilot with some sponsors. Those sponsors who have an established connection with the Canada Vigilance Production stream should submit their reports only to the appropriate Directorates: Therapeutic Products Directorate (TPD), Biologics and Genetic Therapies Directorate (BGTD) or Marketed Health Products Directorate (MHPD) [that is (i.e.) a report no longer needs to be sent in duplicate to multiple directorates]. For the sponsors who have not yet established this connection, they should continue submitting their reports by fax or by courier. The Health Canada website will provide further clarification on Health Canada's ADR reporting requirements.

Improving the quality of CTAs that are submitted by sponsors and gaining efficiencies with CTA screening, regulatory review and safety reporting, will provide benefits to those involved in the conduct of clinical trials, and most of all to Canadians.

Office of Clinical Trials
Therapeutic Products Directorate
Health Canada
1600 Scott Street
Holland Cross, Tower B
5th Floor, Address Locator 3105A
Ottawa, Ontario
K1A 0K9

Clinical Trial Applications

Date Adopted: 2003/06/25
Revised Date: 2011/11/07
Effective Date: 2013/05/29
Revised Date: 2016/03/17

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

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 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 document, 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 Guidance documents.

Table Of Contents

• 1 Introduction
  • 1.1 Policy Objectives
  • 1.2 Policy Statements
  • 1.3 Scope and Application
  • 1.4 Background
  • 2.1 Abbreviations/Definitions
    • 2.1.1 Abbreviations
    • 2.1.2 Definitions
    • 2.2.1 Request for a Pre-Clinical Trial Application (CTA) Consultation Meeting
    • 2.2.2 Pre-Clinical Trial Application (CTA) Information Package
    • 2.2.3 Pre-Clinical Trial Application (CTA) Consultation Meeting Record
    • 2.3.1 Filing a Clinical Trial Application (CTA)
      • 2.3.1.1 Joint Reviews
      • 2.4.1 Clinical Trial Application-Amendment (CTA-A): Clinical
      • 2.4.2 Clinical Trial Application-Amendments (CTA-A) and Clinical Trial Application- Notification (CTA-N): Quality (Chemistry and Manufacturing)
      • 2.4.3 Filing a Clinical Trial Application-Amendment (CTA-A)
      • 2.4.4 Clinical Trial Application-Amendment (CTA-A) Format
        • 2.4.4.1 Clinical Amendments
        • 2.4.4.2 Quality (Chemistry and Manufacturing) Amendments
        • 2.5.1 Screening Process
          • 2.5.1.1 Requests for Clarification during screening
          • 2.5.1.2 Screening Rejection Letter
          • 2.7.1 Research Ethics Board Review
            • 2.7.1.1 Refusals
            • 2.7.5.1 Importation of Additional Drugs
            • 2.8.1 Premature Discontinuation of a Trial
            • 2.8.2 Resumption of a Trial
            • 2.8.3 Study Completion/Site Closures
            • 2.8.4 Safety Reporting Post- No Objection Letter (NOL)
              • 2.8.4.1 Adverse Drug Reactions (ADRs)
              • 2.8.4.2 Adverse Drug Reactions (ADRs) Reporting criteria
              • 2.8.4.3 How to Report
              • 2.8.4.4 Submission of Information
              • 2.8.4.5 Study Endpoints
              • 2.8.4.6 Additional Information

              1 Introduction

              The Food and Drugs Act and the Food and Drug Regulations (herein referred to as the Regulations) govern the sale and importation of drugs for use in human clinical trials in Canada. This document provides guidance on the regulatory obligations pursuant to Part C, Division 5 of the Regulations, Drugs for Clinical Trials Involving Human Subjects.

              1.1 Policy Objectives

              To provide sponsors seeking authorization to conduct a clinical trial in Canada with guidance to support the protection of clinical trial subjects and contributes to the high standards of excellence in research and development in Canada. This document clarifies application and post-authorization requirements and outlines procedures for obtaining authorization.

              1.2 Policy Statements

              With the exception of Phase IV studies, clinical trial sponsors must submit a clinical trial application (CTA) to Health Canada for authorization to sell or import a drug for the purpose of a clinical trial.

              Clinical trial sponsors must conduct clinical trials according to generally accepted principles of good clinical practice that ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons.

              Research Ethics Boards (REBs) have an important role in the oversight of the conduct of clinical trials. Sponsors are required by the Regulations to obtain REB approval for each clinical trial site prior to commencing the trial at that site [C.05.006(1)(c)].

              The Regulations are generally consistent with the principles, definitions and standards found in the International Conference on Harmonisation (ICH) Guidance documents on clinical trials. Where inconsistencies exist, the Regulations take precedence.

              The format for CTAs as outlined in this Guidance document is consistent with that used for other types of drug submissions filed to Health Canada, based on the format of the ICH Common Technical Document (CTD). Although the scope of the ICH CTD does not include applications at the clinical research stage of development, the modular format of the CTD is being extended to CTAs to facilitate the preparation of drug submission information throughout the lifecycle of a drug.

              1.3 Scope and Application

              The information provided in this Guidance document is for clinical trials involving drugs (pharmaceuticals and/or biologics and radiopharmaceuticals) in human subjects. In the Regulations a clinical trial is an investigation in respect of a drug that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.

              This Guidance document applies to all sponsors (e.g., industry, academic, contract research organization, etc.) conducting clinical trials, as specified below:

              • Clinical trials of a product that is not authorized for sale in Canada including clinical trials for Phases I through III of drug development and comparative bioavailability studies.
              • Clinical trials for marketed drugs where the proposed use of the drug is outside the parameters of the Notice of Compliance (NOC) or Drug Identification Number (DIN) application.
              • Clinical Trial Application Amendments (CTA-A) [C.05.008] and Notifications (CTA-N) [C.05.007].

              This Guidance document does not apply to Phase IV clinical trials or clinical trials involving medical devices or natural health products except where indicated.

              This Guidance document supersedes the previous Guidance for Clinical Trial Sponsors: Clinical Trial Applications (June 25, 2003).

              1.4 Background

              The regulatory requirements respecting drugs to be used for the purposes of clinical trials were originally developed in the early 1960s. On September 1, 2001, the regulatory amendments to Part C, Division 5 of the Food and Drug Regulations (Drugs for Clinical Trials Involving Human Subjects) came into force to strengthen protections for clinical trial subjects in Canada.

              Health Canada completed a review of the clinical trials regulatory framework through 2006-2008. This review included input received from stakeholders, and consideration of best practices in other countries, as well as Health Canada's experience with the existing regulatory framework (Clinical Trials Regulatory Review: Targeted Measures for a Strengthened Framework). Subsequently, Health Canada proceeded with a series of initiatives, one of which included consultations on the type of guidance required by industry to assist in meeting regulatory obligations (Spring/Summer 2008). During the consultations, stakeholders noted the need for better guidance on processes, requirements, and roles and responsibilities in clinical trial activities.

              In response to these consultations, the Guidance for Clinical Trial Sponsors - Clinical Trial Applications has been updated to reflect stakeholder concerns and improve clarity and communication. The guidance includes new information for sponsors regarding information needs and processes related to CTAs, CTA-As and CTA-Ns.

              2. Guidance for Implementation

              2.1 Abbreviations/Definitions

              2.1.1 Abbreviations

              ADR Adverse Drug Reaction BGTD Biologics and Genetic Therapies Directorate CIOMS Council for International Organizations of Medical Sciences CR Central Registry CTA Clinical Trial Application CTA-A Clinical Trial Application-Amendment CTA-N Clinical Trial Application-Notification CTSI Clinical Trial Site Information CTD Common Technical Document DIN Drug Identification Number DMF Drug Master File GCP Good Clinical Practice HPFBI Health Products and Food Branch Inspectorate IB Investigator's Brochure ICF Informed Consent Forms ICH International Conference on Harmonisation ITA Investigational Testing Application NOC Notice of Compliance NOL No Objection Letter NSN Not Satisfactory Notice PSEAT-CTA Protocol Safety and Efficacy Assessment Template - Clinical Trial Application QIS Quality Information Summary QIS-PER Quality Information Summary - Positron-Emitting Radiopharmaceuticals QIS-R Quality Information Summary - Radiopharmaceuticals QIU Qualified Investigator Undertaking QOS Quality Overall Summary QOS-CE Quality Overall Summary - Chemical Entities (Clinical Trial Applications) REB Research Ethics Board TPD Therapeutic Products Directorate

              2.1.2 Definitions

              Most of the definitions listed below were taken from the Regulations, and the Health Canada / ICH Guidance Documents E6: Guideline for Good Clinical Practice: Consolidated Guideline (ICH E6)and E8: General Considerations for Clinical Trials.

              1. The risks and anticipated benefits to his or her health arising from participation in the clinical trial; and
              2. All other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial.
              1. in the case of a clinical trial respecting a drug to be used for dental purposes only, a physician or dentist and a member in good standing of a professional medical or dental association; and
              2. in any other case a physician and a member in good standing of a professional medical association.
              1. the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being; and
              2. that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the Immigration Act, that is composed of both men and women and that includes at least:
                 1. two members whose primary experience and expertise are in scientific discipline, who have broad experience in the methods and areas of research to be approved and one of whom is from a medical discipline or, if the clinical trial is in respect of a drug to be used for dental purposes only, is from a medical or dental discipline,
                 2. one member knowledgeable in ethics,
                 3. one member knowledgeable in Canadian laws relevant to the biomedical research to be approved,
                 4. one member whose primary experience and expertise are in a non-scientific discipline, and
                 5. one member who is from the community or is a representative of an organization interested in the areas of research to be approved and who is not affiliated with the sponsor or the site where the clinical trial is to be conducted.

                 2.2 Pre-Clinical Trial Application (CTA) 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.

                 The pre-CTA consultation meeting provides an opportunity for the sponsor to present relevant data, discuss concerns and issues regarding drug development. It also gives Health Canada an opportunity to provide guidance on the acceptability of the proposed trial(s). Sponsors may invite the qualified investigator(s) who will be involved in the proposed trial(s) in Canada to attend the meeting.

                 2.2.1 Request for a Pre-Clinical Trial Application (CTA) Consultation Meeting

                 Requests for a pre-CTA consultation meeting should be submitted in writing by the sponsor to the appropriate Directorate (refer to Appendix 1).

                 Requests should be submitted in the form of a cover letter proposing four dates and times suitable for a pre-CTA consultation meeting. The cover letter should be accompanied by the following information:

                 • A brief synopsis of the proposed study;
                 • A list of preliminary questions to be addressed by the Directorate during the meeting; and
                 • Sufficient information for Health Canada to assess the utility of the meeting and identify the appropriate staff necessary to discuss the proposed issues. This will assist in ensuring efficient use of Health Canada resources.

                 The Directorate will acknowledge the request for consultation in a timely manner. If the Directorate agrees with the request, the acknowledgement letter will confirm the pre-CTA consultation meeting date and indicate the number of copies of the pre-CTA information package to be provided 30 days before the confirmed meeting.

                 2.2.2 Pre-Clinical Trial Application (CTA) Information Package

                 The Information Package, which should be submitted in accordance with current electronic specifications (see Appendix 2), should contain:

                 1. proposed agenda, any prepared slides including a finalized list of questions, and a complete list of attendees [it is recognized that the slides may change prior to the meeting.]
                 2. a brief summary of all data including:
                    1. a tabular listing of completed nonclinical and clinical studies,
                    2. an outline of the observed toxicological manifestations and a discussion of their impact on the use of the drug in humans,
                    3. an outline of the observed adverse events and a discussion of potential safety problems;
                    1. a statement of trial design,
                    2. parameters, values, ranges or limits for indication(s) and clinical use(s), patient study population(s) and routes of administration,
                    3. parameters, values, ranges or limits for dosage form(s), dosage regimen(s) and formulation(s),
                    4. proposed procedures and/or criteria for patient monitoring, clinical efficacy and safety assessments, alternative treatments, premature patient discontinuation and other considerations, as appropriate;
                    1. a summary of the method of manufacture for both drug substance and dosage form,
                    2. relevant flow charts,
                    3. a listing of quality control procedures and specifications,
                    4. a summary of product characteristics, and
                    5. a listing of all production site(s) - only for biologics and radiopharmaceuticals.

                    Should the pre-CTA package be found deficient, the sponsor may be requested to reschedule or postpone the meeting to allow the sponsor to assemble a more thorough package. Please note that the Directorate reserves the right to modify or truncate the proposed agenda as it sees fit to better achieve the stated goals of the meeting.

                    2.2.3 Pre-Clinical Trial Application (CTA) Consultation Meeting Record

                    The sponsor should prepare and send to the appropriate Directorate a written record of the discussions and conclusions of the consultation meeting within 14 days of the consultation date. All records of this consultation will be added to the Central Registry (CR) file for the drug.

                    A copy of the record of discussions and conclusions approved by all parties in attendance at the meeting should be included in the subsequent CTA.

                    2.3 Clinical Trial Applications (CTAs)

                    The sponsor must file a CTA prior to the initiation of the trial [C.05. 005]. CTAs are required for human clinical trials using drugs not authorized for sale in Canada, including clinical trials in Phases I through III of drug development and comparative bioavailability studies; as well as trials involving marketed drugs, where the proposed use of the drug is outside the parameters of the NOC or DIN , e.g., one or more of the following is different:

                    1. Indication(s) and clinical use;
                    2. Target patient populations(s);
                    3. Route(s) of administration; or
                    4. Dosage regimen(s).

                    Sponsors are not required to file a CTA for clinical trials involving marketed drugs where the investigation is to be conducted within the parameters of the approved NOC or DIN [C.05.006(2)]; these trials are referred to as Phase IV clinical trials.

                    Sponsors must conduct all clinical trials, including Phase IV trials, in accordance with Division 5, including the principles of GCPs, labelling requirements and obtaining REB approval.

                    Sponsors should register their clinical trials on one of two publicly accessible registries accepting international clinical trial information and recognized by the World Health Organisation (WHO): ClinicalTrials.gov and Current Controlled Trials International Standard Randomised Controlled Trials Number Register.

                    2.3.1 Filing a Clinical Trial Application (CTA)

                    CTAs should be sent directly to the appropriate review Directorate (refer to Appendix 1).

                    The outer label should be clearly identified with "Clinical Trial Application".

                    2.3.1.1 Joint Reviews

                    CTAs or CTA-As must be submitted to the appropriate lead Directorate / Bureau when they involve the use of:

                    1. pharmaceuticals and biologics or radiopharmaceuticals Footnote 3 ;
                    2. a medical device and drug combination that is classified as a drug; Footnote 4 or
                    3. a natural health product and a drug Footnote 5 .

                    Authorization for the sale and importation of all investigational products to be used within a CTA or CTA-A must be obtained prior to the initiation of the clinical trial or implementation of the protocol amendment.

                    The lead Directorate / Bureau will be responsible for communicating the regulatory decision to the sponsor.

                    A separate Investigational Testing Application (ITA) and CTA must be filed and authorized before the trial can commence for protocols that involve a drug and the use of an unlicensed class II, III, or IV medical device that is not a combination product.

                    2.3.2 Clinical Trial Application (CTA) Format

                    The CTA is composed of three parts (modules) in accordance with the CTD format:

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

                    The CTA should be submitted on electronic media, accompanied by a hard copy cover letter, and be organized in accordance with the current electronic specifications: Guidance Document: Preparation of Drug Regulatory Activities in the "Non-eCTD Electronic-Only" Format.

                    Refer to Table 1 below for guidance on submission content, and to Appendix 2 (where applicable) for Guidance documents that may be useful in the preparation of the application.

                    Table 1: Contents of Submission Package in accordance with CTD Format

                    Module 1 Administrative and Product Information

                    • 1.0 Correspondence
                      • 1.0.1 Cover letter
                        • CTA/CTA-A: For CTA-As, a cover letter indicating the original CTA(s) and relevant CTA-As with file number and control number(s).
                        • CTA-A (Quality)For Biologics and Radiopharmaceuticals only: include a list of all proposed quality changes from the authorized application. Refer to section 2.4.2a.
                        • CTA/CTA-A: Including e.g., a copy of the record of the discussions and conclusions of the pre-CTA consultation meeting or other relevant correspondence with Health Canada, if applicable.
                        • CTA/CTA-A: A listing of the contents of Module 1 (Administrative / Clinical Information), Module 2 (Common Technical Document Summaries) and Module 3 (Quality), if applicable.
                        • CTA/CTA-A: Including the Summary of Additional Drugs Form (refer to Appendix 4).
                        • CTA/CTA-A: Letters authorizing Health Canada to access related files (i.e.: a previously authorized CTA, Drug Master Files, Manufacturing Site Reference Files), if applicable. For example, a letter of access may be required to satisfy requirements for a CTA if a sponsor is utilizing a drug in a clinical trial that has not received a NOC and/or a DIN and the manufacturer of the drug does not wish to disclose confidential information about the drug to the clinical trial sponsor.
                          • 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 should be submitted.
                            • The CTA sponsor should ensure that the supporting DMF (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.
                            • A letter written by the sponsor of the referenced application authorizing Health Canada to access the information in support of the CTA should be submitted.
                            • The referenced information should meet the regulatory requirements for CTAs.
                            • The letter of access should include the file number and control number(s) of the referenced submission(s).
                            • CTA/CTA-A (Clinical): Information regarding refusals by regulatory authorities outside Canada and foreign Research Ethics Boards, if applicable
                            • CTA/CTA-A: This section is for any administrative information that does not have a designated location in the CTD format. This section should NOT contain any scientific information.
                            • 1.4.1 Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA)
                              • CTA: A Protocol Synopsis in the format PSEAT-CTA.
                              • CTA: A copy of the Informed Consent Forms (ICFs) to be used in conjunction with the clinical trial, including a statement regarding the risks and anticipated benefits to the clinical trial subjects as a result of their participation in the clinical trial. ICFs to be used in conjunction with the clinical trial should be prepared in accordance with applicable laws governing consent. The ICH E6 and the Tri-Council Policy Statement (TCPS) provides standards for the ICF.
                              • CTA-A (Clinical): The revised ICFs must be submitted if the changes to the study protocol(s) or other supporting documentation (nonclinical study results, adverse events, revisions to the IB) affect the information in the ICF. The ICF with changes clearly indicated (annotated) should be provided.
                              • CTA/CTA-A (Clinical): 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 clinical trial protocol or amendment, its reasons for doing so and the date on which the refusal was given, if known at the time of submitting the application as per C.05.008(1)(c). Please refer to section 2.7.1 for additional information.
                              • CTA/CTA-A: A list of ongoing clinical trials in Canada for which authorization has been granted by Health Canada, if applicab

                              Module 2 Common Technical Document Summaries

                              This module contains Quality (Chemistry and Manufacturing) Information only. This section does not apply if the drug product to be used in the clinical trial has received a NOC and/or DIN and has not been modified.

                              If the Quality information was previously submitted to, and authorized by Health Canada and has not changed, re-submission of the applicable Quality Summary may not be required. However, sponsors should refer to the control number of the prior application.

                              The Common Technical Document Summaries Module should include:

                              CTA-A (Quality): An applicable updated Quality Overall Summary (QOS) or Quality Information Summary (QIS) containing only the revised sections. The rationale for each proposed change should be submitted and the revised information should be clearly identified. Alternatively, the changes may be listed in a separate document or in a marked up annotated version of the QOS/QIS-R/QIS-PER, as applicable.

                              • 2.1 Table of Contents
                                • CTA/CTA-A (Quality): A listing of the contents of Modules 2 and 3, if applicable.

                                Module 3 Quality (if submitted)

                                • 3.1 Table of Contents of Module 3
                                  • CTA/CTA-A (Quality): A listing of the contents of Module 3.
                                  • CTA/CTA-A (Quality): Literature references related to quality information should be provided here if applicable.

                                  2.3.3 Comparative Bioavailability Trial Application Requirements (Seven Day Administrative Review)

                                  Health Canada's administrative seven (7) day review target applies to applications involving comparative bioavailability studies for pharmaceuticals only where:

                                  • The studies are single-dose studies to be performed on healthy adult volunteers;
                                  • The reference drug product is marketed in Canada, United States, European Union, Australia, Switzerland or Japan; and
                                  • The maximum dose of the study drug does not exceed that specified in the labelling of the reference drug product.

                                  This section does not apply to biologics, radiopharmaceuticals and cellular therapies, which includes Phase I trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies. Additionally, this section does not apply to other comparative bioavailability studies, such as those conducted during drug development of new active substances to assess the impact of changes to dosage forms or manufacturing processes, or studies comparing different routes of administration. For those types of studies please refer to section 2.3.2 for filing requirements and section 2.5 for review process and timelines.

                                  CTAs for comparative bioavailability studies should be filed directly to the Therapeutic Products Directorate, addressed to the attention of the Director. The outer label of the shipping carton should be clearly identified with "Clinical Trial Application for Bioavailability Studies". In general, the CTA filing requirements (section 2.3.2) also apply to the comparative bioavailability studies that meet the criteria provided above, with some exceptions as follows:

                                  • The cover letter to the application should include a rationale for the study;
                                  • The current labelling or PM/Prescribing Information for the reference product in lieu of the IB; and
                                  • A completed Quality Overall Summary - Chemical Entities (Clinical Trial Application - Bioavailability Studies) (QOS-CE (CTA-BA)) template, as well as any additional quality information as outlined in the template.

                                  CTA-A and CTA-Notification (CTA-N) filing requirements (refer to sections 2.4 and 2.6, respectively) also apply to comparative bioavailability studies.

                                  2.4 Clinical Trial Application-Amendments (CTA-As)

                                  CTA-As are applications in which a sponsor proposes information to support changes to a previously authorized application [C.05.008]. CTA-As are required for changes to clinical trial drug supplies that affect the quality or safety of the drug, changes to an authorized protocol that alter the risk to clinical trial subjects, or both.

                                  CTA-As must be authorized by Health Canada prior to implementation of the changes [C.05.008]. However, 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 clinical trial subjects or other persons, the sponsor may immediately make the amendment without prior review by Health Canada. Sponsors must notify Health Canada of this change, provide the relevant rationale in support of the immediate implementation and file a CTA-A that clearly identifies the change and the rationale for immediate implementation of the change within 15 days after the date of implementation of the amendment [C.05.008(4)].

                                  Amendments submitted when the CTA is under review will not be accepted. Where a sponsor wishes to make changes to the CTA under review, the sponsor should withdraw the active CTA and submit the amendment as a new CTA.

                                  2.4.1 Clinical Trial Application-Amendment (CTA-A): Clinical

                                  Sponsors are required to file CTA-As for changes to the protocol made after the original CTA that will impact on the safety of the subjects or will affect the analysis and the interpretation of the safety and efficacy of the drug(s) under investigation. As per section C.05.008(2), a CTA-A must be filed when the proposed amendments to the protocol:

                                  1. Affect the selection, assessment, or dismissal of a clinical trial subject;
                                  2. Affect the evaluation of the clinical efficacy of the drug;
                                  3. Alter the risk to the health of a clinical trial subject;
                                  4. Affect the safety evaluation of the drug; or
                                  5. Extend the duration of the treatment.

                                  Examples of protocol changes that require a CTA-A are provided below to aid in determining whether a CTA-A should be filed. These examples are not all inclusive. When in doubt of whether a CTA-A is warranted sponsors should contact the corresponding Directorate.

                                  Clinical Amendments

                                  Examples include, but are not limited to:

                                  1. Criteria, tests or procedures required to select or dismiss a clinical trial subject. These include changes to eligibility criteria, tests or procedures for selecting the study population, as well as tests, procedures, or criteria for dismissing clinical trial subjects prematurely or at the end of the trial;
                                  2. Criteria, tests or procedures required for the ongoing assessment of clinical trial subjects, including assessment of safety, or evaluation of safety and efficacy. This includes protocol changes as a result of serious unexpected ADRs;
                                  3. Study design, study population, duration of use, objectives, or hypotheses, including adding or discontinuing a study arm that was not included as a provision in the original CTA protocol;
                                  4. Changes in the primary efficacy endpoint(s), important secondary efficacy endpoints [for example (e.g.), those that could be used in support of a marketing application], safety endpoints, sample size estimation, or addition of interim analyses that will affect the analysis and interpretation of the study results;
                                  5. Dose level, dosage schedule, or treatment duration;
                                  6. Changes to the post-treatment follow-up period that may affect the safety evaluation of the drug.
                                  7. Adding or removing a concomitant medication, which may impact on the analysis of efficacy or increase the risk to clinical trial subjects;
                                  8. Criteria for expedited reporting of serious, unexpected adverse drug reactions;
                                  9. Increases in blood volume, changes in procedures, enrolling additional subjects in PK studies or confirmatory testing in PK studies that were not specified in the original CTA protocol; and/or
                                  10. Aspects of the conduct of the study that may increase the risk to the health of clinical trial subjects.

                                  Protocol changes should be reflected in a revised ICF, as applicable. Additionally, new information related to the safety of the drug may affect a subject's decision to participate in the trial, and should be added to the risks section of the ICF. An updated copy of the ICF should be included in the CTA-A, as applicable, with changes clearly indicated (annotated). Refer to section 2.4.3 for additional information on filing a Clinical CTA-A.

                                  Protocol changes that extend the duration of the clinical trial pertain to extensions in the treatment period of individual study subjects. All protocol changes that involve an extension in treatment duration or treatment period require filing of a CTA-A; such CTA-As must be accompanied by an IB or equivalent information to support the extension in treatment duration. Changes in the projected duration of the entire trial, not impacting individual patients' duration of treatment, are normally not considered to require a CTA-A.

                                  2.4.2 Clinical Trial Application-Amendments (CTA-A) and Clinical Trial Application- Notification (CTA-N): Quality (Chemistry and Manufacturing)

                                  Sponsors must file a CTA-A or CTA-N to a previously authorized application when changes that may affect the quality or safety of the clinical trial drug supplies are proposed. Changes to the Quality summary subsections of Module 2 and Module 3 (if applicable) including, but not limited to those listed in Tables 2 to 5 below, warrant the filing of a CTA-A or a CTA-N.

                                  a) For Biologics and Radiopharmaceuticals

                                  A list of all proposed quality changes from the authorized application should be provided in the cover letter.

                                  It should be noted that for Biologics and Radiopharmaceuticals, differences in manufacturing strategies can lead to the production of a novel drug product requiring both non clinical and clinical data to support its use and are considered beyond the scope of an authorized CTA. In such cases, a new CTA is required. Examples of differences in manufacturing strategies include, but are not limited to:

                                  1. Change in the source of drug substance (e.g., from a fermentation process to transgenic milk);
                                  2. Change in the host cells used to express the same coding sequence;
                                  3. Change in the strain of virus used in manufacturing a vaccine;
                                  4. Change in the strain of oncolytic virus used in cancer treatment;
                                  5. Change in the animal source of an immune globulin (e.g., from rabbit to sheep);
                                  6. Change in the source of a radionuclide (e.g., from nuclear reactor to cyclotron or linear accelerator) for labelling kits;
                                  7. Change in the source of the parent radionuclide (e.g., from nuclear reactor to cyclotron or linear accelerator) used in a generator;
                                  8. Change in the design, structure and operation of a radionuclidic generator.

                                  For additional guidance regarding the classification of a quality change, sponsors are encouraged to consult with BGTD.

                                  For a product commercially available and used in clinical trials for which a quality change has been made according to the Post-NOC Changes Guidance document, supporting data are not required in support of the same change affecting the clinical product. The change can be notified to the BGTD with cross-reference to the approved submission filed for the commercial product. In the situation where a change made to the commercial product has not yet been approved and is affecting the clinical material, a CTA-A or a CTA-N must be submitted according to the tables below. For Level 3 changes made to a biologic/radiopharmaceutical, a CTA-N is not required for the clinical product.

                                  Table 1 footnotes

                                  Table 1 footnote 1

                                  For the manufacture of some radiopharmaceuticals, "critical components" (e.g., F-18 radionuclide used to manufacture F-18-FDG and F-18-NaF) are considered analogous to drug substance (consult BGTD).

                                  Table 3: Drug Product (Biologics and Radiopharmaceuticals)

                                  Type of Change		Submission Type
                                  1. Replacement or addition of a drug product manufacturing site involving:	a. production of a drug product (including primary packaging)	Amendment
                                  	b. secondary packaging	Notification
                                  	c. testing [for example (e.g.), release, stability]	Notification
                                  2. Change in the drug product manufacturing process (e.g., scale-up, changes to the formulation process); change from manual synthesis of positron-emitting radiopharmaceutical to use of Automatic Synthesis Unit (ASU) or change in type of ASU		Amendment
                                  3. Deletion of a drug product manufacturer / manufacturing site, primary or secondary packaging site or testing site		Notification
                                  4. Change in the specifications for the drug product, involving:	a. deletion or replacement of a test, relaxation of an acceptance criterion or addition of a test for a new impurity	Amendment
                                  	b. addition of a test (other than a test for new impurity) or tightening of an acceptance criterion	Notification
                                  5. Change in the shelf life for the drug product, involving:	a. (i) Extension - if the approved shelf life is less than or equal to 18 months	Amendment
                                  	a. (ii) Extension - if the approved shelf life is more than 18 months	Notification
                                  	b. Reduction (due to stability concerns)	Amendment
                                  6. Change in the storage conditions for the drug product		Amendment
                                  7. Changes in final product dosage form (e.g., liquid to lyophilized formulation)		Amendment
                                  8. Changes in final product strength		Amendment
                                  9. Change in diluent, involving replacement or addition of a diluent for a lyophilized powder or concentrated solution by a diluent which is commercially available in Canada, is water for injection (WFI) or a salt solution, and after reconstitution, there is no change in the drug product specifications outside of the approved ranges.		Notification
                                  10. Change in radiolytic protective agent or antioxidant		Amendment

                                  b) For Pharmaceuticals:

                                  For a product commercially available and used in clinical trials for which a quality change has been made according to the Post-NOC Changes Guidance, supporting data are not required in support of the same change affecting the clinical product. The change can be notified to the TPD with cross-reference to the approved submission filed for the commercial product. In the situation where a change made to the commercial product has not yet been approved and is affecting the clinical material, a CTA-A or a CTA-N must be submitted according to the table below.

                                  Table 4: Drug Substance (Pharmaceuticals)

                                  Type of Change		Submission Type
                                  1. Replacement or addition of a manufacturing site involving:	a. production of drug substance	Amendment
                                  	b. testing [for example (e.g.), release, stability]	Notification
                                  2. Change in the manufacturing process for the drug substance intermediate or starting material (e.g., reaction conditions, solvents, catalysts, synthetic routes, reagents, etc.)		Amendment
                                  3. Change in the batch size for the drug substance (no impact on quality)		Notification
                                  4. Change in the specification for the drug substance involving test and acceptance criteria:	a. Deletion or replacement of a test, relaxation of an acceptance criterion, or addition of a test for a new impurity	Amendment
                                  	b. addition of a test (other than a test for a new impurity) or tightening of an acceptance criterion	Notification
                                  5. Change in the re-test period (or shelf life) for the drug substance, involving:	a. Extension	Notification
                                  	b. Reduction (due to stability concerns)	Amendment

                                  Table 5: Drug Product (Pharmaceuticals)

                                  Type of Change		Submission Type
                                  1. Addition of a dosage form or strength		Amendment
                                  2. Change in the composition of a dosage form		Amendment
                                  3. Qualitative or quantitative addition, deletion or replacement of a colour or flavour with no negative impact on stability		Notification
                                  4. Change in diluent, involving replacement or addition of a diluent for a lyophilized powder or concentrated solution		Amendment
                                  5. Replacement or addition of a drug product manufacturer / manufacturing site involving:	a. Production of an immediate release drug product (tablet, capsule, liquids, semi-solids) within the same Manufacturer	Notification
                                  	b. Production of an immediate release drug product (tablet, capsule, liquids, semi-solids) to a new Manufacturer	Amendment
                                  	c. Production of a modified release product	Amendment
                                  	d. Production of a sterile drug product	Amendment
                                  	e. Primary packaging (non-sterile products)	Notification
                                  	f. Testing [for example (e.g.), release, stability]	Notification
                                  6. Change in the drug product manufacturing process		Amendment
                                  7. Change in the specification for the drug product tests and acceptance criteria, involving:	a. Deletion or replacement of a test, relaxation of an acceptance criterion, or addition of a test for a new impurity	Amendment
                                  	b. addition of a test (other than a test for a new impurity) or tightening of an acceptance criterion	Notification
                                  8. Change in the shelf life for the drug product, involving:	a. Extension	Notification
                                  	b. Reduction (due to stability concerns)	Amendment
                                  9. Change in the storage conditions for the drug product		Amendment

                                  2.4.3 Filing a Clinical Trial Application-Amendment (CTA-A)

                                  CTA-As should be filed directly to the appropriate Directorate (Appendix 1). The outer label should be clearly labelled with "Clinical Trial Application - Amendment".

                                  For joint reviews, refer to section 2.3.1.1.

                                  2.4.4 Clinical Trial Application-Amendment (CTA-A) Format

                                  Similar to CTAs, CTA-As should be organized and numbered as per the CTD format.

                                  CTA-As should be submitted on electronic media, accompanied by a hard copy cover letter, and be organized in accordance with the current electronic specifications; Guidance Document: Preparation of Drug Regulatory Activities in the "Non-eCTD Electronic-Only" Format.

                                  2.4.4.1 Clinical Amendments

                                  Please refer to section 2.3.2 CTA Format for guidance in completing filing requirements for Clinical CTA-As; subsection 1.4.1 is not applicable.

                                  2.4.4.2 Quality (Chemistry and Manufacturing) Amendments

                                  Please refer to section 2.3.2 CTA Format for guidance in completing filing requirements; subsections 1.2.5.1, 1.2.7, 1.4.1, and 1.7.2 are not applicable.

                                  2.5 Clinical Trial Application (CTA) and Clinical Trial Application-Amendments (CTA-A) Review Process

                                  Health Canada reviews the documents submitted in CTAs and CTA-As to assess the quality of the products and determine that the use of the drug for the purposes of the clinical trial does not endanger the health of clinical trial subjects or other persons, the clinical trial is not contrary to the best interests of a clinical trial subject, and the objectives of the clinical trial may be achieved [C.005.006(1)(b)(ii)]. All CTAs, including those for comparative bioavailability studies, are subject to the 30 day default period from the date of receipt of the completed application as per C.05.005 or C.05.008.

                                  Comparative bioavailability studies that meet the Comparative Bioavailability Trial Application Requirements (section 2.3.3) are targeted to be reviewed within 7 days. Sponsors are reminded that this expedited review process is an administrative target.

                                  An acknowledgement letter will be issued to indicate the start of the review period and to indicate that the Minister is in receipt of a complete application.

                                  This acknowledgement letter will also advise sponsors that if the CTA is authorized, and involves a trial in patients (phase I, II, or III), Health Canada will publish the following information about the clinical trial in Health Canada's publicly accessible database soon after an NOL is issued:

                                  • protocol number
                                  • protocol title
                                  • drug name
                                  • medical condition
                                  • study population
                                  • authorization date
                                  • sponsor name
                                  • Health Canada control number, and
                                  • the start and end date of the clinical trial, if known.

                                  2.5.1 Screening Process

                                  All CTAs and CTA-As will be screened for completeness and if deficiencies are identified at screening, these will be addressed by a Request for Clarification or a Screening Rejection Letter. If the application is considered complete, an acknowledgement letter will be issued to indicate that the 30-day default period commenced on the date of receipt in Health Canada.

                                  2.5.1.1 Requests for Clarification during screening

                                  Requests for Clarification that are issued during screening should be responded to within 2 calendar days.

                                  2.5.1.2 Screening Rejection Letter

                                  A Screening Rejection Letter may be issued when information required under C.05.005 or C.05.008 has not been included in the CTA or CTA-A or responses to Requests for Clarification have not been received in a timely manner. Sponsors will be issued a letter itemizing each deficiency. If the sponsor wishes to resubmit the information and material at a future time, it will be processed as a new CTA or CTA-A, and will be assigned a new control number as per the Management of Drug Submissions Guidance Footnote 6 .

                                  2.5.2 Review process

                                  The sponsor is responsible for resolving issues identified by Health Canada during the review process. Sponsors must provide the requested information within 2 calendar days [C.05.009].

                                  Should the sponsor be unable to provide the requested information within the specified time frame, the submission may be withdrawn and resubmitted without prejudice.

                                  A Not Satisfactory Notice (NSN) may be issued if significant deficiencies are identified during the review of the CTA or CTA-A, or if a timely response to information requested has not been provided. If the sponsor wishes to resubmit the information and material at a future time, it will be processed as a new CTA or CTA-A, and will be assigned a new control number as per the Management of Drug Submissions Guidance.

                                  If the CTA or CTA-A is deemed acceptable, a No Objection Letter (NOL) will be issued within the review period.

                                  2.6 Notifications

                                  Notifications must be provided for changes to CTAs that do not meet the criteria for CTA-As. The changes may be implemented immediately, but Health Canada must be informed in writing, within 15 calendar days of the day of the change [C.05.007]. Information regarding the change should be submitted in the form of a cover letter accompanied by any supporting documentation. This information will be reviewed and added to the file. Notifications should be submitted in accordance with current electronic specifications (see Appendix 2).

                                  Notifications include the following:

                                  1. Changes to the protocol that do not affect the safety of the trial participants and which would not be considered an amendment under section 2.4. Examples include, but are not limited to the following:
                                     1. Minor changes to the inclusion and exclusion criteria, such as laboratory chemistry cut-off values that reflect clinical practice and improve the safety of clinical trial subjects;
                                     2. Increasing the screening period or other administrative changes to accommodate logistical constraints in study conduct that do not affect the safety of the trial participants;
                                     3. Changes to administrative information such as new contact names and numbers and addresses of individuals, organizations, or other entities, involved in the conduct of the trial;
                                     4. Updating the ICF with new safety information that does not require a protocol amendment;
                                     5. Annual Investigator Brochure updates (see section 2.8.5).

                                     2.7 Additional Requirements Prior to Commencing a Clinical Trial

                                     Prior to initiating a clinical trial or implementing an amendment to a clinical trial at a site, the sponsor must ensure that the REB Attestation and Qualified Investigator Undertaking forms have been completed and kept on file by the sponsor, and that the Clinical Trial Site Information form has been filed with Health Canada. For all biologics, the BGTD requires that the lot release information be provided by the CTA sponsor/manufacturer before its use in the trial (see section 2.7.4).

                                     The information required on the Qualified Investigator Undertaking, REB Attestation, HC/SC 3011, and Clinical Trial Site Information Form, is necessary because of differences in signing authority and attestation.

                                     2.7.1 Research Ethics Board Review

                                     Prior to initiating a clinical trial or implementing an amendment to a clinical trial at a site, the proposed trial protocol and ICF must be reviewed and approved by a REB as defined in the Regulations.

                                     The sponsor must:

                                     1. Submit the name of the REB that approved the trial or trial amendment prior to the commencement of the trial or trial amendment at that site (see Clinical Trial Site Information Form);
                                     2. Retain as records a REB Attestation, signed by the REB Chair that approved the protocol or protocol amendment at each site in a manner consistent with GCPs. REBs may wish to use the REB Attestation form provided on Health Canada's website or develop similar documentation that meets the requirements of the Regulations (see additional information below); and
                                     3. Submit information pertaining to the refusal of the protocol for any reason by a REB.

                                     A REB may use its own letter of attestation in lieu of the form provided by Health Canada. If a REB uses its own letter, it should explain how the REB complies with the membership requirements for REBs defined in the Regulations Footnote 7 and must attest to the following 2 points:

                                     • The REB carries out its functions in a manner consistent with GCPs; and
                                     • The REB has reviewed and approved the clinical trial protocol and ICD for the trial which is to be conducted by the qualified investigator named on the attestation for the specified clinical trial site. The approval and the views of the REB have been documented in writing Footnote 8 .

                                     The REB letter does not need to include all the elements contained in PART 1, PART 2 and PART 3 of the Health Canada REB Attestation Form.

                                     If the REB is approving the clinical trial for multiple sites, the sites may be identified by duplicating Part 3 of the REB Attestation as many times as necessary to capture all site addresses approved by the same REB. Only the final page of the REB Attestation would contain the REB representative signature. The additional pages listing multiple clinical trial sites are attached to Parts 1 and 2, and the complete document should be paginated (e.g., 1 of 5, 2 of 5, etc.).

                                     The REB Attestation should not be submitted unless requested by Health Canada but must be available for each clinical trial site as per C.05.012.

                                     2.7.1.1 Refusals

                                     Following regulatory authorization of a CTA or CTA-A, information regarding refusals by other regulatory authorities or REBs should be submitted as a notification. This information will be added to the file.

                                     2.7.2 Qualified Investigators

                                     There must be no more than one (1) qualified investigator at each site. This restriction does not apply to sub-investigators.

                                     Qualified Investigators must complete the Qualified Investigator Undertaking (QIU) or develop similar documentation that meets the requirements of the Regulations [C.05.012(3)(f)].

                                     When the Qualified Investigator is conducting the trial at multiple sites, these sites may be identified by duplicating Part 3 of the QIU form as many times as necessary to capture all site addresses under the responsibility of the same QI. Only the final page of the QIU would contain the QI's signature. The additional pages listing multiple clinical trial sites are attached to Parts 1 and 2, and the complete document should be paginated (e.g., 1 of 5, 2 of 5, etc.).

                                     If there is a change in the Qualified Investigator at a site, a new Clinical Trial Site Information Form must be submitted to Health Canada, and a new QIU form must be maintained by the sponsor.

                                     Please note that the QIU form should not be submitted unless requested by Health Canada butmust be maintained by the sponsor as per C.05.012.

                                     2.7.3 Filing of Trial Commencement Information

                                     Prior to commencement of the clinical trial or implementation of a CTA-A, sponsors are required to complete and submit a Clinical Trial Site Information (CTSI) form for each clinical trial site [C.05.006(1)(d)/C.05.008(1)(c)].

                                     A clinical trial site is the location where trial-related activities are conducted, such as the location where the drug is administered or dispensed (directly or by prescription) to the subject and where the subject returns for subsequent assessment. Locations where ancillary medical procedures such as X-rays, magnetic resonance images (MRIs), or blood collections are conducted do not require CTSI forms.

                                     When the Qualified Investigator will be conducting the clinical trial at multiple sites overseen by the same REB, all sites may be identified by duplicating Part 3 of the CTSI form as many times as necessary. The additional pages listing multiple clinical trial sites should be attached to Parts 1 and 2, and the complete document should be paginated (e.g., 1 of 5, 2 of 5, etc.).

                                     Health Canada recognizes that all information requested in the CTSI form (e.g., dates for Boxes 35 and 47) may not be available at the time of submission. Sponsors are reminded that even if this information is not available when filing the CTA or CTA-A, it is required prior to commencement of the trial [C.05.006(1)(d)/C.05.008(1)(c)]. The forms should be submitted to the appropriate review Directorate (refer to Appendix 1).

                                     If any changes are made to the CTSI form, a revised form should be submitted.

                                     2.7.4 Lot Release Information (for Biologics)

                                     All investigational biologic drug product lots to be used in a clinical trial are subject to the Lot Release requirements as outlined in Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

                                     With the exception of prophylatic vaccines, the BGTD will require that the CTA sponsor/manufacturer provide the Directorate, before its use in the trial, with the following information via the "Fax-back" process on the final product and bulk product of their material:

                                     1. Lot numbers of materials being used during the trial and any Batch Identification Numbers that are assigned to lots received from elsewhere [that is (i.e.) all numbers associated with a particular lot]; and
                                     2. 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.

                                     For investigational prophylatic vaccines lot release for use in an authorized CTA, the BGTD will require the submission of testing protocols and/or Certificates of Analysis before its use in the trial. The BGTD issues a formal release letter for use of a prophylatic vaccine lot in a clinical trial. The lot must not be used until such time as it has been released by the BGTD.

                                     2.7.5 Importation of Clinical Trial Drugs

                                     For sponsors who wish to import a drug into Canada for the purpose of a clinical trial, a No Objection Letter should be provided at the time of importation to facilitate shipment and to demonstrate compliance with section C.05.006 or section C.05.008 of the Regulations.

                                     Any delegation of importation duties to third parties should be clearly articulated through written agreement. Systems must be in place for the monitoring, storage conditions, transportation and disposition of the drug to be imported. Regardless of the agreements in place for the importation of the product, the sponsor ultimately bears responsibility for the correct handling and storage of the product to be used in the clinical trial.

                                     If clinical trial drugs are to be imported, importers should be authorized by the sponsor. This information should be included in Appendix 1 of the HC/SC 3011 form and should be provided at the time of application. If the drugs will be shipped to individual clinical trial sites, Appendix 1 may be replicated as many times as necessary to capture all sites. A copy of Appendix 1 should be included with the shipment along with the NOL.

                                     2.7.5.1 Importation of Additional Drugs

                                     If additional drugs (e.g., comparator, concomitant and rescue medications) are being imported for the purpose of the clinical trial, a list of these drugs should be provided in section 1.2.3 of the CTA, using the Summary of Additional Drugs Form (SOAD) found in Appendix 4 of this guidance. The SOAD may be replicated to capture all additional drugs to be imported. This is to facilitate processing at the Port of Entry.

                                     If this information is not known at the time of application, or changes after the CTA is authorized, sponsors may submit a SOAD to the appropriate review directorate as a CTA-Notification.

                                     The SOAD will be signed by a Health Canada Official and returned to the sponsor. Both a copy of the signed form as well as the NOL (and Appendix 1 of the HC/SC 3011 form, if applicable) should be included with the shipment to facilitate processing at the Port of Entry.

                                     For drugs listed on the SOAD, note the following:

                                     1. Pharmaceuticals: Should have a marketed Canadian equivalent and be sourced from an acceptable foreign jurisdiction (i.e. Australia, Switzerland, Japan, European Union, United States). These drugs should also be found in the protocol.
                                     2. Biologics and Radiopharmaceuticals: For comparators or concomitant drugs marketed in Canada but sourced from a foreign jurisdiction, a rationale should be provided demonstrating the equivalence with the marketed product in Canada. These drugs should also be found in the protocol.

                                     Drugs that are not authorized for marketing in Canada (e.g., new drugs) or products intended to be used outside of the equivalent Canadian label are considered investigational and would not qualify for inclusion on the SOAD, but should be included on the HC/SC Form 3011 at the time of filing. Refer to section 2.3 of this guidance for filing requirements.

                                     2.8 Post-Authorization Requirements

                                     2.8.1 Premature Discontinuation of a 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 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 [C.05.015].

                                     This notification should include:

                                     1. Detailed reason(s) for this action;
                                     2. Description of the impact on the proposed or ongoing trials conducted in Canada;
                                     3. Confirmation that all qualified investigators 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;
                                     4. Confirmation that the sale or importation of the drug to the discontinued sites has been stopped; and
                                     5. 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 or clinical trial site outside Canada, for which there are ongoing trials with the drug in Canada, should also be submitted to the appropriate Directorate if such discontinuation was carried out for safety reasons. The Notification should include information such as that specified under 2.8.1 a), b), and c) above.

                                     2.8.2. Resumption of a Trial

                                     Under section C.05.015(2) of the Regulations, the sponsor may resume the trial in its entirety or at a site that was previously discontinued if the sponsor submits the following information:

                                     1. 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;
                                     2. 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; and
                                     3. The proposed date of re-initiation of the clinical trial at each clinical trial site.

                                     The above information may be submitted as a CTA-Notification if there are no changes to the study protocol or to the Chemistry and Manufacturing, and the trial may resume accordingly. When there has been a change to the study protocol or to the Chemistry and Manufacturing, the information should be submitted with a CTA-A (see section 2.4). The sponsors may only resume the trial when a No Objection Letter (NOL) has been issued from the appropriate Directorate or when the 30 day default period has passed without an objection. Sponsors should also file a completed CTSI form prior to resumption of the clinical trial.

                                     2.8.3 Study Completion/Site Closures

                                     The sponsor is requested to notify the relevant Directorate(s) (via CTA-Notification) when a clinical trial is completed or a clinical trial site is closed.

                                     Notwithstanding a suspension, cancellation or study closure of a clinical trial in Canada, in its entirety, a study is considered to be completed after the last subject globally completes the "end of study" visit as defined in the protocol. The "end of study visit" is the final visit for study-related tests and procedures, including the capture of any final potential study-related adverse events, and usually occurs some time after the subject has completed/discontinued study drug administration. The "end of study visit" is normally an in-person visit, but for some studies it can also be carried out over the telephone.

                                     Some trials, such as oncology trials, involve long-term follow-up for outcomes (e.g., survival) where the subject or the subject's family will be contacted to determine the outcome in question. However, the trial would not be considered to still be ongoing if all subjects enrolled globally have ceased study-related therapies, tests, and procedures, and have completed the "end of study" visit, including any follow-up for safety.

                                     It should be noted, however, that there may be certain scenarios [e.g., gene therapies, drugs with very long half-lives (i.e., several months)] where a study may be considered to be ongoing well beyond the period of study treatment, i.e., where long-term safety monitoring and reporting would be required in accordance with Division 5. The reporting requirements with regards to such long-term follow-up of safety are normally specified in the study protocol and agreed to between the sponsor and Health Canada prior to the authorization of the clinical trial in Canada.

                                     2.8.4 Safety Reporting Post-No Objection Letter (NOL)

                                     2.8.4.1 Adverse Drug Reactions (ADRs)

                                     During a clinical trial the sponsor is required to inform Health Canada, in an expedited manner, of any serious unexpected adverse drug reaction, in respect of the drug that has occurred inside or outside Canada [C.05.014]:

                                     1. Where it is neither fatal nor life-threatening, within 15 days after becoming aware of the information;
                                     2. Where it is fatal or life-threatening, within 7 days after becoming aware of the information. Within 8 days after having initially informed Health Canada of the fatal or life-threatening ADR, submit as complete a report as possible. Follow-up reports of fatal or life-threatening reactions must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar drugs.

                                     2.8.4.2 Adverse Drug Reactions (ADRs) Reporting Criteria

                                     Each ADR which is subject to expedited reporting to Health Canada should be reported individually in accordance with the data element(s) specified in the Health Canada/ICH Guidance Document E2A: "Clinical Safety Data Management: Definitions and Standards for Expedited Reporting". Expedited reports are required for events that meet all of these three criteria: serious, unexpected and a suspected causal relationship.

                                     1. Serious:
                                        Any untoward medical occurrence that at any dose:
                                        • results in death,
                                        • is life-threatening,
                                        • requires inpatient hospitalisation or prolongation of existing hospitalisation,
                                        • results in persistent or significant disability/incapacity, or
                                        • is a congenital anomaly/birth defect.
                                     2. Expectedness:
                                        An "unexpected" adverse reaction is one in which the nature or severity is not consistent with information in the relevant source document(s), such as the IB or Product Monograph. Until source documents are amended, expedited reporting is required for additional occurrences of the reaction.

                                     • All cases judged by either the reporting health care professional or the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as ADRs and should be reported.
                                     • Concomitantly, adverse reactions that are considered to be unrelated to the study drug by both the investigator and the sponsor should not be reported.

                                     2.8.4.3 How to Report

                                     When submitting an ADR report to Health Canada, a complete ADR Expedited Reporting Summary Form (Form 01-03) and the CIOMS Form should be attached and as applicable be mailed or faxed to:

                                     Biologics and Genetic Therapies Directorate
                                     Biologics and Radiopharmaceuticals
                                     Fax: 613-957-0364

                                     Therapeutic Products Directorate
                                     Pharmaceuticals
                                     Fax: 613-941-2121

                                     2.8.4.4 Submission of Information

                                     Health Canada may request a sponsor, at any time during an ongoing clinical trial, to submit information or records kept under C.05.012 in order to assess the safety of the drug. The safety report could include a line listing of all serious events and/or other expected and unexpected ADRs.

                                     2.8.4.5 Study Endpoints

                                     When a fatal or other serious outcome is the primary efficacy endpoint in a clinical trial, the protocol should clearly indicate the serious event(s) that will be treated as disease-related and not subject to expedited reporting.

                                     2.8.4.6 Additional Information

                                     There are situations in addition to the above that may necessitate rapid communication to Health Canada, and appropriate scientific and medical judgment should be applied to each situation. For example, information that might influence the risk-benefit assessment of a drug, or that would be sufficient to consider changes in drug administration, or in the overall conduct of a clinical trial, represent such situations; including:

                                     1. For an "expected" serious ADR, an increase in the rate of occurrence which is judged clinically important;
                                     2. A significant hazard to the patient population, such as lack of efficacy with a drug used in treating a life-threatening disease; and
                                     3. A major safety finding from a newly completed animal study.

                                     This information should be submitted where applicable to either:

                                     Biologics and Genetic Therapies Directorate
                                     Biologics and Radiopharmaceuticals
                                     Fax: 613-957-0364

                                     Office of Clinical Trials, Therapeutic Products Directorate
                                     Pharmaceuticals
                                     Fax: 613-954-4474

                                     Sponsors should refer to ICH Guidance Documents E6: Guideline for Good Clinical Practice and E2A: Clinical Safety Data Management for safety reporting requirements to Qualified Investigator(s) and their Research Ethics Board(s).

                                     2.8.5 Updated Investigator's Brochure

                                     In accordance with ICH GCP, the IB, including all safety information and global status, should be reviewed at least annually and revised as necessary. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. If the sponsor is planning to submit a CTA, or planning or required to submit a CTA-A or CTA-N, the updated IB should be submitted with the application. Otherwise, the updated IB should be submitted separately as a CTA-N, and include a statement confirming that the protocol and/or ICF of all ongoing trials do not require changes as a result of the updated IB. In all cases, the updated IB should be accompanied by a list of changes that clearly describes the sections that have changed, including a rationale for each change.

                                     2.8.6 Records related to Clinical Trial Applications (CTAs) and Clinical Trial Application-Amendments (CTA-As)

                                     As required in Part C, Division 5 of the Food and Drug Regulations [C.05.012]:

                                     1. The sponsor shall record, handle and store all information in respect of a clinical trial in a way that allows its complete and accurate reporting as well as its interpretation and verification.
                                     2. The sponsor shall maintain complete and accurate records to establish that the clinical trial is conducted in accordance with GCPs and the Regulations.
                                     3. The sponsor shall maintain complete and accurate records in respect of the use of a drug in a clinical trial, including:
                                        1. a copy of all versions of the IB for the drug;
                                        2. records respecting each change made to the IB, including the rationale for each change and documentation that supports each change;
                                        3. records respecting all adverse events in respect of the drug that have occurred inside or outside Canada, including information that specifies the indication for use and the dosage form of the drug at the time of the adverse event;
                                        4. records respecting the enrolment of clinical trial subjects, including information sufficient to enable all clinical trial subjects to be identified and contacted in the event that the sale of the drug may endanger the health of the clinical trial subjects or other persons;
                                        5. records respecting the shipment, receipt, disposition, return and destruction of the drug;
                                        6. for each clinical trial site, an undertaking from the qualified investigator that is signed and dated by the qualified investigator prior to the commencement of his or her responsibilities in respect of the clinical trial, that states that:
                                           • the qualified investigator will conduct the clinical trial in accordance with GCPs, and
                                           • the qualified investigator will immediately, on discontinuance of the clinical trial by the sponsor, in its entirety or at a clinical trial site, inform both the clinical trial subjects and the REB of the discontinuance, provide them with the reasons for the discontinuance and advise them in writing of any potential risks to the health of clinical trial subjects or other persons;
                                        7. for each clinical trial site, a copy of the protocol, ICF and any amendment to the protocol or ICF that have been approved by the REB for that clinical trial site; and
                                        8. for each clinical trial site, an attestation, signed and dated by the REB for that clinical trial site, stating that it has reviewed and approved the protocol and ICF and that the board carries out its functions in a manner consistent with GCPs.

                                        Records must be made available to the relevant Directorate within 2 days of a request if there is a concern regarding the use of the drug for the purposes of a clinical trial and a risk to health of the subjects involved in that trial. In any other case, records must be provided within 7 days of a request [C.05.013].

                                        2.8.7 Labelling Requirements

                                        Labelling of clinical trial drug supplies must conform with section C.05.011 of the Food and Drug Regulations. Labels should not be submitted unless requested by the appropriate Directorate.

                                        As required in Part C, Division 5 of the Food and Drug Regulations [C.05.011]:

                                        Despite any other provision of these Regulations respecting labelling, the sponsor shall ensure that the drug bears a label that sets out the following information in both official languages:

                                        1. a statement indicating that the drug is an investigational drug to be used only by a qualified investigator;
                                        2. the name, number or identifying mark of the drug;
                                        3. the expiration date of the drug;
                                        4. the recommended storage conditions for the drug;
                                        5. the lot number of the drug;
                                        6. the name and address of the sponsor;
                                        7. the protocol code or identification; and
                                        8. if the drug is a radiopharmaceutical as defined in section C.03.201, the information required by subparagraph C.03.202(1)(b)(vi).

                                        Appendix 1: Relevant Addresses

                                        Pharmaceutical Drugs

                                        Office of Clinical Trials
                                        Therapeutic Products Directorate
                                        5th Floor, Holland Cross, Tower B
                                        Address Locator: 3105A
                                        1600 Scott Street
                                        Ottawa, Ontario
                                        Canada
                                        K1A 0K9

                                        Clinical Trial Notifications Email:
                                        OCT_BEC_CTA-N-DEC@hc-sc.gc.ca

                                        Clinical Trial Site Information Forms Email:
                                        clinical.trials.site@hc-sc.gc.ca

                                        Biologic and Radiopharmaceutical Drugs

                                        Office of Regulatory Affairs
                                        Biologics and Genetic Therapies Directorate
                                        100 Eglantine Driveway,
                                        Address Locator: 0601C
                                        Ottawa, Ontario
                                        Canada
                                        K1A 0K9

                                        General Enquiries:
                                        Email: BGTD_ORA@hc-sc.gc.ca

                                        Clinical Trial Notifications Email:
                                        BGTDPBTG.CTANDEC@hc-sc.gc.ca

                                        Clinical Trial Site Information Forms Email:
                                        BGTDPBTG.CTSIFILEC@hc-sc.gc.ca

                                        Appendix 2: Useful Internet Websites

                                        • Best Practices for Health Research Involving Children and Adolescents
                                        • Bioavailability and Bioequivalence
                                        • Biologics and Genetic Therapies Directorate
                                        • Clinical Trials for Natural Health Products
                                        • Clinical Trials Regulatory Review: Targeted Measures for a Strengthened Framework
                                        • Good Clinical Practices
                                        • Health Canada
                                        • Health Products and Food Branch
                                        • International Conference on Harmonisation
                                        • Medical Devices Guidance Documents
                                        • Review of the 2001 Clinical Trials Regulatory Framework: Part C, Division 5 of the Food and Drug Regulations (Drugs for Clinical Trials Involving Human Subjects)
                                        • Therapeutic Products Directorate
                                        • Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2nd edition)

                                        Application Preparation

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

                                        • ADR Expedited Reporting Summary for ADRs Occurring During Clinical Trials
                                        • Application Form For An Exemption To Use A Controlled Substance For Scientific Purposes
                                        • CIOMS Form I
                                        • Clinical Trial Manual
                                        • Clinical Trial Site Information Form
                                        • Draft Guidance Document: Applications for Medical Device Investigational Testing Authorizations [2017-10-06]
                                        • E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting - Reminder for Sponsors
                                        • Guidance Document: Preparation of Drug Regulatory Activities in the "Non-eCTD Electronic-Only" Format
                                        • Guidance Document - Development Safety Update Report (DSUR) - International Conference on Harmonisation (ICH) Topic E2F
                                        • Guidance Document - Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals
                                        • Guidance Document Non-Clinical Laboratory Study Data Supporting Drug Product Applications and Submissions: Adherence to Good Laboratory Practice
                                        • Guidance for Industry: Management of Drug Submissions
                                        • Guidance for Records Related to Clinical Trials (GUIDE-0068)
                                        • Guidance on Combination Products
                                        • Importing and exporting health products for commercial use (GUI-0117)
                                        • Health Canada 3011: Drug Submission Application Form for Human, Veterinary, Disinfectant Drugs and Clinical Trial Application/Attestation
                                        • Notice: Preparation of Clinical Trial Regulatory Activities in the "Non-eCTD Electronic-Only"
                                        • Guidance Document - Development Safety Update Report (DSUR) - International Conference on Harmonisation (ICH) Topic E2F
                                        • Post-Notice of Compliance (NOC) Changes: Framework Document
                                        • Post-Notice of Compliance (NOC) Changes: Quality Document
                                        • Preparation of an Application for Investigational Testing - In Vitro Diagnostic Devices (IVDD) V.3 [1999-02-22]
                                        • Protocol Safety and Efficacy Assessment Template - Clinical Trial Application
                                        • Quality Overall Summary - Chemical Entities (Clinical Trial Applications Phase I) (QOS-CE (CTA - Phase I)) [2008-11-12]
                                        • Quality Overall Summary - Chemical Entities (Clinical Trial Applications - Phase II) (QOS-CE (CTA - Phase II)) [2008-11-12]
                                        • Quality Overall Summary - Chemical Entities (Clinical Trial Applications - Phase III) (QOS-CE (CTA - Phase III)) [2008-11-12]
                                        • Research Ethics Board Attestation

                                        For Biologics

                                        Guidance Documents:

                                        • Guidance for Industry Preparation of the Quality Information for Drug Submissions in the CTD Format: Biotherapeutic and Blood Products
                                        • Guidance Document Harmonized Requirements for the Licensing of Vaccines and Guidelines for the Preparation of an Application, Date: 2016-06-16
                                        • Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs, Date: 2005-06-01

                                        For Radiopharmaceuticals/Generators

                                        Guidance Document:

                                        For Radiopharmaceuticals

                                        Templates:

                                        • Blank QIS-R template
                                          • Email: BGTD_ORA@hc-sc.gc.ca

                                          Appendix 3: Outline of a Clinical Trial Application / Clinical Trial Application-Amendment (CTA / CTA-A)

                                          • Module 1 Administrative and Product Information
                                            • 1.0 Correspondence
                                              • 1.0.1 Cover letter
                                              • 1.0.5 Meeting Information
                                              • 1.2.1 Application Forms
                                              • 1.2.3 Certification and Attestation Forms
                                              • 1.2.5 Compliance and Site Information
                                                • 1.2.5.1 Clinical Trial Site Information Form
                                                • 1.3.4 Investigator's Brochure
                                                • 1.4.1 Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA)
                                                • 1.7.1 Protocol
                                                • 1.7.2 Informed Consent Forms
                                                • 1.7.3 Canadian Research Ethics Board (REB) Refusals
                                                • 1.7.4 Information on Prior-related Applications
                                                • 2.1 Table of Contents
                                                • 2.3 Quality Overall Summary (QOS)
                                                • 3.1 Table of Contents of Module 3
                                                • 3.2 Body of Data
                                                • 3.3 Literature References

                                                Appendix 4: Summary of Additional Drugs to Be Imported for a Clinical Trial

                                                This HTML document is not a form. Its purpose is to display the information as found on the form for viewing purposes only. If you wish to use the form, you must use the alternate format below.

                                                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.

                                                Summary of Additional Drugs to be Imported for a Clinical Trial

                                                Clinical Protocol Number (must be assigned)
                                                Clinical Trial Protocol Title

                                                Name of the drug product as stated on the marketed label:
                                                Name of the country where the product is sourced:
                                                Name of the company as stated on the marketed label:
                                                Common name of the active ingredient:
                                                Dosage form:
                                                Strength:

                                                This table may be replicated as many times as necessary to cover all additional medicinal products to be imported.

                                                I, the undersigned, certify that the information and material included in this appendix is accurate and complete.

                                                Name of Authorized Signing Official:
                                                Signature:
                                                Date (YYYY/MM/DD):
                                                Title:
                                                Telephone:
                                                Fax:
                                                Name of Company to which the Authorized Signing Official Belongs:

                                                For Health Canada Use Only

                                                Date Received (YYYY/MM/DD):
                                                Name of Signing Official:
                                                Title:
                                                DSTS Control Number:
                                                Telephone:
                                                Fax:
                                                Signature:
                                                Date Sent (YYYY/MM/DD):

                                                Footnote 1

                                                Before commencement of a trial, the sponsor must ensure that Health Canada and the Research Ethics Board have raised no objections to the Clinical Trial Application.

                                                For further guidance regarding the informed consent process, please see International Conference on Harmonisation E6, in particular section 4.8, and the current version of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, in particular chapter 3.

                                                Single copy is acceptable provided the application is submitted in accordance with current electronic specifications.

                                                Should be submitted in duplicate

                                                Should be submitted in duplicate; the sponsor will be contacted if further information is needed to complete the application pursuant to s. 66 of the Natural Health Products Regulations.

                                                Management of Drug Submissions Guidance 2011/04/01 is located on the Health Canada website.

                                                See definition in C.05.001.

                                                As per the record keeping requirement in C.05.012(3)(h).