Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (GUI-0100)

Disclaimer:

This document does not constitute part of the Food and Drugs Act (the Act) or its regulations and in the event of any inconsistency or conflict between the Act or regulations and this document, the Act or the regulations take precedence. This document is an administrative document that is intended to facilitate compliance by the regulated party with the Act, the regulations and the applicable administrative policies.

Table of contents

• About this document
  • 1. Purpose
  • 2. Scope
  • 3. Introduction
  • 4. Guidance for implementation
  • 5. Regulations and Interpretations
    • 5.1. Interpretation
      • C.05.001
    • 5.2. Application
      • C.05.002
    • 5.3. Prohibition
      • C.05.003
    • 5.4. General
      • C.05.004
    • 5.5. Application for Authorization
      • C.05.005
    • 5.6. Authorization
      • C.05.006
    • 5.7. Notification
      • C.05.007
    • 5.8. Amendment
      • C.05.008
    • 5.9. Additional Information and Samples
      • C.05.009
    • 5.10. Good Clinical Practices
      • C.05.010
      • C.05.010(a)
      • C.05.010(b)
      • C.05.010(c)
      • C.05.010(d)
      • C.05.010(e)
      • C.05.010(f)
      • C.05.010(g)
      • C.05.010(h)
      • C.05.010(i)
      • C.05.010(j)
    • 5.11. Labelling
      • C.05.011
    • 5.12. Records
      • C.05.012
    • 5.13. Submission of Information and Samples
      • C.05.013
    • 5.14. Serious Unexpected Adverse Drug Reaction Reporting
      • C.05.014
    • 5.15. Discontinuance of a Clinical Trial
      • C.05.015
    • 5.16. Suspension and Cancellation (Intent to Suspend)
      • C.05.016
    • 5.17. Suspension and Cancellation
      • C.05.017
• Appendices
  • Appendix A - Glossary
    • Acronyms and abbreviations
    • Terms
  • Appendix B - References
    • Law and Regulations
    • Health Canada Guidances and Documents
    • Other Guidances and Policies

Details and history

Published:
August 20, 2019
Updated:
March 14, 2023, version 2
Consulted:
December 15, 2017 to April 15, 2018 (see the consultation)
Part of topic:
Interpretation of Part C, Division 5 of the Food and Drug Regulations

The following table shows the three (3) types of icons used in this document, and the way they are intended to be used:

Important	Information	Tip
Key or cautionary information for people to know.	Supplementary information like quotes and legal references.	Things for people to do or understand and examples.

About this document

1. Purpose

This guidance document will help anyone who is involved in the conduct of clinical trials of drugs in humans to understand and comply with Part C, Division 5 of the Food and Drug Regulations (the Regulations).

2. Scope

This guidance document applies to you if you are a party involved in the conduct of clinical trials of drugs in human subjects in Canada.

The Regulations clearly establish that the sponsor has the overall responsibility for conducting a clinical trial involving drugs in human subjects. In Canada, a sponsor may transfer responsibility for any or all trial-related duties to other parties. However, sponsors remain accountable in all respects for the trial's data quality and integrity, and subject safety.

The Regulations do not differentiate between a commercial and a non-commercial sponsor (e.g. Sponsor-Investigator) and as such, the same requirements apply.

This guidance document covers the following clinical trials of drugs conducted in humans in Canada:

• Phase I to IV
• commercial or academic
• ongoing or completed
• clinical trials involving pharmaceuticals, biologics, gene therapies, cell therapies, blood products, vaccines and radiopharmaceuticals for human use

This document does not apply to:

• clinical trials involving medical devices
• clinical trials involving natural health products (NHPs)
• observational studies, which do not include drug intervention

3. Introduction

The legislative authority for the Food and Drug Regulations, Part C, Division 5 "Drugs for Clinical Trials Involving Human Subjects" is the Food and Drugs Act (the Act). The Regulations came into force on September 1, 2001 and set out the federal requirements for the sale and importation of drugs used in human clinical trials in Canada, and include the requirement to comply with good clinical practices (GCP). Health Canada does not have jurisdiction over the professional standards regarding practice of medicine, which are enforced by the provincial colleges of physicians.

Part C, Division 5 of the Regulations provides for flexibility to follow international GCP standards in order to satisfy the requirements of the Regulations.

In May 1997, Health Canada adopted the International Conference on Harmonization (ICH) Guidance E6(R1): Good Clinical Practice Consolidated Guideline (ICH E6). GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Adherence to this guideline provides public assurance that the rights, safety and well-being of trial subjects are protected and that the clinical trial data are credible.

Since the finalisation of the ICH GCP Guideline in 1996, the scale, complexity, and cost of clinical trials have increased. Evolutions in technology and risk management processes offer new opportunities to focus on relevant activities resulting in increasing the rigour of clinical trials. ICH E6(R1) was amended in November 2016 to ICH E6(R2) to:

• encourage sponsors to implement improved oversight and management of clinical trials, while continuing to ensure protection of human subjects participating in trials and clinical trial data integrity
• update standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency.

The ICH guidance Integrated Addendum to E6(R1): Guideline for Good Clinical Practice E6(R2) was fully adopted by Health Canada as of April 3, 2019.

It is important to note that local regulations in ICH regions can exceed the requirements of ICH E6. As such, ICH guidelines should be used in conjunction with the relevant federal regulations, guidance documents and any other regional, institutional or local requirements.

Health Canada has recognized a need to provide guidance in the interpretation of Part C, Division 5 of the Regulations, and specifically in terms of its relationship to ICH E6. This guidance document is intended to fulfill this need, as well as to provide additional guidance where is necessary or when ICH E6 does not apply.

Compliance with the Regulations and ICH E6 will further promote the protection of subjects as well as ensure the integrity of the data generated by the trial, whether it is for use in academic publications, or to support new, supplementary or abbreviated drug submissions (NDS, SNDS, ANDS).

For detailed guidance on clinical trial applications (CTA) and amendments (CTA-A), you should refer to Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications and if applicable, to Guidance Document: Preparation of Clinical Trial Applications for use of Cell Therapy Products in Humans.

4. Guidance for implementation

Guidance on interpretation of Part C, Division 5 of the Regulations is provided in this document. In interpreting the Regulations, ICH E6 should be used in conjunction with the Act, the Regulations, and any relevant policies and guidelines.

In this document, where guidance to a specific regulation can be found in ICH E6, the section in ICH E6 is noted. If necessary, or where ICH E6 is not applicable, additional guidance is provided or other guidance documents are referenced.

At all times, where the Regulations exceed the guidance set out in this document or those in ICH E6, the Regulations take precedence.

5. Regulations and Interpretations

For each section below, the exact text from Part C, Division 5 of the Food and Drug Regulations is provided first. This is followed by Health Canada's interpretation (what should be done in order to be compliant).

5.1 Interpretation

C.05.001

5.2 Application

C.05.002

Interpretation

The Regulations apply to the sale and importation of drugs to be used in clinical trials involving humans that are conducted in Canada. As per section C.05.002, no person can sell or import (refer to Glossary (terms) for definitions of sell and import) a drug for the purposes of a clinical trial involving humans unless authorized (refer to section 5.6 Authorization). For Phase IV clinical trials, limited provisions of Part C, Division 5 apply which are set out in subsection C.05.002(2) and described below.

In accordance with subsection C.05.002(2), the sponsor of a Phase IV clinical trial does not have to file a clinical trial application (CTA) for importation and/or sale of the study drug. However, the following does apply:

• the person selling and/or importing the trial drug must be authorized under Part C, Division 5 [C.05.003(a)] (refer to next bullet below)
• a new drug has been issued a NOC [C.05.006(2)(a)] or a drug, other than a new drug, has been assigned a DIN [C.05.006(2)(b)], and the clinical trial is in respect of a purpose or condition of use for which the NOC was issued / DIN was assigned
• the sponsor cannot sell or import a trial drug during a period of suspension or cancellation of the trial [C.05.006(3)]
• the trial has to be conducted according to GCP [C.05.010 (a) to (i)]
• the drug must be labeled according to the Regulations (C.05.011)
• the sponsor must comply with records requirements referenced in this Division [C.05.012, with the exception of C.05.012(3)(e)]
• the criteria for submission of information and samples to Health Canada (C.05.013)
• the criteria for suspension and cancellation of a trial (C.05.016 and C.05.017)

Where a clinical trial is conducted on a marketed drug in order to test the safety and/or efficacy of the product under new conditions of use (that is, outside the conditions for which it has received a DIN or NOC), the sponsor must file a CTA for authorization to conduct the clinical trial in Canada.

Please refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for detailed guidance on the application process and Phase IV studies classification. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

Inspection of Phase IV Clinical Trials

In general, Health Canada does not focus its inspection activities on Phase IV trials. However, because Phase IV studies are to be conducted in accordance with GCP, which includes good manufacturing practices (GMP) requirements, they may be subject to inspection.

5.3 Prohibition

C.05.003

Interpretation

Drugs that are sold and/or imported for the purpose of a clinical trial do not have to meet the regulatory requirements for a DIN (C.01.014) or a NOC (C.08.002 and C.08.003). However, the use of these drugs in a clinical trial (other than Phase IV) must be authorized through the submission of a CTA to Health Canada, including for each CTA-Amendment (CTA-A, see section 5.8 Amendment).

In addition to Part C, Division 5 of the Regulations, the following provisions of Division 1 also apply to any drug sold for a clinical trial whether authorized under C.05.006(1) (CTA) or C.05.006(2) (DIN or NOC for Phase IV):

• disintegration times for drugs in tablet form (C.01.015)
• drugs containing phenacetin in combination with salicylic acid, drugs containing mercury and other ingredients, and drugs described in Schedule C or D to the Act (C.01.036)
• pediatric doses of salicylic acid, acetaminophen and their derivatives and other ingredients (C.01.037 to C.01.039)
• drugs containing chloroform or arsenic (C.01.040)
• use of coloring agents in drug products (C.01.040.2)
• drugs prepared for use in the eye (C.01.064, C.01.065)
• drugs prepared for use through injection or IV (C.01.066, C.01.067)
• instructions for the sale of hypodermic tablets (C.01.070)
• aminopyrine or dipyrone and appropriate warning labels (C.01.131, C.01.133)
• coated tablets containing potassium salts (C.01.134 to C.01.136), and
• distribution of promotional material about chloramphenicol and warning statements (C.01.435)

Importation of Clinical Trial Drugs

The sponsor is the regulated party to whom the authorization to sell and/or import a clinical trial drug is issued. A sponsor who is not based in Canada must have a representative in Canada who is responsible for the import and sale of the drug in Canada and must be able to demonstrate compliance to the applicable regulatory requirements. As per section C.05.005, this person is the sponsor's senior medical or scientific officer residing in Canada who is responsible for providing an attestation with respect to the CTA/CTA-A at the time of filing.

Sponsors should be rigorous in their dealings with contracted third parties, including contract research organizations (CROs), to ensure that sponsor's obligations are met. When third parties have been delegated some of a sponsor's responsibilities, written agreements should be in place to clearly set out the division of responsibilities.

Drugs may be shipped directly from a foreign provider (manufacturer, distributor, etc.) to a clinical trial site in Canada provided that:

1. a No Objection Letter (NOL) has been issued by Health Canada authorizing the importation of the clinical trial material in Phase I-III trials. No such clinical trial drugs should be imported prior to the NOL issuance and the NOL should accompany the package at the time of the importation.
   

   If 30 days have passed and no NOL was obtained, specific requests to import clinical trial drugs should be directed to the Health Product Border Compliance Program at the following generic email account: hc.hpbcp-pcpsf.sc@canada.ca.

2. each party, including individual Canadian clinical trial sites, importing drugs directly (i.e. receiving drug shipment directly from outside of Canada) is identified on Appendix 1 of the Drug Submission Application Form (HC/SC 3011 form) for Phase I-III trials (submitted with application if known at the time or prior to importation at the site). Appendix 1 may be replicated as many times as necessary to capture all importing parties (clinical trial sites or drug depot/central warehouse as appropriate);
3. Clinical Trial Site Information (CTSI) forms for each Canadian site conducting the clinical trial are submitted to Health Canada for Phase I-III trials, prior to the start of the study at the site (also refer to section C.05.010(e) "Clinical Trial Site Information Forms");
4. systems are in place, when appropriate, to monitor the transportation and storage conditions from the foreign source to the various clinical trial sites across Canada;
5. there is documented accountability of the imported drugs used in clinical trials and distributed to various clinical trial sites located in Canada, including the disposition of drugs returned from the clinical trial sites;
6. a written agreement is in place between the sponsor and the qualified investigator (QI) describing their specific responsibilities, and this agreement is available at the clinical trial site; and
7. there is evidence that the drugs used in clinical trials conducted in Canada meet GMP requirements. For example, adequate evidence of GMP compliance would include:
   • certificates of manufacture and certificates of analysis (CoA or batch certificates) for the lots of clinical trial material imported into Canada
   • evidence of approved lot release by a qualified individual.
   For additional information on GMP requirements, refer to the Guidance Document - Annex 13 to the Current Edition of the GMP Guidelines: Drugs Used in Clinical Trials (GUI-0036).

Please refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications and the information available on the Health Canada website in the section entitled Importation and Exportation for detailed guidance on importation of clinical trial drugs, including comparator, concomitant and rescue medications using Summary of Additional Drugs (SOAD) Form.

5.4 General

C.05.004

Interpretation

If a drug or substance is prohibited under the Regulations (refer to section C.05.003), a sponsor may submit a CTA to sell and/or import the drug for use in a clinical trial if the sponsor is able to justify that its use may result in a therapeutic benefit to human subjects. Justification should include scientific evidence that the therapeutic benefits outweigh the risks for that particular drug or substance.

5.5 Application for Authorization

C.05.005

Interpretation

Health Canada Pharmaceutical Drugs Directorate (PDD) and Biologic and Radiopharmaceutical Drugs Directorate (BRDD) are responsible for reviewing the CTAs for authorization to sell or import drugs for the purposes of conducting clinical trials in Canada.

Please refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for detailed guidance on the application process. Additional guidance can be found in the relevant sections of ICH E6, including sections 6 and 7. The relevant Health Canada’s Directorate (PDD or BRDD) should be consulted for further clarification.

5.6 Authorization

C.05.006

Interpretation

In order to sell or import a drug for the purposes of a Phase I-III clinical trial, the sale or importation must be authorized by Health Canada through the submission of a CTA prior to the initiation of the trial or the implementation of the amendment. Sale or importation of a drug for the purposes of a Phase I-III clinical trial is contingent on the following:

1. a CTA must be submitted in accordance with section C.05.005 of these Regulations (see also ICH E6, 5.10)
2. the sponsor should expect to receive a NOL within 30 days of the date of receipt of the complete CTA, indicating that the sponsor may sell or import the drug for the purposes of a clinical trial. However, due to the 30-day default period from the date of receipt of a complete CTA, the sponsor may proceed with the clinical trial after this period without receiving an NOL, provided the REB approval was obtained.
   

   Reasons why sponsor may get a Not Satisfactory Notice (NSN) could include:

   • the information and documents supplied were not provided in accordance with the Regulations
   • insufficient information was provided to enable Health Canada to assess the safety and risks of the drug or the clinical trial
   • based on the assessment of the application or additional information or samples provided on request (C.05.009), Health Canada has reasons to believe the use of the drug:
     • may endanger the health of clinical trial subjects or other persons
     • the clinical trial is not in the best interest of clinical trial subjects
     • the objectives of the clinical trial will not be achieved
3. the sponsor has received, for each clinical trial site, approval from a Research Ethics Board (REB), in respect of the protocol and informed consent referred to in C.05.005(a) and (b)
4. before the sale or importation of the drug to a clinical trial site, the sponsor has submitted a CTSI form (refer to section 5.10) including the following information to Health Canada, if it has not already been submitted at the time of application:
   1. name, address, telephone number, fax number, and electronic mail address of the QI for each clinical trial site [C.05.005(c)(ix)]
   2. name, address, telephone number, fax number and electronic mail address of the REB that approved the protocol and informed consent at each clinical trial site [C.05.005(c)(x)]
   3. name, address, telephone number, fax number and electronic mail address of any REB (in or outside Canada) that has previously refused to approve the protocol, including its reason for doing so and the date on which the refusal was given [C.05.005(d)]
   4. the proposed date for the commencement of the clinical trial at each clinical trial site [C.05.005 (h)]

A sponsor may also not sell or import a drug for the purpose of any clinical trial, including Phase IV clinical trials, if the trial has been suspended or cancelled under either C.05.016 or C.05.017.

Please refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for detailed guidance on the authorization.

5.7 Notification

C.05.007

Interpretation

If a sponsor submits a CTA and has received a NOL, the sponsor may make one or more of the following changes, but the sponsor shall notify Health Canada in writing within 15 calendar days after the date of the change:

1. a change to the chemistry and manufacturing information that does not affect the quality or safety of the drug
2. a change to the protocol that does not alter the risk to the health of a clinical trial subject.

Further to the above, section 5.13.5 of ICH E6 states that:

"If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials".

The impact assessment of this change may require submission of an amendment request to Health Canada instead of a notification. If the change meets the requirements of an amendment to the protocol as described in section C.05.008 (below), the sponsor must submit a CTA-A.

Note that Health Canada's Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications provides numerous examples of notifications. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

5.8 Amendment

C.05.008

Interpretation

Clinical trial application-Amendments (CTA-As) are applications in which a sponsor submits information to support changes to a previously authorized clinical trial. They are required to be submitted when changes are made to the study drug or the protocol that could affect the quality or safety of the study drug, or the risk to clinical trial subjects. Amendments must be authorized by Health Canada prior to implementing the changes.

Prior to implementation of a CTA-A at a site, a qualified investigator should obtain documented approval from the REB (ICH E6, 4.5.2). In addition, sponsors are required to complete and submit a CTSI form for each clinical trial site [C.05.008(1)(c)].

As per subsection C.05.008(4), if a sponsor needs to make an immediate amendment because the clinical trial or use of the drug endangers the trial subjects or other persons, the sponsor may make the amendment without prior review by Health Canada. However, the sponsor must notify Health Canada of the change, and submit a CTA-A within 15 calendar days after the date of implementation of the amendment. Health Canada will issue a new NOL within the 30-day review period.

ICH E6 section 4.5.4 also states that an investigator may deviate from the protocol without prior approval if it is necessary to eliminate an immediate hazard to a trial subject. As soon as possible, the deviation or change, the rationale for the change and, if appropriate, the proposed protocol amendment should be submitted to:

• the REB for review and approval
• the sponsor for agreement, and, if required,
• the regulatory authority (i.e. Health Canada)

Note that Health Canada's Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications provides numerous examples of amendments. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

5.9 Additional Information and Samples

C.05.009

Interpretation

Health Canada may require a sponsor to submit, within two (2) calendar days after receipt of the request, samples of the drug or additional information relevant to the drug or the clinical trial that are necessary to make a determination for issuance of the NOL.

A request for clarification or information may be required if the information and documents submitted in a CTA, or a CTA-A, were insufficient in either of the following ways:

• the information and documents in the application were either not provided in accordance with these Regulations or were insufficient to enable Health Canada to assess the safety and risks of the drug or the clinical trial, or
• based on an assessment of the application or any information or drug samples submitted as additional information Health Canada has reasonable grounds to believe that either:
  • the use of the drug for the purpose of the clinical trial endangers the health of a clinical trial subject or other person,
  • the clinical trial is contrary to the best interests of a clinical trial subject; or
  • the objectives of the clinical trial will not be achieved.

5.10 Good Clinical Practices

C.05.010

Interpretation

The Regulations clearly establish that the sponsor has the overall responsibility for conducting a clinical trial involving drugs in human subjects, including that the clinical trial be conducted in accordance with GCP [C.05.010(a) to (j)].

The ICH guidance Integrated Addendum to E6(R1): Guideline for Good Clinical Practice E6(R2) provides a unified standard on GCP. As a standing member of the ICH, Health Canada is committed to the implementation of ICH guidance. ICH E6(R2) was fully adopted by Health Canada as of April 3, 2019.

C.05.010(a)

Interpretation

The sponsor must ensure that the clinical trial is scientifically sound and clearly described in a protocol.

For clinical trials requiring the filing of a CTA to Health Canada (Phase I-III), compliance with this paragraph is determined at the time of CTA review by the appropriate Directorate (PDD or BRDD) of Health Canada.

C.05.010(b)

Interpretation

The sponsor must ensure that the clinical trial is conducted in accordance with the requirement of the protocol, which has been authorized by Health Canada and approved by REB(s). The site should have a system in place to identify, document, assess and report all the protocol deviations to the sponsor and REB in accordance with the sponsor's and REB's requirements. The sponsor should define and identify the protocol deviations to be reported. It is important to assess the protocol deviations for impact analysis and root cause analysis.

The clinical trial protocol is a study plan. It is designed to ensure that the objectives of the study can be met. In addition, the study protocol standardizes a clinical trial to allow for the external validation and for the generalization of the clinical trial results.

Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki.

C.05.010(c)

Interpretation

The sponsor, whether commercial or academic, is responsible for the establishment of a quality system consisting of documented procedures (standard operating procedures (SOPs), protocol procedures, etc.) in order to assure the quality of every aspect of a clinical trial, in accordance with the Regulations and ICH E6. It is the responsibility of the sponsor to implement a system to manage the quality throughout all stages of the trial process and at all sites.

Sponsors should focus on trial activities essential to the reliability of the results and ensuring human subject protection. Quality management includes the design of efficient clinical trial protocols and tools and procedures for data collection and processing, as well as the collection of information that is essential to decision making (ICH E6, 5.0).

The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected. The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection. Protocols, case report forms (CRFs), and other operational documents should be clear, concise, and consistent (ICH E6, 5.0).

Risk review is a key component to risk-based quality management systems, and Health Canada expects that sponsors will be able to demonstrate that risk control measures are periodically reviewed and remain effective and relevant, taking into account emerging knowledge and experience throughout the trial (ICH E6, 5.0.6).

For additional guidance on risk-based quality management in clinical trials, the sponsor may consult other international guidelines (See Appendix B - References, Other Guidances and Policies).

Quality Assurance and Quality Control

As per section 5.1.1 of ICH E6, the sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and all applicable regulatory requirements.

As part of a quality system, a sponsor is also responsible for securing an agreement from all involved parties to ensure direct access (see ICH E6, 1.21) to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor themselves, and inspection by regulatory authorities, both domestic and foreign (ICH E6, 5.1.2).

It is critical that quality control be applied at each and every stage of data handling to ensure that all data are reliable and have been processed correctly (ICH E6, 5.1.3).

All agreements made by the sponsor with the investigator/institution and any other parties involved with the clinical trial should be in writing as part of the protocol or in a separate agreement (ICH E6, 5.1.4).

Contract Research Organization (CRO)

A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, as per the Regulations. The CRO should implement quality assurance and quality control (ICH E6, 5.2.1).

Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor's contracted CRO(s) (ICH E6, 5.2.2).

Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor (ICH E6, 5.2.3). All references to a sponsor in this guidance document also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor (ICH E6, 5.2.4).

Standard Operating Procedures (SOP)

An SOP may be trial specific or site specific, and may be provided by the site, the institution or the sponsor. As with any quality system documents, there needs to be a mechanism of approval, revision and communication of new and/or revised documents to those parties responsible for the procedures. Health Canada does not require a specific document-type and/or format but there should be documentation that adequately covers all critical study-related activities.

Monitoring and Auditing

Monitoring is essential to assure the quality of every aspect of a clinical trial. Its purpose includes verifying the following:

• that the rights and well-being of human subjects are protected
• that the reported trial data are accurate, complete, and verifiable from source documents
• that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with all applicable regulatory requirements (ICH E6, 5.18.1)

The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in section 5.18.3 of ICH E6 is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g. in the monitoring plan).

In addition to the clear identification and control of risks in the development of an approach, it is also critical to include processes that will be followed to address situations of non-compliance, as well as to identify events which would require either a review or revision of the monitoring plan. Health Canada expects these components to be clearly documented in risk-based monitoring plans.

On-site monitoring is performed at the sites at which the clinical trial is being conducted.

Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g. data managers, biostatisticians).

Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data.

For additional information, refer to the U.S. Food and Drug Administration (FDA) Guidance for Industry - Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring published in 2013.

The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the following:

• the monitoring strategy
• the monitoring responsibilities of all the parties involved
• the various monitoring methods to be used
• the rationale for their use

The plan should also emphasize the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures (ICH E6, 5.18.7).

The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication. Reports of on-site and/or centralized monitoring should be provided to the sponsor (including appropriate management and staff responsible for trial and site oversight) in a timely manner for review and follow up. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. Reporting of centralized monitoring activities should be regular and may be independent from site visits (ICH E6, 5.18.6).

In addition to monitoring, a sponsor may perform audits of trials. An audit is independent of, and separate from, routine monitoring or quality control functions, and is performed to evaluate a trials conduct and compliance with the protocol, SOPs, ICH E6 and applicable regulatory requirements (ICH E6, 5.19.1).

Section 5.20 of ICH E6 states that noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by a QI/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.

If noncompliance that significantly affects or has the potential to significantly affect human subject protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions (ICH E6, 5.20.1).

Equipment and Calibration

Using a risk-based approach, the sponsor should identify critical equipment used in a study and specifications for that equipment. Equipment or measuring devices used to generate critical data (e.g. efficacy and safety endpoints), used for important study-related tasks (e.g. inclusion/exclusion criteria) and/or significantly affecting the safety and well-being of the subjects, as well as data quality and integrity should be considered critical equipment. In addition, if there is a specific level of accuracy that requires a certain equipment type, this may also be considered critical equipment. These examples are provided for guidance and are not exhaustive.

The risk evaluation should be related to the significance of the data in the trial. Any equipment or measuring device used to generate data that is reported on the case report form (CRF) should be assessed by the sponsor, and requirements for range and accuracy should be determined. This requirement may also apply to temperature devices used to monitor storage conditions of the study drug.

The focus should be placed on critical equipment and equipment used solely for the purpose of a clinical trial and unrelated to the delivery of standard-of-care.

The control of risks identified for critical equipment (which may include calibration and/or maintenance) should be reviewed, evaluated, and reported in accordance with the quality management system.

Regardless of the risk-based approach, all equipment used in a study should be calibrated and maintained.

C.05.010(d)

Interpretation

Health Canada's relevant regulations do include certain requirements related to REBs, but Health Canada does not have jurisdiction over how REBs conduct their operations or establish SOPs. The regulatory obligations to obtain the REB approval are the responsibility of the sponsor.

The REB membership is defined in section C.05.001 of the Regulations (refer to Appendix A) and may be reviewed during the inspection, as required.

Health Canada recommends that REBs overseeing clinical trials in Canada operate according to well established and recognized standards such as the ICH E6, the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2 2022), and provincially established standards.

Section 3 of ICH E6 describes the responsibilities, composition and operations of REBs. The responsibility of a REB is to protect the rights, safety, and well-being of all human subjects. An REB should pay special attention to trials that may include vulnerable human subjects (elderly, children, mentally ill, prisoners, etc.). This section also lists the documents that should be provided to an REB in order to obtain ethics approval to conduct a clinical trial.

An REB should review and document a proposed clinical trial within a reasonable time and will document its views in writing, clearly identifying the trial, the documents reviewed and the dates for approval or disapproval (ICH E6, 3.1.2).

When and if approval is given, an REB should conduct periodic reviews of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at a minimum, at least once per year (that is a trial that is considered to be high risk to a human subject will be reviewed more often to ensure that the highest standards are in place to ensure the human subject's safety) (ICH E6, 3.1.4). An REB should follow its established and documented procedures as per ICH E6 section 3.3.

C.05.010(e)

Interpretation

A clinical trial site is the location where trial-related activities are conducted, such as the administration or dispensing of the drug (directly or by prescription) to the subject and where the subject returns for subsequent assessment (see site or trial site definition in Appendix A).

The qualified investigator (QI) is the person who is responsible to the sponsor for the conduct of the trial-related activities at a site (see QI definition in Appendix A).

Delegation Logs

The QI should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties (ICH E6, 4.1.5).

A delegation log has to be legible, adequately completed and clearly identify the names and signatures of key personnel, their key duties, and the start and end dates of those duties. This log can be used as a reference (e.g. by monitors, inspectors), to verify that all personnel delegated trial tasks are appropriately qualified for the tasks they have been delegated.

The delegation log should be completed before commencement of the study and updated as necessary. The QI should sign and date the log prior to a task being delegated. Site personnel should not conduct study specific tasks until the QI has documented the delegation and appropriate training has been completed.

Within the log, a QI may designate other physicians or in some instances other appropriate professionals (PhDs, nurses, optometrists, etc.) to perform critical trial-related procedures and/or to make important trial-related decisions (i.e. sub-investigators). However, the QI is always accountable for the actions and decisions taken.

A QI may also identify 'sub-investigator(s)' (physician or dentist who meets the criteria of a QI) who can, for short absences only, assume the qualified investigator's full responsibilities. It should be well documented who is acting as the QI at any point in time. CTSI and QIU forms are not required to be updated for acting.

When tasks are delegated to a person in charge of other staff (e.g. a nurse manager in charge of nursing staff responsible for the study drug administration, laboratory manager, pharmacist manager, etc.) further sub delegation to individual staff does not need to be documented in the log, provided that evidence of qualification of those individuals is available.

Procedures which are routine (e.g. routine X-ray), or as part of care provided on an ad hoc basis (e.g. emergency room procedures) and are not specific study procedures do not require specific training and delegation from the QI (refer to section C.05.010(g) "Training for clinical research").

Clinical Trial Site Information Forms

Locations where ancillary medical procedures (e.g. imaging, blood collections) are conducted do not require separate CTSI forms. Multiple sites may be identified by duplicating Part 3 of the CTSI form as many times as necessary to capture all site addresses. However, if any changes are made to the CTSI forms (e.g. change of QI) a revised CTSI form should be submitted to Health Canada.

Where the actual dosing of investigational drug(s) occurs, and where the subject returns for subsequent assessments, may affect the CTSIs to be submitted. For example, if the sub-investigators are only doing follow-up visits and the QI is still able to oversee these activities, proper delegation and description of activities at both locations should be sufficient hence, no CTSI form should be filed for the other location.

Please refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for detailed guidance and/or consult the Clinical Trials Frequently Asked Questions (FAQs) for further details and information on QIU and CTSI forms. For further clarifications, contact the appropriate Health Canada Directorate (PDD or BRDD).

C.05.010(f)

Interpretation

The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose (ICH E6, 5.3). As per paragraph C.05.010(f) of the Regulations, the medical care given to subjects, and medical decisions made on behalf of subjects, should always be the responsibility of a qualified physician, or, when appropriate, a qualified dentist (see also ICH E6, 2.7 and 4.3.1).

The sponsor assigns the responsibility of medical care and medical decisions and day-to-day running of the clinical trial site to the QI.

It is recommended that the QI inform a subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed (ICH E6, 4.3.3).

During and following a subject's participation in a trial, the QI should ensure that adequate medical care is provided to a subject for any adverse events (AEs), including clinically significant laboratory values, related to the trial. The QI should inform a subject when medical care is needed for intercurrent illness(es) of which the QI becomes aware (ICH E6, 4.3.2).

Adequate medical oversight of a clinical trial

Every sponsor shall ensure that a clinical trial is conducted in accordance with GCP and shall ensure that at each clinical trial site, medical care and medical decisions, in respect of the clinical trial, are under the supervision of the QI. This means that activities which fall under the purview of medical care must be conducted by qualified, licensed physician or dentist, within their scope of practice/expertise. This could be either the QI, or adequately qualified individual to whom the QI has delegated the activities. All delegated activities must be documented on the delegation log.

The QI is responsible for supervising any individual or party to whom the QI delegates trial-related duties and functions conducted at the trial site (ICH E6, 4.2.5). Evidence of this timely oversight may be assessed during an inspection through the review of signatures and file notes on source data and CRFs, including electronic signatures where applicable, and through interviews with study staff and the QI. Alternative verification methods consistent with ICH principles and adequate to the sponsor may also be acceptable. Proper rationale and justification should be used and the method appropriately documented.

C.05.010(g)

Interpretation

The sponsor must ensure that all individuals involved with the clinical trial (e.g. biostatisticians, clinical pharmacologists, physicians, clinical trial coordinators, etc.) are qualified by education, training and experience to perform their respective task(s) (see also ICH E6, 2.8).

The qualification should be appropriate to the tasks to be performed by the individual.

The sponsor must also ensure that individuals remain qualified throughout all stages of the trial process, from trial design, to conduct of a trial at sites, through to the analysis of data and the preparation of final clinical trial reports (ICH E6, 5.4.1).

The QI should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational drug(s), and their trial-related duties and functions (ICH E6, 4.2.4).

If the QI/institution retains the services of any individual or party to perform trial-related duties and functions, the QI/institution should ensure this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated (ICH E6, 4.2.6).

Training for clinical research

Training should be relevant to the study related duties performed by personnel, and include, at a minimum the relevant sections of trial protocol for which the person is responsible, as well as relevant supporting guidance, including, but not limited to ICH E6. An awareness and understanding of the regulatory requirements (Part C, Division 5) pertaining to delegated trial-related duties is also recommended.

The frequency of training should be commensurate with the activity at the site, and be of sufficient regularity to ensure that new clinical research personnel are promptly trained and existing personnel maintain familiarity with the requirements. The frequency should be decided by the sponsor based on the specifics of the site and protocol.

Documentation of training should include the content of the training such as the learning objectives, who attended and when the training occurred. This may include slide decks from presentations, course manuals, training certificates, meeting minutes and attendance logs, or updated staff CVs with supporting documentation.

C.05.010(h)

Interpretation

Informed consent is defined as a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate (ICH E6, 1.28). Potential participants in a clinical trial have the right to know the foreseeable risks or inconveniences and expected benefits that are part of the study they are thinking about joining [ICH E6, 4.8.10 (g) and (h)].

The risks and inconveniences should not outweigh the anticipated benefits when participating in a trial (ICH E6, 2.2). The rights, safety and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society (ICH E6, 2.3).

Informed consent is documented by means of a written, signed and dated informed consent form (ICF) (ICH E6, 1.28). The ICF must be made available for each subject in either official language or other as appropriate. Freely given informed consent should be obtained from every subject prior to clinical trial participation (ICH E6, 2.9). A clinical trial subject cannot be involved in any aspect of a clinical trial until he/she has gone through the ICF process, either in person or remotely, with a trial staff member (doctor, study nurse, clinical trial coordinator, etc.) and signed the document indicating that he/she understands the information and has agreed to participate in the trial. Neither the investigator, nor the trial staff, should, in any way, coerce or influence a subject to participate or to continue to participate in a trial (ICH E6, 4.8.3). A qualified physician should be available to answer any medical questions that the subject may have regarding his/her participation in the study.

The original, and all amended ICFs and any other written information to be provided to subjects, must be approved by an REB prior to being presented to trial participants (ICH E6, 4.8.1). The QI must have a documented SOP in place for obtaining informed consent. The site personnel to whom the consenting process is delegated to must be trained on the process and comply with the SOP. Subjects must be presented with any REB approved amended ICFs at their earliest visit to the clinical trial site and re-consented as soon as possible, unless there are specific recommendations from the sponsor and/or REB.

In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and adhere to GCP and the ethical principles that have their origin in the Declaration of Helsinki (ICH E6, 4.8.1)

ICFs submitted by sponsors to Health Canada are reviewed as part of their application for authorization to conduct a clinical trial.

Additional guidance on the informed consent document and the process of obtaining the informed consent can be found through ICH E6 (section 4.8), the current version of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2 2022), in particular chapter 3, and/or obtained from the local REB approving the study.

Amended ICFs

Section 4.8.2 of ICH E6 states that clinical trial subjects should be made aware of important new information as soon as it becomes available, as it may affect a subject's willingness to participate. The new information should be explained to the subject or the subject's legally acceptable representative in a timely manner, especially if the new information can have an immediate impact on the subject's health. Any revised written ICF and written information should receive the REB's approval prior to being provided to participants, unless information must be provided immediately for safety.

A subject should sign an amended ICF no later than their next scheduled visit, if possible. It is recommended that a site have a system in place to ensure control over the re-consenting process, including documenting and tracking all versions of the ICF, approvals by Health Canada and the REB and clinical trial subject re-consent. This is especially valuable when there are a large number of amendments and/or subjects enrolled in a study.

Subjects not capable of informed consent

When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject's legally acceptable representative (e.g. minors or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject's understanding. Also, if capable, the subject should sign and personally date the written informed consent (ICH E6, 4.8.12). Written procedures for this process should be followed. The process can be incorporated into an existing SOP for obtaining informed consent or be a stand-alone procedure.

As per section 4.8.15 of ICH E6, in emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative (as defined by provincial requirements), if present, should be requested. When prior consent of the subject is not possible, and the subject's legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval by the REB, to protect the rights, safety and well-being of the subject, and to ensure compliance with applicable regulatory requirements.

The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate (see ICH E6, 4.8.10) should be requested.

Fasting before signing the ICF

The acceptability of such practice would have to be a decision based on a case-by-case basis as every effort must be made to obtain informed consent when the clinical trial subject is in an appropriate state of mind to make an informed decision with respect to his or her participation in the study.

The practice of having a subject fast before the screening visit is sometimes used for the benefit of the subject (subjects coming out of town, elderly or disabled subjects who have difficulty reaching the site, etc.). This practice would allow the subject to consent and start the trial at the same time. Some options to resolve this issue could be to send the ICF by mail or to document (e.g. a note to file) the reason why this method was used. When it is a site's common practice, the site's SOP for obtaining informed consent, must incorporate this process. In addition, documentation must be available to justify this practice, and should include the reason for the decision as well as a risk assessment to ensure any risks to the subject are mitigated.

Electronic ICFs

The use of electronic ICFs is generally considered acceptable if all applicable regulatory and ICH requirements are met.

The process for obtaining informed consent using an electronic form should also be well detailed in an SOP, including how the form will be explained and discussed with the clinical trial subject (will the subject have the option to sign a paper copy, bring a copy home or have access to an electronic signed copy, etc.).

There are also requirements applicable to electronic signatures if that is the method the subject will use to sign the ICF. Electronic signatures are considered acceptable, again only if the electronic system is fully validated. The proper controls should be in place to assure that the signature belongs to the user who applied it. Limited access or passwords should be used accordingly. The clinical trial subject must understand that any electronic signature is equivalent as a handwritten signature on paper.

For more information on computerized system validation, refer to section 5.12 Records (C.05.012) of this document.

C.05.010(i)

Interpretation

The collection and maintenance of clinical trial records, including the retention of records, is a critical component of any clinical trial. The sponsor is responsible to ensure that trial information is recorded, handled and stored in a way that allows its accurate reporting, interpretation, and verification (ICH E6, 2.10).

Further guidance respecting information and records can be found in this document under section 5.12 Records (C.05.012).

C.05.010(j)

Interpretation

Good Manufacturing Practices (GMP) is part of a quality system covering the manufacture and testing of active pharmaceutical ingredients, pharmaceutical, radiopharmaceutical, biological and veterinary products. These practices ensure that these products are manufactured to the highest standards, assuring their safety for use in humans and animals. GMP also applies to the manufacture of drugs to be used in clinical trials.

To see the complete guidelines refer to the Good Manufacturing Practices (GMP) guide for drug products (GUI-0001) or to the Good Manufacturing Practices (GMP) Guidelines for Active Pharmaceutical Ingredients (API) (GUI-0104) available on the Health Canada website.

Additional information regarding the requirements pertaining to GMP for clinical trial drugs is available in Guidance Document - Annex 13 to the Current Edition of the GMP Guidelines: Drugs Used in Clinical Trials (GUI-0036), as well as sections 2.12, 5.14 and 8.2.16 of ICH E6.

The certificate of analysis (CoA) of the investigational drug(s) would be considered adequate evidence of GMP compliance. The alternate approaches to assure GMP compliance would be up to the sponsor to determine and could be considered by Health Canada. Proper justification and rationale should be used. The documentation regarding GMP compliance should be kept by the sponsor.

For additional information, refer to the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications.

Traceability of the investigational drug(s)

All drugs included on the NOL are considered investigational and thus, must be in compliance with Part C, Division 5 of the Regulations. The sponsor of a clinical trial is responsible for ensuring that a clinical trial drug is manufactured, stored and handled in accordance with GMP.

The sponsor should establish and maintain a system to ensure that investigational drugs can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the QI/clinical trial site where the product is used, administration of the drug to clinical trial subjects, to the reconciliation and disposal or destruction of the drug. The system should include collection of sufficient detail to allow linking of each clinical trial drug to the individual subject who received it. Where multiple parties are involved in the distribution chain (e.g. pharmacy, CRO, central warehouse) the sponsor should ensure that the role of each party is clearly outlined in writing.

As per section C.05.012 of the Regulations, records of the clinical trial drug's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused clinical trial drugs, should be available in order to demonstrate traceability.

Essential to this process is adequate labelling in accordance with section C.05.011 of the Regulations (see section 5.11 of this document).

Storage and transportation conditions

Using a risk-based approach, the sponsor should identify critical conditions for storage and transportation taking into consideration the labelling and existing stability data. Scientific/technical justification should exist to demonstrate that product quality is not affected.

Inadequate transportation and storage conditions may affect a sponsor's ability to trace a clinical trial drug as well as have an impact on the quality and safety of the clinical trial drug. For example, inadequate shipping and receiving records may result in missing drugs. In addition, the improper maintenance of transportation and storage temperatures may result in a loss of efficacy of the drug or affect the safety of the drug.

The sponsor must be able to demonstrate that the product was handled and stored according to the temperature range on the label. If there is potential for the drug to be exposed to temperatures outside this range, manufacturers must be able to provide stability data, which proves the drug is not compromised in such conditions. If manufacturers cannot provide this stability data, then they must provide adequate rationale for why such testing was not done or arrangements must be made by the sponsor to ensure the drug is not exposed to temperature extremes (e.g. use of validated shipping containers).

This applies also to marketed drugs used in clinical trials as investigational drugs and applies to all conditions required including ambient temperatures. If the drug product is stored in a controlled environment at the clinical trial site according to the information on the label, a risk-based approach will be used.

Complete guidelines for the transportation and storage of clinical trial drugs can be found in the Guidelines for Environmental Control of Drugs during Storage and Transportation (GUI-0069) and the ICH guideline Q1A(R2) on Stability Testing of New Drug Substances and Products.

5.11 Labelling

C.05.011

Interpretation

As defined in section 2 of the Food and Drugs Act, a label includes any legend, word or mark attached to, included in, belonging to or accompanying any food, drug, cosmetic, device or package. A package includes anything in which any food, drug, cosmetic or device is wholly or partly contained, placed or packed.

The definition of a label permits that the required information may accompany the drug (primary container, secondary container, package inserts, etc.).

As long as a label provides all of the required information in both official languages, it would be considered to have met the requirements of section C.05.011 of the Regulations. However, traceability to the manufacturing lot should be maintained on the label immediately attached to the investigational drug (i.e. primary container) such that its identity can be determined, and, if necessary, which unit was dispensed to each subject.

Adequate labelling of a drug used in a clinical trial is essential to ensure traceability of the drug, through the use of identifying information and lot numbers, to ensure that it is dispensed to the correct clinical trial subject, and to ensure it is stored in the proper conditions, including temperature and has not expired. The labelling must comply with regulatory requirements of section C.05.011 and be coded in a manner that protects the blinding, if applicable (ICH E6, 5.13.1).

It would be up to the sponsor to determine how to comply with the labelling requirements set out in this provision, provided that the system in place is validated, traceable, and does not compromise patient safety or product quality. Proper rationale and justification should be used.

For additional information on labelling, please refer to section 8.7 of Guidance Document - Annex 13 to the Current Edition of the GMP Guidelines: Drugs Used in Clinical Trials (GUI-0036).

Clinical Trial Drug Lot Numbers

The purpose of having a lot number on a drug label is to ensure traceability back to the manufacturer's records, in the event a problem with the drug is identified or a recall is necessary. For blinded clinical trials the sponsor must ensure that labeling information does not compromise the blinding. Labeling of a clinical trial drug with a manufacturer's lot number may compromise a blinded clinical trial.

Identifiers other than a "lot" or "(L)" number (e.g. a batch number, a kit number or a bar code) may be considered compliant with section C.05.011, provided traceability is maintained. Where a bar code is included as the identifier on the label, the code on the drug label should readily link to information (e.g. lot number and expiration date) through a validated computerized system. During an inspection, Health Canada may verify that there is a system of traceability in place to ensure patient safety and that the computerized system, if applicable, is fully validated (refer to section 5.12 Records).

Clinical Trial Drug Expiry Dates

During an inspection, Health Canada may verify that the clinical trial drug has a valid expiration date. The valid expiration date assures that the drug meets the standards for potency, purity and physical characteristics.

If stability studies to support expiry dating for a clinical trial drug are still ongoing at the time of labelling, the following may be considered acceptable in lieu of an expiration date:

• a re-test date on the label if the sponsor has data to support the extended shelf-life of the drug, and
• a manufacturing date is listed on the label, as long as the clinical trial site where the drug is dispensed has a document from the sponsor documenting the shelf-life of the drug. The sponsor must have data to support the shelf-life of the drug. As an example, this principle would apply to radiopharmaceuticals.

The above process should be documented; procedures and quality control systems should be in place and in accordance with the approved CTA. It should also be performed in accordance with GMP principles and specific SOPs. This additional labelling information should be properly documented in both the trial documentation and in the packaging records.

In the cases where a drug product requires reconstitution or further preparation prior to being administered to a subject, the sponsor is responsible for demonstrating that the drug used at the clinical trial site meets all of the requirements of section C.05.011. The reconstitution or preparation of a clinical trial drug should be done in accordance with the clinical trial protocol and be documented. It is recommended that the label for any new packaging of the drug carry an expiration date. The information on the reconstitution or preparation of the drug, and the required storage conditions should be included in accompanying documentation.

The sponsor must be able to demonstrate, through adequate data, that a clinical trial drug maintains its characteristics of potency, quality and safety during its period of use.

Refer to section 8.7 of Guidance Document - Annex 13 to the Current Edition of the GMP Guidelines: Drugs Used in Clinical Trials (GUI-0036) for additional guidance.

Labels of Marketed Drugs Used as Comparators

It is acceptable for a marketed drug used in a clinical trial as comparator (refer to Glossary (terms) for definition of comparator), to be labelled in accordance with its marketing authorization (NOC/DIN), including all relevant sections of the Food and Drugs Act and its associated regulations, provided that the labelling on the marketed drug is appropriate for the trial. The requirements of section C.05.011 would not apply in this case.

However, a marketed comparator drug used off-label must comply with the requirements of section C.05.011, unless it was not considered to be investigational in the context of the particular clinical trial, based on the assessment of the application. For additional information, refer to the Notice to Stakeholders: Statement on the Investigational Use of Marketed Drugs in Clinical Trials. For blinded clinical trials, the sponsor should ensure that the labelling does not compromise the blinding.

5.12 Records

C.05.012

Interpretation

As per subsection C.05.012(4), the sponsor shall maintain all records referred to in this Division for a period of 15 years. Sponsors may also be required to maintain records under provincial law, institutional policies, and contractual agreements with QIs, REBs or others. Where it is not possible to comply with both sets of requirements, the federal Regulations would govern and the records must be maintained for 15 years.

All clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification. This ICH GCP principle applies to all records referenced in this guidance document, irrespective of the type of media used (ICH E6, 2.10).

All clinical trial records shall be made available for inspection (ICH E6, 4.9.7) by Inspectors of Health Canada, in accordance with section 23 of the Act. While a unique identifier is assigned by the QI to each trial subject, to protect the identity of the subject when the QI reports AEs and/or other trial related data (ICH E6, 1.58), clinical trial subjects grant Health Canada Inspectors a direct access to their original medical records by signing the ICF, which should include a statement to this effect as per section 4.8.10 (n) of ICH E6.

Roles and Responsibilities for Records Retention (Sponsors, QIs and REBs)

Many parties usually share the responsibilities of record retention through delegation by the sponsor. It is however the ultimate responsibility of the sponsor to ensure that all parties involved in the conduct of the trial are in compliance with record retention requirements.

Sponsor

Part C, Division 5 of the Regulations clearly establishes that the sponsor who submits the CTA is the party to whom an authorization to sell or import a drug for use in a clinical trial is issued. The sponsor of a clinical trial is ultimately responsible for maintaining all records for the required record retention period.

The sponsor is required to maintain complete and accurate records to demonstrate that the clinical trial is conducted in accordance with the Regulations and GCP (ICH E6, 5.5.6-7).

• As the sponsor bears responsibility for study records, it is recommended that the sponsor clarify with the QI at the outset of the trial what documents are defined as source and how they are to be maintained.
• Sponsors may delegate record retention to third parties (e.g. QIs, CROs, laboratories, and others). As the responsible party for the conduct of a clinical trial, the sponsor should relay their expectations to third parties and expect due diligence from all involved in the management of clinical trial records. As such, written agreements with these third parties should be secured by sponsors, prior to the commencement of the trial to ensure full compliance with the regulatory requirements with respect to records.
• Written procedures and training of personnel in their implementation should be documented to demonstrate that the maintenance and retention of records was conducted correctly and consistently. The procedures may be trial- or site-specific and be provided by the sponsor or the third party that was delegated the responsibility.
• In situations where a sponsor undergoes a change of ownership, the record retention responsibility remains with the sponsor who initially submitted the CTA, unless a written agreement is otherwise secured with the new owner. Furthermore, before the clinical trial begins, the sponsor should have a documented procedure for record retention continuity that outlines the measures to be taken in the event that the sponsor ceases to exist.
• The sponsor should ensure that the QI has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data (ICH E6, 8.1).

Qualified investigator

A QI is responsible for the proper conduct of the clinical trial at his/her site. It should be noted that an independent QI, initiating a clinical trial under his/her own sponsorship, is responsible for all aspects of that trial, both as a QI and as a sponsor.

• The QI should ensure that essential records created and/or used under his/her supervision, including all source documents, are retained in accordance with the requirements of the Regulations and in accordance with the written agreement secured with the sponsor prior to the commencement of the clinical trial (ICH E6 4.9.4).
  

  Sites that neither screen nor enrol any subjects in a given clinical trial and that have not been delegated the responsibility of record retention by the sponsor do not need to retain clinical trial records in accordance with Part C, Division 5. Since the sponsor of a clinical trial is responsible for maintaining all records, the QI should consult the sponsor to confirm record retention requirements prior to destroying any records.

  Clinical trial sites with screen failures but no subjects enrolled in a given clinical trial should retain all records, including ones pertaining to screen failures for the entire record retention period as per Part C, Division 5. All source documents should also be retained for the entire record retention period even if a subject has withdrawn from the clinical trial.

• Appropriate measures should be taken to prevent accidental or premature destruction of the records (ICH E6, 4.9.4).
• Written agreements describing the procedures for records retention in accordance with the Regulations should be in place between all parties concerned.
  • For example, QIs conducting clinical trials within a hospital or a medical clinic should secure a written agreement (e.g. contract, policy, SOP), if applicable, with the institution to ensure that hospital records and/or medical charts of clinical trial subjects are retained according to the federal Regulations as these prevail over provincial laws and regulations when there is a conflict.
  • Agreements should also outline the conditions of record retention, such as the location of records, as well as the procedure to be followed to ensure record retention within the 15-year period in the event that a company ceases to exist or QI ceases her/his affiliation with their institution, for various reasons (e.g. closure of practice or retirement, new position elsewhere, or death).
• The QI may delegate record-related tasks to other parties such as the institution's pharmacy, a local laboratory or a radiological clinic, with the sponsor's agreement:
  • Prior to the commencement of the clinical trial, the delegated tasks should be documented, signed and dated by the QI and the party to whom the functions are delegated. The delegation may be amended if necessary during the course of the clinical trial.
  • The extent of the delegation, including the retention of the records created by the other party, should be clearly stated.
  • Tasks that are not delegated remain under the direct responsibility of the QI or the sponsor, depending on the written agreement secured between these two (2) parties. However, QIs always remain responsible to oversee the delegated tasks because they are responsible for the trial at their site.
• The QI/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete (ALCOAC). Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g. via an audit trail) (ICH E6, 4.9.0).
• Section 4.9.1 of ICH E6 states that the QI should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports. Furthermore, section 4.9.2 of ICH E6 states that data reported on the CRF, that are derived from source documents, should be consistent with the source documents or the discrepancies should be explained.
  • If any changes or corrections are made to a CRF, either written or electronic, the changes should be dated, initialed, and explained (if required) and the original entry should be legible (ICH E6, 4.9.3).
  • All changes made to a CRF, including electronic CRFs, should be traceable/auditable. Sponsors are expected to provide guidance, such as a written procedure, to investigators on how these corrections should be made and documented (ICH E6, 4.9.3).
  • The written procedure should assure that changes or corrections in CRFs made by the sponsor's designated representative are documented, explained, and endorsed by the investigators. It is the QI's responsibility to retain records of the changes and corrections (ICH E6, 4.9.3).

Types of records

Different types of records are created and are to be retained before, during and after the conduct of a clinical trial, in accordance with section C.05.012 of the Regulations and section 8 "Essential Documents for the Conduct of a Clinical Trial" of ICH E6.

Essential documents

Any documentation created and/or used during the conduct of clinical trials that allow the evaluation of the conduct of a study as well as the quality of the data produced during the study (ICH E6, 1.23).

These include, but are not limited to:

• investigator's brochure (including records respecting each change)
• serious adverse event (SAE) and serious adverse drug reaction (SADR) reports that have occurred inside or outside Canada
• chemistry and manufacturing information
• records respecting the enrolment of clinical trial subjects
• records respecting the shipment, receipt, disposition, return and destruction of the drug
• signed and dated QIU forms (Phase I-IV trials)
• protocols and protocol amendments
• REB approved ICF(s)
• signed and dated REB attestations
• standard operating procedures (SOPs)
• site personnel training records
• source documents

Source documents

A type of essential document that consist of original documents, data, and records (ICH E6, 1.52).

These include, but are not limited to:

• signed and dated ICFs
• hospital records
• clinical site and physician office medical charts
• laboratory records
• medical instrument records
• X-rays
• subject diaries
• appointment/scheduling records
• AEs and ADRs records
• pharmacy dispensing records
• drug accountability records

Essential and/or source documents may be in paper, magnetic or electronic form (ICH E6, section 8). It is acceptable for essential and/or source records to be transferred to secondary media (see "Transfer of records to secondary medium" section below).

Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial (ICH E6, 8.1).

A method is expected to be in place to identify those data elements requiring source documentation, and sites can then declare the type of source documents (e.g. chart-based, electronic record, a combination).

Only specific and unique documents that belong solely to the sponsor, the REB, the QI or other entities, must be kept at the conclusion or termination of a trial. Retention of copies of original documents is not a requirement.

The QI/institution should have control of all essential documents and records generated by the QI/institution before, during, and after the trial (ICH E6, 8.1).

In order to allow traceability of all source data, any source documents should be signed and dated by the person collecting, recording, reviewing and/or assessing the information or data.

Signing and dating a source document as evidence that it was reviewed is a common practice often supported by the site internal policies.

This practice is also recommended by Health Canada, although alternative verification methods, consistent with the principles of ICH E6, may also be acceptable (e.g. proper documentation in the progress notes).

In situations where original source documents cannot be retained for the 15-year record retention period due to their deterioration in uncontrolled environment conditions (e.g. thermal paper used for electrocardiograms), certified copies can be acceptable (see "Transfer of records to secondary medium" section below).

A certified copy is a copy (irrespective of the media used) of the original record that has been verified (e.g. by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure as the original (ICH E6, 1.63).

Refer to section 8 of ICH E6 for a more detailed list of essential and source documents.

Electronic records

Electronic records may be generated during clinical trials. They consist of any piece of information that is created, modified, retrieved, and/or transmitted during the conduct of a clinical trial.

These may include, but are not limited to:

• electronic case report forms (eCRFs) including electronic signatures
• electronic subject diaries
• other instruments provided to the QI or subjects to record trial data

• Electronic records should be maintained and retained in accordance with section C.05.012 of the Regulations.
• The validation of an electronic system is performed to confirm that the system's specifications meet the goals and requirements for the clinical trial in a consistent manner. These include, but are not limited to, completeness, credibility and accuracy of recorded information as well as reliability of the system. Therefore, any electronic system used to capture, process, manage and/or archive clinical trial information should be adequately validated and evidence of validation should be kept for the required record retention period and should be readily available for inspection by Health Canada's Inspectors.
• The approach for validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results (ICH E6, 1.65 and 5.5.3).
• As part of the validation process for electronic systems, documentation of the system design specifications and a validation plan based on those should be developed.
• The validation plan should include:
  • objectives and scope
  • nature of and time at which validation activities should be performed
  • delegated personnel for the conduct of the validation
  • security measures
  • main features of the system, including the mode of interaction with other systems and procedures
• Detailed documented procedures for validation activities should be developed and followed at all times to ensure consistency in the performance of the tasks. The SOPs should cover system setup, installation, and use. The SOPs should describe:
  • system validation and functionality testing
  • data collection and handling
  • system maintenance
  • system security measures
  • change control
  • data backup, recovery, contingency planning, and decommissioning.

The responsibilities of the sponsor, QI, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use (ICH E6, 5.5.3).

• The validation results should provide a clear indication that the system can be used as created. As such, a validation report, including detailed test results and an assessment of the results demonstrating that the system has met the specifications, should be produced for each validation test and allow traceability to the delegated person who conducted the activity.
• Any modifications or additions made to the electronic system (e.g. software upgrades or migration of data) can impact its intended functions by altering the quality of validated applications and the system itself. This may affect the integrity of the electronic information and the reliability of the system. Therefore, adequate documented assessment and approval of changes to hardware or software during the course of the clinical trial are required. The impact of such a change should be evaluated and documented, and partial validation of some components of the electronic system may be required.
• The electronic system should allow for the retrieval of the records, the generation of complete and accurate paper copies of the electronic source data as well as provide audit trails for the entire 15-year record retention period.
• Records created, maintained and processed by outsourced systems (i.e. cloud computing) are subject to the same requirements as the data/records generated by company owned systems.
• For electronic medical records system (e.g. hospital-based systems) not under the responsibility of the sponsor, an alternate method to validation could be considered (e.g. printing).

Health Canada expects that sponsors take into consideration the following factors as part of the risk assessment of a computerised system and its associated validation, but not limited to:

• type of research (e.g. commercial vs. non-commercial)
• purpose of the clinical trial (e.g. research for publication vs. drug submission for marketing authorization)
• status of the drug (e.g. market authorized product vs. investigational drug)
• safety profile / history of use of the drug

In addition, the sponsor should periodically review the risk control measures identified in their assessment to ascertain whether the implemented systems remain effective and relevant, taking into account experience and emerging knowledge (ICH E6, 5.0.6).

For additional information on computerized system validation and electronic records, refer to:

• Annex 11 to the Good Manufacturing Practices guide: Computerized Systems GUI-0050
• PIC/S Guidance: Good Practices for Computerised Systems in Regulated "GXP" Environments
• the U.S. Code of Federal Regulations Title 21 Part 11 - Electronic Records; Electronic Signatures
• the U.S. Food and Drug Administration (FDA) Guidance for Industry: Computerized Systems Used in Clinical Investigations
• the Medicines and Healthcare products Regulatory Authority (MHRA) GXP Data Integrity Guidance and Definitions
• World Health Organization (WHO) Annex 5 Guidance on Good Data and Record Management Practices
• the standard Electronic Records as Documentary Evidence, CAN/CGSB-72.34-2017 developed by the Canadian General Standard Board (CGSB).

Pharmacy records

Pharmacy records should be retained as either part of the subject-specific source document or the medical or hospital chart.

These records include, but are not limited to:

• clinical trial drug prescriptions
• calculations for clinical trial drug dispensing
• drug accountability records
• clinical trial drug storage temperature logs

Drug accountability records

Drug accountability records should include the following information on the drug, but not limited to:

• date of arrival on site
• quantity received
• identification (batch/lot number)
• expiration date
• quantity dispensed, on what date and to whom
• quantity returned by subjects, on what date
• quantity and date of destruction or return to sponsor

In order to ensure that subjects received the product(s) according to their randomization, QIs should maintain documentation.

Reconciliation of all investigational drugs received from the sponsor is also required (ICH E6, 4.6.3).

Drug accountability records are required for:

• drugs that are the subject of the clinical trial, and do not have market authorization
• drugs that are the subject of the clinical trial, have market authorization, but are used off-label
• comparator drug, if it does not have market authorization
• comparator drug, if it has market authorization, but its labelling was changed (e.g. for blinding purposes)
• comparator drug, if it has market authorization, but is used off-label (unless it was not considered to be investigational in the context of the particular clinical trial, based on the assessment of the application)
• drugs listed on section 8 (Brand or Proprietary Name) of HC/SC form 3011

Drug accountability records are not required for:

• drugs that are the subject of a Phase IV clinical trial
• comparator drug, if it has market authorization, is used on-label, and hasn't been altered in any manner
• rescue or concomitant medications, authorized for sale in Canada, that may be used on or off-label but are not the subject of the clinical trial (e.g. they are used as supportive medications for known clinical applications)

For example, marketed drugs which are commercially available, for which no CTA has been filed (Phase IV), should be managed as commercial drugs and good practice guidelines for pharmacies followed.

Trial-specific drug accountability logs are required only for drugs specifically labelled as clinical trial supply (i.e. drugs included on NOL).

For additional information on the off-label use of a drug that is authorized for sale in Canada, refer to the Notice to Stakeholders: Statement on the Investigational Use of Marketed Drugs in Clinical Trials.

Laboratory records

The retention of laboratory records allows review and confirmation of the diagnoses and results/reports as well as appropriate further testing, if needed, for the protection and well-being of participating clinical trial subjects.

These records include, but are not limited to:

• normal values and/or ranges for test(s) included in the protocol
• laboratory certification and/or accreditation
• established quality control and/or external quality assessment
• laboratory results/reports
• X-ray films, digital images, microfilms and compact disks

Medical instrument records

In the course of a clinical trial, measurement and laboratory equipment, scientific instruments and other pieces of equipment are generally used. Using a risk-based approach, the sponsor should identify critical equipment used in a study and specifications for that equipment (refer to section C.05.010(c) Equipment and Calibration).

• All service, maintenance, cleaning and calibration records, as well as the product manual for a critical piece of equipment used in the clinical trial, should be retained for the 15-year record retention period. This would include for example certificates, calibration data, and records of faults, breakdowns and misuse of the equipment.
• The manual calibration of certain pieces of equipment or instruments (e.g. body weight scales) does not generate a certificate or a print-out of the calibration data to demonstrate that the calibration was indeed performed and successful. In those circumstances, the QI should retain the calibration procedure and a log stating the following information:
  • dates of calibration
  • device details (type, supplier, and purchase date)
  • person responsible for the instrument
  • person who performed calibrations
  Approved specifications for calibration should also be documented and a record of the actual calibration results kept.
• Certain pieces of equipment or instruments may require frequent automated calibration and consequently generate considerable amounts of print-outs. In these instances, a log should be kept with all of the information listed under the bullet point above; except it should include the name of the person who assessed the calibration data and certified that calibration was successful, instead of the person who calibrated the instrument.
• The manufacturer's warranty cannot replace calibration/maintenance records as equipment calibration assures that equipment works within specifications.

Financial Records

Records pertaining to financial details of the clinical trial include, but are not limited to:

• any subject compensation records
• financial agreements between parties (ICH E6, 4.9.6, 5.9 and 8.2.4)
• insurance statements (ICH E6, 8.2.5)

Financial details related to clinical trial records are at the sponsor's discretion and outside of Health Canada scope.

Refer to section 8 of ICH E6 for more information on this type of record.

Research Ethics Boards (REBs) records

Records relevant to a clinical trial that pertain to the roles and responsibilities of the REB should be retained for 15 years in accordance with Part C, Division 5 of the Regulations.

These records could include, but are not limited to:

• REB membership including roles and responsibilities (e.g. chair, ethics, community representative)
• qualifications of REB members
• REB decisions (e.g. approvals, denials, required modifications, orders to stop clinical trials, etc.)
• communications with sponsors and QIs

Other essential documents that are not unique to the REB (e.g. records of ADRs and reviewed documents) should be retained for a period of at least three (3) years after completion of the trial as per ICH E6.

Transfer of records to secondary medium

The transfer of essential records from their original medium to a secondary one may be acceptable if the conditions described in this section are fulfilled.

Transfer

The transfer process should be validated and documented in appropriate procedures, and should ensure that:

• measures are in place to verify that the transfer is accurate and done by appropriately trained individuals (e.g. attestation or certification of copies by a person not involved in the transfer)
• corrections to the original data can be clearly captured in the secondary medium
• process follows existing standards when possible (i.e. Canadian General Standard Board)
• the secondary medium allows the successful retrieval and use of the records for the entire 15-year record retention period

Where records are copied off-site, a contract signed by the sponsor/QI/institution and the service provider must detail specific requirements such as those for transport to that site, copy quality, storage conditions, and, where relevant, destruction of original documents.

Electronic or Other System

The format and system where documents are retained should also be validated for its intended use.

Features should include the following, but not be limited to:

• design to ensure the tracing of any alterations and updates, if permitted, such as source, date and content (i.e. audit trail)
• back-ups at regular intervals
• security measures in place and documented to protect against data corruption, whether through accidental deletion, equipment failures, material deterioration, or a variety of other hardware and software problems
• controlled access to appropriate individuals (e.g. through use of passwords)
• plan in place for future accessibility (in light of changes over time in technology, personnel, or third-party contractors)
• location of records that permits immediate access to records for inspection

Destruction of original records

The destruction of original paper records following their transfer to a secondary medium may be acceptable with the principles described in this section in place.

In addition, the process to describe the destruction of the original paper records should be documented in appropriate procedures. Considerations should be given to additional requirements that may apply to the destruction of personal/confidential information.

Other considerations

Other requirements may apply to the transfer, storage and destruction of records, including:

• provincial (e.g. medical records)
• institutional
• legal requirements

It is considered acceptable, for example, to scan documents in an electronic format and store them on specific software or networks as well as on other devices such as flash drives (e.g. USB keys). That being said, all requirements stated in this guidance should be met when using any of these storage methods. While only one copy of each document in archive must be retained, whether in hardcopy or electronic format, records from their original medium (e.g. hardcopies) should be kept for as long as they are needed. When a copy is used to replace an original document (e.g. source documents, CRF), the copy should fulfill the requirements for certified copies as defined above (see ICH E6, 1.63).

The above conditions apply to transfers of essential records from an original to a secondary medium performed by all parties involved in the conduct of a clinical trial.

For more information with regards to the transfer of essential records to a secondary medium, refer to the CGSB standard Electronic Records as Documentary Evidence, CAN/CGSB-72.34-2017.

Record retention period

The retention period for all records created and/or used during the conduct of a clinical trial is 15 years in accordance with subsection C.05.012(4) of the Regulations. This period of time will allow for subject follow-up throughout the subsequent stages of drug development, assessment, marketing, as well as provide the ability to assess the impact on the next generation.

Although the retention period of records starts on the date the record is created, sponsors may choose to "start the clock" for retention of all study records upon completion or termination of the trial to simplify the process.

Location of records

Often, third parties (such as QIs, REBs, CROs) retain originals of specific and unique records created by them. Nevertheless, due to their nature, specific records may be retained by more than one party. It should be noted that it is not a requirement for a party to retain multiple and identical copies of an original document. Third parties should consult the sponsor prior to destroying any record.

A detailed list of essential/source records which specifies the party(ies) who should retain them, and where they should be located throughout the period of a trial, is described in section 8 of ICH E6.

All records should be kept in a secure location prior to, throughout and after the conduct of the clinical trial. To maintain the integrity of all records, their location should assure protection from possible damage (e.g. water or fire damage) and from a possible breach in confidentiality for the entire record retention period. As such, access to the records should be restricted to authorized personnel that are adequately trained in the handling and management of clinical trial records according to an established documented procedure.

The sponsor and QI/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval (ICH E6, 8.1).

It should be noted that specific timelines for the provision of clinical trial information to Health Canada are outlined in section C.05.013 of the Regulations (see section 5.13 of this document). These timelines should be taken into consideration when determining the location of the clinical trial records for the retention period.

If the records are stored in the cloud, there should be an agreement between the sponsor and the cloud provider that sets out the parties' respective responsibilities. Direct and immediate access to the records needs to be available for inspectors and provision of passwords or encryption keys to inspectors at the time of inspection.

Examples of observations typically cited under this section of the Regulations include:

C.05.012(1) and C.05.012(2)

• The clinical trial records had errors and/or missing information that did not allow for complete and accurate reporting, interpretation, and verification.
• The sponsor did not always record, handle and store all information for a clinical trial to ensure the data transcribed from the original documents to case reports was accurate and complete.
• The sponsor did not ensure the electronic data system met the requirements for completeness, accuracy, and reliability.
• The sponsor did not always maintain complete and accurate records to show the clinical trial was conducted in accordance with GCP and the Regulations.

C.05.012(3)

• The sponsor did not always maintain complete and accurate records for the use of the drug in the clinical trial, as required by the Regulations.
• The sponsor did not maintain all versions of the Investigator's Brochure, including the rationale for any changes and documentation supporting each change.
• The sponsor did not maintain records of all adverse events occurring from the drug in or outside Canada.
• The sponsor did not maintain records for shipping, receiving, disposing of, returning and/or destroying the drug.
• The sponsor did not maintain records of an undertaking from the QI. This undertaking form must be signed and dated by the QI before the commencement of their responsibilities in the clinical trial.
• The sponsor did not maintain copies of the protocol, informed consent form and/or any amendments to the protocol or informed consent form approved by the REB for the clinical trial site.

C.05.012(4)

• The sponsor did not have provisions in place to keep all clinical trial records for a period of 15 years.

Note: Observations pertaining to "computerized system validation" are usually cited under paragraph C.05.010(c) of the Regulations.

5.13. Submission of Information and Samples

C.05.013

Interpretation

Health Canada may request that a sponsor submit either information or samples of a study drug if the information and documents submitted are insufficient to assess the quality and safety of the drug to be used in the clinical trial. The sponsor must provide the information requested, within 2 calendar days of that request, should Health Canada have reasonable grounds to believe that:

1. the use of the drug endangers the health and safety of a subject or other person
2. the trial is not in the best interests of a clinical trial subject
3. the objectives of the trial will not be achieved
4. the QI is not respecting the undertaking (QIU form) described in C.05.012(3)(f), or
5. information submitted in respect of the drug or the clinical trial is thought to be false or misleading

Furthermore, Health Canada may request that a sponsor submit information or records described in C.05.012, or samples of the drug, within 7 calendar days of the request, in order to assess the safety of the drug or the health of any of the clinical trial subjects or other persons.

Retention Samples of the Drug

Although the Regulations do not specifically state that samples of clinical trial drugs must be kept, in order to be able to fulfill Health Canada's request for a sample, as specified in this section, it is implicit that retention samples should be kept from the start of a clinical trial until the clinical trial report has been prepared.

Retention of Biological Study Samples

The Regulations do not cover biological study samples and do not specify how long they should be kept. If the sponsor chooses to maintain biological study samples (e.g. serum samples), Health Canada recommends that they be kept until the clinical trial report has been prepared to enable confirmation of results, specifically in the event of inconsistent results.

5.14 Serious Unexpected Adverse Drug Reaction Reporting

C.05.014

Interpretation

The collection, assessment and reporting of adverse events (AEs, as defined in Appendix A) is a critical component of the conduct of any clinical trial. It is a sponsor's responsibility to keep records of all AEs in respect of the drug used in a clinical trial, whether those events occur inside or outside of Canada, including information that specifies the indication for use and the dosage form of the drug at the time of the AE [C.05.012(3)(c)]. The assessment of the site AEs should be done by the QI or the delegated sub-investigator(s) (physician or dentist who meets the criteria of a QI) for seriousness, expectedness and causality determination, when they become aware.

Section 4.11.1 of ICH E6 states that all serious adverse events (SAEs, as defined in Appendix A) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g. Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification numbers, and/or addresses. The QI should comply with the applicable regulatory requirement(s) related to the reporting of serious unexpected adverse drug reactions (SUADR, as defined in Appendix A) to the regulatory authority(ies) and the REB.

In accordance with section C.05.014 of the Regulations, it is the responsibility of a sponsor to inform Health Canada, in an expedited manner, of all SUADRs in respect of a drug during the course of a Phase I-III clinical trial (refer to the boxes below for Phase IV trials), whether or not the event occurred inside or outside of Canada:

1. this information must be submitted within 15 calendar days after becoming aware of the event if it is neither fatal nor life threatening
2. if the event is fatal or life threatening, Health Canada must be advised of the event within 7 calendar days after the sponsor first became aware of it.

In cases where the event is fatal or life threatening, the sponsor must submit a complete report to Health Canada within 8 calendar days after the first notification (initial report) to Health Canada of the event. Follow-up reports of fatal or life-threatening reactions must include an assessment of the importance of the event and the implication of any findings, including relevant previous experience with the same or similar drugs.

In addition, in keeping with ICH GCP, the sponsor should expedite reporting of all SUADRs to all concerned QI(s)/institution(s), the REB(s) where required (ICH E6, 5.17.1).

Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH E2A) (ICH E6, 5.17.2).

The sponsor should also submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s) (ICH E6, 5.17.3).

Please refer to the following guidance documents for detailed guidance on how to report:

• Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (Phase I-III trials)
• Reporting Adverse Reactions to Marketed Health Products - Guidance Document for Industry (Phase IV trials).

5.15 Discontinuance of a Clinical Trial

C.05.015

Interpretation

Please refer to section 2.8. "Post-Authorization Requirements" of the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for further information.

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 sponsor is required to notify Health Canada (via CTA-Notification) as soon as possible, but no later than 15 calendar days after the date of discontinuance.

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 (PDD or BRDD) if such discontinuation was carried out for safety reasons.

If a sponsor discontinues the drug development (that is, for any or all indications, routes of administration, or dosage forms), the sponsor must maintain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) (ICH E6, 5.5.8).

If the sponsor discontinues the drug development, the sponsor must notify Health Canada, all the trial QIs/institutions and other regulatory authorities who may be involved (ICH E6, 5.5.9).

5.16 Suspension and Cancellation (Intent to Suspend)

C.05.016

Interpretation

Health Canada shall suspend the authorization to sell or import a drug for the purposes of a clinical trial, in its entirety or at a clinical trial site, if Health Canada reasonably believes that any of the circumstances outlined in C.05.016 (1)(a) through (d) apply. Before suspending under C.05.016, Health Canada will send the sponsor a written notice of the intention to suspend the authorization that indicates whether the authorization is to be suspended in its entirety or at a clinical trial site, and the reason for the intended suspension.

The sponsor then has 30 calendar days after receipt of this notice to provide Health Canada with information or documents that demonstrate that the authorization should not be suspended on the grounds that:

• the situation giving rise to the intended suspension did not exist, or
• the situation giving rise to the intended suspension has been corrected, and will be given an opportunity to be heard as required under the Regulations.

If a suspension is deemed necessary, Health Canada shall suspend the authorization by sending to the sponsor a written notice of suspension of the authorization that indicates the effective date of the suspension, whether the authorization is suspended in its entirety or at a clinical trial site, and the reason for the suspension.

Health Canada shall reinstate the authorization if, within 30 calendar days after the effective date of the suspension, the sponsor provides Health Canada with information or documents that demonstrate that the situation giving rise to the suspension did not exist or it has been corrected. Failure to provide any or adequate information within 30 calendar days after the effective date of suspension will result in cancellation of the authorization, either in its entirety or at a clinical trial site, as the case may be.

Health Canada shall also suspend an open trial as a result of an inspection with a "non-compliant" (NC) rating if Health Canada reasonably believes that any of the circumstances outlined in C.05.016 (1)(a) through (d) apply. In such circumstances, Health Canada would issue a "Notice of Intent to Suspend", along with the Final Inspection Exit Notice (inspection report).

The sponsor would have 30 calendar days to respond to the observations in the Exit Notice. Depending on the deficiencies noted in the conduct of the study, the sponsor may also be requested to provide an impact analysis on the safety of the subjects in the study and the integrity of the collected data at that site. After reviewing the information or documents the sponsor provides, Health Canada would determine whether the situation giving rise to the intended suspension did not exist or has been corrected.

5.17 Suspension and Cancellation

C.05.017

Interpretation

Health Canada shall suspend an authorization to sell or import a drug for the purposes of a clinical trial under section C.05.017, in its entirety or at a clinical trial site, before giving the sponsor an opportunity to be heard if Health Canada has reasonable grounds to believe that it is necessary to do so to prevent injury to the health of a clinical trial subject or other person.

Health Canada shall suspend the authorization by sending to the sponsor a written notice of suspension of the authorization that indicates the effective date of the suspension, whether the authorization is suspended in its entirety or at an individual clinical trial site, and the reason for the suspension.

If Health Canada has suspended an authorization, Health Canada shall:

• reinstate the authorization in its entirety or at a clinical trial site, if within 60 calendar days after the effective date of the suspension the sponsor provides Health Canada with information or documents that demonstrate the situation giving rise to the suspension did not exist or that it has been corrected, or
• cancel the authorization in its entirety or at a clinical trial site, if within 60 calendar days after the effective date of the suspension the sponsor has not provided Health Canada with the required information

Investigator / Institution's Responsibilities

Section 4.12 of ICH E6 sets out the responsibilities of a QI/institution in the event of premature termination or suspension of a clinical trial.

If a trial is prematurely terminated or suspended for any reason, the QI/institution should:

• promptly inform all trial subjects
• ensure appropriate care and follow up of subjects
• where required by regulatory requirement(s), inform the regulatory authority(ies)

Sponsor's Responsibilities

In addition to those requirements set out in the Regulations with respect to the discontinuance, suspension or cancellation of authorisation to sell or import a drug for the purpose of a clinical trial, section 5.21 of ICH E6 states that in the event of such an occurrence, the sponsor should:

• promptly inform the QIs/institutions and the regulatory authority(ies) of the termination or suspension, and provide the reason(s) for the termination or suspension
• promptly inform the REB and provide the reason(s) for the termination or suspension

This can be done by either the sponsor or the QI/institution, as specified by the applicable regulatory requirement(s).

Appendices

Appendix A - Glossary

Acronyms and abbreviations

ADR:

Adverse Drug Reaction

AE:

Adverse Event

ALCOAC:

Attributable, Legible, Contemporaneous, Original, Accurate, and Complete

ANDS:

Abbreviated New Drug Submission

API:

Active Pharmaceutical Ingredient

BRDD:

Biologic and Radiopharmaceutical Drugs Directorate

CGSB:

Canadian General Standards Board

CoA:

Certificate of Analysis

CRF:

Case Report Form

CRO:

Contract Research Organization

CTA:

Clinical Trial Application

CTA-A:

Clinical Trial Application Amendment

CTSI:

Clinical Trial Site Information

CV:

Curriculum Vitae

DIN:

Drug Identification Number

eCRF:

Electronic Case Report Form

E.g.:

Example

FAQ:

Frequently Asked Questions

FDA:

Food and Drug Administration

GCP:

Good Clinical Practices

GMP:

Good Manufacturing Practices

GUI:

Guide/Guidance Document

HC-SC:

Health Canada-Santé Canada

ICF:

Informed Consent Form

ICH:

International Conference on Harmonization

I.E.:

Id Est ("that is")

IEC:

Independent Ethics Committee

IP:

Investigational Product

IRB:

Institutional Review Board

ITA:

Investigational Testing Authorization

MHRA:

Medicines and Healthcare products Regulatory Agency

NC:

Non-Compliant

NDS:

New Drug Submission

NHP:

Natural Health Product

NOC:

Notice of Compliance

NOL:

No Objection Letter

NSN:

Not Satisfactory Notice

PDD:

Pharmaceutical Drugs Directorate

PIC/S:

Pharmaceutical Inspection Co-Operation Scheme

QI:

Qualified Investigator

QIU:

Qualified Investigator Undertaking

REB:

Research Ethics Board

SAE:

Serious Adverse Event

SADR:

Serious Adverse Drug Reaction

SMO:

Site Management Office

SNDS:

Supplemental New Drug Submission

SOAD:

Summary of Additional Drugs Form

SOP:

Standard Operating Procedure

SUADR:

Serious Unexpected Adverse Drug Reaction

SUSAR:

Suspected Unexpected Serious Adverse Reaction

TCPS:

Tri-Council Policy Statement

Vs.:

Versus

WHO:

World Health Organization

Terms

Adverse drug reaction (ADR): means any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.

Adverse event (AE): means any adverse occurrence in the health of a clinical trial subject who is administered a drug, that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.

Clinical trial: means an investigation in respect of a drug for use in humans that involves human subjects and 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.

Comparator (Product): An investigational or marketed product (active control), or placebo, used as a reference in a clinical trial (ICH E6, 1.14).

Drug: means a drug for human use that is to be tested in a clinical trial.

Good clinical practices (GCP): means generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in section C.05.010.

Import: means to import a drug into Canada for the purpose of sale in a clinical trial.

Importer: The sponsor or person designated by the sponsor who is responsible for the import of the drug into Canada for the purpose of sale in a clinical trial. Individual investigators at the clinical trial sites in Canada may serve as Canadian Importers (Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications).

Investigator's brochure: means, in respect of a drug, a document containing the preclinical and clinical data on the drug that are described in paragraph C.05.005(e).

Label: includes any legend, word or mark attached to, included in, belonging to or accompanying any food, drug, cosmetic, device or package.

Observation: A deficiency or deviation from Part C, Division 5 of the Regulations noted by an Inspector during the inspection of a clinical trial that is confirmed in writing in the exit notice. The observations are classified as "critical" (risk 1), "major" (risk 2) or "minor" (risk 3) Risk classification guide for observations related to inspections of clinical trials of human drugs (GUI-0043)

Package: includes anything in which any food, drug, cosmetic or device is wholly or partly contained, placed or packed.

Protocol: means a document that describes the objectives, design, methodology, statistical considerations and organization of a clinical trial.

Qualified investigator (QI): means the person responsible to the sponsor for the conduct of the clinical trial at a clinical trial site, who is entitled to provide health care under the laws of the province where that clinical trial site is located, and who is

1. (a) 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. (b) in any other case, a physician and a member in good standing of a professional medical association.

Research ethics board (REB): means a body that is not affiliated with the sponsor, and

• (a) 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
• (b) that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the Immigration and Refugee Protection Act, that is composed of both men and women and that includes at least
  • (i) two members whose primary experience and expertise are in a 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,
  • (ii) one member knowledgeable in ethics,
  • (iii) one member knowledgeable in Canadian laws relevant to the biomedical research to be approved,
  • (iv) one member whose primary experience and expertise are in a non- scientific discipline, and
  • (v) 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.

Sell: includes offer for sale, expose for sale, have in possession for sale and distribute, whether or not the distribution is made for consideration.

Site or trial site: The location(s) where trial-related activities are actually conducted (ICH E6, 1.59).

Serious adverse drug reaction (SADR): means an adverse drug reaction that requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.

Serious unexpected adverse drug reaction (SUADR): means a serious adverse drug reaction (SADR) that is not identified in nature, severity or frequency in the risk information set out in the investigator's brochure or on the label of the drug.

Sponsor: means an individual, corporate body, institution or organization that conducts a clinical trial.

Standard operating procedure (SOP): Detailed, written instructions to achieve uniformity of the performance of a specific function (ICH E6, 1.55).

Appendix B - References

Law and Regulations

• Food and Drugs Act
• Food and Drug Regulations
• Medical Devices Regulations
• Radiation Protection Regulations

Health Canada Guidances and Documents

• Annex 13 to the Current Edition of Good Manufacturing Practices Guidelines: Drugs Used in Clinical Trials (GUI-0036)
• Risk classification guide for observations related to inspections of clinical trials of human drugs (GUI-0043)
• Clinical Trial Frequently Asked Questions
• Clinical Trial Site Information Form
• Compliance and enforcement policy for health products (POL-0001)
• Compliance and Enforcement Approach and Inspection Strategy for Clinical Trials of Drugs Involving Human Subjects (POL-0030)
• Good Manufacturing Practices (GMP) Guide for drug products (GUI-0001)
• Good Manufacturing Practices (GMP) Guidelines for Active Pharmaceutical Ingredients (API) (GUI-0104)
• Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications
• Guidance Document: Health Canada 3011 (HC/SC 3011): Guidance for Completing the Drug Submission Application Form
• Guidance Document: Preparation of Clinical Trial Applications for use of Cell Therapy Products in Humans
• Guidelines for Environmental Control of Drugs during Storage and Transportation (GUI-0069)
• Health Canada 3011 (HC/SC 3011): Drug Submission Application Form for Human, Veterinary or Disinfectant Drugs and Clinical Trial Application/Attestation
• Importation and Exportation (Health Canada guidance documents on the importation and exportation of health products)
• Notice to Stakeholders: Statement on the Investigational Use of Marketed Drugs in Clinical Trials
• Qualified Investigator Undertaking Form
• Reporting Adverse Reactions to Marketed Health Products - Guidance Document for Industry
• Research Ethics Board Attestation

Other Guidances and Policies

• Annex 11 to the Good Manufacturing Practices guide: Computerized Systems GUI-0050
• Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, International Conference on Harmonization (ICH) Harmonized Tripartite Guideline, Topic E2A
• Declaration of Helsinki
• Electronic Records as Documentary Evidence, Canadian General Standard Board (CGSB), CAN/CGSB-72.34-2017
• ICH Guidance: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice E6(R2)
• Medicines and Healthcare products Regulatory Authority (MHRA) GXP Data Integrity Guidance and Definitions
• PIC/S Guidance: Good Practices for Computerised Systems in Regulated "GXP" Environments
• Reflection Paper on Risk Based Quality Management in Clinical Trials, European Medicines Agency (EMA)
• Stability Testing of New Substances and Products, ICH Harmonized Tripartite Guideline, Topic Q1A(R2)
• Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2 2022)
• U.S. Code of Federal Regulations (CFR) Title 21 Part 11 - Electronic Records; Electronic Signatures
• U.S. Food and Drug Administration (FDA) Guidance for Industry: Computerized Systems Used in Clinical Investigations
• U.S. Food and Drug Administration (FDA) Guidance for Industry: Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring
• World Health Organization (WHO) Annex 5 Guidance on Good Data and Record Management Practices