Draft guidance on proposed new Clinical Trials Regulations (GUI-0100)

This draft guidance is for consultation only. For current guidance please see the existing guidance document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (GUI-0100).

This guidance document is being distributed for comment purposes only. 

Table of contents

• Purpose
• Scope
• Introduction
• Guidance for implementation
• Regulations and interpretations
  • Definitions, words and expressions
  • Interpretation
  • Research ethics board mandate and membership
  • Applicability of the regulations
  • Importation and sale of drugs
  • Authorization to conduct clinical trials
  • Obtaining an authorization
  • Terms and conditions
  • Amendments
  • Transfer of authorization
  • Suspension and revocation
  • Direction to cease conduct
  • National Research Ethics Boards
  • Good clinical practices
  • Provision of information
  • Records
  • Labelling
• Appendix A: Glossary (Terms)
• Appendix B: References

Purpose

This draft guidance has been revised to reflect the proposed Clinical Trials Regulations (CTR). Comments received during the public consultation following publication of the proposed regulations in the Canada Gazette, Part 1, may inform the final version of this guidance document. This guidance document will supersede the former Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (GUI-0100, version 2, March 14, 2023) when the proposed regulations come into force.

Scope

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

Interested parties may include:

• sponsors
• investigators
• contract research organization (CRO)
• site management organization (SMO)
• other service providers that support or monitor clinical trial activities

The proposed Clinical Trials Regulations clearly establish that the sponsor has the overall responsibility for conducting a clinical trial involving drugs in participants. In Canada, a person may conduct a clinical trial under the oversight of a sponsor. However, sponsors remain accountable in all respects for the trial's data quality and integrity, and participant safety.

The Regulations do not differentiate between commercial and non-commercial sponsors (for example, Sponsor-Investigator).

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

Note: Work is underway prior to Canada Gazette II to define the application of clinical trial regulations with respect to clinical trials studying blood as well as cells, tissues and organs.

This document does not apply to:

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

Introduction

The legislative authority for the proposed Clinical Trials Regulations is the Food and Drugs Act (the Act). The proposed Regulations set out the federal requirements for the sale and importation of drugs, the conduct of a clinical trial, and the requirement to comply with good clinical practices (GCP) for human clinical trials in Canada. Health Canada does not have jurisdiction over the professional standards regarding practice of medicine, which are regulated by the provincial colleges of physicians.

The new proposed Regulations provide for flexibility to adopt international GCP standards in order to satisfy the above requirements.

Health Canada adopted the International Council on Harmonization Guidance: Good Clinical Practice Consolidated Guideline (ICH E6). ICH E6 is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve participants.

The ICH E6 Guideline is amended as the clinical trials landscape evolves in scale and complexity. Evolutions in technology and risk management processes offer new opportunities to focus on relevant activities resulting in increasing the rigour of clinical trials. In 2025, Health Canada adopted ICH E6(R3) to provide guidance about topics including:

• expectation for risk-based approaches including Quality by Design principles and Risk Management,
• identifying critical-to-quality factors and having supporting elements that are fit-for-purpose,
• roles and responsibilities for sponsors, investigators and service providers, and
• elements of data governance.

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.

Compliance with the Regulations and ICH E6 will further promote the protection of participants 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 Draft guidance 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.

Guidance for implementation

Health Canada invites readers to note how ICH E6 may be implemented to support the Regulatory requirements. This guidance document may cite instances of this. Note that there may be aspects of the Regulations for which ICH E6 guidance is not applicable. As guidance does not have the force of law, the Regulations always prevail over guidance recommendations.

Regulations and interpretations

For each section below, the exact text from the new proposed Clinical Trials Regulations is provided first. This is followed by Health Canada's interpretation (what should be done in order to be compliant).

Definitions, words and expressions

Definitions, as outlined in section 1(1), along with words and expressions, as outlined in section 1(2) of the proposed Regulations, are available in Appendix A of this guide.

Interpretation

Interpretation

For both single-site and multi-site trials, the trial is considered to have officially started as soon as conduct activities begin at any location (whether it is the main site or a remote site).

Research ethics board mandate and membership

Interpretation

ICH E6 uses the terms "institutional review board" (IRB) and "independent ethics committee" (IEC) interchangeably, the definition of which is consistent with that of a REB. In ICH E6, an IRB or an IEC is defined as:

“An independent body (a review board or a committee, institutional, regional, national or supranational) constituted of medical professionals and non-medical members whose responsibility it is to ensure the protection of the rights, safety and well-being of human participants involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, the suitability of the investigator(s), the facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial participants. The legal status, composition, function, operations and regulatory requirements pertaining to IRBs/IECs may differ among countries but should allow the IRB/IEC to act in agreement with GCP as described in this guideline”.

Note: REBs in Canada are held to more stringent composition requirements than are described in this section for  ICH E6.

Applicability of the regulations

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 (refer to Authorization to conduct clinical trials in this guide).

In addition to the Clinical Trials Regulations, the following provisions of Division 1 also apply to any drug sold for a clinical trial whether authorized under a CTA for Phase I, II and III trials or a DIN or NOC for Phase IV trials):

• 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)

Authorized drugs used in Phase IV clinical trials are subject to the same requirements

The Regulations apply to both the conduct and the sale and importation of drugs used in a clinical trial involving participants in Canada. As per section 8(1), it is prohibited to sell or import a drug for use in a clinical trial (refer to Glossary, Terms, for definitions of sell and import) unless authorized (refer to section 11 Application requirements). For Phase IV clinical trials, limited provisions apply which are set out in subsection 5(2) Exception – drug used as authorized and described below.

Phase IV clinical trials include those trials that involve the use of:

• a new drug that has been issued a notice of compliance (NOC) under subsection C.08.004(1) of the Regulations, if the clinical trial is in respect of a purpose and conditions of use for which the NOC was issued; or
• a drug, other than a new drug, that has been assigned a drug identification number (DIN) under subsection C.01.014.2(1) of the Regulations, if the use of the drug in a clinical trial falls within use or purpose for which the DIN was assigned.

Phase IV clinical trials are performed after the drug has been authorized by Health Canada for the market, and within the parameters of the authorized NOC or DIN application.

In accordance with the proposed Clinical Trials Regulations, 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, where a clinical trial is conducted on an authorized 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 revised Draft Guidance for Clinical Trial Sponsors: Clinical Trial Applications for detailed guidance on the application process, as well as Phase IV studies classification and their requirements. The relevant Health Canada Directorate (Pharmaceutical Drugs Directorate or Biologic and Radiopharmaceutical Drugs Directorate) 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.

Exemptions

Interpretation

Under the proposed regulations, a sponsor would be required to hold an authorization to conduct a clinical trial, unless the sponsor is exempt from section 3.1 of the Food and Drugs Act. This exemption applies to trials involving only drugs that are used according to the conditions outlined in the drugs' respective market authorizations (for example, as per the reasons used in their product monographs). Section 3.1 of the Act states:

Sponsors of clinical trials that involve only these types of drugs would be exempt from section 3.1 of the Act; however, they would still need to comply with certain requirements under the proposed Regulations, such as the good clinical practices provisions.

Service providers and investigators involved in the conduct of a clinical trial on behalf of a sponsor would not be required to hold an authorization. Further, members of a clinical team under the supervision of an investigator or a service provider (for example, physicians or dentists responsible for medical decisions, researchers, nurses, and/or other health professionals) would not be required to hold an authorization. As such, when an authorization is issued for a clinical trial, the sponsor would be the sole holder of that authorization and therefore would also be referred to as the “authorization holder”.

The proposed Regulations would permit all of the above-mentioned persons to conduct a clinical trial if they comply with the authorization or if they conduct a trial that is exempt from section 3.1 of the Act (while still following any applicable requirements). However, they would not be permitted to conduct trial-related activities if the authorization is suspended or revoked (at least in relation to the suspended or revoked part of the authorization), or if the Minister has directed a sponsor to cease conducting the trial. Furthermore, although the proposed Regulations would permit the delegation of clinical trial activities to other parties (service providers, investigators, etc.), the sponsor would remain ultimately responsible for ensuring that the trial is conducted in accordance with the proposed Regulations.

Importation and sale of drugs

Interpretation

Similar to the Food and Drug Regulations (FDR), the proposed Regulations would prohibit persons from importing or selling a drug for use in a clinical trial, unless the sponsor of the clinical trial holds an authorization to conduct the trial or is exempt from section 3.1 of the Act. Additionally, if a drug is to be imported for such a trial, the sponsor/authorization holder must have a representative in Canada who is responsible for the importation of the drug and a representative in Canada who is responsible for the sale of the drug. These representatives could be the sponsor, a person working for the sponsor or working for a third party acting on the sponsor's behalf, and they could be the same person. Where the Minister has suspended or revoked an authorization, or directed a sponsor exempt from section 3.1 of the Act to cease conducting a trial, the prohibitions on importation and sale (and the prohibition on conduct) would re-apply to the respective drug(s) and trial as soon as these persons have been notified.

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 section 26.

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 Draft guidance 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.

Authorization to conduct clinical trials

Application for authorization

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. Furthermore, these programs review CTAs for which the sponsor chooses to apply for the selective collection of adverse events in respect of the drug in the clinical trial if the safety profile of the drug has been sufficiency well-understood.

Please refer to the revised Draft guidance 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 Appendix B. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

During an inspection by Health Canada, inspectors will verify that the information submitted as part of an application is being followed as per paragraph 46(1)(c) in the CTR.

Additional information and material

Interpretation

Health Canada may require a sponsor to submit, within the requested timeframe, 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 authorization.

Typically, 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 participant or other person,
  • the clinical trial is contrary to the best interests of a clinical trial participant, or
  • the objectives of the clinical trial will not be achieved

Obtaining an authorization

The following provisions indicate the conditions and timelines for which an authorization to conduct a clinical trial would be made:

• Paragraph 14 – Contingent authorization
• Paragraph 15 – Conversion of contingent authorization
• Paragraph 16 – Extension

Interpretation

When a CTA is submitted by the sponsor Health Canada will issue the sponsor a contingent authorization within 7 days after the application was submitted. A contingent authorization is not an authorization for the sponsor to conduct a clinical trial.

The Sponsor must wait the required 30 days

In the event that there is no basis for the Minister to object to the clinical trial application, the sponsor would receive a Notice of No Objection (NNO) within 30 days of the date of receipt of the complete CTA, authorizing the sponsor to conduct a clinical trial and also sell or import the drug for the purposes of a clinical trial. Should Health Canada require more time to review the application, the sponsor will be notified of this within the 30-day period. The sponsor may proceed with the clinical trial after this period without receiving an NNO provided the REB approval was obtained.

For further details please consult Draft guidance for clinical trial sponsors: Clinical trial applications.

Examples of inspection observations typically cited under these sections of the Regulations include:

• The drug was sold or imported for use in a clinical trial without seeking authorization from Health Canada or before the end of the 30-day default period
• The drug was sold or imported for use in a clinical trial before the clinical trial site information was submitted to Health Canada

Commencement of conduct of clinical trial at clinical trial site

Interpretation

Commencement of the conduct of a clinical trial must be authorized by Health Canada (see Obtaining an authorization), prior to the start of the trial. The start of a clinical trial at a site is further contingent on the following:

1. 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 11(2)(e) and 11(2)(g)
2. before the sale or importation of the drug to a clinical trial site, the sponsor has submitted a Clinical Trial Site Initiation form 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 investigator for each clinical trial site [11(2)(c)]
   2. the name of any applicable national research ethics boards, or the name and contact information of the research ethics board that approved the protocol referred to in paragraph 11(2)(e)
   3. the proposed date for the commencement of the clinical trial at each clinical trial site [11(2)(l)]

The sponsor must notify the Minister of any changes to the above information, as well as the proposed date for resuming clinical trial activities at a previously closed site, if the sponsor intends to recommence the trial at the clinical trial site.

For the full list of requirements, consult Draft guidance for clinical trial sponsors: Clinical trial applications.

Terms and conditions

Interpretation

The Minister has the ability to impose Terms and Conditions (T&Cs) on an authorization, and amend them, on a case-by-case basis at any time over the lifecycle of a trial to mitigate risks or address uncertainties.  

During the course of their duties Health Canada inspectors may chose to verify that T&Cs, if applicable, are being met and would include these into the scope of their inspections accordingly.

Please refer to the Draft guidance for clinical trial sponsors: Clinical trial applications for detailed guidance on Terms & Conditions.

Amendments

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 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 participants. Amendments must be authorized by Health Canada prior to implementing the changes.

Prior to implementation of a CTA-A at a site, an investigator must obtain approval from the REB as per section 17(1) of the Regulations.

As per subsection 24(1), if a sponsor needs to make an immediate change because the clinical trial or use of the drug endangers the trial participants or other persons, the sponsor may make the amendment without prior review by Health Canada. The Sponsor must notify Health Canada within 7 days of the change and the reasons for the change. The sponsor must ensure that an application for amendment (CTA-A) is submitted to Health Canada within 30 calendar days after the date of implementation of the amendment.

Note that Health Canada's guidance document for clinical trial sponsors, Draft guidance 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.

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

• The sponsor did not notify Health Canada and submit a CTA-A within required timeframes after a change was made that met the criteria for an amendment.

Transfer of authorization

Interpretation

It is important that all the required clinical trial records are transferred completely such that the new sponsor can fulfil their requirements under the Regulations.

Records observations have been made during inspections whereby the required record-keeping was not kept intact. The situation also arises where there is a change in service providers.

For more information see Draft guidance for clinical trial sponsors: Clinical trial applications.

Suspension and revocation

Interpretation

Health Canada may 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 has reasonable grounds to believe that any of the circumstances outlined in section 26 apply. Before suspending under s. 26, Health Canada will send the sponsor a written notice communicating our intent to suspend the authorization. This notice will outline whether the authorization is to be suspended in whole or in part, and the reason for the suspension.

The sponsor has 30 calendar days after receiving the notice of intent to suspend to provide Health Canada with information or material necessary to demonstrate that the authorization should not be suspended on the basis that:

• the situation giving rise to the intended suspension did not exist, or
• the situation giving rise to the intended suspension has been corrected

If the notice arose from an inspection, the details of what gave rise to the intent to suspend can be found in the Inspection Exit Notice. The Inspection Exit Notice will explain each observation (issue or deficiency representing non-compliance with one or more of the Regulations). The sponsor has 30 calendar days to respond to the observations in the Exit Notice and should work with participating investigators and service providers in order to develop a Corrective and Preventive Action (CAPA) plan. 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 participants in the study and the integrity of the collected data at that site. The response to the Inspection Exit Notice will be considered as part of the response to the notice of intent to suspend.

After reviewing all the information the sponsor provides, Health Canada would determine whether the situation giving rise to the intended suspension did not exist or has been corrected.

If Health Canada decides to suspend the authorization it will issue a notice indicating 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 will 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 may result in revoking the authorization, either in its entirety or in part, as the case may be.

Health Canada may suspend an authorization to sell or import a drug for the purposes of a clinical trial under section 27, in its entirety or in part, 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 participant or other person.

In the context of an immediate suspension, Health Canada will send the sponsor a written notice indicating 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.

In the case of immediate suspension, the sponsor would have 60 calendar days, from the date of the suspension letter, to respond with information and material, including samples.

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

• 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
• revoke 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

Notification Requirements for Sponsors: Suspension

To ensure that personnel involved in the clinical trial activities are made aware, a sponsor is required to notify the following parties in writing, without delay, if the clinical trial is suspended:

• investigators
• service providers
• other persons under the sponsor's oversight, and those persons under the oversight of the investigators service providers (above) who help conduct the clinical trial; and
• those that import and/or sell the drug for use in the trial, as the case may be

Additional guidance about notifications of suspension and discontinuation of a trial

In addition to those requirements set out in the Regulations with respect to the discontinuance, suspension or cancellation of authorization, section 3.17.1 of ICH E6 states that in the event of such an occurrence, the sponsor should:

• promptly inform the investigators/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 investigator/institution, as specified by the applicable regulatory requirement(s)

Section 2.6 of ICH E6 sets out the responsibilities of an investigator/institution in the event they decide to prematurely terminate or suspend a clinical trial.

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

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

If an investigator terminates or suspends a trial without prior agreement of the sponsor:

• the investigator/institution should inform the institution where applicable
• the investigator/institution should promptly inform the sponsor and the REB, and provide them with a detailed written explanation of the termination or suspension (ICH E6, 2.6.2)

If a sponsor terminates or suspends a trial (see ICH E6, 3.17.1):

• the sponsor should promptly inform the institution where applicable
• the investigator/institution or sponsor should promptly inform the REB and regulatory authorities and provide them with a detailed written explanation of the termination or suspension (ICH E6, 2.6.3)

If the REB terminates or suspends its approval/favourable opinion of a trial (see section 50 of the Regulations and also ICH E6 1.2.3 and 1.4.9):

• the investigator must inform the institution where applicable
• the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension (ICH E6, 2.6.4) 

Direction to cease conduct

Interpretation

The direction to cease conduct provisions strengthens Health Canada's ability to manage risks and protect the health and safety of participants in Phase IV studies. Similar to the provisions for suspension and revocation (s. 26 to 35) Health Canada will offer sponsors a prior opportunity to be heard if there is no immediate health and safety risk to participants or other persons. Otherwise, Health Canada will direct the sponsor to cease the conduct of the trial immediately to prevent further harm.

Cease with opportunity to be heard: Health Canada can direct the sponsor to cease the conduct of the trial, in whole or in part, if Health Canada believes:

1. The Food and Drugs Act and its Regulations have been violated
2. Information about the product or trial is false or misleading
3. Good clinical practices haven't been followed

Before ceasing under section 38 the Minister will send the sponsor a written notice of the direction to cease the conduct of the clinical trial. This notice will include the reason for ceasing the trial, either in its entirety or in part, and will give the sponsor an opportunity to respond in writing regarding the notice.

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

• the situation giving rise to the intended cease did not exist, or
• the situation giving rise to the cease order has been corrected

If, within 30 days, the sponsor is unable to provide satisfactory information, and a cease is deemed necessary, Health Canada will cease the conduct by sending the sponsor a written notice to cease conduct. This notice will indicate the effective date of the order, specify whether the clinical trial must cease in whole or in part, and provide the reasons for the cease order.

Health Canada will remove the direction to cease if, within 30 days after the effective date of the direction to cease letter, the sponsor provides Health Canada with information or documents that demonstrate that the situation giving rise to the cease order did not exist or it has been corrected.

National Research Ethics Boards

Interpretation

The proposed Regulations permit the use of a National Research Ethics Board (national REB). A national REB would be defined as an REB that is set out on the List of National Research Ethics Boards that is published by the Government of Canada on its website (refer to Definitions subsection 1(1)).

A national REB would still have to meet the requirements for all REBs (refer to section 3). Enabling the use of a national REB is intended to reduce duplicative REB reviews across multiple sites, by allowing a national REB to approve the protocol and informed consent form in respect of all trial sites, therefore reducing the burden on industry and government.

Good clinical practices

The Regulations establish that the sponsor has the overall responsibility for conducting a clinical trial involving drugs in participants, including that the clinical trial be conducted in accordance with GCP [paragraph 46 (1) (a) through (j)].

The ICH guidance Guideline for Good Clinical Practice E6(R3) provides standards and recommendations pertaining to GCP. Health Canada is a standing member of the ICH, and plans to fully adopt ICH E6(R3) by April 1, 2026.

Clinical trial protocols are designed and followed

Interpretation

The clinical trial protocol is a study plan. It is designed to ensure that the objectives of the study can be met. The 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.

For clinical trials requiring the filing of a CTA to Health Canada, compliance with section 46(1)(a) and (b) is determined at the time of CTA review by Health Canada (refer to guidance on section 11 for Application for Authorization requirements and section 18 on Terms and Conditions).

The role of the GCP inspection is not to evaluate the protocol on its design or merits but to verify that the protocol is being followed as written and as authorized.

The sponsor must ensure that the clinical trial is conducted in accordance with the requirements of the protocol (including taking into account any subsequent amendments), which has been authorized by Health Canada and approved by REB(s). At the time of the authorization the Minister may have placed terms and conditions, with the requirements as outlined in section 18, and the trial conduct also needs to take these into account.

“Drugs involved in the clinical trial” refers to the drug(s) being tested, and where applicable, the comparator product(s) and other drug(s) used for the needs of the trial.

Trial sites 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 their root cause and determine their overall impact.

Systems and procedures are implemented

Interpretation

In accordance with the Regulations, the sponsor, whether commercial or academic, is responsible for establishing a quality system that consists of documented procedures to assure the quality of every aspect and stage of a clinical trial. This quality management system must be implemented across all trial sites. In doing so, the sponsor ensures that the trial design and trial conduct, the processes undertaken and the information and data generated are of sufficient quality to ensure reliable trial results, trial participants' safety and appropriate decision making. (ICH E6, 3.9.1).

A risk-based approached should be used while designing and implementing a quality management system. Sections 3.10.1.1 to 3.10.1.6 of ICH E6 provides further guidance. Factors to consider include the following:

• Risk identification: Identify the critical-to-quality factors – those that that are likely to have a meaningful impact on participants' rights, safety and well-being and the reliability of the results (critical to quality factors are further described in ICH E8(R1))
• Risk evaluation: Evaluate the identified risks and existing controls in place to mitigate them
• Risk communication: Document and communicate about the identified risks and the chosen mitigating activities to those taking action or to those that will be affected
• Risk review: The sponsor should periodically review the risk control measures to determine whether the activities are being implemented appropriately, accounting for new information, and determining whether additional controls should be introduced
• Risk reporting: Sponsors should summarize and report important quality issues and document any remedial actions taken

Quality assurance and quality control

As per section 3.11 of ICH E6, the sponsor is responsible for establishing, implementing and maintaining appropriate quality assurance and control processes, and documented procedures to ensure that trials are conducted and data are generated, recorded and reported in compliance with the protocol, GCP and applicable regulatory requirements.

The sponsor is also responsible for securing an agreement from all involved parties to ensure direct access (see ICH E6, Glossary, Direct access) to all trial related sites, source data/documents, and reports. This is to facilitate monitoring and auditing by the sponsor themselves, and inspection by regulatory authorities ICH E6, 3.6.3(d).

It is critical that quality control be applied using a risk-based approach at each stage of data handling to ensure that all data are reliable and have been processed correctly (ICH E6, 3.11.3).

Service providers

A sponsor may delegate any or all of the sponsor's trial-related duties and functions to service providers, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, as per the Clinical Trials Regulations. The service provider should implement quality assurance and quality control that is commensurate with their trial-related duties and functions. The sponsor should provide the service providers with the protocol where necessary as well as any other documents required for them to perform their activities. (ICH E6, 3.6.6 and 3.6.7).

All agreements made by the sponsor with the investigator/institution, service providers, and any other parties involved with the clinical trial should be in writing prior to initiating the activities (ICH E6, 3.6.1). This can be written as part of the protocol or in a separate agreement. 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 service provider (ICH E6, 3.6.9).

Standard operating procedures (SOPs)

An SOP may be trial specific or site specific, and may be provided by the site, the institution or the sponsor. There should be documentation that adequately covers all critical study-related activities.

Examples of critical procedures include, but are not limited to, the following:

• informed consent process
• recording, managing and reporting of adverse events
• storage and handling of clinical trial drugs
• drug accountability
• handling of biological samples
• equipment maintenance and calibration
• training of study personnel
• monitoring (that is, procedure that assures the quality of every aspect of the clinical trial)
• computerized systems, information and data management
• record retention for 15 years

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 for SOPs but there are elements that can support their management and use. These may include:

• title and version number
• date of revision and an effective date (they may coincide)
• a system to ensure that readers have a complete document, such as indicating the page count (resembling a ‘Page X of Y' format)
• ensuring that the SOP is accessible to all locations for the implicated personnel, especially where the relevant activities are carried out; and
• a means of archiving older versions

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 participants 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, 3.11.4).

Section 3.11.4 of ICH E6 provides detailed guidance with respect to monitoring, including:

• selection and qualification of monitors
• extent and nature of monitoring (including site-specific or centralized)
• monitor's responsibilities
• monitoring procedures and activities
• monitoring reports
• monitoring plan

The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. Section 3.11.4 of ICH E6 describes flexibilities in monitoring that is intended to permit varied approaches to improve its effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring exclusively. The sponsor should document the rationale for the chosen monitoring strategy (for example, in the monitoring plan).

On-site monitoring is performed at the sites where 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 (for example, 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.

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.

For additional information, refer to the U.S. Food and Drug Administration (FDA) A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers published in 2023.

The sponsor should develop a monitoring plan that addresses participant protection and data integrity. The plan should describe the following:

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

The plan should focus on aspects that are critical to quality. 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 procedure (ICH E6, 3.11.4.3).

Institution/Investigator-sponsored clinical trials

In the situation where a clinical trial is sponsored by an institution/ investigator, and the trial is conducted by a group of physicians at different sites, it is the institution/investigator identified on the CTA as the sponsor, who is required to monitor the trial at all investigative sites.

This institution/investigator assumes the responsibilities of both the sponsor and the qualified investigator. This would include ensuring that all of the sponsor's obligations under the Clinical Trials Regulations are met at each site, and that each site follows GCP.

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, 3.11.4.6).

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 trial's conduct and compliance with the protocol, SOPs, ICH E6 and applicable regulatory requirements (ICH E6, 3.11.2).

Additional guidance on the selection and qualification of auditors, as well as auditing procedures, can be found in sections 3.11.2.1. and 3.11.2.2 of ICH E6.

Section 3.12 of ICH E6 states that noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator or institution, or by member(s) of the sponsor's staff should lead to appropriate action by the sponsor to secure compliance.

If noncompliance is discovered that significantly affects or has the potential to significantly affect participant rights or safety, or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Where the sponsor identifies issues that are likely to significantly impact the rights, safety or well-being of the trial participant(s) or the reliability of trial results (that is, serious noncompliance), the sponsor should notify the regulatory authority, the REB, and investigators, as appropriate and in accordance with regulatory requirements. (ICH E6, 3.12.2).

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 should be considered critical when they are:

• used to generate critical data (for example, efficacy and safety endpoints) and maintain its integrity
• used for important study-related tasks (for example, participant selection criteria, storage of the study drug) and/or
• significantly affecting the safety and well-being of the participants, including informing the decisions about whether or not a participant should continue the study

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. Records demonstrating fitness for purpose (that is, maintenance and calibration) for equipment must be maintained. 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.

Equipment used in the study classified as medical devices must be licensed in Canada for Class II, III and IV (except Class I) or have an Investigational Testing Authorization (ITA) for use in that study and must be in compliance with the Medical Devices Regulations.

Research Ethics Board (REB) approval

Interpretation

Health Canada's relevant regulations set out requirements for the composition of REBs for the purpose of satisfying federal regulatory requirements, 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 3 of the proposed Regulations 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.

Annex 1, Section 1.2 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 participants. An REB should pay special attention to trials that may include vulnerable participants (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, 1.2.2).

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 participants, to ensure that the highest standards are in place to ensure their safety (ICH E6, 1.2.4). An REB should follow its established and documented procedures as per ICH E6, 1.4.

One investigator for each site

Interpretation

Refer to the definition of Investigator in Appendix A of this guidance (also section 1, Interpretations of the Clinical Trials Regulations. The interpretation of Clinical trial site is provided in section 2(1)of the Regulations.)

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 participant and where the participant returns for subsequent assessment.

Delegation logs

The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties (ICH E6, 2.3.1).

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 (for example, 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 investigator should sign and date the log prior to a task being delegated. Site personnel should not conduct study specific tasks until the investigator has documented the delegation, and appropriate training has been completed.

Within the log, an investigator may designate other appropriate professionals (research staff, nurses, optometrists, etc.) to perform critical trial-related procedures and/or to make important trial-related decisions (that is, sub-investigators). However, the investigator is always accountable for the actions and decisions taken.

An investigator may also identify ‘sub-investigator(s)' who can, for short absences only, assume the qualified investigator's full responsibilities. It should be well documented who is acting as the investigator at any point in time. CTSI forms are not required to be updated for acting.

When tasks are delegated to a person in charge of other staff (for example, 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 (for example, routine X-ray), or as part of care provided on an ad hoc basis (for example, emergency room procedures) and are not specific study procedures do not require specific training and delegation from the investigator (refer to section 46(1)(h) of the Regulations).

Delegated duties, to be captured in a delegation log, are dependent on the trial and may include, but are not limited to:

• obtaining informed consent
• review of participant eligibility (inclusion/exclusion criteria)
• collection, assessment and reporting of (serious) adverse events (AEs)
• investigational drug administration
• investigational drug accountability
• biological samples (collecting, processing and shipment)
• randomization
• any function requiring specific training (for example, psychiatric scales/questionnaires)
• medical history
• physical examination
• maintenance of essential records – data source capture
• case report form data entry
• data query resolution and response (including signature)
• laboratory results review
• correspondence with REB
• an “other task” section should be used to declare and assign functions specific to the protocol

Clinical trial site information forms

The Clinical Trial Site Information (CTSI) form is required to be submitted by clinical trial sponsors prior to initiating a protocol or implementing subsequent amendment(s) at the clinical trial site for trials that are subject to the Clinical Trials Regulations.

Locations where ancillary medical procedures (for example, 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 (for example, change of investigator) a revised CTSI form should be submitted to Health Canada.

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

Please refer to the Draft guidance 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 CTSI forms. For further clarifications, contact the appropriate Health Canada Directorate (PDD or BRDD).

Appropriate supervision for medical care and medical decisions

Interpretation

The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems (see also ICH E6, 2.7.1).

The sponsor assigns the responsibility of medical care, medical decisions and day-to-day running of the clinical trial site to the investigator (refer below to Adequate medical oversight of a clinical trial). However, it should be noted that the medical roles can be distinct from the roles of the investigator.

This means that activities which fall under the purview of medical care must be conducted by a qualified, licensed physician or dentist, within their scope of practice/expertise. This could be either the investigator themself, or adequately qualified individual to whom the investigator has delegated the activities. All delegated activities must be documented on the delegation log.

Such activities include, but are not limited to:

• physical examinations
• review and interpretation of diagnostic and laboratory results
• review and assessment of AEs and serious adverse drug reactions (SADRs), whether or not they are expected
• review of eligibility criteria outlined in the study protocol

Evidence of this 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 investigator. 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.

It is recommended that the investigator inform a participant's primary physician about their participant's involvement in the trial if the participant has a primary physician and if they agree to their primary physician being informed (ICH E6, 2.7.1).

During and following a participant's involvement in a trial, the investigator should ensure that adequate medical care is provided for any adverse events (AEs), including clinically significant laboratory values, related to the trial. The investigator should inform a participant when medical care is needed for intercurrent illness(es) of which the investigator becomes aware (ICH E6, 2.7.1).

Personnel education, training and experience

Interpretation

The sponsor should utilise appropriately qualified individuals for the activities to which they are assigned (for example, biostatisticians, clinical pharmacologists, physicians, data scientists/data managers, auditors and monitors) throughout the trial process. (ICH E6, 3.4).

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

Documentation to support the qualification of individuals must be available for inspection and could include one or more of the following:

• professional licences
• curriculum vitae (CVs)
• copies of degrees, certificates and/or diplomas
• records of participation to training

The investigator should ensure that persons or parties to whom the investigator has delegated trial-related activities are appropriately qualified and are adequately informed about relevant aspects of the protocol, the investigational product(s) and their assigned trial activities (including activities conducted by staff provided by other parties in accordance with local regulatory requirements). Trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfil their delegated trial activities that go beyond their usual training and experience (ICH E6, 2.3.2).

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 pertaining to delegated trial-related duties is also recommended.

Training may take place by various formats, such as:

• sponsor-provided training (for example, during study start-up meetings)
• site-initiated training (for example, during staff meetings or seminars)
• self-training (for example, reading applicable protocols, manuals and presentation slides)
• attending events provided by industry or clinical research associations, as well as educational institutions

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.

Example of observation typically cited under this section of the Regulations includes:

Not all individuals conducting the clinical trial had the education, training and experience to perform their respective tasks.

Informed consent

Interpretation

Informed consent refers to the process by which a participant voluntarily confirms their willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the person's decision to participate (ICH E6, 2.8). 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.

The materials to be provided to participant should explain the following as applicable (ICH E6,2.8.10):

1. The purpose of the trial
2. That the trial involves research and summary of the experimental aspects of the trial
3. The trial's investigational product(s) and the probability for random assignment to the investigational product, if applicable
4. The trial procedures to be followed including all invasive procedures
5. What is expected of the participants
6. The reasonably foreseeable risks or inconveniences to the participant and, when applicable, the participant's partner, to an embryo, foetus or nursing infant
7. The reasonably expected benefits. When there is no intended clinical benefit to the participant, the participant should be made aware of this
8. The alternative procedure(s) or course(s) of treatment that may be available to the participant and their important potential benefits and risks
9. The compensation and/or treatment available to the participant in the event of trial-related injury
10. Any anticipated prorated compensation to the participant for trial participation
11. Any anticipated expenses to the participant for trial participation
12. That the participant's trial participation is voluntary, and the participant may decide to stop taking the investigational product or withdraw from the trial at any time, without penalty or loss of benefits to which the participant is otherwise entitled
13. The follow-up procedure for participants who stopped taking the investigational product, withdrew from the trial or were discontinued from the trial
14. The process by which the participant's data will be handled, including in the event of the withdrawal or discontinuation of participation in accordance with applicable regulatory requirements
15. That by agreeing to participate in the trial, the participant or their legally acceptable representative allows direct access to source records, based on the understanding that the confidentiality of the participant's medical record will be safeguarded. This access is limited for the purpose of reviewing trial activities and/or reviewing or verifying data and records by the regulatory authority(ies) and the sponsor's representatives, for example, monitor(s) or auditor(s), and in accordance with applicable regulatory requirements, the IRB/IEC(s)
16. That records identifying the participant will be kept confidential and, to the extent permitted by the applicable regulatory requirements, will not be made publicly available. If the trial results are published, the participant's identity will remain confidential. The trial may be registered on publicly accessible and recognised databases, per applicable regulatory requirements
17. That the participant or the participant's legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the participant's willingness to continue trial participation
18. The person(s) to contact for further trial information and the trial participant's rights, and whom to contact in the event of suspected trial-related injury
19. The foreseeable circumstances and/or reasons under which the participant's trial participation may be terminated
20. The expected duration of the participant's trial participation
21. The approximate number of participants involved in the trial
22. That trial results and information on the participant's actual treatment, if appropriate, will be made available to them should they desire it when this information is available from the sponsor

The risks and inconveniences should not outweigh the anticipated benefits when participating in a trial. The rights, safety and well-being of the trial participants are the most important considerations and should prevail over interests of science and society (ICH E6, II.1.3).

Informed consent is documented by means of a written (paper or electronic format), signed and dated informed consent form (ICF) (ICH E6, 2.8.7, and Glossary). The ICF must be made available for each participant in either official language or other as appropriate. A clinical trial participant cannot be involved in any aspect of a clinical trial until they have gone through the ICF process, either in person or remotely, and freely give their consent by signing the document indicating that they understand 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 participant to participate or to continue to participate in a trial (ICH E6, 2.8.3). A qualified physician should be available to answer any medical questions that the participant may have regarding their participation in the study.

The Regulations speak to “documented informed consent”. The broad meaning of documented could allow for informed consent to be obtained over alternative approaches, including telecommunications, provided that the method used is adequately documented in the site's informed consent procedures along with a rationale and justification for their use. orally or by other means and then subsequently documented in writing for the purpose of record keeping. The sponsor should have a system in place to ensure that alternative means of obtaining informed consent is demonstrating that the consent is attributable to the participant and often this means having an impartial witness to attest that they were present for the informed consent process with the participant.

The original, and all amended ICFs and any other written information to be provided to participants, must be approved by an REB prior to being presented to trial participants (see section 11(2)(i) of the Regulations and ICH E6, 2.8.1).

The investigator 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. 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, 2.8.1).

Health Canada expects that sponsors can demonstrate that the participant has read and understood the entire informed consent document(s). This could be through initialing each page of the ICF, or a statement included at the end stating that the participant has read and understood all the pages.

The ICF should be paginated to ensure that the complete document is presented to the participant.

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

During a clinical trial inspection, the ICF is reviewed to ensure that:

• the correct version, approved by the REB, has been signed and dated by the participants prior to any study-related procedures
• the statements of risk submitted to Health Canada are included
• additional and specific requests from Health Canada and/or the REB and/or the institution/hospital, have been included
• any new information concerning the safety of the patients/participants has been included
• the participants have been informed of this information in either official languages, or other as appropriate

Additional guidance on the informed consent document and the process of obtaining the informed consent can be found through ICH E6 (section 2.8), 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 2.8.2 of ICH E6 states that clinical trial participants should be made aware of important new information as soon as it becomes available, as it may affect a participant's willingness to participate. The new information should be explained to the participant or the participant's legally acceptable representative in a timely manner, especially if the new information can have an immediate impact on the participant'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. Participants 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.

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 participant re-consent. This is especially valuable when there are a large number of amendments and/or participants enrolled in a study.

Participants not capable of informed consent

If the participant is unable to provide consent themselves (for example, minors, patients with severely impaired decision making capacity), the participant's legally acceptable representative should provide their consent on behalf of the participant (ICH E6, 2.8.5). A written procedure that outlines this process can be incorporated into an existing SOP for obtaining informed consent or it can be a stand-alone procedure.

Where a minor is to be included as a participant, age-appropriate assent information should be provided and discussed with the minor as part of the consent process, and assent from the minor to enrol in the trial should be obtained as appropriate. A process for consent should be considered if, during the course of the trial, the minor reaches the age of legal consent, in accordance with applicable regulatory requirements (ICH E6, 2.8.12).

As per ICH E6 section 2.8.8, in emergency situations, when prior consent of the participant is not possible, the consent of the participant's legally acceptable representative (as defined by provincial requirements), if present, should be requested. If the legally acceptable representative is not available, enrolment of the participant should require measures described in the protocol and/or elsewhere, with documented approval by the REB. (See also the requirements under section 47 of the Regulations and accompanying interpretation that in this guidance document).

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 participant 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 participant fast before the screening visit is sometimes used for their benefit because this practice would allow the participant 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 (for example, 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 participant are mitigated.

Electronic ICFs

The use of electronic ICFs may be acceptable. Requirements include, but are not limited to the following:

• the system must be properly validated (ICH E6, 4.3.4), with documented procedures and appropriate training
• all required elements of section 46(1)(j) and 47 (if applicable) and elements included in ICH E6, 2.8.10 as applicable must be present in the ICF
• the information must be kept for 15 years provision 61(2)(g) and 66(1)

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

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 participant must understand that any electronic signature is equivalent as a handwritten signature on paper.

For more information on computerized system validation, refer to Guidance for section 61 Records of the proposed CTR.

Proper fabrication, handling and storage of trial drugs

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 3.11.4.5.3, 3.15.2 and 3.15.3 of ICH E6.

From an inspection perspective, 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 could be submitted by the sponsor for consideration 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 drug(s)

The sponsor should establish and maintain a system to ensure that drugs can be traced throughout the chain of custody and the sponsor should ensure that the role of each party is clearly outlined in writing. As per sections 61(2)(e) and (f) of the Regulations, records of the clinical trial drug's delivery to the trial site, the inventory at the site, the use by each participant, and the return to the sponsor or alternative disposition of unused clinical trial drugs, should be available in order to demonstrate traceability.

These records should include, but are not limited to:

• dates
• quantities
• batch/serial numbers
• expiration dates
• unique code assigned to the drug(s) and trial participants

Essential to this process is adequate labelling in accordance with section 67 of the Regulations (see section regarding Labelling in this document).

Storage and transportation conditions

The sponsor should identify critical conditions for storage and transportation. Scientific/technical justification should exist to demonstrate that the means used to store and transport the product do not affect its quality.

Factors to be taken into consideration by the sponsor when determining the approach for storage and transportation may include, but are not limited to:

• nature of the drug products (for example, temperature sensitive vs stable tablets)
• modes / distance of transport, and any seasonal variations to be experienced
• special handling precautions (for example, relative humidity, light, use of dry ice)
• level of control of storage conditions (for example, environmentally controlled areas, such as a hospital vs. office clinic)
• product labelling
• transportation container, packaging configuration

Inadequate transportation and storage conditions may affect a sponsor's ability to trace a clinical trial drug and it may have an impact on its quality and safety. 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 should 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 should 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 (for example, use of validated shipping containers).

This applies also to authorized 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 inspection 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.

These guidelines apply both to drugs that require refrigerated or frozen transportation and storage temperatures, and also those that must be transported and stored at ambient temperature.

Other persons involved in clinical trial conduct

Interpretation

This is a new requirement that all other personnel that help conduct a clinical trial are following Good Clinical Practices that are outlined in subsection 46(1). The expectation is that GCP is to be followed as applicable with the person's duties.

Clinical trials involving medical emergencies

Refer to informed consent in this guide as well as subsections 46(1)(j)(k) and section 47 for requirements when obtaining informed consent in a trial involving medical emergencies.

Exception: Drug used as authorized

Interpretation

Drugs that have been issued a notice of compliance and/or a DIN are being used as outlined in their product monograph will already have conditions for handling and storage, including on the packaging and the product leaflet. It is expected that these conditions are to be followed during a clinical trial.

Provision of information

Notification of change

Interpretation

As per section 49 of the Regulations, sponsors that hold an authorization for a clinical trial must notify the Minister, within 15 days of certain changes including:

• changes to names and contact information for the following, as applicable:
  • sponsor or Canadian representative of a foreign sponsor
  • representative(s) responsible for importation and/or sale of the drug in Canada
  • investigator(s)
  • service provider(s)
  • research ethics board(s)
• amendments to the protocol that do not change the risk to participants or other people (that is, amendments that do not have requirements under section 19 of the regulations)
• changes to the chemistry and manufacturing information of a drug that does not affect safety or quality.

Moreover, section 3.15.2 of ICH E6 states that

“If significant formulation changes are made in the investigational product(s)(including active control(s) and placebo, if applicable) during the course of clinical development, the results of any additional studies of the formulated product(s) (for example, 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 19(2), the sponsor must submit a Clinical Trial Application-Amendment (CTA-A). Note that Health Canada's Draft guidance 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.

As per section 50 of the Regulations, sponsors must notify the Minister, within 15 days after becoming aware of a change that includes

• any information referred to in section 11(2)(j) and (k). These involve negative decisions or refusals from REBs or foreign regulators regarding the protocol; and
• changes in names and contact information of the REB(s) that withdrew approval with respect to the protocol or ICF and the reasons for doing so

As per section 51 of the Regulations, sponsors must also notify the minister within 15 days after a service provider begins their services to the sponsor or an investigator in the clinical trial (if this information was not already shared beforehand).

Serious unexpected adverse drug reactions

Interpretation 

The collection, assessment and reporting of adverse events (AEs, as defined in Appendix A; also see ICH E6 glossary) 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. The assessment of the site AEs should be done by the investigator or the person that is delegated to medical decision-making. When they become aware, the adverse event is assessed for seriousness, expectedness and causality is determined.

For all clinical trials for which an authorization has been issued, the reporting of serious unexpected adverse drug reactions to the Minister will be required during the trial. Post-trial reporting may also be required for certain clinical trials.

All serious adverse events (SAEs) should be reported immediately to the sponsor after the investigator reasonably becomes aware of the event. The investigator should also include an assessment of causality (ICH E6, 2.7.2). Exceptions include those SAEs that the protocol or other document (for example, Investigator's Brochure) identifies as not needing immediate reporting (for example, deaths or other events that are endpoints). The immediate reports should be followed promptly by detailed, written reports, including assessment of causality. The immediate and follow-up reports should identify participants by unique code numbers assigned to the trial participants rather than by the participants names, personal identification numbers, and/or addresses.

In accordance with section 52 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.

A complete report of a serious unexpected adverse drug reaction 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. 

Post-trial reporting may also be required by sponsors (who are authorization holders) for certain clinical trials.

In addition, in keeping with ICH GCP, the sponsor and/or investigator should expedite reporting of all SUADRs to all concerned investigator(s)/institution(s), the REB(s) where required (ICH E6, 2.7.2(c), 3.13.2(e)).

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). 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, 3.13.2).

Case reports and summary reports

Interpretation

The Minister may request, on a discretionary basis, case reports and issue-related summary reports related to adverse reactions and serious adverse reactions to the drug. These provisions would be similar, but not identical to, subsection C.01.018(5) (case reports) and section C.01.019 (issue-related summary reports) under the FDR.

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

Draft guidance 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). 

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

• The sponsor did not inform Health Canada within 15 days of becoming aware of serious unexpected adverse drug reactions in or outside Canada that were not fatal or life threatening. 
• The sponsor did not inform Health Canada within 7 days of becoming aware of serious unexpected adverse drug reactions in or outside Canada that were fatal or life threatening.  
• The sponsor did not submit a complete report with an assessment of its findings within 8 days of informing Health Canada of a fatal or life threatening serious unexpected adverse drug reaction. 

Discontinuation of a clinical trial

Interpretation

Please refer to “Post-authorization requirements” of the Draft guidance document for clinical trial sponsors: Clinical trial applications for further information.

Discontinuance of a clinical trial

In the event of the discontinuation of a clinical trial in whole or in part, the sponsor (authorization holder) would be required to notify the following parties:

• without delay, all investigators and the national research ethics board if one was used, about the discontinuance, the reasons why and to advise them of any potential health risks to those involved in the clinical trial
• within 15 days after the discontinuation, the Minister, stating the reasons why and informing about the risks that may be involved in the trial or any other clinical trial that involves the drug

The Sponsor must also stop the importation and sale of the drug used in the clinical trial and take measures to recover unused quantities of the drug that were distributed. Exemptions for the recovery of the drug do not apply to those that are already authorized for sale on the Canadian market and being used in a Phase IV trial.

Investigators who are notified by the trial sponsor of a discontinuation must, without delay, notify the participants and the REB, stating the reasons for discontinuation. Investigators must also advise about the potential health risks to participants and any other persons involved.

Notification of completion

This is a new regulatory requirement with respect to notification of study completion and site closures. Under these regulations, the sponsor (authorization holder) is required to notify the investigators, service providers and Minister of the completion date of the clinical trial and in the case of a trial with a master protocol of the sub-study's completion date within 15 days. The authorization would be deemed revoked in part following the completion of a sub-study or in whole following completion of the clinical trial.

Under these regulations, the sponsor (authorization holder) is required to notify the Minister, investigators and service providers of study completion. This could mean a closed clinical trial site, a sub-study, or the entire study. Closure means when the last visit of the last participant at the final location has finished.

Records

Interpretation

Note: These record-keeping and retention requirements also apply to clinical trials using drugs that will never be marketed regardless of the trial's outcome or the trial data's statistical significance or validity.

Roles and responsibilities

General

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, principle 9.4).

All clinical trial records shall be made available for Health Canada inspectors carrying out their duties. Clinical trial participants grant Health Canada inspectors direct access to their original medical records by signing the ICF, which should include a statement to this effect. A unique identifier is assigned by the investigator to each trial participant, to protect their identity when the investigator reports AEs and/or other trial related data (ICH E6, trial participant identification code, Glossary).

Records, especially 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 (for example, via an audit trail) (ICH E6, 2.12.2).

Sponsors

Many parties usually share the responsibilities of record-keeping and retention through delegation by the sponsor. Nevertheless, the sponsor is still ultimately responsible for ensuring that all parties involved in the conduct of the trial are in compliance with record retention requirements.

• It is recommended that the sponsor clarifies with investigators what documents are defined as source and how they are to be maintained.
• 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, prior to the commencement of the trial to ensure full compliance with regulatory requirements.
• The implementation of written procedures and the training of personnel should be documented. The procedures may be trial- or site-specific and be provided by the sponsor or the third party that was delegated the responsibility.
• Records should be identifiable and version controlled (when appropriate). They should also include authors, reviewers and approvers (as appropriate), dates and signatures (electronic or physical), where necessary.
• In order to fulfil their responsibilities in the conduct of the trial, the sponsor and investigator/institution may need access to or copies of one another's relevant essential records before and during the conduct of the trial. At the end of the trial, each party should retain their essential records (ICH E6, 2.12.11 and 3.16.3(a)).
• The sponsor should not have exclusive control of data captured in data acquisition tools in order to prevent undetectable changes (ICH 3.16.1(l)).
• For activities that are transferred or delegated to service providers by the sponsor or investigator/institution, respectively, arrangements should be made for the access and management of the essential records throughout the trial and for their retention following completion of the trial. The sponsor should retain the essential records in a way that ensures that they remain complete, readable and readily available and are directly accessible (ICH E6, Appendix C)

Investigators

An investigator is responsible for the conduct of the clinical trial at their site. It should be noted that an independent investigator, initiating a clinical trial under their own sponsorship, is responsible for all aspects of that trial, both as a investigator and as a sponsor.

• The investigator should support the sponsor in ensuring that essential records created and/or used under their supervision, including all source records, 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 2.12.12).

  Sites that neither screen nor enrol any participants 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. Since the sponsor of a clinical trial is responsible for maintaining all records, the investigator should consult the sponsor to confirm record retention requirements prior to destroying any records.
  Clinical trial sites with screen failures but no participants enrolled in a given clinical trial should retain all records, including ones pertaining to screen failures for the entire record retention period. All source documents should also be retained for the entire record retention period even if a participant has withdrawn from the clinical trial.

• Appropriate measures should be taken to prevent accidental or premature destruction of the records (ICH E6, 2.12.12, 4.2.7 and 4.3.6).

• Written agreements describing the procedures for records retention in accordance with the Regulations should be in place between all parties concerned.

• For example, investigators conducting clinical trials within a hospital or a medical clinic should secure a written agreement (for example, contract, policy, SOP), if applicable, with the institution. This would be to ensure that hospital records and/or medical charts of clinical trial participants are retained according to the federal Regulations. Where there is conflict between provincial laws and regulations, federal regulations take precedence.
• Agreements should also outline the conditions of record retention. Examples include the location of records, and procedures to ensure record retention. Additionally, these procedures should cover the required retention period in the event that a company ceases to exist or investigator ceases their affiliation with their institution (for example, closure of practice or retirement, new position elsewhere, or death).

• The investigator 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 investigator 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 sponsor, depending on the written agreement secured between these two parties. However, investigator always remain responsible to oversee the delegated tasks because they are responsible for the trial at their site.

• Section 2.12.5 of ICH E6 states that the investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the data acquisition tools completed by the investigator site (for example, CRFs) and in any other required reports (for example, SAE reports). The investigator should review and endorse the reported data at important milestones agreed upon with the sponsor (for example, interim analysis) (see section 3.16.1(o)). Furthermore, section 2.12.6 of ICH E6 states that data reported to the sponsor should be consistent with the source records or the discrepancies explained. Changes or corrections in the reported data should be traceable, should be explained (if necessary) and should not obscure the original entry.

Service Providers

Service providers will also have responsibilities for record-keeping and retention, similar to sponsors, to the extent that they are relevant to the service that they provide. Health Canada may request records produced, maintained and stored by service providers to verify compliance with the Regulations.

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 61 of the Regulations and Appendix C "Essential Records for the Conduct of a Clinical Trial" of ICH E6.

The investigators should define what is considered to be a source record(s), the methods of data capture and their location prior to starting the trial and should update this definition when needed. Unnecessary transcription steps between the source record and the data acquisition tool should be avoided (ICH E6, 2.12.2)

Essential records

Essential records are the documents and data (and relevant metadata), in any format, associated with a clinical trial that facilitate the ongoing management of the trial and collectively allow the evaluation of the methods used, the factors affecting a trial and the actions taken during the trial conduct to determine the reliability of the trial results produced and the verification that the trial was conducted in accordance with GCP and applicable regulatory requirements (ICH E6, glossary). These include, but are not limited to the following:

• investigator's brochure (or similar document), with regards to the elements of s. 11(2)(o) of the proposed regulations
• 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 participants
• records respecting the shipment, receipt, disposition, return and destruction of the drug
• protocols and protocol amendments
• REB approved ICF(s)
• signed and dated REB attestations
• standard operating procedures (SOPs)
• site personnel training records
• source records

Source records

A type of essential record that consist of original documents, data (including relevant metadata), (ICH E6, glossary). 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
• participant diaries
• appointment/scheduling records
• AEs and ADRs records
• pharmacy dispensing records
• drug accountability records

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

For guidance, the assessment of whether a record is essential should take into account the criteria outlined in ICH E6, Section C.3 (Essentiality of Trial Records).

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 records (for example, chart-based, electronic record, a combination).
Only specific and unique records that belong solely to the sponsor, the REB, the investigator 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 investigator/institution should have access to and the ability to maintain the essential records generated by the investigator/institution before and during the conduct of the trial and retain them in accordance with applicable regulatory requirements. (ICH E6, C.1.3).

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

In situations where original source records cannot be retained for the required retention period due to their deterioration in uncontrolled environment conditions (for example, 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 (for example, by a dated signature or by generation through a validated process) to have the same information as the original, including relevant metadata, where applicable (ICH E6, glossary).

Refer to Appendix C 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 participant diaries
• other instruments provided to the investigator or participants to record trial data

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 validation approach should be guided by a risk assessment that considers the system's intended use, the significance of the data and records it collects, generates, maintains, and retains, and the system's potential impact on participant safety, rights, and well-being, as well as the reliability of clinical trial outcomes. (ICH E6, Computerised Systems Validation in glossary and 4.3.4).

A validation plan and documentation of the system design specifications should be a part of the validation process for electronic systems. 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, investigator, 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, 4.3.1 and 4.3.2).

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 (for example, 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, software or operating systems 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 retention period.

Records created, maintained and processed by outsourced systems (that is, cloud computing) are subject to the same requirements as the data/records generated by company owned systems.

For electronic medical records system (for example, hospital-based systems) not under the responsibility of the sponsor, an alternate method to validation could be considered (for example, printing).

The responsibilities of the sponsor for data handling should ensure:

1. the integrity and confidentiality of data generated and managed (ICH E6, 3.16.1(a)).
2. data acquisition tools are fit for purpose and designed to capture the information required by the protocol. They should be validated and ready for use prior to their required use in the trial (ICH E6, 3.16.1(d)).
3. documented processes are implemented to ensure the data integrity for the full data life cycle (see section 4.2 of ICH E6) (ICH E6, 3.16.1(e)).

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 (for example, commercial vs. non-commercial)
• purpose of the clinical trial (for example, research for publication vs. drug submission for marketing authorization)
• status of the drug (for example, 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, 3.10.1 and 4.3.4).

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

Pharmacy records

Pharmacy records should be retained as either part of the participant-specific source record or the medical or hospital chart. These records include, but are not limited to the following:

• 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 the following:

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

The investigator and/or a pharmacist or other appropriate individual should maintain records of the product's delivery, the inventory, the use by each participant (including documenting that the participants were provided the doses specified by the protocol) and the return to the sponsor and destruction or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable) and the unique code numbers assigned to the investigational product(s) and trial participants. (ICH E6,2.10.4).

In a Phase IV clinical trial that does not require a Clinical Trial Application (CTA) drug accountability should be managed in accordance with standard pharmacy practices and applicable good practice guidelines.

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

Retention of laboratory records supports the review and verification of diagnostic results and reports. It also enables appropriate follow-up testing when necessary, thereby helping to safeguard the safety and well-being of trial participants. These records include, but are not limited to the following:

• 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 discs

Medical instrument records

The sponsor should identify critical equipment used in a study and its specifications [refer to section 46(1)(e)].

All service, maintenance, cleaning and calibration records, and product manuals for critical equipment should be retained for the required 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 equipment or instruments (for example, body weight scales) does not generate a certificate or a print-out to demonstrate that the calibration was indeed performed and successful. In those circumstances, the investigator 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 the actual calibration results kept as a record.

Some equipment or instruments may require frequent automated calibration, which can generate large volumes of printouts. In such cases, a calibration log should be maintained that includes all relevant information outlined previously. Additionally, the log must identify the individual who reviewed and verified the calibration data—not just the person who performed the calibration—to ensure proper oversight and confirm that the calibration was successful.

Research Ethics Boards (REBs) records

Records that pertain to the roles and responsibilities of the REB should be retained for the required period in accordance with section 66 of the Regulations. These records could include, but are not limited to the following:

• REB membership including roles and responsibilities (for example, chair, ethics, community representative), as a way of satisfying the characteristics outlined in section 3 of the Regulations
• qualifications of REB members
• REB decisions (for example, approvals, denials, required modifications, orders to stop clinical trials, etc.)

The REB may be asked by investigators, sponsors or regulatory authorities to provide its documented procedures and membership lists (ICH E6 1.5.2)

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 (for example, 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 (that is, 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/investigator/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 (that is, 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 (for example, 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 (for example, medical records), institutional and legal requirements.

It is considered acceptable, for example, to scan records in an electronic format and store them on specific software or networks as well as on other devices such as flash drives (for example, 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 record in archive must be retained, whether in hardcopy or electronic format, records from their original medium (for example, hardcopies) should be kept for as long as they are needed. When a copy is used to replace an original record (for example, source records, CRF), the copy should fulfil the requirements for certified copies as defined above (see ICH E6, glossary).

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-72.34-2024.

Record retention period

As per subsection 66(1), the sponsor shall maintain all records referred to in sections 61, 62, 63(2) and 64(2) for a period of 15 years. Sponsors may also be required to maintain records under provincial law, institutional policies, and contractual agreements with investigators, REBs or others. The federal requirement to maintain records for at least 15 years would not prevent records being maintained for longer periods of time, if doing so were required under provincial law.

The beginning of the retention period is outlined in section 66(2) of the Regulations, but in general, it commences on the day on which the authorization is revoked or the day on which the trial is completed, discontinued or the date the trial was ordered to cease.

Location of records

Often, third parties (such as investigators, REBs, service providers) 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 record. Third parties should consult the sponsor prior to destroying any record.

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 (for example, 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 investigator/institution should maintain a record of where essential records are located, including source records. The storage system(s) used during the trial and for archiving (irrespective of the type of media used) should provide for appropriate identification, version history, search and retrieval of trial records (ICH E6, C.2.4)

It should be noted that specific timelines for the provision of clinical trial information to Health Canada are outlined in the Regulations. Sponsors should ensure they are able to retrieve records in a timely manner when determining the location and the medium of storage.

If the records are stored on a cloud drive, 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.

Labelling

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 sponsor is ultimately responsible for ensuring that the labelling of a clinical trial drug meets the requirements of sections 67 of the Regulations.

Traceability to the manufacturing lot must be maintained on the label affixed to the primary container of the investigational product. This traceability is essential to ensure the drug is dispensed to the correct clinical trial participant, stored under appropriate conditions (for example, temperature), and used within its expiry period. Inclusion of the lot number also facilitates product recall, if necessary.

In blinded trials, labeling must be designed to preserve the blind while still meeting regulatory requirements. As outlined in ICH E6(R3), Section 3.15.2, labeling should be coded in a way that maintains blinding. Use of a manufacturer's lot number on the label may compromise blinding; therefore, a unique identifier system should be implemented to ensure traceability without revealing treatment allocation.

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

For additional information on labelling, please refer to Guidance document – Annex 13 to the current edition of the GMP guidelines: Drugs used in clinical trials (GUI-0036) (currently under revision).

Alternatives to clinical trial drug lot numbers

Where a bar code is included as the identifier on the label, the code on the drug label should readily link to information (for example, 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 support record-keeping (refer to section 61, Records).

Clinical trial drug expiry dates

During an inspection, Health Canada may verify that the clinical trial drug has a valid expiration date (that is, that it is still ‘in-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 participant, the sponsor is responsible for demonstrating that the drug used at the clinical trial site meets all of the requirements of section 67. 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.

Labels of Marketed Drugs Used as Comparators

Sponsors of trials involving drugs that already have an Notice of Compliance or a DIN may choose to use the drug's labelling, that was authorized by the drug's market authorization; however, sponsors in this situation may also choose to re-label a drug.

For blinded clinical trials, the sponsor should ensure that the labelling does not compromise the blinding.

Appendix A: Glossary (Terms)

Note: These definitions explain how terms are used in this document. If there is a conflict with a definition in the Food and Drugs Act or associated regulations, the definition in the Act or regulations prevails. Definitions quoted from other documents will be referred to as such.

Adverse drug reaction (ADR) means any adverse and unintended occurrence in relation to the health of a participant who is administered a drug in a clinical trial, for which there are reasonable grounds to believe that the occurrence could be a noxious response to any dose of the drug.

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

Authorization means, unless the context otherwise requires, a contingent authorization issued under paragraph 14(1)(b) that, under section 15, has ceased to be a contingent authorization and has become an authorization that authorizes the sponsor to conduct a clinical trial in respect of a drug.

Business day means a day other than a Saturday; or a Sunday or other holiday.

Case report means a detailed record of all relevant data associated with the use of a drug in a participant.

Clinical trial means a study, involving human participants, for the purpose of discovering or verifying the effects of a drug, a device or a food for a special dietary purpose. Note: the clinical trials regulations adopts this broad definition from section 2 of the Food and Drugs Act.

Comparator (Product) means a drug (active control), or placebo, used as a reference in a clinical trial.

Drug: means a drug for human use.

In the context of clinical trials, a drug would include a drug for human use that is to be tested in a clinical trial and includes pharmaceuticals, biologics, gene therapies, blood products, vaccines and radiopharmaceuticals (Guidance document for clinical trial sponsors: Clinical trial applications).

See also the definition of “drug” in section 2 of the Food and Drugs Act, which includes any substance or mixture of substances manufactured, sold or represented for use in the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, or in restoring, correcting or modifying organic functions.

Good clinical practices (GCP) means generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of participants and other persons and the reliability of results, including the practices referred to in paragraphs 46(1)(a) to (l).

Consistent with, but further expanded on in the Glossary of ICH E6, which defines GCP as:

“A standard for the planning, initiating, performing, recording, oversight, evaluation, analysis and reporting of clinical trials that provides assurance that the data and reported results are reliable and that the rights, safety and well-being of trial participants are protected.”

Import means import for the purpose of use in a clinical trial.

Importer means the sponsor or person designated by the sponsor who is responsible for the import of the drug into Canada for the purpose being used 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 means a person who, in respect of a clinical trial,

• is entitled to provide health care under the laws of the province in which the main location of a clinical trial site is situated;
• possesses relevant clinical expertise, within their scope of practice, to exercise their profession in the course of the clinical trial given its objectives;
• if the person is not also the sponsor of the clinical trial, is responsible to the sponsor for the conduct of the clinical trial at the clinical trial site; and
• if the clinical trial is conducted at the clinical trial site by a team, is the responsible leader of the team

Investigator's brochure means, in respect of a drug, a document containing the preclinical and clinical data including elements that are described in paragraph 11(2)(o).

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

List of National Research Ethics Boards means the List of National Research Ethics Boards, that is published by the Government of Canada on its website, as amended from time to time.

Master protocol trial means a clinical trial in respect of which the following criteria are met:

• it includes one or more sub-studies;
• the research questions of the sub-studies fall within the scope of those of the clinical trial; and
• a framework exists to support a common organizational approach for the sub-studies and the other parts of the clinical trial as well as to support the sharing of research infrastructure, such as clinical trial sites, resources and personnel.

Material includes samples, except in subsections 11(2), 20(2) and 61(2).

National Research Ethics Board means a research ethics board that is set out in the List of National Research Ethics Boards.

Observation means a deficiency or deviation from the Clinical Trials Regulations noted by an Inspector during the inspection of a clinical trial that is confirmed in writing in the Inspection Exit Notice. (More information in 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.

Participant means a person who participates in a clinical trial.

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

Research ethics board (REB) means a body that has the characteristics described in section 3. ICH E6 uses the terms “institutional review board” (IRB) and “independent ethics committee” (IEC) interchangeably, the definition of which is consistent with that of an REB. In ICH E6, Glossary, an IRB or an IEC is defined as:

“An independent body (a review board or a committee, institutional, regional, national or supranational) constituted of medical professionals and non-medical members whose responsibility it is to ensure the protection of the rights, safety and well-being of participants involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, the suitability of the investigator(s), the facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial participants. The legal status, composition, function, operations and regulatory requirements pertaining to IRBs/IECs may differ among countries but should allow the IRB/IEC to act in agreement with GCP as described in this guideline.”

Note: REBs in Canada are held to more stringent composition requirements than are described in this section for ICH E6.

Sell includes offer for sale, expose for sale, have in possession for sale and distribute, whether or not the distribution is made for consideration. The definition is broad in scope, and could include dispensing of drugs to participants by physicians.

Site or trial site means the location(s) where trial-related activities are conducted. Health Canada's interpretation recognizes that a trial may have multiple sites including locations that are remote from the main location.

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

Serious unexpected adverse drug reaction (SUADR) means a serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the document referred to in paragraph 11(2)(o) that pertains to the drug or on the label of the drug.

The definitions for SADR and SUADR are consistent with those found in the Glossary of ICH E6.

The acronym SUSAR (Suspected unexpected serious adverse reaction) is often used to identify serious adverse reactions that require reporting to a regulatory authority.

These definitions are expanded on in ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH E2A).

Service provider means a person who conducts a clinical trial by providing a service to or on behalf of the sponsor or an investigator, but does not include an investigator or a person to whom the exemption provided for in subsection 6(3) or 7(2) applies.

Sponsor means the person who

• conducts a clinical trial solely or in combination with other persons; and
• takes responsibility for the overall conduct of the clinical trial.

ICH E6 elaborates on this definition in Glossary to include: “An individual, company, institution or organisation that takes responsibility for the initiation, management and arrangement of the financing of a clinical trial.”
Note: The Regulations does not differentiate between a commercial and a non-commercial sponsor.

Sub-study means a study that

• is or is proposed to be part of a clinical trial; and
• is aimed at discovering or verifying the effects of one or more of the drugs used – or proposed by the study to be used – in the clinical trial.

Standard operating procedure (SOP)means detailed, documented instructions to achieve uniformity of the performance of a specific activity (ICH E6, Glossary).

Appendix B: References

Web addresses were accurate at the time of publication of this document.

Law and regulations

1. Food and Drugs Act
2. Food and Drug Regulations
3. Medical Devices Regulations
4. Radiation Protection Regulations

Health Canada guidances and documents

1. Annex 13 to the current edition of good manufacturing practices guidelines: Drugs used in clinical trials (GUI-0036)
2. Risk classification guide for observations related to inspections of clinical trials of human drugs (GUI-0043)
3. Clinical trials Frequently Asked Questions
4. Clinical Trial Site Information Form
5. Compliance and enforcement policy for health products (POL-0001)
6. Compliance and enforcement approach and inspection strategy for clinical trials of drugs involving human subjects (POL-0030)
7. Good manufacturing practices (GMP) guide for drug products (GUI-0001)
8. Good manufacturing practices (GMP) guidelines for active pharmaceutical ingredients (API) (GUI-0104)
9. Guidance document for clinical trial sponsors: Clinical trial applications
10. Guidance document: Preparation of clinical trial applications for use of cell therapy products in humans
11. Guidelines for environmental control of drugs during storage and transportation (GUI-0069)
12. Import and export of drug and health products: Compliance and enforcement
13. Notice to Stakeholders: Statement on the Investigational Use of Marketed Drugs in Clinical Trials
14. Reporting adverse reactions to marketed health products - Guidance document for industry

Other guidances and policies

1. ICH Harmonised Guideline – Guideline For Good Clinical Practice E6(R3)
2. Annex 11 to the good manufacturing practices guide: Computerized systems GUI-0050
3. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, International Council on Harmonization (ICH) Harmonized Tripartite Guideline, Topic E2A
4. Declaration of Helsinki
5. Electronic Records as Documentary Evidence, Canadian General Standard Board (CGSB), CAN/CGSB-72.34-2024
6. PIC/S guidance: Good practices for computerised systems in regulated "GXP" environments
7. Stability Testing of New Substances and Products, ICH Harmonized Tripartite Guideline, Topic Q1A(R2)
8. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2 2022)
9. U.S. Food and Drug Administration (FDA) Guidance for Industry: A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers (April 2023)