Part C, Division 5 of the Food and Drug Regulations "Drugs for Clinical Trials Involving Human Subjects" (GUI-0100): Good clinical practices

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1. Good clinical practices
2. C.05.010(a)
3. C.05.010(b)
4. C.05.010(c)
5. C.05.010(d)
6. C.05.010(e)
7. C.05.010(f)
8. C.05.010(g)
9. C.05.010(h)
10. C.05.010(i)
11. C.05.010(j)

Good clinical practices

Interpretation

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

The ICH guidance Guideline for Good Clinical Practice E6(R3) provides an unified standard on GCP. As a standing member of the ICH, Health Canada is committed to the implementation of ICH guidance. ICH E6 (R3) was fully adopted by Health Canada as of April 1, 2026.

C.05.010(a)

Interpretation

The sponsor must ensure that the clinical trial is scientifically sound and clearly described in a protocol. Quality should be built into the scientific and operational design of clinical trial. Factors critical to the quality of the trial should be identified prospectively (ICH E6, Principle 6).

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

The clinical trial protocol as well as the plans or documents for the protocol execution (for example statistical analysis plan, data management plan, monitoring plan) should be clear, concise and operationally feasible (ICH E6, Principle 8.3).

There should be periodic review of current scientific knowledge and approaches to determine whether modifications to the trial are needed, since new or unanticipated information may arise once the trial has begun (ICH E6, Principle 4.3).

C.05.010(b)

Interpretation

The sponsor must ensure that the clinical trial is conducted in accordance with the requirement of the protocol, which has been authorized by Health Canada and approved by REB(s).

Strategies should be implemented to avoid, detect, address and prevent recurrence of serious noncompliance with GCP, the trial protocol and applicable regulatory requirements (ICH E6,Principle 6.3).

The site should have a system in place to identify, document, assess and report all the protocol deviations to the sponsor and REB in accordance with the sponsor's and REB's requirements.

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

• define and identify the protocol deviations to be reported
• determine trial-specific criteria for classifying protocol deviations as important (protocol deviations that may significantly impact the completeness, accuracy and/or reliability of the trial data or that may significantly affect a participant's rights, safety or wellbeing)(ICH E6, 3.9.3)
• inform the QI or other relevant parties involved in the trial conduct of deviations from the protocol, GCP and the applicable regulatory requirements (ICH E6, 3.11.4.5)
• ensure protocol deviations are adequately assessed for impact and root cause analysis
• taking appropriate action designed to prevent recurrence of the detected deviations. Important deviations should be highlighted and should be the focus of remediation efforts as appropriate (ICH 3.11.4.5.1(b))

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

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

• The clinical trial was not always conducted according to the protocol
• The clinical trial drug was not always used according to the protocol

C.05.010(c)

Interpretation

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

The range and extent of oversight measures should be fit for purpose and tailored to the complexity of and risks associated with the trial. The selection and oversight of QIs and service providers are fundamental features of the oversight process. Oversight by the sponsor includes quality assurance and quality control processes relating to the trial-related activities of QIs and service providers (ICH E6, 3.9.5).

The sponsor should implement an appropriate system to manage quality throughout all stages of the trial process. Quality management includes the design and implementation of efficient clinical trial protocols, including tools and procedures for trial conduct (including for data collection and management), in order to ensure the protection of participants' rights, safety and well-being and the reliability of trial results. The sponsor should adopt a proportionate and risk-based approach to quality management, which involves incorporating quality into the design of the clinical trial (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact on participants' rights, safety and well-being and the reliability of the results (i.e., critical to quality factors as described in ICH E8(R1)). The sponsor should describe the quality management approach implemented in the trial in the clinical trial report (see ICH E3 Structure and Content of Clinical Study Reports). (ICH E6, 3.10).

The quality management system should use a risk-based approach as described in sections 3.10.1.1 to 3.10.1.6 of ICH E6. Risk management includes:

• risk identification
• risk evaluation
• risk control
• risk communication
• risk review
• risk reporting

Risks to critical to quality factors should be managed proactively and adjusted when new or unanticipated issues arise once the trial has begun. (ICH Principle 7.3).

Risk review is a key component to risk-based quality management systems, and Health Canada expects that sponsors will be able to demonstrate that risk control measures are periodically reviewed and remain effective and relevant, taking into account emerging knowledge and experience throughout the trial (ICH E6, 3.10.1.5).

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

Quality assurance and quality control

As per section 3.11 of ICH E6, the sponsor is responsible for establishing, implementing and maintaining appropriate quality assurance and quality 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 the applicable regulatory requirement(s).

The sponsor is also responsible for obtaining agreements from all involved parties to permit monitoring and auditing by sponsors, inspections by regulatory authorities (domestic and foreign) and, in accordance with applicable regulatory requirements, review by REBs, including providing direct access to source records and facilities, including to those of service providers (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).

Agreements made by the sponsor with the QI/institution, service providers and any other parties (for example, independent data monitoring committee (IDMC), adjudication committee) involved with the clinical trial should be documented prior to initiating the activities (ICH E6, 3.6.1).

Service providers

A sponsor may transfer any or all of the sponsor's trial-related activities to a service provider in accordance with applicable regulatory requirements; however, the ultimate responsibility for the sponsor's trial-related activities, including protection of participants' rights, safety and well-being and reliability of the trial data, resides with the sponsor. Any service provider used to perform clinical trial activities should implement appropriate quality management and report to the sponsor incidents that might have an impact on the safety of trial participants or/and trial results (ICH E6, 3.6.6).

The sponsor should ensure appropriate oversight of important trial-related activities that are transferred to service providers, including activities further subcontracted by the service provider (ICH E6, 3.6.9).

Any of the sponsor's trial-related activities that are transferred to and assumed by a service provider should be documented in an agreement. The sponsor's trial-related activities that are not specifically transferred to and assumed by a service provider are retained by the sponsor (ICH E6, 3.6.4).

Standard operating procedures (SOP)

An SOP may be trial specific or site specific, and may be provided by the site, the institution or the sponsor. As with any quality system records, there needs to be a mechanism of approval, revision and communication of new and/or revised records to those parties responsible for the procedures. Health Canada does not require a specific record-type and/or format but 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)
• record retention for 15 years

Monitoring and auditing

The aim of monitoring is to ensure the participants' rights, safety and well-being and the reliability of trial results as the trial progresses (ICH E6, 3.11.4).

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

• QI site monitoring (ICH E6, 3.11.4.1)
• centralized monitoring (ICH E6, 3.11.4.2)
• monitoring plan (ICH E6, 3.11.4.3)
• monitoring procedures (ICH E6, 3.11.4.4)
• monitoring activities (ICH E6, 3.11.4.5)
• monitoring reports (ICH E6, (ICH E6, 3.11.4.6)

The sponsor should determine the appropriate extent and nature of monitoring based on identified risks. Factors such the objective, purpose, design, complexity, blinding, number of trial participants, investigational product, current knowledge of the safety profile and endpoints of the trial should be considered (ICH E6, 3.11.4).

Monitoring may include site monitoring (performed onsite and/or remotely) and centralised monitoring, depending on the monitoring strategy and design of the clinical trial. Monitoring may include remote and secure, direct read-only access to source records, other data acquisition tools and essential record retention systems. The frequency of monitoring activities should also be determined based on identified risks. Monitoring activities and their frequency should be modified as appropriate using knowledge gained (ICH E6, 3.11.4).

Centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of site monitoring or be used on its own. Use of centralised data analytics can help identify systemic or site-specific issues, including protocol noncompliance and potential unreliable data (ICH E6, 3.11.4.2(b)).

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 is tailored to identify potential safety risks, the risks to data quality and/or other risks to the reliability of trial results. 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 monitoring strategy should ensure appropriate oversight of trial conduct and consider site capabilities and the potential burden. The plan should focus on aspects that are critical to quality and should reference the sponsor's applicable policies and procedures. Monitoring of important data and processes performed outside the QI site should be addressed in the monitoring plan (ICH E6, 3.11.4.3).

The requirements of monitoring reports (including their content and frequency) should be described in the sponsor's procedures. Reports of QI site and/or centralized monitoring should be provided to the appropriate sponsor staff as described in the sponsor's procedures in a timely manner for review and follow up. When needed, the report should describe findings requiring escalation for action and resolution. The sponsor should decide on the appropriate action to be taken, and these decisions and the resolution of the actions involved, where needed, should be recorded (ICH E6, 3.11.4.6).

In addition to monitoring, a sponsor should perform audits in a manner that is proportionate to the risk associated with the conduct of the trial (see section 3.10.1.1 of ICH E6). An audit is independent of and separate from routine monitoring or quality control functions, is to evaluate whether the processes put in place to manage and conduct the trial are appropriate to ensure compliance with the protocol, GCP 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 3.12.1 of ICH E6 states that noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by a QI/institution, or by member(s) of the sponsor's staff should lead to appropriate and proportionate action by the sponsor to secure compliance.

If noncompliance that significantly affects or has the potential to significantly affect human participant protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis, implement appropriate corrective and preventive actions and confirm their adequacy unless otherwise justified. 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 (i.e., serious noncompliance), the sponsor should notify the regulatory authority and/or REB, in accordance with applicable regulatory requirements, and/or QI, as appropriate (ICH E6, 3.12.2).

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 Part C, Division 5 of the Regulations are met at each site, and that each site follows GCP.

Equipment and calibration

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

The risk evaluation should be related to the significance of the data in the trial. Any equipment or measuring device used to generate data that is reported on the case report form (CRF) should be assessed by the sponsor. Records demonstrating fitness for purpose (for example. maintenance and calibration) for equipment used for important trial activities must be in place prior to start of trial and 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 or have an Investigational Testing Authorization (ITA) for use in that study and must be in compliance with the Medical Devices Regulations.

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

• The sponsor did not always implement systems and procedures to ensure the quality of the clinical trial
• The sponsor did not always implement systems and procedures to ensure adequate monitoring of the clinical trial
• The sponsor did not always implement systems and procedures to ensure that staff was adequately trained on GCP and the appropriate Food and Drug Regulations
• The sponsor did not always implement systems and procedures to ensure equipment was maintained and calibrated

C.05.010(d)

Interpretation

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

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

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

Section 1 of ICH E6 describes the responsibilities, composition and operations of REBs. The responsibility of a REB is to protect the rights, safety, and well-being of all human participants. An REB should pay special attention to trials that may include vulnerable human 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 and 1.2.3).

When and if approval is given, an REB should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to participants (ICH E6, 1.2.4). An REB should establish, document and follow its procedures including determining frequency of continuing review, as appropriate per ICH E6 section 1.4.

If minors are to be included in a trial, the REB should review the assent information considering the age, maturity and psychological state of the minor population intended to be enrolled, as well as applicable regulatory requirements (ICH E6, 1.2.7).

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

• The sponsor did not get the approval of the REB before the clinical trial began at the clinical trial site
• The sponsor did not get approval from the REB before a protocol amendment was implemented at the clinical trial site

C.05.010(e)

Interpretation

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

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

Only a licensed physician or dentist (if for dental purposes only) is entitled to provide health care under the laws of the province where that clinical trial site is located can assume the role of a QI.

This person must be listed as the QI on the Qualified Investigator Undertaking (QIU) Form. There must be no more than one (1) QI at each clinical trial site.

Delegation logs

The QI should ensure a record is maintained of the persons and parties to whom the investigator has delegated trial-related activities. Documentation of delegation should be proportionate to the significance of the trial-related activities. In situations where the activities are performed as part of clinical practice, delegation documentation may not be required (ICH E6, 2.3.3).

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

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

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

When tasks are delegated to a person in charge of other staff (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 when needed as part of care provided (for example emergency room procedures) and are not specific study procedures do not require specific training and delegation from the QI (refer to section C.05.010(g) "Training for clinical research").

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
• CRF 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

Locations where ancillary medical procedures (for example imaging, blood collections) are conducted do not require separate CTSI forms (PDF format). 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 (PDF format) (for example change of QI) a revised CTSI form should be submitted to Health Canada.

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

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

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

• More than one QI at the clinical trial site was responsible for the clinical trial
• The QI was not a physician or dentist entitled to provide health care under the laws of the province where the clinical trial site was located

C.05.010(f)

Interpretation

The sponsor should have medical personnel readily available who will be able to advise on specific trial-related medical questions or problems (ICH E6, 3.4.1). The sponsor assigns the responsibility of medical care and medical decisions and day-to-day running of the clinical trial site to the QI.

The following applies to the qualifications of trial staff responsible for the medical care of participants under ICH E6:

• A qualified physician or, where appropriate, a qualified dentist (or other qualified healthcare professionals in accordance with local regulatory requirements) who is an QI or a sub-investigator for the trial should have the responsibility for the trial-related medical care and decisions (ICH E6, 2.7.1(a))
• Other appropriately qualified healthcare professionals may be involved in the medical care of trial participants in line with their normal activities and in accordance with local regulatory requirements (ICH E6, 2.7.1(b))
• The QI should inform the participant's primary physician about their involvement in the trial, if the participant has a primary physician and agrees to the primary physician being informed (ICH 2.7.1(d))

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

Adequate medical oversight of a clinical trial

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

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)
• review of eligibility criteria outlined in the study protocol

The QI may delegate trial-related activities to other persons or parties. The QI may be supported by the sponsor in the identification of a suitable service provider(s); however, the QI retains the final decision on whether the service provider intended to support the QI is appropriate based on information provided by the sponsor (see ICH E6 section 3.6.5).

The QI retains the ultimate responsibility and should maintain appropriate oversight of the persons or parties undertaking the activities delegated to ensure the rights, safety and well-being of the trial participants and the reliability of data. The level of the QI oversight of the delegated activities should depend on the nature of the delegated activities and be proportionate to the importance of the data being collected and the risks to trial participant safety and data reliability (ICH E6, 2.3.1). Evidence of this timely oversight may be assessed during an inspection through the review of signatures and file notes on source data and CRFs, including electronic signatures where applicable, and through interviews with study staff and the QI. Alternative verification methods consistent with ICH principles and adequate to the sponsor may also be acceptable. Proper rationale and justification should be used and the method appropriately documented.

An example inspection observation typically cited under this section of the Regulations:

• Medical care and/or medical decisions for the clinical trial were not always under the supervision of the QI at the clinical trial site

C.05.010(g)

Interpretation

The sponsor must ensure that all individuals involved with the clinical trial (for example biostatisticians, clinical pharmacologists, physicians, clinical trial coordinators, etc.) are qualified by education, training and experience to perform their respective task(s) (see also ICH E6, Principle 5.1).

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

The sponsor must also ensure that individuals remain qualified throughout all stages of the trial process, from trial design, to conduct of a trial at sites, through to the analysis of data and the preparation of final clinical trial reports (ICH E6, 3.4).

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

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

The QI should ensure that persons or parties to whom the QI 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 (Part C, Division 5) 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, self-reading)
• events or materials 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.

An example inspection observation typically cited under this section of the Regulations:

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

C.05.010(h)

Interpretation

Informed consent is defined as a process by which a participant or their legally acceptable representative voluntarily confirms their willingness to participate in a trial after having been informed and been provided with the opportunity to discuss all aspects of the trial that are relevant to the participant's decision to participate (ICH E6, Glossary). Potential participants in a clinical trial have the right to know the foreseeable risks or inconveniences and expected benefits that are part of the study they are thinking about joining (ICH E6, 2.8.10 (f) and (g)).

The foreseeable risks and inconveniences should be weighed against the anticipated benefits for the individual participants and society (ICH E6, Principle 1.3). The rights, safety and well-being of the participants are the most important considerations and should prevail over interests of science and society (ICH E6, Principle 1.1).

Informed consent is documented by means of a written (paper or electronic), signed and dated informed consent form (ICF). Obtaining consent remotely may be considered when appropriate (ICH E6, glossary). The ICF must be made available for each participant in either official language or other as appropriate. Freely given informed consent should be obtained and documented from every participant prior to clinical trial participation (ICH E6, Principle 2.1). A clinical trial participant cannot be involved in any aspect of a clinical trial until they have gone through the IC process, either in person or remotely, with a trial staff member (doctor, study nurse, clinical trial coordinator, etc.) and signed the document indicating that they understand the information and have agreed to participate in the trial. Neither the QI, nor the QI site staff should coerce or unduly influence a participant to participate or to continue their participation 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 trial.

The following applies to the Informed Consent process under ICH E6:

• Prior to consenting and enrolling participants, the QI should have the REB's documented approval/favourable opinion of the informed consent materials and process (ICH E6, 2.8.1(a))
• The information should be as clear and concise as possible, use simple language and avoid unnecessary volume and complexity (ICH E6, 2.8.1(b))
• Varied approaches available such as text, images, videos and other interactive methods may be used in the informed consent process (ICH E6, 2.8.1(c))
• Obtaining consent remotely may be considered where appropriate (ICH E6, 2.8.1(d))
• QI should assure themselves of the identity of the participant (or legally acceptable representative) (ICH E6, 2.8.1(e))

The QI must have a documented SOP in place for obtaining informed consent. The site personnel to whom the consenting process is delegated to must be trained on the process and comply with the SOP. Participants must be presented with any REB approved amended ICFMs at their earliest visit to the clinical trial site and re-consented as soon as possible, unless there are specific recommendations from the sponsor and/or REB.

In obtaining and documenting informed consent, the QI 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.

Revised 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 continue trial participation. An assessment should be conducted to determine if re-consent is needed. 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.

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

Participants not capable of informed consent

When a clinical trial includes participants who may only be enrolled in the trial with the consent of the participant's legally acceptable representative, the participants should be informed about the trial in a manner that facilitates their understanding and, if capable, the participant should sign and date the informed consent form or assent form as appropriate (ICH E6, 2.8.13). Written procedures for this process should be followed. The process can be incorporated into an existing SOP for obtaining informed consent or be a stand-alone procedure.

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 enroll 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 section 2.8.8 of ICH E6, 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. When prior consent of the participant is not possible, and the participant's 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, to protect the participant's rights, safety and well-being, and to ensure compliance with applicable regulatory requirements. The participant or the participant's legally acceptable representative should be informed about the trial as soon as possible and consent as appropriate should be requested (see ICH E6, 2.8.8).

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 the benefit of the participant (participants coming from out of town, elderly or disabled participants who have difficulty reaching the site, etc.). 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 is generally considered acceptable if all applicable regulatory and ICH requirements are met.

These requirements include, but are not limited to the following:

• the system must be properly validated (ICH E6, 4.3.4(c), (d) and (g)), with documented procedures and appropriate training
• all required elements (C.05.010(h) and ICH E6, 2.8.10) must be present in the ICF
• the information must be kept for 15 years (C.05.012(4))

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

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

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

An example observation typically cited under this section of the Regulations:

• The sponsor did not always get written informed consent from every person before they participated in the clinical trial or the amended clinical trial

C.05.010(i)

Interpretation

The collection and maintenance of clinical trial records, including the retention of records, is a critical component of any clinical trial. The sponsor is responsible to ensure that trial information is recorded, handled and stored in a way that allows its accurate reporting, interpretation, and verification (ICH E6 Principles 9.4, 9.5 and appendix B.14).

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

C.05.010(j)

Interpretation

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

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

Additional information regarding the requirements pertaining to GMP for clinical trial drugs is available in Guidance Document – Annex 13 to the Current Edition of the GMP Guidelines: Drugs Used in Clinical Trials (GUI-0036), as well as Principle 11, sections 3.11.4.5.3, 3.15 and Appendix C of ICH E6.

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

It should be noted that other marketed drugs to be used in a trial which are not indicated on the NOL (and thus, are not considered investigational drugs) must:

• have received a NOC and/or a DIN, or
• be a marketed Canadian equivalent sourced from an acceptable foreign jurisdiction (i.e. Australia, Switzerland, Japan, European Union, United States), and
• be used within the marketing authorization

For additional information, refer to the Guidance document for Clinical Trial Sponsors: Clinical trial applications.

Traceability of the investigational drug(s)

All drugs included on the NOL are considered investigational and thus, must be in compliance with Part C, Division 5 of the Regulations. The sponsor of a clinical trial is responsible for ensuring that a clinical trial drug is manufactured, stored and handled in accordance with GMP. The sponsor should establish and maintain a system to ensure that investigational drugs can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the QI/clinical trial site where the product is used, administration of the drug to clinical trial participants, to the reconciliation and disposal or destruction of the drug. The system should include collection of sufficient detail to allow linking of each clinical trial drug to the individual participant who received it. Where multiple parties are involved in the distribution chain (for example pharmacy, service provider, central warehouse), the sponsor should ensure that the role of each party is clearly outlined in writing. In addition, when the QI delegates some or all of their activities for investigational product(s) management to a pharmacist or another individual in accordance with local regulatory requirements, the delegated individual should be under the oversight of the QI (ICH E6, 2.10.2).

Where the QI has delegated activities related to investigational product management or aspects of these activities have been facilitated by the sponsor, the level of QI oversight will depend on a number of factors, including the characteristics of the investigational product, route and complexity of administration, level of existing knowledge about the investigational product's safety and marketing status (ICH E6, 2.10.3).

The investigational product may be shipped to the participant's location or supplied to/dispensed at a location closer to the participant (for example, at a local pharmacy or a local healthcare centre). The investigational product may be administered at the participant's location by QI site staff, the participant themselves, a caregiver or a healthcare professional (ICH E6, 2.10.8).

As per section C.05.012 of the Regulations, records of the clinical trial drug's delivery to the trial site, the inventory at the site, the use by each 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 numbers assigned to the drug(s) and trial participants

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

Storage and transportation conditions

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

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)
• transportation container, packaging configuration

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

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

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

Complete guidelines for the transportation and storage of clinical trial drugs can be found in the Guidelines for environmental control of drugs during storage and transportation (GUI-0069) and the ICH guideline Q1A(R2) on stability testing of new drug substances and products.

These guidelines apply not only to drugs that require refrigerated or frozen transportation and storage temperatures, but also those that must be transported and stored at ambient temperature.

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

• The drug was not manufactured in keeping with GMP
• The drug was not always handled and stored in keeping with GMP