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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

On this page

• Regulations and interpretations
  • Interpretation
  • Application
  • Prohibition
  • General
  • Application for authorization
  • Authorization
  • Notification
  • Amendment
  • Additional information and samples

Regulations and interpretations

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

Interpretation

Application

Interpretation

The Regulations apply to the sale and importation of drugs to be used in clinical trials involving humans that are conducted in Canada. As per section C.05.002, no person can sell or import (refer to Glossary (terms) for definitions of sell and import) a drug for the purposes of a clinical trial involving humans unless authorized (refer to section 5.6 Authorization). For Phase IV clinical trials, limited provisions of Part C, Division 5 apply which are set out in subsection C.05.002(2) and described below.
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 or condition 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 clinical trial is in respect of a 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 subsection C.05.002(2), the sponsor of a Phase IV clinical trial does not have to file a clinical trial application (CTA) for importation and/or sale of the study drug. However, the following does apply:

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

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

For requirements regarding the reporting of adverse drug reactions (ADRs) for Phase IV clinical trials, please see the interpretation of C.05.014 in this document.

Please refer to the Guidance document for clinical trial sponsors: Clinical trial applications for detailed guidance on the application process and Phase IV studies classification. The relevant Health Canada Directorate (PDD or BRDD) should be consulted for further clarification.

Inspection of Phase IV clinical trials

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

Prohibition

Interpretation

Drugs that are sold and/or imported for the purpose of a clinical trial do not have to meet the regulatory requirements for a DIN (C.01.014) or a NOC (C.08.002 and C.08.003). However, the use of these drugs in a clinical trial (other than Phase IV) must be authorized through the submission of a CTA to Health Canada, including for each CTA-Amendment (CTA-A, see section C.05.008 Amendment).

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

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

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

Importation of clinical trial drugs

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

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

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

1. a No Objection Letter (NOL) has been issued by Health Canada authorizing the importation of the clinical trial material in Phase I-III trials. No such clinical trial drugs should be imported prior to the NOL issuance and the NOL should accompany the package at the time of the importation; If 30 days have passed and no NOL was obtained, specific requests to import clinical trial drugs should be directed to the Health Product Border Compliance Program at the following generic email account: hpbcp-pcpsf@hc-sc.gc.ca
2. each party, including individual Canadian clinical trial sites, importing drugs directly (i.e. receiving drug shipment directly from outside of Canada) is identified in Clinical Trial Application forms
3. Clinical Trial Site Information (CTSI) forms (PDF format) for each Canadian site conducting the clinical trial are submitted to Health Canada for Phase I-III trials, prior to the start of the study at the site (also refer to section C.05.010(e) "Clinical Trial Site Information Forms")
4. systems are in place, when appropriate, to monitor the transportation and storage conditions from the foreign source to the various clinical trial sites across Canada
5. there is documented accountability of the imported drugs used in clinical trials and distributed to various clinical trial sites located in Canada, including the disposition of drugs returned from the clinical trial sites
6. a written agreement is in place between the sponsor and the qualified investigator (QI) describing their specific responsibilities, and this agreement is available at the clinical trial site
7. there is evidence that the drugs used in clinical trials conducted in Canada meet GMP requirements. For example, adequate evidence of GMP compliance would include:
   • certificates of manufacture and certificates of analysis (CoA or batch certificates) for the lots of clinical trial material imported into Canada
   • evidence of approved lot release by a qualified individual

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

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

An example inspection observation (refer to Glossary (terms) for definition of observation) typically cited under this section of the Regulations:

The sponsor sold or imported for use, a drug for a clinical trial without being authorized under Part C, Division 5 of the Regulations

General

Interpretation

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

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.

Please refer to the Guidance document for clinical trial sponsors: Clinical trial applications for detailed guidance on the application process. Additional guidance can be found in the relevant sections of ICH E6, including Appendices A and B. The relevant Health Canada's Directorate (PDD or BRDD) should be consulted for further clarification.

Authorization

Interpretation

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

1. a CTA must be submitted in accordance with section C.05.005 of these Regulations (see also ICH E6, 3.8.1)
2. the sponsor should expect to receive a NOL within 30 days of the date of receipt of the complete CTA, indicating that the sponsor may sell or import the drug for the purposes of a clinical trial. However, due to the 30-day default period from the date of receipt of a complete CTA, the sponsor may proceed with the clinical trial after this period without receiving an NOL, provided the Research Ethics Board (REB) approval was obtained

3. the sponsor has received, for each clinical trial site, approval from a REB, in respect of the protocol and informed consent referred to in C.05.005(a) and (b)
4. before the sale or importation of the drug to a clinical trial site, the sponsor has submitted a CTSI form (PDF format) (refer to interpretation section of C.05.010) including the following information to Health Canada, if it has not already been submitted at the time of application:
   1. name, address, telephone number, fax number, and electronic mail address of the QI for each clinical trial site [C.05.005(c)(ix)]
   2. name, address, telephone number, fax number and electronic mail address of the REB that approved the protocol and informed consent at each clinical trial site [C.05.005(c)(x)]
   3. name, address, telephone number, fax number and electronic mail address of any REB (in or outside Canada) that has previously refused to approve the protocol, including its reason for doing so and the date on which the refusal was given [C.05.005(d)]
   4. the proposed date for the commencement of the clinical trial at each clinical trial site [C.05.005 (h)]

A sponsor does not have to submit a CTA for authorization to sell or import a drug used in a Phase IV clinical trial. Refer to C.05.002, Application and its interpretation, for a list of the provisions that govern a drug used in a Phase IV clinical trial.

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

Please refer to the Guidance document for Clinical Trial Sponsors: Clinical trial applications for detailed guidance on the authorization.

Examples of observations typically cited under this section 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

Notification

Interpretation

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

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

Examples of notifications may include:

• change of sponsor's address or contact name
• changes made to enable the consent to be read at the appropriate education level
• addition of an observational sub-study to the protocol or other administrative changes

Further to the above, section 3.15.2(e) 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 C.05.008 (below), the sponsor must submit a CTA-A.

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

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

• The sponsor did not notify Health Canada within 15 days of making a change to the drug's chemistry and manufacturing information. The change does not affect the drug's quality or safety
• The sponsor did not notify Health Canada within 15 days of making a change to the protocol. The change does not affect the health risk of a clinical trial participant

Amendment

Interpretation

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

Prior to implementation of a CTA-A at a site, a qualified investigator should obtain documented approval from the REB (ICH E6, 1.4.7). In addition, sponsors are required to complete and submit a CTSI form (PDF format) for each clinical trial site (C.05.008(1)(c)).

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

ICH E6 sections 2.5.4 and 2.5.5 also states that a QI may deviate from the protocol without prior approval if it is necessary to eliminate an immediate hazard(s) to a trial participant. Information on the deviation or change, the implemented change and the subsequent proposed protocol amendment should be submitted promptly to:

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

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

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

• The sponsor did not submit a CTA-A after a change was made to the elements in the design of the study protocol or to the composition/formulation of the study drug that met the criteria for an amendment
• The sponsor did not notify Health Canada within 15 days of implementing an immediate amendment where the clinical trial or the use of the study drug endangered the health of a clinical trial participant or other person

Additional information and samples

Interpretation

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

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

• the information and documents in the application were either not provided in accordance with these Regulations or were insufficient to enable Health Canada to assess the safety and risks of the drug or the clinical trial, or
• based on an assessment of the application or any information or drug samples submitted as additional information Health Canada has reasonable grounds to believe that either:
  • the use of the drug for the purpose of the clinical trial endangers the health of a clinical trial 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

On this page

1. Labelling
2. Records

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 responsible for ensuring that the labelling of a clinical trial drug meets the requirements of section C.05.011 of Part C, Division 5 of the Regulations.

The required information outlined in this section (see box above) must be attached to, included with, or accompany each container of the drug product, and be available in both English and French.

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

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

Adequate labelling of a drug used in a clinical trial is essential to ensure traceability of the drug, through the use of identifying information and lot numbers, to ensure that it is dispensed to the correct clinical trial participant, and to ensure it is stored in the proper conditions, including temperature and has not expired. The labelling must comply with regulatory requirements of section C.05.011 and be coded in a manner that protects the blinding, if applicable (ICH E6, 3.15.2(a)).

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

For additional information on labelling, please refer to section 8.7 of Guidance document – Annex 13 to the current edition of the GMP guidelines: Drugs used in clinical trials (GUI-0036).

Clinical trial drug lot numbers

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

Identifiers other than a "lot" or "(L)" number (for example a batch number, a kit number or a bar code) may be considered compliant with section C.05.011, provided traceability is maintained. Where a bar code is included as the identifier on the label, the code on the drug label should readily link to information (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 ensure patient safety and that the computerized system, if applicable, is fully validated (refer to section 5.12 Records).

Clinical trial drug expiry dates

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

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

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

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

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

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

Refer to section 8.7 of Guidance document – Annex 13 to the current edition of the GMP guidelines: Drugs used in clinical trials (GUI-0036)for additional guidance.

Labels of marketed drugs used as comparators

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

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

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

• The label of the drug did not contain the required information

Records

Interpretation

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

Part C, Division 5 record retention requirements also apply to clinical trials using drugs that will never be marketed regardless of the trial data's statistical significance.

Therefore, clinical trial records created and/or used during the conduct of a statistically negative trial must be retained according to the regulatory requirements as outlined in this document and in the Regulations.

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, Principles 9.4 and 9.5).

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 as per section 2.8.10 (o) of ICH E6. A unique identifier is assigned by the QI to each trial participant, to protect their identity when the QI reports AEs and/or other trial related data (ICH E6, trial participant identification code, Glossary).

Roles and responsibilities for records retention (sponsors, QIs and REBs)

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

Sponsor

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

• As the sponsor bears responsibility for study records, it is recommended that the sponsor clarify with the QI at the outset of the trial what documents are defined as source and how they are to be maintained.
• Sponsors may delegate record retention to third parties (for example QIs, service providers, laboratories, and others). As the responsible party for the conduct of a clinical trial, the sponsor should relay their expectations to third parties and expect due diligence from all involved in the management of clinical trial records. As such, written agreements with these third parties should be secured by sponsors, prior to the commencement of the trial to ensure full compliance with the regulatory requirements with respect to records.
• Written procedures and training of personnel in their implementation should be documented to demonstrate that the maintenance and retention of records was conducted correctly and consistently. The procedures may be trial- or site-specific and be provided by the sponsor or the third party that was delegated the responsibility.
• In situations where a sponsor undergoes a change of ownership, the record retention responsibility remains with the sponsor who initially submitted the CTA, unless a written agreement is otherwise secured with the new owner. Furthermore, before the clinical trial begins, the sponsor should have a documented procedure for record retention continuity that outlines the measures to be taken in the event that the sponsor ceases to exist.
• Records should be identifiable and version controlled (when appropriate) and should include authors, reviewers and approvers as appropriate, along with date and signature (electronic or physical), where necessary (ICH E6, C.2.1).
• In order to fulfil their responsibilities in the conduct of the trial, the sponsor and QI 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 QI/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 (ICH E6, C.2.2). The sponsor and QI/institution should retain the essential records in a way that ensures that they remain complete, readable and readily available and are directly accessible (ICH E6, C.2.6).

Qualified investigator

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

• The QI should retain the essential records for the required retention period in accordance with applicable regulatory requirements or until the sponsor informs the QI that these records are no longer needed, whichever is the longest. The QI should take measures to ensure availability, accessibility and readability and to prevent unauthorised access and accidental or premature destruction of these records (see Appendix C) (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 in accordance with Part C, Division 5. Since the sponsor of a clinical trial is responsible for maintaining all records, the QI should consult the sponsor to confirm record retention requirements prior to destroying any record.
  • 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 as per Part C, Division 5. All source documents should also be retained for the entire record retention period even if a participant has withdrawn from the clinical trial
• Written agreements describing the procedures for records retention in accordance with the Regulations should be in place between all parties concerned:
  • For example, QIs conducting clinical trials within a hospital or a medical clinic should secure a written agreement (for example contract, policy, SOP), if applicable, with the institution to ensure that hospital records and/or medical charts of clinical trial participants are retained according to the federal Regulations as these prevail over provincial laws and regulations when there is a conflict
  • Agreements should also outline the conditions of record retention, such as the location of records, as well as the procedure to be followed to ensure record retention within the 15-year period in the event that a company ceases to exist or QI ceases her/his affiliation with their institution, for various reasons (for example closure of practice or retirement, new position elsewhere, or death)
• The QI may delegate record-related tasks to other parties such as the institution's pharmacy, a local laboratory or a radiological clinic, with the sponsor's agreement:
  • Prior to the commencement of the clinical trial, the delegated tasks should be documented, signed and dated by the QI and the party to whom the functions are delegated. Documentation of delegation should be proportionate to the significance of the trial-related activities (ICH E6, 2.3.3). The delegation may be amended if necessary during the course of the clinical trial
  • The extent of the delegation, including the retention of the records created by the other party, should be clearly stated
  • Tasks that are not delegated remain under the direct responsibility of the QI or the sponsor, depending on the written agreement secured between these two (2) parties. However, QIs always remain responsible to oversee the delegated tasks because they are responsible for the trial at their site
• The QI/institution should maintain adequate source records that include pertinent observations on each of the site's trial participants under their responsibility. Source record(s) should be attributable, legible, contemporaneous, original, accurate, and complete (ALCOAC). Changes to source records should be traceable, should not obscure the original entry, and should be explained if necessary (for example via an audit trail). The QI 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).
• Section 2.12.5 of ICH E6 states that the QI should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the data acquisition tools completed by the QI site (for example CRFs) and in any other required reports (for example SAE reports). The QI 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.
• In addition, the QI should be provided with timely access to data by the sponsor (see section 3.16.1(k)) and be responsible for the timely review of data, including relevant data from external sources that can have an impact on, for example, participant eligibility, treatment or safety (for example, central laboratory data, centrally read imaging data, other institution's records and, if appropriate, electronic patient-reported outcome (ePRO) data). The protocol may provide exceptions for access, for instance, to protect blinding (ICH E6, 2.12.3). Furthermore, the investigator should ensure that data acquisition tools and other systems deployed by the sponsor are used as specified in the protocol or trial-related instructions (ICH E6, 2.12.4).

Types of records

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

Essential records

Documents and data (and relevant metadata) in any format, associated with a clinical trials that facilitate the ongoing management of the trial and collectively allow the evaluation of the methods used, 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 (see Appendix C)(ICH E6, glossary).

These include, but are not limited to:

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

Source records

A type of essential record that consist of original documents or data (includes relevant metadata) or certified copies of the original documents or data, irrespective of the media used (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, including wearables
• X-rays
• participant diaries and medical records
• appointment/scheduling records
• AEs and ADRs records
• pharmacy dispensing records
• drug accountability records

It is acceptable for essential and/or source records to be transferred to secondary media (see "Transfer of records to secondary medium" section below).

The assessment of whether a record is essential and has to be retained 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 QI or other entities, must be kept at the conclusion or termination of a trial. Retention of copies of original documents is not a requirement.

The QI should have access to and the ability to maintain the essential records generated by the QI 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, revieing and/or assessing the information or data.

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

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

In situations where original source records cannot be retained for the 15-year record 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 QI or participants to record trial data

Key concepts include:

• Electronic records should be maintained and retained in accordance with section C.05.012 of the Regulations.
• Systems and processes that aid in data capture, management and analyses, as well as those that help ensure the quality of the information generated from the trial, should be fit for purpose, should capture the data required by the protocol and should be implemented in a way that is proportionate to the risks to participants and the importance of acquired data (ICH E6, Principle 9.2).
• Computerised systems used in clinical trials should be fit for purpose (for example, through risk-based validation, if appropriate), and factors critical to their quality should be addressed in their design or adaptation for clinical trial purposes to ensure the integrity of relevant trial data (ICH E6, Principle 9.3).
• 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 and accuracy of recorded information as well as reliability of the system. Therefore, any electronic system used to capture, process, manage and/or archive clinical trial information should be adequately validated and evidence of validation should be kept for the required record retention period and should be readily available for inspection by Health Canada's Inspectors.
• The approach for validation should be based on a risk assessment that considers the intended use of the system; the purpose and importance of the data/record that are collected/generated, maintained and retained in the system and the potential of the system to affect the well-being, rights and safety of trial participants and reliability of trial results (ICH E6, Computerised Systems Validation in glossary and 4.3.4).
• As part of the validation process for electronic systems, documentation of the system design specifications and a validation plan based on those should be developed.
• The validation plan should include:
  • objectives and scope
  • nature of and time at which validation activities should be performed
  • delegated personnel for the conduct of the validation
  • security measures
  • main features of the system, including the mode of interaction with other systems and procedures
• Detailed documented procedures for validation activities should be developed and followed at all times to ensure consistency in the performance of the tasks. The SOPs should cover system design, setup, installation, and use. The SOPs should describe :
  • system validation and functionality testing
  • data collection and handling
  • system requirement and maintenance
  • system security measures
  • change control
  • data backup, recovery, contingency planning, and decommissioning.
• The responsibilities of the sponsor, QI, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use (ICH E6,4.3.1 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 or software during the course of the clinical trial are required. The impact of such a change should be evaluated and documented, and partial validation of some components of the electronic system may be required.
• The electronic system should allow for the retrieval of the records, the generation of complete and accurate paper copies of the electronic source data as well as provide audit trails for the entire 15-year record retention period.
• Records created, maintained and processed by outsourced systems (i.e. cloud computing) are subject to the same requirements as the data/records generated by company owned systems.
• For electronic medical records system (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 sponsor for data handling should ensure:
  • the integrity and confidentiality of data generated and managed (ICH E6, 3.16.1(a))
  • 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))
  • 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))
  • trial data are protected from unauthorized access, disclosure, dissemination or alteration and from inappropriate destruction or accidental loss (ICH E6, 3.16.1(v))
  • records of the important computerized systems used in a clinical trial such as the use, functionality, interfaces and validation status of each computerized system, and who is responsible for its management should be described. The record should also include a description of implemented access controls and internal and external security measures (ICH E6, 3.16.1(x)(i))
  • the requirements for computerized systems (for example, requirements for validation, audit trails, user management, backup, disaster recovery and IT security) are addressed and implemented and that documented procedures and adequate training are in place to ensure the correct development, maintenance and use of computerized systems in clinical trials (see section 4 of ICH E6(R3)). These requirements should be proportionate to the importance of the computerized system and the data or activities they are expected to process (ICH E6, 3.16.1(x)(ii))
• 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
• the U.S. Code of Federal Regulations Title 21 Part 11 – Electronic Records; Electronic Signatures
• the U.S. Food and Drug Administration (FDA) Guidance for Industry: Computerized Systems Used in Clinical Investigations
• the Medicines and Healthcare products Regulatory Authority (MHRA) GXP Data Integrity Guidance and Definitions (PDF format)
• World Health Organization (WHO) Annex 5 Guidance on Good Data and Record Management Practices (PDF format)
• the standard Electronic Records as Documentary Evidence, CAN/CGSB-72.34-2024 (PDF format) developed by the Canadian General Standard Board (CGSB).

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:

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

Drug accountability records

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

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

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

The QI 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).

Drug accountability records are required for:

• drugs that are the subject of the clinical trial, and do not have market authorization
• drugs that are the subject of the clinical trial, have market authorization, but are used off-label
• comparator drug, if it does not have market authorization
• comparator drug, if it has market authorization, but its labelling was changed (for example for blinding purposes)
• comparator drug, if it has market authorization, but is used off-label (unless it was not considered to be investigational in the context of the particular clinical trial, based on the assessment of the application)

Drug accountability records are not required for:

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

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

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

For additional information on the off-label use of a drug that is authorized for sale in Canada, refer to the Notice to stakeholders: Statement on the investigational use of marketed drugs in clinical trials.

Laboratory records

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

These records include, but are not limited to:

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

Medical instrument records

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

• All service, maintenance, cleaning and calibration records, as well as the product manual for a critical piece of equipment used in the clinical trial, should be retained for the 15-year record retention period. This would include for example certificates, calibration data, and records of faults, breakdowns and misuse of the equipment.
• The manual calibration of certain pieces of equipment or instruments (for example body weight scales) does not generate a certificate or a print-out of the calibration data to demonstrate that the calibration was indeed performed and successful. In those circumstances, the QI should retain the calibration procedure and a log stating the following information:
  • dates of calibration
  • device details (type, supplier, and purchase date)
  • person responsible for the instrument
  • person who performed calibrations

  Approved specifications for calibration should also be documented and a record of the actual calibration results kept.

• Certain pieces of equipment or instruments may require frequent automated calibration and consequently generate considerable amounts of print-outs. In these instances, a log should be kept with all of the information listed under the bullet point above; except it should include the name of the person who assessed the calibration data and certified that calibration was successful, instead of the person who calibrated the instrument.
• The manufacturer's warranty cannot replace calibration/maintenance records as equipment calibration assures that equipment works within specifications.

Financial records

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

• any subject compensation records
• financial agreements between parties (ICH E6,3.5 and C.3.2)
• insurance statements (ICH E6, 3.14.1)

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

Refer to Appendix C of ICH E6 for more information on this type of record.

Research ethics boards (REBs) records

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

These records could include, but are not limited to:

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

The REB should retain all relevant records in accordance with applicable regulatory requirements and make them available upon request from the regulatory authority(ies) (ICH E6 1.5.1).

The REB may be asked by QIs, 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 (i.e. Canadian General Standard Board)
• the secondary medium allows the successful retrieval and use of the records for the entire 15-year record retention period

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

Electronic or other system

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

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

• design to ensure the tracing of any alterations and updates, if permitted, such as source, date and content (i.e. audit trail)
• back-ups at regular intervals
• security measures in place and documented to protect against data corruption, whether through accidental deletion, equipment failures, material deterioration, or a variety of other hardware and software problems
• controlled access to appropriate individuals (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
• 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/SBCGSB-72.34- 20254.

Record retention period

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

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

Location of records

Often, third parties (such as QIs, REBs, 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.

The QIs should keep the sponsor informed of the name of the person responsible for maintaining the essential records during the retention period; for example, when the QIs site closes or a QIs leaves the site (ICH E6, 2.12.13).

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 QI 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 section C.05.013 of the Regulations (see section 5.13 of this document). These timelines should be taken into consideration when determining the location of the clinical trial records for the retention period.

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

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

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

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

C.05.012(3)

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

C.05.012(4)

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

Submission of information and samples

Interpretation

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

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

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

Retention samples of the drug

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

Retention of biological study samples

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

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

• The sponsor did not submit the requested information concerning the drug or the clinical trial, and/or requested samples of the drug, within the required time frame

Serious unexpected adverse drug reaction reporting

Interpretation

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

Section 2.7.2(b) of ICH E6 states all serious adverse events (SAEs) should be reported immediately (after the QI reasonably becomes aware of the event) to the sponsor. The QI should also include an assessment of causality. In accordance with applicable regulatory requirements, the protocol may identify SAEs not requiring immediate reporting; for example, deaths or other events that are endpoints. Subsequent information should be submitted as a follow-up report, as necessary.

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

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

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

The reporting of SUSARs to QI(s)/institutions(s) and to the REB(s) should be undertaken in a manner that reflects the urgency of action required and should take into consideration the evolving knowledge of the safety profile of the product and should be performed in accordance with applicable regulatory requirements. In some regions, periodic reporting of line listings with an overall safety assessment may be appropriate (ICH E6, 3.13.2(d)).

The sponsor should, in accordance with the applicable regulatory requirement(s) and with ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, expedite the reporting to the regulatory authority(ies) of all suspected, unexpected and serious adverse reactions (for example, SUSARs) (ICH E6, 3.13.2(b)).

The sponsor should submit to the regulatory authority(ies) safety updates and periodic reports, including changes to the Investigator's Brochure, as required by applicable regulatory requirements (ICH E6, 3.13.2(a)).

Sections C.01.016 and C.01.017 of the Regulations (listed below), which also refer to prohibition and serious ADR reporting, do not apply to drugs used for the purpose of a clinical trial, except clinical trial drugs used in Phase IV trials.

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

• Guidance document for clinical trial sponsors: Clinical trial applications (Phase I-III trials)
• Reporting adverse reactions to marketed health products – Guidance document for industry (Phase IV trials).

Examples of 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.

On this page

• Discontinuance of a clinical trial
• Suspension and cancellation (Intent to suspend)
• Suspension and cancellation

Discontinuance of a clinical trial

Interpretation

Please refer to section 2.8. "Post-Authorization Requirements" of the Guidance document for clinical trial sponsors: Clinical trial applications for further information.

In the event of the premature discontinuation of a trial (see ICH E6, 3.17.1), in its entirety or at a clinical trial site, for which a CTA or CTA-A has been filed in Canada, the sponsor is required to notify Health Canada with reason(s) for discontinuation (via CTA-Notification) as soon as possible, but no later than 15 calendar days after the date of discontinuance.

Notification of a premature discontinuation of a clinical trial or clinical trial site outside Canada, for which there are ongoing trials with the drug in Canada, should also be submitted to the appropriate Directorate (PDD or BRDD) if such discontinuation was carried out for safety reasons.

Essential records generated prior to discontinuation are expected to be maintained in accordance with GCP and applicable regulatory requirements (ICH E6, Principles 9.4 and 9.5).

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

• The sponsor did not inform Health Canada within 15 days of a clinical trial being discontinued
• The sponsor did not take reasonable measures to ensure the recovery of all unused quantities of the drug (including returns from the subjects after discontinuing the clinical trial)

Suspension and cancellation (Intent to suspend)

Interpretation

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

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

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

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

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

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

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

Suspension and cancellation

Interpretation

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

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

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

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

Investigator / Institution's responsibilities

Section 2.6 of ICH E6 sets out the responsibilities of a QI/institution in the event of premature termination or suspension of a clinical trial.

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

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

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

• the QI should inform the institution where applicable
• the QI/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 QI/institution or sponsor should promptly inform the REB and regulatory authorities 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 ICH E6 1.2.3 and 1.4.9):

• the QI must inform the institution where applicable
• the QI/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)

Sponsor's responsibilities

In addition to those requirements set out in the Regulations with respect to the discontinuance, suspension or cancellation of authorisation to sell or import a drug for the purpose of a clinical trial, section 3.17.1 of ICH E6 states that in the event of such an occurrence, the sponsor should:

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

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

On this page

1. Appendix A: Glossary
2. Appendix B: References

Appendix A: Glossary

Acronyms and abbreviations

Acronym: An identifier formed from the initial letter of each word in a phrase or compound term (for example, "CTA" represents "Clinical Trial Application").

Abbreviation: A shortened form of a word or phrase (for example, "AE" represents "Adverse Event").

ADR

Adverse Drug Reaction

AE

Adverse Event

ALCOAC

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

ANDS

Abbreviated New Drug Submission

API

Active Pharmaceutical Ingredient

BRDD

Biologic and Radiopharmaceutical Drugs Directorate

CGSB

Canadian General Standards Board

CoA

Certificate of Analysis

CRF

Case Report Form

CTA

Clinical Trial Application

CTA-A

Clinical Trial Application Amendment

CTSI

Clinical Trial Site Information

CV

Curriculum Vitae

DIN

Drug Identification Number

eCRF

Electronic Case Report Form

FAQ

Frequently Asked Questions

FDA

Food and Drug Administration

GCP

Good Clinical Practices

GMP

Good Manufacturing Practices

GUI

Guide/Guidance Document

HC-SC

Health Canada-Santé Canada

ICF

Informed Consent form

ICH

International Conference on Harmonization

I.E.

Id Est ("that is")

IEC

Independent Ethics Committee

IP

Investigational Product

IRB

Institutional Review Board

ITA

Investigational Testing Authorization

MHRA

Medicines and Healthcare products Regulatory Agency

NC

Non-Compliant

NDS

New Drug Submission

NHP

Natural Health Product

NOC

Notice of Compliance

NOL

No Objection Letter

NSN

Not Satisfactory Notice

PDD

Pharmaceutical Drugs Directorate

PIC/S

Pharmaceutical Inspection Co-Operation Scheme

QI

Qualified Investigator

QIU

Qualified Investigator Undertaking

REB

Research Ethics Board

SAE

Serious Adverse Event

SADR

Serious Adverse Drug Reaction

SNDS

Supplemental New Drug Submission

SOAD

Summary of Additional Drugs Form

SOP

Standard Operating Procedure

SP

Service Provider

SUADR

Serious Unexpected Adverse Drug Reaction

SUSAR

Suspected Unexpected Serious Adverse Reaction

TCPS

Tri-Council Policy Statement

Vs.

Versus

WHO

World Health Organization

Terms

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 are identified in brackets at the end of the definition.

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

This definition is consistent with, but further expanded on, in glossary of ICH E6, which reads:

"In the pre-approval clinical experience with a new investigational product or its new usages (particularly as the therapeutic dose(s) may not be established): unfavourable and unintended responses, such as a sign (for example, laboratory results), symptom or disease related to any dose of a medicinal product where a causal relationship between a medicinal product and an adverse event is a reasonable possibility. The level of certainty about the relatedness of the adverse drug reaction to an investigational product will vary. If the ADR is suspected to be medicinal product-related with a high level of certainty, it should be included in the reference safety information (RSI) and/or the Investigator's Brochure (IB)".

If the study includes marketed medicinal products, that is, Phase IV: "a response to a drug that is noxious and unintended and that occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of diseases or for modification of physiological function."

Adverse event (AE): means any adverse occurrence in the health of a clinical trial participant who is administered a drug, that may or may not be caused by the administration of the drug, and includes an adverse drug reaction. Further expanded on in glossary of ICH E6, the definition of "adverse event" reads: "Any unfavourable medical occurrence in a trial participant administered the investigational product. The adverse event does not necessarily have a causal relationship with the treatment."

Clinical trial: means an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.

This definition is consistent with the glossary of ICH E6.

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

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).

Consistent with Section 2 of the Food and Drugs Act, a drug is defined as any substance or mixture of substances used in the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, and in restoring, correcting or modifying organic functions.

ICH E6 does not define the word "drug", but the glossary defines "investigational product" (IP) as:

"A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. Investigational products should be considered synonymous with drugs, medicines, medicinal products, vaccines and biological products."

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 good clinical practices referred to in section C.05.010.

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

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

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

This is consistent with the definition of "investigator's brochure" in ICH E6, glossary.

Paragraph C.05.005(e) of the Regulations describes the content that must be included in an investigator's brochure that is submitted to Health Canada.

Appendix A of ICH E6 provides additional guidance on the content of an investigator's brochure.

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

Observation: A deficiency or deviation from Part C, Division 5 of the Regulations noted by an Inspector during the inspection of a clinical trial that is confirmed in writing in the 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, statistical considerations and organization of a clinical trial.

The use of the term "protocol" is consistent with ICH E6, glossary.

In accordance with paragraph C.05.005(a) of the Regulations, the application by a sponsor to sell or import a drug for the purpose of conducting a clinical trial in Canada must submit a protocol as part of their application.

Appendix B of ICH E6 describes the information found in a protocol.

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

1. in the case of a clinical trial respecting a drug to be used for dental purposes only, a physician or dentist and a member in good standing of a professional medical or dental association; and
2. in any other case, a physician and a member in good standing of a professional medical association.

ICH E6 uses the word "Investigator" to describe the individual responsible for the conduct of a clinical trial at a site.

The use of the term "Principal Investigator" is commonly used to refer to an investigator that is leading a team of individuals conducting a trial at a site, and though would have the same meaning as qualified investigator (QI), "Principal Investigator" is not a legally defined term used in Canada.

Note that paragraph C.05.010(e) of the Regulations states that there be no more than one QI at each clinical trial site. However, there may be Sub-Investigators/Co-Investigators in the study under the supervision of a QI.

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

1. the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being; and
2. that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the Immigration and Refugee Protection Act, that is composed of both men and women and that includes at least
   1. two members whose primary experience and expertise are in a scientific discipline, who have broad experience in the methods and areas of research to be approved and one of whom is from a medical discipline or, if the clinical trial is in respect of a drug to be used for dental purposes only, is from a medical or dental discipline,
   2. one member knowledgeable in ethics,
   3. one member knowledgeable in Canadian laws relevant to the biomedical research to be approved,
   4. one member whose primary experience and expertise are in a non- scientific discipline, and
   5. one member who is from the community or is a representative of an organization interested in the areas of research to be approved and who is not affiliated with the sponsor or the site where the clinical trial is to be conducted.

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 glossary of ICH E6, an IRB or an IEC is defined as:

"An independent body (a review board or 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 favorable opinion on, the trial protocol, the suitability of the investigator(s), 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 includes dispensing of drugs to participants by physicians.

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

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

The definitions for SADR and SUADR are consistent with those found in 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: A person or organization (commercial, academic or other) providing a service used by either the sponsor or the investigator to fulfil trial-related activities.

Site or trial site means the location(s) where trial-related activities are actually conducted. The ICH E6 Glossary defines investigator site as "The location(s) where trial-related activities are conducted and/or coordinated under investigator's/institution's oversight."

Health Canada's interpretation is one site equals one trial by one QI at one location (address).

Sponsor: means an individual, corporate body, institution or organization that conducts a clinical trial. ICH E6 elaborates on this definition in glossary to include: "An individual, company, institution or organization that take responsibility for the initiation, management and arrangement of the financing of a clinical trial. A clinical trial may have one or several sponsors where permitted under regulatory requirements."

The sponsor is ultimately responsible for all regulatory requirements regarding the conduct of the trial in Canada. Where a third party, such as a service provider has been delegated by written contract to carry out some or all of the sponsor's responsibilities, they must also demonstrate adherence to the applicable regulatory requirements.

If a physician is identified on the clinical trial application (CTA) as the sponsor, they must assume the responsibilities of both the sponsor and the QI. This would include ensuring that all of the sponsor's obligations under section C.05.010 of Part C, Division 5 are met at all sites at which the trial is being conducted, as well as all other applicable sections of Part C, Division 5.

Note: Part C, Division 5 of the Regulations does not differentiate between a commercial and a non-commercial sponsor.

Standard operating procedure (SOP): 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

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

Health Canada guidances and documents

• Annex 13 to the current Edition of good manufacturing practices Guidelines: Drugs Used in Clinical Trials (GUI-0036)
• Risk classification guide for observations related to inspections of clinical trials of human drugs (GUI-0043)
• Clinical trials Frequently Asked Questions
• Clinical Trial Site Information Form (PDF format) (PDF format)
• Compliance and enforcement policy for health products (POL-0001)
• Compliance and enforcement approach and inspection strategy for clinical trials of drugs involving human subjects (POL-0030)
• Good manufacturing practices (GMP) guidelines for drug products (GUI-0001)
• Good manufacturing practices (GMP) guidelines for active pharmaceutical ingredients (API) (GUI-0104)
• Guidance document for clinical trial sponsors: Clinical trial applications
• Guidance document: Preparation of clinical trial applications for use of cell therapy products in humans
• Guidelines for environmental control of drugs during storage and transportation (GUI-0069)
• Import and export of drug and health products: Compliance and enforcement
• Notice to Stakeholders: Statement on the Investigational Use of Marketed Drugs in Clinical Trials
• Qualified Investigator Undertaking Form
• Reporting adverse reactions to marketed health products – Guidance document for industry
• Research Ethics Board Attestation

Other guidances and policies

• Annex 11 to the good manufacturing practices guide: Computerized Systems: GUI-0050
• Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, International Conference on Harmonization (ICH) Harmonized Tripartite Guideline, Topic E2A
• Declaration of Helsinki
• Electronic Records as Documentary Evidence, Canadian General Standard Board (CGSB), CAN/CGSB-72.34-2024 (PDF format)
• ICH Guidance: Integrated Addendum to E6(R3): Guideline for Good Clinical Practice E6(R3)
• Medicines and Healthcare products Regulatory Authority (MHRA) GXP Data Integrity Guidance and Definitions (PDF format)
• PIC/S Guidance: Good Practices for Computerised Systems in Regulated "GXP" Environments
• Reflection paper on risk based quality management in clinical trials, European Medicines Agency (EMA) (PDF format)
• Stability Testing of New Substances and Products, ICH Harmonized Tripartite Guideline, Topic Q1A(R2)
• Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2 2022)
• U.S. Code of Federal Regulations (CFR) Title 21 Part 11 – Electronic Records; Electronic Signatures
• U.S. Food and Drug Administration (FDA) Guidance for Industry: Computerized Systems Used in Clinical Investigations
• U.S. Food and Drug Administration (FDA) Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring (PDF format)
• World Health Organization (WHO) Annex 5 Guidance on Good Data and Record Management Practices