Risk classification guide for observations related to inspections of clinical trials of human drugs (GUI-0043): Sample observations

The following are general observations that inspectors may note during an inspection. Cited observations in the final inspection exit notice (IEN) will contain specifics or context when required.

This list is not exhaustive. Other observations may be cited where appropriate.

Under the following sections of the Regulations, we have provided, in this order:

1. exact text from Part C, Division 5 of the Regulations
2. generic observation statements that will be published in the Drug and Health Products Inspections Database (DHPID)
3. examples for the observations with different risk classifications (risk 1 and/or risk 2 and/or risk 3)
   • examples can be applied to different regulated parties as applicable
   • these examples are not an exhaustive list

On this page

• Prohibition
• General
• Authorization
• Notification
• Amendment
• Sponsor's obligations for good clinical practices
• Labelling
• Records
• Submission of information and samples
• Serious unexpected adverse drug reaction reporting
• Discontinuance of a clinical trial

Prohibition

C.05.003

Despite sections C.01.014, C.08.002, C.08.002.02 and C.08.003, no person shall sell or import a drug for the purposes of a clinical trial unless:

• (a) the person is authorized under this Division
• (b) the person complies with this Division and sections C.01.015, C.01.036, C.01.037 to C.01.040, C.01.040.2, C.01.064 to C.01.067, C.01.070, C.01.131, C.01.133 to C.01.136 and C.01.435 and
• (c) if the drug is to be imported, the person has a representative in Canada who is responsible for the sale of the drug

C.05.003(a) observation

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

Risk 1 (critical) example:

• The sponsor used a drug in a clinical trial without it being authorized under Part C, Division 5 of the Regulations.

Risk 2 (major) example:

• The sponsor imported a drug intended for use in a clinical trial before it was authorized under Part C, Division 5 of the Regulations.

C.05.003(c) observation

The drug was imported for use in a clinical trial without having a representative in Canada who is responsible for the sale of the drug.

Risk 2 (major) example:

• The sponsor who is not based in Canada did not have a representative in Canada responsible for the sale of the drug that was imported for use in a clinical trial.

General

C.05.004

Despite these Regulations, a sponsor may submit an application under this Division to sell or import a drug for the purposes of a clinical trial that contains a substance the sale of which is prohibited by these Regulations, if the sponsor establishes, on the basis of scientific information, that the inclusion of the substance in the drug may result in a therapeutic benefit for a human being.

C.05.004 observation

A prohibited substance was used in the clinical trial without seeking authorization from Health Canada.

Risk 1 (critical) example:

• The sponsor used a prohibited substance in the clinical trial without receiving authorization from Health Canada.

Authorization

C.05.006
(1) Subject to subsection (3), a sponsor may sell or import a drug, other than a drug described in subsection (2), for the purposes of a clinical trial if:

• (a) the sponsor has submitted to the Minister an application in accordance with section C.05.005
• (b) the Minister does not, within 30 days after the date of receipt of the application, send to the sponsor a notice in respect of the drug indicating that the sponsor may not sell or import the drug for any of the following reasons:
  • (i) that the information and documents in respect of the application
    • (A) were not provided in accordance with these Regulations or
    • (B) are insufficient to enable the Minister to assess the safety and risks of the drug or the clinical trial or
  • (ii) that based on an assessment of the application, an assessment of any information submitted under section C.05.009 or a review of any other information, the Minister has reasonable grounds to believe that
    • (A) the use of the drug for the purposes of the clinical trial endangers the health of a clinical trial subject or other person
    • (B) the clinical trial is contrary to the best interests of a clinical trial subject or
    • (C) the objectives of the clinical trial will not be achieved
• (c) for each clinical trial site, the sponsor has obtained the approval of the research ethics board in respect of the protocol referred to in paragraph C.05.005(a) and in respect of an informed consent form that contains the statement referred to in paragraph C.05.005(b) and
• (d) before the sale or importation of the drug at a clinical trial site, the sponsor submits to the Minister the information referred to in subparagraphs C.05.005(c)(ix) and (x) and paragraphs C.05.005(d) and (h), if it was not submitted in respect of that clinical trial site at the time of submitting the application

(2) Subject to subsection (3), a sponsor may sell or import a drug for the purposes of a clinical trial in respect of:

• (a) a new drug that has been issued a notice of compliance under subsection C.08.004(1), if the clinical trial is in respect of a purpose or condition of use for which the notice of compliance was issued or
• (b) a drug, other than a new drug, that has been assigned a drug identification number under subsection C.01.014.2(1), if the clinical trial is in respect of a use or purpose for which the drug identification number was assigned

(3) A sponsor may not sell or import a drug for the purposes of a clinical trial

• (a) during the period of any suspension made under section C.05.016 or C.05.017 or
• (b) after a cancellation made under section C.05.016 or C.05.017

C.05.006(1)(a)(b) observation

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

Risk 1 (critical) examples:

• The sponsor used a drug in a clinical trial without submitting a clinical trial application (CTA) to Health Canada.
• The sponsor used a drug in a clinical trial:
  • without obtaining authorization or
  • before the 30-day default period from the date the CTA was received

Risk 2 (major) examples:

• The sponsor imported a drug intended for use in a clinical trial without submitting a CTA to Health Canada.
• The sponsor imported a drug intended for use in a clinical trial:
  • without obtaining authorization or
  • before the 30-day default period from the date the CTA was received

C.05.006(1)(c) observation

The drug was sold or imported for use in a clinical trial without getting approval of the protocol and/or the informed consent form (ICF) from the Research Ethics Board (REB).

Risk 1 (critical) example:

• The REB had not approved the protocol and/or the main ICF used in the clinical trial.

Risk 2 (major) example:

• The REB had not approved the protocol and/or the main ICF before clinical trial activities began.

C.05.006(1)(d) observation

The drug was sold or imported for use in a clinical trial before the clinical trial site information (CTSI) was submitted to Health Canada.

Risk 2 (major) example:

• The CTSI form for the clinical trial site was never submitted to Health Canada.

Risk 3 (minor) example:

• The CTSI form for the clinical trial site was submitted to Health Canada after clinical trial activities began at the site.

C.05.006(3)(a) observation

The drug was sold or imported for use in a clinical trial after the authorization was suspended.

Risk 1 (critical) example:

• The drug was used in a clinical trial after the authorization was suspended.

Risk 2 (major) example:

• The drug was imported and intended for use in a clinical trial after the authorization was suspended.

C.05.006(3)(b) observation

The drug was sold or imported for use in a clinical trial after authorization was cancelled.

Risk 1 (critical) example:

• The drug was used in a clinical trial after authorization was cancelled.

Risk 2 (major) example:

• The drug was imported and intended for use in a clinical trial after authorization was cancelled.

Notification

C.05.007
If the sale or importation of a drug is authorized under this Division, the sponsor may make one or more of the following changes if the sponsor notifies the Minister in writing within 15 days after the date of the change:

• (a) a change to the chemistry and manufacturing information that does not affect the quality or safety of the drug, other than a change for which an amendment is required by section C.05.008 and
• (b) a change to the protocol that does not alter the risk to the health of a clinical trial subject, other than a change for which an amendment is required by section C.05.008

C.05.007(a) observation

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.

Risk 2 (major) example:

• The sponsor did not notify Health Canada of a change made to the drug's chemistry and manufacturing information.

Risk 3 (minor) example:

• The sponsor did not notify Health Canada within 15 days of making a change to the drug's chemistry and manufacturing information.

C.05.007(b) observation

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 subject.

Risk 2 (major) example:

• The sponsor did not notify Health Canada of the change to the protocol. The change does not affect the health risk of a clinical trial participant.

Risk 3 (minor) example:

• 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

C.05.008
(1) Subject to subsections (4) and (5), when the sale or importation of a drug is authorized under this Division and the sponsor proposes to make an amendment referred to in subsection (2), the sponsor may sell or import the drug for the purposes of the clinical trial in accordance with the amended authorization, if the following conditions are met:

• (a) the sponsor has submitted to the Minister an application for amendment in accordance with subsection (3)
• (b) the Minister does not, within 30 days after the date of receipt of the application for amendment, send to the sponsor a notice in respect of the drug indicating that the sponsor may not sell or import the drug in accordance with the amendment for any of the following reasons, namely
  • (i) that the information and documents in respect of the application for amendment
    • (A) were not provided in accordance with these Regulations or
    • (B) are insufficient to enable the Minister to assess the safety and risks of the drug or the clinical trial or
  • (ii) that based on an assessment of the application for amendment, an assessment of any information submitted under section C.05.009 or a review of any other information, the Minister has reasonable grounds to believe that
    • (A) the use of the drug for the purposes of the clinical trial endangers the health of a clinical trial subject or other person
    • (B) the clinical trial is contrary to the best interests of a clinical trial subject or
    • (C) the objectives of the clinical trial will not be achieved
• (c) before the sale or importation of the drug, the sponsor submits to the Minister
  • (i) for each clinical trial site, the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the research ethics board that approved any amended protocol submitted under paragraph (3)(a) or approved any amended statement submitted under paragraph (3)(c) and
  • (ii) the name, address and telephone number and, if applicable, the facsimile number and electronic mail address of any research ethics board that has previously refused to approve any amendment to the protocol, its reasons for doing so and the date on which the refusal was given
• (d) before the sale or importation of the drug, the sponsor maintains records concerning
  • (i) the information referred to in paragraph C.05.005(h) and
  • (ii) the information referred to in subparagraph C.05.005(c)(ix), if any of that information has changed since it was submitted
• (e) before the sale or importation of the drug in accordance with the amended authorization, the sponsor ceases to sell or import the drug in accordance with the existing authorization and
• (f) the sponsor conducts the clinical trial in accordance with the amended authorization

(2) For the purposes of subsection (1), amendments are

• (a) amendments to the protocol that affect the selection, monitoring or dismissal of a clinical trial subject
• (b) amendments to the protocol that affect the evaluation of the clinical efficacy of the drug
• (c) amendments to the protocol that alter the risk to the health of a clinical trial subject
• (d) amendments to the protocol that affect the safety evaluation of the drug
• (e) amendments to the protocol that extend the duration of the clinical trial and
• (f) amendments to the chemistry and manufacturing information that may affect the safety or quality of the drug

(3) The application for amendment referred to in subsection (1) shall contain a reference to the application submitted under section C.05.005 and shall contain the following documents and information:

• (a) if the application is in respect of an amendment referred to in any of paragraphs (2)(a) to (e), a copy of the amended protocol that indicates the amendment, a copy of the protocol submitted under paragraph C.05.005(a), and the rationale for the amendment
• (b) if the application is in respect of an amendment referred to in paragraph (2)(e), a copy of the amended investigator's brochure or an addendum to the investigator's brochure that indicates the new information, including supporting toxicological studies and clinical trial safety data
• (c) if the application is in respect of an amendment referred to in any of paragraphs (2)(a) to (f) and, as a result of that amendment, it is necessary to amend the statement referred to in paragraph C.05.005(b), a copy of the amended statement that indicates the new information and
• (d) if the application is in respect of an amendment referred to in paragraph (2)(f), a copy of the amended chemistry and manufacturing information that indicates the amendment, and the rationale for that amendment

(4) If the sponsor is required to immediately make one or more of the amendments referred to in subsection (2) because the clinical trial or the use of the drug for the purposes of the clinical trial endangers the health of a clinical trial subject or other person, the sponsor may immediately make the amendment and shall provide the Minister with the information referred to in subsection (3) within 15 days after the date of the amendment

(5) A sponsor may not sell or import a drug for the purposes of a clinical trial

• (a) during the period of any suspension made under section C.05.016 or C.05.017 or
• (b) after a cancellation made under section C.05.016 or C.05.017

C.05.008(1)(a) observation

The sponsor did not submit a clinical trial application-amendment (CTA-A) after a change was made to:

• the elements in the design of the study protocol or
• the composition/formulation of the study drug that met the criteria for an amendment

Risk 2 (major) example:

• With the exception of C.05.008(4), the sponsor did not submit the CTA-A to Health Canada to obtain authorization before implementing amendments.

C.05.008(1)(b) observation

The drug was sold or imported for use in a clinical trial without:

• obtaining an amended authorization from Health Canada or
• before the end of the 30-day default period

Risk 1 (critical) example:

• With the exception of C.05.008(4), study participants were exposed to undue risk, as the sponsor used a drug in a clinical trial without:
  • obtaining an amended authorization from Health Canada or
  • before the 30-day default period from when the amended CTA was received

Risk 2 (major) example:

• With the exception of C.05.008(4), the sponsor imported a drug intended for use in a clinical trial without:
  • obtaining an amended authorization from Health Canada or
  • before the 30-day default period from when the amended CTA was received

C.05.008(1)(c)(i) and (ii) observation:

The sponsor sold or imported for use the drug in a clinical trial before submitting to Health Canada:

• the contact information of the REB that had approved and previously refused any amended protocol and its reasons and date of refusal

Risk 2 (major) example:

• The sponsor sold or imported for use the drug in a clinical trial before submitting to Health Canada:
  • the REB contact information that previously refused any amended protocol along with its reasons and date of refusal

Risk 3 (minor) example:

• The sponsor sold or imported for use the drug in a clinical trial before submitting to Health Canada the contact information of the REB that approved any amended protocol in a revised clinical trial site information (CTSI) form.

C.05.008(1)(d) observation

The sponsor did not always maintain the required records concerning an amendment.

Risk 3 (minor) examples:

• The sponsor did not provide records on when the amendment began.
• The sponsor did not provide records on the updated contact information of the qualified investigator (QI).

C.05.008(4) observation

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 subject or other person.

Risk 2 (major) example:

• The sponsor did not notify Health Canada within 15 days of an immediate amendment that was implemented in cases where the clinical trial or use of the study drug endangered the health of a clinical trial participant or other person.

C.05.008(5)(a) observation

The drug was sold or imported for use in a clinical trial after the amended authorization was suspended.

Risk 1 (critical) example:

• The drug was used in a clinical trial after the amended authorization was suspended.

Risk 2 (major) example:

• The drug was imported and intended for use in a clinical trial after the amended authorization was suspended.

C.05.008(5)(b) observation

The drug was sold or imported for use in a clinical trial after the amended authorization was cancelled.

Risk 1 (critical) example:

• The drug was used in a clinical trial after the amended authorization was cancelled.

Risk 2 (major) example:

• The drug was imported and intended for use in a clinical trial after the amended authorization was cancelled.

Sponsor's obligations for good clinical practices

C.05.010
Every sponsor shall ensure that a clinical trial is conducted in accordance with good clinical practices and, without limiting the generality of the foregoing, shall ensure that:

• (a) the clinical trial is scientifically sound and clearly described in a protocol
• (b) the clinical trial is conducted, and the drug is used, in accordance with the protocol and this Division
• (c) systems and procedures that assure the quality of every aspect of the clinical trial are implemented
• (d) for each clinical trial site, the approval of a research ethics board is obtained before the clinical trial begins at the site
• (e) at each clinical trial site, there is no more than one qualified investigator
• (f) at each clinical trial site, medical care and medical decisions, in respect of the clinical trial, are under the supervision of the qualified investigator
• (g) each individual involved in the conduct of the clinical trial is qualified by education, training and experience to perform his or her respective tasks
• (h) written informed consent, given in accordance with the applicable laws governing consent, is obtained from every person before that person participates in the clinical trial but only after that person has been informed of
  • (i) the risks and anticipated benefits to his or her health arising from participation in the clinical trial and
  • (ii) all other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial
• (i) the requirements respecting information and records set out in section C.05.012 are met and
• (j) the drug is manufactured, handled and stored in accordance with the applicable good manufacturing practices referred to in Divisions 2 to 4 except sections C.02.019, C.02.025 and C.02.026

C.05.010(b) observation

The clinical trial was not always conducted according to the protocol.

Risk 1 (critical) example:

• The inclusion and exclusion criteria outlined in the protocol were not followed, which resulted in the randomization of participants who should have been excluded. This created undue risk to the participants.

Risk 2 (major) examples:

• The study visits by the QI were not conducted as per the protocol requirements.
• The participant had multiple test samples collected during the clinical trial that were not required by the protocol and to which they did not consent.
• Clinical samples were not always collected, handled and stored in accordance with the requirements in the protocol and associated lab manual.
• It was not always demonstrated that:
  • the clinical trial was conducted in accordance with the protocol and
  • the sponsor and/or REB (as required) were notified of the protocol deviations

Risk 3 (minor) example:

• Multiple participants had study visits that were outside of the visit window outlined in the protocol. These were not documented as protocol deviations.

C.05.010(b) observation

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

Risk 1 (critical) example:

• An incorrect drug dosage than what was required by the protocol was administered to a participant, thus putting their safety at risk.

Risk 2 (major) example:

• The clinical trial drug was not given according to the requirements set out in the protocol.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure the quality of the clinical trial.

Risk 2 (major) examples:

• The site did not have procedures for key clinical trial processes, such as the informed consent process and adverse event recording, managing and reporting.
• There was no agreement between the site and a third party to describe what responsibilities the qualified investigator (QI) had delegated to this service provider.
• The processes at the site for handling, storage and accountability of the study drug were not conducted according to written procedures.

Risk 3 (minor) example:

• The written procedures in place at the site for handling, storage and accountability of the study drug were incomplete.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure that staff was adequately trained on good clinical practices (GCP) and the appropriate Food and Drug Regulations.

Risk 1 (critical) example:

• No system and/or procedure was in place to ensure that key study staff were trained on GCP. As a result, significant deviations from GCP affected the rights and safety of participants and/or the integrity of the study data.

Risk 2 (major) example:

• The systems and/or procedures did not ensure that the QI and study staff listed on the delegation log were trained on GCP before the clinical trial began.

Risk 3 (minor) example:

• The training procedures for the clinical site were deficient to ensure that all information on the training for staff is recorded (for example, when training occurred, what training was provided).

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure the required information was submitted to the Research Ethics Board (REB).

Risk 2 (major) examples:

• The systems and/or procedures were not implemented to notify the REB of the discontinuance and/or restart of the study.
• The systems and/or procedures were inadequate to ensure that the investigator's brochure, protocols and/or informed consent form are submitted to the REB.

Risk 3 (minor) example:

• There was no process for submitting amendments to the investigator's brochure (IB) to the REB (an REB requirement).

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure the required study information was communicated to and/or reviewed by appropriate study personnel in a timely manner.

Risk 1 (critical) example:

• There was no system and/or procedure to ensure that new safety information for the study drug was communicated to the QI. This compromised a participant's safety.

Risk 2 (major) example:

• Inadequate systems and/or procedures meant that important study information (for example, pharmacy manual) and/or other required training were not provided to key study staff members (for example, the pharmacist) who were delegated key study activities (for example, study drug preparation).

Risk 3 (minor) example:

• The systems and/or procedures were deficient to ensure that the updated information (for example, newsletters) was communicated to the study staff.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure adequate monitoring of the clinical trial.

Risk 1 (critical) example:

• There was no system and/or procedure to ensure that the monitoring of the trial was conducted. This posed undue risk to the safety of participants and/or inaccurate data being reported.

Risk 2 (major) examples:

• The systems and/or procedures were inadequate to ensure that corrective actions identified as a result of monitoring visits were implemented.
• The systems and/or procedures were not followed. As a result, most of the monitoring visits were not conducted within the time frames outlined in the monitoring plan.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure equipment was maintained and calibrated.

Risk 1 (critical) examples:

• Participant safety was compromised (for example, administration of an incorrect dose of the study drug) as a result of critical equipment (for example, infusion pump) not calibrated and/or maintained.
• The integrity of the data was compromised as a result of critical equipment used to collect critical data (for example, primary efficacy endpoint) not calibrated and/or maintained.

Risk 2 (major) examples:

• There was no maintenance and calibration program for the refrigerator used to store the investigational product.
• There were no written procedures for calibrating the infusion pumps, scales and centrifuges used in the trial.
• Study-related equipment (for example, weight scale, blood pressure monitor, centrifuge) was not calibrated using a traceable standard and/or defined specification.

Risk 3 (minor) example:

• Some equipment was not calibrated in accordance with the site's written procedures.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to train study staff.

Risk 2 (major) examples:

• The systems and/or procedures to ensure that the site's study staff were properly trained were not implemented (for example, protocol, study manuals).
• The systems and/or procedures were deficient to ensure that the study staff were trained on the electronic systems used during the study.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure that tasks were appropriately delegated to study staff.

Risk 1 (critical) example:

• The systems and/or procedures to ensure tasks were delegated appropriately to qualified study staff were either not in place, were deficient or not implemented. This compromised the safety of participants and/or the integrity of the data.

Risk 2 (major) example:

• The systems and/or procedures were deficient to ensure that the protocol tasks to be performed by specific study staff were on the delegation log.

Risk 3 (minor) example:

• The qualified investigator did not follow the systems and/or procedures for delegating tasks to the study staff before their involvement or participation in the clinical trial.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure that subjects had been properly consented.

Risk 1 (critical) example:

• There was no process on how to obtain informed consent. Study participants had not given their consent before participating in the trial.

Risk 2 (major) examples:

• The systems and/or procedures were deficient to ensure that participants were consented on the new version of the informed consent form (ICF). This failure was not rectified even after several visits to the site.
• The systems and/or procedures were deficient and/or were not followed to ensure that complete ICFs were signed by all participants.

Risk 3 (minor) example:

• There were deficiencies in the systems and/or procedures, as the participant had not initialed some pages of the ICF, as required by the form.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure that study records were maintained and archived.

Risk 2 (major) examples:

• The site had no process to address the archiving of electronic study records.
• There was no system and/or procedure to ensure that pharmacy study-related documents were maintained.
• The site had no process on how the temperature logs would be retained and filed as part of the study records.

Risk 3 (minor) example:

• The systems and/or procedures at the site were deficient to ensure that all study staff's curricula vitae were maintained.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure the drug was handled and stored properly.

Risk 2 (major) examples:

• There was no system and/or procedure to monitor the temperature of the study drug.
• There was no system and/or procedure to verify the shipping conditions of the study drug.
• The site procedure for handling and storing the study drug was deficient. It did not require a temperature monitoring device for the fridge and/or freezer used during the trial.

Risk 3 (minor) example:

• The site did not have a written procedure for receiving the study drug.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure control of the trial drug inventory.

Risk 2 (major) example:

• The site did not have systems and/or procedures in place to ensure the accuracy of the study drug accountability log.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure the electronic systems were validated.

Risk 1 (critical) examples:

• The systems and/or procedures to ensure that the electronic systems used to create, modify and store clinical trial data are validated for their intended use were not in place or were deficient. As a result, the integrity of the data was compromised.
• The systems and/or procedures to ensure the validation for intended use of electronic systems used to perform key activities (for example, study drug management) in a clinical trial were not in place or were deficient. As a result, the integrity of the data was compromised.

Risk 2 (major) examples:

• The systems and/or procedures were deficient to ensure the validation of electronic systems used to perform key activities in a clinical trial was adequate.
• The process of transferring data from 1 system to another was not validated.
• The systems and/or procedures were deficient to ensure that user access to validated systems was adequately controlled and/or authorized.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure adverse reactions or events were documented and reported.

Risk 1 (critical) example:

• There were no systems and/or procedures in place. As a result, the sponsor did not report the serious unexpected adverse drug reaction(s) (SUADR) that occurred at the site to Health Canada.

Risk 2 (major) examples:

• The adverse event experienced by the participant was noted in the source document during a study visit. However, the systems and/or procedures were deficient to ensure that it was reported or assessed as an adverse event in the case report form (CRF).
• The serious unexpected adverse drug reaction (SUADR) reporting process was not clearly communicated to the site at the start of the study.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure that deviations from the protocol were documented and reported.

Risk 2 (major) examples:

• The site had no process for identifying, documenting and reporting deviations from the protocol to the sponsor and Research Ethics Board (REB).
• The systems and/or procedures were deficient to ensure that a deviation pertaining to the storage temperature of the investigational product was reported by the site to the sponsor.

Risk 3 (minor) examples:

• The systems and/or procedures were deficient to ensure that deviation(s) to the protocol submitted to the REB contained all relevant details.
• The site's standard operating procedure (SOP) required the site to document deviations from the protocol. However, it did not describe how to document deviations.

C.05.010(c) observation

The sponsor did not always implement systems and procedures to ensure accurate and complete transcription of data.

Risk 2 (major) examples:

• The systems and/or procedures were deficient to ensure that all the adverse events listed on the adverse event log were recorded in the electronic case report form (eCRF).
• The systems and/or procedures were deficient. As a result, there were numerous transcription errors from the source documents to the eCRF for several participants in the study.

Risk 3 (minor) example:

• The sponsor's systems and/or procedures did not include either sufficient details on data entry into the eCRF at the site and/or a specified time frame for data entry.

C.05.010(d) observation

The sponsor did not get the approval of the REB before the clinical trial began at the clinical trial site.

Risk 1 (critical) example:

• The sponsor failed to obtain REB approval of the protocol and/or the informed consent forms before starting the clinical trial at the site.

Risk 2 (major) examples:

• The site administered non-REB approved questionnaires to participants.
• The clinical trial site was using an advertisement to recruit participants that was not approved by the REB.

C.05.010(d) observation

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

Risk 2 (major) example:

• The clinical trial site implemented a protocol amendment before receiving REB approval.

C.05.010(d) observation

The sponsor did not get approval from the REB before the amended informed consent form (ICF) was implemented at the clinical trial site.

Risk 2 (major) example:

• The revised ICF used at the clinical trial site was implemented and signed by participants before being approved by the REB.

C.05.010(d) observation

The REB did not have the required membership and/or was affiliated with the sponsor.

Risk 2 (major) examples:

• A pharmacist who was delegated and performing study tasks was also a voting member of the REB for the study or the protocol.
• The sponsor could not confirm the members of the REB. Therefore, the sponsor could not demonstrate that the membership met the requirements of Part C, Division 5 of the Food and Drug Regulations.

C.05.010(e) observation

More than 1 qualified investigator (QI) at the clinical trial site was responsible for the clinical trial.

Risk 2 (major) examples:

• More than 1 QI at the site was responsible for the clinical trial.
• More than 1 clinical trial site information form (CTSI) submitted to Health Canada for the same clinical trial site identified more than 1 QI.

C.05.010(e) observation

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.

Risk 1 (critical) examples:

• The QI did not have a medical licence to practise medicine in their jurisdiction.
• The QI did not have a dentist licence to practise dentistry in their jurisdiction.

Risk 2 (major) examples:

• The QI's medical licence to practise medicine in their jurisdiction was expired.
• The QI's dentist licence to practise dentistry in their jurisdiction was expired.

C.05.010(f) observation

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

Risk 1 (critical) example:

• The inclusion/exclusion criteria was not adequately reviewed and/or assessed by the QI/sub-investigator before participants were randomized and dosed.

Risk 2 (major) examples:

• The assessment of adverse reactions and serious adverse drug reactions (for example, severity, seriousness, expectedness, causality) was not always documented by the QI or other delegated physician.
• The QI never accessed the electronic system throughout the study to review the completed questionnaires by the participants. This was required by the protocol.
• Serious unexpected adverse drug reactions (SUADR) were not reviewed within the specified time frame by the applicable medical study personnel.

C.05.010(g) observation

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

Risk 1 (critical) example:

• The study staff were conducting clinical trial activities and/or making trial decisions outside of their professional scope of practice. Therefore, they were not adequately educated and trained to perform the noted activity. As a result, the safety of participants was compromised.

Risk 2 (major) examples:

• The protocol activities were performed by the study staff before they were trained on the protocol, protocol amendments, study systems, electronic case report form and so on.
• The study staff amended the physician's orders for the laboratory requisition, but were not trained for this task.

Risk 3 (minor) example:

• The clinical staff were not trained on the most recent versions of the site's standard operating procedures.

C.05.010(h) observation

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

Risk 1 (critical) example:

• Written informed consent was not obtained from the study participants before their participation in the trial.

Risk 2 (major) examples:

• Participants signed the wrong version of the informed consent form (ICF).
• Even after several visits to the clinical site, participant(s) had not signed the new version of the ICF.

C.05.010(i) observation

The sponsor did not always meet the requirements respecting information and records.

Risk 2 (major) examples:

• The sponsor had not approved the data management plan before the start of the study.
• The source data did not always meet good documentation practice requirements (for example, attributable, legible, contemporaneous, original, accurate and complete (ALCOAC) principles).

Risk 3 (minor) example:

• The sponsor's contact information in Health Canada's clinical trial application (CTA) was not updated after this person left the company.

C.05.010(j) observation

The drug was not manufactured in keeping with good manufacturing practices (GMP).

Risk 1 (critical) example:

• The study drug used to dose participants did not meet the pre-approved release specifications for quality and safety.

Risk 2 (major) examples:

• The study drug was released before the out-of-specification investigation, as required by the protocol or written procedures, had been completed.
• The re-labelling activities for the study drug conducted on-site were not performed according to GMP requirements.
• The drug was not manufactured in accordance with the applicable GMP requirements.

C.05.010(j) observation

The drug was not always handled and stored in keeping with good manufacturing practices.

Risk 1 (critical) example:

• The study drug administered to participants was not stored in the required storage conditions to maintain critical quality and safety attributes. This compromised the safety of participants.

Risk 2 (major) examples:

• The study drug was not stored in accordance with the label requirements.
• The storage temperature of the study drug was not monitored.

Risk 3 (minor) example:

• There was no documentation for assessing minor gaps in the monitoring and/or recording of the study drug temperature.

Labelling

C.05.011

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

• (a) a statement indicating that the drug is an investigational drug to be used only by a qualified investigator
• (b) the name, number or identifying mark of the drug
• (c) the expiration date of the drug
• (d) the recommended storage conditions for the drug
• (e) the lot number of the drug
• (f) the name and address of the sponsor
• (g) the protocol code or identification and
• (h) if the drug is a radiopharmaceutical as defined in section C.03.201, the information required by subparagraph C.03.202 (1)(b)(vi)

C.05.011 observation

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

Risk 2 (major) examples:

• A commercially labelled drug used for a clinical trial and considered to be investigational by Health Canada did not have the investigational product label.
• The study drug label did not have the expiration date of the drug and the sponsor's name and address, as required by the Regulations.

Risk 3 (minor) example:

• The label of the drug has all the required information, but in only 1 of the official languages (English or French).

Records

C.05.012

(1) The sponsor shall record, handle and store all information in respect of a clinical trial in a way that allows its complete and accurate reporting as well as its interpretation and verification.

(2) The sponsor shall maintain complete and accurate records to establish that the clinical trial is conducted in accordance with good clinical practices and these Regulations.

(3) The sponsor shall maintain complete and accurate records in respect of the use of a drug in a clinical trial, including

• (a) a copy of all versions of the investigator's brochure for the drug
• (b) records respecting each change made to the investigator's brochure, including the rationale for each change and documentation that supports each change
• (c) records respecting all adverse events in respect of the drug that have occurred inside or outside Canada, including information that specifies the indication for use and the dosage form of the drug at the time of the adverse event
• (d) records respecting the enrolment of clinical trial subjects, including information sufficient to enable all clinical trial subjects to be identified and contacted in the event that the sale of the drug may endanger the health of the clinical trial subjects or other persons
• (e) records respecting the shipment, receipt, disposition, return and destruction of the drug
• (f) for each clinical trial site, an undertaking from the qualified investigator that is signed and dated by the qualified investigator prior to the commencement of his or her responsibilities in respect of the clinical trial, that states that
  • (i) the qualified investigator will conduct the clinical trial in accordance with good clinical practices and
  • (ii) the qualified investigator will immediately, on discontinuance of the clinical trial by the sponsor, in its entirety or at a clinical trial site, inform both the clinical trial subjects and the research ethics board of the discontinuance, provide them with the reasons for the discontinuance and advise them in writing of any potential risks to the health of clinical trial subjects or other persons
• (g) for each clinical trial site, a copy of the protocol, informed consent form and any amendment to the protocol or informed consent form that have been approved by the research ethics board for that clinical trial site and
• (h) for each clinical trial site, an attestation, signed and dated by the research ethics board for that clinical trial site, stating that it has reviewed and approved the protocol and informed consent form and that the board carries out its functions in a manner consistent with good clinical practices

(4) The sponsor shall maintain all records referred to in this Division for a period of 15 years.

C.05.012(1) and (2) observations

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 record, handle and store all information for the delegation of tasks in the clinical trial to allow for complete and accurate reporting, interpretation and verification.

The sponsor did not always maintain complete and accurate records to show that the clinical trial was conducted in accordance with good clinical practices and the Regulations.

Risk 1 (critical) examples:

• There was no source documentation for each participant to support their eligibility in the trial.
• Records were falsified or misrepresented.

Risk 2 (major) examples:

• There was no documentation to verify that the critical equipment used during the trial was calibrated, as the calibration and/or maintenance records were incomplete.
• There was incomplete documentation showing that the electronic systems were validated.
• The sponsor and involved parties had no written agreement. As a result, it was not possible to identify their roles and responsibilities and to ensure that the trial was conducted in accordance with good clinical practices.

Risk 3 (minor) example:

• The delegated responsibilities were assigned to the study staff by the qualified investigator (QI), but the delegation log was not signed by the QI.

C.05.012(3) observation

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.

Risk 1 (critical) example:

• There were no records on the use of the study drug by all participants in the trial. This compromised their safety.

C.05.012(3)(a)(b) observation

The sponsor did not maintain all versions of the investigator's brochure (IB), including the rationale for any changes and documentation supporting each change.

Risk 1 (critical) example:

• There were no IBs at the site. Thus, there was no documentation to demonstrate that the qualified investigator (QI) had reviewed the safety information noted in the IB.

Risk 2 (major) example:

• The sponsor did not provide the most recent version of the IB to the clinical trial site. This version included an update to the safety profile of the trial drug.

Risk 3 (minor) examples:

• The site did not track the dates when it had received every version of the IB.
• Copies of every version of the IB were not maintained.

C.05.012(3)(c) observation

The sponsor did not maintain records of all adverse events occurring from the drug in or outside Canada.

Risk 1 (critical) example:

• There were no records for the serious unexpected adverse drug reactions (SUADRs) that occurred in and/or outside Canada. Therefore, it was not possible for the QI to assess whether the safety of the participants was adversely affected by any changes to the safety profile of the study drug.

Risk 2 (major) examples:

• The records of all adverse events occurring in or outside Canada were incomplete.
• Complete and accurate records of all adverse events were not maintained at the clinical trial site.

C.05.012(3)(d) observation

The sponsor did not maintain records on the enrollment of all clinical trial subjects.

Risk 1 (critical) example:

• There was no documentation to support every participant's enrollment in the trial. As a result, participants could not be contacted and informed when the drug caused undue risk to the health and safety of clinical trial participants.

Risk 2 (major) example:

• Documentation to support participant's enrollment in the trial was incomplete.

Risk 3 (minor) example:

• Documentation for participants who did not meet the screening criteria and were thus excluded from the trial was incomplete.

C.05.012(3)(e) observation

The sponsor did not maintain records for shipping, receiving, disposing of, returning and/or destroying the drug.

Risk 2 (major) examples:

• The clinical trial site did not maintain records for when the drug was shipped and received.
• There was no documentation to show that the trial drug was returned or destroyed after use, as per the protocol.
• The site inventory log did not reflect the actual inventory of the investigational product being used at the site.

Risk 3 (minor) examples:

• The date of return of the used trial drug was not recorded in the drug accountability log.
• Documentation to support when the trial drug was returned to the pharmacy was incomplete.

C.05.012(3)(f) observation

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.

Risk 2 (major) example:

• There was no documentation showing that the QI attested to performing the clinical trial according to good clinical practice requirements.

Risk 3 (minor) example:

• The QI signed but did not date the qualified investigator undertaking (QIU) form.

C.05.012(3)(g) observation

The sponsor did not maintain the following items approved by the Research Ethics Board (REB) for the clinical trial site:

• copies of the protocol
• informed consent form and/or
• any amendments to the protocol or informed consent form (ICF)

Risk 2 (major) examples:

• The REB-approved protocol and/or protocol amendments were not kept at the clinical trial site.
• The REB-approved ICFs were not kept at the clinical trial site.

Risk 3 (minor) example:

• Not all copies of the REB-approved protocol, protocol amendments and ICFs were available at the site.

C.05.12(3)(h) observation

The sponsor did not maintain a signed and dated attestation by the REB for the clinical trial site.

Risk 2 (major) example:

• The sponsor did not maintain documentation to show that the REB:
  • had reviewed and approved all versions of the protocol and ICF and
  • carries out its functions in a manner consistent with good clinical practices

Risk 3 (minor) example:

• The site did not maintain a copy of the signed and dated REB attestation (REBA) form or equivalent REB letter.

C.05.012(4) observation

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

Risk 2 (major) example:

• The sponsor did not have a process for keeping all clinical trial records for a period of 15 years.

Risk 3 (minor) example:

• The sponsor did not have an approved written procedure for keeping all clinical trial records for a period of 15 years.

Submission of information and samples

C.05.013

(1) The Minister shall require a sponsor to submit, within two days after receipt of the request, information concerning the drug or the clinical trial, or samples of the drug, if the Minister has reasonable grounds to believe that

• (a) the use of the drug for the purposes of the clinical trial endangers the health of a clinical trial subject or other person
• (b) the clinical trial is contrary to the best interests of a clinical trial subject
• (c) the objectives of the clinical trial will not be achieved
• (d) a qualified investigator is not respecting the undertaking referred to in paragraph C.05.012(3)(f) or
• (e) information submitted in respect of the drug or the clinical trial is false or misleading

(2) The Minister may require the sponsor to submit, within seven days after receipt of the request, any information or records kept under section C.05.012, or samples of the drug, in order to assess the safety of the drug or the health of clinical trial subjects or other persons.

C.05.013 observation

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.

Risk 1 (critical) example:

• The sponsor provided false, misleading or deceptive samples of the drug or additional information concerning the drug or the clinical trial.

Risk 2 (major) example:

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

Serious unexpected adverse drug reaction reporting

C.05.014

(1) During the course of a clinical trial, the sponsor shall inform the Minister of any serious unexpected adverse drug reaction in respect of the drug that has occurred inside or outside Canada as follows:

• (a) if it is neither fatal nor life threatening, within 15 days after becoming aware of the information and
• (b) if it is fatal or life threatening, within seven days after becoming aware of the information

(2) The sponsor shall, within eight days after having informed the Minister under paragraph (1)(b), submit to the Minister a complete report in respect of that information that includes an assessment of the importance and implication of any findings made.

(3) Sections C.01.016 to C.01.020 do not apply to drugs used for the purposes of a clinical trial.

C.05.014(1)(a) observation

The sponsor did not inform Health Canada within 15 days of becoming aware of serious unexpected adverse drug reactions (SUADRs) in or outside Canada that were not fatal or life-threatening.

Risk 2 (major) example:

• The sponsor did not report any of the SUADRs in or outside Canada that were not fatal or life-threatening to Health Canada.

Risk 3 (minor) example:

• The sponsor did not report to Health Canada the SUADRs in or outside Canada that were not fatal or life-threatening within 15 days of becoming aware of these incidents.

C.05.014(1)(b) observation

The sponsor did not inform Health Canada within 7 days of becoming aware of SUADRs in or outside Canada that were fatal or life-threatening.

Risk 1 (critical) example:

• The sponsor did not report the SUADRs in or outside Canada that were fatal or life-threatening to Health Canada.

Risk 2 (major) example:

• The sponsor did not report to Health Canada the SUADRs in or outside Canada that were fatal or life-threatening within 7 days of becoming aware of these incidents.

C.05.014(2) observation

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.

Risk 2 (major) example:

• The follow-up of a fatal or life-threatening SUADR report was not sent within 8 days, as required by the Regulations.

Discontinuance of a clinical trial

C.05.015

(1) If a clinical trial is discontinued by the sponsor in its entirety or at a clinical trial site, the sponsor shall

• (a) inform the Minister no later than 15 days after the date of the discontinuance
• (b) provide the Minister with the reason for the discontinuance and its impact on the proposed or ongoing clinical trials in respect of the drug conducted in Canada by the sponsor
• (c) as soon as possible, inform all qualified investigators of the discontinuance and of the reasons for the discontinuance, and advise them in writing of any potential risks to the health of clinical trial subjects or other persons and
• (d) in respect of each discontinued clinical trial site, stop the sale or importation of the drug as of the date of the discontinuance and take all reasonable measures to ensure the recovery of all unused quantities of the drug that have been sold

(2) If the sponsor has discontinued the clinical trial in its entirety or at a clinical trial site, the sponsor may resume selling or importing the drug for the purposes of a clinical trial in its entirety or at a clinical trial site if, in respect of each clinical trial site where the sale or importation is to be resumed, the sponsor submits to the Minister the information referred to in subparagraphs C.05.005(c)(ix) and (x) and paragraphs C.05.005(d) and (h).

C.05.015(1)(a) observation

The sponsor did not inform Health Canada within 15 days of a clinical trial being discontinued.

Risk 2 (major) example:

• The sponsor did not inform Health Canada that the clinical trial was discontinued in its entirety or at a clinical trial site within 15 days after the discontinuance took effect.

C.05.015(1)(c) observation

The sponsor did not:

• inform the qualified investigator (QI) of the discontinuance and the reasons for the discontinuance and/or
• advise the QI in writing of any potential risks to the health of clinical trial subjects

Risk 2 (major) example:

• The sponsor did not inform the QI of the discontinuance of a trial and the reasons for the discontinuation. The sponsor also did not advise the QI in writing of any potential risks to the health of clinical trial participants.

C.05.015(1)(d) observation

The sponsor did not take reasonable measures to ensure the recovery of all unused quantities of the drug (including returns from subjects after discontinuing the clinical trial).

Risk 2 (major) examples:

• The clinical trial site did not return unused quantities of the drug to the sponsor after the clinical trial was discontinued.
• The clinical trial site did not destroy unused quantities of the drug after the clinical trial was discontinued in accordance with the sponsor's requirements.