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

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:

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:

Risk 2 (major) example:

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:

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:

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:

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

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

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

The drug was sold or imported for use in a clinical trial:

Risk 1 (critical) examples:

Risk 2 (major) examples:

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:

Risk 2 (major) example:

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:

Risk 3 (minor) example:

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:

Risk 2 (major) example:

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:

Risk 2 (major) example:

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:

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:

Risk 3 (minor) example:

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:

Risk 3 (minor) example:

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:

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

(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:

(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

C.05.008(1)(a) observation

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

Risk 2 (major) example:

C.05.008(1)(b) observation

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

Risk 1 (critical) example:

Risk 2 (major) example:

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:

Risk 2 (major) example:

Risk 3 (minor) example:

C.05.008(1)(d) observation

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

Risk 3 (minor) examples:

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:

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:

Risk 2 (major) example:

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:

Risk 2 (major) example:

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:

C.05.010(b) observation

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

Risk 1 (critical) example:

Risk 2 (major) examples:

Risk 3 (minor) example:

C.05.010(b) observation

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

Risk 1 (critical) example:

Risk 2 (major) example:

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:

Risk 3 (minor) example:

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:

Risk 2 (major) example:

Risk 3 (minor) example:

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:

Risk 3 (minor) example:

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:

Risk 2 (major) example:

Risk 3 (minor) example:

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:

Risk 2 (major) examples:

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:

Risk 2 (major) examples:

Risk 3 (minor) example:

C.05.010(c) observation

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

Risk 2 (major) examples:

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:

Risk 2 (major) example:

Risk 3 (minor) example:

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:

Risk 2 (major) examples:

Risk 3 (minor) example:

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:

Risk 3 (minor) example:

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:

Risk 3 (minor) example:

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:

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:

Risk 2 (major) examples:

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:

Risk 2 (major) examples:

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:

Risk 3 (minor) examples:

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:

Risk 3 (minor) example:

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:

Risk 2 (major) examples:

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:

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:

C.05.010(d) observation

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

Risk 2 (major) examples:

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:

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:

Risk 2 (major) examples:

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:

Risk 2 (major) examples:

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:

Risk 2 (major) examples:

Risk 3 (minor) example:

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:

Risk 2 (major) examples:

C.05.010(i) observation

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

Risk 2 (major) examples:

Risk 3 (minor) example:

C.05.010(j) observation

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

Risk 1 (critical) example:

Risk 2 (major) examples:

C.05.010(j) observation

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

Risk 1 (critical) example:

Risk 2 (major) examples:

Risk 3 (minor) example:

For help with classifying GMP observations according to risk, please consult the following guide:

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:

C.05.011 observation

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

Risk 2 (major) examples:

Risk 3 (minor) example:

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

(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:

Risk 2 (major) examples:

Risk 3 (minor) example:

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:

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:

Risk 2 (major) example:

Risk 3 (minor) examples:

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:

Risk 2 (major) examples:

C.05.012(3)(d) observation

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

Risk 1 (critical) example:

Risk 2 (major) example:

Risk 3 (minor) example:

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:

Risk 3 (minor) examples:

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:

Risk 3 (minor) example:

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:

Risk 2 (major) examples:

Risk 3 (minor) example:

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:

Risk 3 (minor) example:

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.

Note: The record retention period of 25 years was reduced to 15 years in the Food and Drug Regulations. This came into force on February 11, 2022.

Risk 2 (major) example:

Risk 3 (minor) example:

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

(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:

Risk 2 (major) example:

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:

(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:

Risk 3 (minor) example:

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:

Risk 2 (major) example:

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:

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

(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:

C.05.015(1)(c) observation

The sponsor did not:

Risk 2 (major) example:

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:

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