ARCHIVED  Guidance on applications for drug clinical trials under the interim order: Application guidelines and process

Notice to Reader:

We have replaced the Interim Order No. 2 respecting clinical trials for medical devices and drugs relating to COVID-19. See the regulations notice about the Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations.

On this page

• Pre-clinical trial stage
• Submitting an application
• Clinical trial involving new uses of a marketed drug
• Issuing an authorization
• Additional information before commencing a clinical trial
• Terms and conditions
• Submitting an amendment to a clinical trial authorization
• Changes not requiring an amendment or notification
• Immediate changes/application to amend

Pre-clinical trial stage

Health Canada encourages applicants of COVID-19 drug clinical trials to request a pre-clinical trial phone consultation to discuss the trial before submitting an application. We will prioritize these requests for consultation.

Please refer to the Who to contact section.

Submitting an application

To sell or import a COVID-19 drug for the purpose of conducting a clinical trial, applicants must seek authorization before starting the trial.

The application requirements under Section 20 of IO No. 2 are the same as Division 5 for novel therapies.

To apply for authorization, submit a clinical trial application in accordance with the content and format outlined in section 2.3 of the Guidance document for clinical trial sponsors: Clinical trial applications.

While the application process is the same, applicants must clearly indicate in their application cover letter that they are applying for authorization under IO No. 2. They must also indicate how the drug meets the definition of a COVID-19 drug, including the active role the drug will play in diagnosing, treating, mitigating or preventing COVID-19.

Note: Any applications filed under IO No. 1 that were outstanding when IO No. 1 was repealed will be considered under IO No. 2. The Minister may request more information about a COVID-19 clinical trial submission at any time.

Clinical trial involving new uses of a marketed drug

Health Canada recognizes that in the context of the COVID-19 pandemic, clinical trials may be conducted to determine new uses of already marketed drugs.

IO No. 2 expands on the current policy interpretation to exempt certain requirements for marketed drugs that are considered non-investigational (for example, used as a comparator) or investigational (that is, repurposed drugs for the purpose of COVID-19) if it's determined that use of the drug aligns with the standard medical practice.

(Note: The requirements for marketed drugs apply to drugs marketed in Canada that have been issued a notice of compliance under C.08.004(1) of the Regulations or that have been assigned a drug identification number (DIN) under subsection C.01.014.2(1) of those Regulations and where the clinical trial drug is being used for an indication other than those for which the notice of compliance or DIN was issued.)

For a clinical trial involving marketed drugs where the drug is being used in alignment with standard medical practice but outside its approved indication, the application must include all elements of a standard application package, except for:

• information required under paragraphs 20(2)(e) to (k) (that is, the information contained in the investigator's brochure) and
• information on human sourced excipient in paragraph 20(2)(l)

In place of this information, the applicant must include:

• a copy of the most recent product monograph of the drug (which falls under the definition of label in the Food and Drugs Act) and
• information on how the proposed use of the drug aligns with standard medical practice (that is, whether the drug has been used in the population under study for a sufficient period of time and has an established safety profile in that population), with the following supporting evidence:
  • availability of post-approval safety data and findings
  • dose, dosing regimen, dosage form, route of administration and treatment duration used in the previously conducted studies that are comparable to the planned use of the drug in the proposed study
  • evidence that the patient population from previously conducted studies is representative of subjects in the planned study in terms of demographic characteristics, underlying medical conditions, concomitant drugs and other important factors (for example, cytochrome P450 enzymes (CYP) metabolizer status)
  • exposure in previously conducted (or ongoing, if applicable) studies that contribute to the overall safety database, (for example, exposure to drug, treatment duration)
  • consistency of the safety profile across previous studies
  • knowledge of the mechanism of action of the medicinal product under study or
  • knowledge of the safety profile of approved drugs in the same pharmacologic class

For trials involving such marketed drugs, if Health Canada authorizes the application having determined the drug aligns with standard medical practices (has an established safety profile in that population), the drug will be exempted from the following requirements of IO No. 2:

• labelling requirements under section 33 and
• records requirements under paragraphs 35(2)(a) to (c)

The authorization holder would be required to maintain records on any serious unexpected adverse drug reaction that has occurred inside or outside Canada.

The other requirements laid out in IO No. 2 and this guidance document continue to apply.

Issuing an authorization

When we receive a complete application, we will review the application to determine that:

• the COVID-19 drug that is to be tested in the clinical trial does not endanger the health of clinical trial participants
• the clinical trial is not contrary to their best interests
• the objectives of the clinical trial are achievable

If these conditions are met, we will issue a notice of authorization for the importation or sale of the COVID-19 drug to be tested in the clinical trial and for the conduct of the trial under IO No. 2. Note: This represents a change from the existing Division 5 of the Regulations, which includes a 30-day default authorization.

Under IO No. 2, Health Canada will aim to review clinical trial applications and amendments for COVID-19 drug clinical trials within 14 days.

All other aspects of Health Canada's review process remain the same as under existing guidance, including the screening process and response to clarification requests.

For information on the review process, please refer to section 2.5 of the Guidance document for clinical trial sponsors: Clinical trial applications.

Note: An authorization holder 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. This is in line with existing Division 5 of the Regulations and as per the prohibitions in sections 25 and 26 of IO No. 2.

Any authorizations issued by Health Canada under IO No. 1 and not revoked in whole will be considered authorized under IO No. 2. As such, approval by a research ethics board that was received under IO No. 1 is deemed to be an approval under IO No. 2.

Additional information before commencing a clinical trial

Before a COVID-19 drug can be imported or sold and before a clinical trial can begin, the authorization holder must have obtained approval from the research ethics board at each site. The following information is required:

• name and contact information of the qualified investigator at each site
• name and contact information of the research ethics board at each site who approved the protocol referred to in 20(2)(a) and the informed consent form containing the statement referred to in paragraph 20(2)(b)
• information regarding refusal to approve the clinical trial protocol by any research ethics board and
• the commencement date of the clinical trial at each site

These requirements are the same as those in Division 5 of the Regulations.

To submit this information to Health Canada, use the form and follow the order laid out in section 2.7 of the Guidance document for clinical trial sponsors: Clinical trial applications.

The differences in IO No. 2 and Division 5 of the Regulations are the definitions of qualified investigator and the means of obtaining informed consent. These have been expanded to enable greater flexibility while maintaining high ethical standards.

Terms and conditions

Health Canada may, at any time, impose or amend terms and conditions on the COVID-19 drug clinical trial authorization. This authority allows for flexibility in allowing a trial to proceed while attaching additional conditions and/or limitations on the authorization. These terms and conditions are used to ensure appropriate oversight, manage uncertainties or mitigate risks.

For example, Health Canada could require that the authorization holder submit results of the first phase of a phase I/II study or that a safety summary be submitted at a specified time.

Note: Any terms and conditions that were imposed under IO No. 1 will remain in effect under IO No. 2.

Submitting/fulfilling terms and conditions

Information on the fulfilment of terms and conditions that fall outside the amendment process should be submitted in the form of a notification. This should be titled "Fulfilling Terms and Conditions - Notification." Include a cover letter and any supporting documentation.

Health Canada will review the notification and documentation to determine if the conditions have been met. When we are satisfied that the terms and conditions of the authorization have been met, we will issue a letter indicating this.

Submitting an amendment to a clinical trial authorization

Authorization holders must submit significant changes to the originally submitted protocol (section 20(2)(a)) or chemistry and manufacturing information for the drug being studied (section 20 (2)(m)) for authorization before implementing these changes.

The process for filing an amendment to a clinical trial application under IO No. 2 is the same as filing an amendment under Division 5 of the Regulations.

For information on how to file an amendment and examples of protocol changes that require an amendment, refer to section 2.4.1 of the Guidance document for clinical trial sponsors: Clinical trial applications.

Note: Any applications to amend an authorization that were outstanding when IO No. 1 expired will be considered under IO No. 2.

Changes not requiring an amendment or notification

The existing post-authorization change notification scheme under Division 5 of the Regulations does not apply to COVID-19 drug clinical trials under IO No. 2. Amendments to applications that do not meet the criteria noted above can be implemented without submitting a notification to Health Canada.

Authorization holders should keep records of such changes on file.

Immediate changes/application to amend

If the clinical trial or use of the drug that is being tested endangers trial participants or others, an authorization holder may make an immediate amendment without prior review by Health Canada.

The authorization holder must notify Health Canada of the change and submit an amendment to a clinical trial application within 15 calendar days after the amendment was implemented. Health Canada will aim to issue a decision within 14 days.