Applications for drug clinical trials under the Interim Order: Guidance document

Health Canada has developed this guidance document to support the Interim Order Respecting Clinical Trials for Medical Devices and Drugs Relating to COVID-19 (Interim Order) pursuant to subsection 30.1(1) of the Food and Drugs Act. The document provides guidance to applicants for seeking authorization of and conducting COVID-19 drug clinical trials under the new Interim Order.

Date posted: 2020-05-27

Table of contents

Introduction

Scope and application

The document provides guidance to applicants for seeking authorization of and conducting COVID-19 drug clinical trials under the new Interim Order. Applicants of COVID-19 drug clinical trials may apply for authorization under the Interim Order or under the existing Part C, Division 5 of the Food and Drug Regulations (FDR). Those authorized under the Interim Order would be exempt from Division 5 of the FDR and all other provisions of the FDR, except where described in the Interim Order and subject to certain modified requirements, including:

The Interim Order applies to COVID-19 drug and medical device clinical trials, which are expected to be the predominant therapies related to COVID-19. For guidance on COVID-19 trials using medical devices, please see Applications for Medical Device Clinical Trials under the Interim Order: Guidance Document.

COVID-19 drugs include pharmaceutical drugs and biologic drugs (including vaccines, blood and blood components) that are the subject of a clinical trial. Radiopharmaceuticals (that is Schedule C of the Food and Drugs Act) and natural health products are not in the scope of the Interim Order. The existing Division 5 of the FDR and Guidance would continue to apply for all non-COVID-19-related clinical trials and those that are not in the scope of the Interim Order. 

Policy objectives

The Interim Order is intended to facilitate the conduct of clinical trials to investigate and offer Canadians potential drugs for the diagnosis, treatment, mitigation or prevention of COVID-19, while upholding participant protections and ensuring the validity of trial results.

Policy statements

Health Canada is committed to prioritizing the review of clinical trial applications designed to investigate the diagnosis, treatment, mitigation and/or prevention of COVID-19.

The Interim Order introduces efficiencies to help further facilitate the conduct of COVID-19 clinical trials for both new and repurposed marketed drugs.

Clinical trial authorization holders must conduct COVID-19 clinical trials according to high ethical research standards and ensure the safety of participants is safeguarded throughout. 

As such, many requirements from Division 5 of the FDR that protect those involved in the trials and those that help ensure reliability of results are duplicated in the Interim Order.

To facilitate use of this new pathway, existing Guidance is referenced and the process for submitting applications, amending and providing additional information is maintained.

Where possible and where proper procedures are in place to monitor such activities remotely from the site, clinical trial activities may include virtual recruitment, informed consent, monitoring and/or visits.

Applicants/authorization holders of COVID-19 trials are also encouraged to refer to the Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors for additional considerations when conducting a clinical trial in the context of the COVID-19 pandemic. 

A COVID-19 drug clinical trial authorization under this Interim Order is subject to compliance and enforcement should Health Canada be made aware of issues of non-compliance.

Background

COVID-19 is the infectious disease caused by the most recently discovered coronavirus, SARS-CoV-2. This new virus and disease were unknown before the outbreak began in December 2019 and have since spread around the world. COVID-19 has been known to cause respiratory symptoms, fever, cough, shortness of breath and breathing difficulties. In more severe cases, COVID-19 infection can cause pneumonia, severe acute respiratory distress, kidney failure and death. Older people and those with underlying medical problems, such as high blood pressure, heart problems or diabetes, are more likely to develop serious illness.

On March 11, 2020, the World Health Organization (WHO) declared a global pandemic related to COVID-19. As there are currently no specific authorized therapies or vaccines to effectively treat or prevent COVID-19, there is an urgent need to get such therapeutic products into clinical trials. Clinical trials represent an important step in finding safe and effective treatment options for patients. The Interim Order and this Guidance Document have been developed to ensure that drugs that are integral to the diagnosis, treatment, mitigation or prevention of COVID-19 can be investigated efficiently within a clinical trial. 

Definitions

Unless explicitly listed below or in the Interim Order, all expressions in the Interim Order have the same meaning as under Division 5 of the FDR.  For a full list of applicable definitions, see Section 2.1 of the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications.

Applicant/Authorization Holder is interpreted as having the same meaning as sponsor in Division 5 (that is, sponsor means an individual, corporate body, institution or organization that conducts a clinical trial) and is the person applying or authorized to conduct the clinical trial. (demandeur/détenteur d’une autorisation)

Clinical trial means a study involving human subjects (participants) for the purpose of discovering or verifying the effects of a drug, a device or a food for a special dietary purpose. (essai clinique).

Clinical Trial Site means the location where a qualified investigator conducts or monitors clinical trial activities. (Site d’essai clinique)

COVID-19 means the coronavirus disease 2019 (COVID-19).

COVID-19 drug means a drug for human use that is manufactured, sold or represented for use in relation to COVID-19 (drogue utilisée en lien avec la COVID-19).

COVID-19 drug authorization means an authorization to do any of the following activities:

  1. import or sell a COVID-19 drug that is to be tested in a clinical trial; and
  2. conduct a clinical trial in respect of such a drug (autorisation relative d’une drogue utilisée en lien avec la COVID-19).

Qualified investigator means a person who is a member in good standing of a professional association of persons entitled under the laws of a province to provide health care under their licence in that province and who:

  1. conducts the clinical trial; or
  2. in the case of a clinical trial conducted by a team, who is the responsible leader of that team (chercheur compétent).

Research Ethics Board means a body that is not affiliated with an applicant for a COVID-19 medical device authorization or a COVID-19 drug authorization, or a holder of such an authorization, and whose principal mandate 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 (comité d’éthique de la recherche).

Review of COVID-19 drug clinical trial applications

Pre-clinical trial application interaction with Health Canada

Applicants of COVID-19 drug clinical trials are encouraged to contact Health Canada to request a pre-clinical trial phone consultation to discuss the trial in advance of submitting an application. Health Canada will prioritize the requests for such consultations related to COVID-19 drug clinical trials. Applicants can refer to Annex 1 for the appropriate directorate contact information.

Submitting an application for a COVID-19 drug clinical trial

To sell or import a COVID-19 drug for the purposes of conducting a clinical trial, the applicant must submit a Clinical Trial Application (CTA) to seek Health Canada authorization prior to the initiation of the trial. The application requirements under Section 20 of the Interim Order are the same as Division 5 for novel therapies. Therefore, a CTA for a COVID-19 drug should be submitted 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 CTA cover letter that they are applying for authorization under the Interim Order. They must also indicate how the drug meets the definition of a COVID-19 drug given its direct use in relation to COVID-19, including the active role the drug is intended to play in the diagnosis, treatment, mitigation or prevention of COVID-19.

COVID-19 drug clinical trial involving new uses of a marketed drug

Health Canada recognizes that in the context of the COVID-19 pandemic, trials may be conducted to determine new uses of already marketed drugs. The Interim Order expands on the current policy interpretationFootnote 1 to exempt certain requirements for marketed drugsFootnote 2 that are considered both as non-investigational (for example, used as a comparator) or those that are investigational (that is, repurposed drugs for the purpose of COVID-19) if it is determined that the use of the drug aligns with the standard medical practice.

For a clinical trial involving marketed drugs where the drug is being used outside its approved indication, in alignment with standard medical practice, the application must include all elements of a standard application package except for information required under 20 (2)(e) to (k) (that is, the information contained in the investigator’s brochure) and information on human sourced excipient 20 (2)(l). In lieu of this information, the applicant must also include:

For trials involving such marketed drugs, if Health Canada authorizes the application as per the application requirements and per the determination that the drug aligns with standard medical practices (that is, has an established safety profile in that population), the drug will be exempted from the following requirements of the Interim Order:

In addition, the authorization holder must maintain records respecting any serious unexpected adverse drug reaction that has occurred inside or outside Canada. The remainder of the requirements for authorization holders laid out in the Interim Order and this Guidance Document continue to apply.

Issuance of decision: Clinical trial application and amendments

Upon receipt of a complete application, Health Canada will review the application to determine that the use of a COVID-19 drug that is to be tested in the clinical trial does not endanger the health of clinical trial participants, that the clinical trial is not contrary to their best interests and that the objectives of the clinical trial are achievable.

If these conditions are met, Health Canada will issue a letter 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 in respect of the drug under the Interim Order. Note that this represents a change from the existing Division 5 of the FDR, which includes a 30-day default authorization. Under the Interim Order, Health Canada will aim to review CTAs and Clinical Trial Applications – amendments (CTA-As) 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, response to clarification requests, etc. Please consult Section 2.5 of the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for information on the CTA review process.

Note: In line with existing Division 5 of the FDR requirements and as per the prohibitions under the Interim Order in Sections 25 and 26, 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.

Additional information prior to commencing a clinical trial

Before the COVID-19 drug can be imported or sold or before the clinical trial commences, the authorization holder must have obtained approval from the Research Ethics Board at each site and submit the following information:

These are the same information requirements found under the existing Division 5 of the FDR and should be submitted to Health Canada according to the existing form and manner laid out in Section 2.7 of the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications.

What is different under the Interim Order are the definitions of qualified investigator and the means of obtaining informed consent, which 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 or to 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.

Submitting/fulfilling terms and conditions: Notification to Health Canada

Information regarding the fulfilment of terms and conditions that fall outside the amendment process should be submitted in the form of a notification (titled “Fulfilling Terms and Conditions – Notification”) and include a cover letter and any supporting documentation.

The notification and documentation will be reviewed to determine whether the conditions have been met. Once an authorization holder provides Health Canada with satisfactory evidence that the terms and conditions of the original authorization have been met, Health Canada will issue a letter indicating that the terms and conditions have been fulfilled.

Submitting an amendment to a COVID-19 drug clinical trial authorization

Authorization holders must submit significant changes to the originally submitted protocol 20(2)(a) or chemistry and manufacturing information in respect of the drug being studied 20 (2)(m) to Health Canada for authorization prior to implementing these changes.

The process for filing a Clinical Trial Application-Amendment (CTA-A) under this Interim Order is the same as filing an amendment under Division 5 of the FDR. 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.

Changes not requiring an amendment or notification

The existing post-authorization change notification scheme under Division 5 of the FDR does not apply to COVID-19 drug clinical trials under this Interim Order. Changes to CTAs that do not meet the criteria for an amendment 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 an authorization holder needs to make an immediate amendment because the clinical trial or use of the drug that is being tested endangers the trial participants or other persons, the authorization holder may implement the changes without prior review by Health Canada. The authorization holder 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 aim to issue a decision within a 14-day review period.

Additional requirements

Good Clinical Practices

The Interim Order reiterates that it is the clinical trial authorization holder who has the overall responsibility for conducting the clinical trial in accordance with internationally recognized Good Clinical Practices (ICH E6(R2)).  

All sections of the existing Division 5 of the FDR C.05.010, (Good Clinical Practices) apply under the Interim Order for COVID-19 drug clinical trials (Section 28). Applicants/authorization holders are encouraged to use the existing Guidance Document: Part C, Division 5 of the Food and Drug Regulations - Drugs for Clinical Trials Involving Human Subjects (GUI-0100), Section 5.10, for interpretation/guidance on how to meet the requirements of this section, noting the following changes that have been made under the Interim Order:

Qualified investigator

The regulated health care professionals that are responsible to conduct a clinical trial at a clinical trial site (that is, physicians or dentists) has been expanded to include other health care practitioners, such as nurse practitioners, pharmacists and midwives. This provides greater flexibility to conduct decentralized trials where other health care practitioners/providers may be more available to conduct trials at remote sites given the critical nature and strain on the health care system during the pandemic. They should, nevertheless, have access to medical services in the event that issues arise that specifically require the involvement of a physician.

Labelling

Existing labelling requirements under section C.05.011 of Division 5 of the FDR have been carried over to the Interim Order. This means the authorization holder is responsible for labelling a COVID-19 drug for testing in the clinical trial in accordance with these requirements including in both official languages, unless they are studying off label use of marketed drugs and are exempted (as per the section, COVID-19 Drug Clinical Trial Involving New Uses of a Marketed Drug above). 

For information on labelling requirements, refer to Section 5.11 of the Guidance Document: Part C, Division 5 of the Food and Drug Regulations - Drugs for Clinical Trials Involving Human Subjects (GUI-0100).

Post-authorization authorities

Suspension

Under section 29 of the Interim Order, Health Canada may suspend a COVID-19 drug clinical trial authorization either in whole or in part, if the Department has reasonable grounds to believe that any of the requirements of the original authorization are no longer met, if the requested information was not submitted in the time, form and manner requested or if the authorization holder has contravened the Interim Order or the Food and Drugs Act. For example, Health Canada will have the ability to suspend one arm, or treatment group, of a multi-arm trial, if needed, allowing the rest of the trial to proceed so that other patients can continue to receive a promising therapy.

Additional information and materials

The applicant or authorization holder must supply Health Canada with the requested information, materials or samples to enable Health Canada to issue (in the case of the applicant), amend or suspend a clinical trial authorization within the time, form and manner specified by Health Canada.

Reinstatement

Health Canada must reinstate a suspended trial if the holder of the suspended authorization provides the required information or material in the time, form and manner specified to demonstrate that the situation giving rise to the suspension did not exist or has been corrected. 

Discontinuance of a clinical trial

As per Division 5 (C.05.015), in the event of the discontinuation of a previously authorized COVID-19 drug clinical trial, in whole or in part, the authorization holder must notify the responsible directorate as soon as possible in writing (see Annex 1 for contact information).  They must also inform all qualified investigators in writing, and stop the importation or sale of the drug at each clinical trial site at which the trial has been discontinued. Refer to Section 2.8.1 of the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for information on the requirements and what should be included in the notification.

If the authorization holder discontinues and subsequently wants to resume their trial, they will have to refile a new CTA.

Revocation of a trial

Mandatory revocation

Following the receipt of a notice of discontinuance of the COVID-19 drug clinical trial by the authorization holder, Health Canada must revoke, in whole or in part, the authorization.

Discretionary revocation

Health Canada may, at any time, revoke, in whole or in part, the authorization if the holder of the authorization fails to provide satisfactory information following a suspension. Failure to provide satisfactory information includes not providing the requested information under Section 29(2) in the specified time frame, or if Health Canada determines the information provided does not demonstrate that the situation resulting in the suspension did not exist or has not been corrected. 

Revocation: Notice/transparency

Following a mandatory or discretionary revocation, Health Canada will issue a cancellation letter to the authorization holder either confirming the receipt of the notice of discontinuation (mandatory revocation) or giving reasons for the revocation (discretionary revocation). Information on the status of the COVID-19 drug clinical trial will be updated following a revocation on the Drugs and vaccines for COVID-19 webpage and the Health Canada Clinical Trial database.

Serious unexpected adverse drug reactions

Existing Subsection C.05.014(1) of Division 5 of the FDR, relating to serious unexpected adverse drug reactions (SUADRs), was carried over into Section 34 of the Interim Order. In line with existing Guidance, the authorization holder must inform Health Canada of all SUADRs from a drug during the course of a COVID-19 drug clinical trial as follows: 

Records

Existing requirements under C.05.012 of Division 5 of the FDR regarding the maintenance of complete and accurate records have been carried over into Section 35 of the Interim Order. Refer to Section 2.8.6 of the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications for details on the records that must be maintained. The authorization holder must maintain all records for the period this Interim Order is in force (that is, 1 year), but these should be kept beyond this time frame in line with existing clinical trial guidance/Division 5 requirements. 

General requirements applicable to drugs and devices

Informed consent

In the context of the COVID-19 pandemic, the Interim Order’s section 36 enables two alternate means for the qualified investigator to obtain informed consent when clinical trial participants are unable to consent in person and in writing. For example, due to isolation measures the two alternate means are:

Registration

In line with existing Health Canada policy recommendations and international best practices, to support transparency of clinical trial information, the authorization holder should register their COVID-19 clinical trial after issuance of the authorization. Health Canada encourages registration in publically accessible registries such as ClinicalTrials.gov and ISRCTN.  Authorization holders should use the World Health Organization’s preferred term (COVID-19) in the public or scientific title in order to make these studies easy to search.

The authorization holder should notify the appropriate directorate by email within 5 days of their registration and include “COVID-19 clinical trial registration” in the subject line (see Annex 1 for contact information) and provide the following information:

Health Canada will use this information to maintain a list of authorized clinical trials related to COVID-19 on the Drugs and vaccines for COVID-19 webpage and the Health Canada Clinical Trial database.

Annex 1: Contact information

For pharmaceutical drugs
Therapeutic Products Directorate
Office of Clinical Trials
5th Floor, Holland Cross, Tower B
A/L 3105A
1600 Scott Street
Ottawa, Ontario
Canada K1A 0K9

General enquiries:
Email: hc.oct.enquiries-requetes.bec.sc@canada.ca
Clinical trial notifications:
hc.oct.smd-dgp.bec.sc@canada.ca
Clinical trial registration information:
hc.oct.enquiries-requetes.bec.sc@canada.ca

For biologics (including vaccines, blood and blood components)
Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
100 Eglantine Driveway,
Address Locator: 0601C
Ottawa, Ontario
Canada
K1A 0K9

General enquiries:
hc.brdd.ora.sc@canada.ca
Clinical trial notifications:
hc.brdd.cta-dec.dmbr.sc@canada.ca
Clinical trial registration information:
hc.brddopic.bpcidmbr.sc@canada.ca

Footnotes

Footnote 1

Statement on the Investigational Use of Marketed Drugs in Clinical Trials

Return to footnote 1 referrer

Footnote 2

This section applies to drugs marketed in Canada that have been issued a notice of compliance under C.08.004(1) of the FDR or that has been assigned a drug identification number under subsection C.01.014.2(1) of those Regulations and where the clinical trial drug is being used in respect of an indication other than those for which the notice of compliance or drug identification number was issued.

Return to footnote 2 referrer

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