Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors

From: Health Canada
Updated: March 2, 2022

Overview

The COVID-19 pandemic is having an impact on how clinical trials are being conducted. For example, people participating in trials must practise physical distancing and follow other public health recommendations. Also, clinical trial staff are being transferred to other duties, which is causing some delays.

As set out in paragraph C.05.010(b) of the Food and Drug Regulations (FDR), clinical trials must follow certain requirements of the protocol. Health Canada authorizes this protocol and the Research Ethics Board approves it.

During the pandemic, there may be more deviations from the established protocol. Despite this, it's important to continue to protect patient safety and ensure data integrity.

This notice addresses the concerns of clinical trial sponsors and Canadians. We may update this notice as the pandemic evolves and will continue to provide current information to all stakeholders.

Trials

New trials

Sponsors may continue to file COVID-related or other clinical trial applications and amendments according to Health Canada guidance.

During our review of a clinical trial application, we may ask for more information, as outlined in paragraph C.05.009 of the FDR. If a sponsor is unable to respond within the requested timeline, they should consider withdrawing their application. Sponsors may re-file without prejudice when they have the required information.

For sponsors wishing to file a COVID-19-related trial:

The new Clinical Trials for Medical Devices and Drugs Relating to COVID-19 Regulations (the Regulations) are a temporary measure until the framework established through the Clinical Trials Modernization Initiative is in place. The Regulations published in the Canada Gazette II on March 2, 2022, came into effect on February 27, 2022, following the repeal of the Interim Order No. 2. By maintaining the flexibilities set out by the interim order, the Regulations will continue to:
- facilitate the authorization and implementation of COVID-19-related clinical trials by reducing administrative burden
- uphold the health and safety requirements for trial participants and validity of trial data

For more information on how to apply for clinical trials under the Regulations, see the following guidance document:

Sponsors of clinical trial applications designed to diagnose, treat, mitigate or prevent COVID-19 must clearly indicate in their cover letter if they are filing their clinical trial application under this pathway.

Sponsors still have the option to file their application under Division 5, if they prefer.
Clinical trial applications for a COVID-19 indication are given priority. We are committed to reviewing these submissions within 14 days, as long as there are no deficiencies.

Ongoing trials

Sponsors of a current trial must document the measures they took to stop or lower the risk of becoming infected with COVID-19. Any changes to the approved protocol or status of the study should consider:

the burden on resources due to the COVID-19 pandemic
whether participants are at high risk of contracting the virus
whether these changes still follow public health recommendations
whether adding extra study sites and recruiting more participants should be halted or postponed

Sponsors who cancel a trial or temporarily stop or halt recruitment should:

note the reasons for doing so in the study records
inform Health Canada using a clinical trial application notification (CTA-N)
retrain trial staff if the study is halted for a few months

If a study is temporarily stopped or halted, sponsors should submit a new CTA-N to inform Health Canada when the study resumes.

Participants

Guidelines for managing clinical trial participants are as follows:

carry out eligibility assessments as usual
- ensure that persons enrolled in a trial meet the pre-set eligibility criteria
- document medical oversight when determining a participant's eligibility to take part in the study
inform study participants of any changes to the study and the monitoring plan that could affect their participation and/or their well-being
consider having the participant drop out of the study if their safety may be at risk if they miss a pre-defined study visit
identify all participants affected by a COVID-19-related study disruption with a unique participant identifier, then document the site and describe how a person's participation was changed
discuss risks of using any immunosuppressive agents and strategies to reduce these risks with medical immunology specialists
discuss with local research ethics boards if it's in the best interest of the safety, welfare and rights of the participant to continue the study
consider putting in place different safety monitoring measures if participants no longer have access to the study site

For COVID-19 testing and screening:

If an institution requires people who attend clinical visits to be screened, there is no need to amend the study protocol. The only exception is if the data are being included in a new research objective.

Participants with COVID-19

Sponsors must decide whether to:

pause the participation of someone affected by COVID-19 and not administer the investigational product until the participant has recovered or
halt this person's participation altogether

For someone who contracts COVID-19 while taking part in a study at Canadian sites:

If the person acquired the infection as a result of receiving the investigational drug (a drug that immunosuppressed the patient), it's to be reported as an adverse reaction in accordance with C.05.014 of the FDR.
If the contraction of COVID-19 is unrelated to the study drug(s), the sponsor should determine if the trial was putting the participant at risk (for example, is the trial site posing a risk to study participants?) and if measures need to be implemented to protect other participants.

The sponsor should submit a notification if they made any changes to the study as a result.

You should consider and discuss with your research ethics board whether you should put in place extra mitigation measures or halt or postpone the trial.

Informed consent

When consent can't be obtained in person, sponsors should consider other methods, such as over the telephone, or using fax, Skype or video-teleconferencing.

Sponsors should consider the following:

discuss with the research ethics board different methods of informed consent for the study
- additional institutional requirements may need to be followed
ensure participants always have an opportunity to ask questions before they give their consent
consider accepting a text or email of a picture of a signed and dated written statement for participants who enroll remotely
- this statement should indicate they are voluntarily accepting participation in the trial
if consent is given verbally, read the consent to the prospective participant and provide an opportunity for the person to ask questions
- consider providing the document to the person ahead of time
ensure that in cases of verbal consent, a witness (can be a family member) is present and signs an attestation
- it must be clear that the witness was present during the process regardless of the method of communication (for example, can be on a conference call)
- a scanned copy of the attestation may be forwarded to the investigator by email or a picture of the signed attestation may be sent by email or text
- the conversation should be recorded if it isn't possible to have a witness (this recording becomes part of the trial records)
check to see if your research ethics board has requirements for an attestation (we do not require a specific form)
ensure the method used meets local privacy requirements

Changing sites

The physical site where visits are held may have to be changed. This may cause confidentiality issues around the participant's medical records (electronic health record).

Trial participants will need to consent to the transfer of any identifiers from the original site and be assured that their confidentiality will be protected.

For alternative sites for laboratories, diagnostic imaging, and so on:

verify if these other facilities are able to perform the activities as per the approved protocol
add copies of the normal lab result values and the accreditation certificate of these facilities to your trial records

Reporting an adverse event

Sponsors are expected to continue reporting suspected unexpected serious adverse reactions. The requirements for doing so are set out in C.05.014 of the FDR.

Phase IV trials continue to fall outside the scope of Division 5.

Monitoring

Assess whether other safety assessment methods are possible when participants are unable to come to the investigational sites as specified in the study protocol.

If alternative monitoring is done, careful documentation will be required to capture:

the reason why it was done
the method used to collect the information
the types of data that were collected
who provided the information
how the source of the information was verified

Sponsors will not need to submit an amendment to the protocol.

Make sure to:

prioritize monitoring of critical activities that ensure participant safety and data integrity
consider central monitoring
document any changes and their impact

Collecting and storing samples

Always treat human biospecimens as potentially infectious. Follow your biosafety protocols.

Distributing a product

It's allowed to ship clinical trial investigational products from Canadian sites directly to patients under the FDR.

Product formulations that are acceptable for direct shipment are:

tablets and injectables that a participant may take on their own
medications that don't have to be administered in a hospital or clinic
medications that don't have any special conditions for handling

When transporting, handling and storing investigational products, make sure to reduce the risk of exposure to temperatures outside labelled storage conditions. Please see Health Canada's guidelines for temperature control of drug products during storage and transportation (GUI-0069).

Make sure that:

the investigational drug has been received by the participant (verification is required)
record-keeping complies with the regulatory requirements of section C.05.012 of the FDR
maintain complete and accurate records for a drug used in a clinical trial, including records for shipping, receiving, disposing, returning and destroying the drug
the process in the participant's study record is accurately documented

Deviating from protocol

For clinical trial sites:

ensure there's a system in place to identify, document, assess and report all protocol deviations to the sponsor and research ethics board in accordance with their own requirements
document these deviations to make it easier to analyze the study findings in the future

For sponsors:

define and identify the protocol deviations to be reported (you will not have to report these to Health Canada individually unless the deviations may place participants at risk)
consider other methods to prevent protocol deviations and document the reasons for these deviations
submit an amendment to a clinical trial application (CTA-A) when changes to the protocol meet the definition of a clinical trial amendment (do not file repeated deviations)
consider submitting at regular intervals a cumulative list of deviations occurring in a particular study, rather than individual notifications

For detailed guidance on complying with the regulations, please see the guidance for Part C, Division 5 of the FDR "drugs for clinical trials involving human subjects" (GUI-0100).

Submitting regulatory activities

The COVID-19 pandemic has presented challenges to sponsors who file clinical trial applications (CTA) and amendments (CTA-A).

As an interim measure, CTA(-A)s may be submitted via email to the Pharmaceutical Drugs Directorate (PDD) and the Biologics and Radiopharmaceutical Drugs Directorate (BRDD). Email your submissions as follows:

PDD to oct.smd-dgp.bec@hc-sc.g.ca
BRDD to brdd.ora@hc-sc.gc.ca

Sponsors may use these email addresses until they are able to return to regular working conditions or until further notice by Health Canada. Please note the following email restrictions:

maximum email size accepted by the corporate mail server is 20 megabytes
the regulatory transaction must be provided as a zipped file, in accordance with the guidance document on the preparation of regulatory activities in the "non-eCTD electronic-only" format
submissions should not be password-protected
subject line of the email should state: "CTA(-A), [Product Name], [Protocol Number]"
emails received after 3 pm EST will be considered received the following day

If a CTA(-A) is larger than 20 megabytes, the CTA(-A) may be split and sent under separate emails (for example, 1 email for module 1 and 1 email for modules 2 and 3). The subject lines of the emails should clearly link to one another (for example, "Email 1 of 2: CTA(-A), [Product Name], [Protocol Number]").

Remember that email is not considered a secure method of transmission.
The relevant directorate will aim to issue a CTA(-A) acknowledgment letter within 7 days of receipt.

Contact us

For questions about this notice or the regulation of clinical trials, please contact Health Canada:

For pharmaceutical drugs:

Pharmaceutical Drugs Directorate
Office of Clinical Trials
5th Floor, Holland Cross, Tower B
A/L 3105A, 1600 Scott St
Ottawa ON K1A 0K9
Email: oct.enquiries-requetes.bec@hc-sc.gc.ca

For biologics and radiopharmaceuticals:

Biologic and Radiopharmaceutical Drugs Directorate
Office of Regulatory Affairs
0601C-100 Eglantine Dwy
Ottawa ON K1A 0K9
Email: brdd.ora@hc-sc.gc.ca

For clinical trial compliance:

Regulatory Operations and Enforcement Branch
Clinical Trial Compliance Program
1903C-200 Eglantine Dwy
Ottawa ON K1A 0K9
Email: GCP_BPC@hc-sc.gc.ca

Date modified:: 2022-03-02

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