Management of clinical trials during the COVID-19 pandemic: Notice to clinical trial sponsors
From: Health Canada
Updated: May 6, 2021
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- Changing sites
- Reporting an adverse event
- Collecting and storing samples
- Distributing a product
- Deviating from protocol
- Submitting regulatory activities
- Contact us
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, 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.
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 Regulations. 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:
- To reduce regulatory burden, we have developed a new regulatory pathway, the Interim order respecting clinical trials for medical devices and drugs relating to COVID-19. Sponsors of clinical trial applications for the diagnosis, treatment, mitigation or prevention of COVID-19 must clearly indicate in their cover letter if they are filing their clinical trial application under this new 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.
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.
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 Regulations.
- 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.
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
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 Regulations.
Phase IV trials continue to fall outside the scope of Division 5.
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 Food and Drug Regulations.
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 Regulations
- 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
- 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 Therapeutic Products Directorate (TPD) and the Biologics and Radiopharmaceutical Drugs Directorate (BRDD). Email your submissions as follows:
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.
For questions about this notice or the regulation of clinical trials, please contact Health Canada:
For pharmaceutical drugs:
Therapeutic Products Directorate
Office of Clinical Trials
5th Floor, Holland Cross, Tower B
A/L 3105A, 1600 Scott St
Ottawa ON K1A 0K9
For biologics and radiopharmaceuticals:
Biologic and Radiopharmaceutical Drugs Directorate
Office of Regulatory Affairs
0601C-100 Eglantine Dwy
Ottawa ON K1A 0K9
For clinical trial compliance:
Regulatory Operations and Enforcement Branch
Clinical Trial Compliance Program
1903C-200 Eglantine Dwy
Ottawa ON K1A 0K9
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