- a regulatory submission
- health technology assessment agencies in making reimbursement recommendations
Many health system stakeholders are integrating real-world evidence into their decision-making. This includes Health Canada, Canada's Drug Agency (CDA) and the Institut national d'excellence en santé et en services sociaux (in Quebec).
The following guidance by Health Canada and CDA lays the foundation for using real-world evidence in regulatory approval and health technology assessment:
- Guidance for reporting real-world evidence (PDF)
Expanded access clinical trials should not displace, affect or discourage confirmatory clinical trials from taking place, as confirmatory trials generally aim to generate evidence required for market authorization. For example, sponsors should not:
- divert the supply of investigational drugs to an expanded access clinical trial to the detriment of a confirmatory clinical trial or
- make it difficult to recruit participants in a confirmatory trial (participants may prefer expanded access)
For these reasons, sponsors must account for how they plan to continue any planned or ongoing confirmatory trials as part of their clinical trial application (CTA). This is described in the What to include in an annex to the protocol section.
Who can sponsor
The Food and Drug Regulations (regulations) define a sponsor as "an individual, corporate body, institution or organization that conducts a clinical trial". A manufacturer would always be involved in an expanded access clinical trial, at the very least as the supplier of the investigational drug.
As stated in C.05.006 of the regulations, sponsors of expanded access clinical trials are expected to provide information and documents as part of their CTA. This information must be sufficient for Health Canada to assess the drug's risks and those of the trial.
Sponsors are not required to conduct a prior clinical trial specifically in Canada. However, sponsors of expanded access clinical trials must provide in their CTA substantial evidence from previous clinical trials or other studies to demonstrate that use of the investigational drug is justified:
- for expanded access
- in an expanded study population
Sponsors of an existing clinical trial may add an expanded access arm to an existing clinical trial by submitting an amendment (CTA-A) to the original trial application.
- meet the same information requirements that are applied to all expanded access clinical trials
- for example, the requirements laid out in the following section about an annex to the protocol
Health Canada may find that the requirements or scope for a proposed expanded access arm are very different than those of the original trial. In some cases, we may suggest that the sponsor re-submit the application as a new CTA (not as an amendment to an existing trial).
Quality requirements
Chemistry and manufacturing requirements for expanded access clinical trials are the same as for all clinical trials. The scope and detail of information submitted to support the quality portion of a CTA should be sufficient to adequately assess the drug's characteristics.
For information on quality requirements, consult the following guidance document and notice:
- Quality (chemistry and manufacturing) guidance: Clinical trial applications (CTAs) for pharmaceuticals
- Quality requirements for investigational biologic drugs used in clinical trials: Notice to clinical trial sponsors
The information contained in the investigator's brochure must be specific to the investigational product used in the expanded access clinical trial. A literature-based investigator's brochure would likely not be appropriate for an expanded access clinical trial, given the need to characterize the investigational product being provided to an expanded population of participants.
In addition, quality requirements should generally meet the standard for a phase 3 clinical trial, given the broad participant population that may receive the investigational drug.
Filing a clinical trial application
Like all clinical trials, expanded access clinical trials can be initiated when a sponsor submits a CTA or CTA-A and receives a no objection letter, pursuant to section C.05.005 or C.05.008 of the regulations, respectively.
Sponsors should clearly identify expanded access clinical trials by naming their trial protocol accordingly, by including the words "expanded access" in the title. For example: "An expanded access protocol for the treatment of … with …"
Sponsors proposing an expanded access arm to an existing trial (as an amendment, via a CTA-A) should consider adding "… with an expanded access arm" to the end of the existing trial title.
Sponsors of expanded access clinical trials (or arms of existing trials) should identify that they are offering expanded access in their cover letter.
In some cases, Health Canada may conclude that a clinical trial not identified in the CTA as an expanded access clinical trial does indeed fit the definition of an expanded access clinical trial. We will then suggest to the sponsor that the trial should be identified as such, for transparency and consistency.
In all cases (whether or not the sponsor has agreed to identify the trial as expanded access), Health Canada will assess the trial's risks and the manner they are proposed to be addressed. If applicable, our assessment will include the risk of the trial impeding clinical development and bypassing regulatory review before the drug is allowed to be used broadly in Canada.
If Health Canada is unable to assess the risks of the drug or the clinical trial from the information submitted as part of the CTA or CTA-A, we may notify the sponsor that they may not sell or import the drug. The notice is sent within 30 days after the application has been received.
Expanded access clinical trials may be associated with specific risks, which Health Canada evaluates during a review of a CTA or CTA-A. As described in the Overview section, there's a risk that expanded access clinical trials may:
- expose a broader participant population to risks associated with investigational drugs
- impede clinical development of the drug
- bypass regulatory review before market access
Sponsors should include information about how their protocol proposes to address these 3 risks, as relevant, throughout their protocol and specifically in an annex to the protocol submitted as part of their CTA. Submitted protocols should be consistent with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline:
What to include in an annex to the protocol
The annex to the protocol submitted as part of the CTA or CTA-A for an expanded access clinical trial should contain sufficient information and evidence for Health Canada to assess the risks of the drug and the clinical trial. This information may also appear throughout the protocol.
Table 2 gives examples of information a sponsor may consider submitting as part of the annex to the protocol. The examples demonstrate that their protocol incorporates proposed risk mitigation measures into the trial design.
Every CTA or CTA-A is assessed on a case-by-case basis.
- a defined population of participants is expected to significantly benefit from treatment with the investigational drug because …
- the condition is serious, life-threatening or debilitating
- there is unmet medical need
- the drug presents a significant increase in efficacy or a significant decrease in risk in relation to an existing drug marketed in Canada
- participation is restricted to eligibility criteria commensurate with identified risks from previous clinical trials with the investigational drug
- information on any confirmatory clinical trials ongoing or planned to support an eventual drug submission
- plans, for example as defined in the trial protocol, to complete enrolment in ongoing phase 1 to 3 clinical trials before the launch of an expanded access clinical trial (may include potential participant screening and triaging by the qualified investigator)
- defined inclusion criteria for expanded access clinical trials based on participant exclusion from other ongoing trials, as supported by evidence
- tentative projected timeline to bring the proposed drug to market
- proposed sunset date for the expanded access clinical trial
- proposed size of Canadian participant population, and how access to the drug will be limited to those in medical need who will likely benefit from access
- information on how the drug is potentially transitioning from access under the Special Access Program to access under an expanded access clinical trial
Transparency, equity and fairness
Sponsors should register their clinical trials with an international registry that's acceptable by the World Health Organization, to:
- be transparent about clinical trial information and
- show equity and fairness of access for participants
An example of an acceptable registry is the clinical trial registry operated by the National Institutes of Health in the United States.
Sponsors should register their trial once they have received the no objection letter from Health Canada.
- Clinical Trials Database
- Draft guidance on the registration of clinical trials and public disclosure of results
Information made public by sponsors (for example, through a website) should be sufficient to enable potential participants or their health care providers to contact the trial sponsor to enquire about enrolment.
Sponsors should consider how they convey information about expanded access clinical trials with investigational drugs that have not been authorized for sale by Health Canada. Sections 9(1) and 20(1) of the Food and Drugs Act (act) prohibit advertising any drug or device in a manner that's:
- false, misleading or deceptive or
- likely to create an erroneous impression regarding its character, value, quantity, composition, merit, design, construction, performance, intended use or safety
The act defines "advertisement" as "including any representation by any means whatever for the purpose of promoting directly or indirectly the sale or disposal of any food, drug, cosmetic or device." Health Canada will rely, as a general principle, on the ordinary meaning of "promote," which is to encourage or incite the sale of a health product.
For more information, consult:
Delegating activities outside of the main location of the clinical trial site
There is growing recognition for the need for flexible clinical trial models that facilitate easier and more diverse participation. In Canada, many people live outside urban areas and away from major clinical research networks. This can make it difficult to recruit people from rural or remote areas who face logistical or financial challenges, impacting the ability of potential participants to access investigational drugs that may provide benefits.
All types of clinical trials can adopt a decentralized model. However, in confirmatory clinical trials, not being able to go to a clinical trial site may pose challenges with standardized evaluation of the patient and reliability of the collected data.
In expanded access clinical trials, the emphasis is on providing promising drugs to participants in need and recruiting as diverse a participant population as possible. For this reason, sponsors could consider adopting decentralized clinical trial models to facilitate conducting trial activities outside of the main location of the clinical trial site.
Additional locations where clinical trial activities occur (outside of the main location of the clinical trial site, as delegated and overseen by the qualified investigator) are not considered additional clinical trial sites. As such, additional locations do not require separate clinical trial site information (CTSI) forms.
However, all locations where clinical trial activities occur, including distant locations, are considered to be part of the clinical trial site. They may be inspected as part of a clinical trial site inspection.
With appropriate risk-based safeguards for participants, sponsors may justify delegating drug administration and safety monitoring activities to qualified local health care providers, who may be located in a variety of locations. An example of an appropriate safeguard would be a risk-based monitoring plan that takes into account treatment complexity, participant safety and individual competencies. Local providers could, for example, already be providing health care to the participant (such as their family doctor).
Sponsors could also consider delegating activities to contract research organizations or other service providers through recorded agreements.
Regardless of the model proposed, delegated activities remain under the supervision of the qualified investigator. The qualified investigator is ultimately responsible for medical decisions taken as part of the trial at all locations associated with their clinical trial site.
A decentralized model can support equitable access to all potential participants in need, regardless of where they live. The concept of delegation is:
- broad enough to allow for various scenarios and situations
- governed by regulations as well as the requirements listed in the current ICH Guideline for Good Clinical Practice (ICH E6), as implemented by Health Canada
One or multiple clinical trial sites
To comply with regulatory requirements, a clinical trial must always have at least 1 clinical trial site, which must be listed on a CTSI form.
In addition to complying with the regulations, sponsors must have a qualified investigator (no more than 1) for each clinical trial site. The site must:
- have research ethics board approval before the trial can start at the site and follow all good clinical practice (GCP) requirements
- be able to provide sufficient evidence to Health Canada that all locations where trial activities are taking place comply with the clinical trial requirements
- include a detailed account of these activities in the delegation log
Sponsors could consider opening multiple clinical trial sites and delegate activities from each site. This would help overcome issues related to local legislation, which may have an impact on sharing participant data or on the ability to conduct trial activities approved by a research ethics board based in another jurisdiction. For example, to comply with provincial and territorial requirements, sites could be established in each province and territory, from which activities could be delegated to third parties located in the same province or territory.
Delegation principles
The regulations and ICH guidelines contain important sponsor considerations related to delegation. Health Canada takes these into account when we review a CTA or conduct an inspection.
Generally, as per C.05.010, each individual involved in conducting the clinical trial must be qualified by education, training and experience to perform their respective tasks. This includes third parties who are delegated tasks in additional locations associated with the clinical trial site.
ICH guidelines are as follows:
- Each individual involved in conducting a trial should have the appropriate education, training and experience to perform their respective task(s) (ICH E6, 2.8)
- The investigator should maintain a list (the delegation log) of appropriately qualified persons to whom they have delegated significant trial-related duties (ICH E6, 4.1.5)
- The investigator is responsible for supervising any individual or party to whom they have delegated trial-related duties and functions (ICH E6, 4.2.5)
All locations where delegated activities occur are considered to be part of the investigator's clinical trial site. As previously mentioned, these additional locations do not require separate CTSI forms, but their addresses should be readily available as part of the delegation log. For the purposes of an inspection, all locations associated with a site may be inspected and are expected to comply with good clinical practices and regulatory requirements.
As part of their CTA, sponsors should describe the following in their trial protocol:
- if duties are expected to be delegated
- what participant intervention, monitoring and follow-up activities are expected to occur at decentralized locations and
- how this will be achieved in accordance with good clinical practices and while maintaining patient safety
This also allows sponsors and qualified investigators to appropriately consider and manage risk involved in delegating activities. The protocol should:
- indicate how the sponsor will address the involvement of third parties, potentially required training, equipment, data sharing and facility requirements
- include existing or planned contracts or agreements between the sponsor and other third parties, institutions or locations (and outline specific roles, responsibilities, liabilities and indemnities)
- these agreements should be available at the clinical trial site
A protocol may not necessarily list, in advance of the trial launching, all specific locations where trial activities will occur. In some cases, sponsors may be able to justify delegating activities to a certain type of location or setting, institution or type of health care or service provider. They do not have to know in advance who will ask to participate in a trial or be involved in trial activities.
In their protocol requirements for training, qualification and experience of additional trial personnel, sponsors should address:
- how agreements to manage delegated activities will be established and
- how this will be recorded in a delegation log
Delegation log
Within the delegation log, a qualified investigator may designate other physicians or in some instances other appropriate third parties qualified to perform trial-related procedures or make important trial-related decisions. However, the qualified investigator is always accountable for the actions and decisions taken as part of a clinical trial at a clinical trial site, including at all its associated additional locations.
A delegation log has to be legible, adequately completed and clearly identify the names and signatures of key personnel and delegated third parties, their key duties, and the start and end dates of those duties. This log can be used as a reference (for example, by monitors and inspectors), to verify that all third parties who are delegated trial tasks are appropriately qualified for the tasks they have been delegated.
Sponsors may use electronic formats and e-signatures to facilitate the involvement of participants and third-parties in various physical locations.
The delegation log should be developed before commencement of the study and updated as necessary. The qualified investigator should sign and date the log prior to a task being delegated. Site personnel and delegated third parties should not conduct study-specific tasks until the qualified investigator has documented the delegation, and any required training has been completed.
Delegation and agreements
ICH guidelines recommend that delegation or distribution of tasks be managed through agreements. The protocol may serve as the basis of agreements.
Decentralized clinical trial models, involving the delegation of trial activities, can involve risk for participants, sponsors and qualified investigators. Agreements can support all parties involved in conducting trial activities in knowing their roles, responsibilities and liabilities, and this helps to support participant safety.
Agreements may set out such considerations as:
- individual roles and responsibilities
- how specific trial activities should be conducted, and their setting
- professional liability among investigators, sub-investigators, delegated third parties, health care providers, insurers and sponsors
- safety monitoring and reporting of adverse events
- indemnity coverage for participants
Clearly written agreements can help support health care providers in complying with all applicable laws, regulations and professional standards.
Delegation and participant screening
Medical care and medical decisions are supervised by the qualified investigator.
To address the risk of impeding clinical development of the drug, the qualified investigator is responsible for ensuring that potential participants are screened at the time they enrol in an expanded access clinical trial. Screening is done to determine that potential participants are not able to enrol in ongoing confirmatory trials.
A protocol that proposes to delegate duties related to participant screening and enrolment from the qualified investigator to other personnel or delegated third parties should adequately address this risk.
Delegation and informed consent
As per C.05.010, written informed consent needs to be given in accordance with the applicable laws governing consent. This includes applicable provincial and territorial rules.
In some cases, the informed consent process may need to be carried out in a decentralized context involving several different physical locations. Sponsors and qualified investigators should mitigate any risks to participants when obtaining informed consent in a decentralized context. The trial protocol should include rationale to support:
- delegating duties related to the informed consent process to other personnel or third party or
- obtaining informed consent through a virtual meeting (for example, at a health care provider's office or potential participant's home)
- such meetings should take place in real-time and face-to-face, using both audio and video
Sponsors must provide a trial-specific informed consent form (ICF). This form must clearly and concisely outline:
- the risks and anticipated benefits and
- other information that potential participants require in order to decide if they will participate in the trial
Sponsors must ensure that research ethics board approval has been obtained for the trial protocol and the ICF. Sponsors should ensure that the informed consent process:
- fully informs potential participants of all aspects of the trial that are relevant to their decision to participate, including potential indemnity coverage
- this is documented in an ICF (developed by the sponsor and reviewed and authorized by a research ethics board)
New information that might affect a participant's willingness to continue should be evaluated to decide if their re-consent is necessary. If re-consent is required, such as due to emerging safety concerns or signals from other clinical trials, the new information must be clearly highlighted in the updated informed consent materials. These updated materials should be approved by a research ethics board before they are used.
A written, signed and dated ICF is required as documentation of consent in paper or electronic format. A valid record of the participant's signature must be kept. Documentation should also confirm that the participant received the information, a discussion took place with the qualified investigator or delegated third party and the participant gave consent. The informed consent process must comply with all applicable regulatory requirements and adhere to GCP requirements.
Virtual meeting platforms and electronic signatures may make the informed consent process more efficient for those who live in remote areas. However, sponsors should be careful not to unintentionally discriminate against those who do not have access to, or prefer not to use, virtual platforms. Alternative methods, including in-person consent meetings and physical copies of the ICF, should be available to those who request it.
Delegation and institutional research ethics boards
As with all clinical trials, clinical trial sites of expanded access clinical trials must be authorized by a research ethics board. This approval must be provided to Health Canada as part of the CTSI form before trial activities can begin at a clinical trial site or at its other associated locations.
Some research ethics boards may accept alternate review models, or accept prior ethics reviews and decisions from another board, especially if the institutional board is part of a consolidated or streamlined ethics review network. Indeed, some clinical trial organizations in Canada have facilitated more streamlined approval processes that can now include simultaneous participation and representation from many institutional research ethics boards. Approval from one of these networked research ethics boards may help to streamline required approvals for opening multiple clinical trial sites.
Delegation, data management and privacy
Delegating clinical trial activities to a different physical location than the clinical trial site may require that information and data be shared between those involved in conducting various activities and the qualified investigator. Often, this data will contain participants' sensitive and private medical information.
The collection, transfer, storage and handling of clinical trial data are regulated by federal and provincial personal information and privacy laws. Sponsors should be aware of any local laws and regulations that might have an impact on their trial activities, especially across borders.
- Privacy legislation (Health Data Research Network Canada)
Delegation and safety monitoring plans
Trial activities, including those that have been delegated, should be monitored properly and comply with good clinical practices and regulatory requirements.
Protocols should include a risk-based safety monitoring plan that takes into account treatment complexity, participant safety, individual competencies and intended research outcomes of the expanded access clinical trial. This plan should indicate how the trial will be monitored, compliance assessed, and records collected, reviewed and analyzed for safety outcomes.
Delegation and reporting adverse drug reactions
The regulations state:
- if it is neither fatal nor life threatening, within 15 days after becoming aware of the information and
- if it is fatal or life threatening, within seven days after becoming aware of the information
Agreements can support all parties involved in conducting trial activities in being aware of their roles and responsibilities for reporting adverse drug reactions to the sponsor. In this way, all individuals involved in expanded access clinical trial activities can effectively play their part in supporting participant safety.
Annual reports
The risks of impeding the clinical development of the drug or of bypassing regulatory review before broad marketing of the drug are not static. The risks depend on context and will evolve depending on such things as progress of the drug development program and other factors.
To be able to assess the safety and evolving risks of an ongoing expanded access clinical trial, Health Canada may request that sponsors of such trials submit a report every year. Assessment would start 1 calendar year after trial activities begin, until study completion.
For Health Canada to undertake this assessment, sponsors could be instructed to include the following information in their annual report:
- number of participants enrolled since the last report and total number since the expanded access clinical trial began
- number of third-party individuals involved in administering the drug, if applicable, since the last report and total number since the expanded access clinical trial began
- status of any planned, ongoing or completed confirmatory trials since the last report, or other commitments related to clinical development of the drug made in the CTA
- updates on any other commitments made in the CTA, including proposed milestones for bringing the drug to market
Health Canada may suspend the authorization to sell a drug for the purposes of a clinical trial if there are reasonable grounds to believe that information submitted about the trial is false or misleading (there may be other grounds to suspend). The ability to suspend is outlined in section C.05.016(1) of the regulations.
Expanded access clinical trials with controlled substances
Clinical trials are regulated under Part C, Division 5 of the regulations. However, sponsors who wish to conduct a trial with a controlled substance listed in Schedules I to V of the Controlled Drugs and Substances Act (CDSA) must also comply with this act's requirements.
Under the CDSA, all activities with controlled substances, including the sale, import, export, production, transportation and possession of controlled substances, are prohibited unless authorized under its regulations or by exemption. (Possession is only prohibited for controlled substances listed in Schedules I, II and III to the CDSA).
A qualified investigator requiring a controlled substance for research purposes, which includes administration to humans in a clinical trial, must receive an authorization from Health Canada. This is done by submitting a separate application to the Office of Controlled Substances, after a no objection letter for the clinical trial has been issued by Health Canada.
Applications to perform research with a controlled substance that is a restricted drug listed in the schedule to Part J of the Food and Drug Regulations require additional supporting documents. Upon receipt of an application, the Office of Controlled Substances will identify any additional supporting documents required.
Health Canada applies the following principles for research with controlled substances:
- there is a record of handling
- the risk of diversion in transit is reasonably addressed
- the risk of diversion at the clinical trial site or associated locations is reasonably addressed
Investigational drugs that are restricted drugs must be provided by a licensed dealer who is authorized to conduct regulated activities with the substance.
If the authorized manufacturer is located outside of Canada, a Canadian licensed dealer must import the substance. The licensed dealer must obtain an import permit from Health Canada. Only licensed dealers can apply for import permits.
Learn more about the application process for clinical trials with controlled substances:
To apply to use a controlled substance for clinical trials (must be completed by a qualified investigator):
Researchers should familiarize themselves with all Health Canada notices to stakeholders on the requirements for conducting clinical research with specific controlled substances.
Researchers interested in conducting an expanded access clinical trial with a controlled substance should contact the Office of Controlled Substances to obtain information on associated requirements.
Health Canada also conducts compliance and enforcement activities for all controlled substances and precursors and activities conducted under the CDSA and its regulations. This includes activities conducted in clinical trials. Compliance monitoring and enforcement helps to support the legitimate use of controlled substances, while reducing the risk of diversion.
For information on the principles that Health Canada follows when monitoring compliance and enforcement of controlled substances, visit:
