Guidance on expanded access clinical trials: Overview

On this page

• Purpose, scope and application
• What is an expanded access clinical trial
• Key points
• Background
• Note about guidance documents in general

Purpose, scope and application

The Food and Drug Regulations (the Regulations), made under the authority of the Food and Drugs Act (Act), govern the sale and importation of drugs for use in human clinical trials in Canada, including expanded access clinical trials. This guidance document explains the regulatory requirements for expanded access clinical trials. These requirements are supported by Part C, Division 5 of the Regulations, which pertain to drugs for clinical trials involving human participants.

This guidance document is meant for sponsors, health care providers and potential participants who are interested in, involved in, or participating in expanded access clinical trials involving sites in Canada.

• For potential participants, this document:
  • provides information to support access to investigational drugs through an expanded access clinical trial when appropriate
• For sponsors and health care providers, this document:
  • provides supplemental information on the requirements to conduct an expanded access clinical trial in Canada
  • clarifies the application and post-authorization requirements
  • outlines procedures for obtaining authorization for expanded access clinical trials in Canada

Sponsors should also consult other relevant policy and guidance documents, such as:

• Guidance document for clinical trial sponsors: Clinical trial applications
• Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2022)

What is an expanded access clinical trial

In Canada, an expanded access clinical trial is a type of clinical trial that provides access to investigational drugs that have the potential to treat people living with medical conditions who do not qualify for other clinical trials or are not able to participate in one. “Investigational drugs” are pharmaceutical, biologic, and radiopharmaceutical drugs for human use that are tested or studied in a clinical trial. Please note that clinical trials involving natural health products, veterinary drugs, and medical devices are excluded from the scope of this guidance document.

When appropriate, expanded access clinical trials can utilize more flexible protocols and a decentralized model to facilitate access for a larger, potentially more diverse population of participants, in more accessible settings.

Expanded access clinical trials can sometimes help to facilitate access to drugs before they have been authorized for sale by Health Canada, with adequate justification of expected benefits versus risks to participants. This could include, for example, but not limited to: drugs for some mental health disorders or serious or life-threatening conditions where authorized alternatives may be limited for certain patients.

Since it is a type of clinical trial, an expanded access clinical trial intends to:

• discover or verify the clinical, pharmacological, and pharmacodynamic effects of the drug
• identify any adverse events resulting from the drug
• study the absorption, distribution, metabolism, and excretion of the drug and/or
• assess the drug's safety or efficacy

Key points

Since expanded access clinical trials are a type of clinical trial under Part C, Division 5 of the Regulations, they require the completion of a clinical trial application (CTA), for review by Health Canada. In their applications, sponsors must provide evidence from previous studies to demonstrate that the proposed use of the investigational drug would not endanger the health and safety of participants.

CTAs for expanded access clinical trials follow the same review processes and timelines as other clinical trials, as outlined in C.05.006 of the Regulations. Currently, this includes a review period of about 30 days from the date of receipt of the complete application. Our scientists and physicians review applications to assess whether:

• the risks in using the drug in the trial are considered and would not endanger health and safety
• the best interests of those taking part in the trial have been considered, including that drugs are used in the right way for the participants being studied
• the goals of the trial can be met

All CTAs are assessed on a case-by-case basis.

Learn more about the CTA process.

Using the clinical trials framework to provide expanded access in Canada enables access to investigational drugs while providing safeguards and requirements to protect the health and safety of participants. As stated in C.05.010 of the Regulations, sponsors must ensure that an expanded access clinical trial is conducted in accordance with good clinical practices. The rights, safety and well-being of participants are to be protected in accordance with these principles.

Please refer to the International Council for Harmonisation’s E6 guideline for good clinical practice to learn more about some of the participant protection mechanisms in clinical trials, as well as the E19 guideline to learn more about safety monitoring and safety data collection.

Background

As development of the drug progresses, the goal of late-phase (phases 2 and 3) clinical trials is usually to gather evidence that meets the standards required by drug regulators (Figure 1).

Text description

The flowchart shows the drug development process and where expanded access clinical trials are situated within this pipeline. It outlines the various phases involved in bringing a new drug from initial studies to regulatory approval. The following phases of clinical trials are connected by arrows between each phase, showing progression.

• Phase 1: Initial safety studies that involve administering the drug, usually to healthy volunteers, typically in a small number of participants.
• Phase 2: Studies to evaluate the efficacy of the drug in patients with medical conditions, typically in hundreds of participants.
• Phase 3: Controlled or uncontrolled trials to confirm safety and efficacy of the drug, typically in hundreds to thousands of participants.
• Regulatory Review: Drugs can progress from Phase 3 clinical trials to Health Canada's regulatory review when sponsors apply for market authorization.
• Phase 4: Post-market authorization studies to better characterize long-term effects of a drug for the approved indication.

Expanded access clinical trials, depicted in parallel to the drug development pipeline, provide access to an investigational drug for patients, when enrolment in ongoing trials is not feasible. The size of the trial population will depend on the level of evidence from previous studies about the risks and possible benefits of the investigational drug.

All clinical trials are designed to answer specific research questions and to study the effects of a drug.

Late-phase clinical trials aim to show a statistically conclusive effect on a specific outcome of interest by setting specific criteria for who can and cannot participate.
These controls help protect the safety of participants and make it more likely that the results will lead to reliable and useful findings. But this also means that not everyone will get to participate in a clinical trial if:

• they do not meet the eligibility criteria (the requirements that must be met in order for a person to be included in the study)
• their disease has progressed too far
• they live too far from study sites
• there are no available clinical trials, or ongoing trials are either not recruiting or are in the process of closing

In such cases, potential participants might be able to receive investigational drugs through an expanded access clinical trial. Expanded access clinical trials provide access to investigational drugs that have the potential to treat people living with medical conditions who do not qualify for other clinical trials or are not able to participate in one. They can be designed to facilitate access for a larger, potentially more diverse population of participants, in more accessible settings.

As with other clinical trials, the sale or importation of a drug for an expanded access clinical trial is authorized under Part C, Division 5 of the Regulations. Sponsors of expanded access clinical trials must protect participants in accordance with ethical, medical and quality standards of the clinical trials framework.

Sponsors may propose an expanded access clinical trial before or after market authorization. However, an expanded access clinical trial should only be conducted for drugs that are being (or have been) actively studied in Canada or other countries. A prior clinical trial is not required to have been conducted in Canada.

There must be a strong rationale for initiating an expanded access clinical trial that provides access to a drug before it has been authorized for sale by Health Canada. For example, an expanded access clinical trial could enable access to a drug for a specified population or new indication while a regulatory submission is under review by Health Canada. As part of their rationale, sponsors may refer, for example, to the severity of the condition, lack of available alternatives, or possible increased benefits or decreased risks compared to existing authorized products.

Other examples of when a sponsor may find it useful to conduct an expanded access clinical trial:

• when a sponsor wants to open an arm of an international expanded access program in Canada
• when a traditional clinical trial is unavailable in Canada but there is evidence from international studies to support investigation of and access to the drug in Canada
• when a sponsor wants to study the effects of a drug in a broader, more diverse population (can be before or after market authorization)
• when a sponsor wants to study the long-term effects of a drug in conditions more aligned with the real world

To conduct an expanded access clinical trial, sponsors are expected to provide evidence from other studies in the CTA. This information can help demonstrate that the investigational drug will not endanger the health and safety of participants, and may be beneficial in treating the specific disorder in the population being studied.

Expanded access clinical trials also require an investigator's brochure specific to the investigational product proposed for this type of trial.

Learn more about the type of information that should be submitted in a CTA.

Comparisons to the Special Access Program and other types of clinical trials

Expanded access clinical trials are distinct and separate from Health Canada’s Special Access Program (SAP). Through the SAP, health care professionals may request access to drugs that are not currently authorized for sale in Canada to treat individual patients with serious or life-threatening conditions. Access to these drugs may be considered when conventional therapies have failed, are unsuitable, or are unavailable. Unlike expanded access clinical trials, which have overarching research objectives, SAP is a patient-focused program that provides exceptional access to unauthorized drugs for individual patients in emergency medical situations.

Learn more about SAP and its requirements.

Please note that expanded access clinical trials are not meant to restrict access to other programs or avenues like SAP. SAP is intended for patients in emergency medical situations. Expanded access clinical trials could be helpful for groups of patients looking for longer-term treatment options for serious but not immediately life-threatening conditions, or where other approved alternatives exist.

Expanded access clinical trials are also different from other types of clinical trials, such as extension studies, open-label individual patient clinical trials, and seeding trials:

• Extension studies: In contrast to expanded access clinical trials that allow for the recruitment of new participants who may not have participated in any prior clinical trials, extension studies (also known as extended trials) are associated with a particular prior trial. Extension studies are typically designed to allow participants of a prior trial to continue receiving the drug in a second related study and the sponsor can investigate long-term outcomes. They can allow participants to continue accessing an investigational drug after a prior trial is completed and closed. This can be important in situations where discontinuing access to the investigational drug may adversely affect participants.
• Open-label individual patient (OLIP) clinical trials: An OLIP clinical trial (also sometimes referred to as a “single patient study”) is a type of clinical trial designed for individual participants only. These trials provide access to an unauthorized drug for a participant suffering from a serious or life-threatening condition. In contrast, expanded access clinical trials:
  • can be designed for a broader, expanded population of participants,
  • may be a better option for managing exceptional access for large groups of participants, and
  • may generate more useful evidence given the larger sample size.
• Seeding/marketing trials: Seeding trials are more common in the United States, and have been described as clinical trials designed to promote the use of recently approved drug therapies among health care providers. They are typically designed to fulfill marketing objectives and are unlikely to generate scientific evidence. Unlike seeding trials, which occur after market authorization, expanded access clinical trials can occur during the drug development process and must include research objectives. Because seeding trials occur after market authorization, they do not require a clinical trial application to be submitted to Health Canada, as long as the purpose and condition of use align with the market authorization.

While public-facing guidance does not currently exist on the above types of clinical trials, all clinical trials with unauthorized drugs must follow the same procedures and requirements outlined in Part C, Division 5 of the Regulations. For more information on these requirements, please see the guidance document for clinical trial sponsors: clinical trial applications. Individuals interested in learning more about the different types of clinical trials can reach out to the Office of Clinical Trials at Health Canada (see contact information).

Expanded access clinical trials: Special considerations

As expanded access clinical trials provide access to unauthorized drugs to a broader group of potential participants, they carry unique risks compared to other types of clinical trials.

Sponsors should ensure that expanded access clinical trials do not:

• expose a broader participant population tounjustified risks associated with investigational drugs
  • These investigational drugs have not yet undergone regulatory review for market authorization by Health Canada. For this reason, their efficacy and safety have not been fully evaluated. Sponsors should provide evidence from completed or ongoing clinical trials or other studies to demonstrate that benefit of the investigational drug in a proposed expanded population outweighs possible risks to the health and safety of participants. Sponsors should also continue to monitor the health and safety of participants as the trial progresses.
• impede the clinical development of the drug in Canada
  • There is a risk that these types of trials could divert participants or supply from a confirmatory clinical trial (a trial that generates statistically conclusive evidence of the drug’s efficacy and safety). Sponsors should assess and explain how providing the drug in an expanded access clinical trial could potentially interfere with clinical development in Canada.
• enable broad market access prior to market authorization
  • Broad market access to a drug should only occur after Health Canada has reviewed the drug's safety, efficacy and quality evidence and authorized its sale in Canada. Sponsor protocols should define the Canadian participant population, timelines for bringing the drug to market, and how access will be limited to those in exceptional need.

Sponsors of expanded access clinical trials must meet all applicable regulatory requirements in their CTA and provide specific information in their protocol on these potential risks. See the section on addressing unique risks for more information. 

Note about guidance documents in general

Guidance documents provide assistance to industry and health care providers on how to comply with governing statutes and regulations. They also provide guidance to Health Canada staff on how mandates and objectives should be met fairly, consistently and effectively.

Guidance documents are administrative, not legal, instruments. This means that flexibility can be applied. However, to be acceptable, alternate approaches to the principles and practices described in this document should be supported by adequate justification. They should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As always, Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, to help Health Canada adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read along with the relevant sections of the Food and Drug Regulations and other applicable policy and guidance documents.

This document may be updated in the future to align with any future changes made to the Food and Drugs Act or its regulations.