Draft guidance on expanded access clinical trials: Overview

On this page

• Purpose
• Scope and application
• Policy objectives
• Policy statements
• Background
• Note about guidance documents in general

Purpose

The Food and Drugs Act (act) and the Food and Drug Regulations (regulations) govern the sale and importation of drugs for use in human clinical trials in Canada, including expanded access clinical trials. This draft guidance document explains the regulatory requirements for expanded access clinical trials. These requirements are supported by Part C, Division 5 of the regulations, entitled "Drugs for Clinical Trials Involving Human Subjects".

Scope and application

This draft guidance document is for sponsors, health care providers and potential participants who are interested in, involved in or participating in expanded access clinical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

Health Canada has authorized a number of expanded access clinical trials, including trials that are part of international, multi-site expanded access programs. However, the number of clinical trial sites opened and participants enrolled in Canada has been limited. This document provides additional information about how expanded access clinical trials are managed in Canada.

Expanded access clinical trials are clinical trials, and therefore require the completion of a clinical trial application (CTA), for review by Health Canada.

A clinical trial is an investigation of a drug for use in humans that involves human subjects. The trial is intended to:

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

Our scientists review applications to assess whether:

• any risks in using the drug and in conducting the trial are mitigated
• 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

Sponsors may request a pre-CTA consultation meeting. Such consultations may be particularly useful for new active substances or applications that will include complex issues that may be new to Health Canada.

In this guidance document, "investigational drugs" (pharmaceutical, biologic and radiopharmaceutical) are those that are tested or studied in a clinical trial and have never been authorized for sale in Canada for any indication. Natural health products, veterinary drugs and medical devices are excluded from the scope in this guidance document.

Learn more about the CTA process.

Policy objectives

Clinical trials, including expanded access clinical trials, are investigations that can sometimes help to facilitate access to novel therapies before they have been authorized for sale by Health Canada. This could include therapies for serious or life-threatening conditions where authorized alternatives may be limited for certain patients (for example, related to oncology, rare diseases and some mental health disorders).

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

Sponsors should also consult other relevant guidance documents, including:

• Guidance document for clinical trial sponsors: Clinical trial applications

Policy statements

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. This type of trial can be designed to facilitate access for a larger, potentially more diverse population of participants, in more accessible settings.

As stated in C.05.010 of the regulations, sponsors must ensure that an expanded access clinical trial, like all clinical trials, is conducted in accordance with good clinical practices (GCP). The rights, safety and well-being of clinical trial participants are to be protected in accordance with these principles. This includes obtaining the approval of a research ethics board for each Canadian clinical trial site.

Sponsors must provide substantial evidence from previous studies to demonstrate that the proposed use of the investigational drug in an expanded population does not endanger the health and safety of participants. All CTAs are assessed on a case-by-case basis.

Many types of clinical trials can adopt a decentralized model, as a business decision. Expanded access clinical trial sponsors may consider following a decentralized clinical trial model to facilitate trial participation and to recruit and enrol a diverse population of participants.

This decentralization can involve a qualified investigator at a clinical trial site delegating tasks to a qualified third party in a different physical location. This can include, where appropriate and justified, the delegation of tasks related to administering the drug and associated follow-up and safety monitoring of participants.

The clinical trial site where the qualified investigator is located must be reflected in a clinical trial site information (CTSI) form submitted to Health Canada. Delegated health care providers may be located at other physical locations, which do not require separate CTSI forms or additional research ethics board approvals.

All locations where clinical trial activities occur are considered to be part of the main clinical trial site and may be inspected as part of a clinical trial site inspection. All activities related to the practice of medicine are under provincial or territorial jurisdiction.

Learn more about the ICH E6 guideline for good clinical practice.

Background

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

Long 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. Some sponsors may choose to conduct an extension study to maintain access to the drug for patients from previous trials after those previous trials have closed.
• 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 make it more likely that the results will lead to reliable and useful findings. But this also means that not everyone can participate in these clinical trials for the following reasons:

• they do not meet the eligibility criteria
• their disease has progressed too far
• they live too far from study sites or
• there are no available clinical trials or ongoing trials are not recruiting

In such cases, patients might be able to receive investigational drugs, when appropriate, 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 at any point in the drug development process, even if a clinical trial studying that drug has not been previously conducted in Canada. However, an expanded access clinical trial should only be conducted for drugs that are being actively developed. An example would be a drug under investigation in a study intended to form the primary basis of safety and efficacy, leading to a planned submission for regulatory authorization.

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 new drug for a specified population 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 therapeutic alternatives, or possible increased benefits or decreased risks compared to existing authorized products.

To conduct an expanded access clinical trial, sponsors must provide substantial evidence from previous clinical trials or other studies in a CTA. They must 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.

Expanded access clinical trials compared to other types of clinical trials

Expanded access clinical trials are different from extension studies because they 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. They are designed to allow access, but only for those participants of the prior trial, so that those participants can continue receiving the drug in a second related study and the sponsor can investigate long-term outcomes. Extension studies 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.

Expanded access clinical trials are also different from open label individual patient (OLIP) clinical trials, which are for individual participants only. Expanded access clinical trials, which 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.

Expanded access clinical trials may be designed to collect long-term safety or tolerability data and real-world evidence that can be used to supplement results from confirmatory clinical trials in a regulatory submission. While the evidence generated is often not as reliable as evidence from traditional confirmatory trials, it can characterize effects such as rare adverse reactions or longer-term outcomes that may only appear in larger populations over time. Depending on the research protocol proposed by the sponsor, expanded access clinical trials may be able to generate real-world evidence on treatment use of the investigational drug in a setting that's closer to real-world conditions.

Expanded access clinical trials: special considerations

A drug must receive market authorization before it can be sold in Canada. The purpose of the act and its regulations is to:

• ensure that therapeutic products brought to market are safe, effective and of high quality
• prevent deceptive marketing practices and protect the public from risks and injury from unsafe products

Thus, to meet the threshold for authorization by Health Canada when applying for market authorization, a trial sponsor must demonstrate the safety, efficacy and quality of its therapeutic product. Evidence of this is generally supported by information and data generated through extensive clinical trials and non-clinical research.

It's in the best interest of patients that Health Canada reviews and regulates the drug products they use. We have put in place a framework to enable sponsors to manage a drug's risks over the entire lifecycle of the drug, which includes post-market surveillance activities.

In addition to helping safeguard health and safety, the need to receive authorization, as framed by the act and regulations, is a basic cornerstone of the drug development, commercialization and regulatory process.

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.

There is a risk that expanded access clinical trials may:

• expose a broader participant population to 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 must provide evidence from completed or ongoing clinical trials or other studies to demonstrate that the investigational drug in a proposed expanded population does not endanger the health and safety of patients.
• impede the clinical development of the drug
  • There is a risk that these types of trials could divert participants or supply from a confirmatory clinical trial. Sponsors should be able to demonstrate that providing the drug in an expanded access clinical trial will not interfere with clinical development.
• bypass regulatory review before market access
  • 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 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 the potential risks.

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 must 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 regulations and other applicable guidance documents.