Notice to Stakeholders – Clarification of Requirements Under the Food and Drug Regulations When Conducting Clinical Research With Cannabis

September 18, 2020
Our file number: 20-110553-61

Health Canada is issuing this notice to clinical trial sponsors to clarify key obligations under the Food and Drug Regulations (FDR) for various types of cannabis-based clinical research.

Health Canada recognizes that conducting clinical research (i.e., research carried out on humans) with cannabis is critical to generating high-quality evidence regarding its biological and health effects. Evidence generated from clinical research can be used to better understand the health risks and benefits of cannabis use, inform health policies and protect the health and safety of Canadians. Clinical research also supports the development of cannabis-based drug products that are safe, effective and of high quality.

In Canada, products containing cannabis are legally available for both therapeutic purposes (e.g., cannabis for medical purposes and health products containing cannabis) and non-therapeutic purposes. As a result, clinical research with cannabis can be conducted for both purposes. In this context, the term therapeutic refers to that which is related to the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms. Given the dual purposes of clinical research with cannabis, the Department is issuing this notice to clarify certain key obligations under the FDR when conducting clinical research for therapeutic and non-therapeutic purposes, as well as for other research scenarios. The information in this notice is focused primarily on clinical trial application (CTA) requirements.

Sponsors interested in conducting research with cannabis (whether for therapeutic or non-therapeutic purposes) must also meet certain requirements under the Cannabis Act and its regulations. In addition to a CTA, authorization to conduct research with cannabis must be obtained by applying for a federal cannabis research licence from the Controlled Substances and Cannabis Branch of Health Canada. The Application requirements for cannabis research licences webpage provides more information on how to obtain a research licence from Health Canada under the Cannabis Act and its regulations.

Table of contents

General requirements

Cannabis, whether for therapeutic or non-therapeutic purposes, meets the definition of a drug under the Food and Drugs Act (FDA). Therefore, any research with cannabis that meets the definition of a clinical trial in the FDR is subject to Part C, Division 5 of those regulations.

Under Part C, Division 5 of the FDR, a clinical trial means:

“An investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.”

This definition assumes that the study design of a clinical trial is interventionalFootnote 1 and not observational (see section below on observational studies). The application of this definition does not depend on how data generated from a clinical trial will be used. This means that research that is not intended to support the development of an authorized drug product could still meet the definition of a clinical trial, if any of the criteria set out in the definition above are met.

Division 5 is a set of internationally alignedFootnote 2 regulations under the FDR that govern the sale and importation of drugs for use in clinical trials. These regulations are designed to support research and innovation in an ethical manner to ensure the protection of clinical trial participants, as well as the integrity of the data generated. They also ensure that the same level of scrutiny is applied to all clinical trials, regardless of the drug substance being tested.

Under Division 5, sponsors must file a CTA to conduct a clinical trial. A CTA does not need to be submitted to Health Canada if a clinical trial is investigating an authorized drug product (i.e., one that has received a Notice of Compliance (NOC) or a Drug Identification Number (DIN)) and is used within the parameters authorized under the NOC or DIN (e.g., indication, dosage, formulation, route of administration, etc.).

A CTA to investigate cannabis, or any other drug substance, must contain standard information and documentation to ensure that the trial is properly designed and that participants (and other implicated persons) are not exposed to undue risk. This includes, but is not limited to, a study protocol, informed consent forms, an Investigator’s Brochure (IB), chemistry and manufacturing information, along with other pertinent information.

Approval from a Research Ethics Board (REB) must also be obtained before starting a clinical trial. More information on CTA requirements for drug products can be found in the Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications.

Quality (chemistry and manufacturing) requirements for CTAs involving cannabis are the same as for any pharmaceutical product used in a clinical trial. The scope and detail of information submitted in support of the quality portion of a CTA should enable Health Canada to make an adequate assessment of the characteristics of the drug. Sponsors are expected to submit progressively more detailed quality information through subsequent clinical trial phases. More information on quality requirements can be found in the Guidance Document - Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals.

In addition to CTA requirements, clinical trials in Canada must be conducted in accordance with internationally accepted principles of Good Clinical Practice (GCP). As part of GCP, drugs used in clinical trials must meet Good Manufacturing Practice (GMP) requirements.

Sponsors must also report to Health Canada any serious and unexpected adverse drug reactions (ADRs) that occur during a clinical trial. For more information on ADR reporting, please visit the following webpage: Clinical Trials - Adverse Drug Reaction (ADR) Reporting.

Clinical trials with cannabis for therapeutic purposes or to support the development of a drug product intended for market authorization

Clinical research is essential to understanding the effects of cannabis in a therapeutic context, as well as for the development of drug products that are safe and effective. An increased availability of authorized drugs containing cannabis provides Canadians with a greater selection of therapeutic options to meet their health needs. High-quality research also helps guide practitioners in making evidence-based decisions when prescribing and managing patients using these drugs.

When a clinical trial with cannabis is conducted for therapeutic purposes, or to support the development of a drug product intended for market authorization, standard clinical trial requirements apply (as described above).

In particular, the IB (which is a regulatory requirement described in C.05.005(e) of the FDR) should be prepared in accordance with the Health Canada / ICH Guidance Document E6: Good Clinical Practice: Consolidated Guideline. This means that the data contained in the IB must be specific to the product being investigated, include the results of pre-clinical studies that meet the requirements of ICH M3(R2), include relevant clinical studies, and be updated annually.

Clinical trials with cannabis for non-therapeutic purposes

Clinical research is also needed to better understand the psychological and physiological effects of cannabis for non-therapeutic purposes. For example, this can include investigating the time to onset or duration of effects of a cannabis product, the impact of cannabis use on driving performance, or various types of public health research.

Clinical trials with cannabis for non-therapeutic purposes are currently subject to Part C, Division 5 of the FDR and require the submission of a CTA to Health Canada. However, the Department recognizes that Division 5 may not be ideally suited to regulate research for non-therapeutic purposes using commercially available products containing cannabis sold under the legal framework. Health Canada is exploring options for a more suitable regulatory framework for this type of cannabis research.

In the interim, for clinical trials with cannabis for non-therapeutic purposes, the Department will accept an IB that contains non-product specific pre-clinical and clinical information that focusses on the product’s main active ingredient(s) – for example, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) – rather than the product’s specific formulation (as is normally required under C.05.005(e)). However, the IB must continue to include all the types of information listed under C.05.005(e) on these active ingredients, and must contain sufficient information to support the specific study. The information must be relevant to the product under investigation in terms of route of administration, dosage regimen (dose and frequency) and product form or class (e.g., cannabis extract, edible cannabis, cannabis topicals, dried cannabis or fresh cannabis). The information must also be updated annually, and include recent and relevant clinical trial results.

If sponsors prepare the IB in the above mentioned manner, the clinical trial must be conducted on healthy adults who are current cannabis users, using commercially available products containing cannabis (or those in their final stage of development) that meet GMP requirements, with the same route of administration and same product form that participants have previously used. The dosage regimen of cannabis administered in the trial must not exceed what the participant would usually consume within a similar period of time. If the cannabis is administered through smoking or vaping (of dried cannabis), adequate measures to prevent exposure of other individuals (e.g., research staff or other participants) to second-hand smoke or vapor must be included in the protocol.

All other aspects of Division 5, including (but not limited to) the requirement for REB approval, a qualified investigator at each site, submission of chemistry and manufacturing information, adherence to GCP and adverse reaction reporting requirements, continue to apply.

Please note that this approach cannot be used for clinical trials intended to support the development of a drug product intended for market authorization, or any clinical trial with a therapeutic purpose, despite potentially overlapping types of investigation (e.g., pharmacokinetic studies). In addition, this approach does not apply to trials involving the administration of cannabis extracts (such as vaping liquids – and not dried cannabis) through inhalation (vaping or otherwise), nor to trials using products containing cannabinoids derived from synthetic sources or processes. Under the latter circumstances, a product-specific IB, including the results of pre-clinical studies meeting the requirements of ICH M3(R2), would be required.

When submitting a CTA, sponsors should indicate in their cover letter whether the clinical trial is for therapeutic purposes (which includes trials to support the development of an authorized drug product) or for non-therapeutic purposes.

Please see Appendix A for a tabular summary of these conditions.

Observational studies

Sponsors who intend to conduct an observational study using cannabis do not need to submit a CTA to Health Canada. A study is considered observational if it meets all of the following criteria:

Observational studies still require REB approval.

Serious adverse reactions observed during the course of an observational study should be reported to Canada Vigilance.  Information on cannabis adverse reaction reporting can be found in the Cannabis adverse reaction reporting guide.

Other types of cannabis-based clinical research that are not considered clinical trials

Some cannabis-based research does not meet the definition of a clinical trial, even when human participants are involved. In such cases, sponsors are not required to submit a CTA to Health Canada. However, investigators are still required to obtain a cannabis research licence from Health Canada under the Cannabis Act. Although the Department cannot, in advance, provide a complete list of study protocols that would not meet the definition of a clinical trial, two examples include:

Sponsors should consult the definition of a clinical trial in Part C, Division 5 of the FDR to determine whether their study protocol meets the criteria for a clinical trial. When in doubt, sponsors should consult the Therapeutic Products Directorate’s Office of Clinical Trials (see contact information below).

Clinical research involving parts of the cannabis plant permitted in natural health products

The requirements of the Natural Health Products Regulations apply to clinical trials for natural health products, including those containing permitted parts of the cannabis plant (see section 3.4 of Health Canada’s Health products containing cannabis or for use with cannabis: Guidance for the Cannabis Act, the Food and Drugs Act, and related regulations document for more details on permitted parts). More information about these requirements can be found in the Clinical Trials for Natural Health Products guidance document.

Veterinary research

In order to conduct veterinary drug research or studies using drugs containing cannabis, the investigator or the sponsor is required to submit either an Experimental Studies Certificate (ESC) or a veterinary Investigational New Drug (IND) application to Health Canada’s Veterinary Drugs Directorate (VDD).

For all research or studies to be conducted using a veterinary drug, the objective is to ensure that there is appropriate oversight to cover the overall health and safety of study animals. If the study includes food-producing animals, Health Canada also considers relevant information to address food safety.

Sponsors are strongly urged to request a pre-submission meeting with VDD before submitting an ESC or IND application for research involving cannabis. More information can be found on the veterinary drugs forms and applications page.

Compliance and enforcement

As part of its regulatory responsibilities, Health Canada promotes, monitors, and enforces compliance. As such, Heath Canada Inspectors may conduct inspections of clinical trials under the authority of Section 23 of the FDA. The purpose of these inspections is to verify compliance with Part C, Division 5 of the FDR, which include the requirement to comply with GCP. For more information on compliance and enforcement, please refer to the Compliance and Enforcement Policy for Health Products (POL-0001) and to the various guidance documents available on the Health Canada Good Clinical Practices webpage.

Contact Information:

Office of Clinical Trials – Therapeutic Products Directorate
Health Products and Food Branch
E-mail:  hc.oct.enquiries-requetes.bec.sc@canada.ca

Natural and Non-prescription Health Products Directorate
Health Products and Food Branch
E-mail: nhpd-cta.dec-dpsn@hc-sc.gc.ca

Veterinary Drugs Directorate
Health Products and Food Branch
E-mail: hc.vdd.skmd.so-dgps.dmv.cp.sc@canada.ca

Licensing and Medical Access Directorate
Controlled Substances and Cannabis Branch
E-mail:  hc.sp-licensing-cannabis-licences-sp.sc@canada.ca

Clinical Trial Compliance Program
Regulatory Operations and Enforcement Branch
E-mail: gcp_bpc@hc-sc.gc.ca

Appendix A: When is a product-specific Investigator's Brochure (IB) required to conduct a clinical trial with cannabis?

Type of cannabis product Type of clinical trial Product-specific IB required?
Yes No
Dried cannabis, fresh cannabis, edible cannabis, cannabis topicals, cannabis oil Non-therapeutic purpose  
Therapeutic purpose or intent to market as a drug under the Food and Drug Regulations  
Cannabis extracts Non-therapeutic purpose  
Therapeutic purpose or intent to market as a drug under the Food and Drug Regulations  
Involves inhalation (e.g., vaping - but not vaping of dried cannabis)  
Cannabinoids derived from synthetic sources or processes Non-therapeutic purpose  
Therapeutic purpose or intent to market as a drug under the Food and Drug Regulations  
Footnote 1

A trial in which the treatment assigned to the trial subject is predefined by the trial protocol.

Return to footnote 1 referrer

Footnote 2

The regulations are consistent with the principles, definitions and standards found in the Health Canada / International Conference on Harmonization (ICH) Guidance Documents E6: Good Clinical Practice: Consolidated GuidelineE8: General Considerations for Clinical Trials and E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. These guidance documents, developed through the ICH process, have been adopted by Health Canada. Together, they define parameters for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials.

Return to footnote 2 referrer

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