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

We are revising this notice to reflect Health Canada’s new framework on non-therapeutic cannabis research. For more information on the framework, please refer to the types of research with cannabis.

May 31, 2021
Our file number: 21-109448-84

Health Canada is issuing this Notice to clinical trial sponsors to clarify the approach to various types of clinical research with cannabis.

Health Canada recognizes that conducting clinical research (i.e., research carried out on humans) with cannabis is critical to generating high-quality evidence that 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.

Sponsors interested in conducting research with cannabis must meet certain requirements under the Cannabis Act and its regulations. 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 for research with cannabis - Food and Drugs Act (FDA) and Cannabis Act
• Clinical trials with cannabis for therapeutic purposes, or with intent to market as a drug under the Food and Drug Regulations
• Clinical trials with cannabis for non-therapeutic purposes
• Other types of cannabis-based research that are not considered clinical trials
• Observational studies
• Organoleptic testing, and testing of detection devices
• Clinical research involving parts of the cannabis plant permitted in natural health products
• Veterinary research
• Compliance and enforcement
• Contact Information

General requirements for research with cannabis - Food and Drugs Act (FDA) and Cannabis Act

Any research with cannabis that meets the definition of a clinical trial in the Food and Drug Regulations (FDR) is subject to Part C, Division 5 of those regulations.

This definition only applies to clinical trials that are interventional 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 aligned 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 clinical trial application (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.

Sponsors who are considering undertaking a clinical trial to investigate cannabis are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their specific circumstances and requirements.

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 be sufficient to 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 are conducted in accordance with internationally accepted principles of Good Clinical Practices (GCP). As part of GCP, drugs used in clinical trials must meet Good Manufacturing Practices (GMP), which is a requirement under Part C, Division 5 of the FDR. Health Canada is aware that it may be challenging for some sponsors to obtain GMP-grade cannabis for research, but this requirement is necessary to ensure the consistency of the investigational product throughout the clinical trial(s).

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 with intent to market as a drug under the Food and Drug Regulations

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, standard clinical trial requirements apply (as described above). In addition, sponsors are reminded that, should they plan to seek market authorization under the FDR, studies that do not meet the requirements of Division 5 may not be accepted.

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 should be specific to the product being investigated, include the results of any pre-clinical studies, and any relevant clinical studies, and be updated annually.

Researchers have informed Health Canada that a product-specific IB is not always feasible for cannabis, and acts as an impediment to cannabis research in Canada. In early phase trials, Health Canada may consider that the absence of the full set of product-specific pre-clinical studies in the IB is acceptable if the clinical trial involves a cannabis product that is produced under GMP conditions, and for which there is sufficient evidence of safe human use. Health Canada expects that the sponsor will be developing a product-specific IB, aligned with the requirements of ICH M3(R2), for trials designed to confirm the efficacy and safety of the cannabis product for use in the treatment of a specific disease/condition, and that the IB will be updated as new information accumulates.

Some flexibility may be acceptable for cannabis products where a similar product has received market authorization either in Canada or another member state of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). In this situation, Health Canada may consider the absence of a full set of product-specific pre-clinical studies acceptable in early phase trials if the sponsor can provide information that establishes the similarity of the chemical and physical properties of the investigational product to the marketed product. Synthetic products that are not duplicates of naturally occurring phytocannabinoids, or where a similar product has not received market authorization either in Canada or in an ICH member state, require product-specific pre-clinical studies, even for early phase trials.

The sponsor also needs to provide an attestation that the investigational product is manufactured in a facility that is compliant with GMP.

Sponsors who are considering undertaking a clinical trial to investigate cannabis are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their specific circumstances and requirements.

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 cannabis legal framework. In order to facilitate non-therapeutic cannabis research, it is Health Canada's intention to exempt cannabis used in these studies from the application of the FDA/FDR, and to create a framework under the Cannabis Regulations for non-therapeutic cannabis research. More information regarding this regulatory initiative can be found in this Notice of Intent and this Forward Regulatory Plan.

In the interim, for clinical trials with cannabis for non-therapeutic purposes, the Department may consider the absence of product specific pre-clinical and clinical information acceptable for these studies, provided there is sufficient information on the product's main active ingredient(s) - for example, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). 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 wish to be eligible for this approach, their clinical trials must be conducted on healthy adults who are currently using cannabis, using the same product form/class that participants have normally used and the same route of administration. The dosage regimen of cannabis administered in the trial is not to exceed what the participant would normally have consumed within a similar period of time. Additionally, although the investigational product does not have to be available for retail sale on the legal market (i.e. it may be under development), it must meet the requirements of the Cannabis Regulations for legal retail sale and meet GMP quality requirements. If dried cannabis is administered through smoking or vaping, adequate measures to prevent exposure of other individuals (e.g., research staff or other participants) to second-hand smoke or vapour is to 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.

Sponsors who are considering undertaking a clinical trial to investigate cannabis are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their specific circumstances and requirements.

When submitting a CTA, sponsors are to indicate in their cover letter whether the clinical trial is for therapeutic purposes or for non-therapeutic purposes.

Please see below for a tabular summary of these scenarios.

Type of cannabis product	Type of clinical trial	Eligibility for a non-product-specific IB
		Yes	No
Cannabis products of botanical origin† and synthetics that are duplicates of naturally occurring cannabinoids	Non-therapeutic purpose trial	√††
	Therapeutic purpose early phase trial	√††
	Therapeutic purpose confirmatory trial		√
Synthetics that are not duplicates of naturally occurring cannabinoids	Non-therapeutic purpose trial		√
	Therapeutic purpose early phase trial		√
	Therapeutic purpose confirmatory trial		√
Cannabis products††† where a similar product has received market authorization either in Canada or in an ICH member state	Non-therapeutic purpose trial	√††††
	Therapeutic purpose early phase trial	√††††
	Therapeutic purpose confirmatory trial		√

† Dried cannabis, fresh cannabis, edible cannabis, cannabis topicals, cannabis extracts (including cannabis oil)

†† Information on the main active ingredients and on human use may be considered acceptable

††† Cannabis products of botanical origin or synthetics that are duplicates of naturally occurring cannabinoids

†††† Information that establishes similarity of the chemical and physical properties of the investigational product to the marketed product may be considered acceptable

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

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 Office of Clinical Trials.

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:

• The protocol does not assign to the participants a specific intervention;
• The prescription of a drug containing cannabis or authorization of cannabis for medical purposes is clearly separated from the decision to include the patient in the study;
• The investigator has no control over the prescribing, authorization or administration of the cannabis product;
• The cannabis product being used must be sourced from the legal regulated Canadian market;
• The number of inclusion criteria must be very limited (e.g., adults using cannabis and the ability to provide consent); and
• The collection of data should involve no to minimal health risks.

For observational studies, the sponsors are reminded to consult with their Research Ethics Boards regarding applicable ethics requirements.
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.

Organoleptic testing, and testing of detection devices

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:

• Organoleptic testing (e.g., assessment of consumer preference with respect to taste or smell) of products containing cannabis, provided that the cannabis is in its final form and meets the requirements in the Cannabis Regulations for retail sale.
• Research on the verification, validation or standardization of a device detecting cannabis for judicial or forensic use (e.g., roadside testing devices), provided that the study focuses on the device and not on the properties or effects of cannabis.

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, Health 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