Notice to Stakeholders – Clarification of Requirements under the Food and Drug Regulations and the Controlled Drugs and Substances Act When Conducting Clinical Research with Psilocybin

January 11, 2022
Our file number: 21-121678-792

Health Canada is issuing this notice to clinical trial sponsors to clarify the approach to clinical research with psilocybin. Health Canada recognizes that conducting clinical research (i.e., research carried out on humans) is a critical step in the generation of good quality evidence needed to better understand the potential health benefits and harms associated with the therapeutic use of psilocybin.

Table of contents

• General requirements for research with psilocybin under the Food and Drugs Act (FDA)
• Additional requirements for clinical research with psilocybin under the Controlled Drugs and Substances Act (CDSA)
• Flexibility in the data requirements for a clinical trial application involving psilocybin
• Compliance and enforcement
• Contact information

General requirements for research with psilocybin under the Food and Drugs Act (FDA)

The Food and Drugs Act (FDA) defines a 'drug' as any substance or mixture of substances manufactured, sold or represented for use in:

• (a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals,
• (b) restoring, correcting or modifying organic functions in human beings or animals, or
• (c) disinfection in premises in which food is manufactured, prepared or kept.

As such, any psychedelic substance used for any of the purposes listed above are considered drugs and therefore are subject to the FDA and its regulations.

Furthermore, any research with psilocybin 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.

Part C, 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. The regulations stipulate that no person shall sell or import a drug for the purposes of a clinical trial unless they are authorized to do so under the Division and its sections, and they comply with its requirements. These regulations are designed to ensure the protection of clinical trial participants, while supporting clinical research. Under Part C, Division 5, sponsors must file a clinical trial application (CTA) to conduct a clinical trial if they are investigating a drug that has not received market authorization for the indicated use. A CTA must include a study protocol, informed consent form, an Investigator's Brochure (IB), as well as chemistry and manufacturing information. Information on CTA requirements for drug products can be found in the Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications. Some flexibility in these CTA requirements are described further down in this document.

Chemistry and manufacturing requirements for the sale or importation of psilocybin in a clinical trial are the same as for any other drug that is the subject of 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. Information on quality requirements can be found in the Guidance Document - Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals.

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 (C.05.010(j)). Additional information regarding the requirements pertaining to GMP for clinical trial drugs is available in Guidance Document - Annex 13 to the Current Edition of the GMP Guidelines: Drugs Used in Clinical Trials (GUI-0036), as well as sections 2.12, 5.14.5 and 8.2.16 of ICH E6(R2).

Sponsors must 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.

Approval from a Research Ethics Board (REB) must also be obtained before starting a clinical trial. The REB process is independent of Health Canada.

Sponsors are strongly encouraged to schedule a pre-CTA meeting to discuss their proposal with Health Canada regarding pre-clinical requirements, clinical protocol design, chemistry and manufacturing information and the product development plan, prior to filing their application.

Additional requirements for clinical research with psilocybin under the Controlled Drugs and Substances Act (CDSA)

Although clinical trials are regulated under Part C, Division 5 of the FDR, sponsors interested in conducting research with psilocybin (or any other controlled substance) must also comply with the CDSA requirements as psilocybin is controlled as a restricted drug under the CDSA (it is listed in Schedule III of the CDSA and the schedule to Part J of the FDR). Under the CDSA, the sale, import, export, production and possession of psilocybin is prohibited unless authorized under Part J of the FDR.

If a qualified investigator is seeking to perform research with psilocybin, a clinical trial application must be submitted and a No Objection Letter issued before applying for an authorization under Part J of the FDR. An authorization under Part J of the FDR allows the sale of a restricted drug by a licensed dealer to an institution for the purposes of clinical testing by qualified investigators (see J.01.059(1) of the FDR). In addition to submitting the application form, the qualified investigator must also submit a letter of endorsement or support from their affiliated institution. Health Canada's webpage provides additional information regarding this process, including the application form for an exemption to use a controlled substance for clinical studies, which should be completed by a qualified investigator.

Sponsors should also be aware that the substance must be provided by a licensed dealer under Part J who is authorized to conduct regulated activities with the substance. Should the authorized manufacturer be located outside of Canada, an import permit under J.01.038 of Part J of the FDR must be obtained from Health Canada. Import permits can only be issued to a licensed dealer; this is consistent with the import of other controlled substances. To access Health Canada's application forms for licences and permits, please visit the Controlled Substances webpage. Researchers interested in finding a licensed dealer in order to conduct clinical research with psilocybin can contact the Office of Controlled Substances at the following email address: ocs-bsc@hc-sc.gc.ca.

Flexibility in the data requirements for a clinical trial application involving psilocybin

Clinical research is essential to understanding the effects of psilocybin in a therapeutic context, as well as for the development of drug products that are safe and effective. An increased availability of authorized drugs 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 drugs to patients.

When a clinical trial with psilocybin is conducted, 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 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.

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 psilocybin that is produced under GMP conditions and for which there is evidence of safe use. The IB can be based on information drawn from published literature if the sponsor is able to demonstrate how this information is applicable to their product and if it includes pre-clinical data. The information needs to be sufficient to provide supporting evidence of safe use of their product in the proposed study population. 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 investigational 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 also be acceptable for clinical trials with psilocybin if a similar product receives 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. However, applicants wishing to pursue a New Drug Submission should note that, as a rule, Health Canada generally requires product-specific toxicology data.

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 psilocybin are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their specific circumstances and requirements.

Compliance and enforcement

As part of its regulatory responsibilities, Health Canada promotes, monitors and enforces compliance with legislative and regulatory requirements related to clinical trials and activities with controlled substances and precursors. As such, Heath Canadamay conduct inspections of clinical trial sites under the authority of Section 23 of the FDA. The purpose of these inspections is to verify compliance or prevent non-compliance with the provisions of the FDA and associated regulations, particularly Part C, Division 5 of the FDR, which include the requirement to comply with GCP (C.05.010) and the applicable GMP requirements (C.05.010(j)).

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.

Health Canada also conducts compliance and enforcement activities in relation to all controlled substances and precursors and activities conducted under the CDSA and regulations. This includes activities with psilocybin used in clinical trials. Compliance monitoring and enforcement helps support the legitimate use of controlled substances for valid commercial, medical and scientific activities, and reduces the risk of diversion. For further details, please see Health Canada's Compliance and Enforcement Policy Framework, which identifies the principles that guide Health Canada in monitoring compliance and enforcement of the CDSA and its regulations.

Contact information

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

Office of Controlled Substances - Controlled Substances Directorate
Controlled Substances and Cannabis Branch
E-mail: exemption@hc-sc.gc.ca

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