Notice to stakeholders: Health Canada's expectations regarding risk-management measures for clinical trials involving psychedelic-assisted psychotherapy
- December 5, 2022
- Our file number: 22-111811-471
Health Canada recognizes the growing interest in the use of psychedelic-assisted psychotherapy and of the possible psychological and physical risks to clinical trial participants associated with this type of therapy. Because of these risks, Health Canada is publishing this notice to outline its expectations regarding the implementation of risk-management measures by clinical trial sponsors. Although there are no established clinical practice guidelines for psychedelic-assisted psychotherapy, some best practices are emerging in the literature. This document is intended to reflect these best practices.
The risk-management measures that will be used in proposed clinical trials involving psychedelic-assisted psychotherapy should be outlined in the protocol at the time of the clinical trial application (CTA). Health Canada's assessment of risk-management measures is used to inform the determination of whether the clinical trial would be in the best interests of participants, which is one of the threshold requirements to allow a clinical trial to proceed (see section C.05.006(1)(b)(ii)(B) of the Food and Drug Regulations (FDR)). Sponsors must also ensure clinical trials are conducted in accordance with Good Clinical Practices (GCP), including those mentioned in section C.05.010 of the FDR.
Risk-management measures for CTAs involving psychedelic-assisted psychotherapy
The information in this notice is relevant to all clinical trials involving psychedelic-assisted psychotherapy, including healthy volunteer studies. Currently, the psychedelic drugs most frequently being used in clinical trials in Canada are psilocybin (one of the active ingredients found in "magic mushrooms") and MDMA ("ecstasy").
Psychedelic drugs produce an altered state of consciousness that can last for hours and may affect participants' emotions. MDMA can cause an enhanced sense of well-being, increased extroversion, emotional warmth, empathy toward others, a willingness to discuss emotionally charged memories, enhanced energy, endurance, sociability, sexual arousal and sensory perception. It can also temporarily engender feelings of love and warmth. The use of psilocybin can result in a distorted sense of reality, an altered sense of time, mood changes, anxiety, confusion or fear.
Because of such effects, participants who undergo psychedelic-assisted psychotherapy may be at increased risk for psychological harm. Therefore, the following information and risk-management measures, or proposed comparable alternative risk-management strategies, should be included in CTAs for these drugs to help protect the well-being of participants. The sponsor would be required to provide Health Canada with the rationale for their proposed alternative risk-management strategy. The alternative risk-management strategy will be considered by Health Canada, at time of the review of the application, to determine its acceptability.
Expectations regarding therapists and clinical setting
Health Canada expects that, for all CTAs involving psychedelic drugs, therapists would be properly trained on evidence-informed protocols for psychedelic-assisted psychotherapy, and be licensed to provide psychotherapy by a regulatory body (if applicable in their jurisdiction). Any unlicensed members of the therapy team should be under the direct supervision of a licensed therapist. CTAs should include a full description of the qualifications of the therapists that will be recruited for the trial. Details regarding their credentials and licensing and prior training or experience with psychedelic-assisted psychotherapy should be kept in the trial master file.
Rapport between the clinical trial participant and the therapist is critical to clinical trials designed to evaluate psychedelic-assisted psychotherapy. There should be adequate sessions before and after the administration of the psychedelic drug so that trust can be built. Psychotherapy is believed to be an essential component of the therapeutic potential of psychedelic drugs.
During the phase in which the drug is being administered to the participants, there should be a minimum of two therapists present. The therapists should remain the same throughout the clinical trial for each patient in order to maintain trust. There must also be a licensed physician to provide medical oversight of the clinical trial (as per section C.05.010(f) of the FDR), and to be involved in screening potential participants to ensure that they meet the eligibility criteria to be administered psychedelic drugs. The physician must also have the authority to administer a restricted drug, and should be readily available on site for the duration of the drug's effects to provide adequate access to medical care, if necessary, and to assess the need for change in dosage regimen or optional additional dose during a session, when such a change is allowed by the protocol. This person should be identified in the CTA or in the site form, as they assume responsibility for all medical acts during the clinical trial.
A psychologically safe environment is essential for the duration of the acute drug effects. The setting under which the drug is administered can play an important role in the reduction of the psychological risk associated with the administration of the drug. Consequently, the sponsor may wish to consider selecting a room where the drug is administered that is furnished and decorated in a way that is comfortable and calming for participants. Lodging should be available on the day of the administration of the drug in cases where it is preferable to keep participants overnight to help ensure their safety. Contingency plans should be established for potential serious adverse events. There needs to be check-in visits in the days and weeks following administration of the drug due to a possible worsening of the participant's mental health following completion of psychedelic-assisted psychotherapy treatment sessions.
Throughout the clinical trial, sponsors are required to report any serious unexpected adverse drug reactions (ADRs) to Health Canada. A definition of serious unexpected ADR is provided in section C.01.001(1) of the FDR, and an example in the context of clinical trials involving psychedelic-assisted psychotherapy could be worsened symptoms of Post-Traumatic Stress Disorder or any other serious mental health condition. For more information on how to report serious unexpected ADRs during a clinical trial, please consult the Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications.
Both the physical and psychological risks of psychedelic-assisted psychotherapy should be clearly articulated in the informed consent forms given to participants. Depending on the drug used, the psychological risks may include an unpleasant psychological experience, emotional openness and suggestibility, disordered thoughts, destabilized mood, depression, suicidal thoughts and the transference and countertransference of feelings between the therapists and participants. The physical risks associated with psychedelic drugs can include an increase in heart rate and blood pressure. A copy of the statement, as it will be set out in each informed consent form, that states the risks and anticipated benefits arising to the health of clinical trial subjects as a result of their participation in the clinical trial must be included in the CTA, as per section C.05.005(b) of the FDR. Furthermore, written informed consent must be obtained from every person before that person participates in the clinical trial, but only after that person has been fully informed about the risks and benefits and all other aspects relevant to the decision to participate in the clinical trial, as per section C.05.010(h) of the FDR.
Consent for touch should be obtained prior to the administration of the investigational product, as well as in the therapeutic moment. Any physical contact between the therapist(s) and the participant must be of a non-intimate and non-sexual nature. Aside from protecting a person's body from imminent harm, such as catching them from falling, the use of touch is always optional and contingent on the consent of the participant and the applicable code of ethics.
The recording of sessions is optional; however, if the sessions are being videotaped, consent should be obtained first, including consent regarding how the tapes will be used. The protocol should clarify the need and the purpose for videotaping sessions, specify how the videotapes will be used, the frequency at which they will be reviewed, how long they will be retained, etc. Participants should be allowed to withdraw this consent at any time.
Good manufacturing practices (GMP)
It is also important to note that any investigational product (including psychedelic drugs) used in a clinical trial must meet Good Manufacturing Practices (GMP). This is a requirement under Part C, Division 5 of the FDR [C.05.010(j)]. An attestation should be provided in the CTA (either in the Quality Overall Summary or as an attachment) to confirm that the drug to be used in the clinical trial was manufactured according to GMP standards. GMP ensures that products are consistently produced and controlled according to high quality standards.
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 Canada may conduct inspections of any place where it believes regulated activity is being conducted, which can include a clinical trial site, under the authority of Section 23 of the Food and Drugs Act (FDA). The purpose of these inspections is to verify compliance or prevent non-compliance with the provisions of the FDA and associated regulations.
The Guidance Document: Part C, Division 5 of the Food and Drug Regulations "Drugs for Clinical Trials Involving Human Subjects" (GUI-0100) is available on Health Canada's website. This guidance document will help those involved in the conduct of clinical trials of drugs in human participants in Canada to comply with Part C, Division 5 of the Regulations and to understand the International Council for Harmonisation (ICH) Guidance Document: Good Clinical Practice: Integrated Addendum to E6(R1) ICH Topic E6(R2) in the Canadian context.
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 Controlled Drugs and Substances Act (CDSA) and its regulations. This includes activities with psychedelic drugs 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 for Controlled Substances and Precursors (CS-POL-001) which identifies the principles that guide Health Canada in monitoring compliance and enforcement of the CDSA and its regulations.
Sponsors who are considering undertaking a clinical trial to investigate a psychedelic drug are encouraged to request a pre-application meeting with the Office of Clinical Trials to discuss their specific circumstances and requirements.
- Office of Clinical Trials - Pharmaceutical Drugs Directorate
- Health Products and Food Branch
- E-mail: firstname.lastname@example.org
A qualified investigator looking to perform a clinical trial with a psychedelic restricted drug must apply for an authorization under the Controlled Drugs and Substances Act (i.e. Part J of the FDR) from the Office of Controlled Substances. Health Canada's webpage provides 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. Please email the Office of Controlled Substances should you have additional questions or to submit a completed application form.
- Office of Controlled Substances - Controlled Substances Directorate
- Controlled Substances and Cannabis Branch
- E-mail: email@example.com
Questions regarding Health Canada's responsibilities to promote, monitor and enforce compliance with the legislative and regulatory requirements related to clinical trials and activities with controlled substances and precursors can be directed to the Clinical Trial Compliance Program.
- Clinical Trial Compliance Program
- Regulatory Operations and Enforcement Branch
- E-mail: firstname.lastname@example.org
- Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications
- Notice to Stakeholders: Considerations regarding the proposed use of psilocybin mushrooms in clinical trials, or as a drug accessed through the Special Access Program (SAP)
- 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
- Psilocybin and psilocin (Magic Mushrooms)
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