FDA guidance summary: Considerations for psychedelic clinical investigations
Here’s a summary of the recently released FDA guidance on psychedelic drug development programs. The full document can be found here.
Introduction
This guidance provides general considerations to sponsors. These are not legally enforceable responsibilities, but rather they describe the FDA’s current thinking on a topic and should be viewed as recommendations.
Because this is an emerging area of drug development, there is limited experience configuring programs that support approval of psychedelics. This guidance offers foundational constructs that sponsors should consider.
Psychedelic drug development programs are subject to the same regulations and standards for approval as other drug development programs. However, designing studies to evaluate safety and effectiveness of these compounds presents unique challenges.
Discussion
Chemistry, Manufacturing, and Controls
Chemistry data submitted by a sponsor to FDA may be proprietary. In general, sponsors interested in researching a psychedelic under an IND must either submit their own information or incorporate information previously submitted by a person other than the sponsor when the sponsor has a right of reference for such information.
If using plant material, algae, or macroscopic fungi, the investigational product may be considered a botanical. Although some psychedelic compounds are derived from plants or fungi, drug products that are genetically modified; produced by fermentation of yeast, bacteria, or plant cells; or highly purified substances from natural sources are not botanicals.
Drugs must be manufactured in compliance with current good manufacturing practice. Each phase of the investigation requires sufficient information to ensure identification, purity, and strength of the investigational drug substance and drug product.
Nonclincal
The nonclinical program for psychedelics should follow ICH guidance. However, the following considerations may be unique to psychedelic drugs:
It may be reasonable for some psychedelic studies to be initiated under an IND without the typical animal toxicology testing when extensive human exposure and information are available from previous research and no serious safety concerns were identified.
Although current psychedelic drug development programs are single-dose or intermittent-dose, most of the conditions being studied are chronic. Nonclinical studies to support chronic or chronic-intermittent dosing should be provided if the treatment effect is not durable and repeat dosing is expected.
A thorough evaluation of binding to 5-HT receptor subtypes should be conducted. Binding to 5-HT2B receptors has been linked to heart valvulopathy in humans; If using 5-HT2B agonist, microscopic evaluation of the heart should be conducted in repeat-dose toxicity studies.
Clinical Pharmacology
Sponsors should consider the following clinical pharmacology aspects:
The effect of a high-fat meal on the pharmacokinetics of an oral psychedelic drug early in development to inform clinical study design
Potential drug-drug and drug-disease interactions to inform inclusion/exclusion criteria and prohibited concomitant medications. For example:
Chronic use of SSRIS or MAOIs may reduce the effect of psychedelics.
Chronic use of TCAs or lithium and acute use of SSRIs or MAOIs may potentiate effects.
Long-term exposure to 5-HT2B agonists may induce cardiac valve stiffening. Currently, FDA recommends excluding subjects with valvulopathy or pulmonary hypertension from multiple-dose studies of drugs with this mechanism until this risk is better characterized.
The dose-response relationship for most psychedelics is poorly understood. Sponsors should take appropriate steps to characterize this relationship, for efficacy and safety.
Abuse Potential Assessment
Because psychedelic drugs act on the CNS and many are controlled substances, they must be evaluated for abuse potential during drug development.
Data from the abuse potential assessment and a proposal for drug scheduling under the Controlled Substances Act is required in new drug applications. Should a Schedule 1 psychedelic receive FDA approval, this would assist in rescheduling.
For Schedule I psychedelics, activities must comply with DEA regulations for research, manufacturing, importing/exporting, handling, and storage. The investigator(s) must have a DEA Schedule I registration before initiating nonclinical and clinical studies. Authorization to conduct the research is required for each specific protocol and may need to be supplemented for protocol amendments.
When appropriate, sponsors should use scientifically valid, published research to support the abuse potential assessment. For psychedelics that are not well-characterized, sponsors should conduct a full abuse potential assessment before submitting a new drug application.
An evaluation of psychedelic responses that occur during clinical studies should be obtained through the inclusion of validated subjective scales and monitoring of abuse-related AEs, such as euphoria, hallucinations, stimulation, and emotional lability.
Abuse-related AEs are monitored and reported as a safety concern even if they are hypothesized to be associated with therapeutic response. Investigators and session monitors should be trained to record all abuse-related AEs, including psychedelic ones.
Clinical
Adequate and well-controlled (AWC) clinical studies are required to meet the substantial evidence standard to establish effectiveness in a marketing application. However, the characteristics of psychedelic drugs present challenges in designing AWC studies:
An AWC study uses a design that allows valid comparison with a control. In psychedelic studies, traditional placebos can be problematic. Subjects receiving an active drug can experience functional unblinding because of intense perceptual changes; those given placebo in the context of high expectancy may experience a nocebo effect. An inactive control allows for better contextualization of safety findings. Alternatives to an inert placebo (e.g., sub-perceptual doses of a psychedelic, other psychoactive drugs that mimic aspects of the psychedelic experience) may be considered as well.
In AWC studies, adequate measures are taken to minimize bias. Sponsors should consider the use of video or central raters blinded to treatment allocation and visit number. Blinding questionnaires for subjects and investigators/raters can help evaluate the impact of functional unblinding.
Trial designs across phases 2 and 3 could address different challenges. For example, a trial using a low, middle, and high dose without placebo could be paired with a placebo controlled trial. The trial without a placebo could offer data about dose-response without risk of nocebo effect. The placebo-controlled trial allows better evaluation of safety.
Many psychedelic drug development programs involve administering the drug and then engaging in psychological support or psychotherapy. This additional variable complicates the assessment of effectiveness and presents a challenge for future labeling.
As of the publication date of this guidance, contribution of the psychotherapy component to any efficacy observed with psychedelic treatment has not been characterized.
Psychotherapy interventions have the potential to increase expectancy and performance biases. Sponsors should plan to justify the inclusion of a psychotherapy component and describe trial design elements intended to reduce potential bias or to quantify the contribution of psychotherapy to the treatment effect.
The therapist monitoring the session can usually deduce the treatment assignment by observing the subject’s behavior. Therefore, it is preferable that the session monitor is not involved in post-session psychotherapy because their knowledge of the treatment could bias the delivery of subsequent therapy.
Subjects receiving active treatment with psychedelic drugs remain in a vulnerable state for as long as 12 hours. As such, safety monitoring should include the following:
Observation by two monitors for the duration of the treatment session. If the lead monitor is not a physician, availability of a licensed on-call physician able to reach the clinical site within 15 minutes in the event of a medical emergency.
A healthcare provider with graduate-level training and experience in psychotherapy, licensed to practice independently, serving as the lead monitor. For example:
— Clinical or counseling psychologist (PhD or PsyD)
— Psychiatrist or other physician (MD or DO)
— Master of Social Work (MSW)
— Licensed Clinical Professional Counselor (LCPC)
— Licensed Marriage and Family Therapist (LMFT)
— Psychiatric Nurse Practitioner (Psychiatric NP)
— An assistant monitor with a bachelor’s degree and at least 1 year of clinical experience in a licensed mental healthcare setting
Informed consent should clearly describe that subjects may experience changes in perception, cognition, and judgment that persist for many hours, as well as increased vulnerability and suggestibility during the treatment session.
Sponsors should characterize the durability of response, recommended interdose interval for maintenance of effect, and safety/efficacy of repeat dosing. At a minimum, for treating chronic illnesses like PTSD or MDD, sponsors should evaluate treatment effect at 12 weeks. However, they should follow subjects in an open label extension period for a year beyond Week 12 to monitor for symptom recurrence or, potentially, the need for repeat dosing.
For drugs with functional activity at the 5-HT2B receptor, baseline and follow-up ECGs should be included when drug will be chronically administered. In general, patients with preexisting valvulopathy or pulmonary hypertension should be excluded until the cardiac risk has been characterized.
Sponsors should address how AEs or serious risks are mitigated during the study and if similar strategies can be implemented post marketing. They should consider where the drug would be dispensed and administered if approved and whether gaps exist in the health care system regarding safety. For most drugs, routine risk mitigation measures are sufficient, but FDA may require a REMS to ensure benefits of the drug outweigh risks.
FDA may consider the public health effects of the drug as part of the overall benefit-risk assessment. Public health effects include the drug’s potential effect on risks related to nonmedical use, substance abuse, accidental exposure, and overdose.
