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Unpacking FDA’s Draft Guidance on Psychedelic Research for Clinical Success

Unpacking FDA’s Draft Guidance on Psychedelic Research for Clinical Success

June 26, 2023, marked a historic moment. On this day, the U.S. Food and Drug Administration (FDA) released a draft guidance document titled, “Psychedelic Drugs: Considerations for Clinical Investigations Guidance for Industry.”  

This guidance is poised to reshape the approach clinical development professionals take to psychedelic drug development, with insights into the treatment of various medical conditions, including psychiatric and substance use disorders. 


Background on Psychedelic Research

Recent years have witnessed a resurgence of interest in psychedelic research, punctuated by noteworthy milestones, and influenced by FDA’s guidance. The 1960s marked the counterculture movement, followed by the 1970 criminalization of psychedelics under the Controlled Substances Act. However, the early 2000s saw a revival, with significant events such as Johns Hopkins University’s pioneering study on psilocybin in 2006 and FDA’s granting of breakthrough therapy designations for MDMA (3,4-methylenedioxymethamphetamine) and psilocybin in the treatment of post-traumatic stress disorder (PTSD) and depression. 

In 2020, FDA’s approval of Phase 3 clinical trials for MDMA-assisted therapy for PTSD was a pivotal moment. In 2022, COMPASS Pathways initiated the first-ever global Phase 3 program for psilocybin therapy in treatment-resistant depression. Furthermore, in September 2023, MAPS announced a second positive Phase 3 trial for MDMA-assisted therapy for PTSD, with plans to file a New Drug Application (NDA) in the same year. 

These are just a few highlights. The metrics in psychedelic clinical research from 2013 to the present day are impressive. There have been an impressive 90 completed trials, signifying a substantial and growing body of research in this field. Of these, 36 trials were sponsored by industry or cooperative groups, demonstrating increasing interest and investment from both the private sector and collaborative research efforts. Additionally, 13 multi-center trials have been conducted, highlighting a collaborative and multi-faceted approach to psychedelic research, involving multiple institutions and researchers. 

These metrics underscore the expanding scope and significance of psychedelic clinical research in contemporary medical science. 


FDA Guidance on Psychedelic Clinical Research

FDA’s guidance, focusing on psilocybin, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA), underscores its recognition of their therapeutic potential and willingness to collaborate with researchers in this unique area of drug development. 

Recognizing this novelty, FDA’s guidance refrains from offering a step-by-step manual for study design. Instead, it establishes a robust framework, organized by discipline, to guide sponsors in exploring the therapeutic potential of psychedelic drugs. This approach reflects FDA’s commitment to promoting responsible and effective development in this groundbreaking field of medicine, recognizing the need for specialized guidance in this innovative space. 

"By publishing this draft guidance, FDA hopes to outline the challenges inherent in designing psychedelic drug development programs and provide information on how to address these challenges. The goal is to help researchers design studies that will yield interpretable results capable of supporting future drug applications.”

Tiffany Farchione, M.D.
Director of the Division of Psychiatry in FDA’s Center for Drug Evaluation and Research


Considerations for Researchers Investigating Controlled Substances

FDA’s draft guidance offers practical insights into the drug development process, encompassing trial conduct, data collection, subject safety, and new drug application requirements. For psychedelics classified as Schedule I controlled substances, adherence to Drug Enforcement Administration regulations is paramount during investigations conducted under an Investigational New Drug Application (IND). 

Importantly, the draft guidance from FDA identifies five critical domains: Chemistry, Manufacturing, and Controls; Nonclinical; Clinical Pharmacology; Abuse Potential Assessment; and Clinical.  

We offer a high-level summary of each of these considerations, illuminating FDA’s commitment to fostering responsible and effective development in this groundbreaking field of medicine. 

1. Chemistry, Manufacturing, and Controls

The guidance provides an overview of the CMC requirements for psychedelic drugs. It emphasizes the importance of strict adherence to current good manufacturing practice (cGMP) under section 501(a)(2)(b) of the Federal Food, Drug, and Cosmetic Act, ensuring the highest product quality standards. 

Sponsors interested in researching psychedelic drugs under an IND must submit their own information or incorporate previously submitted data. When dealing with psychedelic drugs derived from plant material, algae, or fungi, these investigational products may be classified as botanicals. However, it is important to understand that genetically modified psychedelic compounds, those produced through fermentation of yeast, bacteria, or plant cells, or highly purified substances from naturally occurring sources are not considered botanicals. 

These distinctions highlight the need for precise classification to ensure consistent quality, purity, and strength in psychedelic drug development, especially when dealing with substances derived from botanical sources. 

2. Nonclinical psychedelic drug development 

In nonclinical testing for psychedelic drug development, FDA relies on the International Council for Harmonisation (ICH) guideline M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals,’ which was adopted in 2010. This guideline serves as a foundational reference for nonclinical safety assessments in drug development. 

FDA’s draft guidance, specific to psychedelic drug development, builds upon this framework and introduces additional considerations. Notably, it highlights a scenario where typical animal toxicology testing may not be obligatory. This exception arises when there is extensive human exposure data available from previously conducted clinical studies, and no serious safety concerns were identified. However, for psychedelic drugs lacking a history of adequate clinical exposure, it is crucial to establish safety through nonclinical studies before initiating human trials. 

Furthermore, FDA underscores the necessity of a comprehensive evaluation of binding to serotonin (5-HT) receptor subtypes, particularly emphasizing the 5-HT2B receptor subtype. This receptor subtype is associated with heart valvulopathy in humans. In cases where the investigational drug exhibits agonistic activity at 5-HT2B receptors, the guidance recommends an extensive microscopic evaluation. This evaluation should encompass heart valve sectioning in both rodent and non-rodent repeat-dose toxicity studies to assess the potential risk of heart valve thickening. 

FDA also expressed concerns regarding long-term exposure to 5-HT2B agonists and advises excluding subjects with pre-existing valvulopathy or pulmonary hypertension from multiple-dose studies until a more comprehensive understanding of these risks is achieved. It is further recommended to conduct baseline and follow-up echocardiograms to assess valve structure, function, and pulmonary artery pressures. 

Lastly, the length and scope of nonclinical studies should align with the nature of the proposed clinical investigations. This consideration is vital, particularly for conditions that necessitate chronic or chronic-intermittent dosing, ensuring that the durability of the treatment effect is substantiated through repeat dosing studies. 


3. Clinical Pharmacology of Psychedelic Therapies 

FDA emphasizes several critical areas in clinical pharmacology. Researchers should assess how a high-fat meal affects the pharmacokinetics of oral psychedelic drugs early in development. This assessment, conducted in the early stages, can provide valuable insights that may necessitate adjustments to the clinical study design to ensure accurate results and safe administration of the drug. 

It is imperative to investigate potential drug interactions involving psychedelic drugs. This includes evaluating interactions with cytochrome P450 enzymes and transporters that could impact the metabolism of psychedelic substances like LSD. Additionally, gastric pH-dependent interactions with acid-reducing agents should be examined to understand their effects on substances like psilocybin. 

FDA underscores the importance of considering drug interactions stemming from the chronic use of selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, or lithium. These interactions can either diminish or potentiate the effects of psychedelic drugs, necessitating careful consideration in clinical study design, inclusion and exclusion criteria, and potential labeling. 

Lastly, FDA recommends that sponsors take steps to characterize the dose-response relationship for psychedelic drugs. This is a crucial aspect to understand both for the drug’s efficacy and safety. Given that the dose-response relationship remains poorly understood for many psychedelic substances, this consideration is vital for ensuring the safe and effective development of these drugs in clinical settings. 

4. Abuse Potential for Controlled Substances 

FDA places a strong emphasis on evaluating the abuse potential of psychedelic drugs during the drug development process. To guide this crucial assessment, FDA recommends referring to its comprehensive 2017 guidance document titled ‘Assessment of Abuse Potential of Drugs,’ which provides detailed instructions and guidelines for conducting abuse potential assessments. 

In general, the agency advises sponsors to rely on scientifically valid published investigations to substantiate the abuse potential assessment, unless the investigational drug lacks sufficient characterization from previous preclinical and clinical studies. This underscores the importance of robust data and research in understanding the potential for abuse associated with psychedelic drugs. 

When it comes to clinical safety reporting, it is imperative to track and report all abuse-related adverse events, including phenomena such as euphoria, hallucinations, stimulation, and emotional lability. Even if these events are hypothesized to be associated with the therapeutic response, they should be monitored and reported as safety concerns. 

Moreover, it is recommended that studies related to abuse potential and dependence be conducted after determining the therapeutic dose range, typically following the completion of Phase 2 clinical studies. This sequential approach ensures that abuse potential is comprehensively assessed in alignment with the drug’s clinical development stages. 

Sponsors are encouraged to initiate discussions with FDA early in the IND stage of drug development to outline their plans for an abuse potential assessment, reflecting the agency’s commitment to responsible and rigorous evaluation of psychedelic drugs. 


5. Clinical Application of Psychedelic Drugs 

FDA acknowledges that the unique characteristics of psychedelic drugs pose challenges when designing adequate and well-controlled clinical studies. One of the primary challenges is related to the use of inert placebos, which may not be suitable for assessing efficacy in this context. FDA recommends considering alternatives to traditional placebos, such as inactive controls that provide better contextualization of safety findings or sub-perceptual doses of psychedelic drugs or psychoactive substances that mimic certain aspects of the psychedelic experience. 

Moreover, the incorporation of psychological support or psychotherapy during or after the subject’s psychedelic experience is highlighted as a complex factor that can complicate both the assessment of effectiveness and product labeling. These considerations underscore the need for innovative trial designs that address the unique challenges posed by psychedelic drugs. 

Additionally, FDA emphasizes the importance of safety monitoring during clinical trials involving psychedelic drugs. Failure to adhere to FDA-recommended safety monitoring may result in a clinical hold. Subjects receiving active treatment with psychedelic drugs are considered vulnerable for up to 12 hours, necessitating stringent safety measures. This includes the presence of two monitors: a healthcare provider with graduate-level training and clinical experience in psychotherapy and an assistant monitor with a bachelor’s degree and at least one year of clinical experience in a licensed mental healthcare setting. 

To mitigate potential bias, FDA recommends that the monitor overseeing active treatment not be involved in the post-treatment psychotherapy session. However, it is important to consider the potential cost implications and availability of trained personnel, given the shortage of mental healthcare providers. 

FDA recommends a factorial study design to separate the efficacy of the psychedelic substance from the psychotherapy component, particularly in psychedelic-assisted psychotherapy studies. This design entails running four arms of the trial: psychedelic with psychotherapy, psychedelic alone, placebo with psychotherapy, and placebo alone. While this approach offers a comprehensive evaluation, it may increase the cost of conducting psychedelic clinical trials due to the need to recruit more subjects to accommodate multiple interventions. 

Lastly, for chronic illnesses, FDA recommends evaluating treatment effects at 12 weeks and maintaining a year-long open-label extension period beyond the Week 12 endpoint to monitor for symptom recurrence or the need for repeat dosing. These considerations are vital for clinical development professionals navigating the intricacies of psychedelic drug trials and align with FDA’s commitment to ensuring the safe and effective development of these innovative therapies. 


Looking Ahead 

The United States continues to dominate planned clinical development activities for psychedelic drugs Graph 1). There is a growing interest in exploring new potential indications, including substance use disorders such as alcohol and opioid addiction, nicotine dependence, pain (particularly cancer-related pain), attention-deficit/hyperactivity disorder, and even stroke. However, several continuing challenges and new opportunities exist in this evolving landscape. 

Psychedelic clinical trialsGraph 1: Psychedelic Clinical Trials by Country 

One challenge is the need to expand the pool of research sites, as there is a limited number of experienced sites, and few have significant relevant trial experience in the field. Preparing for potential first approvals and subsequent off-label use is another consideration that requires careful planning. To reduce the burden of on-site personnel, clinical development professionals are encouraged to explore the use of decentralized clinical trial solutions for open-label follow-up periods, potentially streamlining the research process. 

Additionally, there is ongoing research into the development of next-generation therapeutics that aim to minimize the subjective effects of psychedelic drugs while preserving their therapeutic benefits. This approach addresses concerns related to abuse potential and has the potential to reduce overall healthcare costs and burdens. 

It is important to note that FDA’s draft guidance is primarily based on research conducted using classic psychedelic substances like psilocybin, LSD, and MDMA. As the field continues evolving, we may see further guidance specific to next-generation psychedelic-inspired medications that aim to reduce subjective psychedelic effects while preserving therapeutic benefit. As more research unfolds, additional tailored guidance may emerge. 

Partnering for Success in Psychedelic Drug Development 

Clinical development professionals must stay attuned to these evolving trends and challenges as they respond to the dynamic landscape of psychedelic drug development. At Precision for Medicine, we help you navigate the evolving landscape of clinical product development, including psychedelics. Learn more about expertise and support capabilities to help you successfully manage the unique challenges and opportunities of developing psychedelic therapies.  

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