Contract research organization (CRO) Emmes has extensive experience of conducting such trials for pharmaceutical companies and leading non-profit organizations.
With interest in exploring the therapeutic potential of psychedelic drugs peaking, the company says the process of designing clinical trials to evaluate these compounds presents distinctive challenges. In response to the evolving landscape, the FDA has taken steps to develop draft guidance aimed at outlining essential considerations for sponsors embarking on clinical trials involving psychedelic substances.
Outsourcing Pharma had the opportunity to engage in a conversation with Steffanie Wilson (SW), vice president, director of neuroscience therapeutic research unit and Dominic Ippolito (DI) project leader, clinical research at Emmes.
This was set up to explore the implications of the FDA's draft guidance for advancing these unique therapies to patients who stand to benefit the most. Furthermore, the conversation delved into how the regulatory environment surrounding these therapies has evolved in response to the growing interest and research in the field.
OSP: Could you shed some light on why the FDA has introduced these guidelines? Are similar guidelines typically applied to all drug categories, or is this specific to psychedelics?
SW: Certainly. While the FDA regularly releases guidance for various drug classes and research areas, it's important to note that the draft guidance for psychedelics is tailored to address the distinct challenges associated with conducting research involving psychedelic substances.
OSP: What distinguishes trials for these substances from trials involving other drug types?
DI: Well, trials involving some psychedelic compounds present some unique challenges compared to trials with other drug types. One of the key distinctions is something called ‘functional unblinding’. Essentially, when someone takes a psychedelic, it's pretty evident that they are experiencing its effects. Similarly, if someone is assigned to the placebo group, they can usually tell they haven't received the active substance. This can create challenges in maintaining a well-controlled study because when functional unblinding occurs, it's challenging to ensure that the study results aren't biased.
Another challenge is the presence of expectancy bias. With all the recent attention and excitement surrounding psychedelics, participants in these trials often come in with high expectations, believing they will receive a psychedelic and experience therapeutic benefits. Managing these preconceived notions can be tricky.
Safety considerations are paramount as well. When individuals are given a perceptual dose of a psychedelic drug, they can enter a state of impairment where their inhibitions are lowered, making them more suggestible. The FDA's draft guidance addresses this by suggesting the presence of a second monitor during psychedelic drug sessions in clinical trials.
Psychotherapy plays a crucial role in many ongoing psychedelic studies. This approach, often referred to as ‘Psychedelic-assisted psychotherapy’, involves a period of psychotherapy before and after psychedelic dosing. While many believe this model is vital for achieving therapeutic benefits, it's also challenging to separate the effects of psychotherapy from the effects of the psychedelics themselves. The draft guidance acknowledges this complexity and the need to navigate it effectively.
Additionally, there's the issue of abuse potential and rescheduling. Most commonly studied psychedelics are classified as Schedule I drugs in the United States, meaning they can't be prescribed for any medical purpose. To address this, ongoing trials need to assess the abuse potential of psychedelics thoroughly. This aspect is a focal point in the current draft guidance, and it's an essential factor considered when determining whether a drug should be rescheduled.
OSP: What motivated Emmes to provide feedback on these proposed guidelines? Were there specific areas you found lacking or needing clarification?
SW: Emmes' decision to provide feedback on the proposed FDA guidelines stems from several motivating factors. Firstly, while psychedelic research has experienced a resurgence in recent years, this marks the first instance where the FDA has directly shared its insights on how research in this domain can be structured to align with the agency's priorities. Given Emmes' involvement in psychedelic research over several years, we saw this as a valuable opportunity to contribute our wealth of experience and engage in a meaningful dialogue with the FDA.
Overall, we find the guidance to be largely agreeable and effective in addressing many of the challenges unique to psychedelic research. However, we identified a few areas where additional clarification would be beneficial, and these suggestions are reflected in the comments we have submitted to the FDA.
To give you a few examples, the guidance mentions additional requirements for trials involving chronic dosing of psychedelics but does not provide specifics on what constitutes ‘chronic’ dosing. We suggest that clear definitions in this regard would be helpful for sponsors, especially during the initial planning stages.
The issue of functional unblinding has been mentioned in the document, and while some suggestions are offered, we noted that some alternate study design approaches (e.g. wait list-crossover study design) was not included in the guidance. We were curious for FDA’s perspective on these types of approaches in psychedelic research.
Some suggestions we made were on the operational aspects. The guidance mandates the presence of multiple individuals during dosing sessions. While the reasons for this are understood, we were curious if FDA would be willing to entertain possibilities that may help with the operational burden of this approach, such as having the second monitor being involved via video conference. To this end, we feel it will be helpful to clarify what ‘observation’ by monitors means.
Lastly, the guidance does a good job of outlining the challenges of being able to determine the effects of psychotherapy vs. the effects of the psychedelic being studied. Many of the recommendations in the guidance stem from this, but we also know that there are many psychedelic-assisted psychotherapy treatment models being studied. One can find examples of this study design for indications such as alcohol use disorder. As this is the model intended for real-world implementation, we were curious for FDA’s opinion on whether this type of design will be acceptable in their view. Having said that, this will likely to be an area of ongoing discussion within the field.
OSP: From your perspective, what are some of the potential benefits that could result from these proposed guidelines?
DI: Well, this draft guidance essentially provides us with a roadmap of FDA's priorities, something we didn't have access to before. This is immensely valuable for the entire field, as it not only guides our interactions with the FDA but also shapes early discussions, such as pre-IND meetings. It's a significant step forward for the industry.
OSP: Beyond the current investigated indications, such as the success of psilocybin in severe treatment-resistant depression, major depression, and PTSD, are there other areas where psychedelics might exhibit therapeutic potential?
DI: Absolutely, there's a growing interest in exploring the therapeutic potential of psychedelics in various other indications. Substance use disorders are of significant interest and there is also a growing interest in neurological indications such as headache disorders. It's a fascinating and evolving field of research.
OSP: How might these guidelines influence outsourcing strategies within the psychedelic sector?
SW: Well, these guidelines are poised to make a significant impact. First and foremost, they bring clarity and standardization to the process of conducting psychedelic trials. They lay out the regulatory expectations and requirements for all the key players, including sponsors and CROs. This newfound clarity is a game-changer, as it helps sponsors and CROs align their strategies with regulatory compliance, effectively reducing uncertainties in the outsourcing decisions.
Moreover, these guidelines underscore the importance of maintaining high-quality standards and regulatory compliance, a critical factor in the psychedelic sector where safety and efficacy data hold immense significance. Statistical challenges are quite complex, especially in psychedelic research. That's where specialized expertise comes into play. Sponsors would do well to consider partnering with CROs that have a proven track record and in-depth knowledge of the intricacies of psychedelic research.