European regulatory perspectives on psychedelics - new paper offers consolidated EMA viewpoints
A new paper by the European Medicines Agency (EMA) and the broader European regulatory network has been published in ACS Pharmacology & Translational Science. Among the co-authors is PAREA’s Project Officer, Francisca Silva.
The article, titled “Applying the EU Regulatory Framework to Determine the Benefit−Risk Profile of Psychedelics”, consolidates regulatory insights gained from the EMA’s 2024 Multi-Stakeholder Workshop on Psychedelics and over the development of the psychedelics section in the revised EMA guideline for depression, which comes into force later this month.
PAREA actively contributed to this guideline, submitting several comments during the draft public consultation phase - which were recently published by the EMA - that helped shape the final document.
The paper represents the most comprehensive articulation to date of EMA's perspective on psychedelic medicines. It begins by clarifying the scope and limits of EMA’s remit, noting that issues such as health technology assessment (HTA), the regulation of psychotherapy, and the scheduling of psychedelic substances fall outside its authority. It then explores the methodological challenges, including existing knowledge gaps, and safety considerations in psychedelic drug development and application, and practical suggestions to address them. It finishes by outlining regulatory support tools and platforms available to developers.
Notable takeaways:
While not introducing radically new positions, the paper goes into unprecedented detail on the guidance mentioned in earlier EMA publications regarding methodological challenges. Namely:
It provides concrete examples of instruments that could be used—and how—to assess functional unblinding and expectancy effects, including validated blinding questionnaires. It also draws on the example of the Spravato development programme to illustrate how significant functional unblinding can be addressed in clinical development, notably through the use of independent, blinded raters.
It clarifies the regulatory implications of programmes that incorporate either psychological support or psychotherapy, and acknowledges the challenges of conducting factorial trials to determine the added benefit of conjunct psychotherapy. The paper indicates openness to the use of alternative multi-arm trial designs.
The paper also provides a higher level of detail on safety data collection, emphasising the importance of establishing consensus around the reporting of adverse events related to the subjective experience, both during and after dosing. It highlights the need to clearly distinguish between transient psychological effects and adverse events, and stresses the value of standardised, validated instruments to capture this information. The authors also suggest that all occurrences during the subjective experience—regardless of whether they are considered integral to treatment—should be systematically characterised and, if they require clinical intervention or lead to lasting difficulties, retrospectively classified as adverse events.
While the collection of “positive” adverse events is not specifically mentioned (relevant given the context of the recently issued FDA Complete Response Letter to Lykos Therapeutics on their MDMA-assisted psychotherapy application), the paper reinforces the importance of a comprehensive understanding and documentation of subjective effects in order to adequately inform patients and clinicians of what to expect during treatment. This could also support the identification of predictors for both treatment response and persistent adverse experiences.
While previous outputs had been written within the context of treatment of depression, this paper confirms these considerations are relevant to development in other therapeutic indications, although methodological choices must always be adapted to the specific characteristics of the target patient population. A phased development approach, beginning with populations with the highest unmet need, is broadly supported.
The paper also offers important guidance on the development of risk management plans (RMPs), which are a required component of any marketing authorisation application. In addition to routine pharmacovigilance activities and other real-world safety measures, it highlights the importance of considering additional risk minimisation measures, such as post-authorisation safety studies, educational materials, and controlled access programmes—once again drawing on precedent from Spravato.
The EMA has repeatedly emphasised the importance of early dialogue to address questions pertaining to psychedelics’ development and ensure they are adhering to European regulatory standards. These scientific interactions are also useful to promote bidirectional learning about emerging treatment modalities.
Complementary to the platforms for developers outlined in the paper, the EMA has recently updated its Academia webpage, explaining the forms of support available to academic and non-profit stakeholders.
