New EMA publication reviews psychedelics trials in depression in light of EU regulatory guidance |
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Appropriately marking the start of the global Brain Awareness Week, celebrating progress in brain research, a new European Medicines Agency (EMA) paper, titled “ A review of psychedelics trials completed in depression, informed by European regulatory perspectives”, has been published. Authored by PAREA’s own Project Officer Francisca Silva during her tenure at the EMA, the paper is now freely available online in Neuroscience Applied, a journal of the European College of Neuropsychopharmacology. The piece reviews completed clinical trials investigating psychedelics for depression, focusing on methodological variables of regulatory interest such as: choice of comparators; blinding approaches; population exclusion criteria; the number, length and content of pre-dosing, dosing, and post-dosing sessions; definitions of psychotherapeutic or psychological support frameworks, and required trainings and qualifications for practitioners; and assessments, including measurements of efficacy, safety and of the subjective psychedelic experience. Crucially, the paper contextualises these findings within evolving EU regulatory perspectives on conducting clinical trials with psychedelics, namely recommendations from the new revision of the EMA guideline on the clinical investigation of products for depression. These include considerations pertaining to, for example, blinding and expectancy, population selection, the definition of “set and setting” and the characterisation of the relationship between dose, subjective psychedelic effects, and efficacy and safety. “By reviewing the trials in light of these initial regulatory considerations, I aimed both to offer a clearer picture of the status of current research, how it aligns with EU regulatory perspectives, and what lies ahead for the field.” says Francisca. Key takeaways from the paper include: - As of February 2024, there were eight completed trials of psychedelics for depression, testing psilocybin, LSD, Ayahuasca, or DMT for major depressive disorder or treatment-resistant depression. (The review excluded ongoing or prospectively registered trials and those outside the depression indication. A complete list of studies identified through a systematic search can be found in the paper’s Appendix).
- The trials were classified as phase 2 or 1/2. It was acknowledged that trials at this stage are not inherently designed to answer certain regulatory questions, such as those related to longer-term safety, efficacy, and inter-individual differences. Currently, trials exclude participants with given comorbidities and taking concomitant medications, and development is recommended in more severely affected populations, such as those with treatment resistance, limiting sample representativeness. However, larger trials and real-world evidence can address these knowledge gaps in the future.
- Methodological obstacles known to affect psychedelics trials, such as unblinding and expectancy effects, are not insurmountable and can be mitigated through design strategies like the use of independent outcomes raters and low-dose psychedelic comparators, which many trials are already employing.
- Descriptions of treatment frameworks - referring to non-pharmacological components of the intervention embedded in pre-dosing, dosing and post-dosing sessions, and associated psychotherapy or psychological support - were variable. However, newer trials have provided more detailed information, which may allow to identify common threads in these approaches.
- The importance of enhanced definitions of adverse events, especially in relation to subjective psychedelic effects, and incorporation of long-term safety approaches was highlighted, with PsyPal cited as an example.
While challenges exist in the development and implementation of psychedelic medicines - with clinical investigation being just one piece of the puzzle - the review emphasises that these can be addressed through careful design of development programmes and early regulatory support. This publication once more signals the EMA's openness towards the evidence-based development of psychedelic therapies. |
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