EMA’s New Draft Guideline for the Clinical Investigation of Depression Medicines Includes Section on Psychedelics

The European Medicines Agency’s latest draft Guideline (PDF) on the clinical investigation of medicinal products for the treatment of depression includes a section on psychedelics. We first covered this forthcoming section back in March, when lead editor Marion Haberkamp mentioned that the new section would feature in the draft Guideline at ECNP’s New Frontiers gathering.

The “repurposing of psychedelics”, along with other rapid-acting antidepressants (RAADs), necessitates “separate design strategies”, the document’s executive summary notes. As such, the update to the Guideline provides a new section that covers issues that psychedelic drug developers should consider.

EMA refers to a “new paradigm of psychedelic assisted psychotherapy in the field of MDD”, adding that psychedelics “are currently being recognised in psychiatry as potential treatment options to treat various medical conditions including depression.”

The document states that psychedelic-assisted psychotherapy¹ “faces several challenges mainly related to standardisation, training, monitoring and safety that need to be addressed in specific study designs”.

In terms of the draft guidance, the document notes that—consistent with “all other antidepressants”—double-blind placebo-controlled short-term trials are needed to establish a positive risk-benefit profile, along with trials geared toward establishing the durability of effect.

The draft guidance—which is concise, at around a page long—then details a half-dozen challenges that may be encountered in psychedelic clinical trials.

The first such challenge is most likely the least surprising: the fact that maintaining blind (and thus the primary intended utility of placebo control) can be difficult. The second point is closely related, as it focuses on positive expectancy which can lead to both an “overestimation bias” as well as negative expectancy or a nocebo effect in those that guess that they are not assigned to the active arm. The draft Guideline suggests that strategies such as employing a low-dose or active placebo, or enlisting independent and blinded external raters, might go some way to overcoming these challenges. Interestingly, EMA does not recommend swapping-out facilitators/monitors after the dosing session, which the FDA included in its own draft guidance (to much chagrin!).

The draft guidance also suggests that investigators should seek to characterise a dose-effect relationship. In the case of psychedelics, “the relationship between characteristics of the acute psychedelic experience and clinical improvement” should also be investigated. So too, the draft Guideline notes, should the need for “individualised dosing due to inter-individual variability in drug metabolism, age, sex, or personality”.

Maintenance of effect is the subject of the next point, which reminds sponsors that they need to demonstrate both durability of effects as well as any need for recurrent dosing. On the topic of psychedelic therapies, the draft notes that data on this topic is “very limited”.

Safety is the focus of the next point, which notes that the “ability to change the perception of reality can have unknown implications for depressed patients”, such as anxiety, derealisation and “negative trips”. Other adverse events such as headaches, elevated blood pressure and heart rate, and suicidality are also mentioned as having been reported with the use of psychedelics. “That”, the draft states, “is why psychedelics need to be administered in a controlled environment.”

Unsurprisingly, the draft Guideline notes that drug-drug interactions, at least in the case of regular co-administration, need to be characterised. Interestingly, the safety-related guidance ends by mentioning that “long half-life psychedelics may require long surveillance which can be burdensome for patients, physicians and health care systems.”

Finally, the psychedelics-specific guidance looks at the role of psychotherapy. “The monotherapy setting with psychedelics alone may not be applicable or feasible”, it begins, before noting that the use of psychedelics as therapeutics “is usually embedded in a non-directive psychological support.”

EMA says that trials “need to be able to demonstrate that the effect of the psychedelic assisted therapy is not due to the psychotherapy alone.” The protocol used, including preparatory and integration sessions, should be clearly defined; including where this may need to be tailored to the type of psychedelic administered. “Type, length and frequency of psychotherapy and training need to be standardised to the maximum possible effect, despite ethnic and cultural differences”, the draft Guideline continues. EMA’s expectation of standardisation goes beyond the trial setting and into clinical practice. On this note, the agency expects sponsors to devise a plan to “provide specific training to therapists”.

In closing its psychedelics guidance, EMA encourages sponsors to seek scientific advice prior to initiating their clinical development program. For those that aren’t familiar, ‘scientific advice’ is a facility through which EMA responds to specific questions posed by sponsors.

As we noted in our Dispatch from ECNP earlier this year, uptake of this offering is very low in the psychiatric disease category:

But, drug developers need not navigate these challenges alone, at least with regards to the EMA. Haberkamp was keen to point out statistics on uptake of the EMA’s scientific advice facility, which show a very low level of interaction between EMA and drug developers in the psychiatric diseases category versus, say, infectious diseases.

“Scientific Advice and early dialogue is recommended and is probably helpful”, her slides read. More psychedelic drug developers might be wise to take up the EMA on its offer of advice!

There aren’t any nasty surprises for psychedelic drug developers in this draft Guideline, which summarises the more well-known challenges that sponsors and investigators face. It’s also similar to FDA’s draft guidance in many respects.

There are some notable differences, however. As aforementioned, EMA has (perhaps wisely) steered clear of suggesting sponsors use different facilitators/monitors for integration sessions in an attempt to reduce biases.

EMA also avoids discussing potential risks associated with chronic 5-HT2B agonism, which FDA mentioned a number of times in its draft guidance and prescribed “a thorough evaluation of [receptor subtype] binding” and activity as well as the exclusion of subjects with preexisting valvulopathy or pulmonary hypertension from multiple-dose studies and potentially the inclusion of baseline and follow-up echocardiograms for chronic administration studies (though, “chronic” is as-yet defined). EMA did note that “cardiovascular effects” should be monitored, though this is most likely referring to acute effects during dosing sessions.

However, FDA’s draft guidance goes into much more detail than EMA’s, including guidance on areas like Chemistry, Manufacturing, and Controls (CMC) and preclinical matters. So, any omissions in EMA’s draft Guideline might be best chalked up to brevity, in many cases. (Indeed, the primary focus of the EMA draft Guideline is the clinical investigation of Depression therapeutics, with psychedelics being just one subset of RAADs.)

EMA’s draft Guideline, though shorter, draws some focus to the logistical difficulties that may be encountered in scaling psychedelics due to monitoring requirements (especially in the case of “long half-life” molecules) as well as training therapists.

Psychedelic drug developers are likely to find other updates to the Guidance relevant, such as EMA’s updates to several aspects for trial designs in ‘difficult to treat’ patients and those targeting sub-domains of depression; requirements for new rapid acting therapies; and, monitoring “the degree of suicidal thoughts and behaviour and their change […] with antidepressant therapy by use of validated instruments”.

The draft Guideline is now open to public consultation, which closes on the 31st of March 2024. Comments (which can be anonymous) may be submitted via a webform.