Psychedelic research: evaluating the fast-evolving regulatory roadmap

Fluoxetine was approved to treat depression 35 years ago. Since then, there have been few breakthrough innovations in treating neuropsychiatric diseases such as anxiety, depression, substance use disorders (SUDs), and post-traumatic stress disorder (PTSD). For many indications, progress has been incremental. Psychedelic research, in particular, is gaining momentum. 

Some psychedelics originate in nature and have been used by Indigenous cultures for thousands of years; others are manipulated or manufactured. Regardless, most psychedelic drugs are Schedule I controlled substances, which means that very strict legal and regulatory controls accompany their use.¹ Such restraints have stood solid for decades. Now, however, the speed at which the regulatory landscape is shifting is breathtaking.

The Dutch government offers a prime example. Up until recently, it took a prohibitive stance toward psychedelic research. But in early 2022, the country’s health minister announced his approval of research into psychedelic therapies and increased funding for mental health research.²

Likewise, in December 2022, Health Canada outlined its expectations that clinical trial sponsors will include in their protocols the best-practice risk-management measures they intend to implement in their psychedelic-assisted psychotherapy studies.³  This notice came on the heels of a January 2022 notice that clarified Health Canada’s desired approach to psilocybin research. In the earlier statement, the regulatory agency noted that clinical research “…is a critical step in the generation of good quality evidence needed to better understand the potential health benefits and harms associated with the therapeutic use of psilocybin.”⁴

Despite the tidal wave of renewed interest in psychedelic therapies, there is still much to be learned about them, including their precise mechanisms of action, their long- and short-term safety profiles, the durability of their effect, and their adverse effects—which can be severe. Therefore, regulatory-controlled research into their safety and efficacy is of paramount concern.

Regulatory bodies such as the European Medicines Agency (EMA), the UK Medicines and Healthcare products Regulatory Agency (MHRA), Health Canada, and the US Food and Drug Administration (FDA) are aware of psychedelics’ potential adverse effects. Yet they also recognise that most existing treatments for mental health disorders are only moderately effective. Thus they, too, are taking an evolutionary approach to encourage psychedelic research. Sponsors must understand this rapidly changing regulatory landscape and be able to pivot quickly to optimise their clinical trial strategies.

What sponsors should know about psychedelic drug development

Although some psychedelics have a long history in traditional medicine, regulatory agencies must evaluate psychedelic compounds the same way they assess any other drug. That means sponsors must be prepared to follow the same requirements and deliver the same data as in other studies; there is no “pass” on preclinical work just because the compound being studied is derived from nature or because there are decades-old, published data for select compounds.

However, over the past few years, regulatory agencies in Europe and North America have quietly encouraged research into psychedelic drug development by approving expedited pathways.

In 2021, for instance, a type of fast-track status known as the Innovation Passport Designation was granted by MHRA for dimethyltryptamine (DMT)-assisted therapy for major depressive disorder. In the US, breakthrough therapy designations were given in 2017 and 2019 for psychedelic-assisted therapies for PTSD, treatment-resistant depression, and major depressive disorder (MDD). More expedited pathways have also become available recently, giving sponsors regulatory mechanisms for more efficient drug development. For example, the MHRA launched its Innovative Licensing and Access Pathway (ILAP) in January 2021 with the goal “…to accelerate the time to market, facilitating patient access to medicines. ⁵

Typically, regulators grant expedited pathways when a therapy has the potential to meet unmet clinical needs or work better than available treatments. Solid preclinical data generally is necessary. Still, such regulatory avenues are more efficient and usually urge sponsors to collaborate with regulators throughout the development process.

Expediated pathways available for psychedelics

Psychedelic compounds are assessed by regulators the same way as any other drug.

In addition to the ILAP in the UK, expedited pathways available in the EU and the US include:

• Accelerated assessment. This EU pathway enables faster approval for therapies “…expected to be of major public health interest, particularly from the point of view of therapeutic innovation.”⁶
• Authorisation under exceptional circumstances. This EU pathway permits ongoing safety monitoring and risk/benefit assessments after the therapeutic goes to market. It is reserved for instances when very little data exists, nor can it be gathered—such as with exceptionally rare diseases.⁷
• Adaptive pathways. This EU pathway is typically used when sponsors want to broaden a therapeutic’s indications, but regulators require more data.⁸
• Conditional marketing authorisation. This EU pathway offers short-term approval when the need for immediate drug access outweighs the risk of having little data.⁹
• PRIME (Priority Medicines). PRIME enables early and enhanced scientific and regulatory support from agencies, including the EMA and Health Technology Assessment (HTA) organisations.¹⁰ 
• Breakthrough therapy designation. This US pathway offers early-phase benefits, including greater FDA collaboration. Sponsors must show that the drug “…may have substantial improvement on at least one clinically significant endpoint over available therapy.”¹¹
• Fast track designation. This US pathway most often comes into play at the investigational new drug (IND) stage of drug development.¹²
• Accelerated approval. This US pathway is usually leveraged at later stages in drug development and permits sponsors to use surrogate endpoints to get faster FDA approval. However, they must still conduct Phase IV confirmatory trials.¹³
• Priority review. This US pathway reduces the application review period by several months.¹⁴

These are just some of the options available to sponsors; other countries have expedited pathways as well. Therefore, ensuring an optimal strategy requires advanced planning to determine the best path forward, and ongoing education as the landscape shifts. Partnerships with Contract Research Organisations (CROs) or other experts may be beneficial, especially for sponsors that are less experienced in regulatory-controlled psychedelic research.

Potential challenges of psychedelic research

Very often, the unique logistical issues of psychedelic research pose the most significant potential challenges for sponsors. To that end, sponsors may want to:

• Look at the precedents for psychedelic research. Has the targeted country approved previous research, especially for the same indication? As of 31 January 2022, the transparency afforded by the EU Clinical Trial Regulation 536/2014 (EU-CTR) makes it easier to determine. Engaging countries experienced in clinical trials and approvals for psychedelic compounds may ease the development journey somewhat.
• Gather intelligence about attitudes toward psychedelic research. Some countries/regions are more open than others to psychedelic research. Selecting regions with known openness to it may be beneficial.
• Understand the import/export laws for psychedelics. As few drug distribution vendors handle Schedule 1 compounds, some sponsors limit research to the country where the drug is manufactured to avoid import/export hassles and delays.
• Get to know the manufacturing standards. Even if the compound being researched is natural, regulatory agencies will hold sponsors to the same manufacturing criteria as other drugs. For example, sponsors who grow their own mushrooms for psilocybin research must still meet applicable chemistry, manufacturing, and control (CMC) requirements.
• Ask questions! More and more, regulatory agencies are encouraging sponsors to collaborate with them—especially if they are pursuing an expedited pathway. The ILAP, for example, “…provides applicants with access to a toolkit to support all stages of the design, development and approvals process” as well as “…opportunities for enhanced regulatory and other stakeholder input.”⁵ Health Canada, too, suggests that sponsors should engage them in a pre-submission meeting before submitting the Clinical Trial Application. A sponsor unsure about elements of the drug development process should not hesitate to ask questions. 

Psychedelic research: progress through collaboration

The adage, “It takes a village,” is exceptionally true in psychedelic research today. As the regulatory climate quickly shifts underfoot, sponsors should take full advantage of all avenues for collaboration with regulators—including expedited pathways. Collaborative strategic planning has become more essential than ever as the entire industry moves together to improve treatment options for those with neuropsychiatric diseases.

Sponsors have tremendous opportunities to interact with regulators, give voice to patient stories, and showcase the “why” driving their research. After all, regulatory agencies are not machines; they are made up of people responsible for ensuring patient safety and public health. By embracing regulators as unofficial partners, sponsors can reap the benefits of their guidance throughout the development journey.

References

1. EMCDDA. Classification of controlled drugs. [Internet] European Monitoring Centre for Drugs and Drug Addiction; [cited 2022Dec]. Available from: https://www.emcdda.europa.eu/publications/topic-overviews/classification-of-controlled-drugs/html_en
2. Tap S. The Netherlands should be ‘at forefront’ of psychedelic research, says Dutch government [Internet]. OPEN Foundation. 2022 [cited 2022Dec]. Available from: https://open-foundation.org/netherlands-forefront-of-psychedelics/
3. Government of Canada . Notice to stakeholders: Health Canada’s expectations regarding risk-management measures for clinical trials involving psychedelic-assisted psychotherapy. [Internet] Canada.ca. 2022 [cited 2022Dec]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/expectations-risk-management-measures-clinical-trials-psychedelic-assisted-psychotherapy.html
4. Government of Canada. Notice to Stakeholders – Clarification of Requirements under the Food and Drug Regulations and the Controlled Drugs and Substances Act When Conducting Clinical Research with Psilocybin. [Internet]. Canada.ca. 2022 [cited 2022Dec]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/notice-clarification-requirements-conducting-clinical-research-psilocybin.html
5. Medicines and Healthcare products Regulatory Agency. Innovative licensing and access pathway [Internet]. GOV.UK. 2022 [cited 2022Dec]. Available from: https://www.gov.uk/guidance/innovative-licensing-and-access-pathway
6. EMA. Human Regulatory. Accelerated assessment. [Internet]. European Medicines Agency, 2022 [cited 2022Dec]. Available from: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/accelerated-assessment
7. EMA. Human Regulatory. Pre-authorisation guidance; 1.10. [Internet]. European Medicines Agency, 2022 [cited 2022Dec]. Available from: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/pre-authorisation-guidance#1.-types-of-applications-and-applicants-section
8. Nicotera G, Sferrazza G, Serafino A, Pierimarchi P. The iterative development of medicines through the European Medicine Agency’s Adaptive Pathway Approach. Frontiers in Medicine. 2019;6.
9. EMA. Human Regulatory. PRIME: priority medicines. [Internet]. European Medicines Agency. [cited 2022Dec]. Available from:  https://www.ema.europa.eu/en/human-regulatory/research-development/prime-priority-medicines 
10. FDA. Frequently Asked Questions: Breakthrough Therapies. [Internet] US Food and Drug Administration. [cited 2022Dec]. Available from: https://www.fda.gov/regulatory-information/food-and-drug-administration-safety-and-innovation-act-fdasia/frequently-asked-questions-breakthrough-therapies 
11. FDA. Fast Track Designation Requests. [Internet] US Food and Drug Administration. [cited 2022Dec]. Available from: https://www.fda.gov/drugs/ind-activity/fast-track-designation-requests 
12. FDA. Accelerated Approval Program. [Internet] US Food and Drug Administration. [cited 2022Dec]. Available from:https://www.fda.gov/drugs/information-healthcare-professionals-drugs/accelerated-approval-program 
13. FDA. Priority Review. [Internet] US Food and Drug Administration. [cited 2022Dec]. Available from: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review