Trials and Tribulations: The Path to Approval for a Controlled Substance

In the 1950s and 1960s, research into the use of psychedelics and dissociative hallucinogens demonstrated the great promise of clinical benefit across a range of neurological and psychiatric disorders; however, much of the research ended abruptly following the passing of the Controlled Substances Act (CSA) in 1970 and the subsequent “war on drugs.”¹

Despite evidence to the contrary², these substances were designated as having a high potential for abuse, no medical benefit, a lack of safety under medical supervision, and were generally classified as Schedule I-III drugs under the drug scheduling system³ delineated by the CSA. This, along with societal stigma, made accessing these substances and getting research approval extremely challenging for sponsors, and even investigators, interested in continuing research into their therapeutic benefits.

The 21^st century has seen renewed interest in the benefits of controlled substances, such as psychedelics and dissociative hallucinogens (“controlled substances”) as therapeutics. Given the continued obstacles both to gaining access and authorization to conduct studies into these substances, why is there renewed interest?

Why

According to Johns Hopkins⁴, 26% of adult Americans suffer from a diagnosable mental disorder and many of these people suffer from more than one disorder at a time. Complicating matters even further is the fact that these conditions often coexist with substance abuse disorders. These disorders impact not only the affected individual but also society at large in terms of lost productivity, homelessness, and increased rates of incarceration. Based on the prevalence of these disorders, there is a high unmet medical need for new treatments for patients in the United States and across the globe.

Research has demonstrated the positive impact of controlled substances on a range of disorders, including post-traumatic stress disorder (PTSD), mood disorders (e.g., major depression and anxiety), pain management, and substance abuse disorders². At the time of writing, clinicaltrials.gov⁵ lists more than 450 active studies investigating controlled substances.

In this article, we provide an overview of some of the nonclinical, clinical, regulatory, and other tribulations sponsors may face on the path to approval of a controlled substance and offer suggestions to overcome these challenges.

Clinical Considerations

Design of an efficient clinical trial with a controlled substance requires early consideration of two key factors: safety and site selection.

Participant Safety

Safety is the primary consideration for any clinical trial; however, trials using a controlled substance pose potential unique safety challenges. Sponsors should thus:

• Consider the potential for “bad trips” and severe adverse events (SAEs). These SAEs can include psychotic reactions (i.e., participants may have difficulty understanding what is real and what is not), transient anxiety, and acute physiological adverse events such as nausea, seizures, tremor, and increased heart rate.
• Discuss with participants their expectations for the experience prior to the study (i.e., as part of the informed consent process), throughout the therapy, and during study follow-up. 
• Use relevant, validated methods and tools for assessing changes in symptoms, mood, and general quality of life. These methods and tools may include the Beck Depression scale (e.g., worsening of depression, decrease in anxiety, increased heart rate).

Site Selection

To optimize chances of success for a clinical trial using a controlled substance, the sponsor should:

• Define the optimal site profile early to ensure the engagement of the right sites for the trial. This includes:
  • Ensuring the site has skilled participant-facing staff with experience both in the indication of interest and in controlled substance research.
  • Ensuring the site has trained therapists who are available for the duration of a study and therapists available who can provide “preparation” (pre-dose) and “integration” (post-dose) therapy.
  • Ensuring the site can offer an appropriate setting for a hallucinatory experience. A typical hospital or clinical site may increase the participant’s anxiety, potentially confounding clinical outcomes. An appropriate therapeutic setting for administering controlled substances will include, but not be limited to, the following features:
    • Controlled temperature
    • Carefully curated music
    • Sensory controls, such as eye masks
    • Comfortable bed or couch
    • Familiar items, such as pictures or small objects, that have personal meaning for the participant
• Consider countries that best support clinical trials with controlled substances as the intervention. Some countries offer lower costs, tax exemptions, or a lower barrier to trial approval like Canada.
• The clinical team should have at least two designated caretakers or monitors because multiple caretakers decrease the risk of abuse of a vulnerable subject.

Sponsors may also have to plan for a single treatment of a single individual to have a duration of up to eight hours. This will depend on which controlled substance is under investigation. For example, the active phase of a psilocybin trip – a psychedelic – can take three-to-six hours while a dimethyltryptamine (DMT) trip – another psychedelic – often lasts for 30-45 minutes.

Regulatory Considerations in the United States

The approval process for a controlled substance includes the same interactions with the Food and Drug Administration (FDA) as those of any other drug development program; however, the development of a controlled substance adds another level of complexity. This type of approval requires the sponsor to engage with the FDA and the Drug Enforcement Agency (DEA). The sponsor needs DEA approval to use a controlled substance at all development stages – from the bench to the bedside – and the FDA cannot allow a new drug to be marketed until the DEA has scheduled it. Created soon after the passage of CSA, the DEA’s responsibilities are to implement the terms of the Act. Sponsors of research centered around a controlled substance must therefore consider:

• Applying for a DEA license, which is a requirement for any study of a controlled substance. The application process can take four-to-six weeks, and in many states, the DEA license is required to apply for state registration, which can take another two-to-three weeks. Keep in mind this process can vary from state to state.
• Research and clinical sites must also have a DEA license, must have a plan for secure storage in the pharmacy and at the administration site, a protocol for transportation from the pharmacy to the administration site, and staff that have additional training in the regulatory requirements related to use and storage of a controlled substance.
• Like any other new drug, a controlled substance requires FDA approval before reaching the market; however, the sponsor of a new controlled substance must also apply to the DEA for an interim final rule to schedule the drug.
  • The process of receiving a drug scheduling decision from the DEA can take more than a year and cannot be initiated until FDA marketing approval is complete. Products cannot be marketed to patients until the sponsor receives both DEA scheduling and FDA marketing approvals.
• New Drug Applications (NDAs) and product labels must include information about the potential for abuse, overdose information, and proposal on rescheduling (moving a controlled substance into a different classification or even removing it from the list of controlled substances). 

Conclusion

In this article, we have just scratched the surface of the challenges faced by the sponsor of a drug development program centered around a controlled substance. In addition to clinical and regulatory considerations, the sponsor of a controlled substance must consider legal aspects of the program, challenges for participant enrollment, and funding. Facing these challenges is surely worth the potential benefit. Psychedelics and controlled substances may offer life-changing or even life-saving therapies for people suffering from a range of mental health and substance abuse problems.

For more information on our capabilities, please explore our services. To further the conversation on developing a therapeutic based on a particular controlled substance, please contact Yolande Haydon at yhadon@hallorancg.com.

References

1. Pollan, M. (2019). How to change your mind the new science of psychedelics. Penguin Books.

2. Tupper, K.W., et al (2015). Psychedelic medicine: a re-emerging therapeutic paradigm. CMAJ, 187(14): 1054-59.

3. Drug Scheduling. Accessed August 30, 2022. https://www.dea.gov/drug-information/drug-scheduling

4. Mental Health Disorder Statistics. Published November 19, 2019. Accessed August 30, 2022. https://www.hopkinsmedicine.org/health/wellness-and-prevention/mental-health-disorder-statistics

5. ClinicalTrials.gov. Accessed August 30, 2022. https://clinicaltrials.gov/ct2/home