Under the Controlled Substances Act (CSA) in the United States, drugs that have the potential to be abused are scheduled into one of five Classes or Schedules (CI-V) as controlled substances. The scheduling method makes a distinction between drugs that have abuse potential and are not approved for medical use (i.e., Schedule I) and drugs that are approved for medical use and have abuse potential (Schedules II-V). In the classification, the higher the number of the Schedule, the lower the abuse potential of the drug and the less restrictive the conditions regarding its distribution, storage, and prescribing.

Schedule I, or Class I (CI), drugs are currently restricted to research in the U.S., meaning that they are not approved for medical use, and are deemed at highest risk for abuse.

Recent research on psychedelics and entactogens, both of which are Schedule I, is beginning to demonstrate the potential therapeutic effects of these drugs for various medical indications. Approvals of such drugs for medical or therapeutic use will inevitably result in the rescheduling of these drugs from their current CI status.

In Issue 19 of The Altascientist, we review:

• the regulatory environment and challenges (Drug Enforcement Administration
•  the research site requirements associated with the development of Schedule I drugs for therapeutic 
• required preclinical studies of Schedule I drugs
• required clinical studies of Schedule I drugs
• specialized clinical assessments of Schedule I controlled substances
• formulation, manufacturing, and analytical considerations for Schedule I drugs

Preclinical Assessment of Abuse and Dependency Risks of Schedule I Therapeutics

In addition to safety pharmacology and toxicity studies for psychedelic compounds, abuse potential and dependence evaluation is necessary as part of the final proof of concept for preclinical research. Novel psychedelic drugs for medical use will have to undergo rigorous preclinical assessments to determine the abuse and/or dependence risks that they carry. Based on current evidence, the abuse risks posed by psychedelics are no greater or more onerous than those associated with CII opiates or stimulants. The potential therapeutic benefit and the capacity to properly assess and develop mitigation strategies add to the argument in support of further research on such compounds.

Formulation, Manufacturing and Analytical Considerations for Schedule I Therapeutics

Before any research can be conducted, the active pharmaceutical ingredient (API) has to be formulated and produced in an appropriate dosage form. Choosing a manufacturing partner that already has a CI license will reduce timelines, and ensure that the site has the expertise and experience to work with controlled substances. Once a license is in place for a particular substance, it remains in place as long as the site is in good standing with the Drug Enforcement Administration (DEA). Future projects will therefore be able to start quickly, with less logistical challenge.

The storage and handling requirements maintained by a Schedule I-licensed CDMO are rigorous, with CI material stored in a locked vault dedicated for this purpose, with secure, controlled, and limited access. Detailed records for vault access must be maintained and be available for audit.

Safety Considerations and Guidelines for Schedule I Clinical Studies

As with other new chemical entities (NCEs) entering clinical development, novel psychedelics need to be assessed for safety, pharmacokinetics, and efficacy. Given the drug class and associated risks, abuse/dependence evaluation is a central part of any drug development program. Because of the known serious safety concerns around psychedelic substances, extremely thorough, robust, and precise safety monitoring must be an integral part of the protocol, and the recruitment needs to carefully screen subjects for clinical research eligibility.

How Altasciences Can Help With Schedule I Therapeutic Development

For novel CNS-active Schedule I drugs, tremendous benefit can be achieved by engaging with a drug development partner that has Schedule I licenses across every stage of early-phase development. Integration across preclinical, clinical, bioanalytical, and formulation/manufacturing phases ensures complete continuity, data transfer, information sharing, and efficient, active timeline management. At Altasciences’ CNS Center of Excellence, you have a team of well-recognized experts to ensure that your psychedelic research and studies are conducted with the rigor and efficiency needed to meet regulatory requirements, and fulfill your drug development goals.

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The main objective of first-in-human (FIH) trials is to determine the starting dose of a new drug, one that is low enough to provide minimal to no safety and toxicity risks and allows the highest dosage/benefit for the intended trial.

The manufacture of the drug product for clinical trials is of critical importance, as the formulation, manufacturing, and assessment of a drug candidate during FIH trials can be contributing factors in whether the drug safely provides the correct dosage and, ultimately, gains regulatory approval. Decisions made during early phase development, when the compound is being used in a clinical research setting, provide significant learnings for its progression through later phase research. Integration is key — ensuring that information gathered at the clinic is efficiently incorporated into the manufacturing process is a major contributor to the goal of achieving marketing approval.

In Issue 17 of The Altascientist, we review:

• the role of formulation in drug development
• the impact of formulation on subject safety
• meeting regulatory requirements
• Pharmacy case study: Supporting Regulatory Approval
• Manufacturing case study: Mission Impossible to Possible

The Importance of Drug Formulation in First-in-Human Trials

The first step on the pathway to FIH clinical trials is formulation development. Generally, it is advisable to develop a dosage form that can be produced efficiently and cost effectively, to established quality specifications; simpler dosage forms like oral liquids, powders, tablets, or capsules are favored. Among the favored dosage forms, there are advantages and disadvantages to each. For example, tablets can have a longer shelf life and can accommodate a higher dose of active ingredient than capsules, while capsules are fast acting and can provide a higher drug absorption rate. Some advanced drug delivery systems, such as nanoparticles, require more complex formulations and manufacturing processes, and thus involve increased manufacturing costs, particularly in later development stages and commercialization.

Many of the drugs that enter development fail, even if they make it through FIH studies. Some of the high attrition rate can be attributed to the fact that key performance characteristics — such as solubility and bioavailability — are easily achieved in simple FIH formulations but challenging to replicate in more complex dosage forms for late-stage trials and commercial use. When creating a FIH formulation, it is important to keep in mind the rigors of later stage development and eventual market availability.

The Impact of Drug Formulation on Subject Safety in First-in-Human Trials

Subject safety is always a primary concern in planning clinical studies, and particularly with novel drug products entering FIH trials. The use of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, as well as the employment of adaptive protocols and sentinel dosing are part of the established safety protocols for Phase I studies.

If the candidate drug is considered high risk based on data from preclinical trials, it is preferable to formulate for intravenous administration. A slow intravenous infusion can easily be stopped if serious/severe adverse reactions occur. Likewise, dose escalation needs to be considered during manufacturing to fit the planned dose levels in the FIH study and the data gathered from sentinel dosing. If adjustments are needed based on data from the initial dose plan between cohorts, it is important to be prepared with a plan to titrate dosage, or reformulate the product to ensure maximum effectiveness with minimal safety concerns.

How Altasciences Can Help With Drug Formulation for Your First-in-Human Trials

Significant benefits can be realized with Altasciences’ Proactive Drug Development approach of integrating Good Manufacturing Practice (GMP) manufacturing and clinical testing. Shorter timelines, reduced costs, and improved flexibility are achieved with real-time drug product manufacture, as the development team can evaluate and optimize new formulations in the clinic, based on human data. When clinical trial teams work closely with those involved in formulation and manufacturing process development, collaboration and data sharing minimize risk and help reduce delays. Product development can be started when a quality active pharmaceutical ingredient (API) is ready, the clinical study can start as soon as regulatory approvals are received, and the product is released.

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