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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A first-in-human (FIH) clinical trial is a significant milestone in the development of a potential new drug in that it will be the first opportunity for a drug development sponsor to evaluate the impact of their new chemical entity (NCE) or biologic in humans. Typically, FIH trials with compounds intended for treatment of diseases other than cancers or certain rare non-malignant diseases are conducted using normal healthy volunteers (NHVs), unless there is an ethical concern (such as known toxicity) in administering the investigational drug to an otherwise healthy population.

In Issue 18 of The Altascientist, we provide a stepwise review of how to plan for first-in-human trials to mitigate risk, including:

• Submitting an Investigational New Drug (IND) Application
• Selecting the starting dose
• Designing the trial
• Planning for participant safety
• Identifying and mitigating potential risks
• Recruiting, educating, and retaining study participants
• Planning resources and conducting the trial

Designing a First-in-Human Trial

FIH trials are typically designed as dose-escalation studies, where subjects receive increasing doses of the investigational product based on desired protocol-specified outcomes. Most often, both single ascending dose (SAD) and multiple ascending dose (MAD) studies are included in the early development program. The dose is increased once the safety, pharmacokinetics (PK), or other protocol-specified requirements have been confirmed by a Safety Review Committee (SRC).

During a FIH study, objectives may include:

-    Evaluating safety and tolerance
-    Determining pharmacokinetics (exposure and dose proportionality)
-    Identifying early pharmacological activity relative to exposure level, either based on measured physiologic responses, or on biomarkers of response identified during preclinical testing
-    Assessing observed effects on subsets of participants based on age, gender, or ethnicity
-    Evaluating the therapeutic outcomes in a small group of patients suffering from the targeted disease

At this stage of the investigational product’s lifecycle, a drug may fail simply because the human participant does not respond to the drug in the same manner that was suggested by preclinical testing.

Planning for Study Participant Safety in Fist-in-Human Trials

When testing a drug in humans for the first time, detailed consideration must be given to the risks that exist in any early-phase trial, and also the risks that can be extrapolated from observations in the preclinical testing phase.

In addition to demonstrating to regulatory authorities that the trial has been properly designed to ensure participant safety, Institutional Review Boards (IRBs) will assess whether subject risk has been minimized, and that the potential risks are justifiable in relation to any anticipated benefits. In addition to reviewing the protocol, informed consent, and investigational brochure, IRBs will review safety monitoring plans, including the membership and establishment of a Safety Review Committee (SRC), dose escalation criteria, stopping criteria, reporting of dose-limiting toxicity (DLT), and adverse events.

Recruiting, Educating, and Retaining Study Participants in First-in-Human Trials

FIH trials present an interesting challenge when it comes to participant recruitment, mainly due to the lack of human data and information available to respond to subject questions. A lack of any derived medical benefits from the investigational product is another factor which may negatively impact willingness to participate in a FIH trial.

The education of study subjects on the potential risks and safeguards in place during their participation should be built in at every stage of recruitment. The goal is to provide participants with the background on the drug, how to reasonably interpret animal model results, and the decision-making process for continuing dose escalation. Potential participants must have adequate access to study personnel, physicians, and anyone they need to answer questions prior to and during the study. They should be counseled to consult their primary care physician for guidance prior to joining a trial.

Subjects receive crucial information about the study during the informed consent process, their eligibility interview, their screening visits, study orientations, and throughout the study.

How Altasciences Can Help With Your Firs-in-Human Trials

Altasciences has the in-depth expertise to fully support your FIH trial management. Scientific and regulatory experts, data management and biostatistical experts, and clinical trial monitoring personnel work together with your team to ensure all important elements are being fully addressed. With preclinical, small molecule, and bioanalytical capabilities in-house, we provide a holistic, integrated overview that provides the most efficient, relevant, and robust FIH program for your needs.

A successfully conducted FIH trial provides a solid foundation of knowledge regarding the safety and exposure of an investigational product, at several dose levels, within a relatively short period of time. The data generated can help identify opportunities to accelerate or enhance a compound’s clinical development in the future.

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