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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Microsampling significantly lessens the volume of blood and plasma/serum that is collected and analyzed to determine circulating concentrations of therapeutic drugs, metabolites, and biomarkers in preclinical and clinical research.

In preclinical research, microsampling technology supports the 3Rs of animal research, and allows for less intrusive blood collection procedures.

By definition, clinical microsampling reduces sample volume to less than or equal to 50 microlitres (μL) compared to conventional venipuncture wherein millilitres (mL) of blood volume is collected. In Altasciences’ experience, microsample volumes being analyzed are less than or equal to 20 μL, with some microsampling techniques as low as 5 μL.

In Issue 16 of The Altascientist, we explore the benefits, applications, and considerations of microsampling in preclinical, clinical, and bioanalytical research, including:

• Regulatory considerations
• Case study: Anti-Epileptic Drug Monitoring – Sample Preparation Using Impact-Assisted Extraction
• Case study: Large Molecule – Determination of Rituximab Using a Surrogate Peptide Approach

Benefits of Microsampling in Preclinical Research

Microsampling addresses two of the 3Rs (replacement and reduction) of preclinical research. By eliminating or greatly reducing the use of satellite animals, microsampling can reduce the number of rodents in certain preclinical studies by 30 to 40 percent. Decreasing the number of animals required can have an added benefit of reducing R&D costs related to animals and housing, particularly for toxicokinetic (TK) studies that use satellite animals to minimize repeated conventional blood sampling procedures.

Lower-volume blood draws, from both rodents and non-rodents, taken from less disruptive locations, allow lab animals to recover more quickly, and have fewer sampling-related adverse events compared to conventional sampling. Refinement of the bleeding technique also translates to less animal handling, minimizing stress.

The elimination of satellite animals improves the quality of research data, as scientists conduct all TK analysis using main study animals. This enables direct correlation of exposure with pharmacodynamic and toxicological outcomes.

Benefits of Microsampling in Clinical Research

Microsampling in clinical research reduces patient burden, improves enrollment and engagement, and reduces drop-out. Self-administration facilitates the data collection during studies related to unpredictable clinical episodes, such as acute migraine or epilepsy attacks, and allows episodic sampling to relate efficacy with bioavailability. The dried blood samples can be stored and transported at ambient temperature, eliminating the costly cryopreservation and shipment that conventional wet blood samples demand.

Microsampling also provides a convenient, low-cost way to collect blood and plasma/serum from patients remotely. Individuals in remote geographic locations are able to participate in clinical trials, as they can conduct their blood draws at home.

Bioanalytical Considerations for Microsampling

The accurate analysis of dried blood microsamples requires equipment with high sensitivity and specificity, such as that offered by triple-stage quadrupole mass spectrometry systems paired with liquid chromatography front ends to optimize signal-to-noise ratio. When additional selectivity is required, this can be addressed by accurate mass filtering (e.g., time-of-flight or orbitrap mass spectrometer) or the use of differential ion mobility spectrometry to separate analyte from interference prior to mass selection.

Is Microsampling the Right Option for Your Preclinical or Clinical Study?

Microsampling is not appropriate for all studies and should be considered on a case-by-case basis. In a microsampling drug development program, it is critical to establish the appropriate pharmacokinetic/ statistical considerations to enable correlation/concordance between microsampling and standard blood sampling techniques.

How Altasciences Can Help

Altasciences’ scientific acumen and experience with different microsampling devices, supporting numerous programs, has led to unparalleled expertise in the development of assays and processes for all your drug candidates, from the straightforward to the most complex.

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