Controlled substances offer new possibilities for the treatment of a variety of central nervous system (CNS) indications, such as epilepsy and mental health disorders, including depression. However, some sponsors may be apprehensive about embarking on a controlled substance clinical study, knowing it will present logistical and geographically specific regulatory and IP management challenges due to Drug Enforcement Administration (DEA) controlled-substance regulations.
Fortunately, with the right awareness and experience, a smoothly-managed controlled substance clinical trial is well within reach. These are five practical considerations for planning and executing your next CNS controlled-substance clinical trial.
Given the addictive and hazardous nature of controlled substances, as well as their high street value, security against theft or diversion during clinical trials is a key concern and responsibility for sponsors. For US-based studies, the DEA regulates transportation and storage of Schedule I-V controlled substances (21 CFR 1308) outlined in the 1970 Controlled Substances Act (CSA). Schedule I lists the most tightly controlled drugs and includes high abuse-potential drugs, which currently have no accepted medical use.
In the past, guidance for record-keeping and handling of these drugs was limited to a few paragraphs in the Code of Federal Regulations (CFR), such as 21 CFR 312.62 and CFR 312.69. However, the June, 2022 DEA Researcher’s Manual revision adds much needed detail and clarity surrounding controlled substance handling throughout the research journey, from receipt of clinical trial materials through dispensing or destruction. Deep understanding of the regulatory expectations with thoughtful implementation is the best way for research projects to weather regulatory scrutiny.
Every principal investigator intending to conduct a study on any scheduled substance must register or renew registration with DEA via Form 225. A corresponding state license and/or controlled substance registration must be obtained as well. Variations in regulations from state to state or country to country increase the management complexity. Separate registrations must be obtained for multiple locations where controlled substances will be stored or given.
A wait time of three to six months is possible, to receive a certificate. Generally, registration must be renewed annually, but the first renewal date may occur earlier than that, so be alert and keep every address on file at DEA current.
Beyond registration, a Schedule I researcher must also submit a curriculum vitae and research protocol for evaluation and have obtained approval from their own institution(s). It’s recommended that Schedule I researchers be in compliance with all applicable state laws and regulations before applying for DEA certification.
DEA Form 222
In the U.S., for use and distribution within clinical studies, Schedule I and II drugs must be ordered using DEA Form 222. These numbered, non-transferable forms are issued uniquely to registrants, with unalterable, identifying information.
The purchaser must complete a form, retain a copy and submit the original with the order. Later, once the order has been filled, the purchaser notes when and how much of the order was actually received on their copy of the order form. The supplier retains the original Form 222 with their records. Alternatively, sponsors may use the Controlled Substance Ordering System (CSOS) to submit orders electronically.
Disposal of unused controlled substances
If disposal is performed via a reverse distributor, special rules apply. For Schedule I and II substances, reverse distributors must issue the researcher a DEA Form 222. Once the items have been destroyed, the reverse distributor must submit a DEA Form 41 to DEA.
Sites for controlled substance clinical trials must have DEA anti-theft and diversion prevention plans in place and approved physical security and drug storage facilities (21 CFR 1301.71, 21 CFR 1301.72), such as alarmed, substantially constructed locked cabinets or safes (21 CFR 312.69). Sites must also have trained personnel and systems that ensure consistent performance of correct record keeping and inventory activities. The DEA field office will visit to verify that a site meets security requirements. Local inspections (such as by the Research Advisory Panel of California, RAPC) may take place, as well.
To provide accountability and discourage diversion, researchers must maintain easily accessed, complete, accurate and current records for every Schedule I-V controlled substance that comes into their site and retain them for two years. Similarly, inventories must remain available at certified sites for at least two years.
Feasibility during site selection must also consider any applicable, country-specific regulations. Consultation with partners that know these regulations and also maintain lists of investigators and sites with DEA-related experience can save time and avoid certification delays and errors in study execution later on.
Recruiting patients with mental health disorders may be difficult. They might may not wish to receive placebo or may be apprehensive regarding controlled substances. A partner with subject recruitment and retention experience in CNS studies utilizing controlled substances may have strategies to help subjects see things differently and decrease their reluctance to enroll in a controlled substance study.
CNS trials involving controlled substances face challenging regulatory requirements for startup, supply chain, site operations and patient recruitment. Sponsors must plan carefully to ensure consistent compliance for their controlled substance studies. Organization and experience go hand in hand to make these trials work.
As a full-service CRO with experience managing controlled substance studies, Precision’s experts can help you overcome these logistical obstacles. With a database of investigators and sites with relevant experience, we can support you with feasibility, recruitment and retention, IP management expertise, and more.
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Tracey Owens is a Director of Project and Clinical Trial Management at Precision, having 28 years of experience in managing Phase I-IV clinical trials. Tracey is highly experienced in providing directional oversight on rare disease, CNS, psychiatric and oncology clinical trials. Her experience notably includes: ALS, bipolar disorder, epilepsy, major depressive disorder, schizophrenia, idiopathic hypersomnia, CIDP, traumatic brain injury, multiple myeloma and dementia (including Alzheimer’s and Parkinson’s Disease.)
Lana Smith is a Sr. Project Manager at Precision for Medicine with just over 15 years of clinical study management experience. Her experience includes Phase I-III in multiple therapeutic areas including CNS, Cardiology, Rare Disease, and Oncology. With particular experience in managing large global mega studies.
Precision for Medicine is part of the Precision Medicine Group, an integrated team of experts that extends Precision for Medicine’s therapeutic development capabilities beyond approval and into launch strategies, marketing communication, and payer insights. As one company, the Precision Medicine Group helps pharmaceutical and life-sciences clients conquer product development and commercialization challenges in a rapidly evolving environment.
