January 30, 2023 PAO-01-23-CL-03
Historically, clinical trials for therapeutics classified as controlled substances have largely involved pain medications. In the United States, most of these therapeutics have been opioids, which carry very significant restrictions.
Working with controlled substances significantly increases the complexity of clinical trial design and implementation. The amount of planning required may be greater by several orders of magnitude, with the difficulty increasing as more countries become involved in the clinical studies. This is primarily because international regulations governing the manufacture, packaging, storage, and distribution of controlled substances are not fully harmonized and may differ in critical ways from country to country.
Owing in part to these inherent challenges, few controlled drug studies were performed in the late 2000s and early 2010s. Since that time, however, therapeutic use indicators and international regulations around certain substances have changed. As a result, the number of clinical trials investigating controlled substances has risen dramatically.
Many companies are targeting different indications of controlled substances that previously received U.S. Food and Drug Administration (FDA) approval. They are also targeting new formulations, such as controlled-release dosage forms of existing opioid therapies. There are also a few trials underway today involving U.S. Drug Enforcement Administration (DEA) Schedule I controlled and precursor substances, which were previously rarer. Most of these trials involve cannabis-based therapeutics, a rapidly expanding category of drugs being investigated for a wide range of indications. In addition, companies in countries where previously scheduled drug substances are no longer scheduled are looking to run studies in the United States, where they still are controlled. Others are studying materials that have a lower schedule in the country of origin than in the United States, often as antipsychotic or antianxiety medications.
In the United States, the DEA has oversight over controlled substances and the companies that manufacture, store, and distribute them, as established by the Controlled Substances Act (CSA). Controlled substances include narcotics, stimulants, depressants, hallucinogens, and anabolic steroids in multiple formats. They fall into five schedules depending on their medical use and potential for addiction and thus illegal use and abuse, with Schedule I substances not permitted for public use and Schedule II through V substances available as prescription drugs with decreasing control requirements. The CSA also covers precursors used to make controlled substances and “analogues” that are similar to controlled substances but not used for medical applications.
Any company that wishes to manufacture, store, and/or distribute controlled substances must obtain a license to do so from the DEA. To qualify for a license, they must demonstrate compliance with very specific facility, equipment, procedural, management, documentation, traceability, and other requirements that apply to each Schedule level. Licensed companies receive quotas from the DEA for active pharmaceutical ingredients (APIs) and formulated drug products based on estimates submitted to the agency in April of each year for the following year, including estimates of the quantities of controlled substances that will be produced and the raw materials that will be consumed. The DEA determines an appropriate aggregate annual quota for each substance and assigns specific quotas to each facility. (Notably, quotas only pertain to Schedule I and II substances.)
Much of the requirements for licensed controlled substance manufacturers relate to management systems and record keeping, with reporting of production information and material flows expected on a monthly or annual basis. Detailed biannual reports are also required by the DEA and include information about each batch of controlled substance produced at a given site.
In addition, only staff who have been fingerprinted and have undergone background checks by the DEA are allowed to access the storage facilities containing controlled substances, which must meet very specific design requirements that include multiple locking mechanisms. Extensive internal auditing procedures are also needed to ensure that all documentation is appropriate, that management systems are working effectively, and that other requirements are being met. The DEA itself conducts regular inspections, often unannounced.
For contract development and manufacturing organizations (CDMOs), quotas are required for any controlled substances to be produced for customers, including actual production as well as fill/finish and packaging operations. All controlled substances manufactured by the CDMO must be listed on its license. If a customer onboards a project involving a scheduled material not included in the CDMO’s license, the CDMO must apply for a quota for that substance.
There is leeway for contract manufacturers to apply for quotas later in the year for projects brought to their facilities after April. Additional quotas can also be sought if companies can clearly demonstrate that the assigned quota was insufficient — by showing that all the assigned material has been used or distributed. Since these requests can take weeks for the DEA to process, they often result in production delays. Significant issues can also arise for drug developers if a CDMO fails to provide a controlled product that meets specifications.
Once a quota is issued, communication requirements must be met. For example, before a drug product can be packaged by a CDMO, the CDMO must physically mail Form 222 to the customer stating the exact quantity of material that the DEA has permitted the customer to send to the CDMO and where it must be sent. A copy of the CDMO’s 223 license must also be provided. The same 222 and 223 process must be repeated any time the packaged material is shipped.
One of the biggest challenges to running global clinical trials involving controlled substances in the United States is the differing regulations within other countries. While the DEA regulates controlled substances in the United States, each country has a similar agency with its own regulations. Not all substances that are scheduled in the United States are considered to be controlled substances everywhere and vice versa. Furthermore, even if a substance is controlled in multiple countries, the specific level of scheduling can differ from one country to the next.
Differences tend to be greatest among substances that fall into lower schedules, as narcotics are governed by the International Narcotics Control Board. The one exception is marijuana, with cannabis and cannabis-derived materials falling across the full spectrum of schedule levels across international regulatory agencies.
It is therefore essential for CDMOs to understand how the materials involved in a clinical study are scheduled in each country where trials sites are located. This adds another layer of complexity to the international logistics of these trials and thus more challenges for supply chain operations. For international shipments, additional import and export licenses and permits are generally required. Depots are generally also needed in each country where study sites are located, rather than a single depot serving multiple countries.
For instance, if a controlled substance is to be shipped from the United States to the United Kingdom (UK), the U.S. DEA expects to be provided with the following information:
The decrease in clinical research investigating controlled drug substances is reversing itself. There is growing research involving controlled substances with novel mechanisms of action, not only as alternatives to opioids but also targeting many different indications.
As more of these candidate therapeutics enter clinical trials, often initiated by companies in countries where schedules have been relaxed for certain types of medications (such as cannabis-related APIs and psychedelic mushrooms), the U.S. DEA will need to respond accordingly. Potential therapeutic uses have been identified for these compounds, and clinical studies must be conducted in an appropriate manner for drug candidates based on those compounds.
There are always going to be Schedule I materials, because there will always be some drugs that present the potential for abuse and addiction. However, some medications that are currently strictly scheduled could be regulated differently in the future. Access is already restricted for prescription drugs only available at pharmacies. It would therefore be beneficial to have separate classifications for Schedule I and II materials with no medicinal use and those that have therapeutic value.
PCI Pharma Services is one of the few companies that can handle controlled substances from Schedule I through V, having worked with controlled substances for many years processing a range of batch sizes. As a clinical operation, PCI ran the largest controlled drug study the DEA has ever monitored, and the commercial business also boasts extensive experience with scheduled substances. The types of controlled substances that PCI has worked with include controlled-substance precursors, cannabis derivatives, and 3,4-methylenedioxymethamphetamine (MDMA), among others.
PCI has two manufacturing lines and a significant amount of storage capacity for controlled substances. This includes the ability to store and handle scheduled materials from room temperature through 2–8 °C and down to –80 °C, as the market expands from traditional oral dosage forms to also include injectable dosage forms. Packaging operations are performed in controlled rooms fitted with security cameras; a team of DEA regulatory specialists ensures that PCI’s operations are in full compliance with the agency’s requirements; and PCI’s own project managers and logistics experts have extensive experience running controlled drug studies within and outside the United States.
From a broader global perspective, for example, there are many sites within PCI’s network whose capabilities enable the end-to-end management of controlled substances to support manufacturing, labeling, and distribution. These include our sites in Canada, the UK, and Australia.
PCI is taking steps to increase its capability to support its customers in this area of expertise. Whenever facilities expand, advanced planning takes place to include areas suitable for handling scheduled materials, such as reinforced floors and walls to increase vault storage. Recent investments have ensured that PCI can handle increasingly large quantities of controlled substances, therefore enabling PCI to meet the growing demand for clinical trials involving these substances.
Overall, PCI’s experience with the operational, logistical, and regulatory aspects of clinical trials supply utilizing controlled substances sets the company apart from other outsourcing providers. Together with integrated, end-to-end commercial operations capable of large-scale supply, customers are assured of their product’s speed to patient, study, approval, and commercial launch, wherever their product is within its life cycle.
Rich has been with PCI for 11 years, with a total of 17 years in the clinical supply industry. He is responsible for developing and maintaining PCI’s Global Depot Network, Global Courier Partnerships, and constructing study specific logistics strategies.