A controlled substance is a drug or a chemical whose manufacture, possession or distribution is highly regulated by governments and subject to legislative control. For example, controlled drugs include: illegal drugs, prescription medications and chemicals considered precursors to the production of illegal drugs. These drugs are all considered likely to cause harm to an individual, if not properly used.1
Manufacture and distribution of controlled drugs is closely monitored globally by the United Nations. The construction of an international legal framework for controlled drugs has undergone several stages of development since the 1920 alcohol prohibition in the US. In 1961, the single convention on narcotic drugs was established as a universal system to limit the cultivation, production, distribution, trade, use and possession of narcotic substances strictly to medical and scientific purposes, with special attention to substances produced from plants.2
In 1971, the convention on drugs introduced prescription requirements for controlled drugs as well as a regulatory framework to include the inspection of manufacturers (exporters, importers, wholesale and retail distributors, medical and scientific institutions). The convention also introduced the creation of four schedules for controlled psychotropic substances, which were evaluated mainly based on the risk of creating drug dependency.3
In the US, the comprehensive drug abuse and prevention act, later known as the Controlled Substance Act (CSA), was created in 1970 by the Drug Enforcement Administration (DEA).4 This act consolidated dangerous, legal and illicit drugs into one document and categorised them into five different schedules according to the different levels of control required for their importation and distribution (Table 1). Similar legislative agreements on controlled drugs were also developed in the European Union. In 1988, the United Nation Convention considered the manufacturers, producers, traders, distributors and transporters as the first line of defence in drug control.
| Table 1: Five tier classification system for controlled drugs |
| Schedule I – Controlled Drug Licence. |
| No recognised medicinal use. The production and possession are limited to research and other special purposes. |
| Examples: Dronabinol, Marijuana, Heroin, Acid Diethylamide (LSD) |
| Schedule II – Controlled Drugs. |
| These are subject to safe custody requirements, and need to be stored in a locked receptacle or approved safe. Schedule II drugs are considered to have high potential for abuse. |
| Examples: Opiates (Diamorphine, Morphine and Methadone) |
| Schedule III – Controlled Drugs no register. |
| The abuse potential of these drugs is considered to be less than those drugs under Schedule II. Includes a group of drugs that may lead to moderate or low physical dependence. |
| Examples: Buprenorphine, Dronabinol (Marinol), Ketamine, Testosterone |
| Schedule IV – Controlled Drug-invoice. |
| Drugs exempt from safe custody requirements. Destruction requirements apply only to manufacturers, importers and exporters. The schedule is in two parts: |
| 1. contains most of the benziodiazepines. |
| 2. contains most of the anabolic and androgenic steroids. Abuse may lead to limited physical or physiological dependence. |
| Examples: Diazepam, Clonazepam, Midazolam |
| Schedule V – Low potential for abuse. |
| These drugs contain preparation of certain controlled drugs (e.g. Codeine and Morphine); these are exempt from full control when present in medicinal products of low strength. |
| Examples: Codeine-containing cough medications, Diphenoxylate (Lomotil). |
The market for the lawful use of controlled drugs is calculated to be in excess of US$21bn worldwide; most of it is concentrated in the US.3 Growth of Schedule II drugs has been estimated to be 6% per annum, which is largely associated with applications in the oncology area, where demand for new treatments for cancer-related pain is expected to increase,3 also from the development of less addictive drugs to replace those currently available under Schedule II.
The number of authorisations, licences, quotas and levels of security used to prevent diversion of controlled substances makes it challenging for manufacturers to work with these drugs
The number of authorisations, licences, quotas and levels of security used to prevent diversion of controlled substances makes it challenging for manufacturers to work with these drugs. This becomes particularly evident in the management of the clinical supply chain, which involves the manufacture, packaging, labelling, storage and distribution of these pharmaceutical products to clinical sites for testing. Due to its complexity, this work is increasingly outsourced to specialised clinical trials services companies, who become key partners in helping the pharmaceutical companies navigate the regulatory environment of controlled drugs during testing and commercialisation.
Correct management of products in the clinical supply chain can be more demanding when working with controlled drugs, and some challenges are highlighted here.
Facilities: The focus of controlled drug regulations in the clinical supply chain is to ensure full accountability of the controlled drug through every step in the process. To comply with these regulations, clinical supply partners need to invest in their facilities to provide security requirements, including physical barriers between the controlled drug and the external environment. The legislation indicates that drugs on Schedule II and some on Schedule III should be stored in locked cabinets or safes. The cabinet needs to be made of metal and fixed to the wall and floor, with a registry of all available drugs. Double lock security in the form of a locked cabinet inside a locked room has now become the industry best practice.
The investment in facility infrastructure for compliance with current controlled drug regulations is significant and includes gated facilities, fortified external walls and doors, intruder alarm systems, and monitoring systems such as CCTV cameras. Because of the level of investment necessary for the management of controlled drugs, working together with a clinical supply partner that has the required expertise and infrastructure can represent significant money savings to the pharmaceutical company and an assurance that the medication is being handled according to regulations.
Personnel: Strict, controlled access to production and storage areas is often necessary. All personnel who work with controlled substances need to go through criminal background checks. Standard operational procedures covering security are also needed. Additional employee screening may include an assessment of disciplinary, ethical or criminal activities.
Under the regulations a minimum of two observers must be present to oversee handling of controlled drugs. This translates into having to hire and train extra personnel who have passed security checks
Under the regulations a minimum of two observers must be present to oversee handling of controlled drugs. This translates into having to hire and train extra personnel who have passed security checks. Operators also undergo a rigid training programme covering the regulations that govern the handling of controlled drugs in addition to good manufacturing practice (cGMP) training.
All these requirements can be challenging to adopt for many facilities. A specialised clinical supply partner that has expertise in handling controlled drugs adds value to any pharmaceutical company that has such products in development or on the market.
Import/export requirements
To ship controlled drugs overseas, an application for an import licence within the destination country is required. The import licence is needed as a prelude to applying for an export licence from the exporting country. To avoid delays, clinical supply partners need to ensure that all the information on the import licence perfectly matches the information contained on the export licence. If, for example, a name or any data on the import licence does not match, the licence is denied, potentially adding many months of delay to the distribution process. Regulations allow the quantity of the drug to be shipped to be less than that stated on the licence, but not more than the amount originally authorised. Even if performed correctly, the process from application to receipt of a licence can take up to a month to complete.
In the clinical supply environment, in which a drug is often stored centrally and supplied to clinics on a just-in-time basis, a lead time of a month before product can be shipped is not desirable. To minimise delays, a clinical supply partner can offer to apply for an import licence ahead of time and keep it on file until a product needs to be shipped to a clinical site.
Usually, import licences are valid for a couple of months, which can be costly if several applications are required over time. A clinical supply partner with expertise in handling controlled drugs can manage expectations by helping Sponsors’ stakeholders to understand that the import/export of controlled drugs does not have the same turnaround time as regular medications; partners can work with clinical teams to build realistic timelines into project plans.
Another challenge involves the use of drugs that are listed as controlled in the exporting country, but are not controlled in the countries to which they are being shipped
Another challenge involves the use of drugs that are listed as controlled in the exporting country, but are not controlled in the countries to which they are being shipped. In the case of shipping from the UK products classed as controlled under the UK misuse of drugs legislation of 2001, for example, the exporter must obtain a ‘letter of no objection’ from the importing country to indicate that the drug is not controlled in the destination country. This can prove very challenging when several countries are involved in a clinical trial and the process can take up to six months to be completed. Again a clinical supply partner with expertise in handling these situations can offer solutions, such as the use of a depot in a country where the drug is not controlled. Once the drug is shipped to the depot, it can then be distributed more easily to other countries where it is not controlled.
Additionally, in some cases, an import/export licence cannot be obtained when the application indicates that national quotas for a particular controlled drug have been reached. Early dialogue between the Sponsor and its clinical supply partner during the trial planning and forecasting process enables the clinical supply partner to apply for licences in a timely manner, avoiding delays in the initiation of clinical trials due to import restrictions.
Blinding: Maintaining blinding for trials that involve the use of controlled drugs can also require additional work. The level of detail required in the import/export forms makes it challenging to maintain blinding. In the US, for example, DEA form 222 must be completed by the clinical site and may be seen by a range of stakeholders in the distribution chain. Designing a process through which only unblinded members of the study team are involved in shipment authorisations is key to maintaining blinding in these studies.
When shipping controlled drugs, it is necessary to declare how much of the drug is being shipped; additionally, details such as the amount of drug and placebo often need to be disclosed. While this may not be an issue if sites always receive a combination of active and placebo packs in each shipment, it can be a problem if a shipment contains only one or other product. If this information is not managed carefully, the trial could be seriously compromised. One possible solution is to send import/export licences in sealed envelopes that only customs have access to, and which are retained by customs.
Also, since this problem is most likely to occur with small direct-to-site shipments, it can be avoided through careful IRT design that ensures single-product orders are eliminated. Alternatively, the use of depots in all countries involved in controlled drug studies can be used to eliminate the risk of sites seeing potentially unblinding information on import licences.
The main distribution challenge for controlled drug shipments is selection of couriers and depots that are licensed to handle them
Distribution: The main distribution challenge for controlled drug shipments is selection of couriers and depots that are licensed to handle them. Couriers should ensure that the shipment is discrete and that the box containing the drug does not include markings that could reveal its content. The right clinical supply partners will have relationships and performance metrics in place with appropriately licensed couriers and depots, and can support Sponsors in selecting the best third parties based on specific requirements of a clinical trial.
Returns and destruction: Because of the complexity involved in re-exporting/re-importing unused medication from clinical sites to a central destruction location, clinical supply partners typically advise on reconciliation and destruction of returns locally – either at the clinical trial site itself, or at a central in-country depot.
In summary, selecting a clinical supply partner with the infrastructure, personnel and expertise in handling controlled drugs gives Sponsors assurance that clinical trials will not be compromised by delays due to non-compliance with regulations. This can translate into significant reductions in time and cost associated with trial delays, loss of patients due to unavailability of medication, and damage to relationships with clinicians and regulators.
References
1. Nutt D; King, L and Phillips L. 2010. The Lancet Vol 376: 1552–65.
2. Jelsma M. 2011. Global commission on drug policies, the development of international drug control: lessons learned and strategic challenges for the future. Working paper for the first meeting of the commission Geneva, 24–25 January.
3. Silaika S, 2011. Contract Pharma Jan/Feb feature, last accessed 30.10. 2014. http://www.contractpharma.com/issues/2011-01/view_features/manufacturing-controlled-drugs/
4. The Controlled Substance Act; DEA website; http://www.dea.gov/index.shtml. last accessed on 2.11.2014.