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International Clinical Trials

Out of Danger

A controlled substance is a drug or chemical whose manufacture, possession or distribution is highly regulated by the government and subject to legislative control. Controlled drugs include the following: illegal drugs, prescription medications, and chemicals considered precursors to the production of illegal drugs. These are all deemed to cause harm to an individual, if they are not properly used (1).

Manufacturing and distribution of controlled drugs is closely monitored by the United Nations (UN) on a global basis. The construction of an international legal framework for controlled drugs has gone through several stages of development since the 1920 prohibition of alcohol in the US.

In 1961, the UN 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).

A decade later, in 1971, the Convention introduced prescription requirements for controlled drugs, as well as a regulatory framework to include the inspection of manufacturers (exporters, importers, wholesale and retail distributers, and medical/ scientific institutions). In a groundbreaking move, the Convention also created four schedules for controlled psychotropic substances, mainly evaluated based on the risk of creating drug dependency (2).

In the US, the Comprehensive Drug Abuse and Prevention Act – later known as the Controlled Substance Act – became law in 1970 (3). This legislation 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. Similar legislative agreements on controlled drugs were developed in the EU. Later, in 1988, the UN Convention considered the manufacturers, producers, traders, distributors and transporters as the first line of defence in drug control.

Market Overview

The market for the lawful use of controlled drugs is calculated to be over $21 billion worldwide, with most of it concentrated in the US. Growth of Schedule 2 drugs has been estimated to be 6% per annum. This is largely associated with applications in the oncology area, where the demand for new treatments for cancer-related pain is expected to increase (4), and also the development of new, less addictive drugs, to replace those currently available under Schedule 2.

The number of authorisations, licenses, quotas and levels of security used to prevent diversion of controlled drugs makes it challenging for manufacturers to work with these products. This becomes particularly evident in the management of the clinical supply chain, which involves the manufacture, packaging, labelling, storage and distribution of these drugs to clinical sites for testing.

Due to its complexity, this work is increasingly outsourced to specialised clinical trials service companies, which are key partners in helping pharmaceutical sponsors navigate the regulatory environment of controlled drugs during testing and commercialisation.

Chain Management

Correct management of pharmaceutical products at the clinical supply chain level can be more demanding when working with controlled drugs, and various issues must be considered:

Facility Investment
The focus of controlled drug regulations in the clinical supply chain is to ensure full accountability of the drug through every step in the process. To comply with these regulations, clinical supply partners must provide effective security measures at their facilities, including physical barriers between the controlled drug and the external environment.

This legislation indicates that drugs on Schedule 2 and some on Schedule 3 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. Gated facilities, fortified external walls and doors, intruder alarm systems, and monitoring systems such as closed-circuit television cameras can all be used.

Personnel and Training
Strict and controlled access to production and storage areas is often necessary. All personnel that work with controlled substances must go through criminal background checks. Standard operational procedures covering security are also needed. Additional screening for employees may include an assessment of any disciplinary, unethical or criminal activities.

The regulations indicate that a minimum of two observers must be present to oversee handling of controlled drugs. This translates into having to hire and train extra personnel that have passed security checks. Operators must undergo a rigid training programme covering the regulations governing handling of controlled drugs, as well as receiving training on current Good Manufacturing Practice procedures.

Import/Export Requirements
In order 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 all the information on the import licence perfectly matches that on the export licence. If, for example, a name or any data on the import licence is not the same as the export licence, it 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, where a drug is often stored centrally and supplied to clinics on a just-in-time basis, a lead time of a month before the 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 site.

Usually, import licences are valid for a couple of months, which can be costly if several applications are required over time. The supply partner 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 – and can work with clinical teams to build realistic timelines into project plans.

Shipping Restrictions
Another challenge involves the use of drugs that are listed as controlled in the exporting country, but are not controlled in countries they are being sent to. In the case of shipping such products from the UK – for example, those classed as controlled under the Misuse of Drugs Regulations 2001 – 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.

However, there can be difficulties when several countries are involved in a clinical trial, and the process can take up to six months to be completed. A supply partner with expertise handling these situations can, for instance, use a depot in a country where the drug is not controlled; once the drug is shipped to the depot, it can be distributed more easily to other countries where it is also not controlled.

In addition, 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 their clinical supply partner during the trial planning and forecasting process enables the partner to apply for licences in a timely manner, avoiding delays in the initiation of trials due to import restrictions.

Study Blinding
Maintaining blinding for trials that involve the use of controlled drugs can also pose problems, particularly given the level of detail required on import/export forms. In the US, for example, DEA Form 222 needs to 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 unblended members of the study team are involved in shipment authorisations is key to maintaining blinding in these studies.

When transporting controlled drugs, it is necessary to declare how much of the drug is being shipped, and details such as 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 only contains 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 integrated response technology 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.

Distribution
When it comes to distribution, the selection of couriers and depots that are licenced to handle controlled drugs can be a further dilemma. Couriers should ensure the shipment is discrete and the box containing the drug does not include markings that could reveal its contents. Experienced supply partners have relationships and performance metrics in place with appropriately licenced couriers and depots, and can support sponsors in selecting the best third parties based on the specific trial requirements.

Returns and Destruction
Due to the complexity involved in re-exporting/re-importing unused medication from clinical sites to a central destruction location, supply partners typically advise on reconciliation and destruction of returns locally – either at the trial site itself, or at a central in-country depot.

Finding a clinical supply partner with the infrastructure, personnel and expertise in handling controlled drugs gives sponsors assurance that their trial will not be compromised by delays due to non-compliance with regulations. This, in turn, can translate into significant reductions in time and cost associated with study 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, Drug harms in the UK: A multicriteria decision analysis, The Lancet 376: pp1,552- 1,565, 2010
2. Jelsma M, Global commission on drug policies, the development of international drug control: Lessons learned and strategic challenges for the future, working paper prepared for the first meeting of the commission, Geneva, 2011
3. The Controlled Substance Act. Visit: www.dea.gov/index.shtml
4. Silaika S, Manufacturing controlled drugs: Guidelines for manufacturers and formulation of Schedule II drugs, Contract Pharma, 2011. Visit: www.contractpharma.com/issues/2011-01/view_features/manufacturing-controlled-drugs


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Rachel Griffiths is Technical Services Manager at PCI UK. Rachel joined the company in 2004 and has held leadership roles in Operations and Technical Support. She currently oversees the installation and validation of facilities at PCI's Bridgend site, as well as new technologies and innovations in controlled-temperature packaging, storage and distribution services. With a degree in Microbiology and Virology, Rachel has previous experience as a development and technical support scientist and a product support specialist.
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