The legal matter: controlled substances

Clinical trials can be a regulatory minefield at the best of times, with a complex set of requirements at every step of the way. However, if your trial involves controlled substances, those challenges would be compounded. Since you are dealing, by definition, with a tightly regulated product, you need to be very sure about the relevant laws and be confident that you can meet the requisite standards.

Controlled substances are those defined as having abuse potential. There are a number of laws around the world that determine which drugs fit into this category, with the International Narcotics Control Board playing an important role in monitoring the restrictions.

In the US, the most important law is the Controlled Substances Act (1970), a Nixon-era ruling that lays down a five-tier classification system. The ‘scheduling’ of each drug depends on a number of factors: its potential for abuse, whether or not it has medical uses, and whether abuse of the drug is liable to lead to dependence.

Schedule 1, the strictest classification, includes the likes of heroin, LSD, ecstasy and marijuana. The US Drug Enforcement Agency (DEA) maintains that these drugs have a high potential for abuse, no currently accepted medical-treatment use, and a lack of accepted safety for use under medical supervision. These are the drugs to which the tightest controls are applied, making it difficult for clinical researchers to ascertain whether they may, in fact, have medical uses.

A case in point is marijuana, which, despite having been legalised in certain US states, remains tightly controlled at a federal level. Its scheduling, which remains highly controversial, can ultimately limit the drug’s availability for clinical research studies.

“You have to have a Schedule 1 licence to do a research study on cannabis, MDMA, psilocybin or LSD,” explains Dr Ben Sessa, a UK-based psychiatrist and researcher. “They have to be made in a particular laboratory, they have to be stored in a particular way and you have to have approval from the Home Office to do the research. It costs a lot of money to set up a Schedule 1 licence at your hospital.”

Similarly, researchers wishing to study opioid analgesics need to pay close attention to the scheduling of their substance. While heroin, also known as diamorphine, is Schedule 1, the likes of fentanyl, opium and morphine are Schedule 2, with other opiates classed variously in Schedules 3, 4 or 5.

According to the University of Iowa, the most common substances used in research are pentoarbital (Schedule 2), ketamine and buprenorphine (both Schedule 3) and diazepam (Schedule 4). With ketamine, for example, the drug is best known for illicit recreational use, and has long been approved as an analgesic and anaesthetic, and has human and veterinary applications.

In recent years, a number of research teams have also been conducting trials into its potential as an antidepressant. Janssen, for instance, recently announced the results of two phase III trials into esketamine nasal spray for patients with treatment-resistant depression. “The positive results are exciting, particularly as they mark the first time an antidepressant has achieved superiority versus an active comparator in any clinical trial for major depressive disorder,” explains Husseini K Manji, global therapeutic area head of neuroscience at Janssen Research & Development.

It is clear, then, that controlled substances are a staple part of clinical research. And although the specifics would vary a lot depending on where you are and what you’re testing, there are a few key considerations that apply across the board. Below, we run through some of these requirements.

Registration approvals

The first point is the need for registration, which in the US applies at a state and federal level. Every person connected to the controlled substance – be that the manufacturer, distributor or clinical researcher – needs to obtain registration in advance. What’s more, a separate registration is required for each individual activity and for each of the locations in which the substance would be handled.

Before you can register with the DEA, however, you need to make sure your research protocol has been formally approved by FDA (including all the necessary ethics approvals). This can be a tricky task in its own right.

For instance, the Multidisciplinary Association for Psychedelic Studies (MAPS) is undertaking a $26.7 million plan to make MDMA an FDA-approved prescription medicine by 2021. In 2017, FDA granted the association a Breakthrough Therapy Designation for the treatment of post-traumatic stress disorder (PTSD) with MDMA-assisted psychotherapy. Getting to this point, however, has not been an easy ride: according to psychiatrist Dr Michael Mithoefer, the protocol approvals were very slow to get off the ground.

“In 2001, we began what turned out to be a four-year process of protocol development and obtaining FDA, DEA, and Institutional Review Board [IRB, or Ethics Committee] approvals for our first study of MDMA-assisted psychotherapy for PTSD,” he explained in the MAPS Bulletin Annual Report.

Sourcing the substance

Importing and exporting the drug can also cause a headache, especially when conducting a multinational clinical trial. It’s important to apply for permissions as soon as possible, as requirements vary from country to country and the authorisation process can take a while.

Within the US, the DEA requires the importer-exporter to be a licensed and registered entity. This means you can only use and submit the relevant paperwork if you’ve been granted authorisation ahead of time.

If you’re shipping between jurisdictions, the International Narcotics Control Board plays an important supervisory role. It verifies the authenticity of the import/export permits, as well as the names of the agencies or individuals who have granted them.

There are also various international treaties that establish a framework for importation and exportation. These include the Convention on Psychotropic Substances of 1971 and the Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances (1988).

Even if your trial is taking place entirely on home turf, other complications may arise. In some instances, it may be difficult to source the drug at all, with relatively few companies synthesising controlled substances to good manufacturing practice (GMP) standards.

For instance, a research team at Imperial College London, working with the Beckley Foundation, administered LSD to volunteers in 2016. According to Anna Ermakova, senior researcher at the Beckley Foundation, obtaining the drug was a minefield.

“There was only one company that produced LSD to GMP standards and it’s overseas, so there were very costly import permissions and a lot of problems getting the substance,” she says of the study.

To use another example, until 2016, US researchers could only obtain research-grade marijuana from one source – a campus farm at the University of Mississippi, which grows cannabis under a contract with the National Institute on Drug Abuse (NIDA). This gave the NIDA an enormous amount of say over which studies went ahead. (The law has since changed: any institution is now allowed to apply for permission to grow marijuana for research purposes.)

Storage, security, reporting and disposal

While your trial is under way, the study materials need to be locked away securely and be accessible only to authorised personnel. In the US, physical and digital security controls are required, with the substance typically kept in a locked cabinet in a locked room. The drug must also meet stringent packing requirements with a view to preventing tampering and theft.

You also need to ensure that every activity, movement or transaction is scrupulously recorded, creating an ‘accountability log’ of each drug along with detailed inventory records. On top of that, you’ll need to abide by various mandatory reporting requirements – for example, logging any theft, loss or spillage at the clinical site. In the US, all DEA-related records must be retained for a minimum of two years.

Once the study is complete, any unused supplies of the substance must be properly accounted for, as any discrepancies are likely to prompt a thorough DEA investigation. You should return any unwanted supplies to an authorised third-party company, known as a ‘reverse distributor’, who can correctly and safely destroy the materials on your behalf. A DEA observer must be present.

Planning and approvals

As this rundown makes clear, conducting clinical trials with controlled substances is far from easy – and in some cases, logistical obstacles may pose an impediment to conducting the trial at all. A number of commentators have spoken of a vicious circle in which Schedule 1 substances are deemed to have no medical value, meaning that attempts to investigate that medical value are problematised.

“They’re Schedule 1 because they ‘have no medical uses’, and they have no medical uses because we haven’t done the research because they’re Schedule 1. That’s a frustrating catch-22,” says Sessa. That said, there are procedures in place for researchers who do wish to deal with these substances. It means being prepared for complexities you wouldn’t otherwise encounter.

Be sure to leave enough time for planning and approvals, and be clear in your communications with the regulatory body. Although time-consuming and expensive, the task is resolutely far from impossible, and there are numerous success stories detailing how it has and can be done.