Prescription to patenting: cannabis-derived medicinal products

The UK Government has announced that it will be possible for specialist doctors to prescribe medicinal cannabis to patients from 1 November 2018.

This follows on from a review into the law earlier this year and the decision by the Home Secretary to re-schedule cannabis-derived medicinal products to make prescription easier in appropriate cases. This article examines the background to these developments and the issues of authorisation and exclusivity rights for the manufacture and supply of these drugs.

Restrictions on medicinal cannabis use

Cannabis is a Class B controlled drug under Part II, Schedule 2, of the Misuse of Drugs Act 1971 (MDA 1971), which means it is illegal to possess, supply, produce, or import cannabis in the UK. It is currently also listed in Schedule 1 to the Misuse of Drugs Regulations 2001 (MDR 2001) because it has previously been deemed to have no legitimate use or medicinal value.

While the MDR 2001 allows some controlled drugs to be prescribed for legitimate use, as a Schedule 1 drug, cannabis cannot be legally prescribed by a medical practitioner, except under a specific licence from the Home Secretary. Until recently (see below), such a licence has not been issued to enable the use of a controlled cannabis-derived product outside of a research trial.

What has changed?

Legal and ethical debate concerning the medicinal use of cannabis-derived products is nothing new. However, as a result of the cases of two young children with epilepsy, Billy Caldwell and Alfie Dingley, who have reportedly received therapeutic benefits from cannabis-derived medicinal products, this class of drugs has received new interest.

Earlier in the year, the Home Secretary issued an unprecedented emergency licence to allow access to medicinal cannabis in these cases and, on 19 June 2018, commissioned a two-part review into the drug by the Chief Medical Advisor (CMA) and the Advisory Council on the Misuse of Drugs (ACMD).

In the first part of the review, the CMA concluded that there is "conclusive evidence of the therapeutic benefit of cannabis based medicinal products for certain conditions and reasonable evidence of therapeutic benefit in several other conditions". It was recommended that the whole class of cannabis based medicinal products be removed from Schedule 1 MDR 2001.

In the second part of the review, the ACMD agreed and recommended that a clear definition of what constitutes a cannabis-derived medicinal product should be agreed and these products moved from Schedule 1 to Schedule 2 of MDR 2001. Schedule 2 drugs remain strictly controlled and subject to special requirements but they may be prescribed.

The Home Secretary has agreed with the recommendations, and has asked the Department for Health and Social Care (DHSC) and the MHRA to define cannabis-derived medicinal products so that these can be rescheduled and prescribed. Only products meeting the new definition will be rescheduled and available for prescription. In the short term, an expert panel will advise ministers on applications for licences for the medicinal use of cannabis-derived products.

The compounds of cannabis

Given the number of different varieties of cannabis plant that exist, the MHRA needs to be clear in its definition of cannabis-derived products what exactly is being moved from Schedule 1 to Schedule 2. Cannabis plant varieties do not contain just one compound affecting to their properties, but over one hundred.

These are called cannabinoids and most are also controlled under the MDR 2001. The best known cannabinoids are tetrahydrocannabinol (THC) and cannabinol (CBN). It is THC that gives cannabis its psychoactive effect and it is controlled. CBN, by contrast, has no such effect and is not controlled.

Cannabis plant varieties contain mixtures of THC, CBN and other cannabinoids in different proportions. At one end of the scale, there is cannabis with most of the THC removed (hemp), and at the other, cannabis containing high proportions of THC (skunk).

Many hemp products are sold as food supplements and for other uses but, while pure CBD is not controlled, Home Office research has suggested that it is in fact very difficult to separate THC from CBD and it has so far remained cautious that CBD products containing other controlled carrabinoids (intentionally or otherwise) should themselves be controlled under MDR 2001.

Once defined by the MHRA, it is expected that it will be possible to prescribe cannabis-derived products containing certain proportions of THC and other currently controlled cannabinoids.

Indeed, there is one example of a cannabis derived medicine containing both CBD and THC in approximately a 1:1 ratio that is already licensed in the UK. This is Sativex, which is an oral spray containing cannabis extracts and was exceptionally licensed by the MHRA for prescription use in treating spasticity in adults with multiple scleroisis.

Sativex was exempted from the MDA 1971 and placed in Part I, Schedule 4 of the MDR 2001 in March 2013, on the basis that it has recognised medicinal or legitimate use.

Commercial prospects for cannabis-derived medicinal products

If greater use of cannabis-derived products for medicinal purposes can be expected as a result of re-scheduling, what are the commercial prospects for cannabis-derived product manufacturers that might follow? Given that the ACMD recommended the Home Office should "develop additional frameworks and clinical guidance for 'checks and balances' to maintain safe prescribing of cannabis-derived medicinal products" the extent to which these drugs will be used remains to be seen.

On the basis of newly issued NHS guidance for England, the indications for which the products may be prescribed are limited. The guidance states that the re-scheduled products should only be made available to children with rare and severe forms of epilepsy, adults with vomiting or nausea caused by chemotherapy, and adults with muscle symptoms caused by multiple sclerosis. The list doesn't include chronic pain, which is thought to be one of the main uses of medicinal use of cannabis.

In particular, it is important to emphasize at this stage that the decision to prescribe under Schedule 2 must be made by a specialist doctor – not a GP. These doctors focus on one field of medicine such as neurology or paediatrics and are listed on the General Medical Council's specialist register. They must make decisions on prescribing cannabis-based products for medicinal use on a case-by-case basis, and only when the patient has an unmet special clinical need that cannot be met by licensed products.

Nonetheless, the subject appears to have drawn commercial interest, and some companies are planning to supply the UK with cannabis-derived products to meet the advised medical needs. If more wide-spread research, development and manufacture of cannabis-derived drugs follows, then issues common to conventional small molecule drugs can be expected to arise.

In particular, marketing authorisation and exclusivity protection:

Authorisation

One potential issue is authorisation. The MHRA has already advised manufacturers and retailers of CBD products that they should be regulated as medicines. This means obtaining marketing authorization under the procedures of Directive 2001/83.

Will the same procedures apply to cannabis-derived products that are moved to Schedule 2 MDR 2001 and does this mean that full clinical trials will be needed? If so, it has been pointed out that it could take many years to authorize the many complex combinations of cannabinoids present in the different cannabis varieties. Add to this the different methods of administration possible and their different bioavailabilities.

Exclusivity protection

Another area for consideration is exclusivity protection. The market in generic versions of traditional small molecule drugs already provides a thriving business model that relies on the absence (or expiry) of protection (specifically, patent protection). This model may serve for many cannabis-derived products and so exclusivity protection may not matter.

However, as with other new, innovatory drugs, if investment is to be attracted to the research and development of entirely new cannabis-derived products, investors will want to see exclusivity protection so that their investment costs can be recouped with premium prices. This is more of a challenge for cannabis-derived products.

Firstly, cannabis-derived products are, as the name suggests, derived from cannabis plants. Distinct, uniform and stable new varieties of plant can be protected by plant variety rights, which protect against reproduction and sale by third parties of the plant variety for 25 years.

But, although a plant variety right provides protection for a specific, new variety of plant, it does not protect the cannabinoids that are the active ingredients. Therefore, any product derived from a protected variety of cannabis remains open to competition from products derived from other plants and the cannabinoids that confer their properties.

Secondly, patents are not available for plant varieties. But what about patent protection for cannabinoids? The fundamental issue here is that the right of 20 years exclusivity that is afforded by patent protection requires the product to be new and inventive. However, records of cannabis use as a medicine go back as early as 4000 BC and it was still being used as recently as the 19th and early 20th centuries to treat various forms of pain.

Many cannabinoids are not, therefore, new and inventive. The answer to this problem may be fourfold:

• the isolation of previously unknown cannabinoids with medicinal properties
• the identification of new medical indications for known cannabinoids
• new formulations, and
• the development of new, synthetic cannabinoids.

All are potentially patentable, raising the prospect of commercial interest where there is patient need.

After many years of debate on the medicinal merits of cannabis-derived products, the current steps towards prescription of cannabis derived products in the UK are cautious. Much is to be resolved, not least what the definition of the products to be re-scheduled will be.

The extent and scope to which healthcare professionals will prescribe these products is yet to be seen. More widespread commercial interest may follow and issues of medicinal product authorisation and patent protection with it.

Note: The government is clear that the changes described above do not pave the way towards legalising cannabis for recreational use. DHSC and the Home Office will develop additional frameworks and clinical guidelines to ensure that cannabis-derived medicinal products can be prescribed safely to patients but cannot be traded illicitly.