Two years after the Advisory Council on the Misuse of Drugs (ACMD) recommended that Cannabis Based Products for Medicinal use (CBPM) be moved into Schedule 2 under the Misuse of Drugs Regulations 2001 (MDR), the ACMD reflect and assess the impact of this important regulatory development.
The review, following the ACMD’s 2019 impact assessment framework, unsurprisingly culminates in the recommendation that the current designation of CBPM’s under Schedule 2 remains “appropriate” and no further legislative change should be considered. Interestingly they qualify their recommendation by stating that
“In the event that there is a marked increase in the number of CBPMs achieving marketing authorisation and being individually considered as candidates for rescheduling by the ACMD, the ACMD will again review the scheduling of CBPMs as a whole”
To understand what is meant here we first have to unravel the definition of CBPM’s. There are five distinct categories of what we may consider “cannabis products” defined by the ACMD:
- Cannabis – products not covered under the definition of a medical product so not included in the definition of CBPM’s hence regulated under Schedule 1. This applies to “illicit market” cannabis, even if used by a patient for self-medication.
- CBD Food – products classified as a food ingredient. Not classed as a medicine so not covered under MDR, instead regulated as a Novel Food by the Food Safety Association (FSA) and available over the counter.
- Unlicensed CBPM’s – products classed as medical products and covered by the rescheduling in 2018, hence regulated under Schedule 2. These products have not been through the process for market authorisation with the Medicines and Healthcare Products Regulatory Agency (MHRA), which includes a multitude of clinical trials. From the point of view of the regulators, there is a lack of robust evidence that these products are safe and effective. As a result, these products fall into the unlicensed category and can only be prescribed by a specialist doctor on the General Medical Council (GMC) register under certain conditions. This category makes up the majority of products patients are currently accessing in the UK.
- Licensed CBPM’s – products still classed as a CBPM, hence still regulated under Schedule 2. These products have been granted approval by the MHRA and hence can be prescribed under normal conditions for any other Schedule 2 medicine. A license is granted for a specific condition and any use for a condition outside of the license is defined as ‘off label’ use, treated similar to that of an unlicensed medicine (but preferred to a medicine with no license at all). There are currently no products that fall under this definition.
- Licensed Cannabis Based Medicines – despite the similarity in name, these products are not covered by the definition of CBPM’s as they have been specifically excluded and instead are individually scheduled under the MDR. These products can fall under any schedule from 2-5. There are currently three of these products available, Epidyolex, Sativex and Nabilone.
While all cannabis products share the same common chemical compounds and may be indistinguishable, they are not treated as equal under the law. There is and perhaps always will be (from a regulatory standpoint) a preference for those cannabis products covered by the final two categories. The diagram below shows the process a product currently defined as an unlicensed CBPM would have to go through to become rescheduled under MDR. Also shown is the result the feedback loop could have on the scheduling of CBPM’s as a whole (as outlined in the ACMD statement).
The rationale for this is solid, if CBPM’s are being licensed and reclassified it becomes harder to argue that other unlicensed CBPM’s should remain in Schedule 2. If they truly are a family of medicines with broadly similar risk profiles and levels of efficacy, then it would be fair to assume that the scheduling should reflect this. Despite this being a logical position to take, it does present some issues around incentives. Not diving into the complexities of the pharmaceutical economic model, we must only be aware that for the trials and research to be undertaken there must (in a private model at least) be an economic return. A producer considering the lengthy and expensive process of marketing authorisation for their CBPM is incentivised by the opportunity for supernormal profits under exclusivity protection or wider patient access through licensing, however if an external consequence of such spending is the preferential scheduling of other competitive products, the producers of which operate at a distinct cost advantage, the fair economic decision may be to hold off any research and development. The effect of this may be small, and would not necessarily hinder companies undertaking the required research, however it is always beneficial to understand what unintended consequences may arise. One way of reducing the impact of this potential unintended consequence is to exponentially lower the cost of doing research, thereby flipping the model to incentivise producers to invest in research.
The review includes the ACMD’s rationale for their recommendations to the Home Office, specifically looking at the impact on the following areas:
- prescribing of CBPMs and licensed cannabis-based medicines;
- the market, monitoring, trials and research for CBPMs and licensed cannabis-based medicines;
- professional education, and public knowledge and attitudes towards cannabis, CBPMs, and licensed cannabis-based medicines; and
- crime, enforcement and regulation related to CBPMs and licensed cannabis-based medicines
The majority of the report does not stray far from what we currently understand about the state of medical cannabis in the UK today, however there are some interesting aspects that warrant further discussion.
One area where the report diverges from what is understood by industry insiders is the total number of patients currently being issued private prescriptions. The ACMD projects that in the year November 2019 to October 2020 there were between 149 and 224 unique patients on private prescriptions, a number far below industry estimates of around 2,500. The explanation for such a huge disparity likely lies in the effects of the Covid-19 pandemic – which “led to NHS BSA (Business Services Authority) temporarily suspending the processing of private prescriptions of unlicensed CBPMs”. In light of this the ACMD had to rely on forecasting over this period, which was based on data collected up until February 2020. Structural changes in the supply chain, like the relaxation of import restrictions in March or the roll-out of Project Twenty21, have resulted in a massive increase in private prescriptions which the forecasting model has not taken into account. This highlights an important point that patient numbers are likely to grow in a somewhat discrete fashion as barriers to access are pulled down one by one.
What about the NHS?
Despite the growing number of private prescriptions, access through the NHS is almost non-existent for CBPM’s, whereas licensed cannabis based medicines continue to be prescribed at a steady rate. The reasons for this are addressed by the following paragraph:
“Whereas, for licensed cannabis-based medicines, the manufacturer will be accountable for any harm resulting from the product when used within its licence, it is the prescriber who assumes the responsibility for any harm that occurs as a result of the prescription of an unlicensed CBPM (unless the harm was a result of a defect in the product) [Nutt et al., 2020]. There is also no clear route for physicians to fund treatment with CBPMs. If physicians were to apply for funding, this would need to be an individual funding request (IFR) – an application for funding for a treatment that is not usually given by the NHS, in situations where a clinician believes their patient’s clinical situation is so different to other patients with the same condition that they should have their treatment paid for where others would not”
We see here that the unlicensed nature of CBPM’s presents complications with regards to the funding of the prescription on the NHS, an issue clearly mitigated when the prescription is obtained through private channels and the patient takes control of the funding decision. These barriers are likely to remain and hence we would expect the private ecosystem to continue to provide the fastest and most reliable point of access for patients.
Pricing in the market
“In April 2020, it had been shown that the average price for unlicensed CBPM oils per mg of cannabidiol (CBD) was around 30p per mg, and around 55p per mg for tetrahydrocannabinol (THC)”
The source for this data was not provided, however we can compare these numbers with prices we see on the market today. An official list of available products and their prices does not exist however there have been reports of patients paying 13p per mg of THC and 6p per mg of CBD. Although prices vary across different products, the existence of products at a price level almost five times lower than stated in the report should be highlighted. In such a new and fast developing market we can expect further structural changes and innovations to continue to put downward pressure on prices, hence it is vital that analysis is undertaken using prices that represent not only the current reality but long-term price projections.
Unlike CBPM’s, the prices for licensed cannabis based medicines are publicly available. Using drug tariff prices from June 2020 we calculate the average cost per cannabinoid (weighted average of THC and CBD price) for Sativex to be 21p. This is greater than the average cost per cannabinoid that patients report paying on the market today.
Research and Funding
Since rescheduling, the National Institute of Health Research (NIHR) has approved funding for 3 out 12 applications for studies into medical cannabis – an acceptance rate not too dissimilar to that of other treatment areas. When looking back retrospectively at studies funded before rescheduling they stated
“After a consideration of the aims of those studies funded through the NIHR programme, the ACMD did, however, recognise that a number of the studies related to the harms associated with illicit cannabis, rather than to the study of the therapeutic value of licensed cannabis-based medicines or unlicensed CBPMs”
The acknowledgement of the historical bias in cannabis research is welcomed and sets out the need to correct this imbalance and invest heavily in the study of the therapeutic value of cannabis. Looking at the 3 studies that have successfully achieved NIHR funding, 2 were for Epidyolex as a treatment for Rett Syndrome and the other was for Nabiximols as a treatment for MS. The Wellcome Trust also provided £4m in funding for a Randomised Controlled Trial looking at the use of CBD to treat Ultra High Risk (UHR) psychosis however the ACMD noted that “these studies relate to cannabis rather than unlicensed CBPM’s or licensed cannabis based medicines”.
This statement highlights the aforementioned complexities around the various classifications of cannabis and the implication that research, and hence potential evidence generation, into ‘cannabis’ is not directly applicable to the evidence base in a regulatory process for CBPM’s.
Cannabis and chronic pain
A systematic review of population studies in the UK published in 2016 concluded that chronic pain affects between one third and one half the population of the UK, representing approximately 28 million adults. When we analyse the conditions people most commonly treat with cannabis, both in the UK and abroad, we find chronic pain makes up a significant proportion (see report on UK). In the context of current discussions around the over-use of opioids in pain management and the resulting “opioid epidemic”, the use of medical cannabis is widely documented as providing a viable alternative for chronic pain patients. When evaluating this use of CBPM’s the ACMD said:
“With respect to the status of the international evidence behind the treatment of pain with CBPMs, an International Association for the Study of Pain (IASP) presidential task force has been developed to review and evaluate current clinical evidence for the benefits and harms (including psychiatric risks) of cannabinoids as analgesic drugs. This review will be peer-reviewed and published in ‘PAIN’ (the journal of the IASP), and is intended to inform an IASP Position Statement, expected to be published in early 2021. The work of this taskforce is expected to have a powerful influence on the practice around prescribing unlicensed CBPMs and licensed cannabis-based medicines for the treatment of pain, as well as on the direction of further research in this area”
Until the eagerly awaited IASP Position Statement is published in early 2021 we are left wondering whether this could mark a turning point in the treatment of chronic pain with cannabis, and how this ‘powerful influence’ may manifest itself in the UK. We have to go back 6 years to 2014 to find a previous report into medical cannabis published by the IASP. We look at their position in 2014 and consider what we should expect next year.
If we go by the 2014 report we can expect an overall positive outcome, succinctly summarised by the final paragraph of the report
“Cannabis is not a panacea, and there are clearly patients whose use of cannabis may in fact be impairing their ability to improve their overall quality of life. This is a question of astute clinical judgment, but answers should be based on an adequate knowledge base and patient evaluation. Careful consideration of cannabis use in pain medicine provides an opportunity to deepen and refine our pain-management toolbox, understand our patients’ needs and wishes, strengthen our relationships, and improve the quality of our care, while we wait for more long-term RCTs to provide more definitive evidence”
In the report we see the standard argument put forward, that is, despite the mountains of anecdotal evidence, the RCT data is still lacking and therefore any statement about cannabis’s therapeutic value can not be conclusive. Whilst we still don’t have clarity around efficacy, safety data is better supported.
“In clinical trials, however, the adverse events associated with cannabinoids are similar in quality and quantity to those of many other conventional centrally acting analgesics, and serious adverse drug reactions to cannabinoids are extremely rare”
With the lack of RCT data on medical cannabis, some believe that cannabis should not be prescribed until this evidence base exists, in keeping with standard practice. The main problem with cannabis, clearly acknowledged by the IASP, is that the RCT data may never come, at least under current market conditions
“Although purified analogs and extracts of cannabis are available as prescription medicines, the clinical study of inhaled cannabinoids (through smoking or vaporization) is limited by restricted access to supplies of clinical grade material, lack of intellectual property incentives, and concerns that studying the medical benefits of cannabis runs contrary to global antidrug and anti smoking strategies. Until such issues are addressed, it is unlikely that we will ever see the sort of large-scale phase III trials needed to definitively establish the efficacy of herbal cannabis. Small proof-of-concept studies, as described earlier, remain the best available evidence. Efforts are underway in jurisdictions where medical cannabis use is legal to implement monitoring programs to inform the safety and effectiveness of long-term medical cannabis use in real-world settings. Thus, in drug development terms, we have witnessed this complex botanical drug jump straight from phase II to phase IV.”
Although written in 2014, these ideas are still relevant today as we still face the same misaligned intellectual property incentives and the historical and cultural baggage of cannabis as a recreational drug. Efforts today to generate evidence through large scale registries and monitoring programmes (see Project Twenty21) is a direct result of this need for ‘other’ forms of evidence whilst providing access to patients that see real benefit from cannabis, whether an RCT says so or not.
This pragmatic position of the IASP in 2014 is promising, however there is certainly no guarantee this will reflect their views 6 years later. One thing is for certain, the position that there is a lack of RCT data will likely hold. The Task Force charged with delivering this report consists of 19 experts in the field from around the world. In May 2020 five of the task force’s contingent, including the chair (all from the UK), were co-authors of a systematic review on the RCT evidence of “Cannabinoids, cannabis, and cannabis-based medicine for pain management” which concluded:
“The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.”
It would then be expected that the outcome of the IASP report will somewhat reflect the findings of the meta-analysis. We hope the report will again address some of the reasons for this lack of evidence and suggest a path forward that includes the most important stakeholders, patients. Support for alternative forms of evidence through patient registries would give a significant boost for projects like Twenty21 and similar schemes across the world, an idea also supported by the ACMD.
The ACMD believes patient registries can play a key role in the development of medical cannabis in the UK and tacitly acknowledges the efforts of groups like Drug Science.
“The development of a CBPM patient registry is a very significant step in allowing for a careful analysis of the extent and pattern of prescription of CBPMs and their benefits and risks”
“The availability of a CBPM patient registry should be recognised as crucial for future assessments of the impact of the rescheduling of CBPMs in November 2018. The Government should continue to support the development of an official CBPM patient registry. Depending on whether the official CBPM patient registry is developed to be able to collect all necessary CBPM private prescription data, the Government may wish to consider how the official registry can interact with those in development outside of Government.”
In order to develop a rich patient registry that can provide the insights required, it is vital that sufficient scale is reached. In short, access must come in parallel with evidence generation in this case. It is vitally important that we appreciate the role of the patient in this process, their determination to secure a prescription for a medicine which through the eyes of the regulator is not proven is a courageous step, and their actions will play a part in producing evidence that could support access for those who may have been sceptical or even unaware of CBPM’s as a viable medicine.