Prof Trevor Jones, Chairman | e-Therapeutics Plc
Dr Parveen Bhatarah, Regulatory & Compliance Associate | The Centre for Medicinal Cannabis
In the UK currently, in addition to a few medical cannabis products that have been approved for prescription use, many unapproved cannabis-based products for medicinal use (CBPMs) are being purchased by patients and their parents/carers to treat a range of medical conditions. It is important for the health and wellbeing of such a population that these treatments are based on the use of products with proven quality and reproducibility and that there is sound evidence of both their safety and efficacy.
The literature, especially the popular press, abounds with many anecdotal reports of possible therapeutic efficacy but there remains the need for well-designed clinical studies to establish their true value. In 2018, recognising the potential therapeutic value of some CBPMs, the UK National Institute for Health Research (NIHR) initiated a “themed call” to look at the use of such products for “difficult-to-treat epilepsy or other disorders unresponsive to existing treatments”. Unfortunately, there was a poor response to the call.
Meanwhile, the UK Government has continued to prioritise the need for such studies and special arrangements have been established in the NHS for the prescribing of CBPMs by clinicians on the Specialist Register of the General Medical Council.
The considerable growth of research on CBPMs in recent years now forms the scientific basis for selecting areas of unmet medical need that should be the focus of prioritised, well designed, properly conducted, clinical studies.
The literature, especially the popular press, abounds with many anecdotal reports of possible therapeutic efficacy but there remains the need for well-designed clinical studies to establish their true value.
Early in 2021 the UK Government’s Taskforce on Innovation, Growth and Regulatory Reform (TIGRR) made key recommendations that, if implemented, could see the licensing of certain aspects of the UK’s medicinal cannabis industry moved away from Home Office control to the Department of Health and Social Care or the regulator, the MHRA.
The MHRA is recognised internationally for both its competency in reviewing applications for Product Licences and its speed of review. Importantly, in addition to safety and efficacy it ensures that medicines imported into or manufactured in the UK are sourced from reputable suppliers and manufacturers and are inspected for compliance with Good Manufacturing Practice standards, including confirmation of reproducible quality and stability.
For some years, the MHRA has operated an Early Access to Medicines Scheme (EAMS)and more recently established a new process – the Innovative Licensing and Access Pathway (ILAP) – to improve patient access via the acceleration of the clinical evaluation of medicines; especially those for high unmet need.
Many of the conditions for which a CBPM might be appropriate are likely to be rare disorders. Fortunately, the UK’s rare disease framework has established four key priorities viz:
So, processes and procedures are in place to perform these clinical studies and to obtain rapid regulatory review but, given the experience of the NIHR initiative, a different approach is now required.
The path to more UK clinical trials
What is needed is a new mechanism whereby such trials can be prioritised by an expert group skilled in the field and that the trials are conducted at optimal pace so to ensure the earliest possible benefit to patients. In that respect we should consider what lessons we have learned from the COVID-19 pandemic and how they may be applied to CBMPs.
The establishment in the UK of the RECOVERY trial by the UKRI’s Medical Research Council and the NIHR proved to be an efficient and effective process resulting in the identification and validation of key COVID-19 therapeutic agents; in months rather than the more usual time frame of several years. A similar initiative could be established for identifying CBMPs that could be rapidly evaluated in selected conditions of high unmet need.
It should be noted that CBMPs cover a range of products from single, highly purified, individual cannabinoids e.g., Cannabidiol (CBD) (whether extracted and purified from Hemp or Marijuana plants or chemically synthesized) to extracts containing a number of cannabinoids together with plant constituents such as terpenes and flavonoids. It will be important that companies applying to participate in the prioritised trials demonstrate that such extracts are consistent chemically from batch to batch and have acceptable shelf lives for transport, storage and use.
The steps to the formation of such a Centrally Coordinated initiative would be as follows. First, a working group of clinicians with knowledge of medicinal cannabis (probably selected from the Specialist Register of the GMC) should be convened to identify a short-list of (probably rare/Orphan) conditions. (See appendix). To this group should be added several scientists / researchers with expert knowledge of the current research on Cannabinoids / CBMPs to match and prioritise candidate CBMPs to the short-listed therapeutic areas.
The MHRA would then need to agree a modus vivendi which will probably include establishing a specialised review group within MHRA, agreeing protocols*for each therapeutic indication and a prioritised pathway for review of the clinical trial data.
These model protocols should be discussed with a group of selected experts from the pharmaceutical and biotech industry so that they are codesigned with respect to their scientific and commercial feasibility. Such a group could include members of a consortium drawn from the Association for the Cannabinoid Industry CMC / ACI.
Patient groups in each therapeutic area should be consulted to ensure that the protocols are realistic for the patients and carers and to raise awareness of the initiative with their respective memberships.
Then the Department for Health & Social Care should establish a register of clinical centres (and their specialist clinicians) where clinical trials into CBPMs to full GCP standards can be conducted in the selected therapeutic areas. (This may require further capacity, building on the specialist centres on the GMC list).
Then the NIHCR should .issue a call to companies involved in CBMP R&D requesting proposals for consideration; importantly, including evidence that the product to be clinically evaluated is prepared to GMP standards and is of reproducible quality using adequately validated analytical methodology.
Finally, the programme would prioritise the number of products and therapeutic areas that should be the subject of the initial programmes and provide some seed-funding.
Whilst the cost of conducting the trials, the supply of clinical trial material and the construction and submission of dossiers for regulatory review will be borne by the individual companies participating, given that many of these companies could be relatively small enterprises, it is probable that some other form of financial funding will be required. This could be from one or more of new UK Government Life Science initiatives announced during 2021.In that context, companies that submit proposals and the source of the products could be from within the UK or from other countries. It may be necessary to establish what economic incentives are available to companies depending on their geographical base.
Due to the unique nature of the selected therapeutic areas, it is envisaged that these protocols will be sufficient to determine whether it is acceptable to grant Product Licence approvals on limited data to be followed by the continued acquisition and reporting of “Real World” data both from the subjects involved in the trials and a wider population. This might also include data from carefully designed observational studies.
Further, before a trial begins and as data emerge, discussion should be held with the National Institute for Health and Care Excellence (N.I.C.E.) to agree what parameters will be required for an appropriate Health Technology Assessment. It is encouraging to note the recent announcement that N.I.C.E. is ambitious in the scope and breadth of its review and that it will continue to welcome contributions from all stakeholders.
Some of the CBMPs that emerge from this initiative may face challenges in the context of supply due to a variety of factors, including their legal status / scheduling. These aspects should be thoroughly reviewed as the clinical trials progress to establish whether current requirements may need modification to ensure ease of access by the patients whilst safeguarding the general public. Equally, patient access might be assisted by applying items from the Accelerated Access Collaboration (AAC) and the expansion of the Innovative Medicines Fund.
In conclusion, given the potential therapeutic benefit to patients that recent research has identified for selected medicinal cannabis products, the UK should take the initiative to identify priorities, streamline clinical and regulatory pathways and patient access schemes ensuring that the quality and reproducibility of the products is ensured.
1) Epidyolex and Sativex. GW Pharmaceuticals
4) UK Government Life Science Initiatives
5) Accelerated Access collaborative