Dr Andy Yates, Chief Scientific Officer | Artelo Biosciences
Dr Parveen Bhatarah, Regulatory & Compliance Associate | The Centre for Medicinal Cannabis
Dr Paul Dickinson, Founder | Seda Pharmaceutical Development Services
Steve McConchie, CEO | Aptus Clinical
The UK has a strong history of pharmaceutical Research & Development (R&D) leading to the approval of significant medicines from antibiotics to monoclonal antibodies. More recently, it has been the home for the world’s first biotech focused on developing cannabinoid medicines (GW Pharma acquired by Jazz Pharmaceuticals for $7B in February 2021). Against this backdrop, current interest in the benefits of cannabinoid medicines and the new regulatory freedoms afforded by Brexit should make the UK a “go-to” global hub for cannabinoid R&D and first major market regulatory approval.
lobally respected institutions such as Medical Research Council, NIHR, NHS and the MHRA as well as leading academic cannabinoid research institutions located at the University of Aberdeen, Aberystwyth University, Kings College London, Imperial College London, Manchester Metropolitan University and University of Nottingham make the UK an ideal research environment for the development of cannabinoid based medicines.
Real-life experience by the authors of this paper has shown the difficulties of developing controlled drugs such as cannabinoids as licensing of activities across the R&D supply chain is exclusively controlled by the Home Office and not the MHRA. We make the case that for cannabinoids being developed in an already highly regulated clinical trials environment that the licensing authority should shift from the Home Office to the Department of Health and Social Care (DHSC)/MHRA which will speed development, reduce cost and red-tape and lead to increased R&D expenditure and innovation within the UK.
The current barriers
A perspective from a UK-based full service clinical contract research organisation specialising in the design, set-up and delivery of early phase patient studies in oncology, seeking to attract global companies to conduct their early trials in the UK, is useful in highlighting the challenges in working with Schedule 1 controlled Investigational Medicinal Products (IMP) in the UK.
In recent years, the MHRA (responsible for regulatory approvals), the HRA (responsible for ethical approvals) and NIHR (responsible for clinical research within the NHS) have worked closely together to streamline their processes to support faster trial set-up timelines.
As a result, in our experience, a typical timeline from availability of a final protocol to clinical site initiation (i.e. ready to recruit patients) is 4-6 months for a UK site, which places the UK clinical research ecosystem in a strong competitive position globally. However, our operational experience to date is that securing a Schedule 1 licence from the Home Office is adding at least an additional 3 months to the set-up timeline for each UK site compared to a non-cannabinoid oncology clinical trial.
Reasons for these delays were as follows:
In the experience of this one company, these factors were further exacerbated by resourcing constraints at both the sites and at the Home Office.
The additional complexity, cost and timeline delays directly resulting from the Home Office approvals process has necessitated us to divert some of our trial set-up activities to new sites in Europe and Australia. By way of comparison, the same company achieved set-up of a site in one European country in 5 months. The operational “log jam” caused by the Home Office approval step needs to be addressed if the UK research ecosystem is serious in its stated aim of being a global destination of choice for cannabinoid clinical research.
Current licensing requirements for Schedule 1 agents such as cannabinoids impose almost insurmountable restrictions on the pharmaceutical development activities required to reach the clinical development phase. The ability to identify Contract Research Organisations (CRO)/Contract Development and Manufacturing Organisations (CDMO) with appropriate technical capabilities and quality standards required for project delivery is severely compromised when the additional requirement that each of them is licensed for the possession of controlled drugs is overlaid.
The operational “log jam” caused by the Home Office approval step needs to be addressed if the UK research ecosystem is serious in its stated aim of being a global destination of choice for cannabinoid clinical research.
Pharmaceutical development takes place to convert the active pharmaceutical ingredient into a drug product suitable for its intended use. In the early stages of drug development, this will include design and optimisation of the formulation composition, analysis of the drug substance and drug product and stability testing, process development, scale up and manufacture for preclinical and clinical study supply. It is rare that a single CRO/CDMO could perform the diverse range of processes/analytics required. It is common for aspects such as microbiological testing to be performed by a third-party specialist.
Additionally, in these early phases of development, there is a relatively limited understanding of the compound or product and unexpected results may be observed. To understand the cause of these observations and whether they present risk to patients, investigations using state of the art equipment at specialist CROs (who are even less common) may be required.
Drug substance properties (such as low solubility, poor permeability, or instability within the digestive tract) may necessitate application of advanced formulation techniques. Specialist manufacturing technology may be required, which severely restricts the pool of appropriate CROs/CDMOs suitably equipped to perform formulation, process development and manufacturing activities.
It should be noted that the important phase of pharmaceutical development of cannabinoids (often taking 1-3 years to conduct) is not helped by the 2018 MDR changes which reschedule CBMPs to schedule 2 as they are only rescheduled from schedule 1 to 2 when they are being used for clinical trials (which is not the case in early research as its this research which ultimately leads to clinical trials) and does not cover novel synthetic derivatives of THC or other non-cannabinoid based controlled drugs.
When overlayed with the licensing requirements and controls for the production, possession, storage, supply, and import/export of Schedule 1 agents such as cannabinoids, the challenges are clear. A recent vendor selection exercise to identify a GMP CDMO with a schedule 1 controlled drugs license and the required technical manufacturing capability, lead to a pool of one. While this at least gave us a single way forward, this is a high risk and highly undesirable position to be in. In addition, identifying suitable third-party specialist service providers who also possessed appropriate licences added significant time delays to the project plan. It is our view that under the current licensing requirements, pharmaceutical development of schedule 1 drugs such as cannabinoids is disproportionately challenging.
Two previous reviews conducted in 20171 and 20192 of these difficulties have been conducted by the Advisory Council for the Misuse of Drugs (ACMD) which made a number of extremely useful recommendations which were never adopted by the Home Office. Of particular note is the concept of rescheduling a compound to a temporary “research schedule’ with reduced requirements for the purpose of clinical evaluation. If clinical research continues, this status can be maintained but if trials fail then the compound would revert to Schedule 1. Should a compound get as far as product registration then the legal status of the resulting marketed medicine would be determined in the usual manner.
In the light of our new regulatory environment post-Brexit and our proposal for the MHRA to undertake controlled drug licensing decisions for products with medicinal use we strongly urge that the ACMD recommendations are reviewed again alongside industry consultation and implemented as soon as possible.
Under the current licensing requirements, pharmaceutical development of schedule 1 drugs such as cannabinoids is disproportionately challenging.
A better way
In our proposal, we suggest that the MHRA is well placed to take over the licensing of controlled substances with potential medicinal use for the following reasons.
The MHRA’s mission statement is to provide a leading role in protecting and improving public health and supports innovation through scientific research and development. They are a world-renowned and respected regulatory authority which has previously been a “go-to” lead agency (rapporteur) within Europe to oversee the evaluation of medicine applications; a now defunct role since Brexit.
Furthermore, the MHRA is already set-up to audit, inspect and license within the highly regulated environment of Human Clinical Trials. They have the prerequisite knowledge of the complexity of drug development to be able to grant the appropriate license to the sponsor at the appropriate time point. There are already mechanisms in place such as Scientific Advice in which a sponsor can explain in full their scientific data and development and regulatory approach in which controlled drug licensing decisions can be made.
We believe that with relatively small changes to the legislation and regulatory framework that the UK’s already well-established R&D environment can benefit for becoming the “go-to” home for over 100 ongoing clinical studies with cannabinoids and many more clinical studies for other schedule 1 controlled substances (e.g. LSD, MDMA, Psilocybin) which are currently of high scientific and clinical interest.