Shortly after the change of law in 2018 allowing specialist clinicians to prescribe cannabis-based medicines, the National Institute of Health Care Excellence called for further research before they could give any recommendation to prescribed to the wider population of children and adults diagnosed with drug-resistant epilepsy.
Their two main research questions are :
CBD for severe treatment-resistant epilepsy.
What is the clinical and cost effectiveness of CBD in epileptic disorders in children, young people and adults?
THC in combination with CBD for severe treatment-resistant epilepsy.
Does the addition of THC to CBD have an effect on seizure frequency, brain structure and neuropsychological performance when compared with both CBD alone and placebo in epileptic disorders in children, young people and adults?
It’s taken many years, however the British Paediatric Neurology Association (BPNA)  announced an upcoming NHS trial by University College London (UCL) and the British Paediatric Neurology Association (BPNA) using Ananda Pharmaceuticals MRX formulations for childhood and adult drug-resistant epilepsy:
The trial is a Phase IIIa randomized controlled trial (RCT) funded by the National Institute for Health and Care Research (NIHR) and NHS. It aims to test the safety and efficacy of Ananda’s first generation MRX2 (CBD-only) and MRX2T (CBD + THC isolate) formulations in treating drug-resistant epilepsy in both children and adults. The trials will have up to 500 patients diagnosed with early onset epilepsies or genetic generalised epilepsies. This trial is multi-centred across NHS hospital trusts across England and Wales.
Trial 1 = MRX2 or Placebo vs MRX2T or placebo.
This trial will compare the results of two groups to ascertain whether THC adds any benefit over CBD or placebo. Children diagnosed with early onset epilepsies will be randomly assigned to either group.
Trial 2 = MRX2 or Placebo vs MRX2T or placebo
This trial will randomly select adults who have normal cognitive ability and diagnosed with a genetic generalised epilepsy. Aside from ascertaining efficacy and safety comparing the two groups, this group will be used to ascertain whether THC has any detrimental impact to learning, behaviour, and overall quality of life. Â
Co-Lead: Prof Finbar O’Callaghan and Prof Helen Cross from UCL and Great Ormond Street Hospital (GOSH).
If successful, the trial results could support applications for regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) and other regulatory bodies.
Randomised controlled trials (RCTs) are considered the gold standard in medical research because they compare the effects of different treatments on similar groups of people. However, many experts argue that RCTs aren’t always suitable for assessing medical cannabis products or treating rare diseases.
As Professor Mike Barnes, a consultant neurologist and medical cannabis expert, points out, RCTs are “fine for a new single-molecule pharmaceutical product but don’t lend themselves to the cannabis plant, which is a complex organism.” Second-generation cannabis-based medicines often contain multiple active ingredients—sometimes over ten. RCTs by design test isolated compounds as shown with this trial isolating CBD and THC, potentially overlooking the synergistic effects of other cannabinoids and terpenes.
In this trial, the placebo will include terpenes, compounds found in many plants, fruits, and vegetables, including cannabis. Terpenes are known to have beneficial and possibly medical benefits for humans and may benefit a reduction in seizures. Using terpenes as a placebo has been criticized for potentially skewing results. Typically, you’d use an inert ingredient to add a flavouring to match that of the medicine being tested.
The MRX2T formulation of CBD and THC ratio will be static during the trial. Clinical practice and observational trials suggest that the optimal ratio of CBD, THC, and minor cannabinoids varies from patient to patient for the best therapeutic benefit and seizure control. This inflexibility in trial design will not show the true benefits as seen in real life clinical practice.
Children and adults who are already prescribed either Epidyolex through the NHS or an unlicensed CBPM privately, will be required to stop that medication for a minimum of 8 weeks to allow the levels of CBD or THC to drop below a therapeutic level before entering the trial. For those where great benefit is seen, it’s unethical and potentially dangerous to receive a placebo or just CBD, in particular if the child has previously been prescribed Epidyolex and shown little to no response.Â
Cannabinoid medicines are not taught in medical schools or universities, nor do the NHS provide any training for clinicians. Awareness of the differences between generations of products is severely lacking. If THC at the static ratio used is proven to match or be less effective than placebo or the CBD group, it shouldn’t be taken as the second generation of CBPM’s are ineffective because they contain THC.
We support continued research and clinical trials, Epidyolex has remained restricted to three syndromes of epilepsy, with approx only 200 patients accessing this via the NHS. If successful and upon NICE approval, this trial will help widen access to the first generation of CBD isolate which is a positive step when children have failed all other options. However, while the upcoming trial aims to provide valuable data on Ananda’s MRX formulations and answer the research questions posed by NICE, it highlights the broader challenges of using RCTs to evaluate complex and personalised second generation medical cannabis products, especially for rare diseases where personalised medicine may be more effective. At present a path of acceptable innovative trials adapting to the unique properties of the second generation of CBPMs of which NICE and MHRA would accept as robust enough, do not exist. At present we predict that we will only see further RCT trials in isolated cannabinoids at high costs and decades pass before we see results.
History has already highlighted that across the past 40 years, the number of childhood drug-resistant epilepsies has not fallen (30% of cases). That the RCT model and one size fits all approach has continued to fail in reducing drug-resistant seizures. A new personalised approach is being called for across the epilepsy community in particular rare epilepsies.