DMC0061

 

Written evidence from Epilepsy Action

 

Executive summary

 

 

What next?

 

 

About Epilepsy Action

 

Epilepsy Action is the UK’s leading epilepsy organisation and exists to improve the lives of everyone affected by the condition. As a member-led organisation, we are led by and represent people with epilepsy, their friends, families and healthcare professionals. Epilepsy can affect anyone at any age and from any walk of life.

             

Epilepsy is one of the most common serious neurological conditions in the world. It affects around 600,000 people in the UK. This means that 1 in 100 people in the UK have epilepsy. Around 87 people are diagnosed with epilepsy in the UK every day. The condition is unpredictable and fluctuating, meaning it affects people in different ways and its impact can vary from day to day. Up to 30% of people with epilepsy will not achieve seizure freedom with the treatments currently available.

 

If you require any additional information please contact our Senior Policy and Campaigns Officer, Sam Mountney, at smountney@epilepsy.org.uk.

 

 

  1. Currently available, good quality, clinical evidence focusses largely on a specific compound present in the cannabis plant, cannabidiol (CBD), as an adjunctive treatment for seizures associated with two specific paediatric-onset epilepsy syndromes, Dravet syndrome and Lennox-Gastaut syndrome (LGS)

 

  1. To put this into context, there are over 40 types of epilepsy and up to one hundred active compounds in the cannabis plant. Subsequently the current body of good-quality clinical evidence is limited on two fronts, the types of epilepsy and types of cannabis-based medicines.

 

  1. However, there is emerging evidence that CBD is effective in tuberous sclerosis complex, Febrile Infection-Related Epilepsy Syndrome (FIRES) as well as CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

 

  1. https://www.ncbi.nlm.nih.gov/m/pubmed/30006259/ - ‘Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.’ Devinsky O, et al. 2018.
     
  2. https://onlinelibrary.wiley.com/doi/full/10.1111/epi.13499 - ‘Cannabidiol as a new treatment for drug‐resistant epilepsy in tuberous sclerosis complex’. Hess E. J, et al. October 2016.
     
  3. https://www.ncbi.nlm.nih.gov/pubmed/28188044 - ‘Cannabindoids in treatment resistant epilepsy: a review’. O’Connell B. K, Gloss D, Devinsky O. November 2016.

 

  1. Despite the relative lack of good quality clinical evidence around the efficacy of other compounds found in the cannabis plant for the treatment of epilepsy, there is a growing body of compelling lower quality research as set out above along with strong anecdotal evidence.

 

  1. It is increasingly the case that anecdotal evidence is outpacing clinical evidence in this field. Compelling anecdotal evidence and large scale media attention on specific cases and the rescheduling of some cannabis-based medicines has led to a surge in interest in, and subsequently demand for, cannabis-based medicines for the treatment of epilepsy in the UK.

 

Cannabidiol (CBD)

 

  1. There is good quality clinical evidence of safety and efficacy of pure cannabidol, Epidiolex, as an adjunctive treatment for seizures associated with Dravet syndrome and Lennox-Gastuat syndrome (LGS). This is in the form of double blind placebo controlled trials.

 

  1. https://www.nejm.org/doi/full/10.1056/NEJMoa1714631 - ‘Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome’. Devisky, O et al. May 2018.

 

  1. https://www.nejm.org/doi/full/10.1056/NEJMoa1611618 - ‘Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome’. Devinsky, O et al. May 2017.

 

  1. This high quality clinical evidence contributed to Epidiolex being approved by the U. S. Food and Drug Administration in June 2018 for the treatment of seizures associated with Dravet syndrome and LGS. Epidiolex is being similarly assessed by the EMA who are currently reviewing the Market Authorization Application (MAA) for this treatment.

 

  1. Further assessment processes are under way in the UK and are being conducted by the National Institute for Health and Care Excellence (NICE) and other relevant organisations. It is expected that Epidiolex will be licensed for use in the UK in the first half of this year.

 

  1. There is a lack of similar good quality clinical evidence of the safety and efficacy of Epidiolex for the treatment of other epilepsies. Despite this there is a compelling case to be made that, in light of the clinical evidence set out above, Epidiolex is likely to be similarly safe and efficacious as an adjunctive treatment for other intractable epilepsies.

 

Other cannabinoids including tetrahydrocannabinol (THC)

 

  1. There has been some research into cannabis-based medicines containing CBD and THC as an adjunctive treatment for seizures associated with intractable epilepsies. One such open label trial, linked below, focussed again on children with Dravet syndrome. The trial involved a cannabis plant extract produced by a Canadian company, Tilray, which contains 100 mg/mL CBD and 2 mg/mL THC.

 

  1. https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.621 - ‘A prospective open‐label trial of a CBD/THC cannabis oil in dravet syndrome’ McCoy, B et al. August 2018.

 

  1. Despite the open trials of the kind noted above, there have been no randomised control trials (RCTs) published of the kind that is often needed to prove clinical safety or efficacy.

 

  1. A phase one open label clinical trial of the same Tilray product mentioned above, otherwise known as TIL-TC150, is currently underway in Canada. This trial is looking at TIL-TC150 as an adjunct treatment in children with Dravet syndrome. The study is due to end in October 2019.

 

  1. https://clinicaltrials.gov/ct2/show/NCT02983695

 

  1. From the outset of the debate around cannabis-based products for medicinal use, Epilepsy Action highlighted the need for high-quality clinical evidence around the safety and efficacy of cannabis-based products for medicinal use (CBPMs) containing both THC and CBD, for the treatment of epilepsy.
     
  2. However, under the direction and supervision of senior clinicians and with the agreement of the Home Secretary these products have been made available to at least two children in the UK with intractable epilepsy.
     
  3. Whilst the evidence is largely anecdotal, it is compelling. These products have had a transformative effect on these children and their families including a marked reduction in seizure frequency and severity coupled with distinct improvements in quality of life.
     
  4. It is difficult to uphold a position that allows a handful of children to access a specific treatment that, albeit anecdotally, has shown to provide notable improvements in seizure control and quality of life yet deny these treatments to others in the same or even similar situations. This is especially apt given the nature of these epilepsies, seizure control is unachievable for most people with severe epilepsy syndromes with the treatments currently available.

 

  1. Epilepsy Action believes that cannabis-based medicines, including CBPMs containing both THC and CBD, should be made available for children and adults with severe and treatment-resistant epilepsies where there is individual evidence of safety and efficacy (for example, a patient has previously accessed the treatment abroad and it has shown to be efficacious) or there are similar, comparable cases in which specific cannabis-based medicines have shown to be safe and efficacious.

 

 

Plans for research in the UK

 

  1. A formal call for research proposals in relation to cannabis-based medicines was put out by the National Institute for Health Research (NIHR) late last year.
     
  2. https://www.nihr.ac.uk/funding-and-support/funding-opportunities/?&start=1&custom_in_Specialty=9310

 

Challenges to research

 

  1. Large scale randomised clinical trials (RCTs) of the kind that are commonly required for a medicine to be licensed for use in the UK often take a number of years. This is problematic in relation to cannabis-based medicines due to the large body of anecdotal and ‘trial of one’ evidence that has emerged. When coupled with the political, media and public attention around cannabis-based medicines particularly in the last 12 months the situation for those affected by intractable epilepsies who could potentially benefit is unsatisfactory.

 

  1. There is a need for a more concerted effort to initiate large scale RCTs and also to explore alternative evidence bases such as more formalised clinical reporting of safety and efficacy in those patients who are currently accessing CBPMs containing both THC and CBD in the UK.

 

  1. Even with suitable high-quality research, challenges would remain. One of the main challenges is cost. Using the example of Sativex, a cannabis-based medicine licensed for use in the UK to treat spasticity associated with multiple sclerosis, despite being licensed in light of good clinical evidence it is not routinely prescribed on the NHS in England. The high cost of Sativex has led to the treatment being subject to a ‘do not do’ recommendation from NICE due to it not being considered a cost effective treatment.

 

  1. Another relevant comparison is Everolimus, a disease modifying drug that can be used as an adjunctive treatment for refractory focal onset seizures associated with tuberous sclerosis complex (TSC). Despite being licensed for use in this capacity by the European Medicines Agency (EMA) in January 2017, it will not be routinely commissioned through NHSE until April 2019 (https://www.england.nhs.uk/wp-content/uploads/2018/12/Everolimus-for-refractory-focal-onset-seizures-associated-with-TSC.pdf).

 

  1. A key factor in this delay was the high cost of the drug, around £36 000 per patient per year. Epilepsy Action are concerned that in light of the current price point, access issues are likely to continue even if Epidiolex is licensed for use and a protracted process of negotiations may continue to restrict patient access.

 

  1. There is real concern that even if good quality clinical evidence demonstrates safety and efficacy of some cannabis-based treatments, economic considerations will prevent them from being made routinely available on the NHS in a timely manner.

 

 

  1. The decision to reschedule some cannabis-based medicines from schedule 1 to schedule 2 that came into effect on 1 November 2018 was a welcome change that allows for clinicians to legally prescribe some cannabis-based medicines on a case-by-case basis.

 

  1. Despite the legislative change, associated interim clinical guidance produced by professional organisations including the British Paediatric Neurology Association (BPNA) and the Association of British Neurologists (ABN) is very restrictive and subsequently very few people with epilepsy are able to access cannabis-based medicines.

 

  1. Epilepsy Action’s latest positon in relation to current procedures and guidance around cannabis-based medicines is set out clearly on our website. The post also provides a summary of access routes and associated limitations for specific patient cohorts - https://www.epilepsy.org.uk/involved/campaigns/cannabis.

 

  1. Current procedures for accessing cannabis-based medicines are seemingly more restrictive post-rescheduling compared to the case specific Home Office application process that was in place prior to 1 November 2018. Under the auspices of the Expert Panel system, two children with rare and intractable epilepsies were issued Home Office licenses to access Good Manufacturing Practice (GMP) certified CBPMs containing both THC and CBD on the NHS. Post-rescheduling, we are not aware of any patients with rare and intractable epilepsies who have been prescribed CBPMs containing both THC and CBD on the NHS.

 

  1. In relation to accessing Epidiolex, current procedures fair somewhat better. The extended access scheme for Epidiolex that has been established by the manufacturer, GW Pharmaceuticals, and the National Health Service (NHS) will make the drug available for around 150 children and adults with Dravet syndrome or Lennox-Gastaut syndrome at no cost to prescribers. We are yet to see any figures relating to numbers of prescriptions for Epidioledx from the Department of Health and Social Care/ NHS England. We would hope that Epidiolex being made available through the extended access scheme is being prescribed to patients accordingly but we will not know for sure until relevant data is made available.

 

  1. Despite this scheme, we have heard from parents and carers of children with these syndromes who are yet to access Epidiolex. A degree of uncertainty also remains around the decision making process for accessing Epidiolex through the scheme.

 

  1. The extended access scheme highlights another ongoing issue with the current procedures, cost. Outside of the scheme, Epidiolex and other cannabis-based medicines can legally be prescribed as ‘Specials’, as per the Medicines and Healthcare products Regulatory Agency (MHRA) definition. Under MHRA regulations for ‘Specials’, the costs of prescribing unlicensed medicines are met by the prescribing Trust. Based on the current cost of the treatment in the United States, Epidiolex costs around £25 000 per patient per year. These significant costs could be a disincentive to Trusts who have to sign off and subsequently fund ‘Specials’ prescriptions.

 

  1. Given the cost of the medication and the potential risks associated with prescribing an un-licensed medicine, in certain instances against the advice of professional organisations, the possibility of patients accessing these medicines through this route is currently very slim.

 

  1. We have heard anecdotally of some clinicians who have been willing to prescribe cannabis-based medicines but have subsequently withdrawn prescriptions before they have been made available in light of conversations with indemnity providers, informed by the current interim clinical guidance. There is a perceived risk on the part of some specialist clinicians that prescribing cannabis-based treatments could negatively impact their professional reputation or even lead to them facing disciplinary action.

 

  1. Epilepsy Action believes protocols should be drawn up with the leading clinical bodies and patient representatives that would provide a sound basis for prescribing un-licensed cannabis-based medicines, including CBPMs containing both THC and CBD, in limited circumstances. A good starting point for such a protocol would be the application form developed for applications to the Expert Advisory Panel that considered applications for cannabis-based medicines prior to the change in legislation. This would cover a full evaluation of the other treatment options tried and potentially available. A discussion around the evidence or lack of it for the particular treatment being considered, and a discussion around the risks of the proposed treatment. It should include a protocol for monitoring treatment and criteria for stopping treatment if it is not proving effective.

 

  1. Epilepsy Action believes this would provide a structure for informed patient consent and support for clinicians in deciding when it may be appropriate to prescribe a cannabis-based medicine.

 

 

  1. There is apparent variation in clinician’s knowledge, opinions and willingness to consider cannabis-based medicines for the treatment of intractable epilepsies.

 

  1. While reviewing our own position statements on cannabis-based medicines Epilepsy Action reached out to a number of clinicians to seek their professional views and opinions on this issue. The variation in responses we received is indicative of the current situation when it comes to clinician’s attitudes towards cannabis-based medicines.

 

  1. Epilepsy Action have heard some anecdotal reports of specialist clinicians being unwilling to discuss cannabis-based medicines with patients. We are similarly aware that clinicians are increasingly inundated with patients who want to discuss whether cannabis-based medicines may be suitable in light of media reports and increased public attention on this issue.

 

  1. As with any new potential treatment, specialist clinicians will actively engage with the relevant clinical studies and guidance provided by professional bodies and others in assessing the safety, efficacy and potential suitability of the treatment for their patients. Despite this, cannabis-based medicines are somewhat unique in having previously been positioned as a schedule 1 drug in the UK denoting no known medical benefit. Combined with the common conception of cannabis as an illegal recreational drug, there is a case to be made for additional education and training for prescribing clinicians.

 

  1. A programme of education and training for clinicians around cannabis-based medicines including but not limited to safety, efficacy, dosing and indications would be a welcome step towards ensuring prescribing clinicians have the knowledge and confidence to appropriately and safely prescribe cannabis-based medicines. This would also address some of the institutional and regional variations in specific clinician’s attitudes and approaches to these potential treatments.

 

 

  1. Epilepsy Action believes that the interim clinical guidance from the BPNA and ABN is too restrictive. We have heard from a number of families of children with severe and treatment resistant epilepsies who remain unable to access cannabis-based medicines despite rescheduling. Our concerns are two-fold:
     
  2. Epidiolex is not being made available on NHS prescription to some patients who meet the prescribing criteria as set out by the BPNA and ABN.
     
  3. Other GMP certified CBPMs containing both THC and CBD are not being made available on NHS prescription in any circumstances.

 

Issues accessing Epidiolex

 

  1. The focus on Dravet syndrome and Lennox-Gastaut syndrome in light of the available, good quality clinical evidence has led to patients with other intractable epilepsies being largely unable to access Epidiolex.

 

  1. The BPNA interim clinical guidance does not specify that a patient must have a specific epilepsy syndrome in order to meet the criteria set-out for access Epidiolex. Instead there are three criteria set out in the guidance that children would have to satisfy to meet the BPNA recommendations for when cannabis-based medicines (specifically Epidiolex) should be used:

 

  1. ‘5.2 Prescription of a non‐licensed cannabis‐based product for medicinal use should be used as a treatment of last resort for children who meet the following three criteria:

 

  1. 5.2.1 Have an epilepsy that has proven intractable to treatment with conventional licensed anti‐epileptic drugs given at therapeutic doses.

5.2.2 Have not responded to the ketogenic diet or for whom the diet is inappropriate.

5.2.3 Are not candidates for epilepsy surgery.’ (p.13, https://www.bpna.org.uk/userfiles/BPNA_CBPM_Guidance_Oct2018.pdf)

 

  1. The BPNA guidance does seemingly allow for clinicians to use their discretion when assessing whether a child may be suitable to consider for cannabis-based treatments. Despite this, for reasons set out in the totality of this submission, it is seemingly only through the extended access scheme that children have been able to access Epidiolex since rescheduling. The extended access scheme is restricted to children with Dravet and Lennox-Gastaut syndrome.

 

  1. Interim clinical guidance for adults with epilepsy produce by the ABN is arguably more restrictive. Returning to the epilepsy syndromes with clinical evidence of efficacy, the ABN recommends only prescribing cannabis-based medicines as a last line treatment in cases of carefully diagnosed Dravet syndrome and Lennox-Gastaut syndrome. For other intractable epilepsies the ABN guidance states that ‘we would advise extreme caution if these products are being considered for any other form of epilepsy.’ (p.2, https://www.theabn.org/media/Documents/ABN%20publications/ABN%20guidelines%20Use%20of%20cannabis-based%20products%20in%20neurology%20December%202018%20v2.pdf)

 

  1. For children and adults with intractable epilepsies other than Dravet or Lennox-Gastaut syndrome, accessing Epidiolex through the NHS is incredibly difficult and ultimately it is very unlikely that it will be made available.

 

Issues accessing GMP certified CBPMs containing both THC and CBD

 

  1. The interim clinical guidance produced by both the BPNA and ABN explicitly advises clinicians against prescribing other non-licensed cannabis-based medicines, besides Epidiolex.

 

  1. These other cannabis-based medicines include the GMP certified CBPMs containing both THC and CBD that have been made available initially through Home Office license and subsequently on NHS prescription for two children with intractable epilepsy – Alife Dingley and Billy Caldwell.

 

  1. It is disappointing that since rescheduling, no subsequent NHS prescriptions have been written.

 

  1. Epilepsy Action are similarly concerned about recommendation 5.11 in the BPNA guidance. This recommends transitioning patients who are currently prescribed non-licensed CBPMs containing both THC and CBD to Epidiolex, irrespective of current benefits.

 

  1. Given the apparent improvements in seizure management and quality of life these products have led to for the few who have been granted access, it would seem wholly counterintuitive to transition this group off an effective treatment and on to a different yet similarly un-licensed medication that may be ineffective. Indeed, in the case of at least one child currently receiving CBPMs containing both THC and CBD for intractable epilepsy, it is our understanding that Epidiolex has previously proven ineffective for this individual in the longer term.

 

  1. Epilepsy Action recognises that cannabis-based products, including CBPMs containing both THC and CBD, will not be suitable or effective for all people with epilepsy. We do believe, however, that in light of the observable and positive clinical outcomes in the cases of Alfie Dingley and Billy Caldwell clinicians should be able to consider other non-licensed cannabis-based products for medical use that meet relevant quality standards as a last line treatment for children with severe and treatment resistant epilepsies.

 

  1. The current interim clinical guidance from both the BPNA and ABN effectively prevents clinicians from prescribing CBPMs containing both THC and CBD on the NHS. We have heard from Tannine Montgomery, mother of Indie Montgomery a young girl with Dravet syndrome. Indie was granted a short term license to access CBPMs containing both THC and CBD by the Expert Advisory Panel shortly before rescheduling came into effect. Since rescheduling Indie has had her license revoked. Indie’s paediatrician has highlighted compelling evidence of efficacy, including a 50% reduction in seizure frequency and notable improvements in quality of life yet the very same neurologist has stated that he is unable to prescribe the CBPMs containing both THC and CBD that she was accessing prior to the change in the law.

 

  1. In an excerpt of a letter shared on social media by Tannine, Indies paediatrician notes that, despite compelling clinical evidence, ‘I am duty bound to follow the guidance of the Paediatric Neurologists and my Medical Director, and so regrettably cannot prescribe these medications’. (https://twitter.com/TannineM/status/1091988197444386816)
     

  1. Epilepsy Action would like to see the guidance strengthened by making it very clear that ultimately, if a clinician believes that a cannabis-based medicine may be efficacious in a particular case, then they are able to prescribe it, and would not face professional sanctions. Such products could be either a licenced medicine (if and when Epidiolex is licensed) or an unlicensed but legal compound, as indicated by the Supplementary Information on cannabis-based products for medicinal use issued by the DHSC 20 November 2018.

 

 

  1. Epilepsy Action has not conducted a large scale survey of the views of people affected by epilepsy in relation to cannabis-based medicines. Anecdotally we have experienced very little resistance from members or others affected by epilepsy to the idea of making these products available to those who could benefit.

 

  1. There has been increasing frustration from some people affected by epilepsy, particularly parents and carers of children with severe and treatment-resistant epilepsies, regarding continued access issues to cannabis-based medicines since rescheduling in November 2018.

 

  1. It is likely that this frustration has stemmed in part from the media reporting of cannabis-based medicines. The large scale coverage of specific cases of children with intractable epilepsy who have seen marked improvements in seizure control and subsequently quality of life while using cannabis-based medicines has led to others with similarly intractable epilepsies desperately seeking the same apparent benefits.

 

  1. This messaging is particularly powerful to those affected by rare and treatment-resistant epilepsies who have often tried multiple antiepileptic drugs (AEDs) and other treatment options without success.

 

  1. There is an urgency amongst this cohort to access these treatments in light of the severity of many intractable epilepsies and the risks that are associated with uncontrolled seizures, including an increased risk of Sudden Unexplained Death in Epilepsy (SUDEP). As such, the apparent delay in patients being able to access these treatments further exasperates their concerns.