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Strengthening the evidence for medicinal cannabis and cannabinoids

BMJ 2019; 367 doi: https://doi.org/10.1136/bmj.l5871 (Published 21 October 2019) Cite this as: BMJ 2019;367:l5871

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Industry Response to "Strengthening the evidence for medicinal cannabis and cannabinoids"

Dear Editor,

In their article entitled “Strengthening the evidence for medicinal cannabis and cannabinoids”, Freeman et al.(1) highlight the potential value of alternate trial designs, and the use of patient registries, in the pursuit of strengthening the evidence for medical cannabis.

While it is widely acknowledged that more robust evidence on unlicensed cannabis-based products for medicinal use in humans (medical cannabis, or CBPMs) is required, its use and ease of access is widespread globally, including in countries with high regulatory standards, which has allowed for the accumulation of a substantial body of real world evidence. In Canada, at the end of September 2018 there were 342,103 medical cannabis patients registered on Health Canada’s database.(2) The government of Australia has approved over 17,300 applications for unlicensed medicinal cannabis products.(3) California alone in May 2018 had approximately 916,845 legal medical cannabis patients.(4) In the European Union (EU), medical cannabis was legalised for use in Germany in March 2017, and costs to patients are fully reimbursed. There were over 185,000 prescriptions authorised, and an estimated 60-80,000 patients using medicinal cannabis products in 2018.(5) In Italy, by the end of January 2019, 26,042 medical cannabis prescriptions, attributed to 12,998 patients were registered on the Italian Medicines Agency (AIFA) database to patients who had a mean age of 58 years, 63% of whom were women.(6) More recently, in an effort to meet growing patient demand for medical cannabis, pilot programmes, which have been increasingly viewed as an effective mechanism for controlled access, have been introduced in France, Denmark, and Ireland.(7,8,9) , , This is in contrast to the UK where since November 2018 doctors on the specialist register can prescribe medical cannabis: as of June 2019 only 12 medical cannabis perceptions were prescribed and dispensed in the community and submitted for reimbursement.(10)

The majority of people who seek medical cannabis, according to a systematic review of controlled trials and observational studies, do so to treat their chronic pain conditions, including neuropathic pain, cancer pain, and multiple sclerosis (MS).(11)

As governments around the world continue to try to address patient demand for medical cannabis, it is unlikely that this growing trend for improved access will be easily reversed. Additionally, it is our view that demand from patients in the United Kingdom (UK) is unlikely to be met, especially in the likely event that The National Institute for Health and Care Excellence (NICE) publish negative recommendations about cannabis-based medicinal products. We believe that NICE are using the current paucity of data as justification for restrictive guidance despite the existence of the high quality assessment by the USA’s National Academy of Sciences Engineering Medicine,(12) concluding that there is “conclusive or substantial evidence” to support cannabis’ use in multiple disease states; including chronic pain, chemotherapy-induced nausea and vomiting, and patient-reported MS spasticity. Of additional concern is the fact that many clinical trials have employed the use of surrogate, composite and subjective endpoints, and have failed to allow patients to inform research outcomes. This has often undermined the clinical relevance of these studies, and has resulted in a failure to adequately capture the “real-world” benefits of cannabis in the lives of patients.(13)

We acknowledge the relative paucity of data in relation to the efficacy and safety of medical cannabis, support the need to collect additional data, and are actively involved in research activities to increase the evidence base. One challenge that the medical cannabis industry faces is the rapidly changing regulatory landscape which is increasingly providing access to patients in many developed economies. Specifically, despite innovations in regulatory processes,(14) patient access is increasing far quicker than the time required to implement, analyse, and report on clinical trial data. As an alternative, real world patient registries are an accepted mechanism by which clinical trials can be informed, and are an appropriate way to collect effectiveness and safety data.(14,15,16)14, , This will facilitate access for patients, with the advantage that the risks of illicit access highlighted by Freeman et al(1)1, may be mitigated. Further advantages of a real world registry that complies with EMA guidance(15)15 and other international standards (such as the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance)(17) are that collected data can inform regulatory strategies to support market authorisations to the high standards accepted by regulators. Moreover, this type of high-quality data has also been used to support many drug authorisations by both EMA and FDA i.e. without depending only on randomised trials.(18,19) ,

Given the vast number of patients currently being treated with medical cannabis, the limited numbers of life threatening and serious adverse events, as well as the growing global demand, it is unlikely that it will be possible to restrict medical cannabis in developed economies. This will likely to continue to foster a burgeoning illicit market with the public health consequences that will ensue.

Thus, while an appropriate body of clinical evidence is being developed, we support the patient-focussed provision of medical cannabis, and the collection of real world data within a registry model, to ensure the appropriate collection of safety, effectiveness, quality of life data, as well as patient-valued outcomes, to support the development of appropriate clinical evidence. This will allow patients who could potentially benefit from treatment, to access medical cannabis, and is consistent with the UK Medicines and Healthcare Products Regulatory Agency’s guidance.(20) This specifies that all suppliers should report all suspected adverse reactions (serious and non-serious, including reports of failure of efficacy), along with conducting the enhanced pharmacovigilance activities to support its safe use.

References:
1. Freeman T, Morgan C, Hindocha C. BMJ 2019;367:l5871 doi: 10.1136/bmj.l5871 (Published 21 October 2019) Strengthening the evidence for medicinal cannabis and cannabinoids
2. Health Canada https://www.canada.ca/en/health-canada/services/drugs-medication/cannabi... (last accessed 28th Oct 19)
3. https://www.tga.gov.au/access-medicinal-cannabis-products-1 (last accessed 28th Oct 19)
4. https://www.statista.com/statistics/585154/us-legal-medical-marijuana-pa... (last accessed 28th Oct 19)
5. Lutzhoeft et al, 2019 https://www.twobirds.com/en/news/articles/2019/uk/investing-in-the-futur... (last accessed 28th Oct 19)
6. Roberto Da Cas et al. “The use and safety of Cannabis for medical use in Italy”. Medical Cannabis 2019 Controversies on Cannabis-based medicine Barcelona, Spain.
7. French cannabis committee unveils recommendations for medical cannabis pilot programme in France http://www.allenovery.com/publications/en-gb/Pages/french-cannabis-commi... (last accessed 28th Oct 19)
8. Danish Medicinal cannabis pilot programme https://laegemiddelstyrelsen.dk/en/special/medicinal-cannabis/citizens/m... (last accessed 28th Oct 19)
9. https://www.gov.ie/en/publication/90ece9-medical-cannabis-access-programme/ (last accessed 28th Oct 19)
10. https://www.parliament.uk/business/publications/written-questions-answer...
11. Nugent SM., et al., The effects of cannabis among adults with chronic pain and an overview of general harms. A systematic review. Ann Intern Med 2017;167:319-331
12. National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research. Washington, DC: The National Academies Press http://nationalacademies.org/hmd/Reports/2017/health-effects-of-cannabis... (last accessed 28th Oct 19)
13. Heneghan, Goldacre et al. Trials March 2017. Why clinical trial outcomes fail to translate into benefits for patients i
14. Myrto Lee, Hoan Ly, Clemens C et al. Clin Pharmacol Ther. 2019 Apr; 105(4): 886–898. doi: 10.1002/cpt.1354 Innovation in Regulatory Science Is Meeting Evolution of Clinical Evidence Generation
15. FDA May 2019 draft guidance for comment Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics Guidance for Industry https://www.fda.gov/media/124795/download (last accessed 28th Oct 19)
16. https://www.ema.europa.eu/en/human-regulatory/post-authorisation/patient... (last accessed 28th Oct 19)
17. http://www.encepp.eu/ (last accessed 28th Oct 19)
18. Canadian Agency for Drugs and Technologies in Health - CADTH. Environmental Scan: Use of Real-World Evidence in Single-Drug Assessments. April 2018 https://cadth.ca/sites/default/files/pdf/es0323-rwe-in-single-drug-appra...
19. Hatswell AJ, Baio G, Berlin JA, Irs A, Freemantle N. Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014. BMJ Open 2016;6:e011666
20. Regulatory Advice Unit MHRA November 2018 First Edition “The supply, manufacture, importation and distribution of unlicensed cannabis-based products for medicinal use in humans ‘specials’ https://assets.publishing.service.gov.uk/government/uploads/system/uploa...

Competing interests: The authors are all employed by, and work in the medical cannabis industry.

30 October 2019
Robert A Pawinski
Chief Medical Officer
Dr Ajoeb Baridi, PhD(Cantab), MSc(UU), BSc(UU), Global Medical Director, Senzer Ltd; Dean Billington, BSc, CChem, FRSC, MICR, MRQA. Chief Science Officer Brains Bioceuticals; Dr Jonathan Grunfeld, M.D., MGC Pharmaceutical; Dr Adele Hosseini, B.Pharm, M.Pharm, PhD, Chief Scientific Officer, CMO Bod Australia; Dr Kelly Narine, PhD, Vice President, Global Research and Medical Affairs, Aurora Cannabis Inc.; Dr Jonathan Page, PhD, Chief Science Officer, Aurora Cannabis Inc.; Dr Clive Selwyn, MBBS, BSc (HONS). Medical Director, Spectrum Therapeutics; Jose Tempero, PharmD, MSc, Global Medical Affairs Director, Tilray; Dr Jonas Vanderzwan, MD, CFPC, Medical Director, Weed MD, Aylmer, Ontario, Canada; Dr Mark A Ware, MBBS, MSc. Departments of Family Medicine and Anesthesia, McGill University and Chief Medical Officer, Canopy Growth Corporation; Dr Robert Pawinski, MBChB(UCT), MSc(LSHTM), DTMH (LSHTM), DipOBST(SA). Chief Medical Officer, Althea
Althea
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