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Freeman, TP

Hindocha, C

Morgan, C

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Strengthening the evidence for medicinal cannabisand cannabinoidsAlternative trial designs and patient registries can rapidly generate robust data on efficacy and safetyTom P Freeman senior lecturer 1, Celia Morgan professor of psychopharmacology 2, ChandniHindocha research fellow 31Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, UK ; 2Psychopharmacology and Addiction Lab,Department of Psychology, University of Exeter, UK; 3Clinical Psychopharmacology Unit, Research Department of Clinical, Educational, and HealthPsychology, University College London, UKDraft recommendations by the National Institute for Health andCare Excellence (NICE) did not recommend prescription ofunlicensed cannabis based products to patients on the NHS.1The potential benefits for people with chronic pain wereconsidered too small relative to costs, and the quality of evidencewas rated too low to recommend use in children with severetreatment resistant epilepsy.1 At present, the only way to getcannabis products for medicinal use in the UK is throughprescriptions issued by private clinics2 (which are prohibitivelyexpensive) or the illicit market (which carries risk of prosecutionas well as unknown product content, quality, and safety). Giventhe vocal requests for access to these products from patients andtheir carers,3 stronger evidence is urgently needed so that theseproducts can be made available in situations where they areknown to be effective and safe.Cannabis based medicines vary in their content ofΔ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), whichhave contrasting mechanisms of action, efficacy, and safety.4Some cannabis based medicines include both THC and CBD,which can interact with each other.5 Although evidence fromrandomised controlled trials is stronger for certain formulations(such as CBD for severe treatment resistant epilepsy4), patientshave expressed a preference for treatments such as THCcombined with CBD.3 Gathering evidence for such treatmentsis a priority and can be expedited by using alternative trialdesigns and patient registries.Alternative trial designs and patientregistriesTo compare varied cannabis based products efficiently,randomised controlled trials can follow adaptive designs.6 Forexample, patients can be initially randomised to one of severaltreatment arms such as THC, CBD, or THC combined withCBD. Interim analysis can eliminate treatment arms with poorefficacy or safety at an early stage, while randomisationcontinues to trial arms testing potentially effective doses.Cannabis based products have been investigated for a widerange of medical indications, some of which may shareaetiologies related to the endocannabinoid system.7 Whenmultiple disorders are characterised by the same underlyingmechanism, basket trials can investigate a single targetedintervention across multiple diagnostic categories.8 Alternatively,when different mechanisms are known to give rise to a commonmedical diagnosis, umbrella trials can stratify patients intodifferent treatment arms based on the underlying diseasemechanism, allocating targeted interventions to each group.8Stratification can also occur at the level of the individual patient.N-of-1 trials allow randomised, double blind crossovercomparisons of active and control treatments in a cyclicalmanner sequentially in the same patient.9 These trials canestablish efficacy and safety within an individual, and the resultsfrom multiple patients can be combined with meta-analysis.Such trials have been used to evaluate cannabis based productsin people with chronic pain10 and could be used for otherindications such as severe treatment resistant epilepsy. Theyare ideally suited to situations such as treatment forcompassionate reasons, unlicensed use, and for patients whofail to respond to conventional treatments,11 as is often the casefor cannabis based medicines. Establishing individual patientsas “responders”9 by using n-of-1 trials could provide evidencestrong enough to justify continued prescription.Randomised controlled trials are not the only source of evidence.The European Medicines Agency and the US Food and DrugAdministration have approved many drugs without randomisedtrials.12 Other sources of evidence used to support drug approvalsinclude historical control studies and observational studies.12Where cannabis based medicines are provided on privateprescription,2 patient registries should be set up to generateobservational data on real world clinical practice and outcomes.Correspondence to: T P Freeman t.p.freeman@bath.ac.ukFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5871 doi: 10.1136/bmj.l5871 (Published 21 October 2019) Page 1 of 2EditorialsEDITORIALS on 24 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5871 on 21 October 2019. Downloaded from Such data can be rapidly obtained at minimal cost and may becombined with registries outside the UK—in countries such asCanada and Israel.Need for industry cooperationInitial public funding to support research into cannabis basedproducts has been offered through dedicated calls from theNational Institute for Health Research. However, the UK’sparliamentary health and social care committee has raisedconcerns about the unwillingness of industry to provide cannabisbased products for research13 or to support or conduct clinicaltrials on their products. Greater support from industry couldincrease access to cannabis based products in a research contextand help patients avoid the excessive costs of privateprescriptions.2 Providing access to cannabis based products intrials with informed consent can offer participants balancedinformation on the possible benefits and risks, which areuncertain based on the evidence at present.The current limited evidence for cannabis based productsalongside clear patient demand requires new solutions. Furthertrials are urgently needed, and designs such as n-of-1 trials canprovide rapid evidence to inform treatment and optimise clinicaloutcomes for individual patients.9 Like all research methods,randomised trials have their limitations, such as poorgeneralisability. Data should also be sought from alternativemethods, such as observational data from patient registries,which can be triangulated with other findings to develop a robustevidence base.14Competing interests: We have read and understood BMJ policy on declaration ofinterests and declare TPF is funded by a senior academic fellowship from theSociety for the Study of Addiction (SSA). CH is supported by the National Institutefor Health Research (NIHR) University College London Hospitals BiomedicalResearch Centre. The views expressed here are those of the authors, and do notreflect those of the University of Bath, the University of Exeter, UCL, the SSA, orthe NIHR.Provenance and peer review: Commissioned; not externally peer reviewed.1 National Institute for Health and Care Excellence. Cannabis-based medicinal products.London: NICE, 2019. https://www.nice.org.uk/guidance/indevelopment/gid-ng10124/documents2 Mahase E. Medical cannabis: patients turn to private clinics because of NHS void. BMJ2019;366:l5290. 10.1136/bmj.l5290 314775763 Deacon H. Why I campaign for children like my son Alfie Dingley to be able to get medicalcannabis. BMJ 2019;365:l1921. 10.1136/bmj.l1921 310433914 Freeman TP, Hindocha C, Green SF, Bloomfield MAP. Medicinal use of cannabis basedproducts and cannabinoids. BMJ 2019;365:l1141. 10.1136/bmj.l1141 309483835 Freeman AM, Petrilli K, Lees R, etal . How does cannabidiol (CBD) influence the acuteeffects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. NeurosciBiobehav Rev 2019. 10.1016/j.neubiorev.2019.09.036.6 Berry SM, Carlin BP, Lee JJ, etal . Bayesian adaptive methods for clinical trials. CRCPress, 201010.1201/EBK1439825488.7 Pacher P, Kunos G. Modulating the endocannabinoid system in human health anddisease--successes and failures. FEBS J 2013;280:1918-43.10.1111/febs.12260 235518498 Park JJH, Siden E, Zoratti MJ, etal . Systematic review of basket trials, umbrella trials,and platform trials: a landscape analysis of master protocols. Trials 2019;20:572.10.1186/s13063-019-3664-1 315337939 Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical trial: theultimate strategy for individualizing medicine?Per Med 2011;8:161-73.10.2217/pme.11.7 2169504110 Notcutt W, Price M, Miller R, etal . Initial experiences with medicinal extracts of cannabisfor chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 2004;59:440-52.10.1111/j.1365-2044.2004.03674.x 1509623811 Schork NJ. Personalized medicine: Time for one-person trials. Nature 2015;520:609-11.10.1038/520609a 2592545912 Hatswell AJ, Baio G, Berlin JA, Irs A, Freemantle N. Regulatory approval ofpharmaceuticals without a randomised controlled study: analysis of EMA and FDAapprovals 1999-2014. BMJ Open 2016;6:e011666.10.1136/bmjopen-2016-011666 2736381813 House of Commons Health and Social Care Committee. Drugs policy: medicinal cannabis.2019. https://publications.parliament.uk/pa/cm201719/cmselect/cmhealth/1821/1821.pdf14 Munafò MR, Davey Smith G. Robust research needs many lines of evidence. Nature2018;553:399-401. 10.1038/d41586-018-01023-3 29368721Published by the BMJ Publishing Group Limited. For permission to use (where not alreadygranted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissionsFor personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribeBMJ 2019;367:l5871 doi: 10.1136/bmj.l5871 (Published 21 October 2019) Page 2 of 2EDITORIALS on 24 October 2019 at University of Exeter. Protected by copyright.http://www.bmj.com/BMJ: first published as 10.1136/bmj.l5871 on 21 October 2019. Downloaded from 

Strengthening the evidence for medicinal cannabis and cannabinoids

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Strengthening the evidence for medicinal cannabis and cannabinoids

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