Real World Evidence in Medical Cannabis Research
grid.7445.20000 0001 2113 8111Department of Surgery and Cancer, Imperial College London, London, UK
Sapphire Medical Clinics, UK Medical Cannabis Registry, London, UK
The Centre for Medicinal Cannabis, 18 Hanway Street, London, W1T 1UF UK
Curaleaf International, London, UK
grid.7445.20000 0001 2113 8111Division of Surgery, Department of Surgery & Cancer, Imperial College London, St Mary’s Hospital, Academic Surgical Unit, 10th Floor QEQM, South Wharf Road, London, W2 1NY UK
Abstract
Background
Whilst access to cannabis-based medicinal products (CBMPs) has increased globally subject to relaxation of scheduling laws globally, one of the main barriers to appropriate patient access remains a paucity of high-quality evidence surrounding their clinical effects.
Discussion
Whilst randomised controlled trials (RCTs) remain the gold-standard for clinical evaluation, there are notable barriers to their implementation. Development of CBMPs requires novel approaches of evidence collection to address these challenges. Real world evidence (RWE) presents a solution to not only both provide immediate impact on clinical care, but also inform well-conducted RCTs. RWE is defined as evidence derived from health data sourced from non-interventional studies, registries, electronic health records and insurance data. Currently it is used mostly to monitor post-approval safety requirements allowing for long-term pharmacovigilance. However, RWE has the potential to be used in conjunction or as an extension to RCTs to both broaden and streamline the process of evidence generation.
Conclusion
Novel approaches of data collection and analysis will be integral to improving clinical evidence on CBMPs. RWE can be used in conjunction or as an extension to RCTs to increase the speed of evidence generation, as well as reduce costs. Currently, there is an abundance of potential data however, whilst a number of platforms now exist to capture real world data it is important the right tools and analysis are utilised to unlock potential insights from these.
Background
Cannabis-based medicinal products (CBMPs) are a collective term to describe a preparation or other product that contains cannabis or its derivatives for medicinal use in humans [1]. There are significant barriers to the integration of CBMPs within treatment pathways including ongoing stigma, cost, education, complex pharmacology and a paucity of evidence to inform international and national guidelines [2, 3]. Limited evidence, does, however, support the role of CBMPs in conditions such as chronic pain, neurological disorders, and psychiatric disease [4]. There is also growing evidence of side effects and how the severity and incidence of side effects may differ between patients [4]. The quality of evidence, however, is often insufficient in the opinion of insurers, regulators, and guideline bodies [5].
The National Institute for Health and Care Excellence in the UK has only recommended licensed CBMPs for a limited range of indications [6]. Changes to scheduling as recommended by the World Health Organisation, and within individual countries, recognises the potential medicinal value of cannabis and removes barriers for clinical and research use [1, 7]. However, widespread stigma, complex pharmacology, funding, and challenges in sustaining adequate supply of consistent products continue to act as barriers for clinical research.
Randomised controlled trials (RCTs) are necessary and should continue to be the standard against which medical evidence is upheld. However, they are expensive, time consuming and subject to their own limitations [8]. Whilst these are awaited, there is a requirement to generate evidence of potential benefits and harms to inform policy and clinical practice.
Real World Evidence
RWE is defined as evidence derived from health data sourced from non-interventional studies, registries, electronic health records and insurance data as opposed to the highly controlled setting of RCTs [21]. There is an abundance of this unstructured data, however, the necessary frameworks and governance are needed for the application of this data [22]. It is currently used extensively to monitor post-approval pharmacovigilence [23]. There is clear evidence of benefit in using population-based data to detect safety events associated with specific medications to implement restrictions to reduce harm [21].
Consistent use of RWE to aid regulatory decision making is yet to be normalised, but the promise is apparent [21]. Recently, regulator-supported initiatives have highlighted the desire to incorporate RWE into licensing and guidelines, developing a framework which can incorporate its insights into decisions regarding safety and effectiveness [21, 22]. It is important that studies standardise their methodology according to those set out by regulatory authorities to ensure research has the greatest impact [21, 22]. Moreover, they should seek to directly address questions set out by governing bodies as areas where there is insufficient research [24].
Types of Real-World Evidence for Medical Cannabis
NHS England and NHS improvement published a review on the barriers to accessing CBMPs in the UK [3]. Their recommendations included the need for the collection of structured data, and the development of methods to further support the generation of new evidence, for patients who cannot enrol onto relevant RCTs.
RWE is already being incorporated into the scientific literature on cannabis (Table 1). Early examples utilised state-level records to examine the effects of cannabis laws on opioid misuse. Subsequently there have been examples of online and self-administered survey tools analysing national outcomes. More recently there has been a focus on collecting evidence from clinical registries and databases with evidence generated from patient-reported outcome measures and long-term pharmacovigilance.Regional/National Survey Studies Ware et al. [31] Analysis of self-administered questionnaire study conducted in the UK between 1998 and 2002 Sexton et al. [32] Anonymous online survey analysing medical cannabis users and which conditions they use it to treat focusing on patient perception of efficacy, and physical and mental health Lucas et al. [33] Patients who were registered to a federally authorized licenced producer in Canada were requested to fill out a self-administered survey Lintzeris et al. [34] Cannabis As Medicine Survey (CAMS-18) was an online, anonymous survey given to patients recruited mainly via social media in Australia. The consequent analysis looked at patterns of use and perspectives on medical cannabis Government records analysis Bachhuber et al. [35] Time series analysis of medical cannabis laws and state-level death certificate data in the United States from 1999 to 2010 Piper et al. [36] Analysed data from drug arrest data from the Maine Diversion Alert Program regarding diversion of prescription medications subject to scheduling, such as cannabis Vigil et al. [37] Retrospective cohort study looking at the association between enrolment in the New Mexico Medical Cannabis Program and opioid prescription use Analysis of clinic/dispensary data Bonn Miller et al. [38] Cross sectional study of medical cannabis use from a cannabis dispensary in California. The study highlighted perceived benefits in conditions where medical cannabis had not yet been licensed Gulbransen et al. [39] An audit of all patients who presented to a Cannabis Care clinic in New Zealand. This study highlighted the anxiolytic effects of cannabidiol Rapin et al. [40] A retrospective observational study looking at patients who had been prescribed CBD treatment from data collated from a network of clinics Analysis of registries Habib et al. [27] Looked at the efficacy of medical cannabis for treatment of fibromyalgia. It used data from two hospital registries. The relevant patients also filled out a questionnaire Ueberall et al. [41] Evaluated RWD collected from the German Pain e-Registry. It looked at the efficacy and tolerability of an oromucosal spray composed of THC: CBD. The registry was developed by the Institute of Neurological Sciences on behalf of the German Pain Association Mahabir et al. [42] Analysed data from a registry which contained data on some medical cannabis evaluation clinics in the United States. Database owned by CB2 Insights Databases Quebec Cannabis Registry (Canada) [43] Collated clinical data collected from users of dried medical cannabis with 6000 participants in Quebec Medical Cannabis Real World Evidence [44–46] A Canadian, prospective, non-interventional, observational study led by the University Health Network in Toronto. It aims to explore the benefits of medical cannabis in an observational setting for adults with conditions such as chronic pain, anxiety or depression. The study will evaluate the efficacy and safety of a range of CBMPs selected by the patients themselves after assessment by a clinician. The study currently aims to recruit 2000 participants, with completion due in 2022 UK Medical Cannabis Registry (UK) [47, 48] Captures clinical data on prescribed CBMP formulations, adverse events and patient-reported outcome measures across a myriad of conditions at defined timepoints. The principal aim is to generate evidence demonstrating the effect of CBMPs on health status or health-related quality of life and generate more accurate calculations of adverse effects. Published early experience of improvement in health-related quality of life, sleep and anxiety outcomes across a range of conditions Project Twenty21 (UK) [49, 50] Registry platform for data collection from patients provided prescriptions by licensed producers at subsidised cost for enrolment. Limited to six specific conditions, openly aiming to change healthcare funding decisions. Aims to recruit 20,000 patients with initial data analysis due in 2022 Emerald Clinics (Australia) [51–53] Real world evidence platform utilising clinical registries and patient generated health data to inform clinical care and aid bespoke drug development. They have utilised this as part of a drug development platform for specific CBMP preparations in psychological disease (EMD-003) and irritable bowel syndrome (EMD-004) in top-down driven drug development Minnesota Medical Cannabis Programme (US) [54] This registry collects data on the benefits, risks and outcomes regarding the therapeutic use of medical cannabis. It is run by the Minnesota Department for Health BfArM (Germany) [55] A non-interventional survey on the use of these cannabis medicines, which must be completed by any German physician prescribing medical cannabis CB2 Insights (US) [56] CB2 Insights is a healthcare technology company that uses real world data to monitor, assess, and generate insights to help improve patient outcomes Medical Cannabis Pilot Programme (Denmark) [57] A four-year pilot programme which aimed study patients’ use of medicinal cannabis. The success of the programme has recently led to an extension of the trial period Italian Medicines Agency (Italy) [58] In Italy, prescriptions and patient data are registered with the Italian Medicines Agency. In 2019 26,042 medical cannabis prescriptions, attributed to 12,998 patients had been registered Cannabis a` usage medical programme (France) [59] Initiated by the French National Agency for Medicines and Health Products Safety, the registry will collate information on efficacy and safety data on medical cannabis. It will supply medical cannabis to 3000 patients over 2 years and aims to examine real life use of therapeutic cannabis Medical Cannabis Access Programme (Ireland) [60] A 5-year pilot programme in which certain CBMPs can be prescribed with information on prescribing collected by Ireland’s Health Service Executive
Comparison of Real-World Evidence and Controlled Clinical Trials
Between these study designs it is important to be aware of potential divergence in reported outcomes. RWE has broader inclusion criteria, accounting for factors like non-standard dosing, and is not limited by scope of disease, thereby improving ecological validity [25]. However, some studies have concluded there is little difference between results obtained via RCTs and observational studies [26]. RWE typically has longer patient follow-up and may consequently capture rare but important adverse effects that are not detected within RCTs. Pharmacovigilance is therefore widely accepted as one of the most important roles of RWE.
RWE can bring further clarity on questions that remain unanswered in RCTs. A recent study utilised anonymised surveys of patients with fibromyalgia who consumed cannabis flower [27]. In addition to reporting positive outcomes on depression and pain the study also reported negative aspects of cannabis consumption, for example driving under the influence (72% of patients) [27]. These are findings which are unlikely to be reported by patients in controlled clinical trials for fear of repercussions, or strict inclusion criteria. It can also be useful in collecting data in rare conditions whereby recruitment to RCTs can be limited by the need for defined trial sites.
RWE can improve the efficiency of clinical trials by generating hypotheses, refining eligibility criteria, and exploring drug development tools. Registries can be used to form an infrastructure to conduct a clinical trial, lowering costs whilst maintaining high evidence quality [28]. In supplemented single arm trials the controls are derived from RWE-data sets, providing the opportunity for patient centric study designs. RCTs can also be augmented with real-world data to increase the size of the control group to increase the power of the study. These study designs are particularly useful for rare diseases where participant recruitment is challenging [29].
Limitations of Real-World Evidence
RWE, however, does have limits to its utility. There is variation in the quality and provenance of the data stored in electronic medical records [5]. Furthermore, insurance records typically use coding specific for reimbursement purposes and may not provide all clinically relevant information. RWE can require complex statistical expertise to deduce valid conclusions.
Another limitation is the lack of randomisation, controlled variables and internal validity. This can make it more difficult to derive causative mechanisms behind clinical outcomes. However, this is also one of the strengths of these studies, allowing for generalisability to true clinical practice [22]. Treatment assignment based on the physician as opposed to randomisation, creates selection bias and more specifically stigma biases. RCTs, therefore, are still necessary to establish a strong causal relationship between medication and outcomes [30].
Conclusion
CBMPs are a complex range of pharmaceuticals which pose challenges to traditional pathways of drug development and translation. Development of CBMPs requires novel approaches of evidence collection to address these challenges. RWE can be used in conjunction or as an extension to RCTs to both broaden and streamline the process of evidence generation. Currently, there is an abundance of potential data, however, it is important the right tools and analysis are utilised to unlock potential insights from these.
Abbreviations
- CBD
- Cannabidiol
- CBMPS
- Cannabis-based medicinal products
- FDA
- Food and Drug Administration
- NHS
- National Health Service
- NIHR
- National Institute for Health Research
- RCTs
- Randomised Controlled Trials
- RWE
- Real world evidence
- SATs
- Supplemented single arm trials
- THC (−)
- Trans-Δ9-tetrahydrocannabinol
Acknowledgements
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Funding
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Availability of Data and Materials
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Declarations
Competing interest
SE: Sapphire Medical Clinics. DC: Medical Lead Centre for Medicinal Cannabis. BP: Chief Scientific Officer at Emmac Life Sciences. MHS: Sapphire Medical Clinics Managing Director and Research lead at Emmac Life Sciences.
Ethical Approval
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Consent for Publication
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