Translational Hurdles with Cannabis Medicines

Graham Myfanwy (Orcid ID: 0000-0003-0618-7497)

2 Translational hurdles with cannabis medicines

Translational hurdles with cannabis medicines Running head: Translational hurdles cannabis medicines

Myfanwy Graham1,2,3, Catherine J Lucas1,2,3,4, Jennifer Schneider1,3,4, Jennifer H Martin1,3,4, Wayne Hall3,5,6

1 Centre for Drug Repurposing & Medicines Research, School of Medicine and Public Health, The University of Newcastle, New South Wales (NSW), Australia 2 NSW Cannabis Medicines Advisory Service, Newcastle, NSW, Australia 3 Australian Centre for Cannabinoid Clinical and Research Excellence, Newcastle, NSW, Australia 4 Hunter Medical Research Institute, Newcastle, NSW, Australia 5 The University of Queensland (QLD), Brisbane, QLD, Australia; Centre for Youth Substance Abuse Research 6 The University of Queensland, Brisbane, QLD, Australia; National Addiction Centre

Corresponding author [email protected] (02) 4923 6200 NSW Cannabis Medicines Advisory Service C/o John Hunter Hospital Locked Bag 1 Hunter Region Mail Centre NSW 2310

Key words – Cannabis, Medical Marijuana, Observational Study, Pragmatic Clinical Trial, Safety

Take Home Messages

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/pds.4999

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 2 • It is important that real-world evidence (RWE) is used to complement rather than replace randomised controlled trial (RCT) evidence on cannabis medicines. • Technological advances have created the opportunity to explore diverse and novel sources of cannabis medicine RWE. • Although RWE may be more reflective of real-world clinical practice, it cannot provide conclusive evidence of the safety and efficacy of cannabis medicines. • While acknowledging its limitations, RWE may nonetheless provide some guidance on safety and adverse events of cannabis medicines. • RWE has already had a significant impact on the regulation of cannabis medicines.

Word Count 1717

Conflict of Interest Statement – J.M. has a family member who is a shareholder in a cannabis start-up company in Australia. This has been fully declared to the funding agency and is subject to a governance order from The University of Newcastle regarding management of this potential conflict.

Translational hurdles with cannabis medicines

Global approaches to the regulation of cannabis medicine access vary from legalisation to prohibition. Real-world evidence (RWE) and real-world data (RWD) have become catchphrases in the use of cannabis medicine because of a paucity of safety and efficacy data from clinical trials. In the absence of such data for cannabis medicines, there has been widespread medical use before rigorous evaluation of effectiveness in randomised controlled trials (RCT). In this article, we explore the utility, limitations, and impact of RWE from a pharmacoepidemiologic perspective and its use as a translational research tool in the frenetic and high-stakes cannabis medicines research space.

Cannabinoids and the lack of clinical trial data

The different varieties of the cannabis plant used to prepare products for recreational or medicinal use contain an extremely variable array and amounts of chemical substances. The most well-known and studied substances are the cannabinoids delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD) but cannabis plants also contain other cannabinoids, flavonoids and terpenes whose pharmacology and toxicology are largely unknown. The umbrella terms ‘cannabis medicine’ or ‘medicinal cannabis’ may be used to refer to a wide variety of cannabis formulations, ranging from plant material, galenical preparations,

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 3 standardised and synthetic products. Nonmedical-grade cannabis preparations have a variable and uncertain composition.1 Some medical-grade products contain purified and/or isolated cannabinoids, whereas others contain a chemically complex mixture of cannabinoid and non-cannabinoid constituents. In addition to the chemical complexity of some cannabis medicines, there is also off-label use of standardised formulations, medicinal cannabis programs, and self-prescribed use with medicinal intent. Some of these formulations do not fit well with the usual RCT framework2, whereas others have been subjected to RCT evaluation for certain indications.

RCT data is currently limited for many of the putative clinical uses of cannabis and cannabinoids.3 Even where RCT data is available, the external validity of the evidence may be limited by the rigorous trial designs and the trial setting may not reflect routine clinical practice e.g. in excluding the majority of patients with comorbid conditions who are using other medicines.4 There are significant hurdles to conducting RCTs involving cannabis-based medicines. These include: securing research funding5, the extensive time commitment required to complete trials4, navigating cannabis regulatory requirements, ensuring ongoing product supply and obtaining ethics approval. RWE in the form of pragmatic RCTs and observational studies are intended to complement rather than replace pivotal RCTs. The use of RWE to rapidly fill an evidence void related to the clinical use of cannabis medicines is at odds with the complementary framework in which RWE is intended to be utilised.6 Barriers to undertaking RCTs need to be addressed rather than RWE being used in their place.7

Public pressure for ready access to cannabinoids is driven by wholly favourable, uncritical media portrayal of the putative benefits and safety of cannabis-based medicines. This has enabled cannabinoids to bypass the research and regulatory processes usually completed before widespread clinical use.8 Patient interest has produced a cannabinoid research boom but it will be considerable time before this produces a better understanding of cannabinoid safety and efficacy. Cannabinoid pharmacovigilance research drawing upon well-established pharmacoepidemiologic techniques could help clarify our understanding of the risks and benefits of medical use of cannabinoids. It may be argued that RWE is more relevant to some patient cohorts than findings from RCTs with restrictive exclusion criteria that mean many patient groups are not well represented in clinical trial outcomes. These exclusions may include individuals with complex clinical profiles9 at either end of the age spectrum, those with rare pathology, organ impairment, substance use, co-morbid conditions or polypharmacy. These are precisely the individuals who are using cannabis medicines as a last line treatment. In this context, RWE may be more representative of the population using cannabis-based medicines. Application of RWE also has clear utility in the compassionate consideration of cannabis medicines in certain contexts in conjunction with a focus on rapid progression of research.

RWE sources and challenges

RWD is an umbrella term encompassing data collected from a variety of sources, such as patient registries, electronic medical records10, mobile devices, social media and administrative claims. Research using electronic health data has been employed in pharmacoepidemiology for some time.11 RWE is clinical evidence of potential risks or benefits derived from RWD analysis. A variety of study designs, including observational and pragmatic studies, fall under the banner of RWE6 and hybrid designs incorporate both RWD and RCT components (see Table 1).6 The emergence of RWE is intertwined with rapid information and communications technology advances that have facilitated the capture, linkage and analysis of very large datasets.12

Table 1 Examples of potential benefits and limitations of RWE

Benefits Limitations o Complements pivotal RCT data o Bias and confounding factors o Informs clinical trial design o Placebo effect o External validity o Verification of data accuracy, missing or o Monitoring of adverse events and incomplete data identification of safety signals o Does not constitute conclusive evidence of efficacy o Heterogeneous data

From a public health perspective, epidemiological evidence is one potential source of RWE for exploring potential cannabinoid related harms. Cannabinoid- focused epidemiological studies mainly explore the effects of recreational use and are predominantly related to cannabis smoking. Cannabinoid adverse effects derived from available epidemiological studies include motor vehicle injuries, low birth weight, dependence syndrome, psychosis or schizophrenia, depression, bronchitis, and lung cancer.13 However, careful consideration of the plausibility of alternative hypotheses (such as confounding) is required to avoid mistaken causal inferences. For example, epidemiologic data related to lung cancer and cannabis smoking is an unlikely adverse effect of other dosage forms of cannabis medicines e.g. oral.

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 5 Patient cannabinoid-related registries are one of the main modalities being used to generate RWD in the cannabis research space. There is a spectrum of registries, and examples from around the world are outlined in Table 2 below. A consistent trend across many of the registries is the prevalent use of cannabinoid medicines to treat chronic pain14-16, despite the limited evidence for use in this indication.17 Harmonisation of standard data collected is necessary to pool data from various registries internationally.10 However, RWD obtained from registries does not provide conclusive evidence of efficacy or effectiveness for the same reasons as observational studies of harms arising from recreational use, namely, the challenges in ruling out residual confounding.10

Country Cohort size Date(s) Indication/Focus Key findings Reported limitations Israel18 26 patients Nil Fibromyalgia • Significant improvement reported • Nil reported. from two reported. based on Revised Fibromyalgia hospital Impact Questionnaire responses. registries. • Cessation of medications for fibromyalgia (50%). • Mild adverse effects (30%). Europe The United 941 patients Up until A retrospective analysis • Reported benefit (83%). • Unable to verify the accuracy of Kingdom and (UK 761, February of Sativex (nabiximols, • Discontinued treatment (32%). the data. selected Germany 2015. THC:CBD) oromucosal Reasons for discontinuation included • Potential bias. multiple 178, spray registry data was lack of effectiveness (one-third) and • The ratio of females to males was sclerosis (MS) Switzerland used to report on safety lack of tolerability/adverse events not reflective of the reported centres in 2). and effectiveness in MS (one-quarter). ratio in the wider population of Germany, spasticity. • A break-down of adverse events was patients with MS. and reported, including psychiatric Switzerland adverse events 6%, falls 6%, dizziness (UK registry 3%, fatigue 2% and suicidality 2%. has There is a variable effect upon driving subsequently ability, which worsened (2%) and closed)19 improved (7%).

Denmark 20 Results Results are A three-stage register- • Results pending. • Results pending. pending. expected based evaluation is

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 7 in the first underway of effects and half of adverse effects. 2020. Germany15 4153 Interim Mandatory, anonymous • The most common symptoms • Anonymous therefore unable to evaluation prescriber survey treated include pain (69%), spasticity verify data. February associated with cannabis- (11%) and anorexia/wasting (8%). • Missing data. 2019. based medicine • Adverse events reported grouped by insurance covered product formulation. prescriptions. • Discontinuation rates, most commonly due to insufficient effect. Germany14 800 2017, 12 Anonymous, German • Variable effectiveness reported • Lack of a control group. weeks. pain e-registry data on across different pain classifications. • 12-week evaluation period. adult patients with • Adverse effects (19.1%), with the • Data heterogeneity. severe chronic pain and majority classified as mild. • Missing or incomplete data. add-on THC:CBD • Discontinuation due to inadequate oromucosal spray pain relief (14.1%) and treatment- treatment was analysed. emergent adverse events (4%).

United Projected Results Effectiveness, safety, and • Results pending. • Results pending. Kingdom21 data expected patient-reported collection by year- outcomes. related to end of 20,000 2021. patients. North America

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 8 U.S. registry Registered Up until Analysis of patient • The most common qualifying • Data access issues. data (20 states patients - April 2018. numbers (20 states and condition is chronic pain. • Missing data. and 2016 Washington, DC) • Patients may have multiple Washington, (641,176) qualifying conditions for qualifying conditions. DC)16 and 2017 patient medicinal (813,917). cannabis licenses (14 Patient- states). reported qualifying conditions 2016 (729,843) and 2017 (967,067). Minnesota 22 1120 July 1, Collection of data related • Adverse events uncommon (10.5%). • Response bias. 2015 to to outcomes in patients • Symptom improvement of 30% or • Confounding factors e.g. December with cancer enrolled in greater varied across indications, polypharmacy. 31, 2017. Minnesota’s Medical including fatigue (27%) and vomiting • Does not constitute conclusive Symptom Cannabis Program. (50%). evidence of efficacy. assessmen t within 4 months of program participati on.

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 9 Minnesota23 1660 July 1, Report based on patient, • Adverse events (20-25%). • Nil reported. 2015, to healthcare professional, • Patient-reported benefit rating 6 or 7 June 30, and carer registration in (64%). 2016. Minnesota’s Medical • Health practitioner reported benefit Cannabis Program, rating 6 or 7 (38%). purchase and survey data. Philadelphia 24 Estimated July 15, Registry for medical • Results pending. • Results pending. enrolment 2018, to cannabis use in patients 200. March 31, up to 21 years of age with 2020. autism and autism spectrum disorder.

Patient and practitioner state-wide22 and national surveys 15,25,26 have been used to gather information about patient experiences with cannabis. Some registries have used surveys as a method of data collection. For example, a survey conducted in Minnesota reported a disparity between patient and health practitioner reports of benefits from using cannabis. Sixty-four percent of patients reported a benefit rating of 6 or 7, whilst only 38% of health practitioners did so.23 Surveys are plagued by the challenges in achieving response rate sufficient to minimise sampling and response biases.

Post-marketing data collection by sponsors has historically been a mainstay of pharmacovigilance data collection and plays a significant role in safety signal detection. Data collection may take the form of spontaneous adverse event reporting to registries maintained by sponsors.27 Healthcare professionals, patients, and sponsors may also contribute to larger spontaneous reporting systems (SRS), including the U.S. Food and Drug Administration Adverse Event Reporting System, Canada Vigilance Adverse Reaction Online Database, the European Medicines Agency EudraVigilance and the Australian Database of Adverse Event Notifications. Based on spontaneous adverse event reports to the Italian Phytovigilance database from 2006 to 2018, there were 103 suspected adverse event reports, including 61 reports from Tuscany. An evaluation of 53 reports found that the majority of adverse events were not serious and transient. Missing data and the inability to verify the accuracy of the data were reported as limitations of the analysis.28 SRS are important as clinical trials are unlikely to capture

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 10 all adverse event data, particularly those that occur rarely, those that are more likely in patients who have been excluded from trials and those which manifest after an extended period of use. Missing information and underreporting are significant limitations of SRS.10

Electronic or digital health records are an important source of RWD. There is a disconnect between adverse events observed in clinical and emergency department settings and those reported via SRS.29 Analysis of electronic health records provides a unique opportunity to gather this missing data. Colorado emergency department records highlight risks associated with paediatric poisonings from unintentional ingestion.30 Community pharmacy dispensing records in The Netherlands have also been utilised to report on demographic data.31 Social and digital media provide novel avenues for data collection. One novel approach utilised U.S.-based search engine queries related to cannabis adverse reactions.32 Cannabis use behaviours have also been studied with the use of Facebook’s advertising platform and web surveys.33 Published case reports are another opportunity to gather data. For example, there have been case reports highlighting potential drug interactions between cannabis and warfarin.34 It is highly likely that RWD digital repositories and methods of data collection will become more prominent in the future.

RWE impact – policy and regulatory decision making

Evidence-based clinical practice and regulatory decision making have historically relied on gold-standard RCT data.5 We should not underestimate the complementary value of RWD and RWE sources in guiding policy development and the regulatory decision-making process. This is highlighted by the U.S. Food & Drug Administration RWD and RWE framework and regulatory submission guidance documents.12 Medicinal use of cannabis is one area where public opinion and RWE has had a significant impact upon policy and legislation. Whilst some countries have elected to legalise both medicinal and recreational use, other countries have legalised varying degrees of access for medicinal use.13

RWE challenges

There are many unanswered questions about RWE. As clinicians, we undergo extensive training that advocates basing our clinical practice on the highest quality evidence. Are we satisfied with basing our clinical decision making on RWE? How can RWE evidence be used to complement limited RCT evidence? Reliance on RWE is fraught with risks of widespread test of concept without the safeguards normally implemented in clinical trials. Analysis of heterogeneous sources of

This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 11 RWD related to safety and effectiveness presents challenges in pooling data from multiple streams.5 In some instances, data-linkage techniques are being used to combine RWD from different sources.10

Conclusion

RWE has played a significant role in the emergence of cannabis medicines as a topical issue in healthcare and has had a significant impact on policy and regulatory decision making around the world. Diverse RWD sources provide a unique opportunity to obtain cannabinoid safety and effectiveness information though each has distinct strengths and limitations. Appropriate use of RWE to complement RCT data provides valuable additions to our knowledge base about cannabis medicines and may provide some guidance on the adverse effects and safety of cannabis medicines. However, RWE should not be viewed as a replacement for due diligence in performing RCTs. We also need to address the barriers to the evaluation of cannabis medicines using rigorous research methodologies.

Acknowledgements – Professor Jennifer Martin is the Director of the Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE) which is funded through the National Health and Medical Research Council’s Centres of Research Excellence Program. Professor Martin, Dr Catherine Lucas and Myfanwy Graham are also funded through NSW Health’s Clinical Cannabis Medicines Program.

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