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 This article is protected by copyright. All rights reserved. Translational hurdles with cannabis medicines 4 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,