Anne Katrin Schlag, Rayyan Zafar, Michael Lynskey, Lawrence D Phillips, Alkyoni Athanasiou-Fragkouli, David J Nutt
November 3rd, 2022
Randomised controlled trials (RCTs) have long been considered the ‘gold standard’ of medical evidence. However, there are several issues associated with RCTs such as the lack of a representative sample of the population and the very high costs of the research.
In relation to cannabis-based medicinal products (CBMPs), which often lack traditional RCT evidence, the importance of incorporating real-world data (RWD) to assess the effectiveness and safety of medical cannabis is gradually becoming recognised.
Real World Evidence (RWE) encompasses all forms of clinical data collected outside of the traditional RCT setting. RWE is already being used for pharmacovigilance (monitoring of previously unreported adverse reactions and side effects), after a drug has been approved following a clinical trial. Larger patient numbers can be achieved in this way at a much lower cost than a clinical trial and data can be collected for a longer period of time. Additionally, by using RWE, rare diseases, which would not be cost effective for a pharma company to perform an RCT for, can still be researched. Finally, RWE usually includes more diverse populations who might present with several comorbidities that would have been excluded from an RCT.
Some unique advantages of RWE for the study of medical cannabis include:
- Research in a number of different products (as compared with one product in an RCT)
- Longer monitoring of outcomes
- Collection of data on larger samples
- Data was collected on a representative sample of the population rather than ‘pure’ patients.
Our paper concludes by outlining 12 key recommendations for the value of RWE in relation to medical cannabis. We hope that this paper will help policymakers and prescribers understand the importance of RWE in relation to medical cannabis and help them develop approaches to overcome the current barriers which can be detrimental to patients.
Our key recommendations:
Cannabis has an excellent safety profile and is an established medicine. Concerns about the perceived lack of RCT evidence are misplaced as many patient-centred approaches can be, and have already been, applied.
RWE approaches are the key to accelerate development of clinical effectiveness evidence on CBMPs across a wide range of disorders, so we need to move away from the current focus on RCTs and incorporate RWE results. Patient numbers in RWE for medical cannabis are already much larger and have greater temporal sensitivity (due to ongoing longitudinal data acquisition) than all RCTs to date combined.
RWE can provide data for specific patients that RCT results cannot. The reality of medicine is that for every patient every new treatment is an n=1 experiment. Individual patient outcome measures are the gold standard of the value of the treatment.
RWE provides more ecologically valid data as it can be acquired from a much larger range of patients than RCTs. This is because RCTs usually exclude people with co-morbid conditions, despite such patients being the majority presenting in clinical practice
There is growing consensus amongst practitioners and regulators that RWE is essential to improve the ecological validity of the broader utility and clinical outcomes of new medicines. These advances would greatly help to optimise personal treatment protocols, supporting a move to personalised and precision based medicine- a key goal in 21st century medical practice.
The historic predominance of WEIRD (Western, Educated, Industrialized, Rich, and Democratic) participants in western medicine RCTs means their results are not representative of the general population. Basing efficacy on such a subpopulation leads to ethnic and racial disparities in healthcare. This can be actively combatted through the acquisition of more representative data acquired from the real world.
The European Medicines Agency (EMA) has recently launched their Data Analysis and Real World Interrogation Network (DARWIN EU) to deliver real world evidence on diseases, populations and the uses and performance of medicines, confirming the increasing understanding of the value of RWD.
RWE can address the need for more data to develop the current scientific evidence base. So far, there is no homogenous way of data collection on medical cannabis patients and the number of prescriptions written across countries. In Canada, the development of a large-scale database allows for side-effects to be monitored and managed more effectively. Results can then be incorporated to develop regulation and policy-making.
The available RWE evidence of CBMPs highlight their benefits in various clinical conditions. Specially for treatment-resistant patients and in selected medical conditions, CBMPs can offer an important therapeutic option.
PROs matter. GMC guidance on good medical practice makes it clear that all registered doctors must take into account and respect patients’ views and experience. Ideally, doctors should develop the evidence base together with their patients to better define indications. Areas which have significant data gaps will still require more rigorous studies and RCTs.
The collection of safety data is essential. Doctors and other HCPs need to be able to monitor the outcome of any treatment. Adverse effects must be registered and addressed, e.g., through the yellow card system in the UK or through a medicine-specific database.
Pharmacovigilance will remain important. Any harms need to be reported. Particularly attention should be paid to medical cannabis prescription and dependence. Specific medical cannabis dependence questionnaires have been developed and should be included in clinical pharmacovigilance.
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