Table 1 Examples of Real World Evidence Generation for Cannabis-Based Medicinal Products
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 . However, some studies have concluded there is little difference between results obtained via RCTs and observational studies . 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 . 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) . 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 . 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 .
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 . 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 . 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 .
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.