The importance of dosing studies
The emergence of a federally regulated pharmaceutical framework for medicinal cannabis in Australia has resulted in substantial opportunities for medicinal cannabis companies to undertake research and development (R&D) here.
Within the realms of novel drug development, comprehension and accuracy regarding dosage and titration regimens have extreme significance to the outcome of treatment. With the promise of medical cannabis treating a large list of conditions the importance of dosing studies is becoming increasingly apparent.
In the majority of cases, dose-finding and dosage regimen research are integrated into phase I and II clinical safety and efficacy trials. Upon initiation of a products clinical development program preclinical or pilot research may be conducted. Exploratory studies of this kind are carried out prior to phase I trials, initially test physiological responses to a new drug. Phase I trials assess the preliminary activity and safety of the drug. The exposure and patient variability to exposure are scrutinised to accurately determine an appropriate dose range.
Dosage regimens are further evaluated in phase II trials, commonly a range of doses are assessed for safety and efficacy. Blood sampling at various time-points throughout the program may be collected, this allows for analysis of drug exposure-response data from both phase I and II. Modelling of this data is utilised to generate optimal dosage, dose regime, as well as best practice for phase III trials.
When addressing novel treatments, there is a general agreement that determination of dose for phase III trials should not be selected via hypothesis, but through well designed dose-finding studies. Together dosage information collated from phase I and II should allow for detailed analysis and the ability to refine dosage regimes through the clinical development program.
In the case of medicinal cannabis, knowledge of appropriate dosing given a specific indication is still being revealed. As the industry begins to uncover details of the pharmacodynamics and pharmacokinetics of cannabinoids, further research and development is needed to identify optimal dose, rate and method of administration.
The importance of understanding dosage of cannabis medicines is evident in the phenomena of hormesis. Hormetic responses are defined by a relationship between dose-responses, whereby a low dose of a drug presents a stimulatory effect and increasing doses an inhibitory effect. An example of this can be seen in dosing of cannabidiol for anxiety, where low doses have shown to be more efficacious than high doses.
Due to the extensive variations in cannabis products chemical make-up and the diversity of conditions it can treat, the importance of dose optimization through phase I, II and nonclinical dosing studies cannot be overemphasized. While postmarket dose-optimization research has its place, for safety and ethical reasons, understanding of optimal doses prior to product release is warranted and beneficial to both patient outcomes and the success of a product.
Research in Australia
The construct of Australia’s medical cannabis program, which began in 2016, has provided an environment favourable to R&D. Products are pharmaceutical grade, with highly controlled levels of specific cannabinoids and are administered in forms that ensure controlled and accurate dosage. The Australian government encourages R&D through a globally competitive tax incentive program, which provides offsets of up to 90cents per $1 on eligible R&D investments.
Additionally, Australia has a cost-competitive landscape for conducting clinical trials. When compared with the US, savings of more than 28% have been shown before even accounting for tax incentives. In making such a comparison it is useful to note the ease in initiating research given that Australia has a federally legal framework for cannabis, unlike the US.
A number of other factors contribute to the benefits of conducting clinical studies and dose-related research in Australia. Australia carries out research in alignment with internationally recognised processes and has a distinctly pharmaceutical approach. By adhering to the highest levels of Good Clinical Practice it is ensured that clinical research and data from Australia are recognised by international regulatory agencies – including the European Medical Agency and the US Food and Drug Agency.
Moreover, recent changes in regulatory and ethics approval pathways ensure time- and cost-effective processes in terms of applications and approvals. According to FreshLeaf analytics the number of patients entering the market with pharmaceutical style cannabis products is up to 25,000 in 2019 – offering a willing and appreciable population to meet recruitment needs.
While when compared to other global giants, Australia’s medical cannabis industry is still in its infancy. Yet, by establishing a federally legal medical cannabis framework and with our widely respected pharmaceutical approach, Australia is set to be a highly sought after location for cannabis dose finding research and clinical studies of all kinds.