The Case for N-of-1 Trials
Medical cannabis companies in Australia are frantically undertaking Randomised Controlled Trials (RCTs) in order to obtain the safety and efficacy data that the TGA requires to approve products. This is a extremely costly and lengthy process, and in the meantime, patients in need are struggling to get access to medicines that could significantly improve their lives.
Why is there such a lack of evidence? The global blanket ban on cannabis for the past 70 years has meant that very little research has been done, especially to the quality the TGA expects. Randomised double-blind placebo-controlled studies are few and far between, and aren’t the easiest of studies to do. I recently put together a plan for the full suite of trials in the UK that are required by the TGA, FDA and EMA - it came to an estimate of around $17 million and 10 years of research.
The introduction of N-of-1 trials that determines efficacy of medical cannabis for individual patients is a pathway to allow access and provide data currently lacking. As more and more medical professionals are becoming Authorised Prescribers, and patients are getting access through the SAS scheme, we have an opportunity to conduct n-of-1 trials now and collect the data the TGA requires to approve medical cannabis.
N-of-1 trials consider the individual patient as a single unit of observation when studying the safety and efficacy of a treatment. These trials can utilise study design and statistical techniques associated with standard RCTs, including randomisation and placebo controls.
They occur more frequently than you would think, usually very informally. Have you ever been to a doctor, been prescribed a medication and been told “let’s see if this works for you”, and if it doesn’t you go back and get prescribed something else? That’s personalised medicine utilising informal N-of-1 trials with you as the sole patient.
Some argue that N-of-1 trials don’t have a role to play in clinical medicine, that RCTs are the be all and end all of biomedical research. While there is no doubt that the evaluation of the benefits and problems with new medicines and treatments through RCTs, comparing them with a placebo or the traditional treatment, allows claims on the ultimate effectiveness of those treatments, there is a case that the statistic data needed to show efficacy can be reached using N-of-1 trials.
If multiple N-of-1 trials are combined and evaluated together, it is possible to achieve statistical power. This has been done many times in the past, see the table below for some examples for pain related issues, including the use of cannabis extracts for chronic pain.
The personalised treatment associated with N-of-1 trials are very relevant in the use of medicinal cannabis. Cannabinoids (the compounds in cannabis that have health benefits) interact with your endocannabinoid system, which is slightly different in every person, like a fingerprint. Each person interacts with cannabis differently, and therefore treatment needs to be personalised, which already occurs - ie finding the optimal dose for each the individual. With N-of-1 trials, treatment isn’t as prescriptive as in RCTs or tradition treatment, meaning the optimum outcome for the patient is reached much sooner.
N-of-1 trials aren’t only beneficial to the patient, but to the wallet. They are considerably cheaper than RCTs, and data can collected much faster.
I am not suggesting that N-of-1 trials should replace RCTs. Rather, they should be considered by the TGA when assessing the safety and efficacy of medical cannabis. We need a pathway to allow greater patient access much faster than the current model, and N-of-1 allows this without sacrificing on the understandable and required need for clinical evidence.
Haas, D C, Sheehe, P R 2004, ‘Dextroamphetamine pilot crossover trials and n-of-1 trials in patients with chronic tension-type and migraine headache’, Headache, vol. 44, no. 10, pp. 1029–1037.
Lillie, E O, Patay, B, Diaman, J, Issel, B, Topol, E J, Schork, N J 2011, ‘The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?’, Personalized Medicine, vol. 8, no. 2, pp. 161–173.
March, L, Irwig, L, Schwarz, J, Simpson, J, Chock, C, Brooks, P 1994, ‘N-of-1 trials comparing a non-steroidal anti-inflammatory drug with paracetamol in osteoarthritis’, British Medical Journal, vol. 309, no. 6961, pp. 1041–1045.
Mitchell, G 2015, N-of-1 Trials in Medical Contexts, Springer, London.
Nathan, P C, Tomlinson, G, Dupuis, L L 2006. ‘A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial n-of-1 trials design’, Support Care Cancer, vol. 14, no. 3, pp. 268–276.
Nikles, C J, Yelland, M, Glasziou, P P, Del Mar, C 2005, ‘Do individualized medication effectiveness tests (n-of-1 trials) change clinical decisions about which drugs to use for osteoarthritis and chronic pain?’, American Journal of Therapeutics, vol. 12, no. 1, pp. 92–97
Notcutt, W, Price, M, Miller, R 2004, ‘Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘n-of-1’ studies’, Anaesthesia, vol. 59, no. 5, pp. 440–452.
Samuel, J P, Burgart, A, Wootton, S H, Magnus, D, Lantons, J D, Tyson, J E, 2016, ‘Randomized n-of-1 Trials: Quality Improvement, Research, or Both?’, Pediatrics, vol. 138, no. 2.
Yelland, M J, Nikles, C J, McNairn, N, Del Mar, C B, Schluter, P J, Brown, R M 2007, ‘Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials’, Rheumatology, vol. 46, no. 1, pp. 135–140.