N-of-1 Trials in Practice: A Training Program for Complementary Medicine Practitioners

Authors: Joanne Bradbury and Sandra Grace

An N-of-1 trial is a variant of a crossover trial that involves multiple comparisons between an active and control intervention in a single patient. While the findings from a single N-of-1 trial cannot be generalised to a population, they are nonetheless considered the highest level of evidence for a treatment effect for this patient (Howick et al., 2018). The ability to design a study around an individual patient brings a degree of flexibility that is not possible in conventional group parallel or crossover randomised controlled trials (RCT). Firstly, the research question shifts towards a patient-centred focus, asking does this treatment work for this patient? This is distinct from the traditional generalizable question of does this treatment work, on average, in the population from which a sample of patients - similar to this patient – was drawn? The latter is useful for estimating the likely range of plausible treatment effect sizes for a random patient from a well-defined clinical population (Lewis, 1991). However, it does not predict whether this particular patient will benefit from the treatment. Patients often visit naturopaths and complementary medicine practitioners when conventional treatments do not work for them (Avila, Grace, & Bradbury, 2020; Grace, Bradbury, Avila, & Du Chesne, 2018).

Naturopaths and complementary medicine practitioners generally practice using a holistic approach that places the whole person at the centre of their healthcare. In naturopathic philosophy, tolle totum means to ‘Treat the Whole Person’ (WNF White Paper: Naturopathic Philosophies, Principles and Theories, 2017). Naturopaths treat multiple aspects of the person, simultaneously, and on a range of levels (both symptomatically and constitutionally). Thus, prescribed interventions are frequently complex and multi-factorial. Complex interventions are not readily reducible to a single active ingredient that can be tested for efficacy using group RCT methodology. The mismatch of this treatment approach and research design has hampered the establishment of an evidence base for natural and complementary medicine practitioners. The knowledge of Western herbal medicine has its basis in an ancient, oral tradition. However, without evidence, natural medicine practitioners are vulnerable to criticisms of quackery (Brosnan, 2015) and worse, to exclusions from national health systems and private health insurers who depend upon government subsidies (WNF white paper, 2017).

A physician preparing a herbal remedy, 1224

Fortunately, N-of-1 trial designs are able to better accommodate complex interventions. In addition, the outcomes can be designed around an individual patient to the point where the patient can nominate the most important outcomes for themselves; Patient preference of treatment (blinded) can also be included an important clinical outcome. Two major limitations of implementing N-of-1 trial designs in naturopathic practice include: (i) the intervention cannot be curative (otherwise, there can be no crossovers), and; (ii) there should be no effect for time (i.e. these designs work best in a chronic conditions that do not steadily change over time) (Krone et al., 2020). Single case experimental design (SCED) variants can be utilised to overcome some of the limitations of classic N-of-1 trials, such as the multiple baseline design (MBD) are highly appropriate when the interventions make changes that are long-term and not readily or ethically withdrawn (Tate & Perdices, 2015), such as probiotics and fish oil that correct underlying imbalances or deficiencies. N-of-1 trial designs offer a family of holistic, adaptable approaches to generating evidence in practice (Bradbury, Avila, & Grace, 2020).

Our research team has established an N-of-1 Trials Unit that aims to train natural medicine practitioners in how to implement an N-of-1 trial in practice (Bradbury, Grace, & Avila, 2017). The N-of-1 Trials Unit comprises three academic natural medicine clinicians, an N-of-1 trials coordinator, and a research assistant. There have now been three yearly rounds of cohort training. Each cohort comprises a number of natural medicine practitioners. Practitioners themselves recruit one or more patients from their practices to participate in an overarching N-of-1 trial series or a variant. The research training involves two intensive workshops (before and after the study), and monthly follow up sessions (during the study). The most recent cohort, for instance, recruited patients into a multiple baseline design study of a complex nutritional intervention in psychological distress. The data collection is complete and the analysis and interpretation are ongoing.

Current N-of-1 trials cohort (2019 - 2020)

Individualised feedback has been discussed by researcher and practitioner, and by practitioner and patient and back again to the researchers. Outputs will include a joint publication with participating practitioners, and a process evaluation (after Haynes et al., 2014) of the N-of-1 Trials Unit training program. If natural medicine practitioners were to embrace N-of-1 trial designs in practice, there could be widespread generation of high-quality evidence to support the field of complementary medicine.

About the authors

Dr Joanne Bradbury is a clinical researcher with methodological expertise in biostatistics. Her research interests include nutrition and complementary medicine, stress and positive mental health. 

Professor Sandra Grace is a health services researcher with extensive research experience in models of healthcare, integrative medicine, inter-professional practice and education, and program evaluation.

References

Avila, C., Grace, S., & Bradbury, J. (2020). How do patients integrate complementary medicine with mainstream healthcare? A survey of patients’ perspectives. Complementary Therapies in Medicine, 102317.

Bradbury, J., Avila, C., Grace, S. (2020). Practice-Based Research in Complementary Medicine: Could N-of-1 Trials Become the New Gold Standard? Healthcare, 8, 15.

Bradbury, J., Grace, S., & Avila, C. (2017). N-of-1 trials: Building the evidence for natural medicine, one patient at a time. Journal of the Australian Traditional Medicinal Society, 23, 14-15.

Brosnan, C. (2015). ‘Quackery’in the academy? professional knowledge, autonomy and the debate over complementary medicine degrees. Sociology, 49, 1047-1064.

Grace, S., Bradbury, J., Avila, C., & Du Chesne, A. (2018). ‘The healthcare system is not designed around my needs’: How healthcare consumers self-integrate conventional and complementary healthcare services. Complementary Therapies in Clinical Practice, 32, 151-156.

Haynes, A., Brennan, S., Carter, S., O'Connor, D., Schneider, C. H., Turner, T., & Gallego, G. (2014). Protocol for the process evaluation of a complex intervention designed to increase the use of research in health policy and program organisations (the SPIRIT study). Implementation Science, 9, 113.

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Krone, T., Boessen, R., Bijlsma, S., van Stokkum, R., Clabbers, N. D., & Pasman, W. J. (2020). The possibilities of the use of N-of-1 and do-it-yourself trials in nutritional research. PloS one, 15, e0232680.

Lewis, J. A. (1991). Controlled trials in single subjects. 2. Limitations of use. British Medical Journal, 303, 17.

Tate, R., & Perdices, M. (2015). N-of-1 trials in the behavioural sciences. In J. Nikles & G. Mitchell (Eds.), The Essential Guide to N-of-1 Trials in Health (pp. 19-41). Dordrecht: Springer.

WNF White Paper: Naturopathic Philosophies, Principles and Theories. (2017). Retrieved from http://worldnaturopathicfederation.org/wp-content/uploads/2015/12/White-Paper_FINAL.pdf