N of 1 Trials

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cover_nature12It is recognised that in large, the drive for what is being called ‘precision medicine’ (a medical model that proposes the customization of healthcare, with medical decisions, practices, and/or products being tailored to the individual patient) is the lamentable failure of medications to meet the needs of the majority of people who take them. What I mean by this, is that many of the best selling drugs in the world only have a rate of benefit for the people taking them of between 1 in 3 to 1 in 24 – and it may be larger. Statins for example, regularly touted as a solution to raised cholesterol – and as a result sciences answer to an increasingly disputed marker of cardiovascular risk (Just lowering cholesterol with drugs without sorting out the dietary and lifestyle factors that actually cause heart disease is nonsensical)[1], are a highly questionable treatment when viewing the numbers needed to be treated to see a benefit.[2]

Statin drugs given for 5 years for heart disease prevention (without known heart disease) show that 104 people are needed to take them to prevent one heart attack, or 154 to prevent a stroke, and roughly 1 in 100 develop diabetes as a result and 1 in 10 declare muscle damage, although some reports suggest 1 in 5.[3] Statins Given for 5 Years for Heart Disease Prevention (with known heart disease) 1 in 83 were helped (life saved) 1 in 39 were helped (preventing non-fatal heart attack 1 in 125 were helped (preventing stroke). But 1 in 100 were harmed (develop diabetes) and1 in 10 were harmed (muscle damage).

The realisation that our most common western health problems, namely non communicable diseases are the biggest pressure on health care services and that precision medicine is unlikely to have any meaningful effect on these numbers, the idea of personalised care takes on a more valid role. Back in 2011, prevention of non-communicable disease (NCD) was declared a global priority by the UN, and governments were tasked with a 25 % reduction in premature NCD mortality by 2025.[4] The risk factors to be targeted include unhealthy diets and physical inactivity, which are known to account for up to 80 % of NCD.[5]

Public health care messages designed to encourage behavioural changes, a key part of ensuring compliance and uptake, are frequently lost in the noise of marketing from competing industries – the food and drug industry being the loudest. Studies that focus on a single person — known as N-of-1 trials — will have to be a crucial part of the mix. Clinicians and practitioners have long done these in an ad hoc way. Typically, a doctor may prescribe one drug for hypertension and monitor its effect on a person’s blood pressure before trying a different one, or a practitioner may offer a food supplement, or botanical and track progress, adjusting as needed. But few clinicians or researchers have formalised this approach into well-designed trials or appropriate training— usually just a handful of measurements are taken, and only during treatment and then rarely written up as sequential case studies. Yet most clinicians and practitioners rely on the transfer of empirical knowledge based on these experiences, human stories are still powerful mediators of therapeutic selection, especially in NCD management. Aggregated results of many N-of-1 trials (all carried out in the same way) will offer information about how to better treat subsets of the population or even the population at large.

In the meantime what can one reasonably take from a well written and researched clinical trial of one person? Karl R. Popper (1902–1994), stated that evidence cannot prove any theory correct because other evidence, yet to be discovered, may exist that could be inconsistent with the theory. Hence, theories must be supported by rejecting the opposite (or by at least making it unlikely). This is a common basis for scientific reasoning today.

Case reports fit into this picture. They can start scientific investigation by initiating a hypothesis that is later tested in adequately designed experiments or trials. They can also falsify a hypothesis that has long been accepted as true by providing an example to the contrary. However, they cannot serve as conclusive evidence, but they can provide in a personalised health care a rule of reason.

Clinicians learn from anecdotes-stories they heard at medical school, stories they tell each other, and stories their patients tell them. This is an efficient way to grasp new knowledge-even the most obscure hints and warnings can be made memorable if tagged to real people and actual events.

At the other end we have research published in peer reviewed journals that explore the relevance of hypotheses in a more consistent manner, but there are increasingly questions being raised about the reliability of this.

Richard Horton former editor of the Lancet – recently stated: The case against science is straightforward: “much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”[6]


So where do we look for relevant direction, clarification and opinion, it would seem that as has been in the past a mix of experience observation, application and comparison with multiple research sources offers us a better chance of consistency – but this takes time and energy, and of course competes with that historical desire in all humans to share experiences – my feelings are that nof1 studies will be driven not simply by need, cost of technology but because they tap into an essential human consciousness – emotional satisfaction.[7]


[1] JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart. 2014 Apr;100 Suppl 2:ii1-ii67. View Full Paper

[2] Schork NJ. Personalized medicine: Time for one-person trials. Nature. 2015 Apr 30;520(7549):609-11 View Abstract

[3] Norata GD, Tibolla G, Catapano AL. Statins and skeletal muscles toxicity: from clinical trials to everyday practice. Pharmacol Res. 2014 Oct;88:107-13 View Abstract

[4] UN General Assembly (2011) Political Declaration of the High-level Meeting of the General Assembly on the Prevention and Control of Non-communicable Diseases. New York: United Nations.

[5] World Health Organization (2013) Global Action Plan for the Prevention and Control of NCDs 2013–2020, Geneva: WHO Document Production Services. View Full Paper

[6] Horton,R. Offline: What is Medicine’s 3 Sigma. Lancet. Volume 385, No. 9976, p1380, 11 April 2015  View Abstract

[7] Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Per Med. 2011 Mar;8(2):161-173 View Full Paper

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In this article:

Case Studies, Healthcare, N of 1, Personalised