N of 1 trials provide a unique approach to evaluating the effectiveness of interventions for individuals, rather than assessing their average impact across broad populations. Though now gaining recognition as a valuable tool in both research and clinical practice, the history of N of 1 trials is long and technically fascinating, spanning more than a century. Tracing this evolution sheds light on how medicine and healthcare have progressively shifted towards more personalised, patient-centred approaches.
The Beginnings: Cushny and Peebles in 1905
The origin of the N of 1 trial can be traced to 1905 when Scottish pharmacologists Cushny and Peebles carried out an experiment to examine the effects of different forms of hyoscine on saliva production. They focused on testing the optical isomers of hyoscine on a single individual, using a crossover design - where the same participant received different treatments at separate times. What made this trial particularly interesting was the precision of their approach. By isolating variables and focusing on the responses of a single person, they highlighted how individual pharmacological effects could be studied in depth. At the time, group-based research designs were gaining popularity, and such an individualised method was relatively novel. The work of Cushny and Peebles marked the start of thinking differently about experiments - moving away from a purely group-based design and analysis and towards understanding individual patient responses.
Psychological Applications and Early Use in Medicine
Though Cushny and Peebles’ trial was innovative, it did not lead to widespread adoption at the time. However, a focus on the individual started to gain prominence in the field of behavioural psychology in the 1920s and 1930s. Specifically, B. F. Skinner played a pivotal role in promoting the use of single case designs. Skinner, a pioneer of behaviourism, emphasised the importance of studying individual behaviour and its modification through operant conditioning. His work laid the foundation for using single case experimental designs to assess the impact of interventions on specific behavioural outcomes. In the mid-20th century, investigators in the field of psychology continued to apply single-case experimental designs to understand the effects of various therapies on individual patients. The ability to observe changes in an outcome in an individual person over time made this method particularly useful for tracking progress in patients who received behavioural interventions.
The shift towards applying the N of 1 trial in medical settings came in the 1960s. The key figure here was Kellner, who used N of 1 trials to explore and adjust drug therapies on an individual basis. In 1968, Kellner and Sheffield’s work demonstrated how these trials could be applied to fine-tune pharmacological treatment for mental health disorders, using data on the individual’s response to optimise treatment. This approach was ahead of its time, as much of the medical community relied on large-scale randomised controlled trials (RCTs). However, Kellner & Sheffield’s work helped sow the seeds of personalised medicine by showing that not all patients respond to treatments in the same way, and the trial-and-error approaches that are commonly used in clinical settings could be formalised into a more scientifically rigorous process. Despite these advancements, N of 1 trials remained a niche concept during this period, not yet widely recognised or adopted.
The 1980s and 1990s: A Resurgence of N of 1 Trials
The real turning point for N of 1 trials came in the 1980s. In this period, we saw a resurgence of interest in N of 1 trials, led by Professor Gordon Guyatt at McMaster University in Canada. Guyatt and his colleagues brought a more formalised and structured approach to these trials, conducting several themselves and promoting their use as a tool for evidence-based medicine. Their efforts showed us that N of 1 trials could be a reliable way of deciding which treatments and therapies work best for individual patients. Guyatt is often credited with reviving N of 1 trials for mainstream medical use.
One of the main achievements during this period was the establishment of dedicated N of 1 services, developed by Guyatt in Canada and Eric Larson in the United States. These services provided clinicians with the resources and support to implement N of 1 trials in real-world clinical settings, promoting their use as part of routine clinical practice. By the 1990s, these services were showing that individualised care, supported by N of 1 trials, could outperform treatments supported by RCT-level evidence especially when patient responses to standard treatments were variable or unpredictable. The work conducted by these groups also helped to standardise the way N of 1 trials were conducted, with clear methodologies and protocols developed to ensure that results were reliable and actionable. For instance, a series of papers published by Guyatt et al. in the 1980s and 1990s laid out how to perform these trials with rigour, ensuring that clinicians could have confidence in the results.
Recognition in the Evidence Hierarchy
In 2011, N of 1 trials gained a prominent position within the broader spectrum of medical research. The Oxford Centre for Evidence-Based Medicine (OCEBM) listed N of 1 trials in the upper tier of their Levels of Evidence. N of 1 trials are ranked at Level 1 in the hierarchy, alongside systematic reviews of randomised controlled trials (RCTs). This places them among the most trusted forms of evidence for making individualised treatment decisions. Their presence in this top tier highlights their capacity to generate reliable and patient-specific conclusions, without individual variability obscuring true therapeutic effects, as can happen in RCTs.
For assessing treatment harms, N of 1 trials also appear prominently. In particular, they are situated at Level 1 for the detection of common harms and rare harms, provided they are part of a systematic review or conducted with randomised methods. This emphasises their value in determining both the positive and negative outcomes of therapies in individual patients.
Recent Progress
Building on foundational work in evidence-based medicine, guidelines developed in the last 10 years have aimed to formalise and refine the structure of N of 1 trials, ensuring their utility in clinical research. For instance, the CONSORT extension for N of 1 trials (CENT), a guideline published in 2015, offers a comprehensive framework for the clear documentation and reporting of such trials. This ensures that N of 1 trials adhere to high standards of rigour, transparency and reliability. Further reinforcing these efforts, the SPIRIT extension for N of 1 trials (SPENT) published in 2019 focuses on the planning and protocols necessary for high-quality trials. SPENT provides guidelines that ensure N of 1 trials are well-designed. Together with the SCRIBE Statement, which addresses the proper reporting of Single Case Designs in health research, these guidelines demonstrate a commitment to precision, transparency, and replicability in trial methodologies.
The Present Scenario
N of 1 trials continue to grow in popularity and are considered to be a valuable tool in healthcare, particularly with the movement towards personalised medicine and patient-centred care, where personalised interventions are proving increasingly important for improving patient outcomes.N of 1 trials can fill an important gap, These trials are especially applicable in situations where there is variability in patient response to treatments, or where RCT evidence is inconclusive. For example, in chronic pain management, N of 1 trials have been used to compare different pain relief medications to find the best option for a specific patient. This reduces the guesswork and provides more targeted treatment, which can often result in better outcomes.
What makes these trials so significant today is their ability to address the variability between individuals. While RCTs are highly effective for establishing general treatment guidelines, they do not account for the complexities of each patient’s physiology, genetics, and lifestyle. N of 1 trials fill that gap by making the patient the focus of the trial, using their own data to guide treatment decisions. As personalised medicine grows in prominence, so too will the role of N of 1 trials, which are perfectly suited for this kind of personalised care.
The Future of N of 1 Trials
Looking ahead, N of 1 trials are expected to become even more integral to healthcare, driven by advances in technology and data analysis. Digital health tools, such as wearable devices and health apps, are already making it easier to collect continuous data from patients. Real-time data collection allows N of 1 trials to be conducted more efficiently, and provide more detailed information on how treatments are affecting a patient’s daily life.
With machine learning and artificial intelligence on the rise, there is also potential for the automated analysis of N of 1 trial data. Algorithms could be developed to predict which treatments might work best for an individual based on their personal health data, improving the precision and speed of decision-making in clinical practice. These technologies could help streamline the process, making it easier for healthcare providers to implement them in routine practice.
Additionally, there’s potential for N of 1 trials to be used in drug development. As pharmaceutical companies move towards more personalised therapies, particularly in areas like oncology and rare diseases, these trials offer a way to assess the effectiveness of drugs at a highly specific level. As personalised medicine continues to evolve, N of 1 trials will not only help refine treatments but also accelerate the approval process for new drugs by offering precise, patient-specific data. This shift towards tailored therapies has the potential to transform clinical care, ensuring that each patient receives the most effective treatment based on their unique biology and needs.
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