History and Development of N-of-1 Trials

As interest in individualized treatment in medicine has increased, significant changes have occurred in clinical research methods. One of these innovations, N-of-1 trials, is a revolutionary step in the creation of personalized treatment plans by examining the treatment processes applied under the individual's own control. However, the origins and development of these trials go back a long way.

Early Years of N-of-1 Trials

The foundations of N-of-1 trials date back to the 17th century. The English surgeon Richard Wiseman, while serving as surgeon to King Charles II, recommended lace stockings as a treatment for a patient with edema. This experiment led to a reduction in the swelling in the patient's legs. However, when the patient removed the stockings, severe edema and sores reappeared. Wiseman's simple crossover experiment went down in history as an important example that laid the foundations of N-of-1.

In the 18th century, Caleb Parry developed this method further, cross-comparing various treatments. Using the rhubarb plant, his studies showed that the costly Turkish rhubarb was no more effective than the cheaper English rhubarb. However, Parry's studies did not yet have the methodological robustness needed to provide an unbiased assessment of treatment effects. These studies showed that treatment trials need to be more scientifically grounded.

The Birth of Modern N-of-1 Trials

By the mid-20th century, Paul Martini's book on methodological principles took the first scientific steps towards controlled crossover trials. However, it was not until the 1950s that controlled trials in individual patients were taken seriously enough by the clinical community. In 1953, Hogben and Sim published a study emphasizing how individual patient trials could be methodologically designed and evaluate treatment effects. Unfortunately, this work did not resonate and it would be some time before modern N-of-1 trials would develop.

In 1986, a group of clinical researchers from McMaster University in Canada revived N-of-1 trials. These researchers conducted randomized N-of-1 trials to evaluate treatment effects in individual patients. In this trial in a patient with asthma, they concluded that the drug theophylline caused more harm than good. This successful outcome demonstrated that more precise and personalized decisions can be made in individual treatment processes, and N-of-1 trials have become a cornerstone of personalized medicine.

Current Use of N-of-1 Trials

N-of-1 trials are particularly useful in situations where treatment effects vary widely from person to person. For fast-responding symptomatic treatments such as chronic pain or asthma, these trials are an effective way to determine the most appropriate treatment for the individual. They can also be useful for rare diseases or special patient groups not included in clinical trials. While in traditional parallel-group randomized controlled trials, many patients are excluded because they do not meet the criteria, N-of-1 trials offer suitable solutions for these patients.

After the success of the first N-of-1 trial, McMaster University began offering this method as a service. In two years, 57 N-of-1 trials were completed, resulting in a 39% change in treatment plans. Despite this success, the clinical community gradually lost interest in N-of-1 trials and the service was discontinued. However, N-of-1 trials continued to be implemented in many countries through different research services.

The Future of N-of-1 Trials

While N-of-1 trials have great potential in personalized medicine, there are challenges to their implementation. In particular, the laborious preparation of drugs and placebos has made this method difficult to be widely adopted. However, with the proliferation of mobile health devices and the development of digital platforms, it has become possible for N-of-1 trials to reach wider audiences. For example, “Trialist”, a mobile application developed at the University of California, Davis, is designed to facilitate N-of-1 trials, and the effects of trials with this method on patient outcomes are being investigated.

In conclusion, N-of-1 trials are of great importance, especially in personalized treatment planning, and could be a key element of personalized medicine in the future. By enabling patients to take a more active role in the treatment process, these trials strengthen the patient-physician relationship and ensure that treatment decisions are more scientifically based.

References

• Mirza, R. D., Punja, S., Vohra, S., & Guyatt, G. (2017). The history and development of N-of-1 trials. Journal of the Royal Society of Medicine, 110(8), 330-340.

  
  

• Gabler, N. B., Duan, N., Vohra, S., & Kravitz, R. L. (2011). N-of-1 trials in the medical literature: a systematic review. Medical care, 49(8), 761-768.

  
  

• McDonald, S., Quinn, F., Vieira, R., O’Brien, N., White, M., Johnston, D. W., & Sniehotta, F. F. (2017). The state of the art and future opportunities for using longitudinal n-of-1 methods in health behaviour research: a systematic literature overview. Health Psychology Review, 11(4), 307-323.