N-of-1 Trials: When is ethics approval needed?

One of the most common questions clinicians and researchers ask when planning an N-of-1 trial is whether ethics approval is required. The answer is not always straightforward. Because N-of-1 trials can be conducted either as part of routine clinical care or as formal research, the need for Institutional Review Board (IRB) or Human Research Ethics Committee (HREC) approval depends on the purpose and design of the trial. Although the distinction is often presented as clinical care versus research, many N-of-1 trials include elements of both. Determining whether ethics approval is required therefore depends on the primary purpose of the trial, the level of risk involved, and how the findings will be used.

Evidence-based clinical care

In routine clinical care, N-of-1 trials are used to help determine the most effective treatment for an individual patient when uncertainty exists about the best management approach. They are commonly undertaken when a patient has not responded as expected to standard treatment, has experienced adverse effects, or when there is uncertainty about whether a treatment is providing meaningful benefit.

Where the primary aim is to guide clinical decision-making and improve outcomes for a single patient, rather than to generate knowledge that extends beyond that individual, an N-of-1 trial may be considered part of routine clinical practice and may not require formal ethics approval. However, the absence of a requirement for formal ethics review does not remove the need for ethical practice. Clinicians should obtain informed consent, respect patient autonomy, protect privacy and confidentiality, minimise potential risks, and ensure that participation aligns with the patient’s preferences and best interests.

Clinical research

In contrast, when an N-of-1 trial is designed to answer a broader research question or generate knowledge that may inform future clinical practice, it is generally considered research and typically requires ethics approval. These studies commonly involve predefined protocols, systematic data collection, standardised outcome measures, and plans to disseminate findings through publications or presentations. They may also evaluate novel interventions, treatment strategies, or diagnostic approaches that have implications beyond the individual participant. Independent ethics review helps ensure that research is scientifically sound, participant welfare is protected, risks are appropriately managed, and the rights of participants are respected throughout the study.

When is the distinction unclear?

The boundary between clinical care and research is not always clear. Some N-of-1 trials are undertaken primarily to improve an individual patient’s care while also contributing to broader knowledge. In these situations, determining whether ethics approval is required may depend on factors such as the purpose of the trial, whether it departs from routine clinical practice, the level of risk, and institutional or national requirements. When uncertainty exists, researchers and clinicians should seek advice from their local ethics committee or research governance office before commencing the trial.

A practical framework

Recognising that these decisions can be challenging, Bas Stunnenberg and colleagues developed a practical ethical framework and decision flowchart to help clinicians determine whether an N-of-1 trial should be considered routine clinical care or medical research requiring ethics approval (Stunnenberg et al., 2020). Their framework encourages consideration of the trial’s purpose, design, level of risk, and intended use of the findings, providing a structured approach to ethical decision-making.

Key takeaways

N-of-1 trials occupy a unique position at the interface of clinical care and research. Whether ethics approval is required depends less on the study design itself and more on why the trial is being conducted and how the results will be used. By carefully considering these factors and seeking advice when needed, clinicians and researchers can use N-of-1 trials to advance personalised healthcare while ensuring participants receive appropriate ethical protection. 

References

Stunnenberg BC, Deinum J, Nijenhuis T, Huysmans F, van der Wilt GJ, van Engelen BGM, van Agt F. N-of-1 Trials: Evidence-Based Clinical Care or Medical Research that Requires IRB Approval? A Practical Flowchart Based on an Ethical Framework. Healthcare (Basel). 2020;8(1):49. 

Further reading

Defelippe VM, van Thiel GJMW, Otte WM, et al. Toward responsible clinical N-of-1 strategies for rare diseases. Drug Discovery Today. 2023;28(10). 

Crowden A, Guyatt G, Stepanov N, Vohra S. Research Ethics and N-of-1 Trials. In: Nikles J, Mitchell G, editors. The Essential Guide to N-of-1 Trials in Health. CRC Press; 2015. pp. 125 to 133.