The promise and challenges of N-of-1 studies for rare disease clinical development

With over 10,000 rare diseases affecting patients worldwide, approximately 70% of these conditions manifest in childhood.

Yet only 5% have an approved therapy, and none offers a cure, leaving a significant unmet medical need.

Due to the limited number of patients for large-scale trials in rare paediatric diseases, N-of-1 clinical trials provide an innovative, personalised approach to treatment development.

In these studies, a single patient receives an investigational treatment while simultaneously serving as his or her own control, enabling a rigorous assessment of the treatment’s safety and efficacy based on the individual disease progression.

While the N-of-1 design offers immediate potential benefits for the individual patient, the detailed, personalised outcomes collected can also contribute to broader precision medicine strategies. These outcomes can inspire novel treatments for rare diseases, where generalised data is often scarce.

Despite the inherent challenges in designing and conducting N-of-1 studies, creative solutions are emerging. These solutions reflect the same ingenuity and collaboration that parents of rare disease patients embody every day.

Understanding disease mechanisms
Unlike more common conditions such as diabetes or cancer, rare diseases often lack a clear treatment path. To develop a drug or therapy, researchers need to understand the mechanisms behind the disease.

However, rare conditions, especially those driven by specific genetic mutations, are often not well understood. Relevant animal models may be unavailable or inadequate, making the development of personalised treatments a significant challenge.

For example, when developing a treatment for a rare genetic disorder, scientists often work directly with the patient and the family to collect unique biological samples.  These samples, such as skin, blood, or tissue, help develop patient-specific therapies.

In N-of-1 studies, these individualised approaches are essential, but they also require a deeper scientific investment and innovation. The design of such trials requires a clear understanding of the patient’s genetic and phenotypic profile.

Developing a manufacturing process
Once a potential treatment is identified, it must undergo rigorous manufacturing processes to ensure its safety, quality, and effectiveness in humans. For common diseases, pharmaceutical companies have established processes to scale up drug production for large populations.

However, for rare diseases, particularly those requiring personalised treatments, scaling up is challenging. The costs of small-batch manufacturing often present a significant barrier.

While many companies may be willing to undertake these efforts for more profitable treatments, N-of-1 trials often depend on goodwill, research funding, or philanthropic support to cover manufacturing costs.

Navigating regulatory hurdles
In rare disease treatments, the regulatory process presents additional complexities. The FDA and other regulatory agencies base their safety standards on large-scale clinical trials involving thousands of patients.

But for N-of-1 studies, these standards may not be relevant or feasible. There are also ethical considerations related to disease severity, patient safety, and the potential for unanticipated side effects.

Families must play an active role in discussions about the risks and benefits of participation, ensuring that their unique circumstances and needs are factored into the trial design. Even if a treatment is developed, there are additional burdens on the patient and the family.

COAs and MCID
For rare diseases, developing effective clinical outcome assessments (COAs) can be particularly challenging due to symptom heterogeneity and limited natural history data.

COAs should capture the patient’s lived experience and disease progression, utilising rigorous qualitative methods to determine what constitutes meaningful outcomes.

Defining a minimal clinically important difference (MCID) – the smallest change in a treatment outcome that would be considered clinically meaningful – is especially difficult in rare diseases, where standardised MCID data may be unavailable.

However, collecting natural history data before treatment can help establish a baseline and provide a more accurate measure of change during the trial.

Given that N-of-1 trials lack the statistical power to apply MCID universally, an individualised approach to data collection is required. Qualitative methods and natural history data can help identify what constitutes a meaningful change for each patient.

The genotype-phenotype variability adds complexity, as symptoms may vary widely even among patients with the same genetic disorder. These factors must be considered when defining relevant COAs.

Harnessing technology
In recent years, families affected by rare diseases have increasingly turned to technology to find experts, track symptoms and connect with other families facing similar challenges. The pharmaceutical industry can also leverage these tools to enhance N-of-1 studies.

Digital wearable devices, video analysis and motion analysis technologies allow researchers to gather data remotely, reducing the need for patients to travel to clinics for in-person assessments. These technologies offer the potential to track outcomes in more natural settings.

Moreover, these tools can decentralise clinical trials, reducing the burden on patients and families while also enabling trials to be conducted at scale. Continuous rather than intermittent data collection can provide more reflective data sets.

Encouraging collaboration
Many successful N-of-1 studies have been driven by collaboration between families, researchers and regulatory agencies. The involvement of parents and caregivers is crucial to ensure that the trials are designed to meet the needs of rare disease patients.

Pharmaceutical companies must also step up, embracing the role of active collaborators in developing innovative clinical trial designs. This collaboration could unlock future breakthroughs in rare disease research and treatment.

By working together, stakeholders can push the boundaries of what’s possible. They can create more inclusive trials that focus on the needs of the individual patient, rather than a generalised population.

Personalised medicine is increasingly seen as the future of healthcare. For rare disease patients, this approach offers high hopes for effective treatments.

Both patients and the pharmaceutical industry stand to benefit from N-of-1 studies, which allow for highly individualised treatments tailored to the unique needs of each patient.

While N-of-1 trials present financial and logistical challenges, they also provide opportunities for significant breakthroughs in medical science.

For families of rare disease patients, the stakes are high, and even small improvements in symptoms can make a profound difference in their quality of life.

By embracing innovation, collaboration and technology, the pharmaceutical industry can help ensure that no patient is left behind in the quest for effective, personalised treatments.

The success of N-of-1 studies could not only lead to more tailored therapies for rare diseases but also open new doors for developing treatments for common diseases with similar underlying genetic mechanisms.