N=1: Redefining Clinical Pathways for Ultra-Rare Disease Treatment

By Rob Freishtat, MD, MPH and Marshall Summar, MD

We stand at an extraordinary crossroads in medicine. This year, a young patient at Children's Hospital of Philadelphia received a treatment that would have been pure science fiction just decades ago — a therapy designed specifically for their unique genetic condition. This wasn't a one-size-fits-all drug rolled out to thousands of patients. This was precision medicine at its most precise – a treatment created for an audience of exactly, and uniquely, one.

Welcome to the N=1 frontier, where the promise of personalized medicine meets its ultimate test. Here, traditional clinical development faces challenges we haven’t yet encountered. And yet, this represents perhaps the greatest opportunity to revolutionize how we think about drug development, regulatory approval, and patient care.

The Challenge: When Standard Approaches Fail

For generations, medical progress has followed a predictable path. We identify a disease affecting large populations, develop treatments, test them in controlled trials with hundreds or thousands of patients, and scale successful therapies across similar patient groups. This system has delivered undeniable results for common conditions.

But what happens when the entire patient population is one person?

Rare diseases collectively affect 30 million Americans — nearly one in ten of us. Yet within this vast category lies a hidden complexity. While some rare diseases affect thousands of patients, others affect dozens, and some affect just a single individual worldwide. These ultra-rare conditions are true N=1 cases, representing both medicine's greatest challenge and its most profound opportunity.

Consider the mathematics: our "gold standard" randomized controlled trial requires over 100 patients to detect even robust treatment effects. When your entire patient population consists of a single person, traditional clinical trial methodology doesn't just become difficult: it becomes impossible. We're trying to fit square pegs into round holes, and patients are paying the price.

The Regulatory Dilemma: Built For Many, Failing The Few

Current FDA approval pathways were architected for a different era, designed around large patient populations and statistical certainty. When facing N=1 scenarios, these frameworks don't bend, they break. How do you conduct a placebo-controlled trial when there's only one patient? How do you demonstrate statistical significance with a sample size of one?

The regulatory system recognizes this challenge but struggles to address it systematically. Fortunately, Expanded Access Programs and single-patient Investigational New Drug applications do exist. The FDA’s Expanded Access Program offers a route for patients with serious conditions to obtain investigational therapies outside of clinical trials. Yet, its complexity and administrative burden deter many clinicians and researchers from pursuing this option. Similarly, single-patient Investigational New Drug (IND) applications provide a targeted approach for N=1 cases but remain underutilized due to the significant resources required and persistent uncertainty regarding approval. Perhaps most frustratingly, even when these pathways work, insurance coverage remains elusive because payors typically require FDA approval, creating a catch-22 that leaves patients and families stranded.

These barriers reflect a system still grappling with how to adapt its frameworks for truly individualized medicine, where traditional regulatory and reimbursement models fall short.

The Economic Reality: Where Traditional Models Collapse

Numbers don’t lie. Developing a new therapy costs tens to hundreds of millions of dollars. When pharmaceutical companies can spread these costs across thousands or tens of thousands of patients, the math works. When the beneficiary population is one person, the traditional business model collapses entirely.

This isn't about pharmaceutical greed, it's about fundamental economics. No sustainable business model exists for spending $100 million to help one patient, regardless of how desperately they need help. This economic reality has created a systematic gap in our healthcare system, leaving the most vulnerable patients behind.

The Breakthrough Opportunity: Reimagining The Possible

Here's where the story becomes exciting rather than hopeless. The N=1 challenge is forcing us to completely reimagine how drug development, regulatory approval, and healthcare economics can work. The innovations emerging from this necessity could transform medicine far beyond rare diseases.

The ripple effects are already beginning:

Platform Approaches: Instead of developing individual therapies, we're creating platforms that can be quickly adapted for multiple unique conditions. Each N=1 success builds infrastructure, making the next case faster and less expensive.

Regulatory Innovation: The FDA is pioneering new frameworks specifically designed for ultra-rare conditions, moving beyond traditional trial requirements toward approaches based on biological rationale and unmet medical need. This could revolutionize approval pathways across medicine.

Collaborative Models: Organizations like the Bespoke Gene Therapy Consortium, nLorem Foundation, and N=1 Collaborative are pioneering unprecedented partnerships between government, industry, academia, and patient advocates. These collaborations are creating entirely new models for medical innovation.

Economic Creativity: Venture philanthropy, patient advocacy funding, and innovative risk-sharing models are emerging to fill gaps left by traditional pharmaceutical economics. These approaches could reshape how we fund medical breakthroughs across all disease areas.

Real Progress, Real Patients

This isn't theoretical. Patients are receiving life-changing N=1 therapies today. The nLorem Foundation provides antisense oligonucleotide treatments for patients with non-recurring genetic mutations. The N=1 Collaborative is developing frameworks to make single-patient trials routine rather than exceptional. Government initiatives spanning from the NIH to the European Union are building the infrastructure to support systematic N=1 approaches.

Each success creates momentum for the next. Every N=1 therapy developed makes subsequent cases faster, cheaper, and more accessible. We're not just treating individual patients, we're building the future of personalized medicine.

The Path Forward: From Exception To Standard Practice

The transformation required isn't incremental, it's fundamental. We need new clinical trial methodologies designed for small populations. We need regulatory frameworks that can evaluate safety and efficacy without traditional statistical models. We need economic models that make N=1 therapies sustainable. We need legislative support to solidify these innovations into standard practice.

Most importantly, we need a dedicated regulatory pathway for ultra-rare diseases that recognizes their unique challenges and opportunities. This pathway should be grounded in unmet medical need, disease severity, and biological rationale rather than traditional trial scale. Such an approach could serve as an international model, much like the transformative Orphan Drug Act of 1983.

The Imperative: Why This Matters Beyond Rare Disease

The N=1 frontier represents more than compassionate care for the rarest patients. It represents the leading edge of truly personalized medicine, where treatments are designed not just for specific diseases but for specific individuals.

The innovations being forged in the N=1 space today will reshape how we approach cancer treatment, autoimmune conditions, psychiatric disorders, and countless other areas where individual variation matters as much as shared pathology. The methodologies, regulatory frameworks, and collaborative models emerging from N=1 work will become the foundation for next-generation medicine.

We have the scientific capability to create these therapies. We have organizations pioneering new collaborative models. We have regulatory agencies willing to innovate. What we need now is to leverage the groundswell to create the momentum needed to make systematic change rather than accepting one-off exceptions.

The N=1 frontier isn't just about helping the rarest patients, though they deserve our help. It's about building the infrastructure for medicine's future, where truly personalized care becomes not the exception, but the standard. The patients waiting for N=1 therapies today are the pioneers of tomorrow's medical paradigm.

The question isn't whether we can afford to invest in N=1 medicine. The question is whether we can afford not to.

About The Authors:

Rob Freishtat, MD, MPH, is the President and Co-Founder of Uncommon Cures, where he leads the development of innovative clinical trial programs for rare diseases on a global scale. He holds a Doctor of Medicine (MD) from the University of Maryland and a Master of Public Health (MPH) from George Washington University.

Marshall Summar, MD, is the CEO of Uncommon Cures and an Emeritus Professor of Pediatrics at George Washington University. An international leader in rare diseases and clinical genetics, he has pioneered innovative models for clinical care and therapeutic development to improve outcomes for children and families worldwide.