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While there have been significant strides in the development of drugs for rare diseases over the past few decades, only 5% of rare diseases have FDA-approved treatments. This scarcity of orphan drugs – defined as medications that treat rare diseases that affect less than 200,000 individuals in the US – leaves many patients waiting years for life-saving treatments. Orphan drug development is hampered by various challenges, such as business concerns over pricing and demand, small patient populations limiting clinical trials, and complex regulatory pathways that slow down approval. However, with recent technological advances and innovative strategies for trial design, there is new momentum to overcome these barriers and bring faster, more equitable treatments to patients with rare conditions. Sano recently held a roundtable discussion with experts from biotech and pharma alongside the World Orphan Drug Congress in April 2025 to surface ideas and strategies for this purpose. Key insights are summarized in our whitepaper. In this blog, we conduct a deep dive into elements of patient-driven trial design that could transform clinical trials for rare disease.
Patient motivation as an enabler
The lack of available treatments has simultaneously represented a burden and an impetus for patient agency, leading to the establishment of countless PAGs and organizations that facilitate access to novel treatments. As a result of more awareness and guidance, It has become increasingly common for patients to drive the direction of their treatment. High patient engagement represents a significant opportunity for recruitment into appropriate trials for which they are eligible and from which they could benefit. It also provides opportunities to further involve patients in trial design with aspects such as patient-defined endpoints, shared decision making protocols, and patient-reviewed messaging.
Ensuring a good fit for patients and clinical trials using pharmacogenomics
Another promising strategy for maximizing patient impact and providing potentially life-saving treatment is the use of pharmacogenomic stratification by leveraging genetic biomarkers to enrich for likely responders. By aligning trial eligibility more closely with patients’ biological profiles, developers can improve recruitment efficiency and sustain patient engagement. A study in 2023 revealed that only 0.32% of clinical trials with pharmacogenomics were in the field of rare disease (2/619). This reflects a severe lack in integrating advances into rare disease trials. Better matching patients to trials not only accelerates enrollment but also ensures participants are more informed, motivated, and likely to benefit from their involvement. In parallel, patient engagement and motivation are key to streamlining pharmacogenomics over time.
Overcoming small patient numbers through natural history studies
One effective strategy to address the challenge of small patient populations in rare disease trials is using natural history studies as a reference point for evaluating treatment outcomes. Natural history studies are observational studies that track disease progression over time, in addition to demographic, environmental, and genetic variables. Beyond bypassing the difficulty of finding an adequate number of rare disease patients for new trials, the advantages of natural history studies for rare disease are many. Natural history studies can help chart disease trajectory and track responses to the standard of care, therefore representing a control group for new drug trials. In addition, the availability of genetic data represents a unique opportunity to identify biomarkers for risk stratification and response to treatment.
However, certain risks and weaknesses may lead to hesitation among trial organizers. Experts specifically mentioned the need for thoughtful design of the cohort to maximize comparability with the trial group. And, the inclusion of overly stable patients who may not represent typical disease progression could distort trial efficacy. Accordingly, ensuring that natural history cohorts are well matched to trial populations, particularly in age and other key variables, will be essential and reinforces the need to urgently expand and invest in natural history studies as a cornerstone of rare disease research.
To accelerate progress in rare disease drug development, it's clear that we must evolve beyond traditional trial models. Patient-driven design, thoughtful use of pharmacogenomics, and natural history data are just the beginning. To explore additional strategies, including integrating multi-omics data, leveraging AI for innovative patient-finding, and recommendations for advancing toward a more patient-centered and efficient research ecosystem, access the full whitepaper here.
