Rare disease drug development: Barriers and solutions

Rare disease drug development operates under a unique set of structural constraints. Patient populations are small and dispersed, diagnostic timelines are long, and the economics of development often discourage investment, even when the science is ready. These challenges are not new, but they remain unresolved for the vast majority of the estimated 7,000 known rare diseases.

In a recent webinar, Charlotte Guzzo, COO of Sano Genetics, led a discussion on these challenges and the emerging solutions that could shift the landscape. The conversation featured Harriet Holme, chair and founder of PCD Research, whose professional and personal experiences provide a grounded perspective on what is working, what is not, and what needs to change. This blog covers key highlights from the discussion.

Key Takeaways

• Diagnostic Gap: Rare diseases take an average of 4.7 years to diagnose, despite 80% being genetic and detectable at birth.
• Early Intervention: Newborn genetic screening and prenatal initiatives are critical for preventing irreversible damage and improving trial readiness.
• Technological Integration: Utilizing LLMs and unified data platforms (like the NHS biobanks) can identify potential patients before formal diagnosis.
• Regulatory Shifts: Moving toward gene-based proof-of-concept trials can streamline approvals and reduce costs for variant-specific therapies.
• Collaborative Models: Success in rare disease drug development requires breaking silos between academia, industry, and patient advocates.

About the speakers

Harriet Holme is a drug development clinician at Weatherden, where she supports biopharma teams with clinical strategy, asset selection, and KOL liaison. She studied medicine at Cambridge and was an NIHR clinician scientist in pediatric hemato-oncology in London and Oxford. Her PhD at the Institute of Cancer Research focused on cancer drivers and synthetic lethality in osteosarcoma. Harriet is also the founder and Executive Chair of PCD Research and a member of the LifeArc Rare Disease National Task Force. Her expertise spans genetic therapies, anti-cancer agents, and novel anti-microbials, from spin-out through Phase 2.

Charlotte Guzzo is Chief Operating Officer at Sano Genetics, where she helps lead the development of Sano’s precision patient platform. With a background in clinical operations and strategic leadership, Charlotte focuses on connecting patient identification, genetic qualification, and longitudinal engagement in a single operational layer. This gives sponsors auditability and recontact capability across programs, rather than limiting value to isolated study outcomes.

Harriet’s journey to rare disease research

Harriet's path into rare disease research began during her academic career in pediatric oncology. Her PhD at the Institute of Cancer Research focused on synthetic lethality in osteosarcoma, grounding her in the genetics of disease at a molecular level. The birth of her son, who has a rare condition, shifted her focus from oncology to rare disease drug development and led her to found PCD Research, an organization working to advance treatments for primary ciliary dyskinesia (PCD). This combination of clinical research experience and firsthand exposure to the gaps in rare disease care shapes much of the perspective she brought to the discussion.

Challenges in rare disease drug development

Harriet highlighted several key barriers that persist despite decades of policy attention. Since the Orphan Drug Act went into effect in 1983, more than 600 drugs have been approved for rare diseases. Yet the vast majority of the estimated 7,000 known rare conditions still have no approved treatment. The structural challenges remain substantial:

• Diagnostic delays: It takes an average of 4.7 years to diagnose rare diseases, even though 80% have a genetic origin detectable at birth. This means patients often miss the window for early intervention and are harder to identify for clinical trials.
• Fragmented patient populations: Without comprehensive registries or newborn genetic screening, locating and enrolling patients in clinical trials is challenging. Many patients remain undiagnosed or are managed outside of specialist centers, making them invisible to recruitment efforts.
• Economic viability: The small market size for individual rare diseases often deters investment in drug development, particularly for conditions where the addressable patient population numbers in the hundreds or low thousands.
• Regulatory hurdles: While frameworks such as FDA orphan designation, expedited programs, and rare disease-specific guidance exist to support development, current regulations still require separate approvals for therapies targeting different genetic variants, increasing time and costs. The regulatory infrastructure has improved, but it has not kept pace with the complexity of genetically defined rare diseases.

Solutions for rare disease research

The discussion covered a number of solutions to address these challenges, including:

• Prenatal and newborn screening: Harriet outlined the importance of initiatives like the UK's 100,000 Genomes Project and newborn genetic screening programs. Early diagnosis does more than improve individual patient outcomes; it directly affects trial feasibility. Patients identified earlier are more likely to be reachable, trackable, and eligible for intervention before disease progression narrows the treatment window. For sponsors, this means that investment in screening infrastructure is not separate from clinical development strategy. It is foundational to it. Regulatory bodies, including the FDA, have published pediatric-specific guidance that reflects the growing recognition that rare disease development often begins with pediatric populations and requires tailored approaches.
• Data integration and registries: Unified data platforms that connect health system records, biobanks, and research registries can make it significantly easier to identify and recruit patients for clinical trials. Harriet highlighted the NHS as one example, but the principle applies broadly: when patient data is fragmented across disconnected systems, eligible patients remain invisible to study teams. Computational approaches, including large language models, can support this by identifying clinical patterns consistent with rare disease phenotypes in electronic records, potentially flagging patients who have not yet received a formal genetic diagnosis.
• Regulatory innovation: Harriet suggested using gene-based proof-of-concept trials to simplify the approval process for new therapies. By building on existing knowledge from these initial trials, regulators could streamline approvals for similar treatments. This direction aligns with emerging FDA guidance on complex innovative trial designs, real-world evidence, and patient-focused drug development, all of which create pathways for sponsors to use adaptive and evidence-driven approaches in rare disease programs. The regulatory landscape is evolving, but sponsors need to engage with these frameworks proactively to shape how they are applied.
• Collaborative efforts: Harriet spoke about how PCD Research has successfully partnered with organizations like Harwell and the Nucleic Acid Therapeutics Accelerator. She highlighted that collaboration between academia, industry, investors, and patient advocates is essential to overcoming the fragmentation that limits progress in rare disease treatment and driving progress in rare disease treatment.

Outlook for rare disease treatments

The discussion concluded with a clear-eyed view of the path ahead. Scientific tools like CRISPR, patient-derived models, and genetic therapies are advancing rapidly, creating opportunities that did not exist a decade ago.

However, scientific capability alone does not guarantee patient access. As industry observers have noted, rare disease and gene therapy programs face growing pressure from investment reallocation and economic uncertainty, even as the pipeline expands. The risk is that promising therapies stall not because the science fails, but because the surrounding infrastructure cannot support efficient development.

Harriet closed the conversation by reinforcing that aligning the ecosystem is critical: diagnostics, regulatory frameworks, trial design, patient identification, and long-term engagement all need to work together. Transforming scientific innovation into tangible patient outcomes requires not just better therapies, but better systems for getting those therapies to the patients who need them.

Conclusion

The challenges discussed in this webinar are not abstract. They define the day-to-day reality for sponsors developing therapies for rare and genetically defined diseases: long diagnostic timelines, fragmented patient populations, regulatory complexity, and the need for cross-sector collaboration. Harriet's work in both clinical and advocacy domains illustrates what becomes possible when these challenges are addressed through integrated, systems-level thinking rather than isolated interventions.

For sponsors designing or executing rare disease programs, the implication is clear: investment in diagnostics, data infrastructure, patient engagement, and regulatory strategy needs to be coordinated from the outset, not layered on after enrollment falls behind.

Watch the full webinar here.