Rare disease drug development is evolving. What does this mean for evidence strategies?

In 2025, half of the FDA's novel drug approvals were for rare diseases. Alongside this significant share, the FDA's latest Accelerating Rare disease Cures (ARC) report highlights efforts to advance innovative clinical trial designs and alternative approaches to evidence generation. These developments create new opportunities for rare disease developers and raise an important strategic question: how can sponsors translate evolving evidence approaches into successful development and patient access across international markets?

Rare diseases are becoming a major focus of drug development

According to the FDA's latest ARC annual report, 23 of the 46 novel medicines approved by its Center for Drug Evaluation and Research (CDER) in 2025 were treatments for rare diseases.

This is particularly significant given the substantial unmet medical need. More than 10,000 rare diseases and conditions have been identified, affecting an estimated 25–30 million people in the US alone. Yet the vast majority still lack approved treatments.

Developing medicines for these conditions presents unique challenges. Patient populations are often small and geographically dispersed, disease progression may be poorly understood, and validated clinical endpoints are frequently unavailable. These characteristics make conventional clinical trials difficult to conduct and can limit the amount of evidence available to support regulatory decisions.

The FDA has increasingly recognised the need to address these challenges. Through its ARC programme, launched in 2022, the agency is working to advance regulatory science and support more effective approaches to rare disease drug development.

The high proportion of rare disease approvals does not mean that development has become easier. Rather, together with the FDA's ongoing initiatives, it highlights the growing importance of finding scientifically appropriate ways to evaluate treatments for small patient populations.

Evidence generation is becoming more innovative

A central theme of the ARC report is the development of methods that better reflect the realities of rare disease research.

Traditional randomized controlled trials remain an important standard, but they are not always feasible for very small or heterogeneous patient populations. The FDA is therefore advancing work on innovative trial designs, alternative statistical methods, natural history studies, and the use of biomarkers and surrogate endpoints.

These approaches can help biotech and pharma to generate meaningful evidence when conventional methods are difficult to apply.

Natural history data, for example, can improve understanding of how a disease progresses without treatment. This information can support endpoint selection, inform trial design, and potentially contribute to external comparisons. Similarly, biomarkers and surrogate endpoints may offer opportunities to evaluate treatment effects earlier, provided their use is scientifically justified.

The FDA is also developing guidance on statistical considerations for rare disease clinical trials, reflecting its continued attention to the methodological challenges of small studies.

The important development is not a reduction in evidence standards, but a broader range of approaches to generating reliable evidence.

This is also reflected in recent regulatory decisions. In October 2026, the FDA granted accelerated approval to Ultomiris (ravulizumab) for adults with primary IgA nephropathy at risk of progression. The decision was based on a reduction in proteinuria, while longer-term evidence is still needed to confirm the expected clinical benefit.

The example illustrates how evidence generation can continue beyond an initial regulatory decision, with different types of evidence contributing at different stages of a medicine's development.

From regulatory innovation to international market access

As evidence generation evolves, sponsors have opportunities to rethink how clinical development programmes support decisions across multiple markets.

For rare disease treatments, this is particularly relevant. Limited patient populations mean that collecting additional evidence later in development can be difficult. Decisions about trial design, endpoints, natural history studies, and long-term follow-up may therefore influence not only regulatory approval but also subsequent assessments of clinical value.

In Europe, evidence is evaluated across several stages, including regulatory assessment, health technology assessment (HTA), and national reimbursement decisions. Although these processes have different objectives, they often rely on overlapping clinical information.

This creates an opportunity to design evidence programmes that serve multiple purposes from the outset.

For example, natural history studies may support both clinical trial design and the interpretation of treatment benefits. Patient-relevant endpoints can strengthen the understanding of disease burden and clinical value, while longer-term follow-up data can help address questions about the durability of treatment effects.

The strategic advantage is not necessarily to generate more evidence, but to generate evidence that is relevant to multiple stakeholders and decisions throughout the product lifecycle.

By anticipating regulatory and market-access requirements early, sponsors can make more informed development choices and improve the potential value of the evidence they collect.

Systemix view: better disease understanding to accelerate drug development

The FDA's latest report highlights the growing importance of rare diseases in pharmaceutical innovation and the need for more effective approaches to evidence generation. For sponsors, this creates opportunities to rethink how patient insights and disease-specific knowledge can support drug development.

A critical starting point is a comprehensive understanding of the disease landscape. Bringing together patient data, natural history information, diagnostic and treatment pathways, and unmet medical needs helps identify evidence gaps and better understand the challenges patients face.

At Systemix, we focus on building comprehensive disease landscapes that connect these insights and provide a stronger foundation for development decisions. By understanding patient populations, disease progression, and existing care pathways, sponsors can better inform clinical development strategies, patient identification, and evidence generation.

As rare disease research advances, a deeper understanding of diseases and the patients affected by them becomes increasingly valuable in accelerating the development of much-needed treatments.

Related reading

FDA's new rare disease framework: what it means for drug developers

EU pharma package: orphan exclusivity and HTA evidence

The Joint Clinical Assessment and rare disease

Sources

1. FDA, CDER. Accelerating Rare disease Cures (ARC) Program, Year Four: Annual Report.

2. Regulatory Focus (RAPS). CDER approved 46 novel drugs in 2025, half for rare diseases, 13 January 2026.

3. AstraZeneca. Ultomiris approved in the US for IgA nephropathy, 21 October 2026.