How natural history studies are being co-designed with sponsors

What natural history studies do

A natural history study in rare disease is a longitudinal observational study capturing disease progression, clinical features, biomarkers, and outcomes in the absence of (or independent of) a specific therapeutic intervention. In rare disease, natural history studies are foundational evidence for:

• Understanding the disease's clinical course in heterogeneous patient populations
• Identifying potential clinical trial endpoints and their natural variability
• Supporting external-comparator approaches to single-arm trial designs
• Establishing the baseline against which therapeutic effect can be measured

Historically, natural history studies in rare disease were academic-led projects funded through grants and patient organisations, with sponsor involvement (if any) downstream of study completion.

Why co-design has emerged

Three forces have moved the field toward co-design:

• Regulatory expectation. The use of natural history data as external comparator for single-arm trial designs requires data quality, governance, and methodological characteristics that grant-funded academic studies do not always achieve
• Commercial necessity. The number of rare-disease assets in development has increased substantially, and the natural history data the field needs to support those programs cannot be supplied through the historical grant-funded model alone
• Patient organisation maturation. Many rare-disease patient organisations have built infrastructure (registries, longitudinal cohorts, assessment networks) that benefits from sponsor-funded operational continuity

How co-design works

Successful co-design models share several characteristics:

• Independent academic governance. The natural history study is led by an academic principal investigator with editorial independence. Sponsor involvement is in funding, design input on commercial-relevant aspects, and access to data through a defined governance framework
• Patient organisation as a structural partner. The patient organisation is involved in design decisions affecting patient experience and is a co-decision-maker on data sharing and use
• Defined data-use framework. The framework specifies what the sponsor can and cannot do with the data, what the academic group can and cannot publish, and what the patient organisation can and cannot share with the broader patient community
• Multi-sponsor models where the indication has multiple competing assets. Rather than each sponsor funding its own natural history study, a multi-sponsor consortium funds a single high-quality study with shared access

Where it works and where it does not

Co-design works well in:

• Indications with established patient organisations and academic networks
• Conditions where the natural history is sufficiently well-characterised to design an informative study
• Settings where a single high-quality study can serve multiple sponsors' needs

Co-design is harder in:

• Ultra-rare conditions without established patient organisations
• Conditions where the disease heterogeneity is so substantial that a single study cannot serve all relevant patient subpopulations
• Competitive environments where sponsors are reluctant to share data even within a defined governance framework

What this means for commercial teams

Natural history co-design is a strategic commercial input, not a research-team responsibility. The framework matters for the regulatory submission, the HTA submission, and the post-marketing evidence commitments. Commercial teams that engage with natural history co-design early shape the evidence base around their commercial needs more effectively than commercial teams that engage with the data only at the point of using it.