Rare diseases are individually uncommon, collectively significant
Rare Disease Day, coordinated by EURORDIS, highlights conditions defined in the European Union as affecting fewer than 1 in 2,000 individuals (EURORDIS, 2024). Although each condition is rare in isolation, more than 6,000 rare diseases have been identified globally, collectively affecting over 263 million people worldwide (Nguengang Wakap et al., 2020). Approximately 72% of rare diseases are genetic in origin, and many manifest in childhood (Nguengang Wakap et al., 2020).
Behind these epidemiological estimates are individuals and families who frequently experience prolonged diagnostic journeys, fragmented care pathways, limited disease-specific expertise, and few therapeutic alternatives (Dharssi et al., 2017). For many, uncertainty is not a transient phase but a defining feature of the disease trajectory.
Scientific uncertainty therefore translates directly into lived uncertainty.
Structural constraints in conventional evidence generation
Randomized controlled trials remain central to causal inference and regulatory decision-making. However, rare and ultra-rare conditions introduce intrinsic structural constraints. Eligible populations are small and often geographically dispersed. Clinical heterogeneity complicates endpoint definition and stratification. Ethical considerations may limit placebo-controlled designs. Recruitment timelines may exceed practical development windows (Schmidli et al., 2020).
Consequently, therapies for rare diseases are frequently evaluated based on single-arm trials, surrogate endpoints, or limited-duration follow-up (Food and Drug Administration (FDA), 2023). Regulatory authorities have formally acknowledged the need for methodological flexibility in these contexts. The U.S. Food and Drug Administration outlined the role of real-world evidence in regulatory evaluation (Food and Drug Administration (FDA), 2018) and subsequently issued guidance on externally controlled trials (Food and Drug Administration (FDA), 2023). Similarly, the European Medicines Agency has issued guidance addressing the design and regulatory use of registry-based studies (European Medicines Agency (EMA), 2019).
The central scientific challenge is therefore not the elimination of uncertainty, but its systematic and transparent reduction.
Real world evidence as an extension of clinical trials
For individuals living with rare diseases, clinical trials typically represent a limited interval within a lifelong disease course. Understanding long-term outcomes, treatment durability, safety profiles, and healthcare utilisation requires longitudinal observation beyond controlled trial environments.
Real world evidence can contribute to natural history characterisation, external control arm construction, long-term effectiveness assessment, and burden-of-disease quantification (Franklin et al., 2021; Schmidli et al., 2020). However, observational research requires rigorous methodological safeguards. Confounding, selection bias, immortal time bias, and outcome misclassification must be explicitly addressed. Foundational causal inference approaches, including propensity score methodology (Rosenbaum and Rubin, 1983), remain critical, particularly in small populations where analytical assumptions exert proportionally greater influence on results.
In rare disease research, methodological transparency is not optional. Each patient included in a dataset represents a meaningful fraction of the total affected population. Analytical discipline is therefore both a scientific and ethical imperative.
Nordic registry infrastructure and longitudinal insight
The Nordic countries provide a distinctive and internationally recognised infrastructure for population-based health research. Nationwide health and population registers in Sweden, Denmark, Finland, and Norway enable individual-level linkage across demographic, hospital, prescription, and mortality data within defined population denominators (Ludvigsson et al., 2016; Schmidt et al., 2014; Sund, 2012; Bakken et al., 2020). The ability to link data longitudinally across care settings and over extended time horizons has positioned the region as a coherent platform for pharmacoepidemiological and outcomes research (Furu et al., 2010; Laugesen et al., 2021).
For rare diseases, this ecosystem enables systematic cohort identification, linkage of diagnostic and treatment histories, and evaluation of outcomes across extended time horizons. When conducted in accordance with established methodological guidance for registry-based studies (European Medicines Agency (EMA), 2019), such designs can strengthen the totality of evidence submitted for regulatory and health technology assessment review.
Registry data do not replace randomized trials. They extend them by situating controlled evidence within real healthcare systems and real patient trajectories.
Scientific responsibility and methodological competence
Rare Disease Day is often framed as an awareness initiative. It is also a reminder of scientific responsibility. Limited population sizes amplify the impact of analytical imprecision. Overstated conclusions or inadequately controlled bias may influence regulatory and reimbursement decisions in ways that directly affect patient access (Schmidli et al., 2020; Franklin et al., 2021).
Conversely, careful study design, transparent reporting of assumptions, and robust sensitivity analyses can meaningfully reduce uncertainty and support more informed decision-making (Franklin et al., 2021). In rare diseases, rigorous epidemiology is therefore not only a technical discipline but an ethical obligation to the communities represented in the data.
At Ciencia Research, our work is grounded in the careful design and execution of real world studies in complex and small-population contexts, with particular experience in Nordic registry environments and cross-national data harmonisation.
A recent example is a cross-national population-based register study on haemolytic disease of the fetus and newborn conducted across Sweden, Finland, and Denmark (Kwok et al., 2025). Using linked nationwide registers, the investigators assembled a longitudinal multi-country cohort and demonstrated clinically meaningful differences in maternal characteristics, delivery patterns, and neonatal outcomes, including poorer outcomes among neonates requiring intrauterine or postnatal transfusions (Kwok et al., 2025). The study illustrates how Nordic registry ecosystems can support robust longitudinal analyses in small and clinically complex populations while preserving complete denominators and real world care pathways.
The study includes Kelvin H.M. Kwok of Ciencia Research and reflects our direct experience in cross-national registry methodology, cohort construction, data harmonisation, longitudinal outcome assessment, and transparent epidemiological analysis in rare and rare-adjacent disease contexts.
On Rare Disease Day, we recognise both the individuals living with rare conditions and the responsibility of the scientific community to generate robust, decision-relevant evidence on their behalf.
Reducing uncertainty in small populations requires methodological discipline, collaboration, and humility.
Author
Pernilla Meijer
Chief Executive Officer
Ciencia Research
Ciencia Research partners with pharmaceutical and biotechnology companies to generate rigorous, decision-relevant real world evidence across therapeutic areas. Our expertise spans evidence strategy, advanced epidemiology, registry-based research, and regulatory- and HTA-aligned evidence development, with particular strength in Nordic data environments.
In rare disease contexts, we support sponsors in addressing evidentiary uncertainty where methodological precision is critical.
For discussion on evidence-generation strategy, please contact:
- Pernilla Meijer | pernilla.meijer@cienciaresearch.com | +46 708 89 34 35
References
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Dharssi, S., Wong-Rieger, D., Harold, M. and Terry, S. (2017) ‘Review of 11 national policies for rare diseases in the context of key patient needs’, Orphanet Journal of Rare Diseases, 12, 63. Read here
European Medicines Agency (EMA) (2019) Guideline on registry-based studies. London: EMA.
EURORDIS (2024) What is a rare disease? Available at: https://www.rarediseaseday.org/what-is-a-rare-disease/ (Accessed: 27 February 2026).
Food and Drug Administration (FDA) (2018) Framework for FDA’s Real-World Evidence Program. Silver Spring, MD: FDA.
Food and Drug Administration (FDA) (2023) Considerations for the design and analysis of externally controlled trials for drug and biological products. Guidance for Industry.
Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, Pawar A, Bessette LG, Lee H, Garry EM, Gautam N, Schneeweiss S. Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative. Circulation. 2021 Mar 9;143(10):1002-1013. doi: 10.1161/CIRCULATIONAHA.120.051718. Epub 2020 Dec 17. PMID: 33327727; PMCID: PMC7940583. Read here
Furu, K., Wettermark, B., Andersen, M., Martikainen, J.E., Almarsdóttir, A.B. and Sørensen, H.T. (2010) ‘The Nordic countries as a cohort for pharmacoepidemiological research’, Basic & Clinical Pharmacology & Toxicology, 106(2), pp. 86–94. Read here
Kwok, K.H.M., Gissler, M., Thunbo, M.Ø., Hsia, E.C., Tjoa, M.L., Liu, S., Almgren, M., Stefanovic, V., Pedersen, L.H. and Wikman, A. (2025) ‘Clinical characteristics and outcomes of pregnancies at-risk of hemolytic disease of the fetus and newborn in Sweden, Finland, and Denmark: a population-based register study’, AJOG Global Reports, 5(3), 100544. Read here
Anton Pottegård, Sigrun Alba Johannesdottir Schmidt, Helle Wallach-Kildemoes, Henrik Toft Sørensen, Jesper Hallas, Morten Schmidt, Data Resource Profile: The Danish National Prescription Registry, International Journal of Epidemiology, Volume 46, Issue 3, June 2017, Pages 798–798f, Read here
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Rosenbaum, P.R. and Rubin, D.B. (1983) ‘The central role of the propensity score in observational studies for causal effects’, Biometrika, 70(1), pp. 41–55. Read here
Schmidli, H., Häring, D.A., Thomas, M., Cassidy, A., Weber, S. and Bretz, F. (2020) ‘Beyond randomized clinical trials: use of external controls’, Clinical Pharmacology & Therapeutics, 107(4), pp. 806–816. Read here
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