Rare Disease Treatments: Navigating the Economics of Global Innovation

Over the past four decades, rare disease drug development has evolved from a scientific aspiration into a central pillar of biopharmaceutical innovation. Regulatory reforms, scientific breakthroughs, and sustained investment have transformed once fatal or untreatable conditions into addressable therapeutic categories. In the United States, Europe, and Japan, orphan drug policies have reduced development risk, enabled smaller and more flexible trials, and extended market exclusivity for therapies targeting small patient populations. As a result, rare disease therapies now account for more than 40% of new drug approvals in recent years.¹

Yet the success of rare disease innovation has exposed a new and increasingly consequential challenge: access. While regulatory systems have adapted to scientific realities, reimbursement and health technology assessment (HTA) frameworks have not kept pace. Patients, clinicians, and manufacturers are encountering a growing disconnect between approval and real-world availability, a phenomenon that has become known as the value–access paradox. Therapies that regulators deem appropriate for patients often struggle to secure timely, consistent, or equitable reimbursement once they enter the market.

This article, the second installment in a broader rare disease thought leadership series, examines the economic and structural forces driving this access gap. Drawing on global pricing and reimbursement data, it argues that the central bottleneck facing rare disease therapies today is not regulatory feasibility, but the misalignment between pricing models, evidence standards, and payer decision-making across markets.

What are the economics behind rare disease pricing?

Public discourse around rare disease drugs often centers on price. Annual costs exceeding hundreds of thousands or even millions of dollars have drawn scrutiny from payers, policymakers, and the media. These concerns are not unfounded, but they are frequently oversimplified. The economics of orphan drug pricing reflect a more complex interaction between development costs, investor expectations, regulatory incentives, and market size.

Contrary to common assumptions, rare disease drug development is not uniformly more expensive than development in larger indications. Analyses adjusting for trial size, duration, and capitalized costs suggest that average research and development expenditures for orphan drugs may be lower than for non-orphan therapies.^2.3 Smaller trials, greater acceptance of surrogate endpoints, and more flexible regulatory pathways reduce development burden. High prices, therefore, cannot be explained by cost alone.

Instead, pricing in rare disease markets is best understood through an innovation premium lens. Because patient populations are small, often numbering in the hundreds or thousands, manufacturers must generate sufficient revenue per patient to justify investment, compensate for risk, and support continued innovation. This logic underpins pricing models that incorporate not only cost recovery, but also the monetized value of health gains and avoided downstream medical expenses.

This dynamic has evolved over time in the United States. While median orphan drug prices have remained relatively stable over the past decade, mean prices have increased sharply (Figure 1). This divergence reflects the growing influence of ultra-high-cost therapies, particularly gene therapies, cell therapies, enzyme replacement products, and oligonucleotide-based treatments, that pull the average upward without redefining the entire orphan drug category.

The significant difference in mean median pricing has important implications. It suggests that access pressure is not driven by orphan drugs as a class, but by a subset of therapies whose pricing challenges legacy payer financing models. Historically, payers tolerated high orphan drug prices because patient populations were small and budget impact was limited. Today, that assumption is increasingly strained. An estimated 25–30 million Americans live with a rare disease, and as multiple therapies launch within the same indications, cumulative spending can escalate rapidly.⁴ The result is mounting payer scrutiny and heightened sensitivity to affordability, conditions that set the stage for access friction once therapies move beyond approval.

Regulatory success, access failure

From a regulatory perspective, rare disease drug development has never been more efficient. Scientific standards and review processes have converged across major markets, enabling faster designation, parallel scientific advice, and more predictable approval pathways. Orphan drug frameworks in the US, European Union, and Japan now share common principles, including incentives for unmet need, flexibility in trial design, and expedited review.

This convergence results in a dramatic reduction in the time lag between orphan drug designation in the US and subsequent designation in Europe and Japan over the past decade (Figure 2A). What once took years now often occurs within months, signaling increasing alignment across regulatory agencies.

However, regulatory harmonization has not translated into harmonized outcomes. Interestingly, only a fraction of orphan drug designations ultimately convert into approvals across all major markets, and this conversion rate has not improved commensurately with regulatory alignment (Figure 2B) In recent years, no therapy designated as orphan in the US has achieved designation and approval across the US, EU, and Japan simultaneously (data not shown).¹

This divergence underscores a critical insight: regulation is no longer the primary constraint on global rare disease development. Instead, downstream factors, most notably reimbursement expectations and market access feasibility, are increasingly shaping launch sequencing, geographic prioritization, and investment decisions. In many cases, manufacturers delay or forgo filings in certain markets due to anticipated reimbursement challenges rather than regulatory hurdles.

In other words, regulatory success has exposed the limits of access systems that were never designed to absorb a growing pipeline of high-cost, evidence-constrained therapies.

Why does geography matter in global access?

While regulatory approval is increasingly harmonized, access to rare disease therapies remains profoundly shaped by national, and sometimes regional, reimbursement systems. Analysis performed by Arya illustrates the magnitude of this divergence, showing that the time from approval to pricing, reimbursement, and positive HTA outcome can vary from weeks to several years depending on geography (Figure 3A-C).¹ A summary of US, United Kingdom, EU4 (i.e., Germany, France, Italy and Spain), and Japan access systems is described in Figure 4.

United States: speed with fragmentation

The US remains the largest and fastest-moving orphan drug market globally, largely because it lacks a centralized HTA body that formally evaluates cost-effectiveness at launch. Manufacturers set list prices upon approval, and coverage decisions are made by a fragmented mix of commercial insurers, Medicare, and Medicaid programs. Mandatory coverage requirements for Medicaid and limited price negotiation mechanisms in Medicare have historically enabled rapid uptake of orphan drugs, even at very high prices.^5.6

However, this permissive pricing environment comes at the cost of uneven and unpredictable access. Commercial payers frequently impose prior authorization requirements, restrictive clinical criteria, and step therapy, while state Medicaid programs vary widely in how they interpret medical necessity for ultra-high-cost therapies. As orphan drug spending grows, payers have increasingly relied on utilization management rather than price controls, shifting access risk onto providers and patients. The result is a system that enables fast market entry but produces some of the most pronounced disparities in real-world access across payer types.

EU4: centralized approval, divergent economics

In Europe, the contrast between centralized regulation and decentralized reimbursement is most visible in Germany, France, Italy, and Spain. All four countries receive the same European Medicines Agency (EMA) approval, yet access outcomes differ dramatically.

Germany operates the most permissive access model. Under the AMNOG framework, orphan drugs enter the market immediately at the manufacturer’s list price following EMA approval, with an automatic assumption of additional benefit at launch.⁷ Price negotiations occur only after real-world uptake begins, enabling rapid access and relatively predictable reimbursement. However, reassessments frequently lead to price reductions, particularly when benefit is deemed non-quantifiable or marginal.

France offers early access through its Accès Précoce program, allowing patients to receive therapies prior to full HTA review and price negotiation.⁸ While this accelerates initial availability, final reimbursement decisions are heavily dependent on clinical added value (ASMR) ratings, which are often constrained by limited comparative evidence. This frequently results in lower negotiated prices and delayed confirmation of long-term access.

Italy employs a nationally coordinated but operationally complex system. Managed entry agreements, often tied to patient registries and outcomes tracking, are common, reflecting an explicit attempt to manage uncertainty.⁹ However, sequential national and regional decision-making introduces substantial delays, meaning access can vary widely across regions even after reimbursement approval.

Spain represents the slowest and most fragmented of the EU4 systems. Multiple layers of national, regional, and hospital-level evaluation create prolonged timelines, particularly for high-cost orphan therapies.¹⁰ Limited use of outcomes-based agreements further constrains flexibility, making Spain one of the most challenging major markets for timely rare disease access.

United Kingdom: structured rigor with high evidentiary Bar

The United Kingdom’s National Institute for Health and Care Excellence (NICE) operates one of the most transparent yet demanding HTA systems for rare disease therapies. While the Highly Specialised Technologies (HST) pathway offers higher cost-effectiveness thresholds for ultra-rare conditions, most orphan drugs are assessed under the standard Technology Appraisal process, where traditional quality-adjusted life year-based (or QALY) thresholds and penalties for uncertainty dominate decision-making.

Although appraisal timelines have improved over the past decade, the UK continues to exhibit some of the longest delays between approval and reimbursement among major markets. Positive outcomes are less frequent, and access is often conditional on confidential discounts or managed access agreements, reinforcing the UK’s reputation as a high-bar, slower-access environment.

Japan: fast access with predictable price erosion

Japan presents a distinct access archetype. Orphan drugs benefit from priority review and, once approved, receive automatic national reimbursement, eliminating regional variability and ensuring rapid, equitable access. However, Japan balances this speed with systematic price control. National list prices incorporate premiums for innovation and unmet need at launch, but mandatory annual or biannual price revisions steadily reduce reimbursement levels based on real-world utilization and updated value assessments.

This model enables early patient access while maintaining long-term budget discipline, though it limits revenue durability relative to the United States and Germany. Japan’s approach illustrates that rapid access and affordability controls can coexist, albeit with trade-offs for manufacturers.

The evidence–value gap

At the heart of the access challenge lies a fundamental misalignment between regulatory and payer evidence requirements. Regulators assess whether a therapy’s benefit–risk profile justifies approval, given the realities of rare disease science. HTA bodies, by contrast, must determine whether the magnitude and certainty of benefit justify reimbursement within finite healthcare budgets.

This divergence creates what is often referred to as the evidence–value gap. Regulators accept single-arm trials, surrogate endpoints, adaptive designs, and natural history comparisons when randomized controlled trials are infeasible. Payers and HTA bodies, however, rely on comparative effectiveness, durability of response, and cost-effectiveness metrics, criteria that are difficult to satisfy at launch in small populations.

Cost-per-QALY frameworks exacerbate this tension. Designed for common conditions with large datasets and established comparators, these models systematically disadvantage rare disease therapies. High per-patient costs distributed across small populations yield unfavorable ratios, even when therapies deliver substantial clinical benefit or address severe, life-threatening conditions. Although societal preferences often support higher willingness-to-pay thresholds for severe or pediatric diseases, these considerations are inconsistently reflected in formal HTA criteria.

The result is a paradox: therapies that meet regulatory standards and address profound unmet need may still fail to secure timely reimbursement. Conditional approvals and post-launch evidence requirements offer partial solutions, but they also introduce circular dependencies, manufacturers need reimbursement to generate real-world evidence, while payers require real-world evidence to justify reimbursement.

How do you close the gap between approval and access?

As rare disease innovation accelerates, the defining challenge of the next decade will be access sustainability. Addressing this challenge does not require dismantling existing regulatory or reimbursement systems. Instead, it demands better alignment between them.

First, evidence planning must begin earlier. Historically, manufacturers engaged regulators early and payers late. In rare disease development, this sequencing no longer works. Joint scientific advice mechanisms, such as parallel regulatory-HTA consultations, can help align expectations around endpoints, comparators, and evidence generation before pivotal trials begin.

Second, trial design and data infrastructure must evolve. Adaptive and platform trials, shared control arms, and multinational natural history databases can strengthen evidence packages without expanding patient burden. High-quality registries and real-world evidence systems are essential to demonstrating durability and comparative value post-approval, but they require coordination and methodological consistency to influence HTA outcomes meaningfully.

Third, payment models must better reflect clinical reality. Outcomes-based agreements, annuity-style payments, and managed entry schemes offer mechanisms to align cost with demonstrated benefit, particularly for one-time or high-cost therapies. While operational complexity has limited adoption, these models are increasingly necessary as traditional insurance structures strain under cumulative orphan drug spending.

Ultimately, closing the rare disease access gap requires reframing success. Scientific breakthroughs and regulatory approvals are necessary, but they are no longer sufficient. The true measure of progress lies in whether patients can access therapies in a timely, equitable, and sustainable manner.

Rare disease drug development has proven that innovation is possible. Ensuring that innovation reaches patients will be the next, and perhaps most important, test for global healthcare systems.

Methodology

Figure 1: Analysis for Figure 1 was conducted using data from Global Data (December 2025), following the subsequent methodology. Annual cost for all drugs receiving an Orphan Drug Designation and approval in any indication in the US is calculated based on the ex-manufacturer cost for each designated daily dose recommended by the FDA for the given drug in the US, projected out over one year. This sample is divided based on the year in which the drug was first approved in the United States, spanning from 2012 to 2022.

Figure 2: Analysis was conducted using data from Global Data (November 2025), following the subsequent methodologies. A) Average Gap from US to ex-US Orphan Designation Date represents the average number of days between the US Orphan Designation Date and the Orphan Designation Date in the EU and Japan. Values are calculated as the average of all drugs with a US Orphan Designation date within one of three distinct five-year periods from 2010 to 2014, 2015 to 2019, and 2020 to 2024. B.) The percentage of US Orphan Drug Designations was calculated, including all indications in which a drug received the designation, that then received an Orphan Drug Designation in the UK, EU, or Japan in the same indication. Data is organized by the year that the US Orphan Drug Designation was received for the specific indication, from 2007 to 2024.

Figure 3:Analysis was conducted using data from Global Data (November 2025), following the subsequent methodologies. A) Average Time to Pricing represents the average number of days between the Approval Date and the date of the first pricing entry across all drugs receiving an Orphan Drug Designation in the given country (US, UK, Germany, France, Italy, Spain, and Japan). This sample is organized into three distinct five-year segments based on the first approval date for a drug in the given country—2010 to 2014, 2015 to 2019, and 2020 to 2024—and each data point represents the Rare Disease Access Gap: Navigating the Economics of Global Innovation | 36 average time to pricing for selected drugs approved in the country in the given period. B) Average Time to Reimbursement represents the average number of days between the Approval Date and the date of the first reimbursement entry across all drugs receiving an Orphan Drug Designation in the given country (UK, Germany, France, Italy, Spain, and Japan). This sample is also organized into 3 distinct 5-year segments based on the first approval date for a drug in the given country, and each data point represents the average time to reimbursement for selected drugs approved in the country in the given period. C) Average Time to HTA Outcome represents the average number of days between the Approval Date and the date of the first positive HTA assessment result across all drugs receiving an Orphan Drug Designation in the given country (UK, Germany, France, Italy, Spain, and Japan). This sample is also organized into 3 distinct five-year segments based on the first approval date for a drug in the given country, and each data point represents the average time to HTA outcome for selected drugs approved in the country in the given period.

References

1. Edwards, N.; Bianco, M.; Spruce, J.; Khan, N. The Orphan Advantage: How Rare Disease Assets Are Redefining Biopharma Deal Strategy. ARYA Consulting Partners. 2026.
2. Edwards, N.; Spruce, J.; Bianco, M.; Kim, K.; Law, P.; and Khan, N. Beyond the Odds: The Rare Disease Winning Formula. ARYA Consulting Partners. 2025.
3. Jayasundara, K.; Hollis, A.; Krahn, M.; Mamdani, M.; Hoch, J. S.; and Grootendorst, P. Estimating the Clinical Cost of Drug Development for Orphan versus Non-Orphan Drugs. Orphanet Journal of Rare Diseases, 2019 14(1).
4. Han, Q.; Fu, H.; Chu, X.; Wen, R.; Zhang, M.; You, T.; Fu, P.; Qin, J.; and Cui, T. Research Advances in Treatment Methods and Drug Development for Rare Diseases. Frontiers in Pharmacology, 2022 13, 971541.
5. Ollendorf, D. A.; Chapman, R. H.; and Pearson, S. D. Evaluating and Valuing Drugs for Rare Conditions: No Easy Answers. Value in Health: The Journal of the International Society for Pharmacoeconomics and Outcomes Research, 2018 21(5), 547–552.
6. Costa, E.; Ajith, V.; Al Khaldi, A. F.; Isgrò, A.; Lee, K. J.; Luigetti, R.; Pasmooij, A. M. G.; StoyanovaBeninska, V.; Trachsel, E.; Vaillancourt, J.; and Thirstrup, S. Addressing Global Regulatory Challenges in Rare Disease Drug Development. Drug Discovery Today, 2025 30(10), 104462.
7. Gandjour, A.; Schüßler, S.; Hammerschmidt, T.; and Dintsios, C. M. Predictors of Negotiated Prices for New Drugs in Germany. The European Journal of Health Economics : HEPAC : Health Economics in Prevention and Care, 2020 21(7), 1049–1057.
8. Bourdoncle, M.; Juillard-Condat, B.; and Taboulet, F. Patient Access to Orphan Drugs in France. Orphanet Journal of Rare Diseases, 2019 14(1), 47.
9. Villa, F.; Di Filippo, A.; Pierantozzi, A.; Genazzani, A.; Addis, A.; Trifirò, G.; Cangini, A.; Tafuri, G.; Settesoldi, D.; and Trotta, F. Orphan Drug Prices and Epidemiology of Rare Diseases: A Cross Sectional Study in Italy in the Years 2014-2019. Frontiers in Medicine, 2022 9, 820757.
10. Zozaya, N.; Villaseca, J.; Abdalla, F.; Ancochea, A.; Málaga, I.; Trapero-Bertran, M.; Martín-Sobrino, N.; Delgado, O.; Ferré, P.; and Hidalgo-Vega, A. Strategic Discussion on Funding and Access to Therapies Targeting Rare Diseases in Spain: An Expert Consensus Paper. Orphanet Journal of Rare Diseases, 2023 18(1), 41.

About the Author

Nathan Edwards, PhD specializes in business development, new product planning and early brand strategy. He helps companies lay the foundation for successful launches through data-backed strategies spanning pricing and contracting and indication assessment to portfolio strategy. Nathan integrates both commercial and access insights into early asset development to maximize market opportunity.

About Ayra Consulting Partners

Arya Consulting Partners is a global, full-service boutique consulting firm that partners with biopharma companies to navigate complexity and support growth. We combine deep therapeutic expertise, real-world insights, and end-to-end commercialization capabilities with a people-first approach. Our mission is simple: deliver strategies that create measurable results and lasting impact for our clients, our people, and the communities we serve.