Beyond rarity: Building RWE strategies for the next generation of orphan drug markets

Rarity is no longer enough. As orphan drug markets become more crowded and payers challenge evidence, price, and durability claims with increasing scrutiny, manufacturers need to rethink how they prove value. This article explores how to use real-world evidence as a strategic access lever to help orphan assets defend unmet need, quantify comparative benefit, address long-term uncertainty, and differentiate in increasingly competitive rare disease markets.

The orphan drug landscape is shifting

The global orphan drug market now exceeds $200 billion and is projected to continue growing at a double-digit annual rate, significantly outpacing the broader pharmaceutical market. Gene therapies, precision biologics, and disease-modifying treatments have transformed rare diseases from a niche segment into a major revenue driver. But the assumption that orphan status alone secures pricing and reimbursement success no longer holds. Orphan drugs increasingly face the same evidence scrutiny, price negotiations, and competitive pressures as therapies in larger, more crowded markets. As a result, evidence strategy has become a critical commercial consideration.

Formal orphan drug protections and the informal goodwill historically afforded by payers are narrowing as healthcare budgets come under increasing pressure:

• In Germany, the GKV-FinStG reform lowered the turnover threshold that triggers a full reassessment for orphan drugs from €50 million to €30 million in annual sales. The consequences are tangible: An IQWiG analysis found that in more than 50 percent of cases where orphan drugs underwent a regular benefit assessment, the added benefit granted at launch by law was not confirmed. Orphan drugs that lose their added benefit rating face challenging price renegotiations, and several manufacturers have chosen to withdraw products from the German market rather than accept unfavorable terms (including Translarna). 
• In the UK, NICE's Highly Specialised Technologies program offers a higher ICER threshold of £100,000 to £300,000 per QALY, but only for ultra-rare conditions affecting fewer than 300 patients. Many orphan drugs are therefore assessed through the standard STA route at £25,000 to £35,000 per QALY (as of 2026). 
• Similar challenges are evident across Europe: The 2024 W.A.I.T. Indicator Survey found that only 42% of EMA-approved orphan drugs were available to patients across the EU on average, with full reimbursement rates even lower.

At the same time, manufacturers considering launching into previously underserved orphan spaces will face growing competition. R&D investment in orphan drugs remains strong, with multiple late-stage products within each indication. This is particularly evident in Duchenne muscular dystrophy and cystic fibrosis, where more than 15 drugs are currently in clinical development, including several registrational trials (see Excerpt 1). Without a carefully planned and well thought out competitive evidence and positioning strategy, these drugs may struggle to secure favorable payer reviews.

How RWE can address four critical challenges?

As evidence requirements increase and orphan markets become more competitive, RWE is becoming an increasingly important lever for manufacturers to ensure that their orphan drug investments deliver favorable returns. RWE can strengthen the evidence base needed to meet evolving payer and HTA requirements, and it may serve as a competitive differentiator in increasingly crowded orphan indications. Four recurring challenges illustrate where RWE can have the greatest impact.

Challenge 1: Demonstrating the full burden of disease

Rare disease patient registries exist for many indications, but they are often small, heterogeneous, and inconsistently curated. They capture survival and hospitalization data, but rarely the full picture of what living with the disease costs patients, caregivers, and health systems. Without a clear characterization of the natural disease trajectory, manufacturers can’t fully define unmet need or appropriately anchor the value of a new intervention against a credible baseline during HTAs/payer assessments. This risks the unmet need of the disease and the value of the new treatment being incompletely understood by payers and may result in conservative ICER modelling assumptions during cost-effectiveness assessments that systematically undervalue the treatment.

How RWE addresses this: Identifying existing high-quality registries or supporting the set-up of prospective disease registries that capture key clinical milestones, patient-reported outcomes, healthcare resource utilization, and caregiver burden can help close these evidence gaps. Supporting the understanding of the natural disease trajectory in rare orphan diseases that are not yet fully understood can help regulatory and HTA bodies better contextualize and value the treatment effect of new orphan drugs. In the example of Brineura (cerliponase alfa), a natural history registry highlighted the deterministic course of a rare neurodegenerative disease (neuronal ceroid lipofuscinosis type 2) and the value of the intervention to G-BA in Germany (see Excerpt 2).

Excerpt 2. Case study of the G-BA reassessment for Brineura (cerliponase alfa).

Challenge 2: Demonstrating therapeutic value  without a comparator

Orphan drugs are routinely approved based on single-arm trials, as randomized control trials (RCTs) are often not feasible or ethically appropriate. However, HTA bodies and payers still require a quantification of the relative benefit versus existing standard of care. In the absence of a comparator, they often rely on conservative assumptions, which can translate into lower benefit ratings and pricing challenges.

How RWE addresses this: External control arms (ECAs) construct a synthetic comparator from real-world data, contextualizing single-arm trial results against the natural disease course. When designed prospectively with pre-specified matching variables, aligned inclusion criteria, and robust bias controls, ECAs can have a meaningful impact during HTA assessments. The critical success factor is timing: an ECA planned alongside the pivotal trial, using identified data sources with compatible endpoints, is fundamentally more credible than one constructed retrospectively from available data. In the case of Libtayo (see Excerpt 3), one critical success factor for acceptance of the indirect comparison was using RWE from the same registries, ensuring better comparability to the ECA. 

Excerpt 3. Case study of the TC reassessment for Libtayo (cemiplimab).

Challenge 3: Demonstrating long-term efficacy and safety

For disease-modifying or curative-intent therapies, clinical trial data may span only 12 to 24 months, while pricing rationale assumes decades of benefit. A gene therapy priced based on lifetime cure value but supported by only two years of follow-up data presents a clear challenge for payers. The economic model depends on assumptions about durability that the clinical trial evidence cannot yet demonstrate. When evidence on the durability of the effect is absent, payers often respond with mechanisms designed to manage uncertainty, including conditional reimbursement, mandated registries, and discounted assumptions. These measures can directly reduce the assessed value of the therapy.

The case of Zolgensma in spinal muscular atrophy (SMA) exemplifies this tension: priced at more than $1 million per treatment, the therapy face substantial payer scrutiny on its long-term durability. In Germany, the G-BA mandated that Zolgensma may only be prescribed by physicians participating in a registry study documenting motor function outcomes (anwendungsbegleitende Datenerhebung). In the UK, NICE tied reimbursement to a managed access agreement requiring further data collection. In France, HAS required continued post-launch evidence collection through real-world registries. 

How RWE addresses this: Post-launch registries with predefined long-term endpoints can help sustain reimbursement at initial price levels by addressing uncertainty around long-term durability. Companies that plan early can shape post-launch evidence generation and even proactively propose post-launch data collection approaches to defend targeted prices. For example, for Hemgenix (etranacogene dezaparvovec), CSL Behring negotiated an outcome-based agreement in Germany, linking payment to real-world treatment success. This landmark agreement is the first such agreement accepted by the GKV-SV, potentially paving the way for future products with similar challenges.

Challenge 4: Demonstrating differentiation in increasingly competitive orphan markets

Single-drug orphan markets are becoming the exception rather than the rule. SMA now has three mechanistically distinct therapies; hemophilia A has four approved factor and non-factor treatments; and diffuse large-B-cell lymphoma (DLBCL) features multiple CAR-T therapies alongside bispecific antibodies. As clinical development timelines often overlap, indirect comparisons can become an important differentiator, even if they are frequently challenge by HTA bodies and payers. 

How RWE addresses this: Post-launch registries can reveal which patients or subpopulations benefit most from which specific therapies, supporting more differentiated positioning within increasingly crowded treatment landscapes. As the registry infrastructure matures, comparative trials between several available treatments within a registry (e.g., registry (randomized) clinical trials) are becoming increasingly feasible. These studies may provide valuable comparative evidence for clinicians and guideline discussions in a setting without head-to-head trial data at launch (see Excerpt 4). Manufacturers are likely to increasingly face the pressure to proactively plan for well-designed comparative studies to address payer questions and counter competitive pressure.

Excerpt 4. Bachy, Emmanuel, et al. "A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nature medicine 28.10 (2022): 2145-2154.

Building an RWE strategy for long-term success

Addressing these challenges requires more than commissioning individual studies. It requires embedding RWE into the product lifecycle from pre-clinical planning through loss of exclusivity, with clear accountability and commercial considerations at each stage.

Pre-launch: Lay the groundwork early

Decisions made during Phase II and III design will determine what evidence will be available at launch. Early planning of external control arms (ECAs) should begin here to increase the likelihood of payer acceptance. 

Key considerations include:

• Confirming the availability of high-quality disease registries to ensure that relevant descriptions of the natural trajectory of the disease can be drawn. Relying solely on regulator– or payer-imposed registries results in limited control over the outcome measurements, and usefulness for clinicians or payer reassessments. 
• Ensuring registry endpoints align with HTA-relevant outcomes (e.g. QALY-compatible patient-reported outcomes, healthcare resource utilization) to avoid discovering at submission that critical comparator or burden data is missing.
• Evaluating the value of advocating for or directly establishing infrastructure for prospective disease registries. 
• Seeking pre-submission scientific advice through EMA, NICE, and the G-BA to ensure evidence generation plans meet requirements.

Launch and post-launch: Future proof your evidence strategy

During the launch phase proactive planning for landscape changes becomes critical, as orphan disease landscapes are becoming increasingly crowded and dynamic. 

Manufacturers should prepare for:

• Changes in the standard of care during an ongoing registrational study, rendering the trial comparator irrelevant. Proactive planning to lay groundwork for comparisons versus registry data and indirect treatment comparisons is critical, in addition to a strong defense of comparator selection for pivotal trial.
• Shifts in competitor evidence and positioning strategy that may redefine relevant sub-populations and evidence thresholds for assessments. Companies should strategically evaluate what competitors may do in terms of evidence generation to develop a competitor-ready evidence strategy. 
• Rapidly changing unmet need, quality of life, and treatment burden for patients with advancing therapies. A robust future-proof value story narrative and supportive evidence is critical. This can include mapping more nuanced metrics of continued disease burden, such as toxicity burdens or patient adherence, in specific sub-populations if needed.

Building the right internal infrastructure

Execution requires more than evidence planning. It also requires structural change. 

Three operational shifts are particularly important:

1. Cross-functional alignment: Medical, HEOR, and Market Access teams should be aligned from Phase II onwards. Evidence plans must be fit for purpose at HTA submission, which means access perspective needs to be critically considered when trial endpoints, registry protocols, and post-launch evidence plans are designed.
2. Global guidance, local execution: RWE generated in Germany carries limited weight in Japan or the UK. Locally generated evidence, aligned to local practice standards and data sources, is what national and regional payers find most persuasive. A global evidence framework prevents duplication and protocol heterogeneity, while enabling market-specific execution.
3. Anticipatory rather than reactive planning: RWE is most valuable when data collection begins before payers request it. This requires a mindset shift, proactively treating RWE as a market access investment rather than a payer-mandated requirement.

Conclusion

Orphan drugs are no longer commercial safe havens. Payer and HTA evidence requirements are becoming increasingly stringent and competitive landscapes more crowded. When designed strategically and executed with rigor, RWE directly addresses the four structural challenges that determine the commercial success of new orphan drugs: disease characterization, comparative evidence, long-term confirmation of efficacy and safety, and competitive differentiation. 

Companies that integrate RWE into their lifecycle strategy from the clinical development phase through post-launch commercialization will be able to secure favorable pricing outcomes, broader access, and stronger clinical positioning. Aligning evidence generation with payer requirements is crucial to fully capture the value of RWE investments.

To discuss how you can build a winning RWE strategy for your orphan assets, please reach out to our experts.