Collectively, an estimated 6,000 to 7,000 distinct rare diseases affect 300 to 400 million people worldwide. Despite this substantial global burden, people living with rare diseases experience significant delays in diagnosis, and approved treatments exist for only around 5% of rare diseases. [1,2]
Historically, progress in rare disease research has been constrained by a combination of scientific, clinical, and commercial challenges. [3,4] Small, heterogeneous patient populations make research and diagnosis difficult, while limited commercial incentives have historically reduced investment in drug development. Over the past two decades, global advocacy and cross-sector collaboration have increased awareness of rare diseases and targeted treatments are now beginning to change outcomes for patients. In 2025, the World Health Organization formally recognised rare diseases as a global public health priority through its resolution “Rare diseases: a global health priority for equity and inclusion”, acknowledging the substantial challenges faced by individuals living with rare diseases and calling for the integration of rare disease policies within national health systems.[5] In 2026, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) proposed a new Rare Disease Therapies Regulatory Framework designed to provide a more flexible and proportionate approach to evaluating innovative therapies while acknowledging the realities of rare disease development.[6]
Although this is a positive shift, people living with rare diseases continue to experience delays in access to new medicines. Recently, the criteria for appraisal via the Highly Specialised Technologies (HST) route by the National Institute for Health and Care Excellence (NICE) was tightened.[7] As a result, a higher proportion of therapies for rare diseases now face appraisal via the Single Technology Appraisal (STA) route, a framework based on the assumption that large patient populations enable robust randomised controlled trials (RCTs), validated endpoints, and mature long-term follow-up; all of which are uncommon in rare diseases. An analysis of orphan versus non-orphan medicines appraised via the NICE STA process reported that orphan medicines were subject to a significantly longer mean time to decision making compared with non-orphan medicines (340 days versus 277 days, respectively), and were more likely to undergo more than one appraisal committee meeting (ACM).[8]
Delays in HTA of rare disease derive from a range of sources:
- Challenges in determining clinical effectiveness of the new medicine versus standard of care;
- Lack of long-term data and reliance on surrogate endpoints;
- Challenges capturing meaningful health-related quality of life (HRQoL) outcomes;
- Limited healthcare resource use data.
Together, these challenges create uncertainty that can delay reimbursement decisions and, ultimately, patient access.
Challenges in evidence generation
Clinical evidence
The gold standard for generation of clinical evidence is large-scale RCTs which are frequently conducted in more common diseases where the pool of patients is sufficient to achieve statistical power in validated clinical outcomes. Conversely, rare diseases may affect only a few hundred to thousand patients globally, making RCTs impractical, unethical, or even impossible.
Rare disease research is frequently complicated by diagnostic delays, geographically dispersed populations, and substantial clinical heterogeneity. These factors can significantly restrict recruitment. This is compounded by ethical challenges; for diseases with no alternative treatments, clinical equipoise is often lacking which prohibits the conduct of RCTs, or requires adaptive trial designs that limit the length of the comparative period. Outcome measurement presents further challenges as many rare diseases lack validated clinical endpoints, necessitating the use of surrogate outcomes to demonstrate efficacy. While often appropriate, surrogate endpoints can increase uncertainty during HTA evaluation, particularly when the relationship between the surrogate and long-term patient benefit is unclear.
In the absence of direct comparative evidence from RCTs, manufacturers must frequently rely on indirect treatment comparisons to estimate relative effectiveness. However, comparator data are often limited to single-arm trials, retrospective observational studies, case series, and/ or natural history data. In addition to having an increased risk of bias, these studies may collect baseline and efficacy data that differ to those collected in the trial of interest, complicating or preventing treatment comparisons and overall introducing uncertainty to HTA decision making.
Health related quality of life outcomes
Generation of HRQoL outcomes is also subject to challenges; generic preference-based measures often are not sufficiently sensitive to accurately represent and capture the HRQoL burden in rare diseases and are therefore unable to fully demonstrate the benefits of new treatments. Additionally, rare diseases often affect children and/ or result in cognitive impairment requiring proxy completion by parents/ caregivers, introducing further uncertainty in HRQoL data. Furthermore, the absence of representative instruments mean that the face validity of elicited utility values may be unknown, further increasing uncertainties in the cost-effective analysis of new treatments for rare diseases.
Healthcare resource utilisation evidence
Evidence of healthcare resource use is often fragmented. Small patient populations, specialist referral pathways, and geographical variation in clinical management across centres make it difficult to accurately quantify healthcare costs and long-term disease burden, creating additional challenges when estimating the economic impact of a new treatment.
Implications for HTA
Taken together, these limitations mean that evidence packages submitted for rare disease therapies frequently contain greater uncertainty than those developed for more common conditions. Combined, these factors often necessitate multiple NICE AMCs and lead to delays in, or even lack of, patient access to innovative therapies.
What can technology developers do to mitigate these challenges?
While uncertainty cannot be eliminated entirely in rare disease research, there are strategies in which technology developers can strengthen the evidence base and improve confidence among regulators, payers, and HTA bodies.
A multi-stakeholder approach to data collection
Effective evidence generation must be informed by a multi-stakeholder approach; although a clinical outcome may satisfy the evidence requirements of regulators and payers, to what extent is this useful if the outcome does not capture aspects of the disease that are most important to patients? Patient and caregiver experts, healthcare professionals, and regulatory and payer representatives should be involved throughout the market access journey to ensure the collection of evidence that fully captures the patient experience, but that can also inform comparative effectiveness estimates, and satisfies the requirements of both regulatory and HTA bodies.
Multi-stakeholder communication can be sought through advisory boards that bring together healthcare professionals, patient advocacy groups, patients, caregivers, and healthcare decision makers. For more information about this approach, termed a ‘multi-stakeholder panel (MSP)’, please refer to the following Multi-stakeholder panels: Empowering market access and HTA success through stakeholder collaboration.
Real-world evidence
One of the most valuable investments in rare diseases is the development of robust natural history studies and patient registries. As well as reliable and regulated platforms for access, data collected provide critical insights into disease progression, survival, symptom burden, and healthcare use. In the absence of a traditional control group, natural history data can establish an important benchmark against which treatment outcomes can be assessed.
Real-world evidence is becoming increasingly important and recognised by HTA bodies, particularly in rare diseases. Patient registries, electronic health records, and observational studies can provide valuable information on treatment outcomes in routine clinical practice and, in some cases, support the construction of external control arms. While these approaches cannot fully replicate randomisation, they can provide important context and help reduce uncertainty associated with single-arm studies.
Where possible, real-world evidence collection should be designed in parallel with clinical trials to ensure the collection of data that can inform clinical effectiveness estimates. Often, real-world study populations do not match those of the trial, important disease characteristics are not collected, or clinical outcomes differ to trial outcomes, making comparisons challenging. A multi-stakeholder approach should also be applied to the design of real-world studies of rare diseases to incorporate patient-relevant outcomes that fulfil the requirements of regulatory and HTA bodies, and permit clinical effectiveness estimates.
Early engagement
Early engagement with regulatory and HTA bodies is one of the most effective ways to mitigate evidence uncertainties in rare disease development. Manufacturers should seek scientific advice as early as possible, ideally before phase 3 trial design, to align on key aspects of evidence generation, including study design, endpoint selection, comparator choice, and approaches to managing uncertainty.
The new MHRA-NICE aligned pathway offers scientific advice from the combined perspective of regulators and payers, ensuring that evidence that meets the requirements of both perspectives can be planned for. This initiative is a recent advancement in the UK market access journey; however, technology developers should take advantage of the opportunity to seek joint advice that could aid in evidence generation to accelerate access to new therapies. For more information about the potential impacts of the aligned pathway, please see the following blog Bridging the Regulatory-HTA divide | G&L Scientific.[9]
Managed access agreements
Increasingly, managed access agreements and post-launch evidence generation programmes are beginning to play a role in expediting patient access to new therapies. These approaches recognise that, in some circumstances, waiting for additional evidence to reduce uncertainty in cost-effectiveness analyses may significantly delay access to potentially transformative therapies. Instead, they allow evidence generation to continue after launch, reducing uncertainty over time while enabling earlier patient access. A key example of this is the ultra-orphan medicines pathway, introduced to NHSScotland in 2018. This initiative permits the SMC to approve medicines for ultra-orphan diseases for use in NHSScotland, providing the HTD commits to a three-year period of data collection to be presented for appraisal following the interim access period.[10] At present, 18 therapies have made available via the ultra-orphan medicines pathway, of which 14 remain in the data collection phase, and four have been reassessed by the SMC with each being accepted for use via routine prescribing in NHSScotland.
In summary
Ultimately, the goal of HTA remains unchanged: to support informed decisions that maximise patient benefit while ensuring responsible use of healthcare resources. In rare diseases, achieving that goal requires a willingness to balance uncertainty with unmet need, recognising that the pursuit of perfect evidence should not become a barrier to meaningful clinical progress. Through early stakeholder engagement, innovative evidence-generation strategies, and continued collaboration between manufacturers, patients, clinicians, regulators, and HTA bodies, it is possible to strengthen decision-making while accelerating access to innovative therapies.
References
- The Lancet Global Health. The landscape for rare diseases in 2024. The Lancet Global Health. 2024;12(3):e341. doi:10.1016/S2214-109X(24)00056-1
- Chaudhary A, Kumar V. Rare diseases: a comprehensive literature review and future directions. Journal of Rare Diseases. 2025/07/03 2025;4(1):33. doi:10.1007/s44162-025-00099-6
- Noble-Longster J. Health technology appraisal of gene and cell therapies for rare diseases. 2024. https://tolleyhta.com/health-technology-appraisal-of-gene-and-cell-therapies-for-rare-diseases/
- Stainer L, Snell T. Challenges and opportunities in rare disease modelling. 2024. https://tolleyhta.com/challenges-and-opportunities-in-rare-disease-modelling/
- World Health Organization. Rare diseases: a global health priority for equity and inclusion. 2025. https://apps.who.int/gb/ebwha/pdf_files/EB156/B156_CONF2-en.pdf
- Medicines and Healthcare products Regulatory Agency. Draft rare disease therapies regulatory framework. https://www.gov.uk/government/consultations/draft-rare-disease-therapies-regulatory-framework
- National Institute for Health and Care Excellence. HST routing criteria (refined April 2025). 2025. https://www.nice.org.uk/guidance/ta1153/documents/h-s-t-checklist
- Clarke S, Ellis M, Brownrigg J. The impact of rarity in NICE’s health technology appraisals. Orphanet Journal of Rare Diseases. 2021/05/13 2021;16(1):218. doi:10.1186/s13023-021-01845-x
- McDermot E, Noble-Longster J, Prentice E. Bridging the Regulatory-HTA divide. 2026. https://gandlscientific.com/knowledge-hub/bridging-the-regulatory-hta-divide
- Scottish Government. Ultra-orphan medicines pathway: guidance. Accessed 9th August, 2026. https://www.gov.scot/publications/ultra-orphan-medicine-pathways-guidance/