skip to Main Content
+44 (0) 20 3828 6228, +44 (0) 20 3816 9524

Market access for ultra-orphan therapies in Europe


As we learn more about mechanisms of disease development, therapies are becoming increasingly specialised, and are targeting smaller numbers of patients. Such advances include development of enzyme replacement and gene therapies offering potential long-term benefits from a single treatment in patients with rare diseases; chimeric antigen receptor (CAR)-T cell therapies involving adaptation of immune cells from individual cancer patients for delivery back into the same patient; and understanding the distinct genetic fingerprint of individual tumours allowing the development of therapies which target ever smaller subpopulations of affected patients.

While these all represent undoubted technological advances and offer the possibility of marked improvements in outcomes for the eligible patients, specialisation and personalisation provide market access challenges. Technological advances are likely associated with high R&D costs and numerous unsuccessful candidate therapies may add to these costs.

When only a small number of patients are eligible to receive a new technology, manufacturers have less opportunity to recoup development costs, meaning high per-patient costs are inevitable, and are essential if pharmaceutical companies are to continue to be incentivised to develop specialised technologies. A small eligible patient population also means that performing robust randomised clinical trials (RCTs) is difficult, so convincing regulators and health technology assessment (HTA) agencies of clinical benefit may be challenging and is likely to provide further barriers to justifying high costs.

Here we discuss how HTA agencies in major European markets are addressing these challenges and summarise the outcomes of recent HTAs assessing therapies for ultra-orphan diseases. Table 1 summarises the outcomes of assessment in England/Wales, France, and Germany, while Table 2 summarises factors which were key drivers of the decision-making processes in these countries.

Table 1: Outcome of assessment of ultra-orphan drugs by NICE HST, HAS, and G-BA

Table 2: Factors that were key drivers in the decision-making process for NICE HST, HAS, and the G-BA

England and Wales

The National Institute for Health and Care Excellence (NICE) has a traditional cost-effectiveness threshold of £20,000 – £30,000 per quality-adjusted life year (QALY) gained. In 2014, NICE introduced the highly specialised technologies (HST) programme for innovative new therapies for diseases affecting ≤1: 50,000 people. This system recognised that HSTs were unlikely to meet the traditional NICE cost-effectiveness threshold and did not require cost-utility analysis. Instead, manufacturers were required to demonstrate value for money.

Seven HSTs were assessed under the original HST criteria and six were recommended. Confidential price discounts were important in securing recommendation in 3 of the 6 assessments, and managed access agreements, involving collection of additional data, were required in 3 of the 6 assessments, including one which require both a price discount and managed access agreement. These requirements may have been important in helping NICE manage the uncertainty associated with high-cost drugs for which strong RCT evidence, or evidence of long-term benefits, was not available.

In April 2017, the HST programme was amended to include cost-utility analysis with a cost-effectiveness threshold of £100,000 per QALY gained. The amended system includes an incremental system of weighting applied to the QALYs if the therapy does not meet the £100,000 threshold but offers a gain of at least 10 QALYs. Under this system, the cost-effectiveness threshold is effectively modified up to a maximum of £300,000 for therapies which offer an incremental gain of at least 30 QALYs. At the time of writing, a single HST has undergone assessment within this new system. Strimvelis was considered to have a most plausible ICER of <£120,000 per QALY and resulted in a gain of 14.0-19.6 QALYs. After the QALY weighting was applied, the treatment was recommended.

NICE have also introduced a budget impact test which allows NHS England to delay funding for a new therapy for up to 2 years if the expected budget impact will exceed £20 million in any of the first 3 years following introduction. However, given that the HST programme applies to therapies for very small patient populations, this threshold may not affect many HSTs and is perhaps more likely to affect treatments for more common diseases such as breast cancer, lung cancer, diabetes, or hypertension even if they fall within the traditional cost-effectiveness threshold.


The Haute Autorité de Santé (HAS) do not have a process which is comparable to the NICE HST programme for ultra-orphan products. However, HAS consider medical benefit (SMR) and additional medical benefit (ASMR) of orphan medical products to be proven at marketing authorisation if the expected budget impact is <€30 million per year.

From a review of HAS guidance for the drugs which have undergone NICE HST assessment (all except Strimvelis have been assessed in France), it is evident that despite the stated orphan drug criteria and the likelihood of relatively modest budget impacts due to small patient populations, HAS have assessed the SMR and ASMR of each of these drugs. All seven of the drugs assessed have been recommended for reimbursement, however the ASMR ratings have ranged from II to V, with three receiving ASMR IV, or V. These ASMR ratings will have meant that confidential pricing arrangements were likely to be required to secure reimbursement in France.


The system for orphan drugs in Germany has similarities to the French system, with additional benefit considered proven at marketing authorisation if a budget impact threshold of €50 million per year is not exceeded. The Federal Joint Committee (G-BA) do, however, assess the extent of medical benefit.

Six of the eight drugs assessed by NICE HST have undergone assessment in Germany. Eculizumab was assessed prior to routine benefit assessment while Strimvelis has yet to be assessed. The extent of additional benefit rating has been minor in two cases and not quantifiable in the other four, reflecting the absence of strong RCT data, and meaning that pricing negotiations would have been essential for a positive reimbursement decision.


Despite differences between systems, ultra-orphan medical products are generally recommended for reimbursement across these major European markets. It appears that the potential HTA challenges associated with low data quality are being managed by the requirement for additional data collection and by acceptance of marketing authorisation as an indication of clinical benefit in France and Germany.

The relatively small population sizes mean that budget impact thresholds have not provided a barrier in any of the three countries. As described, budget impact thresholds are perhaps more likely to be barriers to therapies for common diseases rather than rare ones. In all three countries, discounts on the high drug prices are likely to have been required. Patient access schemes were required by NICE, while the low ASMR ratings from HAS and low extent of additional benefit ratings from the G-BA may have proved challenging in price negotiations.

The future of market access for ultra-orphan therapies

While each ultra-orphan drug may individually adhere to currently required budget impact thresholds, there is potential that the combined budget impact of many ultra-orphan drugs may provide a challenge for payers in the future. The introduction of the £100,000 per QALY gained threshold into the NICE HST process may represent an attempt to make the achievement of a positive recommendation more challenging, limiting the combined budget impact of future HSTs. However, it remains to be seen whether this threshold influences the rate of positive HST recommendations or the cost of new HSTs.