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Assessing the impact of rarity on French HTA and pricing decisions

With changes to the pricing and access processes such as the new Accord Cadre and the soon-to-be implemented ATU reform likely to impact pricing and access of orphan products in France, we look at how French payers have in the past valued rarity


Pricing and market access in France operates on a dual system, under which health technology assessments (HTAs) are conducted first with the aim of informing subsequent pricing negotiations. To do this, the HTA body, the CT (Commission de la Transparence – Transparency Commission), provides guidance in two main forms: a comparative clinical benefit rating, the ASMR (Amélioration du Service Médical Rendu) and a target patient population.

In the case of rare diseases, however, there seems to be an intrinsic flaw in this system, as comparators are often not available and epidemiology estimates are often unreliable. This leaves CEPS (Comité Economique des Produits de Santé, pricing committee) with many uncertainties in managing pricing negotiations.

We set out to understand how French payers manage these uncertainties and assess the value they place on rarity. We analysed 22 non-oncology orphan drugs (ODs) that received EMA approval between July 2012 to the end of 2019, focusing on chronic, non-curative treatments.

Dosing assumptions followed EMA or HAS (Haute Autorité de Santé) guidelines. The number of patients eligible for treatment and ASMR ratings were taken from CT (Avis) reports. Annual treatment costs (ATCs) were calculated using ex-manufacturer list prices (Tarif de responsabilité HT) in Legifrance, or ATUc prices.

Relationship between ATC and eligible patient number
In accordance with previous CRA analyses in the UK and Germany, our analysis showed a correlation between the reimbursed ATC and the eligible patient number defined by the CT.

An interesting example of the importance of eligible patient number in pricing negotiations in France is Kalydeco. Kalydeco was first assessed by the CT in May 2013 for cystic fibrosis patients aged six years and older who had at least one G551D mutation in the CFTR gene, with an estimated eligible patient number of 80 and an ATC of approximately €235,000.

Kalydeco obtained ASMR 2 (important improvement, eligible for EU-level price) for this indication, so discussions with CEPS would have focused on patient numbers. In October 2019, Kalydeco was assessed by the CT for an expanded indication in multiple additional mutations, for a total additional five eligible patients, and again obtained an ASMR 2. Since the assessment in June 2020, the Kalydeco ATC has decreased to approximately €220,500 – a change almost exactly inversely proportional to the population increase.

Additional factors beyond eligible patient number
Looking at reimbursed products, Spinraza and Orkambi both sit above the trend and offer valuable insights into factors beyond eligible patient numbers.

Spinraza is indicated for the treatment of 5q spinal muscular atrophy (SMA) and was granted SMR (Service Médical Rendu, overall clinical benefit) Important and ASMR 3 (moderate improvement) in SMA types I and II, SMR Important and ASMR 5 (no improvement) in SMA type III and SMR Insufficient (not reimbursed) in SMA type IV.

The CT calculated that there would be 230 eligible patients for SMA types I and II collectively, and 70 eligible patients for SMA type III.

While the low patient number is undoubtedly a factor in the high price of Spinraza, the high ASMR rating in the majority of patients, along with high unmet need, severity and the paediatric nature of SMA (especially type I and II) could also be major factors in its pricing.

Orkambi was first assessed by the CT in December 2016 for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. However, Orkambi price negotiations were not completed until three years later, in December 2019, by which time it had been assessed by the CT for two additional indications: patients between six and 11 years of age (February 2019) and those over two years of age (December 2019).

Orkambi was granted ASMR 4 in all three assessments and given a negotiated ATC of approximately €138,500. Although its price is above the trend, it sits much lower than the likely price benchmark, Kalydeco (€235,000, also from Vertex).

While the lower ASMR rating of Orkambi (ASMR 4 vs ASMR 2) and higher eligible patient population (2,500 versus 80 patients) are likely to have played a role, the higher price benchmark appears to have driven the relatively high price
of Orkambi.


Figure 1. Distribution of ASMR ratings (all products) Source: CRA analysis; ASMR definitions: ASMR 1: major improvement; ASMR 2: important improvement; ASMR 3: moderate improvement; ASMR4: minor improvement; ASMR5: no improvement; Only ASMR 1, 2 & 3 can benefit from faster access through the price notification procedure

Rarity, ASMR rating and price
To explore the reasons behind the non-linearity of, and deviations from, the trend, we investigated whether rarity was an influencing factor in the ASMR rating.

Despite the high unmet need generally perceived in rare diseases, the number of unfavourable ASMR ratings (ie, ASMR 4 or ASMR 5) illustrates the challenges in providing methodologically robust clinical data, as well as the importance of the availability of a clinical comparator or existing treatment (Figure 1).

It also demonstrates that, unlike in Germany where the G-BA (Gemeinsamer Bundesauschuss, German Federal Joint Committee) automatically grants ODs a minimum of an ‘unquantifiable additional benefit’ upon initial assessment – only reassessed if the annual budget impact exceeds €50m – OD designation does not guarantee a positive assessment in France.

The ATCs for the reimbursed products with the highest ASMRs (Kalydeco, Strensiq: ASMR 2; Kanuma: ASMR 3) were among the highest ATCs in the analysis, suggesting a relationship between ASMR and ATC.

However, as prices of ASMR 1-3 products are freely set up to the average price in Germany, the UK, Spain and Italy, and only volume is negotiated with CEPS in France, these high prices are not intrinsically indicative of a willingness by payers to pay higher prices.

The analysis also shows that some products with lower ASMRs achieved relatively high reimbursed ATCs. Examples include Galafold (ASMR 4) and Cerdelga (ASMR 5). The relatively high prices of these products suggest that the relationship between ASMR and ATC includes other factors such as disease prevalence, unmet need, the existence of a clinical or pricing comparator therapy and the robustness of clinical evidence.

Payers in France seem to value treatments for conditions with low patient numbers, although other factors seem equally able to affect the achievable price. Specifically, the CT assessment – which in turn depends on submitting clinical evidence that is deemed methodologically appropriate – is critical in achieving a premium list price outcome for rare disease drugs. Low patient numbers and OD status will not exempt manufacturers from presenting comparative clinical data, if possible, or deter the CT from granting low ASMR ratings.

While France should still be seen by OD manufacturers as an attractive market where high list prices are achievable, the specific evidence requirements should be considered early in development to maximise pricing outcomes.

The views expressed herein are the authors’ and not those of Charles River Associates (CRA) or any of the organisations with which the authors are affiliated.

Cécile Matthews is a Vice President in the Life Sciences Practice, Bhavesh Patel is a Principal in the Life Sciences Practice, Owen Male is a Consulting Associate in the Life Sciences Practice, all at CRA

16th December 2022

Cécile Matthews is a Vice President in the Life Sciences Practice, Bhavesh Patel is a Principal in the Life Sciences Practice, Owen Male is a Consulting Associate in the Life Sciences Practice, all at CRA

16th December 2022

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