Kymriah - a tale of two indications

Kymriah, a tale of two indications – how Health Technology Assessments have assessed CAR-Ts


Kymriah (tisagenlecleucel) has been hailed as a breakthrough therapy for the treatment of two indications: B-cell acute lymphoblastic leukaemia (ALL) in children and adults <25 and for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, this breakthrough therapy also comes with a hefty EU price in the region of €320,000. How have EU Health Technology Assessment (HTA) bodies determined whether this price represents value for money for each of the indications?


NICE was the first EU HTA body to provide their assessment of Kymriah for ALL, publishing their positive opinion 10 days after the EMA approval, representing one of the fastest funding approvals in the 70-year history of the NHS. Novartis struck a deal with NHS England to offer Kymriah at a confidential discount to the list price of £282,000, this enabled NICE to consider it to be cost-effective, despite limitations over the long-term clinical evidence. Kymriah was given the green-light to enter the NHS via the Cancer Drugs Fund (CDF) where additional evidence is being captured to determine its long-term effectiveness.

Kymriah was also approved, for ALL, by the Scottish Medicines Consortium (SMC) under its ultra-orphan and end of life process. It was accepted on condition of a confidential discount which reduces its incremental cost-effectiveness to £25,000/QALY, considered acceptable by the SMC.

However, it is a different situation for the DLBCL indication. NICE initially rejected Kymriah for DLBCL as they were concerned over the limited clinical evidence from a single-arm study and a small observational study which only suggested, but could not demonstrate, that Kymriah provided good response rates, overall survival and progression-free survival. They requested longer follow-up data and also noted there are no data comparing Kymriah with salvage chemotherapy (the comparator). Additionally, as ~£50,000/QALY Kymriah was not considered cost effective as it was not determined to be an end of life treatment. As such, Kymriah was was refused entry into the CDF. NICE did finally accept Kymriah for DLBCL into the CDF when Novartis provided additional evidence from a CORAL extension study providing additional evidence that it could prolong life. NICE also changed their opinion and now consider Kymriah to be an end-of-life treatment, enabling Kymriah to be considered likely to be cost effective at £50,000/QALY. Unfortunately, the same cannot be said for the SMC who have rejected Kymriah for the DLBCL indication highlighting the cost of treatment is not aligned with the clinical evidence and that there is a high level of uncertainty over its cost-effectiveness.


In France Kymriah for ALL was given an ASMR of III with HAS stating that whilst they consider it to be innovative, the absence of direct comparison with usual management, and lack of maintenance of clinical efficacy in the longer term meant the long-term clinical value was difficult to determine.

Similarly, for the DLBCL indication, HAS had concerns over the short-term efficacy data on complete response (approximately 24% of the ITT population); uncertainties in the amount of effect, because of a lack of direct comparison with usual management, and the maintenance of clinical efficacy in the longer term. However, they did note that therapeutic options for DLBCL are limited. This resulted in an HAS, considering the current state of the data, giving Kymriah an ASMR IV.

When granting access for both the ALL and DLBCL indications the HAS have specifically requested that Novartis provide additional clinical data collected from real world evidence studies within France and to submit this on an annual basis for reassessment.


In Germany, both indications, as a result of the AMNOG law which states that orphan drugs automatically have a clinical benefit, are considered as having an additional clinical benefit. However, for both ALL and DLBCL the G-BA evaluation made it very clear that the additional benefit was not quantifiable as they concluded all the clinical data submitted was not robust. For both indications they concluded there was a high degree of bias in the phase II trials (due to them being open label) and as a result, no reliable conclusions could be made on the extent of the added benefit Kymriah offers in the treatment of ALL or DLBCL. Specifically, for the ALL indication, the G-BA has stated that the clinical assessment will be reassessed before March 2020 when the full results from the clinical studies are completed. It is feasible that during this evaluation they may consider the additional clinical benefit to be quantifiable.

Despite this lack of clinical uncertainty, Novartis have been successful in putting in place an innovative treatment-based outcome agreement with, GWQ Service Plus, a service provider for medium-sized health insurance companies. This is a pilot project in the German health system, with the aim of sharing the financial burden of these high cost treatments. Within the agreement Novartis have agreed to pay back a proportion of the drug cost should patients not survive for a pre-agreed period of time.

Summary of Kymriah’s Health Technology Assessment evaluations for ALL and DLBCL

ASMR: l’amélioration du service médical rendu; CDF: Cancer Drugs Fund; FAD: Final Appraisal Document; HAS: Haute Autorité de santé; MA: Marketing Authorisation; PAS: Patient Access Scheme

It is clear that HTA bodies recognise the innovative nature of Kymriah and that there is a willingness to fund is treatment. However, it is also clear that the current level of clinical evidence is not sufficient to demonstrate its true clinical value and that payers are implementing processes such as inclusion in the CDF in the UK; annual re-evaluation by HAS or the innovative outcomes agreement in Germany, whilst additional clinical evidence is collated to demonstrate its true clinical value in both these indications.

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