In June 2018, Chimeric-Antigen Receptor T-cell (CAR-T) therapies Kymriah (Novartis) and Yescarta (Gilead) received EMA market authorisation, enabling them to take their first steps into the European market.
The arrival of CAR-T therapies as novel cancer treatments has been greatly anticipated in England. Earlier this year, the UK government announced support for three new specialist centres capable of conducting CAR-T therapy. In addition, in as early as 2016, the National Institute for Health and Care Excellence (NICE) in collaboration with the University of York conducted a mock assessment of a CAR-T therapy, which suggested that CAR-Ts were likely to be cost-effective for NHS use, depending on the price.
Despite these positive indications, recent draft NICE recommendations (appraisal number: TA10214) have not recommend the use of Yescarta in diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma after two or more systemic therapies. NICE’s assessment acknowledged the good response rates, overall survival and progression-free survival in patients, but noted a lack of comparator data vs. standard of care of salvage chemotherapy. In addition, whilst Yescarta did meet NICE’s criteria to be considered a life-extending end-of-life treatment, it was not considered cost-effective with a cost per quality adjusted life year in excess of the £50,000 threshold. NICE’s independent assessment committee did consider the eligibility of Yescarta for inclusion into the Cancer Drugs Fund (CDF), which would have enabled interim reimbursement until new data on efficacy and side effects was collected from clinical trials. However, Yescarta did not enter the CDF, as Gilead “had not made a case” for inclusion into the CDF and “incremental cost-effective ratios (ICERs) were above the range to be considered cost-effective”.
Gilead’s negative recommendation was thought to be a negative signal for CAR-Ts in England. However, on 5th September 2018, NHS England announced that a commercial agreement has been agreed with Novartis for its CAR-T, Kymriah. The agreement was reached only 10 days after market authorisation for Kymriah and represents one of the fastest funding approvals in the 70-year history of the NHS. The rapid decision-making timeline is in-line with NICE’s new appraisal process for Cancer Drugs, which aims to have final recommendations published within 90-days of market authorisation. The agreement represents the first commercial deal for Kymriah agreed by Novartis in Europe and means that children and young people in England with B cell acute lymphoblastic leukaemia (ALL) will be able to receive treatment with Kymriah from three specialist centres. NHS England also reported that NICE has approved Kymriah for use within the CDF.
The significant differences in outcomes for Yescarta and Kymriah in England is striking and likely to have been influenced by a number of factors, including:
- Patient population
- Novartis’ commercial agreement is for use of Kymriah in children and young people with Acute lymphoblastic leukaemia (an estimated 30 eligible patients each year). In contrast, Yescarta was considered for older patients and in a significantly larger patient population, which may have contributed to the negative recommendations
- Pricing
- The list price for Kymriah is reported to be £282,000 per patient. Details of the commercial agreement and actual cost to the NHS remain confidential. However, NHS England Chief Executive Simon Stevens has described the rapid agreement as a demonstration of how “flexible” companies could succeed in gaining access, suggesting substantial discounts may have been agreed. The official list price for Yescarta remains confidential, and it is possible that Gilead may have been unwilling to agree significant price reductions required by NHS England
- Clinical data
- The NICE report providing draft recommendations for Yescarta noted significant data gaps, demonstrating the importance of robust trial data for CAR-Ts. NICE have not yet made their recommendation document publicly available for Kymriah. It will be interesting to note any comments on strength of clinical data
Overall, the situations Novartis and Gilead have faced with Kymriah and Yescarta, indicate that whilst NICE and NHS England are open to CAR-T therapies, they require robust and extensive clinical data and confidential price discounts. It is important to note that Kymriah has been recommended for use in the CDF, which is reserved for drugs with significant remaining clinical uncertainty requiring further data collection. Funding for Kymriah is therefore currently limited for the duration of its CDF data collection agreement (a maximum of two-years), after which Novartis will be required to resubmit to NICE for routine funding. Patient population size may also be a consideration for NICE. In addition to its marketing authorisation in ALL, Kymriah is also approved in DLBCL and it will be interesting to see how NICE assesses this additional indication. Furthermore, it will be interesting to see the findings from the Scottish Medicines Consortium (SMC) in Scotland, once their health technology assessment (HTA) reviews have been completed.
It should also be noted that NICE’s negative recommendation for Yescarta has been provided in draft guidance. NICE has historically had a high rate of draft negative recommendations changing to final positive recommendations. It will therefore be interesting to watch NICEs final recommendations for Yescarta (expected to be published December 2019). It will be fascinating to observe how NICE assesses other advanced therapies and if Kymriah is the exception rather than the new normal.