The price of a cure – how cell and gene therapies are challenging HTA frameworks
What are cell and gene therapies?
Cell and gene therapies represent revolutionary advancements in medicine that have the potential to treat, modify, or even cure diseases at the cellular or genetic level. Cell therapies involve the transplantation of whole cells, such as stem cells, to replace damaged tissues, while gene therapies involve introducing, altering, or removing genetic material within a patient’s cells to treat or prevent disease. Often indicated for rare and ultra-rare diseases, these therapies provide therapeutic options for indications where there are often no alternatives. Cell and gene therapies are classified as Advanced Therapy Medicinal Products (ATMPs) in the European Union and many other regulatory jurisdictions, including the UK.
What are the challenges of conducting HTA on ATMPs under the current HTA frameworks?
ATMPs pose unique challenges when it comes to determining their value, cost effectiveness and impact, due to:
Limited clinical evidence: reflective of the rare disease spaces which ATMPs address, clinical trials for ATMPs are often single-arm, have very small sample sizes, and use surrogate endpoints.
Durability uncertainties: since ATMPs are purported to be curative, payers want to see demonstrations of sustained benefit over patients’ lifetimes. However, since they are novel treatments, there is a lack of evidence for the duration of improvements they can provide, leading to challenges in quantifying their value over a lifetime horizon
High costs: high price tags are often attached to ATMP products because they are tailored to individual patients – making them expensive to develop, manufacture, and administer – and usually pose significant logistical hurdles. In addition, the rare disease indications of ATMPs means the scope of potential patients is small, creating a greater challenge for manufacturers to recoup costs. Whilst high upfront costs may reflect a value-based price, they may also pose short-term acquisition costs and long-term value return trade-off complications for both national health services and commercial insurers.
Translation of therapeutic and economic value: accounting for the whole socio-economic value of ATMPs when conducting cost-efficacy evaluations is a challenge. Due to a residual uncertainty relating to their benefit, ATMPs may receive prices which do not reflect the value of the therapy according to the manufacturers. Subsequently, this makes the field unattractive from a research and development perspective.
Is HTA reform needed to improve access to ATMPs? And should this include a differential process for ATMPs?
Whether there should be HTA reform or differential HTA processes for ATMPs when undergoing HTA is a hotly debated topic. Some stakeholders argue that EU and UK HTA systems – primarily based upon cost-effectiveness models – may not currently be capable of fully encapsulating the value of these therapies. This has led some to believe that these current frameworks may require augmenting, for example, implementing modifiers to relax strict cost-effectiveness thresholds, such as the severity modifiers used by NICE in the UK.[1] Severity modifiers take into account absolute QALY shortfall, helping to incorporate the benefit of the product over the patient’s whole socio-economic life into the model, thus improving the accuracy of value projections. This was utilised recently during the highly specialised technology (HST) NICE evaluations for Casgevy – a gene-edited autologous haematopoietic stem cell therapy developed to treat sickle cell disease – where the implementation of a severity modifier proved pivotal in securing reimbursement for the treatment.[2]
Innovative payment models are emerging as a promising solution to share the risk between manufacturers and payers and to address the effectiveness and financial uncertainties relating to ATMPs. These models, such as outcome- and financial-based contracts, function as risk-sharing schemes, often utilising annuity payments to link reimbursement to the actual performance of the therapy over time. Additional approaches such as subscription models may also be utilised. For example, Novartis has negotiated several payment agreements with payers for Zolgensma, a gene therapy for spinal muscular atrophy. The agreement between Novartis and AIFA features a pay-for-performance model delivered via instalment payments dependent on patients achieving outcome milestones at 12, 24, 36 and 48 months.[3] Approaches such as these not only alleviate the immediate budget impact on healthcare systems but also ensure reimbursement is achieved based upon the long-term durability of the treatment effects.
However, while ATMPs become increasingly common, there is a chance that their prices may decrease, leading to concerns that awarding them differential treatment now may cause challenges in the future if prices were to decrease to levels comparable to other orphan or rare disease drugs. This could arise due to many factors, including regulatory streamlining and standardisation through economies of scale, for example, evolutions in the tools, timings, and changes in regulations regarding viral vector batch testing. However, if ATMPs retain prices based on their value propositions, price drops may be unlikely.
What is the EU doing to improve access to ATMPs?
The new EU HTA regulations, which came into effect on the 12th of January for ATMPs and oncology drugs, include the Joint Clinical Assessment (JCA), Joint Scientific Consultations (JSC), and increased horizon scanning. This should improve access to early advice for manufacturers of ATMPs so they can design evidence generation plans according to the requirements of regulatory and HTA bodies; although there have been criticisms surrounding the number of slots available for JSCs which may limit its ability to be impactful for some manufacturers.
Additionally, the increased collaborative work between the EU member states under the JCA may be a boon for real-world evidence generation through early access schemes and post-market launch. To further increase the EMAs capacity to prioritise ATMPs, the Committee for Advanced Therapies (CAT) was composed; the CAT will contribute to scientific advice in cooperation with the Scientific Advice Working Party (SAWP) and advise the CHMP on medicinal products which require ATMP expertise.[4] The increased focus on ATMP products should enable earlier discussions so that manufacturers can develop improved cost-over-time evaluations of their products.
Conclusion:
Cell and gene therapies challenge traditional HTA due to their high costs, limited clinical data, and uncertainties around long-term benefits. These challenge conventional cost-effectiveness models, spurring calls for HTA reforms which incorporate more innovative approaches, such as severity modifiers and outcomes-based contracts, featuring flexible or annuity payment models. Current EU initiatives, including expanded horizon scanning, increased scientific consultations and the JCA, are paving the way for earlier dialogue and improved evidence generation for ATMPs. Ultimately, aligning HTA frameworks with the evolving nature of ATMPs is essential to ensure patients gain timely access to these ground-breaking treatments while safeguarding healthcare sustainability.
References:
1. NICE Board says new method allowing greater weight to be given to severe diseases is working [Internet]. NICE website: The National Institute for Health and Care Excellence. NICE; 2024. Available from: https://www.nice.org.uk/news/articles/nice-board-says-new-method-allowing-greater-weight-to-be-given-to-severe-diseases-is-working
2. The National Institute for Health and Care Excellence (NICE). Draft guidance consultation Exagamglogene autotemcel for treating severe sickle cell disease in people 12 years and over [Internet]. 2024. Available from: https://www.nice.org.uk/guidance/ta1044/documents/draft-guidance
3. Howle J. Italy Reimburses Zolgensma Through “Payment at Result” Model, Priced at EUR 2.155 M | EVERSANA [Internet]. 2021. Available from: https://www.eversana.com/2021/03/18/italy-reimburses-zolgensma-through-payment-at-result-model-priced-at-eur-2-155-m/
4. Committee for Advanced Therapies (CAT) | European Medicines Agency (EMA) [Internet]. 2009. Available from: https://www.ema.europa.eu/en/committees/committee-advanced-therapies-cat
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Written by Sophie Burr, Farhaan Jamadar
Decisive Dialogue 15th April 2025