Cell and gene therapies (CGTs) hold great promise for treating life-threatening conditions, however the high associated costs may prohibit widescale adoption. But how do you measure the cost-effectiveness of a treatment designed to save people’s lives?
Health technology assessments (HTA) are essential when determining whether a new treatment can be funded and adopted by healthcare systems. Distinct from regulatory approval, these evaluations rely on a demonstration of cost-effectiveness. This is typically measured using metrics like the incremental cost-effectiveness ratio (ICER), which compares the treatment to the standard of care in terms of the differences in cost and health impact.
A common method of quantifying health impact is using quality-adjusted life years (QALYs), representing a prediction of the number of years added to a person’s life weighted by quality of life (QOL). These measures help quantify the balance between the cost of a treatment and the improvement it brings to patients’ health outcomes and QOL. When applied to cell and gene therapies, these evaluations face unique challenges, particularly for rare diseases.
A critical aspect of these evaluations is how we define and measure both QOL and clinical efficacy. How this is done in clinical testing will ultimately affect how the cost-effectiveness of a therapy is assessed. There are a variety of challenges associated with measuring cost-effectiveness of CGTs for rare diseases, which should be considered when in the early stages of planning and designing clinical studies.
To help illustrate these challenges, let’s consider Sickle Cell Disease (SCD) as an example.
Quality of life is a crucial parameter in health economic evaluations because it reflects a broader view of the impact of a treatment on people’s lives. Typically, QOL is measured using standardised questionnaires, for example, the EQ-5D, which assesses factors such as mobility, self-care, pain, anxiety and depression. However, while these methods are widely used, they have notable limitations that can have a significant impact on the accuracy of the cost-effectiveness evaluation. If the QOL data captured is not sufficiently sensitive or representative of people’s experience, there is a risk that the effect of the treatment can be over or underestimated.
Addressing health psychology
Some standardised QOL questionnaires may not account for the unique perspective of patients who have managed a chronic condition over time. For example, SCD patients endure chronic pain and frequent episodes of severe discomfort and will therefore have different thresholds of pain than others. They may also have developed coping mechanisms to manage pain and come to terms with the impact of SCD on their daily lives. When asked how much SCD affects their lives, patients who have learned to accept the challenges of their condition may not report low QOL ratings in spite of facing significant challenges. This can lead these questionnaires to overestimate QOL. When evaluating a new therapy in an HTA, if baseline QOL is overestimated, the improvement of QOL related to the therapy will not be captured accurately, skewing the results of the cost-effectiveness evaluation.
QOL variability
Another important aspect to consider is the variability in patients’ QOL over time, and therefore when it is measured. People with SCD, for example, experience vaso-occlusive crises (VOCs) when circulation is obstructed, causing acute episodes of pain. The impact of SCD on a person’s daily life may fluctuate depending on the frequency, severity and recency of these VOCs. If QOL assessments are conducted during periods of stability, the true impact of these crises may be underestimated. Therefore, it’s crucial to consider the timing of QOL measurements in relation to episodes of severity.
Caregiver QOL
Cost-effectiveness evaluations consider quality of life improvements for patients but can also account for improvements for caregivers. In rare chronic diseases, where patients may require constant care, the impact on caregivers’ QOL can be profound. Measuring impact on carers’ QOL in evaluations can help to provide a more comprehensive picture of the treatment’s overall impact on the wellbeing of the patient and the people close to them.
Clinical efficacy
Quality of life measurements help adjust estimates about the impact of a therapy to ensure they account not only for the number of years added to a person’s life, but also the quality of those years. When assessing the cost-effectiveness of a therapy, the clinical efficacy, as demonstrated in clinical trials, will be closely evaluated to ensure the therapy is achieving its intended outcomes. For rare diseases, defining and measuring clinical efficacy is particularly challenging due to small patient populations and variability in disease progression.
In sickle cell disease, how a vaso-occlusive crisis is defined in a clinical trial and any subsequent evaluations plays a key role in understanding the impact of a therapy on health, QOL and the cost of care. This was raised in draft consultation guidance documents from the National Institute for Health and Care Excellence (NICE), regarding the ongoing appraisal of exagamglogene autotemcel for treating SCD. For example, as part of this appraisal, discussions took place regarding whether VOCs should be defined solely by hospitalisations.
Hospitalisation is measurable, which can aid in the consistency of the definition of VOCs in the health economic modelling. However, using hospitalisation to characterise VOCs may risk overlooking the impact of a therapy on reducing incidents that do not result in hospitalisation. The majority of people living with SCD are of Black African or Caribbean descent. This is a population that faces bias and discrimination, experiencing systemic health inequalities related to care quality and access, which ultimately impacts health outcomes. People with SCD may avoid hospitalisation where possible due to poor past experiences, as well as stigmas they have faced when seeking hospital treatment. If a crisis is managed at home, but VOC episodes are defined by hospitalisation, the impact of the therapy on reducing VOCs will not be accurately captured. This is just one of many ways that health inequalities need to be closely analysed and accounted for in health economic evaluations.
Discounting
The metrics that companies use to capture clinical efficacy has an important role in the evaluation of a new therapy’s impact. In the case of CGTs, another important factor is the characterisation of long-term value, as applied by health economic evaluation bodies. For example, NICE applies a concept known as discounting of health effects, to ensure that the results of a cost-effectiveness appraisal reflect the current value of the future benefits when compared to immediate costs. Simply put, discounting of health effects means that in the health economic model, benefits delivered in the future are worth less than those delivered sooner. This can make it difficult to demonstrate cost-effectiveness for therapies like CGTs, which have long-term potential value, but high initial costs. Therefore, a lower discounting rate can be applied in special cases when it is determined that the therapy meets certain criteria, including that the therapy is made for “people who would otherwise die or have a severely impaired life,” is “likely to restore them to full or near-full health” and that the “benefits are likely to be sustained over a very long period.”
This begs the question: what qualifies as “severely impaired?” What does “full or near-full health” really mean? An appraisal committee will need to determine that a therapy is likely to restore a patient with a severely impaired life, to full health. However, this can be difficult to define. It could include both biological markers (such as organ function) and QOL measures, but these criteria are open to interpretation. This should be considered when demonstrating clinical effectiveness, such that meaningful increases in QOL are shown as well as clear evidence of sustained, irreversible effects in the target population.
To ensure that health economic evaluations accurately reflect the true value of a therapy, it’s crucial for manufacturers to design clinical trials that include comprehensive QOL measures and robust definitions of clinical efficacy. This means going beyond standard metrics to account for the complexities of living with a rare, chronic condition, and considering methods of capturing the full impact of the treatment on patients and their caregivers, over time.
Manufacturers must also consider metrics that translate to cost savings, such as reductions in hospitalisations, in order to demonstrate cost-effectiveness. However, this must be done cautiously, ensuring the evaluation is balanced. Relying solely on metrics such as hospitalisation can overlook significant improvements in symptoms and QOL that represent meaningful health gains. It’s crucial to address health disparities in health economic evaluations by considering the broader context of patients’ lives and healthcare experiences.
Early consideration of the health economic evaluation, and consultation with health economic experts, is key to ensuring that clinical studies capture the data needed to demonstrate an accurate depiction of cost-effectiveness.
By better understanding the health economics of cell and gene therapies, we can take a step closer to making them more widely accessible to the patients that would benefit from them.
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