Resultado de los análisis de correlación múltiple con Statgraphics

A key issue regarding the cost-effectiveness results and implications for the‘hypothetical’decisions was whether the panel considered that existing criteria considered within the TA process in relation to EoL and 1.5% discounting (applied to costs and health outcomes) could be applied. The panel accepted that, based on the patient numbers, current prognosis and the likely treatment benefit, CAR T-cell therapy for relapsed/refractory ALL would be likely to meet existing criteria for EoL. However, the panel also noted that the existing criteria might need to be reconsidered more generally for therapies with curative potential. It was argued by one panel member that the EoL criteria were developed to cover scenarios in which people with conditions such as cancer with a short life expectancy were given some extension but whose life expectancy was still short. It was suggested that different QALY weights might need to be considered over a longer period of projected survival benefits for therapies that have curative potential.

The use of the 1.5% discounting was also discussed by the panel. Although it was noted that the existing criteria had been developed in response to a similar decision context, the panel was also aware that the criteria had been applied in only one previous appraisal (the TA for which it was developed212_{). The lack of}

precedent was noted and the panel concluded that its application could generate significant debate in future appraisals. Hence, no conclusion was reached during the panel meeting about its application to CAR T-cell therapy. The use of stepped discounting recommended by the UK Treasury was discussed by the panel but was considered to be more relevant for interventions that might have important intragenerational impacts (e.g. immunisation) as opposed to longer-term intergenerational effects.

In addition to the concerns it noted in relation to the possible biases and additional uncertainty arising from comparisons based on single-arm trials, the panel raised questions about whether or not there were wider structural uncertainties relevant to regenerative medicines and cell-based therapies that were not fully captured within the analyses presented. The panel concluded that identifying sources of potential bias and appropriately reflecting structural sources of uncertainty would be important considerations in future appraisals, and

manufacturers would need to clearly report how these had been addressed within their submissions. The panel discussed the sequence of assessments presented in the cost-effectiveness section and the exploratory approaches to quantifying decision uncertainty based on an assessment of the scale of

the consequences associated with each decision using population NHEs. The panel agreed that these exploratory approaches provided a clearer and potentially important distinction between the different evidence sets and the impact of alternative pricing schemes. The panel also acknowledged that such assessments provided important information that could help to inform its deliberations. However, the panel further noted that, although such assessments were helpful and represented a useful starting point for deliberations, they were not necessarily sufficient to inform its final decisions. In particular, the panel expressed difficulty in determining how to interpret the numbers presented without a formal reference point to establish whether the consequences were sufficiently high to impact on their decisions and/or potential research recommendations.

The panel acknowledged that the estimates of the consequences represented a theoretical upper bound to the value of further research. However, the panel concluded that it would be important to explore these consequences further, in terms of both the underlying distribution (as opposed to the expected mean value of the consequences) and needing to decompose the overall estimate in relation to specific sources of uncertainty. This latter aspect was considered particularly important in determining the extent to which particular sources of uncertainty could be resolved by additional research, the type of research that might be most appropriate and, finally, whether this research would be feasible following a positive approval. The panel was also aware of the relevance of existing published work128_{and work by the NICE DSU}211_that

would be important to consider in any review of potential processes or methods.

Prior to a more detailed discussion of the specific decision scenarios, the panel outlined a number of more general considerations related to the cost-effectiveness evidence and results:

1. In discussing the appropriate cost-effectiveness threshold for the purpose of NICE decision-making, the panel was clear that £50,000 per QALY (assuming that the EoL criteria applied) represented an absolute upper bound to the range that NICE would consider acceptable. The panel concluded that other

considerations (e.g. innovation) would not be applied in conjunction with the higher threshold considered in an EoL appraisal. Furthermore, the panel also considered that the upper end of the range was unlikely to be considered appropriate in the presence of significant evidential uncertainties.

2. The panel concluded that, if the hypothetical price of CAR T-cell therapy had been set using the conventional cost-effectiveness threshold range (£20,000–30,000 per QALY), this could have mitigated some of these uncertainties, increasing the likelihood of a positive recommendation.

3. The panel appreciated that there was a difference between the deterministic estimates of the ICER and the probabilistic estimates of the ICER because of the non-linearity between the parameter inputs and the model outputs (i.e. mean costs, QALYs and ICER). The panel also noted that, for some analyses, these differences resulted in ICER estimates that could have a material impact on its decisions (i.e. situations in which the deterministic and probabilistic estimates lie on either side of the cost-effectiveness threshold). The panel concluded that the probabilistic estimates were the more appropriate basis for informing its decisions. 4. The panel raised issues regarding the possible nature and magnitude of any irrecoverable costs that

might be incurred by the NHS and the implications for its decisions. The panel concluded that an_‘exit strategy’for the NHS would be a key consideration for interventions that appear highly promising but for which significant uncertainties and irrecoverable costs may exist.

5. The panel acknowledged that the different pricing schemes had important impacts both in terms of the ICER and in terms of the allocation of any risk between the NHS and manufacturers. The concept of the_‘leasing approach’was identified as a potentially important option and there was consensus among the panel that this warranted further exploration by NICE and manufacturers (e.g. logistics, costs and overall feasibility). 6. The panel recognised the various issues and challenges likely to be faced by the manufacturers of

regenerative medicines and cell-based therapies. The panel also noted that many of the issues and implications identified did not appear to be specific to these types of therapies but were also apparent in appraisals of more conventional products. However, the panel acknowledged that the challenges may be faced more routinely by manufacturers of regenerative medicines and cell-based therapies and that the resulting levels of uncertainty (and the potential scale of the consequences) may exceed those that existing committees might conclude could be appropriately dealt with by existing processes and the current methods guide.