Modelling approaches for histology-independent cancer drugs to inform NICE appraisals

Background The first histology-independent marketing authorisation in Europe was granted in 2019. This is the first time a cancer treatment has been approved based on a common biomarker rather than the location in the body where the tumour originated. This research aims to explore the implications for NICE appraisals. Methods Targeted reviews were undertaken to determine the type of evidence likely to be available at the point of marketing authorisation and the analyses required to support NICE appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate endpoints. We identified approaches to address these challenges by reviewing key statistical literature addressing the design and analysis of histology-independent trials and undertaking a systematic review to evaluate the use of response endpoints as surrogate outcomes for survival endpoints. We developed a decision-framework to help inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision making. Results We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for NICE appraisals. Bayesian hierarchical methods may provide a useful vehicle to assess the level of heterogeneity across tumours and to estimate pooled treatment effects for each tumour, which can inform whether the assumption of homogeneity is reasonable. Our review suggests that response endpoints may not be reliable surrogates for survival endpoints. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were also identified as presenting potential challenges to NICE appraisal, including: the cost of testing; baseline risk; quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support NICE appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. Conclusions Adequately designed and analysed basket studies which assess the homogeneity of outcomes and allow borrowing of information across baskets where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current NICE methods guide. Further research Further exploration of Bayesian hierarchical methods could help inform decision makers determine whether these is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate endpoints. Funding This project was funded by the National Institute for Health Research (NIHR) HTA programme (NIHR127852).