The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal

Abstract

BackgroundThe National Institute for Health and Care Excellence (NICE) commissioned a ‘mock technology appraisal’ to assess whether changes to its methods and processes are needed. This report presents the findings of independent research commissioned to inform this appraisal and the deliberations of a panel convened by NICE to evaluate the mock appraisal.MethodsOur research included reviews to identify issues, analysis methods and conceptual differences and the relevance of alternative decision frameworks, alongside the development of an exemplar case study of chimeric antigen receptor (CAR) T-cell therapy for treating acute lymphoblastic leukaemia.ResultsAn assessment of previous evaluations of regenerative medicines found that, although there were a number of evidential challenges, none was unique to regenerative medicines or was beyond the scope of existing methods used to conceptualise decision uncertainty. Regarding the clinical evidence for regenerative medicines, the issues were those associated with a limited evidence base but were not unique to regenerative medicines: small non-randomised studies, high variation in response and the intervention subject to continuing development. The relative treatment effects generated from single-arm trials are likely to be optimistic unless it is certain that the historical data have accurately estimated the efficacy of the control agent. Pivotal trials may use surrogate end points, which, on average, overestimate treatment effects. To reduce overall uncertainty, multivariate meta-analysis of all available data should be considered. Incorporating indirectly relevant but more reliable (more mature) data into the analysis can also be considered; such data may become available as a result of the evolving regulatory pathways being developed by the European Medicines Agency. For the exemplar case of CAR T-cell therapy, target product profiles (TPPs) were developed, which considered the ‘curative’ and ‘bridging to stem-cell transplantation’ treatment approaches separately. Within each TPP, three ‘hypothetical’ evidence sets (minimum, intermediate and mature) were generated to simulate the impact of alternative levels of precision and maturity in the clinical evidence. Subsequent assessments of cost-effectiveness were undertaken, employing the existing NICE reference case alongside additional analyses suggested within alternative frameworks. The additional exploratory analyses were undertaken to demonstrate how assessments of cost-effectiveness and uncertainty could be impacted by alternative managed entry agreements (MEAs), including price discounts, performance-related schemes and technology leasing. The panel deliberated on the range of TPPs, evidence sets and MEAs, commenting on the likely recommendations for each scenario. The panel discussed the challenges associated with the exemplar and regenerative medicines more broadly, focusing on the need for a robust quantification of the level of uncertainty in the cost-effective estimates and the potential value of MEAs in limiting the exposure of the NHS to high upfront costs and loss associated with a wrong decision.ConclusionsIt is to be expected that there will be a significant level of uncertainty in determining the clinical effectiveness of regenerative medicines and their long-term costs and benefits, but the existing methods available to estimate the implications of this uncertainty are sufficient. The use of risk sharing and MEAs between the NHS and manufacturers of regenerative medicines should be investigated further.FundingThe National Institute for Health Research Health Technology Assessment programme.

Estimating the Clinical Pipeline of Cell and Gene Therapies and Their Potential Economic Impact on the US Healthcare System

“…2,3 Currently, healthcare systems in the United States and Europe are actively considering this emerging challenge 4 but at varying speeds and in varying ways. For example, the National Institute for Health and Care Excellence in the United Kingdom is seeking to extend existing methods for assessing cost-effectiveness to regenerative medicines 5,6 and to recognize innovation at the same time. 7 Cell and gene therapies can present financing challenges from different directions.…”

Establishing the cost of implementing a performance-based, managed entry agreement for a hypothetical CAR T-cell therapy

“…As outlined in the University of York paper [5], a CAR T-cell therapy with immature evidence base, and a hypothetical list price of several hundred thousand pounds may present the NHS with a sizeable uncertainty in terms of being cost-effective, as well as affordability issues. An MEA using a 10-year performance-based staged payment approach (i.e.…”

“…In response to the 2013 House of Lords’ inquiry into regenerative medicines, a special National Institute for Health and Care Excellence (NICE) study and Expert Panel were set up, which included the Cell and Gene Therapy Catapult and The Centre for Health Economics (CHE) Technology Assessment Group (University of York), to review a hypothetical CAR T-cell therapy in relapsed (two relapses or more) or refractory B-Acute Lymphoblastic Leukaemia (rB-ALL) within the context of a NICE Technology Appraisal (TA) framework [5]. Different hypothetical evidence sets in terms of data maturity were assessed; it was concluded that performance-based reimbursement mechanisms would go further in supporting a favourable HTA decision where there is a combination of great uncertainty (due to e.g., less mature data sets), and a potentially substantial patient benefit.…”

“…Therefore, the evaluation recommended that innovative payment mechanisms for managing and sharing financial risk such as performance-based MEAs should be developed [5]. …”

“…remission and therefore survival) are sustained, reduces payer decision uncertainty compared to a fixed acquisition cost, whilst providing an exit strategy for the National Health Service (NHS) if the purported clinical benefits did not materialise [5]. …”