Funding and reimbursement of cell and gene therapies pose a major challenge as payers consider how to evaluate a commercial proposition that is completely divergent from the traditional pharmaceutical model. Commenters, including the Regenerative Medicine Experts Group in the UK, have suggested that the current Health Technology Assessment (HTA) methodologies, such as the National Institute for Health and Care Excellence (NICE), are unsuitable for evaluating a potentially curative treatment.
In response to this, NICE conducted an ‘exploratory study of appraisal’, commissioning research from the University of York to determine the suitability of the current methodology in evaluating an emerging cell therapy. The report, Exploring the assessment and appraisal of regenerative medicines and cell therapy products, published in March 2016, outlined how a hypothetical Chimeric Antigen Receptor T-Cell (CAR-T) therapy for paediatric relapsed/refractory Acute Lymphoblastic Leukaemia (Ped-ALL) would be assessed.
The report concluded that the ‘Technology Appraisals framework is applicable to regenerative medicines and cell therapy technologies’, but changes will be required to the methods and processes, including the discounting rate, price and payment models, as well as varying parameters. This hypothetical evaluation highlights that, while certain parameters may be relaxed for cell and gene therapies, the established requirements for safety, efficacy and cost-effectiveness will still apply. Additionally, solutions are needed at the hospital level to ensure suitable funding mechanisms exist to accommodate such novel therapies.Manufacturers entering this space must actively navigate the reimbursement pathway and overcome the evidence challenges to secure access to patients.
Mock assessment of a CAR-T therapy
The hypothetical CAR-T therapy was tested in two different profiles: as a bridge to haematopoietic stem cell transplantation or as a curative therapy. The data for the research was derived from published data on CAR-T pipeline therapies, but was not related to any particular product. The hypothetical therapy gave up to 10 additional quality-adjusted life years (QALYs), representing a 10-year life extension at full health. Three different evidence sets were evaluated:
- The minimum set: 60-80 patients, median follow-up approximately 10 months (the minimum data considered potentially sufficient for CAR-T therapy to be granted conditional regulatory approval)
- The intermediate set: 60-80 patients, maximum follow-up of five years
- The mature set: 120-140 patients, maximum follow-up of five years.
The research team set a hypothetical price for both the bridging therapy and the curative therapy, based on a price that would result in an incremental cost-effectiveness ratio (ICER) near to the maximum allowed by NICE (£50,000/QALY gained). The price for the bridging therapy was set at £356,100 for a QALY gain of 7.46 and £528,000 for the curative intent and a QALY gain of 10.07. All of the data sets were based on a single arm clinical trial design with historical controls being used as the comparator. The data, along with a summary of the clinical and cost-effectiveness evidence, were presented to a mock Technology Appraisal Committee which followed the usual NICE methodology to determine how NICE would assess the therapy.
While the hypothetical price of £528,000 per patient seems reasonable for a curative therapy, NICE emphasises that this is not necessarily indicative of the price actual therapies will be able to achieve. Many cell therapies require additional, costly procedures for administration such as an allogeneic stem cell transplant as well as adjuvant therapies. The question then becomes: is the cost of these complicated procedures deducted from the potential headline price of £500,000? If so, how much of the per-patient price could the cell therapy manufacturer receive?
NICE’s methodology and cell therapies
The headline results of the research, according to NICE, determined that its evaluation method is appropriate but that modifications will be necessary:
- The NICE appraisal methods and decision framework are applicable to regenerative medicines and cell therapies.
- Quantifying and presenting clinical outcome and decision uncertainty was key to the Expert Panel consideration of the hypothetical example products.
- Where there is a combination of great uncertainty but potentially very substantial patient benefits, innovative payment methodologies need to be developed to manage and share risk to facilitate timely patient access while the evidence is immature.
- The annual discounting rate (the standard 3.5% vs. 1.5%, which has only been permitted in one prior case) applied to costs and benefits was found to have a very significant impact on analyses of these types of technologies.
There is an additional conclusion that can be made – payers have a low willingness to accept uncertainty. Even with the five-year data set (an evidence package that exceeds that expected at launch for many cell therapies), payers showed concern regarding low patient numbers and the use of a single arm study. Payers do not like uncertainty and tend to take a conservative approach when pricing and reimbursing products without sufficiently robust data. Unless payers are willing to take a chance, it may be extremely challenging for cell and gene therapy manufacturers to attain reimbursement.
Developing an innovative therapy is not enough to result in commercial success
Local funding questions remain unanswered
Questions remain as to how treatment centres are to be funded for cell therapies. Many transplant centres in England, and in other countries, are funded with a single, fixed payment to treat patients upon hospital admission. In the case of stem cell transplant, hospitals are given a fixed amount of money to cover the cost of a patient from day zero to six-to-nine months post-transplant. As a result, there may be no existing mechanism for these centres to obtain funding for any additional, and costly, services (eg, processed cells in a CAR-T). As such, it is critical for manufacturers to engage early with the treatment centres as new funding pathways and contracts will, most likely, be required.
Evidence gathering for commercial success
Given the methodological difficulties associated with assessing cell therapies, clinical development programmes should be designed to minimise uncertainty wherever possible. For example, a well-designed phase II trial could complement the phase III data, providing outcomes data over a longer period of time. This is of particular importance to those cell therapies where there is limited data from the pivotal trial available at launch. Additionally, data from patients in the phase III trial should continue to be collected post launch – this will enable manufacturers to gather the robust evidence package so desired by payers across the globe.
Targeting a specific patient population (or subpopulation) may change the value and, hence, the price and reimbursement potential of a cell therapy. As noted in the University of York’s research, the price potential of a curative hypothetical therapy results in a higher price than one that is used as a bridge to transplant. Cell therapy manufacturers should choose their trial populations with care, limiting them to those patients where the greatest payer-perceived benefit can be demonstrated.
Manufacturers of cell and gene therapies should be aware that developing an innovative therapy is not enough to result in commercial success. Early entrants will need to be willing to enter outcomes-based agreements to reduce the risk that is so unappealing for national payers. Moreover, it is critical to engage early with treatment centres to ensure funding processes are present and workable – only in this way can manufacturers be confident that their therapies will be reimbursed and, most importantly, that patients will gain access.
