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Commentators at the ISPOR Europe 2019 conference in Copenhagen debated the challenges that exist with valuing and financing potentially curative treatments, including cell and gene therapies, and cancer immunotherapies. With several recent regulatory approvals of high-cost advanced therapy medicinal products (ATMPs), discussion has ensued in earnest on how to determine their clinical value, and whether traditional reimbursement and health technology assessment (HTA) processes are sufficient to assess these innovative treatments.

These innovations have demonstrated unprecedented treatment effects in some of the most high-risk patient populations, often providing long-term durable responses, with increasing numbers of patients being considered cured. However, there are a number of challenges that exist with the valuing and funding of these treatments, including high upfront treatment costs, uncertain evidence bases, small patient populations, system disruption, and uncertainty regarding the inclusion of additional elements of value which are not part of standard cost-effectiveness methods. Novel reimbursement techniques have been employed by manufacturing companies across the globe, centering around pay-for-performance arrangements, milestone payments over various durations, and combinations of the two. Over the short and medium term, all these developments will lead to significant changes in how healthcare systems assess innovations within HTA pathways. Furthermore, they will impact how financing systems evolve, especially with respect to risk sharing on potential outcomes.

Risk-sharing schemes are likely to be central to the affordability of curative therapies
Perhaps no country has greater familiarity than Italy when it comes to outcomes-based agreements, which have been managed by the Italian Medicines Agency (Agenzia Italiana del Farmaco; AIFA) via a centralized, nationwide, web-based registry system since 2006. The well-established processes that are in place seem ripe to accept the launches of the new cell and gene therapies that require greater clinical evidence to address the question of uncertainty. AIFA’s payment-by-results scheme, which is the most widely adopted among the agreements, requires total reimbursement to the payers for non-responders, while its newer scheme of payment at results will adjudicate payment for responders at specific milestones. The implementation of these processes is not without obstacles, but AIFA has done so for more than 100 registries to date. Other countries new to this space are in a great position to reap the learnings from AIFA’s well-established system, while accounting for the peculiarities of their own markets.

In an educational symposium titled “Can We Afford Curative Therapies Without Sharing Risks?”, Jay Jackson from Xcenda highlighted the main issues regarding pricing and reimbursement of ATMPs in the US. Without a central governing body managing access to therapies, payers and insurance companies currently lack techniques to negotiate prices for high-cost ATMPs. Payers are eager to enter into novel payment mechanisms, primarily annuity models and value-based contracts, to manage the costs and risks associated with ATMPs; however, significant hurdles exist. One of the main issues is patient mobility, with patients moving between insurers every 2–3 years in the US. Not only does this make payers reluctant to pay high upfront costs for beneficiaries who are likely to move on to be covered by another plan in the long term, but it also hinders their ability to enter into novel financial agreements with manufacturing companies. Jackson concluded that no one-size-fits-all strategy exists in the US, and stressed that early engagement with payers surrounding budgetary forecasts and measurable efficacy/safety outcomes is pivotal to market success.

From the UK perspective, Christian Hill, CEO of MAP BioPharma, questioned whether the current HTA processes were sufficient for the assessment of innovative ATMPs. ATMPs can be assessed through two different HTA routes in the UK, the standard NICE single technology appraisal (STA), or a highly specialised technology (HST) appraisal. Therapies that qualify as an HST are subject to higher quality-adjusted life year (QALY) thresholds, ranging from £100,000 to £300,000 per QALY, whereas drugs assessed under the STA are held to the same cost-effectiveness measures as for conventional therapies, typically £20,000 to £30,000 per QALY. With potentially a ten-fold difference in the incremental cost-effectiveness ratio (ICER) threshold, Hill questioned the disparity in pricing and reimbursement outcomes between these two HTA routes, and the inability to accurately predict via which route a novel ATMP will be assessed. Nonetheless, for all ATMPs, pricing and long-term affordability are key issues, with patient access schemes, commercial access agreements, and managed access arrangements frequently required by NICE for therapies to meet cost-effectiveness thresholds. Looking forward, a NICE methods review is currently ongoing and is exploring the potential for new effect modifiers which could allow higher ICER thresholds for ATMPs, as well as developing more sophisticated methods of assessing uncertainty within the STA process. Further opportunities include a new commercial framework (at NICE and NHS England separately), which may open different types of agreements that would enable patient access to ATMPs.

Stève Bénard, managing director of Stève Consultants, questioned the use of standard HTA and pricing processes for ATMPs in France due to the significant risk of restricting access to innovative treatments, discordance between ATMP prices and public budget constraints, and a requirement to negotiate a fixed price for therapies with very unclear real-life benefits. All ATMPs require funding via the liste en sus in France, the high-cost hospital reimbursement list which provides extra funding on top of the diagnosis-related group (DRG). As ATMPs often gain regulatory approvals based upon one-arm clinical trials with short durations, Bénard highlighted that gaining inclusion on this list can be very challenging as inclusion criteria center around demonstrating a significant benefit in efficacy/safety versus the appropriate comparator. Considering these issues, there have been significant delays in the pricing and reimbursement negotiations for recently approved ATMPs in France, with only Gilead’s Yescarta and Chiesi’s Holoclar finalizing a national funding agreement so far. Bénard highlighted that companies manufacturing ATMPs will frequently be required to collect real-world evidence (RWE) data or conduct post-marketing trials, which will almost always be associated with an HTA re-assessment and a lower price being negotiated. Furthermore, he expects outcomes-based agreements with requirements for RWE to be more commonplace within French reimbursement for ATMPs.

The Federal Joint Committee (Gemeinsamer Bundesausschuss; G-BA) in Germany is starting to implement mandatory disease registries in cases of non-conclusive evidence for ATMPs at time of market launch. With orphan therapies gaining an automatic initial added benefit rating in Germany, disease registries will aid with data collection in the real-world setting, enabling the G-BA to make informed decisions regarding a drug’s added benefit in the longer term. Furthermore, these registries will facilitate risk-sharing agreements with manufacturing companies, including installment-based payments and payment-by-results schemes. Risk-sharing schemes have already been agreed for CAR-T therapies in Germany, with another confirmed for bluebird bio’s Zynteglo. Going forward, Thomas Mittendorf, managing director of Xcenda, stated that German payers are keen to discuss potential pay-for-performance schemes with manufacturing companies prior to the launch of high-impact ATMPs in order to help decrease uncertainty surrounding long-term durability and manage affordability.

Concluding the session, Jackson stressed that the pharma industry must be the driver in addressing affordability challenges of high-cost ATMPs. As therapies potentially offering a cure may not be cost effective under traditional terms, affordability must be discussed openly between payers and manufacturing companies, with payers expecting the industry to provide solutions on a country-by-country basis. Conditional reimbursement is expected to be linked to in-market RWE data collection in the future, thus companies must pursue unique, customized market access strategies for different products in each country of interest. 

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