OBJECTIVES: New gene and cellular based therapies offer potential cures for diseases but are projected to cost over $1M per patient. This research assessed potential innovative payment methodologies for future expensive therapies in the US and EU-5 markets, outlining the viability and changes required for alternatives to succeed the current one-time upfront payment scheme. METHODS: Secondary research was conducted to understand schemes currently utilized in Europe and to identify proposed alternative reimbursement methodologies for funding expensive therapies in the US.  An in-depth online survey of twelve US Executive Payers was conducted, which assessed perceptions of expensive therapies, budget impact, proposed alternative payment schemes, and implementation challenges. RESULTS: In Europe, alternative schemes support the funding of innovative and expensive therapies such as alipogene tiparvovec (Glybera):  the NUB pathway in Germany provides hospitals added payment; managed entry agreements minimize budget impact (i.e., ranibizumab in the UK); performance/outcomes based agreements maximize cost-effectiveness (i.e., ranibizumab in Italy). US Payers cite the need for alternative reimbursement schemes when 1) the price is ≥$2M; or 2) the number of qualified patients is >1/100,000. Alternative payment schemes cited as most viable include: annuity based (in which fixed payments are submitted by the Payer over time, assuming continued effectiveness) and pooled risk funding (whereby funds from multiple government sources/Payers are aggregated for reimbursing high-cost drugs).  Key challenges and requirements to implement these alternative schemes include: changes in patient privacy laws and Payer to Payer collaboration policies, patient tracking systems, and need for third party arbitration. CONCLUSIONS: EU countries are experienced with risk sharing schemes and see expanded implementation with high priced therapies. US Payers favor a performance based scheme linked to annuity payments.  However, multiple legal challenges must be overcome as the schemes tested are based upon long-term patient tracking and would require changes in the healthcare infrastructure.