OBJECTIVES: Advanced-therapy medicinal products (ATMPs), such as gene therapy, cell therapy and tissue engineering are a new class of medicines in the EU. ATMPs offer prospects in prevention and treatment of fatal and/or chronic debilitating diseases where no effective treatments exist. However, with complicated mechanisms of actions and benefits often being anticipated in the longer term, it is challenging to demonstrate hard clinical evidence and create robust cost-effectiveness models that Payers have come to expect at the launch of pharmaceuticals. Thus, manufacturers face difficulties when negotiating the price for ATMPs and may not be able to realize their full potential. This paper aims to use case studies of ATMPs launched in EU5 to outline access pathways and review the clinical and economic evidence requirements.  METHODS: Secondary research identified ATMP approvals since 2008 and a framework was created to develop hypotheses on clinical and economic evidence requirements, considering alternative routes to market. Hypotheses were then validated during in-depth interviews with key stakeholders across EU5.  RESULTS: Payers are yet to be convinced about the full benefit of ATMPs and are reluctant to pay premium prices if they are not sure about long-term efficacy and safety. Additionally, in their cost-benefit analyses, Payers tend to consider only the direct costs associated with a condition, ignoring broader societal benefits and savings in the long run. Therefore, price negotiations are sometimes lengthy. Risk sharing and novel payment-by-result schemes are often agreed to mitigate risks.  CONCLUSIONS: Payers are not yet familiar with the potential value of ATMPs, and, in most cases specific evaluation criteria don’t exist. Manufacturers need to invest in educating Payers on the huge differences between ATMPs and traditional therapies, particularly to show that manufacturing costs are substantial, and work together to identify relevant measures for clinical and economic evaluations of this new therapy class.