Background:Adaptive pathways (AP) are prospective planned approaches to regulation and coverage of drugs. Through iterative phases of evidence gathering, it aims to reduce uncertainties while balancing timely access for patients and level of  available evidence. The concept assumes that all phases from development to clinical routine use through reimbursement are integrated. If AP did develop from regulatory perspective, many payers remain resistant. The aim of this research is to discuss payer’s position on AP. Discussion:Payers show an increasing resistance to uncertainty and their decisions are mainly driven by evidence robustness.  Regulators are integrating foregone alternative treatment opportunities in decision making and increasingly registering drugs with limited evidence and larger benefit estimates. Time from development initiation to marketing authorization (MA) decreases overtime (compassionate use, accelerated assessment, conditional MA, MA under exceptional circumstances); On the opposite, time from MA to reimbursement expand with an increasing number of products denied reimbursement due to limited evidence. This gap between regulators and payers continues to increase and AP may widen this gap.  While managed entry agreements were thought to help managing uncertainty, it happens, in most of the cases, to be used as disguised cost-containment tools. Only coverage with evidence development (CED) with escrow agreements remain an appropriate tool to address uncertainty, but is rarely used. The difficulty to reverse reimbursement decision makes payers very sensitive to uncertainty. AP is unlikely to address the payers concern unless they are directly involved in identifying risk, designing mitigation plan, and monitoring the uncertainty. Conclusion:AP may contribute to widen the gap between regulators and payers. Only CED with escrow agreement may be an appropriate tool to address payers' uncertainty. However, AP pilot projects with expected high benefit will exercise pressure on payers to issue reimbursement.