Combinations of high-cost branded drugs are becoming a reality. The synergistic value of combining two potent drugs is expected to considerably bolster the benefit to the patient in terms of efficacy and, in some cases, even safety. However, the synergistic cost of using branded combinations increases exponentially due to longer treatment durations, thus making the total treatment cost unaffordable to European health systems. This poster aims to explore the pricing and reimbursement issues that health systems will encounter during the evaluation of branded combination therapies and potential solutions to make these combinations affordable by the healthcare systems and ensure patient access to innovative drugs. To meet these objectives, an in-depth review of published sources was conducted, including a thorough analogue assessment. Moreover, targeted interviews with twenty payers involved at different levels of pricing and market access decision-making in the EU5 were also conducted to support analysis. Research revealed that synergistic costs of already expensive monotherapies, further exacerbated by longer duration of treatment, exceed payers’ cost thresholds. Therefore, on one hand payers will struggle to award a value-based price for the individual drugs as well as for the combination and will look to discount and/or restrict access. On the other hand, as this approach will not reflect the combination’s synergistic value and could threaten the life-cycle indications of each compound, manufacturers may not launch in some markets, thus, limiting patient access. Consequently, it is important to find a balance in setting a value-based price for individual indications and for the combinations to ensure broad patient access. Aligning patient, payer and manufacturer needs is paramount to find a win-win-win solution. In the context of brand-on-brand combinations, traditional pricing models are not the solution and alternative approaches need to be adopted.