Abstract Introduction Protocol-driven trial activities contribute to the utility gain demonstrated in the phase III clinical trial of a new drug. If this utility gain cannot be distinguished from the effects of the new drug itself, protocol-driven trial costs cannot be easily dismissed for consistency reasons. This study aims to estimate the impact of including per-patient costs of phase III clinical trials on the incremental cost-effectiveness ratio (ICER). Methods The analysis utilized a modeling approach with secondary data from an ad-hoc literature review, considering both societal and payer perspectives. While the costs of phase III clinical trials may cancel out during the period of “normal” life-years due to the incremental cost calculation, they do not cancel out when differential early treatment termination occurs (e.g., due to differential mortality). Assuming the presence of differential mortality, per-patient phase III trial costs were calculated for the period of added life-years. These costs were then included in the ICER of a new drug, under the assumption that direct patient-related costs constitute 30–70% of the total trial costs. Capital costs were also incorporated from a societal perspective. Results Based on assumptions of $40,000 out-of-pocket expenses per patient enrolled in a phase III trial and a life expectancy gain of three months, incremental costs increased by $27,000 from a societal perspective. From a payer perspective, the estimate was $12,000. Conclusions The costs of phase III trials are a relevant component of the ICER, and excluding it is generally not appropriate for consistency reasons. Properly considering these trial costs is essential for a comprehensive evaluation of a new drug’s cost-effectiveness.