OBJECTIVES: To identify specific challenges for modelling to support health technology assessment (HTA) submissions using trial data where the comparator is the physician’s choice (PC). METHODS: Most clinical trials are designed globally or internationally, with minimal consideration of individual market needs. It is increasingly common for investigational drugs to be compared against a mix of PC treatments because a standard of care (SOC) is not always clearly defined. We searched a clinical trials database for registered trials where PC was the comparator. Based on the standard requirements for pharmacoeconomic models to support HTAs, we evaluated trial information to identify specific modelling challenges. RESULTS: We found 49 registered trials using PC as the comparator and identified four specific challenges that require guidance from HTA bodies. (1) One or more drugs used in PC regimens may not be licensed for an individual market, rendering their use problematical. (2) Comparison made against individual PC drugs results in lower patient numbers for comparison, reducing analysis credibility. (3) Analysis against individual PC drugs requires breaking randomisation, which jeopardises trial design integrity. (4) Involvement of a PC mix results in the need for a full incremental analysis, which might lead to application rejections in circumstances where the new treatment may only have incremental benefits over some of the individual treatments. CONCLUSIONS: The use of PC as a comparator in clinical trials poses challenges that are likely to slow the process of access to effective, innovative treatments. HTA agency involvement early in the life cycle of a technology would facilitate a shared understanding of evidence requirements. HTA agencies should develop clear guidelines on how PC efficacy and cost should be used for pharmacoeconomic modelling.