OBJECTIVES: The choice of comparator drug is a critical factor in successful market access, pricing and reimbursement by national payer bodies. Varying requirements specified for the comparator selected have led to approaches that differ by country. Legislation introduced in Germany in particular has affected studies in progress. As HTA agencies differ per country, the objective of the analysis which covers Germany, UK and France is twofold: - Do market access regulations influence trial design? - Do the chosen trial designs cover national pricing and reimbursement regulations? METHODS: Published benefit assessments from selected HTA agencies websites such as G-BA, NICE and HAS were used to analyze diabetes drug assessments in terms of requested comparators and final recommendation. Furthermore, Clincialtrials.gov was used to analyze the trials in diabetes and their design. RESULTS: Of the 49 HTA assessments by G-BA, HAS and NICE analyzed, 10 assessments (20%) had an inappropriate comparator chosen.  This resulted in eight negative recommendations, one positive with restrictions and one positive recommendation. Most of the HTA assessments with a positive outcome presented head-to-head or adjusted indirect comparisons. Unadjusted indirect comparisons were mainly rejected; and a mixed approach was allowed in France and England but not recommended in Germany. CONCLUSIONS: Having solely marketing authorization (EMA) in mind when designing a trial can lead to an unsuccessful drug launch with regards to national pricing and reimbursement decisions. More specifically, the choice of comparator is considered as the most important factor for benefit assessment in Germany and the methodology applied is crucial to obtaining a positive outcome. In France and England, the use of specific guidelines for the choice of comparators and comparison methodology developed by NICE and validated by the HAS, is particularly relevant to obtain a positive outcome.