OBJECTIVES: German HTA agency requires evidence about the additional benefit of a new pharmaceutical versus an appropriate comparator as basis for price negotiations. This is challenging when head-to-head studies (H2HS) or randomized placebo-controlled trials (RPCTs) are missing and particularly in dermatology, where topical therapies in registration trials are usually compared to their individual vehicle. The aim of this research was to describe different approaches to assess the additional benefit of a new topical therapy under these limitations. METHODS: For ingenolmebutate-gel (IMG) and the appropriate comparator diclofenac-hyaluronic-acid (DHA) bibliographic literature search was conducted for RCTs followed by sequential screening on H2HS, comparable endpoints, RPCTs, common bridge comparator, H2HS of vehicles alone, RPCTs of vehicles. The similarity of vehicles was assessed by comparison of efficacy and safety profile. The lack of H2HS demands to conduct the following approaches depending on the comparability of vehicles: 1. An adjusted indirect comparison due to Bucher 1997 (vehicles are placebo-like or adequately similar) 2. Linkage of direct comparisons due to Wells 2009 (possible when H2HS or RPCTs of vehicles are available) 3. Mixed treatment comparison (MTC) (prerequisites as mentioned for Bucher). RESULTS: 5 RCTs for IMG versus 3 RCTs for DHA were identified with comparable endpoints. No RPCTs for topical therapies or for their vehicles, no H2HS of vehicles, no bridge comparator and no clear evidence for the adequate similarity of both vehicles could be detected. Therefore, the prerequisites of all available statistical methods are not met and cannot thoroughly be applied. Notwithstanding these limitations, Bucher (RR[95%KI]: 4.14[2.03;8.47]) and MTC both favor IMG significantly while Wells showed non-inferiority (RR[95%KI]: 0.8[2,03;8,47]) in the primary endpoint of IMG versus DHA. CONCLUSIONS: A definition of adequate similarity for vehicles by German HTA agencies is needed to enable the use of methodologically sound indirect comparisons or MTCs in reimbursement dossiers.