OBJECTIVES: The gold-standard pivotal trial design has three arms with experimental medicine, placebo and active control however, often marketing authorisation is granted on placebo controlled (PLAc) trial(s). While PLAc trials are often still acceptable to the European Clinical Trials Directive and European Medicines Agency (EMA), they are less acceptable to Health Technology Assessment (HTA) bodies. The latter request an (in)direct comparison versus the relevant active comparator(s) (AC) to demonstrate the added value of existing standard of care. We have investigated the hurdles encountered during HTA assessments for those drugs with marketing authorization based solely on PLAc studies. METHODS: We identified those drugs approved since 2010 by EMA based only on PLAc trials. We then reviewed the HTA assessments for these drugs in France (HAS), Germany (G-BA) and the UK (NICE and SMC) and compared these HTA assessments to others where the trial included an AC. RESULTS: Applications for 41 (45 indications) of the 220 drugs approved by EMA between 2010 and end of 2012 were based exclusively on PLAc trials. The number of indications already assessed and recommended (percentage) by HTA bodies are 19 and 11 (58%) for NICE, 33 and 18 (55%) for SMC, 24 and 20 (83%) for HAS, and 18 and 12 (67%) for G-BA. When compared to all HTAs irrespective of comparator being placebo or AC assessed since 2010, lack of an AC seemed to have no impact in HAS (83% vs 75% favorable opinion among all assessments) and G-BA (67% vs 58%) assessments but had a negative impact on SMC (55% vs 85%) and NICE (58% vs 64%) recommendations. CONCLUSIONS: The impact of no direct comparison with an AC varies across countries. The analysis seems to indicate that in absence of head-to-head data HTA agencies will accept indirect evidence against the right AC.