OBJECTIVES: To determine the necessary requirements of a first-in-therapy product to support positive HTA review. METHODS: An initial broad search was conducted to identify first-in-therapy products launching in recent years into disease areas with no alternative treatments.  The products identified were eculizumab for paroxysmal nocturnal haemoglobinuria (PNH), pregabalin for fibromyalgia, vigabatrin for infantile spasms, tetrabenazine for tardive dyskinesia (TD) and chorea of Huntington’s disease, pirfenidone for idiopathic pulmonary fibrosis (IPF), and amifampridine for Lambert-Eaton myasthenic syndrome (LEMS).  These products were then examined within NICE, SMC, NCPE, PBAC and CADTH websites, and information collated on clinical endpoints, HTA comparators and assessment outcomes to provide an understanding of the requirements of first-in-therapy products for positive review. RESULTS: Of the drugs selected, 4 were assessed by HTA bodies.  Due to a lack of alternative therapies, all but one product assessed carried out trials against placebo.  Clinical endpoints were based either on metrics agreed upon by KOLs, quality of life measures, or both.  Out of the seven drugs studied, only vigabatrin received positive recommendation due to strong trial data and inclusion of an active symptomatic comparator.  A number of first-in-therapy products were actually rejected by HTAs in select countries.  Pregabalin was rejected due to unconvincing trial data despite a favourable cost per QALY and eculizumab was rejected due to too high an incremental cost per QALY.  CONCLUSIONS:  We can conclude that based on the products assessed, first-in-therapy products do not typically receive special consideration when assessed by HTA bodies.  An active comparator, use of recognized endpoints and the quality of data remain as important requirements for positive review.  Furthermore, demonstrated cost-effectiveness is required even in a novel disease area, thus, it will be necessary to evaluate this earlier in development.  More focused studies need to be carried out to ascertain this trend on a country-by-country basis.