Methodology of the brodalumab assessment of hazards: a multicentre observational safety (BRAHMS) study.

INTRODUCTION: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections. METHODS AND ANALYSIS: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed. ETHICS AND DISSEMINATION: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: EUPAS30280.

[Appropriate use of trastuzumab in Lazio Region: therapeutic scenarios and estimation of possible savings for the Regional Health Service.] / Utilizzo appropriato del trastuzumab nel Lazio: scenari terapeutici e stima del possibile risparmio per il Servizio Sanitario Regionale.

BACKGROUND: The availability of subcutaneous (SC) and intravenous (EV) formulations of trastuzumab and the recent release of the biosimilar EV version (10/2018) increase the offer for the treatment of patients with breast or gastric cancer HER2 positive. In this context, it is necessary to build therapeutic scenarios form avalible data in order to estimate the potential savings for the Regional Health Service (RHS) taking into account the appropriateness of use and patient's preferences. AIM: To evaluate the available comparative evidence regarding the effectiveness and safety of the different trastuzumab formulations; to analyze the supply of trastuzumab by type of administration (EV/SC) in Lazio in 2018, identifying the most appropriate use; to hypothesize a cost-effective scenario for the Regional Health Service (SSR) in 2019. Mehods. With the working group formed by clinicians and methodologists, we analysed the evidence of efficacy and safety available to date for the different formulations of trastuzumab, also taking into account the recent availability of biosimilars and with particular regard to the phenomenon of the potential switch between different therapeutic options. In addition, for the year 2019 the available economic impact assessments were also simulated with data from the Lazio Region. Through the datas from direct pharmaceutical products, the transtuzumab cycles supplied in 2018 were identified separately for the available formulations (EV/SC). For each cycle of therapy, starting from the date of delivery, the possible presence of a concomitant treatment (± 2 days) was investigated, tracing the type and method of administration. The treatments (concomitant with trastuzumab) were identified for which there were conflicting modes of administration. In addition, the supply of SC per dispensing structure was evaluated and, on the basis of this information, a scenario of use was hypothesized that takes into account costs and plausible consumption. RESULTS: A review of the literature summarized the available evidence on the efficacy and safety of the use of trastuzumab in the recorded therapeutic indications. The review was discussed with the working group and used to reproduce, at regional level, the estimates of the economic impact of the different therapeutic choices possible with trastuzumab. As regards the data on the use of trastuzumab, in the Lazio Region in 2018, 22,214 treatment cycles were observed (at a cost of 33 million euro) for 2,407 patients; new users accounted for 52.2%. 46.8% of the cycles were administered via SC; the use of the biosimilar was observed from October onwards and involved 143 cycles (0.6%). In 68.4% of the cycles trastuzumab was administered in monotherapy; among the therapies associated with trastuzumab, the most frequent was pertuzumab (n=4,258, 19.2% of the total cycles), followed by paclitaxel (n=1,364, 6.1% of the total cycles). Among the cycles of trastuzumab in concomitant therapy (N=7,022), 17.3% was administered via SC despite the presence of other drugs administered via EV. The prescriptive pattern of trastuzumab was heterogeneous for the different delivery structures. The SC administration presents a variability in the supply from 26% to 70% (interquartile range) and does not seem to be related to the type and volume of activity of the hospital. If the biosimilar EV is expected to account for 55% of consumption by 2019, thus reducing the use of the EV originator to 10% and the SC originator to 35%, savings of more than €7 million. CONCLUSIONS: Through the use data of the different formulations available for trastuzumab and taking into account the prescriptive appropriateness (and patient preferences), it has been possible to identify a SSR scenario of economic convenience due to the greater use of the biosimilar.