Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The “introduction” of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers.

This chapter describes how the different ICARUS unmanned search and rescue tools have been evaluated and validated using operational benchmarking techniques. Two large‐scale simulated disaster scenarios were organized: a simulated shipwreck and an earthquake response scenario. Next to these simulated response scenarios, where ICARUS tools were deployed in tight interaction with real end users, ICARUS tools also participated to a real relief, embedded in a team of end users for a flood response mission. These validation trials allow us to conclude that the ICARUS tools fulfil the user require‐ ments and goals set up at the beginning of the project.

This chapter describes two unmanned ground vehicles that can help search and rescue teams in their difficult, but life-saving tasks. These robotic assets have been developed within the framework of the European project ICARUS. The large unmanned ground vehicle is intended to be a mobile base station. It is equipped with a powerful manipulator arm and can be used for debris removal, shoring operations, and remote struc- tural operations (cutting, welding, hammering, etc.) on very rough terrain. The smaller unmanned ground vehicle is also equipped with an array of sensors, enabling it to search for victims inside semi-destroyed buildings. Working together with each other and the human search and rescue workers, these robotic assets form a powerful team, increasing the effectiveness of search and rescue operations, as proven by operational validation tests in collaboration with end users.

BackgroundManaged entry agreements (MEAs) are a set of instruments to facilitate access to new medicines. This study surveyed the implementation of MEAs in Central and Eastern Europe (CEE) where limited comparative information is currently available.MethodWe conducted a survey on the implementation of MEAs in CEE between January and March 2017.ResultsSixteen countries participated in this study. Across five countries with available data on the number of different MEA instruments implemented, the most common MEAs implemented were confidential discounts (n = 495, 73%), followed by paybacks (n = 92, 14%), price-volume agreements (n = 37, 5%), free doses (n = 25, 4%), bundle and other agreements (n = 19, 3%), and payment by result (n = 10, >1%). Across seven countries with data on MEAs by therapeutic group, the highest number of brand names associated with one or more MEA instruments belonged to the Anatomical Therapeutic Chemical (ATC)-L group, antineoplastic and immunomodulating agents (n = 201, 31%). The second most frequent therapeutic group for MEA implementation was ATC-A, alimentary tract and metabolism (n = 87, 13%), followed by medicines for neurological conditions (n = 83, 13%).ConclusionsExperience in implementing MEAs varied substantially across the region and there is considerable scope for greater transparency, sharing experiences and mutual learning. European citizens, authorities and industry should ask themselves whether, within publicly funded health systems, confidential discounts can still be tolerated, particularly when it is not clear which country and party they are really benefiting. Furthermore, if MEAs are to improve access, countries should establish clear objectives for their implementation and a monitoring framework to measure their performance, as well as the burden of implementation.

Purpose: Quality of life (QOL) is an important area of research in many scientific disciplines, and the findings could help in designing strategies to improve QOL for various clinical conditions. Chronic low back pain is a frequent medical condition that has a detrimental effect on QOL. The goal of this study was to examine the QOL of people with chronic low back pain in Bosnia and Herzegovina (BIH), and to assess the impact of demographic variables such as age and gender on the QOL. Methods: The study sample consisted of 50 people with low back pain, between 19-79 years of age (mean age 51.2, SD- 13.1 years). There were 35 females (70%) and 15 males (30%) in the sample. The instrument used for measuring the QOL was World Health Organisation Quality of Life scale BREF (WHOQOL BREF). Results: The study demonstrated that low back pain has a detrimental effect on QOL. There was a significant effect of age and gender on certain domains of QOL. Conclusions: Older age is a risk factor for lower QOL of people with chronic low back pain. Females are more likely to have lower scores on the psychological domain of QOL,and therefore need effective psychological interventions aimed at improving their QOL.

It is well-known that somatic mutations resulting in increased number of neoantigens (“immunogenic antigens”) may enhance anti-tumor immune cell reaction. Also, high tumor mutation burden (load) [TML] is associated with improved response, durable clinical benefits and better outcome if a cancer is treated with immune check point inhibitors [anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) drugs] [1]. A subset of colorectal carcinomas (CRC) and other cancers characterized by mismatch repair deficiency (MMR) and/or microsatellite instability high (MSI-H) profiles may be particularly sensitive to the PD-1/PD-L1 blockade with immune check point inhibitors due to the common PD-L1/PD-L1 expression [2-9]. Several therapeutic antibodies inhibiting either PD-1 (nivolumab, pembrolizumab) or PD-L1 (MPDL3280A, Medi4736, BMS-936559) have been developed and approved for the treatment of various malignancies including malignant melanoma, non-small cell lung carcinoma, renal cell carcinoma, bladder carcinoma, Merkel cell carcinoma, and classical Hodgkin lymphoma [10]. A pivotal phase 2 study by Le et al. [11] highlighted the importance of mismatch-repair status in prediction of the clinical benefit of immune checkpoint blockade with pembrolizumab (anti-PD-1 drug) [11]. The study included 41 patients with progressive cancers of both CRC and non-colorectal origins and known MSI status. For CRC patients, the objective response rate and progression-free survival rate were 40% and 78%, respectively for mismatch repair-deficient tumors and 0% and 11% for mismatch repair-proficient CRCs. A novel study by Le et al. [12] (ClinicalTrials.gov number, NCT01876511) represents an extended analysis on the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers. The study included 86 patients with 12 different histologic cancer subtypes and proved mismatch repair-deficiency status assessed by either polymerase chain reaction (PCR) or immunohistochemistry. The data presented in this study indicate objective radiographic responses in 53% of patients while complete responses were achieved in 21% of patients. Based on this and previous data, on May 23, 2017, the U.S. Food and Drug Administration (FDA) granted accelerated approval to anti-PD-L1 drug pembrolizumab (KEYTRUDA®, Merck & Co.) for adult and pediatric patients with unresectable/metastatic MSI-H/MMR deficient solid tumors (regardless the histotype) that have progressed following prior treatment and without satisfactory alternative treatment modalities. The approval also covered MSI-H CRC patients who progressed following treatment with a classic cytotoxic therapy (fluoropyrimidine, oxaliplatin, and irinotecan). Taken together, these results revolutionize the cancer treatment paradigm as for the first time the cancer treatment was based solely on the molecular characteristics of cancer (in this case microsatellite instability/MSI/ status) regardless the tumor morphology (histotype). This appears to be “the FDA’s first tissue/site-agnostic approval”. Certainly, there are still ongoing but unresolved issues regarding these treatments including other merging predictive biomarkers (optimization of PD-L1 and PD-1 evaluation, e.g. tumor versus immune cell expression; cutoffs for positivity; selection of detection antibodies), tumor mutational load and the tumor neoantigen heterogeneity/specificity [13-15]. Further studies should also elucidate the mechanisms of recently described resistance to immune checkpoint inhibitors [16-18].