Facilitators and Barriers of Incremental Innovation by Fixed Dose Combinations in Cardiovascular Diseases.

Despite the availability of affordable pharmaceuticals treating cardiovascular diseases (CVDs), many of the risk factors remain poorly controlled. Fixed-dose combinations (FDCs), a form of incremental innovation, have already demonstrated improvements over combinations of single medicines in adherence and hard clinical endpoints. Nevertheless, there are many barriers related to the wider use of FDCs in CVDs. Our aim was to identify these barriers and explore system-level facilitators from a multi-stakeholder perspective. Identified barriers include (i) hurdles in evidence generation for manufacturers, (ii) limited acceptance of adherence as an endpoint by clinical guideline developers and policymakers, (iii) limited options for a price premium for incremental innovation for healthcare payers, (iv) limited availability of real-world evidence, and (v) methodological issues to measure improved adherence. Initiatives to standardize and link healthcare databases in European countries, movements towards improved patient centricity in healthcare, and extended value assessment provide opportunities to capture the benefits of FDCs. Still, there is an emerging need to facilitate the generalizability of sporadic clinical evidence across different FDCs and to improve adherence measures. Finally, healthcare payers need to be convinced to pay a fair premium price for the added value of FDCs to incentivize incremental innovation in CVD treatment.

Breast cancer stage and molecular subtype distribution: real-world insights from a regional oncological center in Hungary.

OBJECTIVE: Examining the distribution of breast cancer (BC) stage and molecular subtype among women aged below (< 45 years), within (45-65 years), and above (> 65 years) the recommended screening age range helps to understand the screening program's characteristics and contributes to enhancing the effectiveness of BC screening programs. METHODS: In this retrospective study, female patients with newly diagnosed BC from 2010 to 2020 were identified. The distribution of cases in terms of TNM stages, severity classes, and subtypes was analysed according to age groups. RESULTS: A total of 3282 women diagnosed with BC were included in the analysis. Among these cases 51.4% were detected outside the screening age group, and these were characterized by a higher TNM stage compared to those diagnosed within the screening age band. We observed significantly higher relative frequency of advanced BC in the older age group compared to both the screening age population and women younger than 45 years (14.9% vs. 8.7% and 7.7%, P < 0.001). HR-/HER2- and HER+ tumours were relatively more frequent among women under age 45 years (HR-/HER2-: 23.6%, HER2+: 20.5%) compared to those within the screening age range (HR-/HER2-: 13.4%, HER2+: 13.9%) and the older age group (HR-/HER2-: 10.4%, HER2+: 11.5%). CONCLUSIONS: The findings of our study shed light on potential areas for the improvement of BC screening programs (e.g., extending screening age group, adjusting screening frequency based on molecular subtype risk status) in Hungary and internationally, as well.

[New opportunities offered by digital technology in melanoma malignum screening.] / A digitális technológia kínálta új lehetoségek a melanoma malignum szurésében.

INTRODUCTION: In Eastern and Central Europe, Hungary has the third highest incidence of melanoma after the Czech Republic and Slovakia. In order to improve the efficiency of melanoma diagnostics and screening, several technological developments have been made in recent years, one is the integrated automated total body mapping and digital dermatoscopy. OBJECTIVE: The aim of this targeted literature review is to demonstrate the potential of new digital technologies developed for total body mapping in relation to melanoma screening. METHOD: Targeted literature review was performed to collect information. We searched in publicly available databases for guidelines and recommendations as well as scientific publications on screening and early detection of melanoma. RESULTS: We identified 15 international guidelines and recommendations summarizing screening and early detection of melanoma. We did not find any Hungarian guidelines on melanoma screening. We analyzed 2 clinical, 5 observational studies and 8 systematic reviews on the effectiveness of digital dermatoscopy and automated total body mapping. We found 10 studies that investigated the complementary role of machine learning algorithms in the early diagnosis of melanoma. DISCUSSION: Digital dermatoscopy and total body mapping can help identify skin malignancies or new melanoma at high-risk individuals. Due to the lack of reliable data of melanoma screening programmes on cancer mortality, population-based melanoma screening is not recommended by international guidelines. CONCLUSION: International guidelines highlight the role of automated total body mapping and sequential digital dermatoscopic imaging in screening of individuals at increased risk of melanoma. Orv Hetil. 2022; 163(49): 1943-1951.

The impact of the war on maintenance of long-term therapies in Ukraine.

Due to the Russian invasion, which started on 24 February 2022, the Ukrainian healthcare system is facing multiple challenges. A great number of healthcare facilities have been destroyed, while availability of other ones is often limited due to a lack of qualified medical staff. Certain services, e.g. cancer therapies, have been seriously disrupted. Moreover, millions of Ukrainians with chronic conditions are also suffering as due to war-related problems with execution of their long-term therapies. Availability of drugs is particularly limited in the occupied regions. According to the national statistics, as of 18 August 2022, about 505 pharmacies were damaged in Eastern Ukraine and 47 completely ruined. Moreover, the invaders have been blocking humanitarian aid provided to these territories by the Ukrainian government or other countries. Fortunately, in the areas controlled by the Government of Ukraine, the acute shortage of medicines, observed at the beginning of the war, has already been eliminated. Nevertheless, not all drugs are now fully available, even in the areas where no military attacks occur. The economic availability of drugs is also profoundly influenced by the significant increase in the cost of medications and the fall in average salaries. The Government of Ukraine is trying to minimise the impact of these war-related challenges by adopting a new legislation. This includes, among others, simplification of procedures for licensing, quality control and import of medicinal products to Ukraine. Other measures involve securing displaced people with the option of benefiting from local healthcare facilities, broadening the scope of the ePrescription system, authorizing primary care doctors to issue prescriptions to refugees, increasing the number of drugs reimbursed for long-term therapies, etc. These solutions, however, cannot balance all the harmful consequences the war in Ukraine brings in terms of maintenance of long-term therapies. Therefore, in order to minimise this negative impact, Ukraine still needs urgent international support in this area.

The role of low-dose computed tomography in lung cancer screening / A kis sugárdózisú komputertomográfia szerepe a tüdorákszurésben

Introduction: Lung cancer is a serious public health problem in Hungary, but currently there is no nationwide screening program for the early detection of the disease. Several technological developments have been carried out recently to improve the effectiveness of lung cancer screening. Low-dose computed tomography (LDCT) is one of these technologies. Objective: The objective of this study is to provide an overview on guidelines and recommendations related to the application of LDCT as a novel lung cancer screening modality and to summarize the scientific literature and screening practices of other countries. Method: We performed a targeted literature review to collect information about LDCT in lung cancer screening. We searched in publicly available databases for guidelines and recommendations as well as scientific publications on screening and early detection of lung cancer. Results: In our literature search, we identified 16 guidelines and recommendations for lung cancer screening and LDCT. Regarding the efficacy of LDCT lung cancer screening, 10 foreign randomized controlled trials and 2 Hungarian trials were reviewed. Information on screening practices of 10 European countries were identified. Discussion: Evidences suggest that LDCT screening improves the detection of lung cancer, especially at early stages, and reduces cancer-specific mortality. Conclusion: In summary, in the high-risk population, LDCT can be considered an effective screening modality for the early-stage detection of lung cancer and for reducing lung cancer mortality. The ongoing Hungarian and foreign pilot programs may provide futher evidence for the implementation of a nationwide LDCT lung cancer screening program.

Review of the scientific literature on the use of automated breast ultrasound for screening / Az automatizált emloultrahang-daganatszurés szakirodalmi áttekintése

Several technological developments have been carried out recently to improve the effectiveness of breast cancer screening. Most of them have emerged as a complementary method to mammography. Automated breast ultrasound is one of these technologies. The objective of this study is to provide an overview on guidelines and recommenda-tions related to the application of automated breast ultrasound as a screening modality and to summarize the scien-tific literature. Targeted literature review was performed to collect information. We searched in publicly available databases for guidelines and recommendations as well as scientific publications on screening and early detection. We found substantial amount of information about automated breast ultrasound mainly for patients with dense breast; however, breast cancer screening guidelines have not yet incorporated this technology. 9 clinical studies were in-cluded in the review, most of them were single-arm studies with relatively short follow-up time. Most of them were performed in the USA. Results were presented mainly for short-term outcomes of breast cancer screening: sensitiv-ity, specificity, tumor detection rate and recall rate. The opportunity for retrospective evaluation of the images and the reproducibility are considered the most important advantages. Evidence suggest that the cancer detection rate can be improved compared to mammography alone in women with dense breast. The main disadvantages of this technology are the high recall and false positive rates. Further scientific evidence is required to reduce uncertainty related to the use of automated breast ultrasound for breast cancer screening.

Secondary primary malignancies after treatment with chemo-immunotherapy in treatment-naïve patients with CLL: a systematic literature review.

OBJECTIVES: In chronic lymphocytic leukemia (CLL), therapy-related cytotoxicity and the resulting immunodeficiency are thought to contribute to the development of secondary primary malignancies (SPM). Here, we analyzed clinical trial data on the occurrence of SPM following chemo-immunotherapy (CIT) regimens in treatment-naïve CLL patients. METHODS: A systematic literature search was conducted covering multiple databases between 2003 and 2019. Data from relevant clinical trials on the proportion of patients with SPMs were extracted. Then, the number of SPM patients/person-years was calculated by taking into account the trials' follow-up time. Finally, a random-effects meta-analysis to pool the rates from individual studies was performed. RESULTS: We identified 22 studies reporting SPM data available for analysis. Random-effects meta-analysis estimated that the number of SPM patients/1000 person-years was 24 (95%CI: 19-29). Results from trials with cancer-specific data indicated 19 (95%CI: 14-26) solid and 9 (95%CI: 6-12) hematological SPM patients/1000 person-years. These estimations did not change significantly when sub-groups were analyzed by CIT regimens. CONCLUSION: Although pooling data with the intention to analyze adverse event rates is challenging, our study concluded that for CIT regimens, SPM should be considered an important adverse outcome. Different regimens showed similar trends; however, other clinical and demographic factors also have profound impact.

Development of a breast cancer screening protocol to use automated breast ultrasound in a local setting.

Introduction: The sensitivity of mammography screening is lower in women with dense breast. Increasing the efficacy of breast cancer screening have received special attention recently. The automated breast ultrasound (ABUS) shows promising results to complement mammography. Our aim was to expand the existing breast cancer screening protocol with ABUS within a Hungarian pilot project. Methods: First, we developed a protocol for the screening process focusing on integrating ABUS to the current practice. Consensus among clinical experts was achieved considering information from the literature and the actual opportunities of the hospital. Then we developed a protocol for evaluation that ensures systematic data collection and monitoring of screening with mammography and ABUS. We identified indicators based on international standards and adapted them to local setting. We considered their feasibility from the data source and timeframe perspective. The protocol was developed in a partnership of researchers, clinicians and hospital managers. Results: The process of screening activity was described in a detailed flowchart. Human and technological resource requirements and communication activities were defined. We listed 23 monitoring indicators to evaluate the screening program and checked the feasibility to calculate these indicators based on local data collection and other sources. Partnership between researchers experienced in planning and evaluating screening programs, interested clinicians, and hospital managers resulted in a locally implementable, evidence-based screening protocol. Discussion: The experience and knowledge gained on the implementation of the ABUS technology could generate real-world data to support the decision on using the technology at national level.

Systematic review of real-world studies evaluating the impact of medication non-adherence to endocrine therapies on hard clinical endpoints in patients with non-metastatic breast cancer.

Breast cancer, one of the most common malignancies, is associated with significant economic and health burden both at the patient and societal level. Although medication non-adherence to endocrine breast cancer therapies is common, so far only limited systematic evidence has been available on its quantitative consequences, as previous systematic reviews focused mainly on factors contributing to medication non-adherence. The objective of this review was to explore the implications of medication non-adherence to endocrine therapies on hard clinical outcomes in breast cancer based on real-world studies. A systematic literature review was conducted on PubMed; empirical evidence on hard clinical endpoints (i.e., survival, disease-free survival, metastasis and recurrence) were extracted from uni- or multivariate statistical analyses from retrospective or prospective cohort studies. Of the 2,360 identified records, 12 studies met the inclusion criteria. Two studies identified significant positive association between medication non-adherence and the risk of distant metastasis, three articles between medication non-adherence and the recurrence of breast cancer, two studies between medication non-adherence- and non-persistence and of worse disease-free survival and eight articles between medication non-adherence and mortality. There was only one study where the positive association between medication adherence and survival did not apply to all subgroups. The strong evidence on the negative health consequences of non-adherence to breast cancer treatments indicates the need for the regular monitoring of medication adherence. Furthermore, explicit inclusion of adherence enhancing interventions into health policy agenda would be warranted to improve medication adherence also at a system level.

Patient-reported symptom burden of chronic graft versus host disease: a systematic literature review.

INTRODUCTION: Chronic graft-versus-host disease (GVHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation (HSCT) leading to high morbidity and quality of life issues. We conducted a systematic literature review on the patient reported symptom burden of chronic GVHD. AREAS COVERED: English-language articles published between 2005 and November 2018 were searched using CENTRAL, EMBASE and MEDLINE. Studies that used the 2005 or 2015 National Institute of Health consensus criteria for the diagnosis and staging of chronic GVHD were included. EXPERT OPINION: Patient reported symptom burden was widely assessed in the literature (n = 38). The Lee Chronic GVHD Symptom Scale was the most frequently used instrument (n = 28), followed by the NIH Patient-reported Symptom scores (n = 11). Association of symptom burden with clinical outcome assessment endpoints (e.g. mortality) and with quality of life measures was investigated by fairly low number of studies with limited generalizability. By systematically investigating the influencing factors of symptom burden this review helps to better understand patients' perceptions and may help improving the management and care of chronic GVHD. However, data on influencing factors was quite diverse, which indicates that specific questions identified as research gaps need to be incorporated in randomized clinical trials in a more systematic way.

A systematic literature review of incidence, mortality, and relapse of patients diagnosed with chronic graft versus host disease.

INTRODUCTION: Chronic graft-versus-host disease (chronic GVHD) is a leading cause of late death and contributes significantly to morbidity following hematopoietic stem cell transplantation. This study aims to provide a systematic literature review on incidence, mortality, and relapse of chronic GVHD patients. Areas covered: The authors searched for English-language articles published between 2007 and 2017 using PubMed. Studies that applied the 2005 or 2015 NIH Consensus Criteria for the diagnosis and staging of chronic GVHD, and had a cohort size of at least 100 patients were included. Expert opinion: The authors found a wide variation of incidence rates, which can be explained by heterogeneity in the characteristics of study samples and applied transplantation protocols. Chronic GVHD was associated with higher non-relapse mortality (NRM), superior overall survival (OS) and lower risk of relapse. Studies indicated an increased risk for NRM and worse OS in the presence of more severe disease. Future therapies should focus to reach a delicate balance between controlling disease severity among patients diagnosed with chronic GVHD and preserving the graft versus tumor effect which goes along with chronic GVHD and results in improved OS and decreased relapse rate. Nonetheless, factors predicting disease severity still need to be further understood.

Humanistic burden of patients with chronic graft-versus-host disease - systematic literature review of health-related quality of life and functional status.

INTRODUCTION: Chronic graft-versus-host disease (GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to provide a systematic overview of evidence on the health-related quality of life (HRQoL) and functional capacity of HSCT patients with National Institutes of Health (NIH)-defined chronic GVHD. Areas covered: English-language articles published between 2007 and 2017 were searched using PubMed. Studies that used the 2005 or 2015 NIH consensus criteria for the diagnosis and staging of chronic GVHD and had a cohort size of at least 100 patients were included. Expert opinion: Disease severity and organ involvement were the most important predictors of HRQoL and functionality in chronic GVHD patients. Further, identified predictors of HRQoL were nutrition status and functional capacity, while functional status was also associated with disease symptoms, nutrition status, age, and survival. Data regarding the effect of symptom bother on HRQoL were limited. Our findings confirm that the management of chronic GVHD should focus on improving not only clinical outcomes but also on HRQoL and functional capacity. Therefore, to evaluate new treatment options it is recommended to include patient relevant endpoints into prospective studies. This study also highlights the importance of nonpharmacological aspects in the management of chronic GVHD.

Methods for Measuring Multiple Medication Adherence: A Systematic Review-Report of the ISPOR Medication Adherence and Persistence Special Interest Group.

BACKGROUND: A broad literature base exists for measuring medication adherence to monotherapeutic regimens, but publications are less extensive for measuring adherence to multiple medications. OBJECTIVES: To identify and characterize the multiple medication adherence (MMA) methods used in the literature. METHODS: A literature search was conducted using PubMed, PsycINFO, the International Pharmaceutical Abstracts, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library databases on methods used to measure MMA published between January 1973 and May 2015. A two-step screening process was used; all abstracts were screened by pairs of researchers independently, followed by a full-text review identifying the method for calculating MMA. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to conduct this systematic review. For studies that met the eligibility criteria, general study and adherence-specific characteristics and the number and type of MMA measurement methods were summarized. RESULTS: The 147 studies that were included originated from 32 countries, in 13 disease states. Of these studies, 26 used proportion of days covered, 23 used medication possession ratio, and 72 used self-reported questionnaires (e.g., the Morisky Scale) to assess MMA. About 50% of the studies included more than one method for measuring MMA, and different variations of medication possession ratio and proportion of days covered were used for measuring MMA. CONCLUSIONS: There appears to be no standardized method to measure MMA. With an increasing prevalence of polypharmacy, more efforts should be directed toward constructing robust measures suitable to evaluate adherence to complex regimens. Future research to understand the validity and reliability of MMA measures and their effects on objective clinical outcomes is also needed.

Behind the subcutaneous trastuzumab hype: evaluation of benefits and their transferability to Central Eastern European countries.

INTRODUCTION: Trastuzumab, the standard treatment for HER-2 positive breast cancer, may be associated with access restrictions in countries with severe economic constraints. This study aimed to compare intravenous (IVT) and subcutaneous trastuzumab (SCT) forms and to explore the transferability of value propositions to Central and Eastern European (CEE) countries. Areas covered: After screening 376 abstracts, 42 articles were included in the final review. Statistical test results were rarely reported; therefore, the similarity of adverse event profiles of SCT and IVT could not be validated. Potential time savings for patients due to subcutaneous administration was not validated in CEE settings, where patient's waiting time for treatment administration is fairly long. Standard patient reported outcome instruments were rarely used to confirm the preference of patients/health care professionals to SCT over IVT. Moreover, feasibility of self/home administration of SCT, especially in case of concomitant intravenous chemotherapies, was not considered. Cost comparisons considered neither the patent expiry of IVT nor the incremental cost of potential differences in adverse events. Expert commentary: Potential benefits of SCT were not tested by any studies in CEE countries. The main policy objective should be to facilitate the uptake of multisource biologicals in lower income countries with access barriers.

Inhaled antibiotics for the treatment of chronic Pseudomonas aeruginosa infection in cystic fibrosis patients: challenges to treatment adherence and strategies to improve outcomes.

BACKGROUND: Inhaled antibiotics (ABs) are recommended for use in the therapy of chronic Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). The aim of this systematic literature review was to identify level of adherence to inhaled ABs and to determine predictors and consequences of nonadherence in CF. METHODS: A systematic literature search of English-language articles was conducted in April 2015 using Medline and Embase. No publication date limit was applied. The literature screening was conducted by two independent reviewers. All of the included studies were assessed for quality. RESULTS: The search yielded 193 publications, of which ten met the inclusion criteria and underwent data extraction. Seven studies focused on inhaled tobramycin, one on inhaled colistimethate, one on inhaled levofloxacin, and one on inhaled aztreonam lysine. Medication adherence to inhaled ABs was analyzed by pharmacy refill history, daily phone diary, parent and child self-reports, vials counting, or electronic monitoring. In randomized controlled trials (n=3), proportion of adherent patients (>75%-80% of required doses taken) ranged from 86% to 97%; in prospective cohort studies (n=3), adherence rates ranged between 36% and 92%, and in retrospective studies (n=4) it ranged between 60% and 70%. The adherence to inhaled ABs in CF was found to be associated with the complexity of treatment, time of drug administration, age of patients, treatment burden (adverse events, taste), and patient satisfaction. CONCLUSION: The high diversity of adherence data was because of the different study designs (randomized controlled trials vs real-world studies) and the lack of a commonly accepted consensus on the definition of adherence in the reviewed articles. Routine adherence monitoring during CF care, discussing the possible reasons of suboptimal adherence with the patient, and changing treatment regimens on the basis of patient burden can individualize CF therapy for patients and may improve the level of adherence.

The cost-effectiveness of ulipristal acetate tablets in treating patients with moderate to severe symptoms of uterine fibroids.

OBJECTIVES: Ulipristal acetate is a selective progesterone receptor modulator that has been demonstrated to be an effective 3-month pre-operative treatment for moderate to severe symptoms of uterine fibroids in adult women of reproductive age. The aim of this analysis was to assess the cost-effectiveness of 5mg ulipristal as an add-on therapy to standard pre-surgical observation and treatment in Hungary. STUDY DESIGN: A Markov model was developed using a 10-year time horizon. Ulipristal was compared with pre-surgical observation and immediate hysterectomy. The model comprised the following mutually exclusive health states: mild, moderate, severe, or persistent severe excessive bleeding disorder; myomectomy; post-myomectomy with mildly to moderately excessive bleeding disorder; post-myomectomy with severely excessive bleeding disorder; hysterectomy; post-hysterectomy; post-menopause; and death. Transition probabilities and utility values were obtained from clinical trials and the scientific literature. Resource utilisation and unit costs were derived from a consensus panel of clinical experts, National Health Insurance Fund tariffs, and publications. RESULTS: Adding a 3-month course of ulipristal to pre-operative observation was predicted to achieve an additional 0.021 quality-adjusted life years (QALYs) at an estimated incremental cost of €397, which would result in an incremental cost of €19,200/QALY. When 3 months of ulipristal therapy was compared with immediate hysterectomy, the incremental cost-effectiveness ratio was reduced to €3575/QALY. The results were most sensitive to the utility value of the post-hysterectomy health state but responsive to changes in other model parameters. CONCLUSIONS: The results of this analysis suggest that adding ulipristal treatment to standard pre-surgical therapy represents a good value for money in Hungary. The inclusion of societal benefits may considerably reduce the cost-effectiveness ratio.

Factors associated with medication adherence in patients with chronic obstructive pulmonary disease.

BACKGROUND: Predictors of medication adherence are not well known in chronic obstructive pulmonary disease (COPD). It is therefore necessary to identify factors associated with adherence to improve the effectiveness of COPD management within real-world situations. OBJECTIVES: The goals of this study were to estimate adherence to respiratory medication and to identify factors related to adherence in COPD patients. METHODS: This was an observational, cross-sectional study conducted on a sample of COPD outpatients. The following information was obtained: adherence to respiratory therapy (Morisky Medication Adherence Scale), age, gender, smoking status, COPD severity [Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage], lung function [post-bronchodilator forced expiratory volume in 1 s (FEV(1))], treatment regimen for COPD, COPD medication costs per month paid by the patient and health-related quality of life (EuroQol 5-dimension questionnaire). A multivariate logistic regression analysis was performed to identify the independent predictors of adherence. RESULTS: Of the 170 participants (mean age 63.8 years, 41.8% male), 58.2% reported optimal adherence. Adherence to respiratory therapy was associated with age, current smoking status, number of respiratory drugs, number of daily respiratory drug doses and quality of life (p < 0.005). Adherence to respiratory therapy was not related to gender, GOLD stage, FEV(1) or COPD medication costs. CONCLUSIONS: Adherence to COPD medication regimens is poor. Less frequent dosing regimens could be an effective method to enhance adherence to respiratory therapy. Quality-of-life monitoring within clinical practice settings could facilitate improved medication adherence.