Switching from Nusinersen to Risdiplam: A Croatian Real-World Experience on Effectiveness and Safety.

(1) Background: Data on combination or sequential treatment of spinal muscular atrophy (SMA) with disease-modifying drugs (DMDs) are missing and the latter field is poorly understood. The currently available data of patients on risdiplam previously treated with nusinersen are coming from exploratory research mainly focused on safety. Our aim was to investigate the real-world effectiveness (hypothesising non-inferiority) and safety profile of risdiplam in a paediatric-and-adult nusinersen-risdiplam spinal muscular atrophy switch cohort. (2) Methods: A retrospective and anonymous collection of relevant demographic and clinical data for all Croatian SMA patients switched from nusinersen to risdiplam up to September 2023 (reimbursed by Croatian Health Insurance Fund-CHIF) was performed using the CHIF database and associated reimbursement documentation. Patients were included in effectiveness and safety analysis if they met the following inclusion criteria: (i) risdiplam was reimbursed by the CHIF; (ii) the patient received at least six doses of nusinersen before the switch to risdiplam; (iii) there was no relevant pause between the latter disease-modifying drugs; (iv) availability of all prespecified studied data and parameters. (3) Results: In total, 17 patients met the inclusion criteria (58.9% female; median age 12.75 (3.0-44.5) years). In our 'switch' cohort, we demonstrated a non-inferiority of risdiplam to nusinersen in the SMA 1 (+1.0 in CHOP INTEND; p = 0.067), SMA 3p (+0.7 in HFMSE; p = 0.897), and SMA 3a (+0.8 in RHS; p = 0.463) subpopulations, during a one-year follow-up period. There were no reports on respiratory function worsening, feeding worsening, and no lethal events. No new safety concerns were identified, except for the weight gain that arose as a new potential adverse drug reaction 'signal' in two patients. (4) Conclusions: We have reported pivotal real-world findings on switching SMA patients from nusinersen to risdiplam and demonstrated its effectiveness (non-inferiority), safety, and tolerability in a heterogenous paediatric-and-adult 'switch' cohort; this will further increase the quality and standards of care as well as safety of a notable portion of SMA patients, especially for those who demand the switch from nusinersen to other DMDs for clinical or personal reasons.

Advancing rare disease treatment: EMA's decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation.

Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency's Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.

The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products.

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.

Share of and Absolute Costs of Informal Care in Five Subpopulations of Outpatients with Dementia in Croatia: A Latent Profile Analysis.

BACKGROUND: High heterogeneity exists in estimates of the share of and absolute costs of informal care (IC) for individuals diagnosed with dementia. OBJECTIVE: To assess the differences in the share of and absolute costs of IC between subpopulations defined by latent profiles of activities of daily living (ADLs), neuropsychiatric symptoms, and global cognitive functioning. METHODS: We performed a nested cross-sectional analysis of data collected from 2019-2021 at the Zagreb-Zapad Health Center, Zagreb, Croatia, from a sample of patients and their caregivers. The outcome was the share of costs of IC in the total costs of care estimated using the Resource Utilization in Dementia questionnaire. We used latent profile analysis of six principal components of the Alzheimer's Disease Cooperative Study ADLs inventory, Neuropsychiatric Inventory and Mini-Mental State Examination, and conducted the analysis using beta and quantile regression. RESULTS: We enrolled 240 patients with a median age of 74 years; 78% were women. The annual cost for treatment and care for one patient was 11,462 (95% confidence interval 9,947; 12,976) EUR. After the adjustment for covariates, five latent profiles were significantly associated with the share of costs and absolute cost of IC. The adjusted annual costs of IC ranged from 2,157 EUR, with a share of 53% in the first latent profile, to 18,119 EUR, with a share of 78% in the fifth latent profile. CONCLUSION: The population of patients with dementia was heterogeneous, and there were relatively large differences in the share and absolute costs of IC between particular subpopulations.

Effectiveness of Nusinersen in Type 1, 2 and 3 Spinal Muscular Atrophy: Croatian Real-World Data.

(1) Background: To investigate the real-world effectiveness and safety profile of nusinersen in Croatian paediatric and adult spinal muscular atrophy (SMA) patients. (2) Methods: A retrospective and anonymous collection of relevant demographic and clinical data for all Croatian SMA patients treated with nusinersen and reimbursed by the Croatian Health Insurance Fund (CHIF) between April 2018 and February 2022 was performed through searching the CHIF database and studying the associated reimbursement documentation. All patients who received at least one dose of nusinersen were included in the baseline clinical-demographic overview and safety analysis, whereas only subjects who had completed six doses were included in the effectiveness analysis. (3) Results: Fifty-two patients [61.5% male; median age 13.4 (0.1-51.1) yr.] received nusinersen treatment. In SMA type 1 and type 3 paediatric patients, statistically significant motor function improvement (CHOP INTEND 10.8 ± 10.3 vs. 20.0 ± 15.8, p = 0.003; HFMSE 49.6 ± 7.9 vs. 53.1 ± 7.7, p = 0.008; respectively) was achieved immediately after 4 loading doses of nusinersen and remained statistically significant onwards. Average improvements in HFMSE motor performance in SMA type 2 patients after four, five, and six doses of nusinersen were +6.0, +10.5, and +11.0 points, respectively. In SMA type 3 adult patients, no significant improvement in RHS motor performance or the 6-Minute Walk Test (MWT) was demonstrated. During the study period, 437 doses were administered without any new safety concerns appearing. (4) Conclusions: Our RWD findings indicate that nusinersen is an effective and safe treatment in a heterogeneous group of paediatric patients with all types of SMA; however, no significant benefit (but only RHS and 6MWT maintenance) was demonstrated in SMA type 3 patients who started nusinersen after >18 years of age.

Cost effectiveness of antihypertensive drugs and treatment guidelines.

PURPOSE: Arterial hypertension (AH) is associated with a high economic burden for the individual patient and for society in general. The study evaluates antihypertensives and their cost-effectiveness, comparing diuretics (D), beta-blockers (B), angiotensin converting enzyme inhibitors/angiotensin-II receptor blockers (A) and calcium channel blockers (C) with no intervention (NI). METHODS: The study included five health states in a Markov model. Cost values included average cost of the drugs used, treatment in hospital and treatment in general practice (collected from Croatian Health Insurance Fund). The study was conducted separately for 65-year old men and women, with an initial probability of cardiovascular death risk of 2% and heart failure risk of 1%. The results were presented in terms of increase in QALYs and associated financial savings or costs in euros (€). RESULTS: Results for men (compared with NI): treatment with D resulted in a QALY increase of 0.76 and €886 in savings, treatment with C in an increase of 0.74 QALYs and €767 in savings, treatment with A in an increase of 0.69 QALYs and €834 in savings, treatment with B resulted in an increase of 0.40 QALYs, but with an additional cost of €41. Results for women (compared with NI): treatment with D resulted in an increase of 0.93 QALYs and €987 in savings, treatment with C in an increase of 0.89 QALYs and savings of €855, treatment with A in an increase of 0.86 QALYs and savings of €991, treatment with B in an increase of 0.48 QALYs, but with an additional cost of €148. CONCLUSIONS: Treatment of AH with D, C and A is cost effective compared with the no-intervention scenario. Diuretics are the most cost-effective first-line treatment. The scenario with beta-blockers resulted in additional QALY when compared with no intervention, but also additional costs; therefore, based on our results, this therapy would not be recommended as first-line treatment.

Nonclinical data supporting orphan medicinal product designations in the area of rare infectious diseases.

This review provides an overview of nonclinical in vivo models that can be used to support orphan designation in selected rare infectious diseases in Europe, with the aim to inform and stimulate the planning of nonclinical development in this area of often neglected diseases.

Antihypertensive Drugs in Croatia: What Changes the Drug Usage Patterns?

PURPOSE: Possible factors that could influence changes in patterns of prescribing antihypertensives could be identified by monitoring national trends in hypertension treatment. The choice of pharmacologic treatment in people with hypertension has important therapeutic and financial implications, due to the fact that the financial costs associated with hypertension continue to increase. The aims of our study were to identify and analyze changes in the usage of antihypertensive drugs in Croatia from 2000 to 2016 and to identify the changes in prescribing patterns as well as mean prices per defined daily dose (DDD). METHODS: Data on consumption in Croatia were obtained from the International Medical Statistics database. According to the World Health Organization's Collaborating Center for Drugs Statistics Methodology, per-annum volumes of drugs are presented in DDD per 1000 population per day (DDD/1000), while data on financial expenditure are presented in euros. FINDINGS: The consumption of drugs for cardiovascular disease in Croatia during the period from 2000 to 2016 increased 150.81%, while financial expenditure in the same period increased 47.32%. The most frequently prescribed subgroup was agents acting on the renin-angiotensin system (RAS). Their share among antihypertensives increased from 39.13% (2000) to 53.39% (2016). The share of diuretics in the same period decreased from 20.16% in 2000 to 12.73% in 2016. IMPLICATIONS: The prescribing patterns of antihypertensive drugs in Croatia have changed, which could be a result of a combination of different factors, such as changes in laws, pharmaceutical marketing, and guidelines on hypertension therapy. The most prescribed subgroup in all of the investigated years was agents acting on the RAS, mainly because of the increased prescribing of combinations of RAS agents plus diuretics. The financial implications of legal changes and the introduction of new generic drugs led to decreased cost per DDD of antihypertensives during the investigated period, but the total expenditure on antihypertensives in Croatia increased due to increased consumption.

Is there a reason for concern or is it just hype? - A systematic literature review of the clinical consequences of switching from originator biologics to biosimilars.

INTRODUCTION: While prescribing biosimilars to patients naive to a biologic treatment is a well-accepted practice, switching clinically stable patients from an originator to a biosimilar is an issue for clinicians. Well-designed clinical trials and real-world data which study the consequences of switching from an originator biologic treatment to its biosimilar alternative are limited, especially for monoclonal antibodies. Areas covered: A systematic literature review was conducted on PubMed to identify evidence of the consequences of switching from original biologics to biosimilars. References of included papers were also scrutinized. After a title-, abstract- and full text screening, out of the 153 original hits and 77 additional ones from screening the references, 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) were included. Expert opinion: Preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access. Indeed, it is the opinion of the authors that the concern of switching to biosimilars is overhyped.

Decrease in Oxidative Stress Parameters after Post-Ischaemic Recombinant Human Erythropoietin Administration in the Hippocampus of Rats Exposed to Focal Cerebral Ischaemia.

Recombinant human erythropoietin (rhEpo) is a multi-functional drug with antioxidant potential. However, the underlying molecular mechanisms of its action are still unclear. The purpose of this study was to investigate the effects of rhEpo on the brain infarct volume as well as on the levels of the neuronal damage, oxidative stress parameters and active caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2) and haemeoxygenase-1 (HO-1) expressions in the hippocampi of rats exposed to the right middle cerebral artery occlusion (MCAO) for 1 hr. Ischaemic animals received either vehicle or rhEpo (5000 IU/kg, i.p.) immediately or 3 hr after the induction of ischaemia. Sham-operated, vehicle-treated animals served as the control group. Rats were killed 24 hr after the onset of the ischaemic or sham experimental procedure. MCAO caused ipsilateral brain infarction within the striatum and cortex. In the CA1 region of the hippocampi, we did not find significant neuronal loss, but a statistically significant rise in the active caspase-3 and Nrf2 protein expressions was registered. We detected also significant increases in the hippocampal levels of oxidative stress parameters (thiobarbituric acid-reactive substances, superoxide dismutase, glutathione peroxidase). Post-ischaemic administration of rhEpo significantly reduced the brain infarct volume, decreased levels of all tested oxidative stress parameters and increased the Nrf2 expression level. These findings suggest that decrease in oxidative stress parameters in the hippocampus could be an early indicator of post-ischaemic neuroprotective effect of rhEpo in rats exposed to focal cerebral ischaemia and that this effect could be attributable to additional post-ischaemic activation of Nrf2 endogenous antioxidant system.

Incremental cost-effectiveness pharmacoeconomic assessment of hepatitis C virus therapy: an approach for less wealthy members of the common market.

AIM: To develop a new method of health-economic analysis based on a marginal approach. METHODS: We tested the research hypothesis that a detailed comparative a priori incremental cost-effectiveness analysis provides the necessary input for budget impact analysis about the proper order of introduction of new therapies, and thus maximizes the cost-effectiveness bounded by the total budget constraint. For the analysis we chose a combination therapy for the treatment of hepatitis C virus (HCV) genotype 1 (GT1) infection, which was approved by the European Medicine Agency in 2015. We used the incremental cost-effective approach to assess the increase in the percentage of patients achieving sustained virological response (SVR) and the expenditure per additional SVR modulated by the new therapy's market entrance dynamics. Patient subpopulations were differentiated by their response to previous treatment, presence of cirrhosis, and HCV GT1 subtype. Final parameters were estimated by Monte Carlo simulations. RESULTS: The new combination therapy had high efficacy, shorter duration, and was better tolerated than alternative interventions. The research hypothesis was confirmed: gradual introduction of the new therapy on the market, based on a priori incremental cost-effectiveness analysis, would result in average increase in successfully treated patients by 20%-40%, while additional costs would approximately be between 8%-40%, ie, ?21000-52000 per additional patient achieving SVR. CONCLUSION: We showed the new combination therapy to be cost-effective for certain patient subpopulations, especially for experienced cirrhotic HCV GT1 patients. Results of the analysis are in agreement with the latest recommendations for HCV patients' treatment in Croatia. This economic evaluation could serve as a starting point for negotiations between pharmaceutical industry and insurance companies.

Benefits of investment into modern medicines in Central-Eastern European countries.

Transferability of current evidence and expressing value of innovative pharmaceuticals according to health system objectives Due to the scarcity of healthcare resources, decision-makers often expect monetary benefits--including cost savings or productivity gain--from innovative medicines. Manufacturers try to fulfill this expectation by expressing the benefits of innovative technologies in monetary units citing approaches from the scientific literature. Unfortunately, currently available evidence has limited relevance and transferability in Central-Eastern European (CEE) countries. This study aims to summarize how innovative pharmaceuticals in CEE countries may contribute to WHO-defined health system objectives, including health gain, equity in health, financial protection, responsiveness, equity in finance and financial sustainability. References in this study are also mainly based on international examples; therefore, additional policy research from CEE countries is necessary to validate assumptions. If CEE politicians can rely on credible arguments based on local research evidence, they may improve long-term strategies and policy decisions related to healthcare innovation.

Drug usage by outpatients in Croatia during an 8-year period: Influence of changes in pricing policy.

OBJECTIVE: The aim of our study was to investigate the changes in drug usage and financial expenditure according to legal changes in Croatia during the period 2001 - 2008, especially considering pricing policy. MATERIALS: The data on outpatient drug usage during the studied period was obtained from the Croatian National Health Insurance (CNHI). CNHI maintains a database on drugs prescribed by primary health care physicians and dispensed by pharmacies. METHODS: The data was calculated and presented in defined daily doses (DDD) per inhabitant per year for antibiotics and in DDD/1,000 inhabitants/day for other drugs. The data is also presented in Euro/DDD and the financial expenditures are presented in Euros. RESULT: During the investigated period drug usage increased 81.33%, while financial expenditure increased 77.23%. While total DDD/1,000 increased ~ 10% every year, financial expenditure increased 10 - 20% annually until 2006, but since then there have been no significant changes. CONCLUSION: Pricing policy changes could influence drug financial expenditure considerably in the short-term, but it is also important to apply a combination of measures for drug expenditure control. Numerous interventions from authorities from different countries all over the world, prove that there is still no so called "gold standard" which could restrain growing usage and expenditure of drugs. Clinical pharmacologists and clinical pharmacists should be included in these processes.

Temporal and regional changes of superoxide dismutase and glutathione peroxidase activities in rats exposed to focal cerebral ischemia.

Reactive oxygen species are important cause of tissue injury during cerebral ischemia and reperfusion (I/R). Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) are intracellular enzymes responsible for endogenous antioxidant defense of tissues affected by I/R. The aim of this study was to examine temporal and regional changes of SOD and GSH-Px activities in animals exposed to transient focal cerebral ischemia. Male Wistar Hannover rats were subjected to the right middle cerebral artery occlusion for 2 h. The animals were sacrificed immediately, 0·5, 1, 2, 3, 6, 24, 48, 72 or 168 h after ischemic procedure. SOD and GSH-Px activities were determined spectrophotometrically in the hippocampus and parietal cortex, both unilaterally and contralaterally to the occlusion. Sham-operated animals were used as the control group. Our results indicated that transient focal cerebral ischemia causes significant changes in SOD activities in the hippocampus and parietal cortex such as in GSH-Px activities in the parietal cortex, unilaterally and contralaterally to the lesion in rats during different reperfusion periods. Statistically significant activation of GSH-Px was registered neither in the right nor in the left hippocampus of ischemic animals.

Dilemma of antiepileptic drugs withdrawal in symptomatic epilepsy.

A successful treatment of epilepsy depends on numerous factors such as etiology, genetics and environmental impact. An exact diagnosis, treatment and an adequate selection of antiepileptic drugs (AED) are important from the very beginning. The patient with symptomatic epilepsy caused by the brain tumor (low-grade astrocytoma in the left parietal lobe, surgically removed 17 years after the first manifestation of illness) is presented in this study. He has been seizure free for 6 years. The represented case study deals with the risk-benefit analysis of the discontinuation of the prescribed antiepileptic treatment that has lasted for 23 years.

Medical and bioethical issues in a pregnant woman with epilepsy: case report.

A case report of a minor, pregnant girl with epilepsy caused by a brain tumour is presented. There are several aspects which make the presented case complex from medical, but also from the bioethical point of view. The decision about keeping the pregnancy or not is the most important bioethical dilemma for the patient and family. A detailed medical multidisciplinary approach and later balanced explanation of the medical situation to the patient are of extreme value for helping the patient's decision. It is also important to enhance the activities in pregnancy counselling for a woman with epilepsy which will result in a planned pregnancy as a prerequisite for a positive pregnancy outcome.

Centralized national ethical review of clinical trials in Croatia.

AIM: To present the Croatian system of ethical review of clinical trials and assessment outcomes of the applications reviewed by the Croatian Central Ethics Committee. METHODS: Clinical trial applications reviewed by the Croatian Central Ethics Committee, which has the legal mandate to review clinical trials of medicinal products and medical devices, were retrospectively analyzed from May 2004 to the end of 2008 according to the number, research area, and type of opinion issued. Applications from 2008 were analyzed separately according to the study phase, participants (adult trials vs pediatric trials), and sponsor (commercial trials vs academic trials). Data were analyzed by descriptive statistics. RESULTS: Since its establishment in 2004, the Croatian Central Ethics Committee has reviewed 407 trials. The greatest number of clinical trials was in the field of oncology (n = 69), mental and behavioral disorders (n = 52), and endocrine, nutritional, and metabolic diseases (n = 50). In the initial assessment of clinical trials, 60% applications received a conditionally positive opinion. In 28% of applications, the opinion had to be postponed because additional documentation or explanations were required. In 2008, the Croatian Central Ethics Committee reviewed 99 trials, most of which were phase III trials (n = 57). Five clinical trials included pediatric population and 3 were academic clinical trials. CONCLUSION: The model of centralized clinical trial review seems to be appropriate for the current number of clinical trials conducted in Croatia. The efficient and standardized review process of clinical trials by the Central Ethics Committee may positively affect the increasing number of clinical trials conducted in Croatia. Future development includes the transparency of the clinical trials through a publically available database and establishing the basis for conducting academic clinical trials.

The effects of problem-based learning integration in a course on rational drug use: a comparative study between two Croatian medical schools.

PURPOSE: Young doctors write prescriptions regularly from their first day of practice. We investigated final-semester students' perceptions of their training in relation to prescribing in two Croatian medical schools with different clinical pharmacology (CPT) teaching styles (Zagreb: problem-based and Rijeka: lecture-based course). METHODS: A total of 315 students (220 in Zagreb, 95 in Rijeka) underwent a 4-week-long course in CPT in the academic year 2006/2007. We compared the impact of different educational methods on student performance using an MCQ assessment. After the training, students completed a paper questionnaire on prescribing skills and knowledge of pharmacotherapy. RESULTS: Students in Rijeka were significantly more satisfied with their traditional lecture-based course. Only 56% of Zagreb students and 54% of students from Rijeka felt confident about their prescription-writing skills. Only 8% of Zagreb and none of Rijeka students had written more than six prescriptions during their entire medical curriculum. There was no difference in the participants' levels of factual knowledge of rational pharmacotherapy. CONCLUSION: The style of learning about medicines did not affect students' factual knowledge. Only half of the student cohort felt confident about their ability to prescribe medicines, and few had practiced this skill during their medical training.