Challenges for Economic Evaluations of Advanced Therapy Medicinal Products: A Systematic Review.

OBJECTIVES: Advanced therapy medicinal products (ATMPs) are drugs for human use for the treatment of chronic, degenerative, or life-threatening diseases that are based on genes, tissues, or cells. This article aimed to identify and critically review published economic analyses of ATMPs. METHODS: A systematic review of economic analyses of ATMPs was undertaken. Study characteristics, design, sources of data, resources and unit costs, modeling and extrapolation methods, study results, and sensitivity analyses were assessed. RESULTS: A total of 46 economic analyses of ATMP (from 45 articles) were included; 4 were cell therapy medicinal products, 33 gene therapy medicinal products, and 9 tissue-engineered products. 30 therapies had commercial marketing approval; 39 studies were cost-utility analysis, 5 were cost-effectiveness analysis, and 2 were cost only studies. Four studies predicted that the ATMP offered a step change in the management of the condition and 10 studies estimated that the ATMP would offer a lower mean cost. CONCLUSIONS: Comparison with historical controls, pooling of data, and use of techniques such as mixture cure fraction models should be used cautiously. Sensitivity analyses should be used across a plausible range of prices. Clinical studies need to be designed to align with health technology assessment requirements, including generic quality of life, and payers should aim for clarity of criteria. Regulators and national payers should aim for compatibility of registers to allow interchange of data. Given the increasing reliance on industry-funded economic analyses, careful critical review is recommended.

Barriers for the evaluation of advanced therapy medicines and their translation to clinical practice: Umbrella review.

Advanced therapy medicinal products (ATMPs) are a fast-growing field of medicine with wide potential application. Nevertheless, so far, only 19 have obtained European Union (EU) marketing authorisation and only 13 of these have translated successfully into clinical practice. This study conducts an umbrella review to identify the main barriers for the evaluation of ATMPs and their translation into clinical practice across the development lifecycle. 71 systematic reviews were included, of which 50 dealt primarily with effectiveness and safety, 13 with translation from pre-clinical to human subjects. Others dealt with economic issues and translation from health technology assessment to market access. The literature highlights the importance of synergistic research groups or networks that collaborate across the in-vitro science, preclinical and clinical investigation phases, and the role of private investor capital and public-private collaborations. Most ATMPs reviewed seem to have a favourable safety profile although considerable uncertainties remain. Randomised controlled trials are not always feasible in these patient groups. Greater sharing of data is recommended, both at preclinical and post-marketing real world evidence. There are considerable variations between EU countries in how they regulate hospital exemption for ATMPs, and this can lead to inequitable access for patients.

Decline of Admission for Acute Coronary Syndromes and Acute Cardiovascular Conditions during COVID-19 Pandemic in Veneto Region.

Background: The present study aimed to examine longitudinal trends in hospitalizations for acute coronary syndrome (ACS) before and during the COVID-19 pandemic, by reviewing the data from 13 hospitals of the Veneto Region, in the north-east of Italy. Methods: We performed a multicenter, retrospective analysis including all the consecutive patients presenting with ACS and other acute cardiovascular (CV) conditions (defined as heart failure, arrhythmias, cardiac arrest and venous thromboembolism) hospitalized in 13 different hospitals of the Veneto Region covering a population of 2,554,818 inhabitants, during the first (between 15 March 2020 and 30 April 2020) and second (between 15 November 2020 and 30 December 2020) COVID-19 pandemic waves (the 2020 cohort). Data were compared with those obtained at the same time-windows of years 2018 and 2019 (the historical cohorts). Results: Compared to the historical cohorts, a significant decrease in the number of ACS cases was observed in 2020 (−27.3%, p = 0.01 and −32%, p < 0.001, comparing 2018 versus 2020 and 2019 and 2020, respectively). The proportion of patients hospitalized for acute CV conditions decreased during the first and second wave COVID-19 pandemic when compared to the historical cohorts (−36.5%, p < 0.001 and −40.6%, p < 0.001, comparing 2018 versus 2020 and 2019 and 2020, respectively). Pearson's correlation evidenced a significant inverse relationship between the number of COVID-19 cases and both ACS hospital admissions (r = −0.881, p = 0.005) and hospitalizations for acute CV conditions (r = −0.738, p = 0.01), respectively. Conclusions: The decrease in hospitalizations for ACS and other acute CV conditions will strongly affect future patients' management since undiagnosed nonfatal CV events represent a source of increased (and unknown) CV morbidity and mortality.

Takotsubo Syndrome during COVID-19 Pandemic in the Veneto Region, Italy.

Background: During the COVID-19 pandemic, the risk of SARS-CoV-2 infection, the public health measures of social distancing, the freedom limitations, quarantine, and the enforced homeworking under the lockdown period, as well as medical causes including COVID-19 infection per se, may have caused major emotional distress, especially in the most vulnerable patients. We aimed to evaluate the variations in the number of admissions due to Takotsubo syndrome (TTS) during the COVID-19 pandemic in the Veneto region. Methods: We retrospectively reviewed and analyzed the number of admissions because of TTS in 13 Divisions of Cardiology located in the Veneto region, the northeastern area of Italy, covering a population of more than 2.5 million inhabitants, during the two major pandemic waves of COVID-19 (the first between 15 March and 30 April 2020 and the second between 15 November and 30 December 2020) that occurred in 2020. Results: In total, 807 acute coronary syndromes were admitted in the 13 enrolling hospitals. Among these, 3.9% had TTS. Compared to the corresponding 2018 and 2019 time periods, we observed a significant increase in the number of TTS cases (+15.6%, p = 0.03 and +12.5%, p = 0.04, comparing 2018 to 2020 and 2019 to 2020, respectively). Geographical distribution of the TTS cases reflected the broad spread of the SARS-CoV-2 infection with a significant direct relationship between TTS incidence and the number of COVID-19 infections according to Pearson's correlation (r = 0.798, p < 0.001). Conclusions: The higher incidence of TTS during the 2020 COVID-19 pandemic waves, especially in the areas that were hit hardest in terms of morbidity and mortality by the SARS-CoV-2 infection, suggest a strong direct and/or indirect role of COVID-19 in the pathogenesis of TTS.

Use of Patent Information to Characterize Trends in the Therapeutic Applications of Extracellular Vesicles Derived from Mesenchymal Stem Cells (MSC-EVs).

Extracellular vesicles derived from mesenchymal stromal cells (MSC-EVs) are gaining interest for medical purposes. The promising therapeutic effects exhibited in both preclinical and clinical studies have suggested that they may become an alternative for certain applications to cell-based therapies, which are subjected to stricter regulations. The commercial exploitation of these candidates requires a proper patent strategy from both the industry and public research organizations. Here, we performed a global patent literature analysis to identify key players and therapeutic applications in the field. Our results showed an increasing rate of patent publications since 2009, with Asia (specifically China) leading the patenting activity. The therapeutic use of MSC-EVs within patent literature covers a wide range of diseases, in which "Dermal and Wounds," "Neurology" and "Cardiovascular" are the main therapeutic areas. Moreover, most of these patents include "productby- process" claims, since the therapeutic effects of MSC-EVs could be influenced by their manufacturing process. Our results followed scientific and clinical literature trends.

Challenges in the diagnosis of peripartum cardiomyopathy: a case series.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is usually characterized by overt heart failure, but other clinical scenarios are possible, sometimes making the diagnosis challenging. CASE SUMMARY: We report a case series of four patients with PPCM. The first patient presented with acute heart failure due to left ventricular (LV) systolic dysfunction. Following medical treatment, LV function recovered completely at 1 month. The second patient had systemic and pulmonary thromboembolism, secondary to severe biventricular dysfunction with biventricular thrombi. The third patient presented with myocardial infarction with non-obstructed coronary arteries and evidence of an aneurysm of the mid-anterolateral LV wall. The fourth patient, diagnosed with PPCM 11 years earlier, presented with sustained ventricular tachycardia. A repeat cardiac magnetic resonance, compared to the previous one performed 11 years earlier, showed an enlarged LV aneurysm in the mid-LV anterolateral wall with worsened global LV function. DISCUSSION: Peripartum cardiomyopathy may have different clinical presentations. Attentive clinical evaluation and multimodality imaging can provide precise diagnostic and prognostic information.

Generation of a novel human dermal substitute functionalized with antibiotic-loaded nanostructured lipid carriers (NLCs) with antimicrobial properties for tissue engineering.

BACKGROUND: Treatment of patients affected by severe burns is challenging, especially due to the high risk of Pseudomonas infection. In the present work, we have generated a novel model of bioartificial human dermis substitute by tissue engineering to treat infected wounds using fibrin-agarose biomaterials functionalized with nanostructured lipid carriers (NLCs) loaded with two anti-Pseudomonas antibiotics: sodium colistimethate (SCM) and amikacin (AMK). RESULTS: Results show that the novel tissue-like substitutes have strong antibacterial effect on Pseudomonas cultures, directly proportional to the NLC concentration. Free DNA quantification, WST-1 and Caspase 7 immunohistochemical assays in the functionalized dermis substitute demonstrated that neither cell viability nor cell proliferation were affected by functionalization in most study groups. Furthermore, immunohistochemistry for PCNA and KI67 and histochemistry for collagen and proteoglycans revealed that cells proliferated and were metabolically active in the functionalized tissue with no differences with controls. When functionalized tissues were biomechanically characterized, we found that NLCs were able to improve some of the major biomechanical properties of these artificial tissues, although this strongly depended on the type and concentration of NLCs. CONCLUSIONS: These results suggest that functionalization of fibrin-agarose human dermal substitutes with antibiotic-loaded NLCs is able to improve the antibacterial and biomechanical properties of these substitutes with no detectable side effects. This opens the door to future clinical use of functionalized tissues.

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. RESULTS: Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). CONCLUSIONS: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.