Publications by authors named "Giuseppe Traversa"

49 Publications

Impact of Prior Antibiotic Use in Primary Care on Resistance to Third Generation Cephalosporins: A Case-Control Study.

Antibiotics (Basel) 2021 Apr 16;10(4). Epub 2021 Apr 16.

Department of Medical Sciences and Public Health, Faculty of Medicine and Surgery, University of Cagliari, 09124 Cagliari, Italy.

Research is lacking on the reversibility of antimicrobial resistance (AMR). Thus, we aimed to determine the influence of previous antibiotic use on the development and decay over time of third generation cephalosporin (3GC)-resistance of . Using the database of hospital laboratories of the Autonomous Province of Bolzano/Bozen (Italy), anonymously linked to the database of outpatient pharmaceutical prescriptions and the hospital discharge record database, this matched case-control study was conducted including as cases all those who have had a positive culture from any site for 3GC resistant (3GCREC) during a 2016 hospital stay. Data were analyzed by conditional logistic regression. 244 cases were matched to 1553 controls by the date of the first isolate. Male sex (OR 1.49, 95% CI 1.10-2.01), older age (OR 1.11, 95% CI 1.02-1.21), the number of different antibiotics taken in the previous five years (OR 1.20, 95% CI 1.08-1.33), at least one antibiotic prescription in the previous year (OR 1.92, 95% CI 1.36-2.71), and the diagnosis of diabetes (OR 1.57, 95% CI 1.08-2.30) were independent risk factors for 3GCREC colonization/infection. Patients who last received an antibiotic prescription two years or three to five years before hospitalization showed non-significant differences with controls (OR 0.97, 95% CI 0.68-1.38 and OR 0.85, 95% CI 0.59-1.24), compared to an OR of 1.92 (95% CI 1.36-2.71) in those receiving antibiotics in the year preceding hospitalization. The effect of previous antibiotic use on 3GC-resistance of is highest after greater cumulative exposure to any antibiotic as well as to 3GCs and in the first 12 months after antibiotics are taken and then decreases progressively.
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http://dx.doi.org/10.3390/antibiotics10040451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073604PMC
April 2021

Safety of switching between rituximab biosimilars in onco-hematology.

Sci Rep 2021 Mar 16;11(1):5956. Epub 2021 Mar 16.

Hospital Pharmacy Unit, Trento General Hospital, Autonomous Province of Trento, Trento, Italy.

Comparable clinical efficacy and safety of the reference rituximab (MABTHERA) and its biosimilars has been established in randomized trials. However, safety concerns are often raised when switching from reference to biosimilar products and between different biosimilars. In this prospective observational study we aimed at evaluating the safety of switching between reference and biosimilar rituximab (TRUXIMA and RIXATHON) at Trento General Hospital (Italy). All patients (n = 83) with Non Hodgkin's Lymphoma (NHL, n = 72) and Chronic Lymphocytic Leukemia (CLL, n = 11) who received rituximab between March 2018 and March 2019 were asked to take part in the study. In 2017 and 2018 two tenders were carried out and two different biosimilars became available in the hospital, these were used sequentially. Thus, patients with or without previous treatments with the originator rituximab either received a biosimilar or were switched between different biosimilars. The incidence of adverse events in these groups of patients is described. The study population received 465 rituximab infusions and all received biosimilars. Fifty patients (60%) experienced at least one switch between different biosimilars or between rituximab originator and biosimilar, whereas 33 (40%) received one of the two biosimilars and one patient received reference rituximab. Adverse events (n = 146) were reported in 71 patients (84.5%). Treatment-related grade 3-4 events were reported in 5 patients (5.9%), whereas grade 1 rituximab related infusion events were observed in 6 patients (7.1%). No safety signal emerged in association with the use of a specific biosimilar nor with the practice of switching. Adverse events were similar, in terms of seriousness and frequency, to those described in the literature, providing further support to the clinical safety of rituximab biosimilars.
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http://dx.doi.org/10.1038/s41598-021-85563-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966361PMC
March 2021

Turmeric (Curcuma longa L.) food supplements and hepatotoxicity: an integrated evaluation approach.

Ann Ist Super Sanita 2020 Oct-Dec;56(4):462-469

Dipartimento Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, Rome, Italy.

Introduction: Turmeric is the common name for the rhizome of Curcuma longa L. In the recent years, food supplements containing turmeric have been marketed and widely used by an increasing number of consumers. Spontaneous reports of suspected adverse reactions to food supplements are collected within the Phytovigilance system.

Methods: An ad hoc multidisciplinary group investigated the suspected cases of hepatotoxicity reported to the Italian Phytovigilance system associated with the assumption of turmeric food supplements with the methodology specific to pharmacovigilance as well as for the evaluation of the quality and safety of food supplements.

Results: A cluster of 28 spontaneous reports of acute hepatitis, mostly with cholestasis, associated with turmeric products were sent to the Italian Phytovigilance system in the first six months of 2019. In all cases, except one, the causality assessment was at least possible. The suspected products were collected and analysed for the presence of drugs, heavy metals, aflatoxins, pesticides, synthetic dyes and pyrrolizidine alkaloids.

Conclusion: On the basis of the results of all the activities performed by multidisciplinary group, regulatory intervention was taken. This study highlights the importance of developing an integrated evaluation approach for the evaluation of the adverse effects associated with the use of food supplements.
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http://dx.doi.org/10.4415/ANN_20_04_08DOI Listing
December 2020

Direct healthcare costs of chronic kidney disease management in Italy: What cost-savings can be achieved with higher biosimilar uptake and more appropriate use of erythropoiesis-stimulating agents?

Pharmacoepidemiol Drug Saf 2021 01 16;30(1):65-77. Epub 2020 Nov 16.

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.

Purpose: Erythropoiesis-stimulating agents (ESAs), are used for treating chronic kidney disease (CKD)-related anemia, contributing to CKD costs. The study was aimed at investigating direct healthcare costs of CKD patients treated with ESAs and the potential savings achievable by increasing the use of biosimilars and preventing inappropriate ESA use.

Methods: A multi-center, cohort study was conducted using claims databases of five large Italian geographic areas. Yearly mean direct healthcare costs per patient were estimated, stratifying by CKD stage. The total yearly cost and potential savings related to ESA use were estimated: (a) considering 25/50/75% of originator ESA substitution with biosimilars; (b) eliminating inappropriate ESA dispensing.

Results: During the study period, the ESA-related yearly mean cost represented 17% of total yearly costs in stage I-III, decreasing to 13% in stage IV-V and 6% in dialysis. Among originator users, assuming a 25% of biosimilar uptake, the annual cost-savings of ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialysis. Among incident ESA users for which hemoglobin levels were available, 9% started inappropriately ESA treatment, increasing to 62.0% during the first year of maintenance therapy. Hypothesizing prevention of the first inappropriate ESA dispensing, the total yearly cost-savings would amount to €35 772, increasing to €167 641 eliminating the inappropriate dispensing during maintenance therapy.

Conclusions: Higher use of lowest cost ESA, prevention of inappropriate ESA use as well as other strategies aimed at slowing down the progressive renal impairment are essential for minimizing clinical and economic burden of CKD.
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http://dx.doi.org/10.1002/pds.5152DOI Listing
January 2021

Anticancer drug prices and clinical outcomes: a cross-sectional study in Italy.

BMJ Open 2019 12 10;9(12):e033728. Epub 2019 Dec 10.

Department of Epidemiology of the Regional Health Service Lazio, Rome, Italy

Objective: To investigate whether the prices of new anticancer drugs correlated with their relative benefit despite negotiation.

Design: Retrospective cross-sectional study correlating new anticancer drugs prices with clinical outcomes.

Setting: We did a retrospective cross-sectional study including all new anticancer drugs approved by the European Medicines Agency (EMA) (2010-2016) and reimbursed in Italy.

Main Outcomes And Measures: Information on clinical outcomes-in terms of median overall survival (OS), median progression-free survival (PFS) and objective response rate (ORR)-was extracted from pivotal trials as reported in the European Public Assessment Reports available on the EMA website. Cost of a full course treatment was estimated on negotiated official and discounted prices. Regression coefficients β, their levels of significance p and the coefficients of determination R were estimated adjusting by tumour type.

Results: Overall, 30 new anticancer drugs (with 35 indications) were available for analysis. Where data on OS were available, we observed no correlation between the improvement in median OS (in weeks) and negotiated price (R=0.067, n=16 drugs for 17 indications). When the clinical outcomes were expressed as improvements in the median PFS or ORR, 25 drugs (29 indications) were available for the analysis, and again, there was no correlation with prices (R=0.004 and 0.006, respectively).

Conclusions And Relevance: Our results suggest that the prices of anticancer drugs in Italy do not reflect their therapeutic benefit. Drug price negotiations, which is mandatory by law in Italy, do not seem to ensure that prices correlate with clinical benefits provided by the cancer drugs. These results call for further efforts to establish the standard determinants of drug prices available at the time of negotiation. These findings need to be confirmed in other countries where price negotiations are in place. Moreover, further investigations may verify whether outcome data obtained after drug marketing would improve the correlation between prices and therapeutic benefit.
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http://dx.doi.org/10.1136/bmjopen-2019-033728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924817PMC
December 2019

In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study.

BioDrugs 2020 Feb;34(1):55-64

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.

Background And Objectives: Switching between different erythropoiesis-stimulating agents (ESAs) during the first year of therapy is frequent (15-20%), much more so toward reference products than biosimilars. The objectives of this study were to investigate the frequency and identify the potential predictors of switching between biosimilar and originator ESAs during the first year of treatment in patients with chronic kidney disease (CKD), or chemotherapy-related anemia from six large Italian geographic areas in the years 2009-2015.

Methods: A retrospective cohort study was conducted using six Italian regional claims databases (≥ 13 million inhabitants) during 2009-2015. Among incident epoetin users, the frequency of single, multiple, and backward switch during the first year of treatment was evaluated. Using frailty Cox models, potential predictors of first switch were identified. All analyses were stratified by the main indications for use.

Results: Among 102,240 incident epoetin users, 15,853 (15.5%) switched to another epoetin during the first year of therapy; only 18% of these switched to biosimilars. Single switch was more common (62.2% of the switchers) than multiple (23.5%) or backward switch (14.3%). In cancer, the cumulative number of transfusions and iron preparations dispensed, as well as hyperparathyroidism, were predictors of switching. In CKD, the cumulative number of transfusions, number of vitamin A/D preparations dispensed, and CKD severity increased the probability of switching.

Conclusions: Switching between ESAs was frequent in both CKD and cancer patients. The number of cumulative transfusions and severity of disease seemed to affect the switch.
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http://dx.doi.org/10.1007/s40259-019-00385-yDOI Listing
February 2020

Effectiveness and Safety of Switching Originator and Biosimilar Epoetins in Patients with Chronic Kidney Disease in a Large-Scale Italian Cohort Study.

Drug Saf 2019 12;42(12):1437-1447

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.

Introduction: Real-world data on the comparative effectiveness and safety of switching among different epoetins (including originators and biosimilars) are limited. In light of current debate about interchangeability, prescribers, some patient groups and decision makers are calling for additional post-marketing evidence on the clinical effects of switching between originator and biosimilar epoetins in chronic kidney disease (CKD) patients.

Objective: The objective of this study was to evaluate the effectiveness and safety of switching versus non-switching and of switching from originator/biosimilar epoetin alpha (ESA α) to any other epoetin in CKD patients.

Methods: An observational, record-linkage, multi-database, retrospective cohort study was carried out in four Italian geographical areas. All subjects with at least one ESA α dispensing between 1 January 2009 and 31 December 2015 were retrieved. Switching was defined as any transition between originator/biosimilar ESA α to any other epoetin in a series of two consecutive prescriptions up to 2 years. Switchers were matched 1:1 with non-switchers by baseline propensity score and by duration of ESA α treatment. Switchers and non-switchers were followed up from switching date to a maximum of 1 year. Lack of effectiveness and safety of switching versus non-switching were evaluated through Cox regression models (hazard ratio [HR], 95% confidence interval [CI]). A direct comparison between the two switcher categories (switchers from originator/biosimilar ESA α to any other epoetin) was also performed.

Results: Overall, 14,400 incident users of ESA α for anaemia due to CKD (61.4% originator, 38.6% biosimilar) were available for analysis. During the follow-up, we found no differences on effectiveness (HR 1.02, 95% CI 0.79-1.31 originators; HR 1.16, 95% CI 0.75-1.79 biosimilars) and safety outcomes (HR 1.08, 95% CI 0.77-1.50 originators; HR 1.20, 95% CI 0.66-2.21 biosimilars) between switchers and non-switchers of ESA α. Cumulative probabilities of recording an adverse event, either in terms of lack of effectiveness or safety issue, were the same for two switching categories CONCLUSIONS: In this large-scale Italian observational multi-database study, switching versus non-switching as well as switching from biosimilar/originator ESA α to any other epoetin in CKD patients is not associated with any effectiveness and safety outcomes.
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http://dx.doi.org/10.1007/s40264-019-00845-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858470PMC
December 2019

Comparative Effectiveness of Two Tiotropium Formulations: A Retrospective Cohort Study.

COPD 2018 10;15(5):418-423

a Pharmacoepidemiology Unit, National Center for Drug Research and Evaluation , National Institute of Health (ISS) , Rome , Italy.

The effectiveness of the tiotropium Respimat formulation in routine clinical practice is still an open issue due to concern about the generalizability of the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial findings. Our aim was to compare the incidence of acute respiratory events between new users of tiotropium Respimat and HandiHaler. The study population comprised patients aged ≥45 years resident in two Italian regions who received a first tiotropium prescription (HandiHaler or Respimat) between 1 July 2011 and 30 November 2013. The cohort was identified within the database of drug prescriptions reimbursed by the Italian National Health Service. Clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for respiratory events, including chronic obstructive pulmonary disease (COPD) exacerbation, respiratory failure, hypoxemia/hyperventilation and pneumonia, during the exposure period. The hazard ratios were estimated for the propensity score matched groups with Cox regression. After matching, 31,334 patients with incident tiotropium prescriptions were included. Similar incidence rates of the primary outcome between the Respimat and HandiHaler users were identified (adjusted hazard ratio 0.95, 95% CI 0.84-1.07). No differences emerged in the subgroup analyses conducted according to the baseline characteristics of the tiotropium users. This study confirms the findings observed in the TIOSPIR trial in a more heterogeneous population that included patient subgroups with severe respiratory disease and unstable COPD.
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http://dx.doi.org/10.1080/15412555.2018.1554032DOI Listing
October 2018

The Role of European Healthcare Databases for Post-Marketing Drug Effectiveness, Safety and Value Evaluation: Where Does Italy Stand?

Drug Saf 2019 03;42(3):347-363

Laboratory of Pharmacoepidemiology and Healthcare Research, Unit of Biostatistics Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.

Enormous progress has been made globally in the use of evidence derived from patients' clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.
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http://dx.doi.org/10.1007/s40264-018-0732-5DOI Listing
March 2019

[Adaptive studies to assess drug effectiveness].

Epidemiol Prev 2018 May-Aug;42(3-4):251-253

Istituto superiore di sanità, Roma.

The clinical development of drugs is based on a consolidated model that adopts, as a reference, the conduct of consecutive dose-finding and activity studies (the phases), up to the classical randomized controlled trials (RCTs), which are strictly regulated by a study protocol. This model is likely to be too rigid, since it cannot incorporate the information that gradually becomes available. To overcome, at least partly, this limited flexibility, so-called adaptive designs have been proposed: in these designs, it is possible to introduce changes and also to modify relevant aspects of a single design on the basis of results/information obtained in the study itself. This article presents the main characteristics of these designs and discusses the precautions to be taken into account in the application in clinical studies.
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http://dx.doi.org/10.19191/EP18.3-4.P251.073DOI Listing
February 2019

Comparative Safety of Originator and Biosimilar Epoetin Alfa Drugs: An Observational Prospective Multicenter Study.

BioDrugs 2018 Aug;32(4):367-375

Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.

Background: Erythropoiesis-stimulating agents (ESAs) are biological molecules approved for the treatment of anemia associated with chronic renal failure. Biosimilars were licensed for use in Europe in 2007.

Aim: This study aimed to compare the safety profile of biosimilars with respect to the reference product in a nephrology setting.

Methods: A prospective study was conducted in four Italian regions between 1 October 2013 and 30 June 2015. The study population included patients aged ≥ 18 years undergoing hemodialysis and treated with epoetins as per the clinical practice of the participating centers. The two comparison cohorts included patients treated with either an originator or a biosimilar epoetin alfa. Each patient was followed up until occurrence of any safety outcome of interest (grouped into three major categories), switch to a different ESA product, transplant or peritoneal dialysis, death, or end of the study period, whichever came first.

Results: Overall, 867 subjects were included in the study (originator: N = 423; biosimilar: N = 444). Biosimilar users were older than originator users (median age of 76 vs 64 years, respectively), more frequently affected by arrhythmia (29.3 vs 22.5%), and less frequently candidates for transplantation (3.8 vs 18.2%). Cox-regression analysis showed no increase in risk of safety outcomes in biosimilar users, even after adjusting for confounding factors: 1.0 (95% confidence interval [CI] 0.7-1.3) for any outcomes; 1.1 (95% CI 0.7-1.8) for problems related to dialysis device; 0.9 (95% CI 0.6-1.5) for cardio- and cerebro-vascular conditions; 0.9 (95% CI 0.6-1.5) for infections.

Conclusion: This study confirms the comparable safety profiles of originator and biosimilar epoetin alfa drugs when used in patients receiving dialysis.
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http://dx.doi.org/10.1007/s40259-018-0293-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061296PMC
August 2018

Cardiovascular diseases monitoring: lessons from population-based registries to address future opportunities and challenges in Europe.

Arch Public Health 2018 28;76:31. Epub 2018 Jun 28.

1Department of Cardiovascular, Dysmetabolic and Aging-associated Diseases, Istituto Superiore di Sanità (ISS), Via Giano della Bella, 34 00162 Rome, Italy.

Background: Population-based registries implement the comprehensive collection of all disease events that occur in a well-characterized population within a certain time period and represent the preferred tools for disease monitoring at a population level. Main characteristics of a Population-based registry are to provide answers to defined research questions, also related to clinical and health policy purposes, assuring completeness of event identification, and implementing a process of case adjudication (validation) according to standardised diagnostic criteria.

Methods: The application of a standard methodology results in the availability of reliable and comparable data and facilitates the transferability of health information for research and evidence-based health policies. Although registries are extremely useful, they require considerable resources to be implemented and maintained, high cost and efforts, to produce stable and reliable indicators.

Results: Thanks to available health information and information technology, current administrative databases on hospital admissions and discharges, medication use, in-patient care utilization, surgical operations, drug dispensations, ticket exemption and invasive procedures are increasingly available. They represent basic sources of information for implementing Population-based registries.Main strengths and limitations of Population-based registries are described taking into consideration the example of cardiovascular diseases, as well as future challenges and opportunities for implementing Population-based registries at European level.

Conclusions: The integration of population-based registries and current administrative health databases may help to complete the picture of the disease rebuilding the evolution of the disease as a continuum from the onset to the possible consequent complications.
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http://dx.doi.org/10.1186/s13690-018-0283-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022302PMC
June 2018

[Conflict of interest and public health body: the bias and the rule].

Epidemiol Prev 2018 Mar-Apr;42(2):105

Dipartimento di diagnostica e sanità pubblica, Università di Verona.

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http://dx.doi.org/10.19191/EP18.2.P105.032DOI Listing
February 2020

Pattern of Use of Biosimilar and Originator Somatropin in Italy: A Population-Based Multiple Databases Study During the Years 2009-2014.

Front Endocrinol (Lausanne) 2018 13;9:95. Epub 2018 Mar 13.

Unit of Clinical Pharmacology, A.O.U. Policlinico "G. Martino", Messina, Italy.

Purpose: Somatropin [recombinant growth hormone (rGH)] is approved in children and adults for several conditions involving growth disturbances and the corresponding biosimilar is available in Italy since 2006. No population-based data are available on the pattern of rGH use in Italian clinical practice. This study aimed at exploring the pattern of biosimilar and originator rGH use in six Italian centers, where different policy interventions promoted biosimilar use.

Methods: This population-based, drug-utilization study was conducted in the years 2009-2014, using administrative databases of Umbria, Tuscany, and Lazio Regions and Local Health Units of Caserta, Treviso, and Palermo. Naïve rGH users were characterized, and prevalence of use and discontinuation were assessed over time.

Results: Among 6,785 patients treated with rGH during the study years, 4,493 (66.2%) were naïve users (males/females = 1.3), mostly affected by GH deficiency. The prevalence of rGH use increased from 2009 to 2010, remaining stable thereafter, but it was heterogeneous across centers (twofold higher prevalence of use in center n.2 than centers n.4 and 1 in 2014). Biosimilar rGH uptake increased over time but was low (7.8% in 2014) and heterogeneous as well. Discontinuation of rGH therapy occurred in 54.0% of naïve users, more frequently in females than males (58.1 vs. 50.9%). During the first year of treatment, discontinuation was frequent (39.9%), but no statistically significant differences were observed in treatment persistence for biosimilar vs. originator rGH ( > 0.05).

Conclusion: Geographical heterogeneity in the prevalence of rGH use was observed. Similarly, the biosimilar rGH uptake was low and variable across centers. Post-marketing monitoring is required to continuously monitor the benefit-risk profile of rGH, thus guaranteeing greater savings than only promoting lowest cost rGH.
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http://dx.doi.org/10.3389/fendo.2018.00095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859012PMC
March 2018

[Which efficacy trials for drugs for rare diseases?]

Epidemiol Prev 2017 Sep-Dec;41(5-6):318-319

Dipartimento epidemiologia del Sistema sanitario regionale, Regione Lazio, Roma.

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http://dx.doi.org/10.19191/EP17.5-6.P318.099DOI Listing
February 2019

Italian consumption of plasma-derived factor VIII after the SIPPET study.

Blood Transfus 2017 05;15(3):283-284

Department of Epidemiology, Lazio Regional Health Service, Rome, Italy.

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http://dx.doi.org/10.2450/2017.0035-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448841PMC
May 2017

Cardiovascular safety of tiotropium Respimat vs HandiHaler in the routine clinical practice: A population-based cohort study.

PLoS One 2017 21;12(4):e0176276. Epub 2017 Apr 21.

Pharmacoepidemiology Unit, National Centre for Epidemiology, National Institute of Health, Rome, Italy.

The cardiovascular safety of tiotropium Respimat formulation in the routine clinical practice is still an open issue. Our aim was to compare the risk of acute myocardial infarction and heart rhythm disorders in incident users of either tiotropium Respimat or HandiHaler. The study population comprises patients aged ≥45 years, resident in two Italian regions with a first prescription of tiotropium (HandiHaler or Respimat) between 01/07/2011-30/11/2013. The cohort was identified through the database of prescriptions reimbursed by the Italian National Health Service. Comorbidities and clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for acute myocardial infarction and/or for heart rhythm disorders during the exposure period. Hazard ratios were estimated in the propensity score-matched groups through Cox regression. After matching, 31,334 patients with incident prescription of tiotropium were included. The two groups were balanced with regard to baseline characteristics. Similar incidence rates of the primary outcome between Respimat and HandiHaler users were identified (adjusted hazard ratio 1.02, 95% CI 0.82-1.28). No risk difference between Respimat and HandiHaler emerged when considering clinical events separately. This large cohort study showed a comparable acute cardiovascular safety profile of the two tiotropium formulations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400270PMC
September 2017

Can systematic reviews contribute to regulatory decisions?

Eur J Clin Pharmacol 2017 Apr 7;73(4):507-509. Epub 2017 Jan 7.

IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.

Introduction: The new call on independent research on drugs issued in October 2016 by the Italian Medicines Agency (AIFA) explicitly reported that proposals based on systematic reviews were not admissible, and no justification or explanation for this choice was given. Prompted by this policy decision, here, we briefly discuss the potential usefulness of systematic reviews in responding to regulatory needs. First, systematic reviews, by collecting, analysing and critically appraising all relevant studies on a specific topic, may be used by different stakeholders as a basis for making clinical and policy recommendations, including regulatory recommendations. Second, systematic reviews may advance knowledge as primary clinical research does. Third, systematic reviews may be particularly useful to detect signals of unknown adverse effects. Fourth, systematic reviews may be used to identify knowledge gaps.

Proposal: Systematic reviews may simultaneously produce new findings and summarize existing knowledge, with the potential of informing regulatory decisions more pragmatically and more rapidly than other research designs. We suggest that national and international calls on independent research on drugs should not put primary clinical research against systematic reviews, as it implies a focus on the methods instead of on the questions being asked. As most calls only broadly define the research areas and the topics to be covered, we argue that it should be up to the applicant to make a proposal on which design provides the most valid and useful answer, and up to the assessors to carefully check the validity, feasibility and relevance of such a proposal.
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http://dx.doi.org/10.1007/s00228-016-2194-yDOI Listing
April 2017

[Biomedical research from philanthropy to scarcity.]

Recenti Prog Med 2016 Oct;107(10):507-509

Istituto Superiore di Sanità.

Some huge information technology companies have increased investment in biomedical research: recently Google, Microsoft, and Facebook. The latter presented the ambitious Zuckerberg-Chan Initiative involving three major Californian universities: UC San Francisco, Berkeley and Stanford. These important private investments arouse reflections. First, investing in scientific research improves the corporate image of the most generous companies and it is a great marketing strategy. Second, the availability of private funds is surely useful, especially if these funds are directed to relevant projects, and produce studies conducted and disseminated in a transparent way. Third, private funding should not replace public ones, representing an integration that will not likely affect the determination of the research agenda, which should remain the prerogative of public institutions. Fourth, the researchers involved in public funded projects should benefit from the margin of freedom that private industry promises, both in the decision of research pathways and in their course. Finally, the scarcity of resources is likely to divert energy and attention of the public researchers and this aspect should be considered by decision makers when determining size and recipients of research funding.
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http://dx.doi.org/10.1701/2454.25698DOI Listing
October 2016

How did the Introduction of Biosimilar Filgrastim Influence the Prescribing Pattern of Granulocyte Colony-Stimulating Factors? Results from a Multicentre, Population-Based Study, from Five Italian Centres in the Years 2009-2014.

BioDrugs 2016 Aug;30(4):295-306

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.

Background: Granulocyte colony-stimulating factors (G-CSFs) are biological products for which the main indication of use is chemotherapy-induced neutropenia. Biosimilars of G-CSFs have been available in Europe since 2007.

Objective: The objective of this study was to investigate the prescribing pattern of G-CSFs in five Italian centres using different healthcare policy interventions to promote the use of biosimilars in routine care.

Methods: This retrospective, population-based drug utilization study was conducted during the years 2009-2014 using the administrative databases of the Caserta, Treviso and Palermo Local Health Units (LHUs) and the Tuscany and Umbria regions. G-CSF users were characterized and the prevalence of use, proportion of biosimilar users and switching pattern of different G-CSFs were evaluated over time and across centres.

Results: Overall, 30,247 patients were treated with G-CSFs in the years 2009-2014, of which 29,083 (96.2 %) were naïve users. The overall prevalence of G-CSF use increased from 0.8 per 1000 inhabitants in 2009 to 1.1 per 1000 in 2014. An increase in the proportion of the use of the biosimilar filgrastim by the total G-CSF users was observed in all centres: from 0.2 % (2009) to 66.2 % (2014). However, heterogeneity across different centres was reported, with the largest increase in Treviso LHU (from 0 to 89.1 % from 2009 to 2014). During the first year of treatment, switching between different G-CSFs was frequent (20.3 %).

Conclusions: Heterogeneity in the use of G-CSF and, in particular, biosimilar filgrastim across different Italian centres was observed, probably due to different regional healthcare policy interventions. During the first year of treatment, switching between different G-CSFs was frequent. Considering the impact of biological drugs on pharmaceutical expenses, it is necessary to harmonize healthcare policies promoting the use of biological drugs with the lowest cost.
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http://dx.doi.org/10.1007/s40259-016-0175-4DOI Listing
August 2016

Italian program for independent research on drugs: 10 year follow-up of funded studies in the area of rare diseases.

Orphanet J Rare Dis 2016 Apr 12;11:36. Epub 2016 Apr 12.

Department of Epidemiology, Lazio Regional Health Service, Via Cristoforo Colombo 112, 00147, Rome, Italy.

Background: In 2005 the Italian Medicines Agency (AIFA) started a program on independent research on drugs, with the aim to promote clinical research in areas of limited commercial interest. For 3 years (2005-2007) an area of the program was reserved to studies in the field of rare diseases. There is a concern that public funding of research may be wasted. We investigated the outcome of the program.

Methods: We conducted a cohort study on the projects that were funded by the AIFA in the area of rare diseases. The outcomes were the proportion of published studies, time to publication, impact factor of the publishing journals and relevance for clinical practice. We retrieved published articles through a literature search in peer reviewed biomedical journals indexed by Pubmed. We used the Kaplan-Meier method to estimate the cumulative probability of publication by time from project starting to publication.

Results: During the period 2005-2007, 62 projects were funded in the area of rare diseases. Most of the studies (n 39; 63%) had a randomized design and in 22 (35%) the control group received an active treatment. For 39 studies (63%) we retrieved a publication in a peer reviewed journal. The median time to publication was 74 months and, at the maximum period of follow up (109 months), the cumulative probability of publication reached 77%. The median impact factor was 5.4 (range 1.4-52.4). Considering the clinical relevance, more than 30% of the published articles presented conclusive findings; an additional 10% of the studies reached potential breakthrough findings.

Conclusions: Even though it takes time to set up and conduct a funding program for independent research on drugs, the results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest.
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http://dx.doi.org/10.1186/s13023-016-0420-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828875PMC
April 2016

Switching Between Epoetins: A Practice in Support of Biosimilar Use.

BioDrugs 2016 Feb;30(1):27-32

Pharmacoepidemiology Unit, National Centre for Epidemiology, National Institute of Health, Viale Regina Elena 299, 00161, Rome, Italy.

Background: The acceptability of switching between reference drugs and their biosimilars is often disputed. It is unclear whether this concern is specific to the use of biosimilars or is relevant to the practice of switching between any biological drugs.

Objective: The objective of this study was to quantify the occurrence of switching between different erythropoiesis-stimulating agents.

Methods: A retrospective drug utilization study was conducted in the Umbria region (Italy). The study population included all residents who received their first epoetin prescription between 1 July 2011 and 31 December 2014. The Umbria drug prescription database and the regional archive of residents were used to gather information. Switching was defined as any transition between different epoetins (different substances and/or different products of the same substance) in a series of two prescriptions. The probability of switching was described in relationship to the duration of treatment in a survival analysis.

Results: Overall, 3258 subjects received prescriptions of epoetins. Among the 2896 patients with at least two prescriptions, 354 (12.2%) experienced one or more switches. The probability of switching depended on the duration of treatment: approximately 15% of users switched within 12 months of observation and 25% switched within 2 years. Switching was not limited to reference and biosimilar epoetins and it affected patent and off-patent epoetins equally.

Conclusions: Switching between different epoetins was related to the duration of use and most episodes of switching involved epoetins that have never been contrasted in a comparability exercise. The present level of switching may provide reassurance to physicians when taken together with other sources of comparative evidence.
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http://dx.doi.org/10.1007/s40259-015-0155-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746226PMC
February 2016

Antihypertensive drug use during pregnancy: a population based study.

Ann Ist Super Sanita 2015 ;51(3):236-43

Reparto di Farmacoepidemiologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, Rome, Italy.

Purpose: The study aimed at assessing if the European guideline on the use of antihypertensive drugs (AD) in pregnancy are followed in clinical practice. We also evaluated the association between the use of non-recommended drugs and individual characteristics.

Methods: This study analyzed a cohort of 86 171 singleton deliveries occurring between 2009-2010 in the Lombardy region, Italy. Women with first prescription of AD during pregnancy were considered as incident users. Methyldopa, labetalol and nifedipine were considered as "recommended drugs"; all other AD were considered as "non-recommended". Odds Ratio and 95% confidence intervals were estimated.

Results: Among the 1009 patients (1.2%) exposed to AD during pregnancy, 675 (66.9%) were incident users. Among the incident users, 31% received non-recommended drugs; this proportion decreased to 18% among women who started treatment in the third trimester. Women with at least four concomitant diseases had an elevated risk of receiving non-recommended drugs in pregnancy (OR 2.68; 95% CI 1.10-6.73).

Conclusions: Exposure to recommended antihypertensives increased during pregnancy. Nevertheless, a fraction of users that continued or began treatment with non-recommended medications was still present.
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http://dx.doi.org/10.4415/ANN_15_03_12DOI Listing
January 2017

[Considerations on what we can (and what we should not) ask to registries].

Recenti Prog Med 2015 Sep;106(9):444-54

This article presents a summary of the discussion which took place during the works of PRIER II in the session dedicated to the methodology of registries. Following a thorough analysis of the possible methods and the limits which deal with the collection of clinical data through the registries, the different points of view were compared, perhaps the most relevant, related to this activity. All this has been done by taking advantage by the possibility to observe aspects from different points of view. In particular, the exercise considered those who have to deal with the methodological aspects of the registries as an operator of public health or as a private operator who creates services for companies. The final goal, again, was to line up a few essential points accompanied by reasoning and comments useful to anyone who wants to address the issue of registries from the methodological point of view.
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http://dx.doi.org/10.1701/1996.21594DOI Listing
September 2015

[Considerations on limits and profits of registries].

Recenti Prog Med 2015 Sep;106(9):425-35

The article collects the summary of the discussion occurred in the setting of PRIER II, in the session dedicated to the taxonomy of registries. Shown below, some specific contributions by health professionals working at the regional departments, which deal with registries, as well as the contribution on the same subject by specialists working at some pharmaceutical companies. In particular, after the presentation summarized in the article by prof. Giuseppe Costa1, the contributions, respectively by a representative of the Emilia-Romagna Region, of a health and hospital service and by the PRIER II workgroup, are following. Finally, a collective work with all participants to the working group took place to focus on all the issues considered to be crucial in defining clinical registries. At the same discussion table, institutional representatives of the regulatory national and regional branch were also invited to take into consideration the points of view of all public and private registry users, in particular in their benefits, limits and purposes. Going through the discussion on a specific check list and deepening a number of statements identified by the working group, a list of key points, essential to characterize each clinical registry, was produced.
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http://dx.doi.org/10.1701/1996.21590DOI Listing
September 2015

[Vaccines are drugs].

Epidemiol Prev 2015 ;39(3):145-6

Reparto di farmacoepidemiologia, Istituto superiore di sanità, Roma.

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July 2017

Risk factors influencing the prescription of tiotropium Respimat formulation: a population-based cohort study.

BMJ Open 2015 May 25;5(5):e006619. Epub 2015 May 25.

Pharmacoepidemiology Unit, National Centre for Epidemiology, Italian National Institute of Health, Rome, Italy.

Objectives: The study aims at investigating the influence of several factors on the probability of receiving one of the two tiotropium formulations (Respimat or Handihaler).

Design: Drug utilisation study.

Setting: All residents in the Region Umbria, Italy, aged ≥45 years, who received prescriptions of tiotropium during 2011-2012.

Participants: Two groups of patients were studied: (1) incident users of the two tiotropium formulations (ie, without tiotropium prescriptions in the previous 6 months); (2) switchers from Handihaler to Respimat. Users of the two formulations were compared with regard to baseline characteristics and medical history. The adjusted OR of receiving Respimat was estimated for several factors.

Results: Incident users of the two formulations (4390 participants) had similar characteristics. They were older and with more comorbidities than patients included in randomised control trials (RCTs). Among prevalent users of Handihaler, the probability of switching to Respimat was greater in patients with severe respiratory disease (users of ≥4 respiratory drugs: adjusted OR=4.62; 95% CI 2.46 to 8.69) and among β-blocker users (adjusted OR=1.76; 95% CI 1.13 to 2.75). Age above 75 years and lipid-lowering drug use reduced the probability of switching. A positive association was also found between neurological conditions and the use of Respimat.

Conclusions: When starting tiotropium treatment, the choice between the two formulations is weakly affected by comorbidities and chronic obstructive pulmonary disease severity. Instead, these characteristics influence the likelihood of switching from Handihaler to Respimat. Since tiotropium users in clinical practice are more severe than those included in RCTs, further aetiological studies are needed to compare the safety profile of the two formulations in routine care.
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http://dx.doi.org/10.1136/bmjopen-2014-006619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452750PMC
May 2015
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