The timelines for the price and reimbursement authorization in Italy 2018-2020.

Objective: This investigation aimed to guarantee the principles of transparency in public administration; to inform citizens about the time to patient access to reimbursed medicines; to assess the duration of the P&R process for the first time in the period 2018-2020; and to evaluate whether and how the SARS-CoV-2 (COVID-19) pandemic affected the P&R activity. This study analyzed the timelines of pricing and reimbursement procedures submitted in Italy by the pharmaceutical marketing authorization holder (MAH) from 2018 to 2020. Methods: The analysis was run through an AIFA web-based platform that collects data about P&R procedures for each step of the Italian Price and Reimbursement (P&R) procedure, including dates of the Technical Scientific Committee (CTS) and Price and Reimbursement Committee (CPR) meetings from January 2018 to December 2020. On this basis, four indicators were developed relating to the completion time of each stage of the P&R negotiation process and were defined in terms of days. In this regard, descriptive analyses, graphical boxplots, and survival curves (Kaplan-Meier) were carried out, studying these indicators in relation to the typology of pharmaceutical procedures. Results: Overall, in the period 2018-2020, 57.1% of the 2,445 procedures entered were represented by the Off-patent pharmaceuticals procedures (generics, biosimilars, copies, and/or parallel trade). In 2020, the overall process duration for Off-patent pharmaceuticals procedures was equal to 129.8 average days [95% CI: (122.3-137.2)], with a median value of 108.0, whereas for In-patent pharmaceuticals procedures, it was equal to 283.1 average days [95% CI: (267.8-298.5)], with a median value of 284.0. Over time, the trend of the entire duration of the P&R process tended to decrease. In terms of estimated timing for the conclusion of each stage of the P&R negotiation process, the difference between Off-patent and In-patent pharmaceutical procedures was statistically significant by the Log-Rank test. Discussion and conclusion: This is the first study to examine the time of the P&R process in Italy, from MAH submission to the publication of the final decision in the Italian Official Journal. The time span considered is 3 years, including the first year of the COVID-19 pandemic. Compared to European average times, in Italy, the time necessary for evaluation, authorization for reimbursement, and definition of the price of a medicine can be considered satisfactory.

The impact of direct acting antivirals on hepatitis C virus disease burden and associated costs in four european countries.

BACKGROUND AND AIMS: We assessed the clinical and economic impact of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) in England, Italy, Romania and Spain. METHODS: An HCV progression Markov model was developed considering DAA eligibility and population data during the years 2015-2019. The period of time to recover the investment in DAAs was calculated as the cost saved by avoiding estimated clinical events for 1000 standardized treated patients. A delayed treatment scenario because of coronavirus disease (COVID-19) was also developed. RESULTS: The estimated number of avoided hepatocellular carcinoma, decompensated cirrhosis and liver transplantations over a 20-year time horizon was: 1,057 in England; 1,221 in Italy; 1,211 in Romania; and 1,103 in Spain for patients treated during 2015-2016 and 640 in England; 626 in Italy; 739 in Romania; and 643 in Spain for patients treated during 2017-2019. The cost-savings ranged from € 45 to € 275 million. The investment needed to expand access to DAAs in 2015-2019 is estimated to be recovered in 6.5 years in England; 5.4 years in Italy; 6.7 years in Romania; and 4.5 years in Spain. A delay in treatment because of COVID-19 will increase liver mortality in all countries. CONCLUSION: Direct-acting antivirals have significant clinical benefits and can bring substantial cost-savings over the next 20 years, reaching a Break-even point in a short period of time. When pursuing an exit strategy from strict lockdown measures for COVID-19, providing DAAs should remain high on the list of priorities in order to maintain HCV elimination efforts.

Forecasting Hepatitis C liver disease burden on real-life data. Does the hidden iceberg matter to reach the elimination goals?

BACKGROUND & AIMS: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030. METHODS: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals. RESULTS: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals. CONCLUSION: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required.

Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis.

PURPOSE: To analyse safety and efficacy of treatment based on ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in the sub-group of GT1 patients older than 65 years. METHODS: We collected data extracted from the ABACUS compassionate-use nationwide Italian programme, in patients with cirrhosis due to hepatitis C virus (HCV) Genotype-1 (GT1) or 4 and at high risk of decompensation. GT1-HCV-infected patients received once-daily ombitasvir/paritaprevir, with the pharmacokinetic enhancer ritonavir (25/150/100 mg) and twice-daily dasabuvir (250 mg) plus Ribavirin (RBV) (OBV/PTV/r + DSV + RBV) for 12 (GT1b) or 24 (GT1a) weeks. Endpoints were to evaluate safety and efficacy, the latter defined as HCV RNA negative 12 weeks after the end of treatment (SVR12). RESULTS: Patients who suffered any adverse event (AE) were 74/240 (30.8%); 13/240 (5.4%) discontinued the treatment. A multivariate analysis found albumin < 3.5 g/dL (OR 2.04: 95% CI 1.0-4.2, p < 0.05) and hypertension (OR 4.6: 95% CI 2.3-9.2, p < 0.001) as variables independently associated with AE occurrence. The SVR12 was 95% (228/240). Multivariate analysis identified baseline bilirubin < 2 mg/dL (OR 4.9: 95% CI 1.17-20.71, p = 0.029) as the only variable independently associated with SVR12. CONCLUSION: Our findings suggest that OBV/PTV/r + DSV + RBV is safe and effective in real-life use in patients with compensated cirrhosis, HCV-GT1 infection, and age over 65.

The Italian compassionate use of sofosbuvir in HCV patients waitlisted for liver transplantation: A national real-life experience.

BACKGROUND & AIMS: This study aimed to assess the real-life clinical and virological outcomes of HCV waitlisted patients for liver transplantation (LT) who received sofosbuvir/ribavirin (SOF/R) within the Italian compassionate use program. METHODS: Clinical and virological data were collected in 224 patients with decompensated cirrhosis and/or hepatocellular carcinoma (HCC) receiving daily SOF/R until LT or up a maximum of 48 weeks. RESULTS: Of 100 transplanted patients, 51 were HCV-RNA negative for >4 weeks before LT (SVR12: 88%) and 49 negative for <4 weeks or still viraemic at transplant: 34 patients continued treatment after LT (bridging therapy) (SVR12: 88%), while 15 stopped treatment (SVR12: 53%). 98 patients completed SOF/R without LT (SVR12: 73%). In patients with advanced decompensated cirrhosis (basal MELD ≥15 and/or C-P ≥B8), a marked improvement of the scores occurred in about 50% of cases and almost 20% of decompensated patients without HCC reached a condition suitable for inactivation and delisting. CONCLUSIONS: These real-life data indicate that in waitlisted patients: (i) bridging antiviral therapy can be an option for patients still viraemic or negative <4 weeks at LT; and (ii) clinical improvement to a condition suitable for delisting can occur even in patients with advanced decompensated cirrhosis.

The Italian compassionate use of sofosbuvir observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function.

Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study.

BACKGROUND: We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. METHODS: In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. FINDINGS: 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83-12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. INTERPRETATION: Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. FUNDING: Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo.

MONITORING REGISTRIES AT ITALIAN MEDICINES AGENCY: FOSTERING ACCESS, GUARANTEEING SUSTAINABILITY.

OBJECTIVES: The AIFA (Agenzia Italiana del Farmaco--Italian Medicines Agency) Monitoring Registries track the eligibility of patients and the complete flow of treatments, guaranteeing appropriateness in use of pharmaceutical products, according to approved indications. METHODS: This study describes the Italian pharmaceutical context and the aims and functioning of AIFA Monitoring Registries, focusing on the applications to the Managed Entry Agreements (MEAs) and HTA approaches. RESULTS: The AIFA Monitoring Registries System has been operational in Italy since 2005. In 2012, the system became part of the NHS Information Technology system, aiming at enhancing appropriate use of pharmaceuticals and efficiency of the administrative activity. Currently, seventy-six medicines are monitored through the system, corresponding to fifty-eight therapeutic indications; individual treatments recorded are more than 515,000, for a population of approximately 505,000 patients. For each monitored product, patients eligible for treatment are registered in the specific therapeutic indication dynamic monitoring database to collect epidemiologic and clinical data, including data on the safety profile, and ex-post information missing at first evaluation stage. CONCLUSIONS: AIFA Monitoring Registries allow the evaluation of the pharmaceuticals' performance in clinical practice and may promote innovation and quicker access to medicines at affordable prices, for the benefit of patients.

Piloting international production of rapid relative effectiveness assessments of pharmaceuticals.

BACKGROUND: This article describes the lessons learned from an international pilot assessment using the first version of the HTA Core Model® and Guidelines for rapid Relative Effectiveness Assessment (REA) of pharmaceuticals based on input from three different perspectives: the assessors, the users (health technology assessment organisations) and the marketing authorisation holder. METHODS: A pilot assessment was performed of pazopanib for the treatment of advanced or metastatic renal cell carcinoma for which 54 individuals from 22 EUnetHTA member organisations from 16 European countries gave their contribution. The work was divided in eight domain teams. Subsequently, results of these domain teams were synthesised in one pilot report. Feedback on the outcomes of the pilot was gathered throughout the project and through structured surveys. RESULTS: The first version of the assessment was produced in six months and consisted of 55 question and answer pairs, 8 domain reports and a synthesis section that combined the results from the different domains. The organisation of the pilot required intense coordination. Main points of criticism on the assessment were the lengthiness of the document and overlap of information throughout the assessment. CONCLUSIONS: A reduction in the number of authoring organisations and individuals participating is necessary to avoid information overlap and increase efficiency in undertaking the assessment. Involving several organisations (e.g. five) in an in-depth review could still ensure the benefit of broad participation from various countries. The focus of a rapid REA should be on the first four domains of the Model.

Biosimilars: the paradox of sharing the same pharmacological action without full chemical identity.

The use of biotech medicines is increasing, with consequent mounting expenses for National Health Systems (NHSs). Biosimilars should be considered an opportunity to improve access to care. On the other side, the general public might suspect to receive low-quality medicines to save money. Actually, no drugs with a lesser degree of pharmaceutical quality with respect to existing alternatives can be authorized on the ground of a lower price. Biosimilars can be authorized only if their quality is of the same level as that of the originator. There is no chemical identity between biosimilars and the originators: any differences in quality attributes must be justified and shown not to impact on the safety and efficacy of the biosimilar by scientific investigations including pre-approval nonclinical and/or clinical studies. The biosimilar safety profile may be different from the originator or change over time for the same product. Hence caveats limiting the widespread use of biosimilars yet exist and should be solved by education on the main biological issues of biotech medicines, and on continuous update of the rules set up by the Regulatory Authorities to assess biosimilarity and to monitor post-approval safety.

Pricing and reimbursement of pharmaceuticals in Italy.

In Italy the price setting of medicines reimbursed by the National Health Service is regulated at the central level by AIFA, the national regulatory authority. Prices of non reimbursed medicines are indeed freely established, with some limitations, by pharmaceutical companies. To contain pharmaceutical expenditure and rationalise the whole sector the following measures have been introduced in the past years: a threshold to public pharmaceutical expenditure (PPE); a reference price system (RPS) for off-patent medicines; a pay-back mechanism as an alternative to price cut. In 2008 Italy launched a reform of the pharmaceutical expenditure governance system with the aim to introduce stability and promote development and competitiveness in the pharmaceutical sector.

Some considerations on the kinetics of pathogenic prions formation.

Literature data, respective to kinetics of infectivities due to prion diseases, have been here reconsidered. The autocatalytic phenomenon of prion replication and the process of advancement of the infection are also considered. A model describing the interconversion from "normal" into "pathogenic" prions, and the subsequent growth of the infection, is proposed. This model takes into account the existence of two different steps: the first, slower, in which the interaction between the two different prions, with the transformation of normal prions into the pathogen ones, takes place. The second one, very fast, in which the degree of advancement of the infection assumes the form of an irreversible, rapid trend.