Probabilistic cost-effectiveness analysis of controlled ovarian stimulation with recombinant FSH plus recombinant LH vs. human menopausal gonadotropin for women undergoing IVF.

BACKGROUND: The association of recombinant FSH plus recombinant LH in 2:1 ratio may be used not only to induce ovulation in anovulatory women with hypogonadotropic hypogonadism but also to achieve multiple follicular developments in human IVF. The aim of this analysis was to estimate the cost-effectiveness of Controlled Ovarian Stimulation (COS) with recombinant FSH (rFSH) plus recombinant LH (rLH) in comparison with highly purified human menopausal gonadotropin (HP-hMG) in the woman undergoing in vitro fertilization (IVF) in Italy. METHODS: A probabilistic decision tree was developed to simulate patients undergoing IVF, either using r-FSH + r-LH or HP-hMG to obtain COS. The model considers the National Health System (NHS) perspective and a time horizon equal to two years. Simulations were reported considering the number of retrieved oocytes (5-9, 10-15 and > 15) and transition probabilities were estimated through specific analyses carried out on the population of 848 women enrolled in the real-life. RESULTS: The model estimated that patients undertaking therapeutic protocol with r-FSH + r-LH increase the general success rate (+ 6.6% for pregnancy). The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) of r-FSH + r-LH was below the willingness to pay set at €20,000 for all the considered scenarios. CONCLUSIONS: The cost-utility analysis demonstrated that the r-FSH + r-LH is a cost-effective option for the Italian National Health System (NHS).

The headache under-response to treatment (HURT) questionnaire, an outcome measure to guide follow-up in primary care: development, psychometric evaluation and assessment of utility.

BACKGROUND: Headache disorders are both common and burdensome but, given the many people affected, provision of health care to all is challenging. Structured headache services based in primary care are the most efficient, equitable and cost-effective solution but place responsibility for managing most patients on health-care providers with limited training in headache care. The development of practical management aids for primary care is therefore a purpose of the Global Campaign against Headache. This manuscript presents an outcome measure, the Headache Under-Response to Treatment (HURT) questionnaire, describing its purpose, development, psychometric evaluation and assessment for clinical utility. The objective was a simple-to-use instrument that would both assess outcome and provide guidance to improving outcome, having utility across the range of headache disorders, across clinical settings and across countries and cultures. METHODS: After literature review, an expert consensus group drawn from all six world regions formulated HURT through item development and item reduction using item-response theory. Using the American Migraine Prevalence and Prevention Study's general-population respondent panel, two mailed surveys assessed the psychometric properties of HURT, comparing it with other instruments as external validators. Reliability was assessed in patients in two culturally-contrasting clinical settings: headache specialist centres in Europe (n = 159) and primary-care centres in Saudi Arabia (n = 40). Clinical utility was assessed in similar settings (Europe n = 201; Saudi Arabia n = 342). RESULTS: The final instrument, an 8-item self-administered questionnaire, addressed headache frequency, disability, medication use and effect, patients' perceptions of headache "control" and their understanding of their diagnoses. Psychometric evaluation revealed a two-factor model (headache frequency, disability and medication use; and medication efficacy and headache control), with scale properties apparently stable across disorders and correlating well and in the expected directions with external validators. The literature review found few instruments linking assessment to clinical advice or suggested actions: HURT appeared to fill this gap. In European specialist care, it showed utility as an outcome measure across headache disorders. In Saudi Arabian primary care, HURT (translated into Arabic) was reliable and responsive to clinical change. CONCLUSIONS: With demonstrated validity and clinical utility across disorders, cultures and settings, HURT is available for clinical and research purposes.

Human papillomavirus 9-valent vaccine for cancer prevention: a systematic review of the available evidence.

In 2014, the Food and Drug Administration approved a new human papillomavirus 9-valent vaccine (9vHPV), targeting nine HPV types: HPV types 6, 11, 16, and 18, which are also targeted by the quadrivalent HPV vaccine (qHPV), plus five additional high cancer risk HPV types (HPV types 31, 33, 45, 52, and 58). The aim of the current study was to systematically retrieve, qualitatively and quantitatively pool, as well as critically appraise all available evidence on 9vHPV from randomized controlled trials (RCTs). We conducted a systematic review of the literature on 9vHPV efficacy, immunogenicity and safety, as well as a systematic search of registered, completed, and ongoing RCTs. We retrieved and screened 227 records for eligibility. A total of 10 publications reported on RCTs' results on 9vHPV and were included in the review. Sixteen RCTs on 9vHPV have been registered on RCT registries. There is evidence that 9vHPV generated a response to HPV types 6, 11, 16 and 18 that was non-inferior to qHPV. Vaccine efficacy against five additional HPV type-related diseases was directly assessed on females aged 16-26 years (risk reduction against high-grade cervical, vulvar or vaginal disease = 96·7%, 95% CI 80·9%-99·8%). Bridging efficacy was demonstrated for males and females aged 9-15 years and males aged 16-26 years (the lower bound of the 95% CIs of both the geometric mean titer ratio and difference in seroconversion rates meeting the criteria for non-inferiority for all HPV types). Overall, 9vHPV has been proved to be safe and well tolerated. Other RCTs addressed: 9vHPV co-administration with other vaccines, 9vHPV administration in subjects that previously received qHPV and 9vHPV efficacy in regimens containing fewer than three doses. The inclusion of additional HPV types in 9vHPV offers great potential to expand protection against HPV infection. However, the impact of 9vHPV on reducing the global burden of HPV-related disease will greatly depend on vaccine uptake, coverage, availability, and affordability.

The economic burden of musculoskeletal disorders on the Italian social security pension system estimated by a Monte Carlo simulation.

The aim of the study is to estimate the pension costs incurred for patients with musculoskeletal disorders (MDs) and specifically with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in Italy between 2009 and 2012. We analyzed the database of the Italian National Social Security Institute (Istituto Nazionale Previdenza Sociale i.e. INPS) to estimate the total costs of three types of social security benefits granted to patients with MDs, RA and AS: disability benefits (for people with reduced working ability), disability pensions (for people who cannot qualify as workers) and incapacity pensions (for people without working ability). We developed a probabilistic model with a Monte Carlo simulation to estimate the total costs for each type of benefit associated with MDs, RA and AS. We also estimated the productivity loss resulting from RA in 2013. From 2009 to 2012 about 393 thousand treatments were paid for a total of approximately €2.7 billion. The annual number of treatments was on average 98 thousand and cost in total €674 million per year. In particular, the total pension burden was about €99 million for RA and €26 million for AS. The productivity loss for AR in 2013 was equal to €707,425,191 due to 9,174,221 working days lost. Our study is the fi rst to estimate the burden of social security pensions for MDs based on data of both approved claims and benefits paid by the national security system. From 2009 to 2012, in Italy, the highest indirect costs were associated with disability pensions (54% of the total indirect cost), followed by disability benefits (44.1% of cost) and incapacity pensions (1.8% of cost). In conclusion, MDs are chronic and highly debilitating diseases with a strong female predominance and very significant economic and social costs that are set to increase due to the aging of the population.

How can the results of Health Technology Assessment (HTA) evaluations applied to vaccinations be communicated to decision-makers and stakeholders? The ISPOR Rome Chapter Project.

HTA is considered the most comprehensive and transparent method of supporting decision-makers in their choices in Public Health. HTA on vaccines is being performed by many experts. However, they often present their studies to colleagues, but not to decisionmakers, who should be the main target and current users. It is therefore crucial to improve the transfer of scientific data to decision- makers and all stakeholders. The aims of the present project are: 1) to set up a team of experts to collect economic evaluations and HTA studies on vaccines and assess their actual use in decision-making processes; 2) to constitute regional working groups in order to identify the critical aspects of the communication process and identify the most appropriate method of data transfer. Systematic reviews of economic evaluations and HTA on vaccines and their actual use in decision-making will be used to draw up the basic documents for discussion by the 3 regional working boards. The working groups will discuss the current scientific evidence and communication methods and will try to implement a model of technology assessment with well-defined and objective criteria, in order to better fit pharmaco-economic and HTA methods to the field of vaccinations. Improving the transfer of HTA results to stakeholders, particularly decision-makers, will enable decisions to be taken on the basis of scientific evidence, and appropriate, sustainable actions to be undertaken.

The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases.

Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthropathies, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, comprise a group of chronic disorders characterized by an immune-mediated pathogenesis. Although at clinical presentation these diseases appear unrelated, they have been recognized to share similar pathogenic mechanisms. Data from epidemiological and genetic studies further support the concept that IMIDs are interrelated, as they can co-occur in the same patient and share a similar genetic susceptibility. The specific aetiologies of IMIDs remain unknown, but all are known to involve dysregulation of the immune system, including an over-expression of the pro-inflammatory cytokine tumour necrosis factor (TNF). The pivotal role played by TNF in the pathogenesis and pathophysiology of IMIDs has been documented by extensive preclinical and clinical investigations, and confirmed by the efficacy of anti-TNF biotechnological drugs, such as etanercept, infliximab and adalimumab, in the therapeutic management of these disorders. In this narrative review, we discuss the available data on the TNF-dependent pathogenesis of IMIDs and associations among the different disorders. Although much remains to be discovered about the pathogenesis and aetiology of IMIDs, their common inflammatory pathological features may explain why they can be successfully targeted by anti-TNF drugs. Among these, adalimumab, a fully human monoclonal antibody, has been approved for treatment of nine distinct IMID indications and it is likely to become a valuable therapeutic tool for this complex cluster of chronic inflammatory disorders.

anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.

Adalimumab in the treatment of immune-mediated diseases.

Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.

Hospital resource utilisation from HPV-related diseases in England: a real-world cost analysis.

BACKGROUND AND OBJECTIVE: HPV (human papillomavirus) is the virus most often responsible for sexually transmitted infections. The burden of HPV-related diseases on hospital resources represents a major public health problem. The objective of this study was to quantify the lifetime economic burden of HPV-related diseases based on hospital resources from the perspective of National Health Service (NHS) in England. METHODS: Patients' data were extracted, anonymised and aggregated by NHS digital from Hospital Episode Statistics (HES) database of patients admitted in 2015 and followed for three years. Data on hospitalizations were identified according to the International Classification of Diseases (ICD-10 CM). Health Resource Group (HRG) tariffs and National Reference Costs were used to estimate the hospitalization costs of anal, cervical, genital, oropharyngeal cancers as well as anogenital warts and cervical dysplasia. RESULTS: A total of 19,296 hospitalized patients were included in the estimation model, (39% was male and 61% female. At admission, the average age was 60 and 50 years old, respectively). Life-time costs per patients diagnosed with oropharyngeal cancer were £16,911 (£17,142 for male and £16,334 for female), penile cancer £12,539, vaginal cancer £12,676, anal cancer £13.773 (£12,590 for male, £14,525 for female). Cervical cancer accounted for £12,721, whereas cervical dysplasia for £3932. Resource used for hospitalized patients with anogenital warts was equal to £872 (£884 and £856 for men and women, respectively). On average, outpatient accounted for 39% of the total lifetime costs. CONCLUSION: The results of this study highlight that a substantial amount of resources is utilized for the treatment of HPV-related diseases at hospital level in England. These measures have the potential to inform policy decisions to ensure an optimal use of the NHS resources.

Multiple sclerosis in Italy: cost-of-illness study.

This study estimates the direct costs of multiple sclerosis (MS) in Italy from the perspective of the National Health System. Patients diagnosed with MS for ≥1 year prior to study entry were included in the analysis; neurological disability was assessed using the Expanded Disability Status Scale (EDSS). Cost variables were analyzed according to: MS phenotype, disease course over the previous year and EDSS rating. A total of 510 patients were included in the analysis. Overall costs were significantly higher for relapsing-remitting MS and secondary progressive MS than for primary progressive MS (P < 0.05). Costs were higher for EDSS scores 0.0-3.5 and 4.0-6.0 than for scores > 6.0 (P < 0.05). The extrapolated data gave an estimated annual direct cost of MS per patient of 18,030. In conclusion, relapsing-remitting MS or secondary progressive MS phenotypes and lower estimated EDSS scores appear to be associated with higher costs.

Human papillomavirus in Italy: retrospective cohort analysis and preliminary vaccination effect from real-world data.

INTRODUCTION: The objective of this study was to estimate the lifetime risk of hospitalization associated with all major human papillomavirus (HPV)-related diseases in Italy. Moreover, a preliminary vaccination effect was also performed. METHODS: A retrospective, nonrandomized, observational study was developed based on patients hospitalized between 2006 and 2018 in Italy. All hospitalizations were identified through administrative archives, according to the International Classification of Diseases (ICD-9 CM). Information related to the hospital discharges of all accredited public and private hospitals, both for ordinary and day care regimes, was taken into account. We included hospitalizations related to resident patients presenting one of the ICD-9-CM codes as primary or secondary diagnosis: genital warts (GW); 'cervical intraepithelial neoplasia (CIN)' (067.32-067.33); 'condyloma acuminatum' (078.11); 'anal cancers' (AC) (154.2-154.8); oropharyngeal cancers (OC): 'oropharyngeal cancer'(146.0-146.9) and 'head, face and neck cancers' (171.0); genital cancers (GC): 'penis cancer' (187.1-187.9) and 'cervical cancer' (180.0-180.9). Data were stratified by birth year and divided into two groups: (a) cohort born before 1996 (not vaccinable) and (b) cohort born after 1997 (vaccinable-first cohort that could be vaccinated at the beginning of immunization schedule in girls since 2008 in Italy). Disease-specific hospitalization risks for both groups were estimated by sex, year and age. RESULTS: Epidemiological data demonstrate that the peak hospitalization risk occurred at 24-26 years of age for GW (both male and female); 33-41 and 47-54 years for AC males and females, respectively; 53-59 and 52-58 years for OC males and females, respectively; and 54-60 and 39-46 years for GC males and females, respectively. Focusing on GW and GC, vaccinable females demonstrate a significant reduction in hospitalization risks (- 54% on average) compared to nonvaccinable females until 21 years of age (maximum follow-up available for girls born after 1997). Comparing the same birth cohort of males, no differences in hospitalization risk were found. CONCLUSIONS: These results support the importance of primary prevention strategies in Italy and suggest that increased VCRs and time of observation (genital cancers for which vaccination is highly effective, have a latency of some decades) will provide useful information for decision-makers.

Time to market and patient access to new oncology products in Italy: a multistep pathway from European context to regional health care providers.

AIM: The main purpose of this study was to identify each sequential phase followed by an oncology product, from European assessment until to patient access in each Italian region (IR). METHODS: A panel of oncology products approved by the European Medicines Agency (EMA) in the period 2006-2008 was considered. The explored sequential phases included the times to market for: the EMA; pharmaceutical companies; the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA); and IRs as final providers of health care. The IR's time to market was also analyzed by a Cox regression model. RESULTS: The overall mean time required before patients access was 2.3 years. EMA accounted for the greater proportion of time (31.8%), followed by AIFA (28.2%). However, the duration for both pharmaceutical companies and IRs was associated with the highest variability. An oncology product authorized with a risk-sharing agreement showed an early access in the IRs. On the contrary, the introduction in IRs having a compulsory formulary was delayed. Both a high forecast of economic impact and a high oncology product price can also delay the patient access. CONCLUSION: The process before patient access to an oncology product is time and cost consuming. This study identifies the main predictors that affect the missing overlap between market and patient access in Italy.

Health and economic impact associated with a quadrivalent HPV vaccine in Italy.

OBJECTIVE: The aim of this study was to determine the health impact and cost-effectiveness of introducing a human papillomavirus (HPV) vaccination programme with a quadrivalent vaccine alongside the existing cervical cancer screening programme in comparison to the current context in Italy. METHODS: A US Markov model was adapted to the Italian context, assuming under base case 80% vaccine coverage rate, lifetime duration of protection in a cohort of girls aged 12 years and discount rates of 1.5% and 3% for health benefits and costs, respectively, and estimating direct medical costs. RESULTS: The HPV vaccination in association with the current screening programme would allow to avoid 1432 cases of cervical cancer (-63.3%) and 513 deaths (-63.4%) compared to screening only, with an incremental cost-effectiveness ratio (ICER) of 9569 euros per additional quality-adjusted life-year (QALY) gained. The sensitivity analysis highlighted that this model was robust to all parameters presenting uncertainties as the ICERs ranged from 2,781 euros to 48,122 euros per QALY gained. CONCLUSION: This study showed that HPV vaccination in adolescent girls would be a beneficial and cost-effective public health programme in Italy.

Rationale and budget impact of bimonthly use of Cetuximab in patients with recurrent and/or metastatic head and neck cancer.

BACKGROUND: In recurrent and/or metastatic head and neck squamous cell cancer, Cetuximab is administered once a week, followed by weekly doses. We present the clinical rationale of a different schedule of maintenance Cetuximab and we estimate the potential economic benefits on the health care budget from a societal perspective in Italy. METHODS: A budget impact (BI) excel-based model was developed comparing a base case scenario of 100% weekly administration with a dose of 250 mg/m2 to an every-other-week (EOW) administration at 50% or 100% with a dose of 500 mg/m2 . RESULTS: In the EOW, 50% scenario it was calculated a cost reduction of €347 000 of which 70% attributable to indirect costs, increasing to €694 000 after 4 months. CONCLUSIONS: In our analysis, we showed that this simplified schedule could also reduce the costs of treatments both for the health system (direct costs) and for the society (indirect costs).

Economic burden of HPV9-related diseases: a real-world cost analysis from Italy.

INTRODUCTION: The objectives of this study were to estimate the economic burden of HPV in Italy, accounting for total direct medical costs associated with nine major HPV-related diseases, and to provide a measure of the burden attributable to HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 infections. METHODS: A cost-of-illness incidence-based model was developed to estimate the incidences and costs of invasive cervical cancer, cervical dysplasia, cancer of the vulva, vagina, anus, penis, oropharyngeal, anogenital warts, and recurrent respiratory papillomatosis (RRP) in the context of the Italian National Health System (NHS). We used data from hospital discharge records (HDRs) of an Italian region and conducted a systematic literature review to estimate the lifetime cost per case, the number of incident cases, the prevalence of HPV9 types. Costs of therapeutic options not included in the diagnosis-related group (DRG) tariffs were estimated through a scenario analysis. RESULTS: In 2018, the total annual direct costs were €542.7 million, with a range of €346.7-€782.0 million. These costs could increase considering innovative therapies for cancer treatment (range €16.2-€37.5 million). The fraction attributable to the HPV9 genotypes without innovative cancers treatment was €329.5 million, accounting for 61% of the total annual burden of HPV-related diseases in Italy. Of this amount, €135.9 million (41%) was related to men, accounting for 64% of the costs associated with non-cervical conditions. CONCLUSIONS: The infections by HPV9 strains and the economic burden of non-cervical HPV-related diseases in men were found to be the main drivers of direct costs.