The role of quantitative bias analysis for nonrandomized comparisons in health technology assessment: recommendations from an expert workshop.

The use of treatment effects derived from nonrandomized studies (NRS) in health technology assessment (HTA) is growing. NRS carry an inherently greater risk of bias than randomized controlled trials (RCTs). Although bias can be mitigated to some extent through appropriate approaches to study design and analysis, concerns around data availability and quality and the absence of randomization mean residual biases typically render the interpretation of NRS challenging. Quantitative bias analysis (QBA) methods are a range of methods that use additional, typically external, data to understand the potential impact that unmeasured confounding and other biases including selection bias and time biases can have on the results (i.e., treatment effects) from an NRS. QBA has the potential to support HTA bodies in using NRS to support decision-making by quantifying the magnitude, direction, and uncertainty of biases. However, there are a number of key aspects of the use of QBA in HTA which have received limited discussion. This paper presents recommendations for the use of QBA in HTA developed using a multi-stakeholder workshop of experts in HTA with a focus on QBA for unmeasured confounding.

IOEASMA: an integrated clinical and educational pathway for managing asthma in children and adolescents.

BACKGROUND: Due to the lack of real life clinical and educational studies, "Io e l'Asma" Centre performed this implementation research (IR). Evaluate long-term effectiveness on bronchial asthma control of an integrated clinical and educational pathway for asthmatic children and adolescents. METHODS: An observational retrospective pre-post intervention IR study was conducted among 262 children with asthma, ages 6-15 yrs. The intervention protocol included three clinical visits 8 weeks apart; an educational course at visit 1, post intervention consisted in two follow-up visits 6 months apart. The primary outcome was to verify the percentage of children who achieved bronchial asthma control at each visit. Secondary outcomes were based on daily therapy modulation, hospital admissions and the number of school days missed. An economic assessment was also included. RESULTS: Two hundred sixty two children with bronchial asthma completed the pathway and were included in the analysis. The percentage of children who obtained disease control increased from 44% at visit 1 to 79% at visit 3 and at 1-year follow-up was 83%. Hospital admissions represent 11% of children: 8% before the intervention, 2% during the intervention, and 1% before and during the intervention; no hospitalizations related to bronchial asthma exacerbations were reported during the 2 follow-up visits. CONCLUSIONS: The therapeutic-educational pathway was adapted according to the international guidelines and the primary performance indicators. Our findings confirmed that the clinical plus educational approach, shared between specialists and family physicians, is an effective template for asthma management. These findings also demonstrated a strong economic advantage.

Italian regional health service costs for diagnosis and 1-year treatment of ADHD in children and adolescents.

The main aim of this study was to estimate the costs associated with diagnostic assessment and 1-year therapy in children and adolescents enrolled in 18 ADHD reference centres. Data concerning 1887 children and adolescents from the mandatory ADHD registry database during the 2012-2014 period were analysed. The overall diagnostic and treatment costs per patient amounts to €574 and €830, respectively. The ADHD centre, the school as sender, and the time to diagnosis constitute cost drivers. Non-pharmacological therapy resulted as being more expensive for patients concomitantly treated with drugs (€929) compared to those treated with psychological interventions alone (€590; p = 0.006). This study gives the first and reliable estimate of the costs associated with both diagnosis and treatment of ADHD in Italy. Although costs associated with mental disorders are difficult to estimate, continuing efforts are need to define costs and resources to guarantee appropriate care, also for ADHD.

Biological agents and biosimilars: Essential information for the internist.

Biologics embrace a wide range of substances synthesized by cells or living organisms by means of different biological processes, including recombinant DNA technology, controlled gene expression, or antibody technologies. A biosimilar establishes similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise. Minimizing development costs and accelerating their market access create a convergence of interests between health services, worried about sustainability, and generic manufacturers. While the demonstration of bioequivalence is sufficient for small synthetic molecules, this approach is not scientifically applicable to a copy of biological drug constituted by large and complex molecules, which are similar but not identical to the originator and are also subject to different post-translational processes. Internists should be confident that the development process of biosimilars ensures a comparable risk-to-benefit balance with the originators. On the basis of available evidence and pharmacovigilance network, there are no grounds to believe that the use of a biosimilar carries more risks for the patient than the use of an originator. Since the first biosimilar was authorized in Europe in 2006, no clinical alerts have raised red flags about the established EMA biosimilar pathway. In this article, we discuss some of the most frequent concerns raised by clinicians about biosimilars and try to explains the scientific principles underlying the biosimilar concept established in the EU in order to license biosimilar drugs.

A scoping review of cost-effectiveness of screening and treatment for latent tubercolosis infection in migrants from high-incidence countries.

BACKGROUND: In low-incidence countries, most tuberculosis (TB) cases occur among migrants and are caused by reactivation of latent tuberculosis infection (LTBI) acquired in the country of origin. Diagnosis and treatment of LTBI are rarely implemented to reduce the burden of TB in immigrants, partly because the cost-effectiveness profile of this intervention is uncertain. The objective of this research is to perform a review of the literature to assess the cost-effectiveness of LTBI diagnosis and treatment strategies in migrants. METHODS: Scoping review of economic evaluations on LTBI screening strategies for migrants was carried out in Medline. RESULTS: Nine studies met the inclusion criteria. LTBI screening was cost-effective according to seven studies. Findings of four studies support interferon gamma release assay as the most cost-effective test for LTBI screening in migrants. Two studies found that LTBI screening is cost-effective only if carried out in immigrants who are contacts of active TB cases. DISCUSSION AND CONCLUSIONS: Our findings support the cost-effectiveness of LTBI diagnostic and treatment strategies in migrants especially if they are focused on young subjects from high incidence countries. These strategies could represent and adjunctive and synergistic tool to achieve the ambitious aim of TB elimination.

Management of vaccinations in Italy: a national survey after healthcare regionalization.

OBJECTIVES: The main aim of this study was to describe the effects of regional organization and performance in managing vaccinations, in the light of the institutional devolution recently introduced in Italy. METHODS: We analysed (1) the general organization of regions for vaccination programmes, (2) the management of four vaccination programmes (combined measles-rubella-parotitis, varicella for children, influenza, and pneumococcal 23-valent for adults). First, we conducted preliminary face-to-face interviews with 16 regional managers of the infective disease prevention departments. Subsequently, we sent them a standardized questionnaire to obtain comparable information on general organization and on the four specific vaccination programmes considered. In all, 14 regions were eventually included. RESULTS: The survey showed a widespread lack of regional staff involved in the management of vaccinations and a geographical variation in the availability of computerized data collection. We recorded poor coverage for varicella and pneumococcal 23-valent vaccinations compared to MRP and influenza. Prices of the four vaccines varied widely among regions, with only a weak correlation between prices and volumes. LIMITATIONS AND CONCLUSIONS: The major limitation of the survey was the lack of information available at regional level. The piecemeal diffusion of computerized systems and the widespread lack of sufficient staff should mainly explain this. Economic incentives could be offered to regions that achieve national targets. Such incentives should encourage collaboration between central and regional authorities consistent with institutional trends in regional devolution.

Risk sharing agreements: what lessons from Italy?

Italy is one of the few countries that have matured substantial experience of risk-sharing agreements so far. The first performance-based arrangement was agreed in July 2006, and as of October 2010, eighteen contracts have been in force.The complex management of discount schemes is entirely based on Web registries run by AIFA, the Italian drug agency. The system validates each prescription and automatically requests the hospital pharmacy by e-mail to release the drug. If a patient meets nonresponder criteria, the hospital pharmacist should apply for pay-back to the manufacturer. There are still some important question marks to address. First of all, nonresponders have to be documented by health authorities, otherwise any undocumented nonresponder will be paid as a success. Another question concerns pre-set timing. Although the scientific rationale of the nonresponder criteria for each drug has not been made public, time frames appear too short to allow a reliable assessment. Another question is whether regions, which are financially accountable in Italy for pharmaceutical expenditure, are really able to claw back refunds from manufacturers. Unfortunately here again there are no official figures, and regions do not seem yet able to quantify the amount of pay-back matured in the 4 previous years. The delayed and incomplete availability of pay-back procedures may be one explanation.

Modeling in pharmacoeconomic studies: funding sources and outcomes.

OBJECTIVES: The prime objective of this study was to investigate whether sponsorship by the pharmaceutical industry affected the results of full economic evaluations (FEE) based on modeling. In particular, we focused on the flourishing literature based on Markov models, by far the most widely exploited tool for estimating lifetime costs and benefits. METHODS: We made a literature search of the international database PubMed to find all the studies on pharmacological treatments based on Markov models published in English in the period January 1, 2004 to June 30, 2009. We selected the FEEs focused on single drugs only, specifically cost-effectiveness and cost-utility analyses. Two hundred articles including FEEs based on Markov models were considered eligible. For the analysis, we classified the FEEs into two groups according to whether or not they had financial backing from the pharmaceutical industry. We then assessed the main conclusions, which were classified as (i) "favorable," (ii) "doubtful," and (iii) "unfavorable." RESULTS: Of the 200 articles, 138 (69 percent) were sponsored and 162 (81 percent) reached favorable conclusions. Sponsored studies were much more likely to report favorable conclusions than nonsponsored ones (95 percent and 50 percent, p < .001), the former even omitting unfavorable conclusions. CONCLUSIONS: The review found a substantial share of studies supported by the pharmaceutical industry, almost all concluding in favor of the drug studied, without any unfavorable conclusions at all. These results confirm also in the field of pharmacoeconomic studies that the best way of limiting confounding factors is by clearly distinguishing assessors from manufacturers and marketers of any new technology.

Continuing Medical Education in six European countries: a comparative analysis.

OBJECTIVE: We examined Continuing Medical Education (CME) systems in a sample of six EU countries: Austria, Belgium, France, Italy, Norway, and the UK. The aim of this comparative study was to assess the main country-specific institutional settings applied by governments. METHODS: A common scheme of analysis was applied to investigate the following variables: (i) CME institutional framework; (ii) benefits and/or penalties to participants; (iii) types of CME activities and system of credits; (iv) accreditation of CME providers and events; (v) CME funding and sponsorship. The analysis involved reviewing the literature on CME policy and interviewing a selected panel of local experts in each country (at least one public manager, one representative of medical associations and one pharmaceutical manager). RESULTS: CME is formally compulsory in Austria, France, Italy and the UK, although no sanctions are enforced against non-compliant physicians in practice. The only two countries that offer financial incentives to enhance CME participation are Belgium and Norway, although limited to specific categories of physicians. Formal accreditation of CME providers is required in Austria, France and Italy, while in the other three countries accreditation is focused on activities. Private sponsorship is allowed in all countries but Norway, although within certain limits. CONCLUSIONS: This comparative exercise provides an overview of the CME policies adopted by six EU countries to regulate both demand and supply. The substantial variability in the organization and accreditation of schemes indicates that much could be done to improve effectiveness. Although further analysis is needed to assess the results of these policies in practice, lessons drawn from this study may help clarify the weaknesses and strengths of single domestic policies in the perspective of pan-European CME harmonization.