Anna Padula

Economic evaluation of human papilloma virus vaccination in the European Union: a critical review

The human papilloma virus (HPV) vaccine is a new and expensive vaccine potentially effective in the prevention of a cancer. We reviewed the economic evaluations (EEs) on the vaccine in the EU to assess their potential contribution to public decision-making in a fairly homogeneous setting where HPV vaccination has been widely adopted. A literature search on PubMed selected EEs on HPV vaccines in the EU for the period 2007–2010 using the terms “HPV vaccines” and “Costs and cost analysis.” Fifteen articles were eventually selected. All studies were based on modelling techniques, either “cohort” or “dynamic transmission”: three were cost utility, three cost-effectiveness, and the remainder included both. The ten studies explicitly assessing one of the two vaccines were all sponsored by their manufacturer, while the five studies unrelated to the vaccine type were funded by public agencies. Apart from two studies, utility estimates were always obtained from three US sources. Direct costs were always vaccination, diagnosis and treatment of related pathologies. Incremental cost-effectiveness ratio (ICER) results were less favourable when life years gained were valued rather than quality-adjusted life years, genital warts were excluded, and booster doses and extension of vaccination to men were included in the base-case analysis. All but one of the sponsored EEs recommend in favour of the vaccination strategy, which is dominant in one English study. The ICER results were very sensitive to discount rates, followed by duration of protection and vaccine price. At such an early stage, when the vaccines’ efficacy have been demonstrated by well-designed studies, it is not possible (and not even reasonable) to wait for several years to measure their effectiveness; public decision-makers might benefit more from EEs designed to indicate sustainable prices using realistic estimates of crucial variables like coverage rates, rather than referring to a large number of assumptions in order to show acceptable cost-effectiveness.

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

Abstract 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.

‘Appropriateness’ in Italy: A ‘Magic Word’ in Pharmaceuticals?

Appropriateness is the term largely used in Italy in the debate on efficient allocation of health-care services. Various domestic laws mention it, stressing its importance for enhancing the performance of the Italian National Health Service (INHS). The latest finance law even introduced a ‘Commission for the Promotion of Appropriateness in the INHS’, aiming at ‘leading a continuous evaluation of existing and forthcoming health care services and assessing their economic impact’ [1]. Focussing on drug therapies, a recent triennial planning law [2] described various measures to improve prescription appropriateness and control of pharmaceutical expenditure, such as updating the National Medicines Formulary (the Italian positive list) on the basis of efficacy and cost-effectiveness criteria and redefining the rules for patients’ access to reimbursement. During the last few years several regional health authorities approved measures aimed at improving prescription appropriateness [3]. At central level, AIFA (Agenzia Italiana del Farmaco), the main authority for drugs in Italy, adopted four tools for the appropriateness of drug prescriptions [3]: (1) the socalled ‘AIFA notes’, which define the reimbursement regimens for many drugs and encourage physicians to limit prescriptions to the indications with proven efficacy; (2) price caps for single drugs or therapeutic classes within managed entry agreements [4] contracted with pharmaceutical industry; (3) ‘therapeutic plans’, which state the clinical conditions for reimbursement and limit it only to labelled therapeutic indications; (4) ‘monitoring registries’, which track the eligibility of patients and the complete flow of treatments according to approved indications. To measure the appropriate use of medicines, AIFA has recently identified a set of indicators focussed on prescription behaviours, consumption of medicines, and compliance to prescribed therapies [3]. Finally, AIFA has issued a formal definition of appropriateness, describing it as the ‘adequacy of the actions adopted to manage a disease, concerning both the patient’s needs and the correct use of resources’ [5], a far-reaching definition indeed.

Dutch guidelines for economic evaluation: ‘from good to better’ in theory but further away from pharmaceuticals in practice?

Economic evaluation (EE) is still a historically young discipline in healthcare. Originally started as a technique for assessing investments in the public sector, EE has been applied to healthcare since the last decades of the previous century and disseminated rapidly to many countries, thanks partly to a successful English manual, which was later translated into many other languages. The first edition of the manual mainly referred to EE on health procedures, services or programmes, and not to products like drugs. Then, very soon, the Canadian State of Ontario and Australia issued the first pharmacoeconomic guidelines for drugs reimbursement, followed later by many Western European countries (e.g. The Netherlands, Norway, Portugal and Sweden). Last year the Dutch National Health Care Institute issued new guidance for EE in healthcare. Although the latest guidelines (Box 1) go beyond drugs (differently from the past), covering five further areas (prevention, diagnostics, medical devices, longterm care and forensics), pharmaceuticals are still the main field of application. Several elements of novelty reflect the methodological developments in EEs, two of which have been judged the most important recommendations for drugs: value of information analysis and indirect medical costs. Both concern EE ‘borderline’ subjects coping with uncertainty. The first is a statistical tool intended to be useful for assessing uncertainty related to the consequences of inappropriate decision-making in healthcare; the second concerns the unrelated future medical costs induced during the life years gained indirectly from a technology which prolongs the life of patients. In general, although we do not dispute that the new Dutch guidelines can be considered a scientific step forward in improving the requirements for EEs in healthcare, moving from good to better recommendations and still open to further improvement in the future, we still feel that health decisionmakers should be fully aware of the general intrinsic limits of EE that have been underlined in the last two decades, moving from theory to practice. Thus, here we critically analyse the main key points for conducting an EE, underlining the main weaknesses of EE as pragmatic tools for public decision-making, particularly in the perspective of pharmaceutical pricing and reimbursement.

Real-world evidence in economic evaluations: Really realistic?

Real-world evidence is an emerging worldwide paradigm that claims to join the forces of academia, research institutes and industry to advance in the field of data science, particularly pharmaceuticals. Although appealing, the concept is still controversial and so a common, technical definition is currently lacking in the literature. According to the ISPOR task force report published almost 10 years ago, real-world evidence can be defined as that drawn from ‘data used for decision making that are not collected in conventional randomized controlled trials (RCTs)’. In practice, while randomised controlled trials are the acknowledged ‘gold standard’ for efficacy, their selected populations, idealised conditions and limited time horizons may be considered intrinsic limits to assess effectiveness and costs. The sources of real-world data can be various, the main ones, in order of rigour, being: (i) registries (prospective observational cohort studies); (ii) electronic health records (mainly e-medical charts); and (iii) administrative databases (typically retrospective data). Real-world evidence is expected to support rational decision-making, especially after market approval of drugs. This has recently encouraged regulatory authorities to fast-track drugs to market as soon as possible, e.g. the European Medicines Agency through its ‘adaptive licensing’. Ideally, once preliminary efficacy and safety have been assessed, the evaluation of relative effectiveness and cost-effectiveness is postponed after marketing approval, relying on real-world data for evidence. Thus, real-world sources are potentially vital for economic evaluations. To explore the current state of the art of the subject, we first conducted a literature review of European full economic evaluations which claimed to be based on real-world data and then discussed the policy implications from a third-party payer’s perspective. Real-world and economic evaluations

Older anti-TNF-α agents: why not group them for common indications in the EU?

Introduction Tumor necrosis factors (TNF) are a group of cytokines that can cause cell death by apoptosis. TNF-α, the best-known member of this class, has a central role in the pathogenesis of various immune-mediated diseases such as rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis (Ps), psoriatic arthritis and Crohn’s disease.[1] Consequently, in the last decades, several TNF-α antagonists have been developed for therapeutic application in a wide range of disorders in rheumatology, dermatology and gastroenterology. TNF-α can be inhibited with two main types of immunosuppressant bio-agents: a monoclonal antibody such as infliximab (IFL) [2] and adalimumab (ADA),[3] or a circulating receptor fusion protein such as etanercept (ETN).[4] IFL, a chimeric human/mouse antibody, can be considered the “pioneer” of this class of drugs. First approved by the European Medicines Agency (EMA) for the treatment of RA in 1999, it gradually achieved positive recommendations for many other indications (Table 1). It is administered by intravenous infusion lasting 2 h at a dosage based on body weight at first, then a maintenance regime every 8 weeks.[2] ETN and ADA are the first “followers” of IFL: both were first approved for the same indication (RA) by the EMA, respectively, in 2000 and 2003. While ETN has shown no real benefit for gastroenteric disorders, ADA has currently the same indications as IFL (Table 1). Both are injected subcutaneously, weekly or twice-weekly for ETN and every 2 weeks for ADA.[3,4] Two other TNF-α antagonists (certolizumab and golimumab) have now been approved. Although no comparative clinical trial has ever evaluated the relative efficacy of these bio-agents, their “place in therapy” appears to be substantially equivalent in their common indications [5,6] and their safety profiles too can be considered similar.[7] When the IFL patent expired in 2013, EMA approved two specialties containing the same biosimilar,[8] with the same therapeutic indications as the originator and the same dosing regimens, pharmaceutical forms and strengths.[9] Biosimilars of ETN and ADA should follow in the next few years.[10] Here we critically review the full economic evaluations conducted in the European Union (EU) settings on the three older TNF-α inhibitors in their main common indications, to assess whether they can provide useful information to health authorities for purchasing strategies in the light of the changing “competitive arena”. Right now, the three agents are still priced separately in most EU countries.

Economic Evidence of Pneumococcal Vaccination in Older Adults: Uncertain Modelling or Competitive Tendering?

Diseases caused by Streptococcus pneumonia contribute considerably to morbidity and mortality worldwide [1]. The main types of illness are grouped as bacteremic pneumococcal pneumonia (BPP) and non-bacteremic pneumococcal pneumonia (NBPP), the latter causing less serious manifestations [1, 2]. Pneumococcal vaccination for infants has been widely debated in the last decade following the launch of the new and expensive conjugate vaccines (PCVs); unlike the old and cheap 23-valent polysaccharide vaccine (PPV23), PCV vaccines are immunogenic in children under 2 years of age [3]. Lately, the debate has shifted to the extension of PCV13 (the only PCV approved for adults) to at-risk and older adults instead of PPV23, which is still adopted in many European countries for campaigning on this population target. This hot debate [4, 5] is fuelled by two crucial issues that are still uncertain. First, although PPV23 has been shown to be effective in older adults, the extent and especially the duration of its protection are still doubtful [6, 7]. Second, vaccination of infants with PCVs (unlike with PPV23) provides herd immunity that has an impact on serotype replacement [8] and thus prevents disease in all ages [9], elderly included. Against this background, economic evaluations (EEs) of pneumococcal vaccines for adults published so far have had to rely on many assumptions [4, 10]. Very recently, the CAPiTA (Community-Acquired Pneumonia Immunization Trial in Adults) study (a Dutch clinical trial supported by the manufacturer) [11] showed that PCV13 is efficacious in preventing two thirds of BPP (75 %) and around half the NBPP (45 %) cases in older adults. The Spanish CAPAMIS (Community-Acquired Pneumonia, Acute Myocardial Infarction and Stroke) cohort study [12] (funded by public authorities) confirmed that PPV23 is effective against both BPP (62 %) and NBPP (48 %) in adults C60 years [5], although only for up to 5 years after vaccination. Here we critically review the most recent EEs published in the EU focussed on the elderly, to assess their potential contribution to public decision making and examine whether sponsorship by manufacturers influenced the results, as happened for studies focussed on infants [13].

The puzzle of drug delivery in Italy: who wins?

The Italian National Health Service (INHS) is a three-tiered (central–regional–local), highly decentralized public service, mainly funded by general taxation, which provides universal and comprehensive health care coverage throughout the country, including pharmaceuticals [1]. Once they have satisfied national regulations, the 19 Italian regions and 2 autonomous provinces (all governed by elected politicians) can autonomously manage and control the services delivered by their hospital trusts and local health authorities. Reimbursable drugs fall into two different classes in Italy: (i) Class A, drugs for severe and chronic diseases; (ii) Class H, drugs dispensed only in the hospital setting. Dispensing reimbursable drugs of Class A through pharmacies is historically remunerated by the INHS on the basis of a fixedmargin (30.35%) of the public price [2], corrected by a regressive discount by drug price band and pharmacy turnover since 1997, with a further overall discount (1.83%) since 2010. Obviously, dispensing Class H reimbursable drugs does not involve any distribution margin as these drugs are directly purchased and delivered by health authorities. From about a decade now, regions [3] can also opt for special delivery for a specific subclass of drugs listed inClass A, those in the so-called ‘Hospital-Territory Formulary’ (PHT, Prontuario OspedaleTerritorio). According to the Italianmedicines agency,AIFA (Agenzia Italiana del Farmaco), ‘the PHT should guarantee therapeutic continuity between intensive therapies in hospital (Class H) and chronic/short-term therapies in the community (Class A)’. In practice, these drugs can be dispensed to patients either by hospitals (like Class H) or by community pharmacies (like the whole of Class A) through what is termed ‘distribution on behalf’ (DPC, Distribuzione Per Conto). In both cases, medicines are purchased directly by health authorities, but in DPC they are still delivered by community pharmacies according to specific contracts signed with regions by their local associations. Here, we analyze the general PHT experience in the last decade, and particularly that of DPC, critically discussing its strengths and weaknesses.

Pharmaceutical care in Italy and other European countries: between care and commerce?

Pharmaceutical care (PhC) has been a highly debated concept since the first American definition in the early 1990s [1]. PhC was soon adopted internationally and many definitions have followed in other continents (including Europe), rapidly acknowledging the pharmacist’s pivotal role in PhC, and community care as its main setting of application [2]. After a brief summary of the debate in the literature on the definition of PhC and its activities in Europe, we discuss the potential implications of its introduction in countries like Italy, where PhC is backed by the Italian Association of Private Pharmacies (Federfarma) [3]. Italy has at the same time a ‘Beveridgian’ public service for healthcare funding (the Italian National Health Service) and a predominance of private pharmacies (around 90% of the total), traditionally hereditarily owned by single pharmacists, for the delivery of reimbursed drugs in community care [4].

Competition in pharmaceuticals: more product- than price-oriented?

The classic economic theory of perfect competition underlies a market in which products are fully homogeneous, consumers are price takers and there are no ‘entry or exit barriers’ [3]. Competitors can only set different prices as a market strategy. Striving to maximize their profit, firms will sell a product as long as its marginal revenue is higher than the marginal cost. With the entry of new competitors, the price will slip down to the marginal cost in the long run, making this an ideal situation for consumers. In early 1990s Hotelling introduced the more realistic, modern concept of product competition based on quality differentiation [4], which enables firms to compete beyond pricing in many markets. Competitors try to differentiate their products and compete more on quality than price in markets such as fashion, where product quality is highly valued by customers. To maximize profits, the best mix of product quality and price will mainly depend on the type of market. However, competitors need to differentiate their products to deter tough price competition and to be able to keep setting prices higher than marginal costs for a long period to maximize profits. Introduction