Katelijne van de Vooren

Italian risk-sharing agreements on drugs: are they worthwhile?

Both payers and manufacturers have shown increasing interest in risk-sharing schemes, since they are expected to serve as a mechanism for reducing uncertainty through greater investment in collecting clinical evidence once a new drug is already being used in a health care system. The underlying philosophy is to pay only for patients responding to therapy, a very challenging issue in a clinical perspective, while appealing from a political viewpoint. Recently, an international group of experts proposed to call them ‘‘Performance-Based Risk-Sharing Arrangements’’, a highly complex definition indeed [1]. These contracts exist in many varieties, generally as a reaction to the increasing costs of expensive new drugs, while more data are still needed to thoroughly assess their effectiveness. In principle, they could provide additional options to payers and manufacturers, to boost overall efficiency [2]. The ambitious goal is to help reduce the likelihood of payers adopting technologies that turn out not to be cost effective, while at the same time helping manufacturers earn profitable prices to invest in future innovative technologies. Italy is one of the countries that started early with these agreements: AIFA, the Italian drug agency, agreed on its first contract in July 2006 [3]. The complex management of these schemes, now called managed entry agreements (MEAs) by AIFA, and similar to the patient access schemes in the UK, is entirely based on web-registries. Hospital consultants are required to complete an on-line prescription form, with the patient’s identification data, therapeutic indication and dosages. The system validates each prescription and automatically requests the hospital pharmacy to release the drug. Every single prescription is tracked to monitor appropriate use of innovative and expensive specialist drugs. AIFA has published on its website a very accurate estimate of the time required by a hospital consultant and a pharmacist to complete the most important forms, even splitting these estimates for expert and non-expert professionals [4]. However, the negligible average times estimated to complete some forms—e.g. 30 s for an experienced consultant for forms focused on diagnosis, 10 s for a pharmacist for those needed for dispensing—hardly seem realistic, taking account of the varieties of drugs and indications. Twenty-nine MEAs were in force as of October 2012 [5], for 25 drugs (Table 1). Three different types of agreement can be stipulated with pharmaceutical companies: (1) costsharing (CS, n = 11), (2) risk-sharing (RS, n = 2) and (3) payment-by-results (PbR, n = 16). CS implies just a price discount, usually limited to the first 2–3 months or cycles of therapy. These discounts are normally monetary and manufacturers are expected to do a pay-back. The other two contracts are based on the rates of ‘‘non-responders’’. The manufacturer is expected to pay back part of (RS) or the full price (PbR) for each non-responding patient. If a patient meets ‘‘non-responder’’ criteria, the hospital pharmacist should apply to the manufacturer for pay-back not later than the end of the year; the manufacturer can accept or reject the proposal (requiring arbitration) [5].

A critical systematic review of budget impact analyses on drugs in the EU countries.

BackgroundBudget impact analysis (BIA) is a relatively recent technique that is supposed to be complementary to more established economic evaluations (EEs).ObjectiveWe reviewed the BIAs published on drugs in the EU since December 2008, to assess whether these studies have improved in quality in the last few years.MethodsWe conducted a literature search on the international databases PubMed and EMBASE. The selected articles were screened using a two-step approach to assess (1) their main methodological characteristics and (2) the level of adherence to the latest BIA definition. The assessment was made by two independent reviewers and any disagreement was resolved through discussion.ResultsEventually, 17 articles were reviewed. Thirteen referred to a stand-alone BIA not accompanying a full EE, only nine focussed on a new treatment, 15 were sponsored by the manufacturer of the drug of reference, all but one claiming savings for healthcare budgets. The quality of methods was poor in many of the studies, and only a few of them attempted to estimate real local costs in a credible way. Therefore, the crucial items that in theory make a BIA different from other types of EEs were often the major points of weakness of the studies reviewed.ConclusionsOur review confirmed that the BIA is not yet a well-established technique in the literature and many published studies still fail to reach an acceptable quality. In particular, BIAs funded by pharmaceutical companies appear to be tailored to show short-term savings induced by new, highly priced products.

Pricing Human Papillomavirus Vaccines

Cervical cancer (CC) is the second most common female cancer worldwide, mainly affecting women aged between 35 and 55 years. It has important consequences in terms of life-years lost. There are around 60 000 new cases per year in Europe and almost half of these die from the disease. The high-risk types of human papillomavirus (HPV) are a recognized cause of CC. Cervical screening programmes that achieve high coverage and include effective follow-up and treatment of women with abnormal results can reduce CC incidence by over 80%. HPV vaccine is the first available against a cancer. It has a complementary role in the prevention of CC, parallel with screening programmes using Pap smears and DNA tests. The European Medicines Agency (EMA) has approved twoHPVvaccines. The quadrivalent vaccine (Gardasil , Sanofi-Pasteur MSD) protects against HPV types 6, 11, 16 and 18, and the bivalent vaccine (Cervarix , SKF) only protects against types 16 and 18. Types 16 and 18 are responsible for about 73% of all CC cases in Europe. Both vaccines prevented more than 90% of precancerous lesions associated with types 16 or 18 among HPV-naive women in large phase III trials. The low oncogenic HPV types 6 and 11 mainly cause genital warts (90%), low-grade neoplasia and recurrent respiratory papillomatosis. Both vaccines are administered on a three-dose schedule in 6 months. To our knowledge, HPV vaccines are the most expensive of all available vaccines, their manufacturers claiming the high prices reflect a major R&D investment and relatively complex manufacturing processes. ‘Sky-high prices’ might be a major hurdle for vaccination programmes in many countries, in view of widespread pressure on healthcare budgets. As of July 2010, vaccination advisory bodies had passed a recommendation in favour of HPV vaccination in 21 of 29 European countries (27 EU countries plus Norway and Iceland), 18 of them having actually included it in their national vaccination programme. Countries where it is not yet included are mostly Eastern European countries with generally lower healthcare budgets. Here we describe the Italian situation as regards HPV vaccine prices, in the hope that some interesting lessons can be drawn for elsewhere.

Regional tenders on biosimilars in Italy: An empirical analysis of awarded prices

OBJECTIVE The goal of the present study is to assess the awarded prices and thus the real level of competition the regional tenders referring to biosimilars in Italy achieved. METHODS We conducted a web-based analysis to collect detailed information on regional biosimilar tenders, up to December 2012. We identified 191 lots referring to the three off-patent biologicals (somatropin, epoetin and filgrastim) mentioned in the 24 tenders that took place during the study period (2008-2012). A multiple linear regression analysis was conducted to assess the relationship between prices awarded (dependent variable) and potentially explanatory variables (base quantities, bioagent, number of competitors, purchasing region and time). RESULTS While the price of somatropin stayed steady, those of filgrastim and epoetin dropped steeply. The mean number of competitors was lowest for somatropin and highest for filgrastim. One additional competitor was associated with about a 10% reduction in the price on average. The benefits of having many competitors did not fade with increasing numbers of companies. DISCUSSION Our analysis confirms the theory that worthwhile savings can be generated in tenders, once the bid is designed in such a way that competition can produce its effects, i.e. allowing more than one manufacturer to tender. However, most of the Italian regional tenders on off-patent bioagents do not seem to exploit potential competition to the full.

Market-access agreements for anti-cancer drugs

Newly marketed pharmaceuticals command increasingly high prices, particularly in oncology where single treatment cycles can be very costly, even though data at market approval are usually inadequate to describe thoroughly their effectiveness and cost-effectiveness. Both manufacturers and payers have shown interest in solutions to achieve rapid access for patients – known as ‘market-access agreements’. Although the literature offers a variety of definitions, these agreements can be roughly grouped under two main types: financial-based and performance-based. Financial-based schemes focus on the budget impact of a new drug and usually consist of price/dose discounts. Performancebased schemes involve collecting clinical evidence once a new drug has been marketed in a healthcare system and lead to payment only for patients responding to therapy, an objective which is methodologically and practically challenging while not without political appeal. The underlying strategy is to help reduce the likelihood of payers adopting technologies that turn out not to be cost-effective, while at the same time helping manufacturers increase market access time and take profit. Market-access agreements can also be considered an opportunistic way for manufacturers to keep official prices high such as maintaining a common European price, while granting health authorities confidential rebates, thus preventing parallel trade and undermining effective external reference pricing. The English and Italian health services have been the first countries to introduce market-access agreements on specific drugs. These contracts are now called Managed Entry Agreements (MEA) in Italy and Patient Access Schemes (PAS) in England and Wales. We focus on the area of oncology, where many new drugs are costly and fall under these arrangements. Italy

Tendering and value-based pricing: lessons from Italy on human papilloma virus vaccines

Cervical cancer is the second most common female cancer worldwide, mainly affecting women aged between 35 and 55 years. It has important consequences in terms of life-years lost. The high-risk types of human papilloma virus (HPV) are a recognised cause of cervical cancer. HPV vaccine is the first available against a cancer. The European Medicines Agency has approved two HPV vaccines. The quadrivalent vaccine protects against HPV types 6, 11, 16 and 18, and the bivalent vaccine only against types 16 and 18. Types 16 and 18 are responsible for about 73% of all cervical cancer cases in Europe. The low-oncogenic HPV types 6 and 11 mainly cause genital warts (90%), low-grade neoplasia and recurrent respiratory papillomatosis. To our knowledge, HPV vaccines are the most expensive of all available vaccines, their manufacturers claiming the high prices reflect a major research and development investment and relatively complex manufacturing processes. Vaccination advisory bodies have passed a recommendation in favour of HPV vaccination in most EU countries. Both the bivalent and the quadrivalent vaccines are used in Italy for the prevention of cervical cancer. The Italian National Health Service, a public service funded by general taxation, has three institutional tiers: the Department of Health; Regional Health Authorities; and Local Health Authorities. Since 2001, a Constitutional Law has increased regional autonomy (so-called ‘regionalisation’ or ‘devolution’) in healthcare policy, which leads the Regional Health Authorities to develop different economic strategies. Most Regional Health Authorities run tender schemes to exploit potential competition between the two vaccines manufacturers. The regions of Lombardy and Piedmont recently held tenders, both of which were awarded to the bivalent vaccine manufacturer which offered its vaccine for E34.47 per dose while the most recent one (Veneto region) went to the quadrivalent vaccine at E32.75. This price illustrates the steep decline which started in 2007 with the first regional tender for HPV vaccines. The current tender prices indicate substantial savings for the Italian National Health Service, as the ex-factory prices per dose negotiated by AIFA (the Italian agency for drugs) are E95 for bivalent vaccine and E104 for quadrivalent vaccine. The Italian experience demonstrates that tendering may be associated with worthwhile price reductions even where competition is limited, with only two manufacturers offering products for sale. It appears that the same has been achieved with tendering in other EU countries like Sweden and the UK, although tender prices are considered commercial in confidence in these countries. Some indication of prices paid in the UK may be gained from The Department of Health’s Commercial Medicines Unit, which provides mean prices paid for pharmaceutical products. Differences between the two vaccines can be addressed through adding a ‘quality score’ in tender clauses (as in the recent UK tender and in three regional tenders in Italy), in an attempt to maximise cost-effectiveness rather than simply minimise cost. Economic theory suggests that tendering procedures may achieve important savings when purchasing power is high on the demand side, where there are potential suppliers for similar products (shifting the balance of power to the buyer) and where there is perfect information. A further tangible benefit of tendering is when it increases the transparency of prices, at least in the countries where they are publicly available and discounts become directly observable between different contracting authorities. If low prices achieved through tendering are sustained over time, highly centralised and long duration tenders could force some manufacturers out of the market, generating dominant positions. This could erode competition and lead to future price increases. Such a negative scenario depends largely on the size of the tender setting, and in countries like Italy the

HPV Vaccination for Boys? Talking Economic Sense

Vaccination against human papilloma virus (HPV) is the first example of vaccination registered for prevention of a cancer. HPV virus infection has one of the strongest cause–effect relationships with cervical cancer (CC) ever seen in related cancer research. More than 100 HPV types exist, but only a few have been proved oncogenic. Two vaccines against HPV are marketed at present. The quadrivalent vaccine protects against types 6, 11, 16, and 18 and has indications for CC and genital warts (GWs), while the bivalent one protects against types 16 and 18 and is indicated only for CC. On average, efficacy is high (>95%) for both vaccines in preventing type-specific high-grade and low-grade cervical intra-epithelial neoplasia (CIN), vulval and vaginal intraepithelial lesions, and slightly lower in preventing other genital HPV-related cancers and GWs for the quadrivalent vaccine only; the longest follow-up is 7 years so far [1], although a much longer duration is expected. The health authorities of most Western European countries introduced HPV vaccination quite rapidly once it was approved, but only for adolescent girls [2]. Despite the rapid introduction, however, coverage is still unsatisfactory in many jurisdictions. A quick search on the Internet found 76.4% coverage in England [3], 63.8% in Italy [4], 52.5% in the Netherlands [5], and 77.3% in Spain [6], all countries with a tradition of public vaccination campaigns. Except for Scotland where coverage reaches 86.9%, these figures are not very impressive compared with the average immunization rate of around 90% for childhood vaccinations against diphtheria, tetanus, and pertussis (DTP), measles, and polio. Vaccination is cited in health economics as the typical example of how to achieve “positive externalities.” This means some individuals benefit without cost from decisions made by others, like massive vaccinations whose benefits extend to unvaccinated subjects thanks to the “herd immunity” effect in epidemiology. However, this is hardly the case for HPV vaccination since at present it is limited to females. The low immunization rates could provide an argument for extending vaccination to males, to achieve the greatest possible protection from CC and its precursors for females in a shorter time. Historically, the implementation of gender-based vaccination policies has not been really effective and tends to be confusing for the public [7]. When considering extension to boys, the potential positive effects on men should be evaluated as an additional advantage for the quadrivalent vaccine, i.e., the prevention of GWs and HPV-related male cancers. Other considerations come into play as well [8]. For instance, women-only vaccination cannot protect men who have sex with men. More in general, vaccinating males seems equitable since both sexes contribute to HPV transmission. It would be helpful if the decision on male extension were supported by economic evidence. However, HPV vaccination seems to be a typical field where economic evaluations (EE) built on modeling suffer their greatest limitations in contributing to rational decision making [9]. EEs on HPV vaccination can be considered mere exercises in long-term forecasting, projecting short-term clinical evidence into the distant future on the basis of various heterogeneous assumptions and estimates, most of them highly optimistic, making these models potentially misleading and of scant utility for public policy purposes. It is easy to predict that male extension will roughly double expenditure, which would be hardly balanced by additional benefits without including higher coverage, since GWs and HPV-related male cancers are much less burdensome than female CC. However, economic theory reminds us that EE can be expected to be a useful decision-making tool only when market competition is lacking. Otherwise, even when competition is minimal (for instance, only two competitors), prices can always fall steeply, as the Italian experience has shown [10]. In Italy free HPV vaccination for 12-year-old girls started in 2008. The vaccination campaign was devolved to the 20 Italian regions, which are responsible for planning local healthcare services and allocating financial resources within the Italian National Health Service (INHS). In order to lower the high prices negotiated at national level, each region purchased vaccines through tenders. Over 2 years prices almost halved thanks to competition between the two HPV vaccines. Since the extension to boys would add secondary goals to the primary one (CC), the two vaccines can hardly be considered equivalent, the quadrivalent one being more effective in this new scenario. To take this into account, a “quality score” could be added in tender clauses (like in the recent UK tender [11] and in three regional tenders in Italy) so as not to consider only the best price offered. The prices from public tenders in countries like Italy, Sweden, and the UK could be used as “international benchmarks.” Rather than estimating cost-effectiveness on the basis of too many unsustainable assumptions (including prices held high by manufacturers), it might be worth assessing an “opportunity cost” to evaluate sustainability in health care, i.e., the cost of an alternative that must be forgone in order to pursue a new action. For instance, we estimated that it would cost less than 45 million euros to extend vaccination to 12-year-old boys in Italy at the current market price (€50 ¥ 3doses ¥ ~290,000 boys). This is less than the yearly expenditure now borne by the INHS for a biological agent reimbursed as second-line treatment for metastatic colorectal cancer, providing on average 4.7 months extra life expectancy for an incurable disease with a median age of over 70 years at diagnosis. Particularly in a period of recession and widespread cuts to public expenditure, the most pressing question is where to allocate scarce financial resources, e.g., in end-of-life treatments to extend a very poor quality life for a handful of months or in an adolescent vaccination that may well give lifelong prevention for a cancer. Public health experts are in the right position to advise decision makers on whether or not to extend HPV vaccination to boys, while health economists can help make the potential choice sustainable in practice.

Biosimilar Versus Generic Drugs: Same But Different?

Research and development characterizes the pharmaceutical industry, and the flow of new drugs is protected by patents to remunerate this investment. Once a patent expires, price competition is possible, since any manufacturer can copy the originator product. This circumstance justifies the place in the pharmaceutical market for generics and biosimilars, i.e. off-patent medicines to be sold at lower prices than their originators. While generics have been widely used throughout the world for decades, this is not yet the case for the more recent biosimilars, of which only six have been approved by the European Medicines Agency (EMA) so far [1]. Here, we compare these two types of off-patent medicines to highlight their differences, particularly what makes biosimilars peculiar beyond the way they are produced. We mainly refer to Western European countries, since generics have been in use there for decades alongside in-patent drugs.

Regional HTA in Italy: Promising or confusing?

We assessed the actual implementation and achievements of regional HTA in Italy. We conducted a web-based analysis (updated until July 2012). Six key elements were identified: availability of official documents, existence of a specific workgroup, involvement of external organizations, formal funds for HTA, publication of HTA reports, and membership of HTA networks. Then, we searched all HTA reports retrieved by key words to analyze whether their contents included clinical efficacy, economic evaluation, legal issues, ethics and organization. Two researchers analyzed the information separately, as a double check. Sixteen regions have formally established a structured workgroup inside their organizations. Specific funding for HTA activities could be traced in six regions, web-available reports only in four. Around 91% of the total reports concerned drugs. Contents mostly focused on epidemiological and clinical issues, economic evaluation was often restricted to a brief analysis of costs. Only a few reports mentioned organizational implications; ethical, legal and social issues were lacking. This survey showed a very uneven picture of HTA in the Italian regions. As expected, not all the regions were able to perform HTA, probably on account of their wide differences in size, tradition and skills in the health care field.

Pricing of forthcoming therapies for hepatitis C in Europe: beyond cost-effectiveness?

The worldwide economic crisis has put enormous pressure on national health care expenditures, not only in developing countries but also in developed ones. Some have adopted various cost-saving measures to keep pharmaceutical expenses sustainable, which are one of the most variable shares of the health care budget, and thus easier to influence. To back hard choices on pricing and reimbursement, decision-makers increasingly require full economic evaluations (FEEs), which are becoming popular in the general attempt to gain efficiency in the allocation of scarce resources [1]. We take as an example the new drugs for hepatitis C, widely debated at present. Although these drugs seem to be a good step forward in the struggle against this illness, they pose a major threat to pharmaceutical expenditure because of their sky-high prices combined with large target groups. After a brief introduction on the epidemiology of hepatitis C and its treatment options, we critically analyze the FEEs published in the EU on the first generation of direct-acting antivirals (DAAs) indicated for hepatitis C, to assess their contribution to rational decision-making according to the key drivers of their results [2]. We focused on this new subclass of drugs to draw lessons for the forthcoming generation of even more effective anti-HCV therapies, offering both greater efficacy and safety. Epidemiology and treatment