Alessandro Curto

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.

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

Pharmaceutical Price Schemes in Europe: Time for a ‘Continental’ One?

Although a basic concept of economic theory is that the price of a good depends on demand for it, the health sector is an exception and pharmaceutical pricing is a clear example of ‘market failure’, with drugs considered special ‘merit goods’ rather than common ‘consumer goods’ [1]. From the demand side, patients are not normal consumers; instead, medical doctors decide therapies on their behalf (the so called ‘principal-agent relationship’) and pharmaceutical expenses are mostly funded by ‘third-party payers’ throughout the world [2]. From the supply side, the pharmaceutical industry—by definition profit-oriented like any private industry—seeks to price its in-patent drugs as high as possible, to maximize the return on research and development (R&D) expenses during the global period of monopoly rent. As a consequence, price competition in the pharmaceutical market is hampered even when alternatives with similar efficacy are available. Historically, regulation schemes for drug prices have been an unavoidable policy response to control public health expenditure [3]. This is particularly true during periods of financial crisis, when resources become really scarce, as is currently the case in many countries. We discuss the current EU price regulation schemes for drugs from a third-party payer’s perspective, using the well known management tool of Porter’s competitive business strategies [4]. Starting from three main conceptual approaches to price a good (cost/reference/value-based), we mainly consider Western EU countries as examples, where pharmaceutical price regulation has a long tradition (and, through reference pricing, influential in Eastern European countries too). Then, we discuss policy implications and future scenarios from a European integrated perspective.

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.

European Medicines Agency: leave the UK but remain the same

The current period of unprecedented financial crisis has raised growing doubts on the results so far achieved by the European Union, starting from economy and welfare, and pharmaceuticals are hardly an exception. The so-called ‘Brexit’ has formally raised the question of the European Medicines Agency moving from Great Britain to an EU Member State in the near future. After its inception in 2005, the European Medicines Agency – a big agency indeed, with a budget of E324.7 million and 890 employees in 2015 – has been mainly criticised as being too cosy with the pharmaceutical industry, which contributes around 70% of its budget, rather than patients’ interests. Here we discuss the European Medicines Agency’s role so far in the different steps of the European drug regulatory procedure and envisage an alternative scenario for the future, with a general proposal for redesigning its scope before the presumed move.

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

Personalized medicine and economic evaluation in oncology: all theory and no practice?

The clinical definition of personalized medicine (PM) is closely related to that of pharmacogenomics. Ideally, PM could lead the pharmaceutical industry to differentiate products by subgroups of patients with the same pathology and find new gene targets for drug discovery. Here, we focus on the potential impact of PM on the design of clinical trials and economic evaluations limited to oncology (its first and main field of application). Then, we assess the European economic evaluations focused on trastuzumab and cetuximab, the two drugs usually mentioned as emblematic examples of targeted therapies. Clinical results of PM in oncology have not been as encouraging as hoped so far. Of course, economic evaluations on targeted therapies cannot help overcome the lack of clinical evidence for most of them. The two paradigmatic examples of cetuximab and trastuzumab indicate that the methodological implications on economic evaluations debated in the literature are more theoretical than practical.