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1、H E A L T H C A R E Generics Launch Strategies in the EU The impact of IP variations and national market acceptance by Peter Norman 2 About the author Peter Norman is a pharmaceutical consultant and analyst based in Burnham Beeches, near Windsor, England, with specialist knowledge of the respiratory
2、 disease and inflammation markets. He has written and presented widely on various aspects of respiratory disease, generics, orphan drugs, and on developments in therapeutic markets. Dr. Norman has over 20 years experience of the pharmaceutical industry in both R the patent cliff in Europe 119 10 Tab
3、le of tables Table 1: EU Member States and the value of their pharmaceutical markets in 2009 20 Table 2: Top 20 best selling drugs ($m), 2009 54 Table 3: European patent expiration dates for leading biological products 55 Table 4: Data requirements for MAAs for generic and biosimilar products 59 Tab
4、le 5: European sales of biologicals with no biosimilar available ($m), 2009 67 Table 6: European sales of biologicals with no biosimilar available ($m), 2009 (ctd 1) 68 Table 7: Availability of generic perindopril products in the 5 major EU markets 73 Table 8: Top 10 generic companies in the world i
5、n 2009 94 Table 9: Tevas key EU acquisitions, 200210 96 Table 10: Sandozs key EU acquisitions, 200010 97 Table 11: Promising generic opportunities in Europe, 20112012 121 Table 12: Promising generic opportunities in Europe, 20132015 122 11 Executive summary Introduction ? Europe provides the largest
6、 market for generic drugs in the world, but is highly fragmented with regard to the acceptance, and the market penetration, of generic drugs. ? Within the EU five countries (France, Germany, Italy, Spain and the United Kingdom (UK), are normally classed among the worlds seven major pharmaceutical ma
7、rkets but differ markedly in both pharmaceutical market value and the usage of generic drugs. ? Currently the three most significant generic markets within the EU are Germany, Poland and the UK, while that in France is becoming increasingly important. The generics markets in Spain and, especially, I
8、taly are developing more slowly. ? A number of other countries, including the Netherlands, Hungary, Romania and Denmark also have well developed generics markets of reasonable value. Patent protection ? In Europe the freedom to launch a generic product is constrained by patents and additional period
9、s of marketing exclusivity while filing for approval is also constrained by a period of exclusivity for the data in the originators original dossier submitted with its marketing submission. ? The dates that these define generally differ between European countries although there is a higher degree of
10、 convergence than there used to be. ? Patent approval is now almost always on an international basis via the European Patent Office, but patents are maintained on a national basis subject to the continued payment of the requisite fees by the patent holder. If maintained the term of a patent is 20 ye
11、ars from the date of the priority application. ? The period of marketing exclusivity is usually extended beyond the term of the patent, for up to 5 years, by the grant of a Supplementary Protection Certificate. These are to compensate for regulatory delays 12 that erode the effective patent lifetime
12、 but are granted on a national basis; and may be extended by an additional six months for drugs which have been evaluated in approved trials in younger (pediatric) patients. ? The period of data exclusivity varies between EU countries and is either 10 years (France, Germany, Italy, the UK, Sweden an
13、d the three Benelux countries) or 6 years (other countries including Spain) and precludes filing of a generic marketing application prior to the end of the exclusivity period, but is 10 years for all centralized applications. ? Companies can seek to expedite filing of generics by successfully challe
14、nging patents in the courts. Currently all such challenges can only be effected at the national level, and not across the EU. Generic approval processes ? The EU offers multiple pathways for approval of generics with four alternatives available since 1998. ? The centralized procedure provides commun
15、ity wide approval and provides the simplest option for companies seeking to market generic products across much of the EU, with all applications made to the EMA. ? The decentralized procedure is an increasingly popular method of achieving multinational approval while utilizing application to a natio
16、nal authority. However, not all national authorities accept such applications and popular authorities have capacity limitations. ? Use of the decentralized procedure has largely supplanted the mutual recognition procedure as it offers a speedier approval in all countries applied for, although the or
17、iginal authorization is also from the selected national authority. ? National approval remains an option, providing approval solely in the country where authorization is sought, but is less flexible and better suited to use by companies that do not wish to market generics in more than one country wi
18、thin the EU. 13 ? Another consideration for developers is that there are pronounced differences between granting of marketing authorizations and approval of reimbursement in the different EU countries. While the events are concurrent in Germany and the UK, there can be a delay of up to 200 days in a
19、 number of other countries. Biosimilars ? The term biosimilars is used to describe “generic“ biological therapeutics, to denote that the product is biologically similar but not chemically identical (in contrast to generics of small molecule therapeutics). ? Europe has led the way in developing a leg
20、islative pathway to deal with biosimilars and is the only major market where multiple biosimilar products are currently approved for use. ? Biological therapeutics represent an increasingly high proportion of the worlds best selling drugs and offer a valuable new challenge to the developers of gener
21、ics. ? In contrast to generics, the development of biosimilars imposes high entry barriers; technologically in respect of producing therapeutics, financially because of the much greater costs of development compared to generics, and legislatively with respect to the requirements of the distinct appr
22、oval process established for such products by the EU. ? There has been a steady growth in the rate of filing MAAs for such biosimilars, and in the number of such products that have been granted marketing approval. ? Although many biosimilar products have been approved in Europe, commercial success h
23、as been much more limited to date with Germany the only major market in which biosimilar products (especially epoetins) have had much impact. ? The clear commercial opportunities offered by biosimilars, allied to a reducing number of generic opportunities, have prompted both leading generics compani
24、es and major pharmaceutical companies to explore the opportunities in this area. 14 Case studies ? Four case studies illustrate how different approaches have been employed with respect to major generic opportunities. ? The development of two generic ACE inhibitors highlights the pitfalls of trying t
25、o achieve commercial success in a high value market segment where many generic substitutes are available. The resulting highly competitive market environment hinders achieving significant commercial success. ? The use of product lifecycle and patent strategies by the original developer to hinder gen
26、eric market entry is highlighted by the examples of omeprazole (Losec) and esomeprazole (Nexium). This case also highlights distinct differences in the five major EU markets with respect to product usage. ? In 2009 clopidogrel bisulfate (Plavix) was the second best selling drug in the world and shou
27、ld have been spared generic competition in Europe until 2013. Generic companies have successfully circumvented key patents by gaining approval of alternative salts of clopidogrel. Because these are directly substitutable for Plavix these generics have halved European sales of Plavix in 2010. ? The b
28、est selling drug in the world, with 2009 sales of $13.3bn, Lipitor (atorvastatin calcium) offers the most attractive opportunity that the generics industry has ever had. This prompted widespread attempts, mostly by Ranbaxy, to invalidate the key patents relating to atorvastatin. Although generally u
29、nsuccessful Ranbaxy reached an agreement with Pfizer granting it a license to sell generic atorvastatin after specified dates in various countries. This may enable Ranbaxy to recover its significant costs. In contrast in Eastern Europe branded generics have been successfully exploited by nationally
30、based (generic) companies. Generic companies ? The supply of generics has traditionally been the focus of specialist generics companies and not of interested to major pharmaceutical companies. Recent years have seen substantial consolidation within the generics industry, with the emergence of major
31、multinational generics companies, and a revival of major pharmaceutical companies interest in the supply of generic products. 15 ? Teva has emerged as the dominant player, with an aggressive acquisition strategy and is now a leading generics provider in all the major European markets. ? Novartiss ge
32、nerics division Sandoz is the leading generics provider in Europe and holds a dominant share of the (most significant) German market. ? Mylan, the leading US generics company, only established a European presence when it acquired Merck Generics. It now holds leading positions in the several European
33、 markets but not Germany. ? Icelandic-based Actavis has a significant presence in the European generics market, primarily in Eastern Europe, with only modest market shares in the major (Western) European countries. ? Sanofi-aventis and Pfizer are both actively developing their generics business, fol
34、lowing Daiichi Sankyos example with its acquisition of Ranbaxy. ? Significant independent European generics companies include German-based Stada, Slovenian-based Krka and Hungarian-based Egis with strong presences in Germany and Eastern Europe. ? The fragmented nature of the European market facilita
35、tes opportunities for new entrants, but also highlights the need to develop clear strategies that are focused upon the country or countries in which such entrants seek to compete. Strategic options ? In launching a new generic product the five questions the developer needs to address are: Why?, What
36、?, When?, Where? and How? ? Identifying the right products to develop requires access to accurate sales data in countries of interest. This needs augmenting by an analysis of the (expected) competitive environment. ? Collectively the European market potentially offers many significant opportunities
37、for new generic products in the period 2011 to 2014, but only two such opportunities in 2015. ? Patent challenges from generic companies are much rarer in Europe than in the US, in part because (currently) patents must be challenged in the courts of individual member states. 16 ? The UK, Germany and
38、 France all offer very attractive market opportunities to the generic supplier, while the Netherlands, Romania, Poland and Spain also offer significant opportunities, whereas Italian market conditions are currently unattractive. ? Approval of a new generic is best sought via filing a MAA for major c
39、ommercial opportunities or widespread marketing across Europe, while use of the mutual recognition process is likely to be preferred by smaller companies or where marketing of the generic is intended to be limited. ? The complications of the fragmented European market, and the different requirements
40、 in each country, suggest that the use of local partners will often be advantageous for smaller generic companies seeking to establish a new generic product. ? Despite the various problems that can arise there are significant opportunities for generic companies, both large and small, to launch new g
41、eneric products in the European market. And it also offers scope for new entrants to become established. 17 Chapter 1 Introduction Summary ? Europe provides the largest market for generic drugs in the world, but is highly fragmented with regard to the acceptance, and the market penetration, of gener
42、ic drugs. ? Within the EU five countries (France, Germany, Italy, Spain and the United Kingdom (UK), are normally classed among the worlds seven major pharmaceutical markets but differ markedly in both pharmaceutical market value and the usage of generic drugs. ? Currently the three most significant
43、 generic markets within the EU are Germany, Poland and the UK, while that in France is becoming increasingly important. The generics markets in Spain and, especially, Italy are developing more slowly. ? A number of other countries, including the Netherlands, Hungary, Romania and Denmark also have we
44、ll developed generics markets of reasonable value. 18 Europe In consideration of the global generic market Europe provides the largest market for generic drugs in the world but this remains highly fragmented with regard to the acceptance, and the market penetration, of generic drugs. This is influen
45、ced by a multitude of factors which will be considered while discussing strategies for the introduction of generics in Europe. In 2009 the European Generic Medicines Association (EGA) estimated that generics accounted for about 50% of the volume of pharmaceutical sales in Europe but only 18% of the
46、market by value. Figure 1: Generic market penetration (%) in Europe, 2006 0% 10% 20% 30% 40% 50% 60% 70% Czech Republic Poland Slovakia Sweden Slovenia Norway Netherlands UK Hungary Germany France Spain Belgium Denmark Switzerland Portugal Austria Finland Italy Ireland Market share By value By volum
47、e 0% 10% 20% 30% 40% 50% 60% 70% Czech Republic Poland Slovakia Sweden Slovenia Norway Netherlands UK Hungary Germany France Spain Belgium Denmark Switzerland Portugal Austria Finland Italy Ireland Market share By value By volume Source: European Generics Association BUSINESS INSIGHTS The average ma
48、rket penetration of generics within the EU, by volume, is 27% according to the EGA. The variations between countries are clearly evident in the data presented by the EGA (Figure 1) comparing the market penetration by country although these data show 2006 figures and are likely to under represent the
49、 current level of generic penetration in many of these countries. In 2006 total European sales of generic drugs 19 were $27.8 billion (bn), split almost equally between Western Europe, where generic penetration is typically low, and Central and Eastern Europe, where generic penetration is high. This difference reflects the evolution of the markets in these areas over the past 50 years. The EU The European Union (EU) now encompasses 27 countries (member states) which range dramatically in size from $1m from Italian sales of generic omeprazole were amongst the first movers bu