Perrigo pays US$540mn to purchase Paddock · Perrigo has signed a definitive agreement to buy privately-owned US generics firm Paddock Laboratories for US$540 million in cash. The

1 February 2011

Ireland’s EirGen gets FDA plant approval 2Strides seals deal for Brazil 3hospital tie-upActavis goes green for Icelandic plant 3Formulations grow at India’s Unichem 4Latvia’s Olainfarm targets 4new marketsHospira deal shifts the shape of Orchid 6Aurobindo sells its Chinese plant stake 6

MARKET NEWS 7

US states push on pay-for-delay deals 7EU Commission will examine settlements 7German firms fight AOK fund 8CGPA rails against Canadian IP report 9Legislators correct FDA on exclusivity 9

PRODUCT NEWS 10

France adds Ketalar rival to répertoire 10Pharmachemie spars over 11Dutch nebivololWatson has to wait for buccal fentanyl 12Glenmark must pay for ‘at risk’ launch 13Parexel helps Merck develop biosimilars 13FDA limits strength of 14US acetaminophenLovastatin returns to hurt 15Apotex CanadaCipla makes polypill for unique research 17

FEATURES 20

India and China forge ahead 20while Europe plays catch-upAPI and generics intelligence expert,Thomson Reuters’ Kate Kuhrt,outlines to Mike Rice the latest trendsin product supply.

REGULARS

Paragraph IV Watch – doxepin 16hydrochloride

Events – Our regular listing 18

Price Watch UK – Our regular 19look at pricing trends in the UK

People – Livesey joins Lupin’s 23unit in Switzerland

COMPANY NEWS 2

PPerrigo has signed a definitive agreement to buy privately-owned US generics firmPaddock Laboratories for US$540 million in cash. The figure represents a multiple of

about 10-times Paddock’s earnings before interest, tax, depreciation and amortisation(EBITDA) of US$53.1 million for the year ended 30 September 2010. Perrigo anticipatesthe transaction will close by the end of June. Additional sales of around US$200 millionare expected by Perrigo in the fiscal year ending June 2012. It believes a tax benefit fromthe acquisition should also save the firm around US$95 million over the next 15 years.

Acquiring Paddock allows Perrigo to expand its core range of “extended topicals”, whichincludes dermatology, nasal and respiratory products as well as suppositories. Three of Paddock’stop five products fell into this category, Perrigo said, whilst the other two were hormonalproducts that represented a new category for Perrigo. In total, Paddock’s portfolio comprisesmore than 35 products.

Paddock also boasts a pipeline of more than 25 abbreviated new drug applications (ANDAs)pending approval by the US Food and Drug Administration (FDA). Of these, around 10 containparagraph IV certifications – including two first-to-file opportunities – whilst the remainingANDAs include three candidates that could be first to reach the market, and five products thatshould face limited competition. Approvals for around half of the pending ANDAs wereanticipated this year, Perrigo said, adding that other products in development also representedseveral potential first-to-file or first-to-market opportunities.

Noting the “excellent development and manufacturing capabilities across a spectrum ofniche dosage forms”, Perrigo’s chairman and chief executive officer, Joseph Papa, pointed outthe acquisition included an 18,800sq m research and manufacturing facility in Minneapolis. Costsynergies were not the primary motivation for the acquisition, Papa added, noting that Paddockwas “already a lean organisation”. The deal “solidifies Perrigo’s leading position in the extended-topical space and strengthens our ability to offer new products into the market”, he maintained. G

Preparing guidelines on biosimilar beta-interferon and follitropin alpha are among thetasks listed on the 2011 work plan of the biosimilar medicinal products working party

(BMWP) within the European Medicines Agency (EMA).Last year, the EMA released for comment concept papers on both beta-interferon and

follitropin (Generics bulletin, 23 April 2010, page 12). At that time, the agency said thebeta-interferon guideline would give recommendations “on the choice of appropriate speciesand models to be used for the comparison of the pharmacodynamic effects of the test andreference products, as well as for the requirements for toxicological studies”.

According to the work plan, the BMWP is also this year to finalise guidelines on biosimilarmonoclonal antibodies and on immunogenicity assessment of monoclonal antibodies intendedfor in vivo clinical use. Interested parties have until 31 May this year to comment on the draftversions of the two guidelines (Generics bulletin, 3 December 2010, page 1).

Revisions are also timetabled for the overarching guidelines on ‘similar biological medicinalproducts’ as well as on clinical and non-clinical issues relating to biosimilars containingbiotechnology-derived proteins as the active substance. Guidelines on biosimilar recombinanthuman insulin and low molecular-weight heparins will also be reviewed.

Two workshops on monoclonal antibodies are planned, one covering immunogenicityContinued on page 10

Beta-interferon high on BMWP’s agenda

Perrigo pays US$540mnto purchase Paddock

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Russian company Akrikhin Pharmaceuticals and MJ Biopharmof India have reached an agreement on “scientific and technical

co-operation”. The deal was sealed at a recent Russia-India Forumduring which Naprod Life Sciences and Pharmasyntez signed amemorandum of intent to jointly procure raw materials and to makeoncology drugs in Russia, and Dr Reddy’s struck a wide-rangingbiotechnology partnership with Russian firm R-Pharm (Genericsbulletin, 14 January 2011, page 10).

Speaking recently in New Delhi, India, Akrikhin’s vice-presidentIvan Tyulyaev said the firm’s partnership with MJ and its Marvelaffiliate had taken “a new strategic direction” by moving into oncologyproducts. The two firms have existing tie-ups covering antiparasitic,cardiovascular, hormone and tuberculosis drugs, while Akrikhin alsohas tuberculosis alliances with Indian firms Ipca and Lupin, as wellas an antiretrovirals partnership with Emcure.

Highlighting the firm’s key role in the Russian government’s‘Pharma 2020’ initiative to develop the local pharma industry, Tyulyaevsaid Akrikhin was “ready to create a joint venture with an Indianstrategic partner”. Potential partners, he said, should bring technologicalexpertise and a portfolio of products suitable for the Russian market.They should also be ready to invest in building production facilities.

Four years ago, Poland’s Polpharma acquired a strategic stakein Akrikhin (Generics bulletin, 23 March 2007, page 3). G

COMPANY NEWS

2 GENERICS bulletin 1 February 2011

STRATEGIC ALLIANCES

Akrikhin pushes intooncology with MJ Bio

Irish research and development company EirGen Pharma has obtainedUS Food and Drug Administration (FDA) approval for its high-

containment oral solid-dose facility in Waterford, Ireland. Two oralsolid-dose oncology products that were within the scope of the pre-approval inspection have also been approved. Furthermore, preparationsare underway to launch the cancer therapies later this year throughstrategic partners in the US.

EirGen described the facility approval as “a significant milestone,paving the way for entry to the US market”. The company startedmarketing products in Europe and Canada through sales and marketingpartners towards the end of 2009. It is also poised to enter Japan, asthree products will be submitted for regulatory approval to the country’sPharmaceuticals and Medical Devices Agency (PMDA) this year.

In total, EirGen has over 20 projects in its pipeline, 15 of whichhave successfully completed bioequivalence studies and are awaitingregulatory approval in the European Union and the US.

EirGen focuses on developing, registering and manufacturingtablets and capsules for categories with high barriers to entry. Its high-containment facility is licensed to make cytotoxic and oncology drugs,as well as steroidal and immunosuppressant molecules. The plant canalso handle moisture-sensitive compounds. In addition, EirGen – whichprovides contract development, manufacturing and packaging services –has licences for manufacturing and packaging high-potency products. G

MANUFACTURING

Ireland’s EirGen getsFDA plant approval

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Actavis has formally opened “the world’s only pharmaceuticalmanufacturing facility completely powered by renewable energy”.

By using geothermal energy, the revamped tablet manufacturing andpackaging facility in Hafnarfjördur, Iceland, has a neutral carbonfootprint and uses no carbon fuels.

“This site is 100% powered by geothermal energy, and is thereforethe most eco-friendly pharmaceutical facility in the world,” insistedActavis’ chief executive officer Claudio Albrecht. By investing aroundC8 million (US$11 million) in expanding the Hafnarfjördur site, Actavishas increased its capacity in Iceland by 50% to 1.5 billion tablets. Thefacility serves as Actavis’ main development and launch site for Europe,with 96% of its output being exported to other European countries.

Speaking at an opening ceremony attended by Iceland’s presidentOlafur Ragnar Grimsson, Albrecht said the facility expansiondemonstrated Actavis’ commitment to continuing to invest in Iceland.Pointing out that the project – which had been delivered “on time andon budget” – would create 70 to 100 jobs, Albrecht said Actavis wasdelivering on its promise of maintaining high-quality production andresearch and development jobs in Iceland, even though the group’sheadquarters had recently moved to Switzerland (Generics bulletin,15 October 2010, page 20).

With Actavis having enjoyed its best-ever year in 2010, he added,the increased capacity would help the company to maintain service levels.

Grimsson thanked Albrecht for investing in Iceland and hailedActavis’ success in a difficult economic environment.

Actavis currently operates 14 manufacturing sites in 12 countries,but the company is continuing to optimise its production infrastructure.The firm has a factory in Malta that provides products for ‘day-one’launches. There are also high-volume solid-dose facilities in Dupnitsa,Bulgaria; Alathur, India; and Elizabeth, US. Factories in China,Indonesia, Russia, Serbia and the UK serve local markets, while semi-solids plants are in Troyan, Bulgaria and Lincolnton, US. Actavis’cytotoxic oncology portfolio is sourced from sites in Nerviano, Italy,and Bucharest, Romania.

Meanwhile, Actavis has extended until 31 January a letter of intentto strike an insulin deal with Poland’s Bioton (Generics bulletin, 3December 2010, page 1). G

COMPANY NEWS

3GENERICS bulletin1 February 2011

MANUFACTURING

Actavis goes greenfor Icelandic plant

Strides Arcolab’s Agila Specialties subsidiary has signed anagreement with Brazil’s BioChimico to form a joint venture that

will target the country’s hospitals market. Agila will hold a 52% stake.Each company will transfer certain intellectual property into

the joint venture and will share marketing rights. Strides’ Brazilianfacility in Campos and BioChimico’s two plants in Itatiaia and Riode Janeiro will make injectable drugs “on a pre-determined costmodel” and will transfer them to the joint venture for distribution.

Arun Kumar, Strides’ vice-chairman and chief executive officer,said the deal with BioChimico – which had a “leading position inanaesthetics” – would allow the Indian firm to “tap fully the Brazilianhospitals market opportunity” and would complement the company’sexisting supply deal with South Africa’s Aspen Pharmacare (Genericsbulletin, 26 March 2010, page 9). Kumar’s counterpart at BioChimico,Christoph Gross, insisted the alliance would “unleash unique economiesof scope and scale”.

Latin America currently makes up around 8% of Strides’ sales. G

STRATEGIC ALLIANCES

Strides seals deal forBrazil hospital tie-up

South Africa’s Aspen Pharmacare has finalised its deal to buySigma’s Pharmaceuticals division for A$900 million (US$892

million) after the Australian firm’s shareholders approved the acquisitionin an extraordinary meeting. The effective date of change of ownershipis 31 January, just over five months after Aspen announced its bid(Generics bulletin, 3 September 2010, page 3).

Aspen’s group chief executive, Stephen Saad, said the deal wouldenable the South African company to “accelerate growth in itsAustralian business and also to stimulate expansion plans into thebroader Asia-Pacific region”.

Sigma’s Pharmaceuticals division includes the company’s genericsbusiness, as well as its OTC brands such as Herron, prescriptionbrands, orphan drugs, medical products and a contract-manufacturingunit. The firm will keep its pharmacy retail and wholesaling division.G

MERGERS & ACQUISITIONS

Aspen completes Sigma deal

Pharmstandard has made its first acquisition in Ukraine by purchasinga 55% shareholding in Biolek. The deal comes after Ukraine’s

antimonopoly committee granted the Russian company permission inNovember to purchase a majority stake in the Ukrainian firm.

Biolek’s sales in 2009 were US$13.3 million, Pharmstandardsaid. In 2010, this figure was expected to increase by 23% to US$17.7million, the Russian company added. Domestic sales currently accountfor around three-quarters of the Ukrainian firm’s turnover. However,Pharmstandard’s chief executive officer, Igor Krylov, said the companywas planning to increase Biolek’s export sales to Russia and elsewhere.

Pointing out that Ukraine was Pharmstandard’s second-largestmarket after Russia, Krylov said the deal would enable Pharmstandardto diversify its product range by adding antivirals, hormones, vaccinesand serums, as well as oncological and immunobiological drugs. G

MERGERS & ACQUISITIONS

Pharmstandard buys BiolekTorrent Pharmaceuticals has wound up a wholly-owned subsidiary

in Japan before it started operating. However, the Indian firmrecently started operating in Mexico and plans to enter the Romanianand UK markets in the near future.

In the Indian firm’s financial third quarter ended 31 December2010, domestic turnover 21% higher at Rs2.74 billion (US$60.2million) – predominantly from branded generics – contributed almosthalf of Torrent’s group net sales, which rose by a fifth to Rs5.55 billion.

Torrent Brazil and Heumann in Germany each posted 15%advances to Rs1.02 billion and Rs760 million respectively, whileformulations exports to the rest of the world – including Europe andthe Commonwealth of Independent States (CIS) – grew by 22% toRs780 million. Torrent’s operating profit rose by 5% to Rs1.15 billionas it invested in developing products for the US and Europe. G

BUSINESS STRATEGY/THIRD-QUARTER RESULTS

Torrent shelves Japanese unit

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Indian company Unichem Laboratories increased its internationalformulations sales by 35.9% to Rs268 million (US$5.90 million) in

the firm’s financial third quarter ended 31 December 2010. NicheGenerics in the UK achieved a turnover of £2.17 million (US$3.48million), while Unichem’s subsidiary in the US contributed US$0.79million. But the firm registered no sales through its Brazilian unit.

International turnover from active pharmaceutical ingredients(APIs) edged up by 1.6% to Rs135 million, while the Indian firm’sdomestic API sales climbed by 39.1% to Rs57 million (see Figure 1).

Formulations sales in India – where Unichem recently signed ananti-counterfeiting deal to protect key brands such as its Losar (losartan)antihypertensive and Trika (alprazolam) anxiety remedy (Generics

bulletin, 14 January 2011, page 10) – improved by 11.0% to Rs1.49billion, representing just over three-quarters of group turnover aheadby 14.1% to Rs1.97 billion.

The higher API sales and “an adverse product mix” reducedUnichem’s gross margin by just over a percentage point to 66.0%.Commissioning new domestic plants at Baddi and Sikkim – as well ashigher staff and sales and marketing expenses – cut the firm’s operatingprofit by a fifth to Rs324 million. G

COMPANY NEWS


THIRD-QUARTER RESULTS

Formulations growat India’s Unichem

Third-quarter sales Change Proportion(Rs millions) (%) of total (%)

Formulations 1,491 +11.0 76APIs 57 +39.1 3India 1,547 +11.9 78

Formulations 268 +35.9 14APIs 135 +1.6 7International 403 +22.1 20

Others 20 +43.9 1

Unichem Labs 1,971 +14.1 100

Figure 1: Breakdown by business and region of Unichem Laboratories’ sales inthe three months ended 31 December 2010 (Source – Unichem)

Registering products and opening local sales offices in south-eastEurope, central Asia and south-east Asia are among the strategies

underpinning Olainfarm’s double-digit organic sales growth target.The Latvian firm – which intends “to become the leading

manufacturer of finished-dosage forms and pharmaceutical chemicalsin the Baltic States” – currently sells products in around 30 countries,although its main focus is on its home market and the Commonwealthof Independent States (CIS). While the company is keen to strengthenits position in CIS countries in central Asia, Olainfarm is alsoconsidering initiatives “with Chinese, Indian, Nordic and South Africanpartners”. Furthermore, the firm said it would “continue efforts to identifyco-operation opportunities regarding active pharmaceutical ingredient(API) production, with an emphasis on multinational partners”.

Makes own API for most productsAt present, Olainfarm says it makes the API for around three-

quarters of its products. Its API factory has been approved by the USFood and Drug Administration (FDA).

The Latvian firm’s nine best-selling products account for 85% ofgroup sales. These are led by the dementia drug Neiromidin (ipidacrine)that accounts for 22% of sales, followed by the anxiety drug Noofen(phenibut) with 14%. The “unique” antihistamine Fenkarol (phencarol)and the urinary anti-infective Furamag (furazidine) each account for11% of Olainfarm’s turnover.

Nearly half of Olainfarm’s sales ahead by 24% to C26.8 million(US$36.4 million) in the first nine months of 2010 were made in Russia.Ukraine made up 15% of sales, Belarus 10% and Kazakhstan 5%, whilethe Latvian firm achieved 6% of its turnover in its domestic market.Other significant markets include Georgia, Uzbekistan and the UK.

For the whole of 2010, Olainfarm expects to raise its turnoverby about a tenth to around C35 million. G

BUSINESS STRATEGY

Latvia’s Olainfarmtargets new markets

JB CHEMICALS AND PHARMACEUTICALS said higherformulations sales lifted its turnover by 9.4% to Rs2.17 billion(US$47.9 million) in the three months ended 31 December 2010.Formulations exports rose by 5%, aided by diclofenac approvals inthe US, whilst domestic formulations sales also achieved “goodgrowth”. Ongoing efficiency and cost-containment initiatives acrossthe business raised JB’s earnings before interest, tax, depreciationand amortisation (EBITDA) by a fifth to Rs535 million. G

IN BRIEF

INDOCO REMEDIES improved its pre-tax profit by just over a thirdto Rs105 million (US$2.30 million) on turnover up by a fifth toRs1.15 billion in the three months ended 31 December 2010. G

IN BRIEF

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Selling its generic injectables business to Hospira for US$400million last year has fundamentally altered the shape of Orchid

Chemicals and Pharmaceuticals’ business, reverting the Indian firm topredominantly a supplier of active pharmaceutical ingredients (APIs).

As Figure 1 shows, Orchid’s API sales more than trebled to Rs3.39billion (US$75.0 million) in the firm’s financial third quarter ended31 December 2010. Due to a long-term supply agreement with Hospira(Generics bulletin, 9 April 2010, page 4) – as well as higher sales toother major players – APIs accounted for almost three-quarters ofgroup turnover that was ahead by a third to Rs4.79 billion. Orchid’searnings before interest and tax (EBIT) almost trebled to Rs949 million.

Global sales of finished-dose formulations – which a year previouslyhad made up the bulk of Orchid’s turnover – accounted for less thana fifth of group sales in the September-December 2010 quarter.Formulations sales more than halved to Rs919 million after Orchid soldthe injectables business to Hospira, although the Indian firm said ithad enjoyed “steady growth” from its oral cephalosporin antibioticsincluding cefdinir capsules, cephalexin suspension and cefprozil tablets.

In the US – where Orchid last year acquired the sales andmarketing company Karalex Pharma (Generics bulletin, 18 June 2010,page 3) – the firm believes eight of the 39 abbreviated new drugapplications (ANDAs) it has filed to date are first-to-file opportunities.Settlements with the innovator are in place for four of these drugs. Ofthe 16 regulatory submissions it has made in the European Union(EU), 10 are for cephalosporins.

Orchid has to date filed 81 drug master files (DMFs) in the USand submitted 21 certificates of suitability (CoS) in the EU. G

COMPANY NEWS


THIRD-QUARTER RESULTS

Hospira deal shiftsthe shape of Orchid

Third-quarter sales Change Proportion(Rs millions) (%) of total (%)

APIs 3,393 +203 71Formulations 919 -54 19Others 474 -5 10

Orchid 4,786 +33 100

Figure 1: Breakdown by business of Orchid Chemicals and Pharmaceuticals’sales in the three months ended 31 December 2010 (Source – Orchid)

1 February 2011 Issue 145

Editor: Aidan FryAssistant Editor: DavidWallaceAssistant Editor: Matt StewartAssociate Editor: DeborahWilkesProduction Controller: Debi MinalSubscriptions andMarketing Manager: Val DavisEditorial Director: Mike RiceEditorial enquiries: GENERICS bulletin,54 Creynolds Lane, Solihull,West MidlandsB90 4ER, UK.

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India’s Aurobindo has agreed to sell a majority stake in its wholly-owned Chinese subsidiary, Aurobindo Datong Bio Pharma (ADBP),

to China’s Sinopharm. ADBP produces a penicillin-G derivative, 6-APA,most of which it supplies to its parent company.

State-owned Chinese distributor and manufacturer Sinopharm –which claims to be the country’s largest pharmaceutical and healthcaregroup with 2009 sales of US$9.7 billion – will initially acquire a 51%shareholding in ADBP before increasing this stake to 80.5%. Aurobindowill retain the remaining 19.5%, allowing the Indian company to ensurean “uninterrupted supply of raw materials at a competitive price”.

Divesting a majority stake in its Chinese subsidiary followedAurobindo’s “paradigm shift from active pharmaceutical ingredients(APIs) to a formulations business” over the past six years, the Indiancompany said. In the year ended 31 March 2010, ADBP made a lossbefore tax of Rs350 million (US$7.76 million) on turnover of Rs1.95billion. Aurobindo said this was “due to [a lack of] economies of scale”.

Sinopharm said it would “significantly enhance the capacity” ofADBP’s manufacturing facility and would relocate the plant “asrequired by local government in China”. The Chinese firm plans tomake the ADBP business the core of an antibiotics centre in Datong. G

DIVESTMENTS

Aurobindo sells itsChinese plant stake

Valeant plans to make at least five acquisitions or partnership dealsoutside the US – including one of “significant size” – by the end of

this year. Integrating Biovail by mid-2011 is to bring annual synergiesof more than US$250 million, in part by closing plants and cutting jobs.

Organic product-sales growth of 8% in 2011 was expected to boostthe year’s total revenues to between US$2.1 billion and US$2.3 billion,the company said. Between US$485 million and US$530 million wouldcome from branded generics, with sales expected to reach betweenUS$225 million and US$245 million in Europe and between US$260million and US$285 million in Latin America. Having in 2009 acquiredMexican generics firm Tecnofarma, Valeant last year bought Brazil’sBunker and Delta (Generics bulletin, 7 May 2010, page 3). G

BUSINESS STRATEGY/RESULTS FORECAST

Valeant intends to acquire

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Attorneys-general from 32 US states have urged the US SupremeCourt to hear a dispute over a patent-litigation settlement for

ciprofloxacin between the originator Bayer and generics firmsincluding Teva’s Barr and Watson.

Highlighting differences in the approaches of the US Second,Sixth and Eleventh Court Circuits, the attorneys-general insist they“need guidance as to the legality of reverse-payment agreements thatclearly eliminate generic competition and impact our states’ budgetsand citizens”. Therefore, they argue in their amicus curiae brief, theSupreme Court must grant a writ of certiorari to hear the case.

The attorneys-general – led by California’s Kamala Harris – takeissue in their letter with the Court of Appeals for the Second Circuit’sruling last year that the ciprofloxacin settlement was legal because thepatent litigation was not a sham, the compound patent at issue had notbeen procured by fraud and the settlement did not exceed theexclusionary scope of the patent.

The attorneys-general maintain the court’s ruling was “based onthe flawed assumption that the statutory privileges of a patenteeinclude the right to collude with and pay competitors to divide upmarkets”. Through a ‘reverse payment’, Bayer delayed competitionto its Cipro antibiotic blockbuster for six years, they allege. “By payingthe generics [firms] US$398 million, Bayer estimated it was able topreserve more than US$1.6 billion in monopoly profits,” they claim,adding that the generics firms made “more than double what they wouldhave made had they invalidated the Bayer patent and launched”.

“Had the patent been strong, Bayer would not have had to paysuch a huge sum to block the generics,” the attorneys-general continue.“The exclusionary power of the Bayer patent was not viewed assufficient to induce the generic to quit the market, so Bayer paid forthe market exclusion that the patent could not provide.”

Accusing the Second Circuit of “a curious ‘bury-your-head-in-the-sand’ approach”, the amicus curiae brief points out that patentlitigants can settle without reverse payments. Furthermore, it adds, manyasserted patents are either invalid – having been granted by examinersworking under extreme pressure – or not infringed. “The presumptionof patent validity is simply a procedural device for allocating the burdenof proof to an infringer,” the attorneys-general assert.

Meanwhile, Barr and parent company Teva, Mylan and Ranbaxyhave objected to Cephalon’s motion to compel documents from theUS Federal Trade Commission (FTC) in a case pending before aPennsylvania district court. Highlighting a “heightened risk ofinadvertent disclosure of trade secrets”, the generics firms have arguedthat their disclosures to the FTC as required by the 2003 MedicareModernization Act (MMA) contained some of their “most highlysensitive and proprietary information”.

Around 40 branded and generics firms also filed a memorandumof opposition to Cephalon’s motion. The FTC insisted that the requesteddocuments – which relate to studies on patent settlements it conductedin 2002 and 2010 (Generics bulletin, 3 September 2010, page 16) –were irrelevant to its dispute with Cephalon over Provigil (modafinil). G

MARKET NEWS


PATENT LITIGATION

US states push onpay-for-delay deals

The European Commission has called on selected generics firms andbrand companies to submit for examination certain patent settlement

agreements concluded in the European Union last year. The monitoringexercise is a second follow-up to the Commission’s pharmaceuticalsector inquiry of 2009. After examining the agreements to check forpotential problems under antitrust and competition law, the Commissionwill publish a report on the agreements by the end of June. It did notidentify the companies involved.

In 2010, the Commission reported on the findings of an initialmonitoring exercise that showed a significant decrease in the numberof potentially problematic patent settlements. Just nine of the 93settlements it had examined – or fewer than 10% – “fell into the categorythat might attract scrutiny” (Generics bulletin, 16 July 2010, page 1).This compared to 45 out of 207, or 22%, of settlements betweenJanuary 2000 and June 2008 that were covered by the Commission’spharmaceutical sector inquiry. Joaquín Almunia, the Commission’svice-president in charge of competition policy, said the latest exercisewas important “to assess whether this positive trend is confirmed andto identify potentially problematic patent settlements”. G

PATENT LITIGATION

EU Commission willexamine settlements

Details of educational events and associated hospitality extended toprescribing healthcare professionals by members of Australia’s

Generic Medicines Industry Association (GMiA) between 1 April and 30September 2010 last year have been posted on the association’s website.Reports from Mylan’s Alphapharm, Ascent and Hospira are available.

Under the GMiA’s self-regulatory code of practice – which wascleared by the Australian Competition and Consumer Commission(ACCC) last year (Generics bulletin, 12 November 2010, page 14) –member companies are obliged to report events to ensure doctors are notunduly influenced in their prescribing decisions. Since 1 December 2010,firms also have to disclose events for other healthcare professionals.

Meanwhile, GMiA has welcomed Spirit Pharmaceuticals as amember company. The Sydney-based firm – which holds more than20 product approvals from the country’s Therapeutic GoodsAdministration (TGA), and has a further 15 products currently underevaluation – joins Alphapharm, Apotex, Ascent, Hospira and Sigma. G

INDUSTRY ASSOCIATIONS

GMiA firms disclose events

A2.5% rise to 3.99 million in the number of generics packs soldfailed to stop the value of Portugal’s generics market by retail prices

sliding back by 11.9% to C49.8 million (US$67.6 million) in October2010, according to the country’s regulatory agency, Infarmed.

In the first 10 months of last year, generics volume sales grew by10.7% to 36.8 million packs, although price-cutting regulations in placesince the middle of last year (Generics bulletin, 18 June 2010, page 13)limited value sales to C518 million, a rise of 6.9%. In value terms,penetration rose by 1.6 percentage points to 19.2% of the total medicinesmarket, whilst volume penetration was 2.4 points higher at 18.1%. G

MARKET RESEARCH

Portuguese value declines

FDA – the US Food and Drug Administration – has made John Taylorits acting principal deputy commissioner after Joshua Sharfstein left tobecome Maryland’s secretary of health and mental hygiene. G

IN BRIEF

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Raising the data-exclusivity term for small-molecule drugs in the USfrom five years to the 12 years applied to biological drugs would

lead to an extra 228 drug approvals over the next 50 years and wouldraise the average life expectancy by 1.7 months, according to a studyfunded by Interpat, an association of originator pharmaceutical firms.

The study published in the January 2011 issue of Health Affairsjournal is claimed to be “the first to calculate the financial and socialcosts of limiting access to trial data”. The researchers – led by DanaGoldman, director of the Schaeffer Center for Health Policy andEconomics at the University of South California – estimated thatextending data exclusivity by seven years would increase sales of adrug over its lifetime by 5% on average. The European Union alreadyoffered up to 11 years of data exclusivity, they pointed out.

Longer term would raise drug costsAcknowledging the impact on drug costs, the researchers conceded

that “Americans in the early 2020s would bear the cost of increasingdrug spending”. However, “people turning 55 in 2060 could expectincreased life expectancy as a result innovation in the interceding years”.

“Elected officials are unlikely to embrace legislation that wouldresult in higher drug prices,” Goldman believed, “but our researchsuggests that legislation to extend data exclusivity would spur innovationthat would benefit future generations.” G

MARKET NEWS


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INTELLECTUAL PROPERTY

Brand industry fundsUS call for 12 years

Malta’s Medicines Authority is preparing a public informationleaflet about generic medicines after a survey found that more than

85% of consumers were not aware of the difference between genericsand originator products. The leaflet is part of a wider public-awarenesscampaign to provide consumers and healthcare professionals with moreinformation on medicines. A general information leaflet on medicineshas also been produced and will be distributed to all pharmacies inMalta and Gozo, as well as door-to-door in some areas. The MedicinesAuthority has also created a website and a Facebook page providinginformation on regulation and safety, along with a telephone helpline. G

INFORMATION CAMPAIGNS

Malta starts awareness push

Pharmaceutical companies are threatening substantial savings toGermany’s drugs bill by challenging tenders in court, according

to Christopher Hermann, chief negotiator for a leading statutory healthinsurance fund, the AOK. But the association representing the country’slargest generics players, Pro Generika, insists firms are merely usingtheir legitimate legal rights to defend themselves against the AOK’shuge market power.

Pointing out that the AOK tenders effectively shut out for two yearsany firm that did not get a supply contract, Pro Generika’s recently-appointed managing director Bork Bretthauer argued that “it is thenorm that in a state under the rule of law that different legal stanceshave to be clarified in court”. “Legal rules also apply to Germany’slargest alliance of funds,” he insisted.

Even with the ensuing legal expenses, Hermann maintained thattenders were the best way for Germany to control its drugs bill. “Thecosts for agreeing and implementing rebate contracts are less than 1%of the sum saved,” he asserted, adding that the AOK expects itscombined tenders to save it C720 million (US$970 million) this year.Cumulative savings for all of Germany’s statutory health insurancefunds since tenders began in 2007 would total around C3 billion bythe end of 2011, he forecasted.

Hermann’s assertion came as Germany’s federal union ofpharmacists’ associations, ABDA, criticised insurance funds over a lackof transparency on savings and the administrative burden imposed onpharmacists. Citing statistics from Germany’s ministry of health, ABDAsaid the AOK had saved C257 million through rebate contracts in thefirst nine months of 2010.

Meanwhile, the AOK has started to inform successful bidders inits sixth tender for supply contracts. To date, the fund has awardedcontracts for 28 of the 87 molecules and combinations covered by itslatest tender. These contracts will run for two years from 1 June 2011(Generics bulletin, 1 November 2010, page 10).

However, contracts for the other 59 active ingredients are beingheld up by legal disputes. “Unfortunately the medicines law that cameinto effect on 1 January 2011 gave pharmaceutical companies newopportunities to disrupt rebate contracts,” Hermann complained. Thenew medicines law shifted responsibility for overseeing tenders andcontracts from Germany’s social courts to its civil courts (Genericsbulletin, 3 December 2010, page 26). G

PRICING & REIMBURSEMENT

German firms fightAOK fund on tender

MEB – the Dutch Medicines Evaluation Board – will address issuesincluding electronic submissions and variations at a public meetingon marketing authorisations to be held on 22 February. G

IN BRIEFLIECHTENSTEIN now recognises marketing authorisations grantedin Austria, provided the state was named as a concerned memberstate in a mutual-recognition or decentralised EU application. G

IN BRIEF

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Agroup of US senators has written to Food and Drug Administration(FDA) Commissioner Margaret Hamburg to stress that the

country’s biosimilars legislation does not provide market exclusivity,but rather 12-year data exclusivity, for original biological drugs.Members of the House of Representatives have sent a similar letter.

The legislators were responding to a question raised by the FDAahead of a public workshop. This was: “What factors should the agencyconsider in determining whether a modification to the structure of thelicensed reference biological product results in a change in safety, purityor potency, such that a subsequent biological license application (BLA)may be eligible for a second 12-year period of marketing exclusivity?”

“The act does not provide market exclusivity for innovatorproducts,” stressed Senators Michael Enzl, Kay Hagan, Orrin Hatchand John Kerry. “It provides data exclusivity.”

Insisting that companies were free to generate their own data tosupport a full BLA, the senators said the Biologics Price Competitionand Innovation Act explicitly precluded exclusivity for supplementsto BLAs, as well as subsequent BLAs from the same company fornon-structural changes or structural changes that did not result in achange in safety, purity or potency.

“If a manufacturer modifies an approved product to produce achange in safety, purity or potency,” they stated, “the modified productis rightly considered a new product.” G

MARKET NEWS


BIOGENERICS

Legislators correctFDA on exclusivity

Canada’s Generic Pharmaceutical Association (CGPA) has criticisedthe Canadian Chamber of Commerce for advocating “on behalf

of brand-name drug companies” longer periods of market exclusivityin Canada. A report published by the Canadian Intellectual PropertyCouncil (CIPC) under the banner of the Chamber of Commerce “omitskey information regarding Canada’s intellectual-property regime forpharmaceuticals and how it compares with other jurisdictions”, theCGPA said. It also provided “a one-sided perspective” on brandcompanies’ investments in Canada.

The report recommends strengthening intellectual-propertyprovisions in three areas: “levelling the playing field” between brandcompanies and generics firms by granting brand companies an“effective right to appeal” adverse rulings on patent challenges;providing “internationally competitive protection” for brand-companydata by bringing Canada’s data-exclusivity provisions more closelyinto line with those of the US and European Union (EU); and protectingbrand companies against delays during the approval process by adoptinga five-year patent-term restoration (PTR) system.

Perrin Beatty, president and chief executive officer of the CanadianChamber of Commerce, said the report indicated that Canada had to“keep pace if we want to fulfill the promise of creating jobs andinvestment in our pharmaceutical sector”. However, CGPA presidentJim Keon argued that the proposals would “add billions of dollarsto prescription drug costs”. Furthermore, he pointed out, they were“precisely the same proposals put forward by the EU as part of thecurrent trade negotiations with Canada”.

It was not clear why the Chamber of Commerce would want to“enrich the EU at the expense of Canada’s healthcare system andCanadian businesses”, Keon stated, claiming that the Chamber had“chosen the narrow economic interests of brand-name drug companiesover the interests of every other Canadian employer that funds drug-benefit plans”. “More than 20 years of experience have proven thatlonger periods of market monopoly for brand-name drugs will notresult in increased investments in Canada or increased spending onresearch into new drugs,” he added.

Instead, Canada’s public and private drug plans should focus onincreasing generic penetration in the wake of recent generic price cuts,Keon said. Measures aimed at cutting prices by 50% in Ontario(Generics bulletin, 23 April 2010, page 9) and Quebec (Genericsbulletin, 3 December 2010, page 13) had “dramatically reduced” thecost of generics, meaning that “the potential savings through greateruse of generic prescription have never been greater”, he argued.

Keon also responded to a report published by Canada’s PatentedMedicine Prices Review Board (PMPRB) that suggested generics costsubstantially less in foreign markets than in Canada by pointing outthat the PMPRB’s findings were based on sales data from 2007.“There is little value in publishing sales data that is three years old,”Keon stated, adding that the report did not take into account “significantreductions in retail or reimbursed generic drug prices that have occurredin more than 90% of the Canadian market”.

According to data from IMS, generics are used for 57% of allprescriptions in Canada, but account for only a quarter of the C$23billion (US$22.7 billion) spent annually on prescription drugs in thecountry. The average price of a brand prescription is C$67, whilst theaverage price of a generic prescription is just C$26. “Generic drugsare the only component of Canadian healthcare where costs are actuallydecreasing,” Keon said. G

INTELLECTUAL PROPERTY

CGPA rails againstCanadian IP report

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Laboratoire Renaudin’s generic rival to Pfizer’s Ketalar (ketamine)anaesthetic has been added to France’s répertoire of generic

equivalents. The injectable solution is available in 10mg/ml and 50mg/mlstrengths. Venipharm’s generic version of Ipsen Pharma’s Tenstaten(cicletanine) 50mg antihypertensive capsules has also been listed.

Teva’s 60mg raloxifene coated tablet has been put into a newgroup with Eli Lilly’s Evista as a reference product. Raloxifene hadpreviously only been listed on the répertoire under Lilly’s Optrumabrand, with a generic 60mg coated tablet manufactured by Synthon.Laboratoires Leurquin’s rival to Meda Pharma’s Prioderm (malathion)5mg/ml head-lice lotion has also been added. Authorised genericsof AstraZeneca’s proton-pump inhibitor Inexium (esomeprazole)20mg and 40mg gastro-resistant tablets have also been listed. G

PRODUCT NEWS


ANAESTHETICS

France adds Ketalarrival to répertoire

KV Pharmaceutical will potentially have to wait another threemonths for the US Food and Drug Administration (FDA) to review

Gestiva, the brand named in the US generics firm’s recent US$120million loan facility. Hologic’s new drug application (NDA) for thehydroxyprogesterone caproate injectable for preventing pre-term birthhas had its ‘action date’ extended by the FDA from 13 January to13 April, after the agency asked for additional material. “In light ofthis new information [from Hologic],” KV said, “the company isevaluating its liquidity outlook.”

Clearance under the terms of a consent decree was recently givenby the FDA for KV to return to market with its first product (Genericsbulletin, 17 September 2010, page 3). This was shortly before thefirm agreed the loan package. The first tranche of US$80 million isavailable upon approval of Gestiva, and will be used to pay off aUS$60 million bridging loan, make a milestone payment to Hologicand provide working capital. The second of two further conditionaltranches of US$20 million will depend on KV having the liquidity topay Hologic a second milestone fee a year after Gestiva approval. G

GYNAECOLOGICAL DRUGS

FDA Gestiva delay troubles KV

GLENMARK will be able to launch a rival to GlaxoSmithKline’sMalarone (atovaquone/proguanil) 250mg/100mg tablets in theUS later this year, after the US Food and Drug Administration(FDA) approved its abbreviated new drug application (ANDA).The Indian firm can launch its generic with 180-day exclusivityin the third quarter of this year under the terms of a patent settlementagreement with the brand company, which will grant Glenmark aroyalty-bearing licence (Generics bulletin, 23 April 2010, page12). According to IMS Health, US sales of the malaria treatmentwere US$56 million in 2009.

PROLOR BIOTECH – which has former Ivax head Phillip Frost asits chairman – has struck a licensing deal with Israel’s Yeda for‘Reversible PEGylation’ technology that is claimed to “enhance thehalf-life and improve the biological activity of a variety of peptidesand small molecules”. The deal covers all indications apart fromhaemophilia, and excludes insulin-based treatments.

MYLAN has started shipping acarbose 25mg, 50mg and 100mgtablets in the US. The diabetes treatments will compete with Bayer’sPrecose original and generics from Impax, Roxane and Watson.

CALCITONIN medicines are being reviewed by the EuropeanMedicines Agency (EMA) to investigate possible increased riskof prostate cancer progression and other types of malignancies.Initiated by the UK, the formal review by the EMA’s committee forhuman medicinal products (CHMP) will look at all available dataon the acute bone-loss medicine after two randomised, double-blind,placebo-controlled clinical trials suggested an increased frequencyof malignancies. The CHMP is also reviewing Baxter’s productionof dialysis solutions at its Irish Castlebar plant. Baxter said it couldnot guarantee the solutions would be endotoxin-free.

AUROBINDO has received authorisation to market zidovudine100mg and 250mg capsules in Germany. A 40-capsule pack of theantiretroviral agent has a retail list price of C205.54 (US$278.99).

SANDOZ has recalled two batches of its Zarzio (filgrastim)biosimilar in the UK after cracks were identified in a small numberof 30MU/0.5ml and 48MU/0.5ml syringes during routine inspections.

RELIANCE GENEMEDIX said it had submitted an application tothe European Medicines Agency (EMA) for erythropoietin(EPO). The Irish firm – which already supplies EPO in India andis seeking approvals in several other markets – said it had postponedwork on granulocyte-colony stimulating factor (G-CSF) to conserveits cash resources.

THE INDIAN PATENT OFFICE has rejected a patent applicationfor atazanavir bisulphate – the active ingredient in Bristol-MyersSquibb’s Reyataz antiretroviral – due to a lack of inventive step.

DR REDDY’S AND WOCKHARDT are among the companies thathave launched pantoprazole 20mg and 40mg delayed-releasetablets immediately upon the expiry on 19 January of paediatricexclusivity attached to US patent 4,758,579. Mylan’s Matrix andTorrent also recently gained final approvals for the proton-pumpinhibitor. Sun and Teva both launched rivals to Pfizer’s Protonix‘at risk’, although both now face damages after a jury in New Jerseylast year upheld the ‘579 patent (Generics bulletin, 7 May 2010,page 15). Kudco chose not to launch at risk. Intellipharmaceuticssaid it had not been sued by Pfizer over its abbreviated new drugapplication (ANDA) for a rival to Protonix. G

IN BRIEF

Continued from front pageassessment and the “impact on perception of risks” and a seconddedicated to biosimilar monoclonals. The latter will be held afterexternal consultation on the final guideline.

Meetings of the BMWP are scheduled for 22-23 February, 29-30 June and 25-26 October, with Christian Schneider as chairpersonand Martina Weise as vice-chairperson.

During 2011, the BMWP intends to continue “reinforcing thenetworking and exchange of experience” with other regulatory agenciessuch as Health Canada and the US Food and Drug Administration(FDA). It plans to explore “further international exchange” and holdmeetings and briefing sessions with stakeholders. Moreover, the BMWPpledged to contribute to the scientific advice, authorisation and post-authorisation duties performed by EMA committees. G

BIOGENERICS

Beta-interferon high on agenda

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Apotex has asked a Michigan district court to issue a declaratoryjudgement of non-infringement against two patents listed against

Forest’s Lexapro (escitalopram) antidepressant in the Orange Bookmaintained by the US Food and Drug Administration (FDA). Forestreported Lexapro sales of US$587 million in the third quarter of 2010.

In a court filing, Apotex asserts that it has filed paragraph IVcertifications against US patents 6,916,941 and 7,420,069, both of whichare entitled ‘Crystalline composition containing escitalopram’ and expireon 12 February 2023, including six months of paediatric exclusivity.

Pointing out that Forest and its partner Lundbeck had not sued overeither patent within the 45-day window that would have triggered anautomatic 30-month stay on final approval for Apotex’ abbreviated newdrug application (ANDA), the Canadian firm said it had offered theoriginators confidential access to its ANDA. Thus, Apotex argued, ithad met the criteria for a declaratory judgement outlined in the MedicareModernization Act (MMA) that came into effect on 8 December 2003.

Approval blocked by first-filer Ivax“Teva’s Ivax submitted the first paragraph IV certification to the

‘941 and/or ‘069 patents and secured a period of 180-day exclusivitythat will delay the approval of Apotex’ non-infringing products, absenta declaratory judgement from this court,” the Canadian firm said.

While Teva lost its challenge to the only other Lexapro patent listedin the Orange Book – reissued patent RE3,712, for which paediatricexclusivity expires on 14 March 2014 (Generics bulletin, 21 September2007, page 14) – it retained 180-day exclusivity by virtue of not havingbeen sued over the ‘941 and ‘069 patents.

Apotex cited last year’s Court of Appeals ruling on Teva’s disputewith Eisai over donepezil as a precedent for a declaratory judgementtriggering another ANDA applicant’s 180-day exclusivity period to clearthe path for other approvals (Generics bulletin, 15 October 2010, page 1).

Caraco had three years ago secured a Court of Appeals ruling thata covenant not to sue did not preclude it from seeking a declaratoryjudgement of invalidity or non-infringement against the ‘941 patent(Generics bulletin, 18 April 2008, page 1). However, the affiliate ofIndia’s Sun Pharma subsequently settled its dispute with Forest andLundbeck (Generics bulletin, 1 August 2009, page 22). G

PRODUCT NEWS


ANTIDEPRESSANTS

Apotex seeks rulingon Lexapro patents

Teva has launched an OTC diclofenac-based analgesic and anti-inflammatory spray in France under the name Tevalgiespray.

Available in a 15ml or 30ml bottle of diclofenac sodium 4% solution,Teva says that the product acts quickly and effectively due to its strongconcentration and “innovative formulation”. Effects are measurablewithin 30 minutes of use, the Israeli company claims.

Trade-press advertising recommends Tevalgiespray to treat anypain or inflammation caused by day-to-day activities or sport, alsoboasting that the product is portable and easy to apply. Theadvertisement depicts two rugby players grappling with each otherduring a tackle, with the player being tackled spraying himself withthe product as he grimaces in pain. Imitating the sound of the spray,the advertisement’s slogan reads “Dites pscchhhittt!!! à la douleur”,or “Say pscchhhittt!!! to pain”. G

ANALGESICS

Teva tackles pain in France

Teva’s Dutch subsidiary Pharmachemie is battling Janssen over theantihypertensive nebivolol. Pharmachemie markets nebivolol 5mg

tablets in the Netherlands, having obtained a marketing authorisationfrom the Dutch Medicines Evaluation Board (MEB) in February 2008.But Janssen alleged infringement of the Dutch version of Europeanpatent EP0,334,429, which expired on 15 March 2009. However,Janssen’s protection was extended by a supplementary protectioncertificate (SPC) that ran until 17 October 2010.

According to Pharmachemie, three key claims of the ‘429 patentwere invalid due to lack of novelty, inventive step and utility. Firstly,the Teva subsidiary argued, the claims lacked novelty in light of Janssen’sprior-art US patent 4,654,362; secondly, the chemical structure andstereochemistry of nebivolol had been disclosed in a 1987 GuildfordForum presentation entitled ‘HPLC-fluorescence method for thedetermination of the new ß-adrenoreceptor blocking agent nebivololin human plasma’; and thirdly, the potentiation effect described in the‘429 patent did not occur in the racemic mixture nebivolol.

The district court in The Hague, the Netherlands, was notconvinced by Pharmachemie’s argument that the US ‘362 patentcreated a “one-way road” that led inevitably to nebivolol and theinvention claimed in the ‘429 patent.

Opportunity to produce more evidenceBut it was more sympathetic to the generics firm’s citation of the

Guildford Forum presentation in September 1987, ruling thatPharmachemie should be given the opportunity to produce furtherevidence that the presentation had disclosed nebivolol’s structure andstereochemistry. The potentiation argument was put on ice pendingresolution of the presentation defence.

Further proceedings in the case – which also involves the wholesalerMosadex, Pharmachemie’s distributor for its nebivolol tablets – arescheduled for 18-21 April.

The Hague district court also noted that the High Court of Englandand Wales had in 2008 found four claims of the ‘429 patent invalid dueto obviousness and lack of novelty in light of the Guildford Forumpresentation (Generics bulletin, 1 August 2008, page 19). The patenthad also been partially annulled in Germany and Hungary, it added. G

ANTIHYPERTENSIVES

Pharmachemie sparsover Dutch nebivolol

Sandoz must defend itself against a second charge of US patentinfringement regarding Pfizer’s Vfend (voriconazole) injectable

antifungal after the originator brought a suit in a Delaware district court.Having already in 2008 filed a paragraph IV challenge to Pfizer’s

US patent 6,632,803 – which expires on 2 June 2018 – Sandoz last yearfiled an additional paragraph IV certification to US patent 5,364,938,which expires on 15 November 2011. Pfizer said it had sued within the45-day window that would trigger an automatic 30-month stay on finalapproval of Sandoz’ abbreviated new drug application (ANDA), unlessthere was an earlier court ruling.

Mylan could soon launch voriconazole tablets in the US under theterms of a patent-litigation settlement with Pfizer (Generics bulletin,30 October 2009, page 15). In the first nine months of 2010, Pfizerreported total US Vfend sales ahead by 6% to US$187 million. G

ANTIFUNGALS

Sandoz is sued over Vfend

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Watson Pharmaceuticals has secured final US approval for fentanylcitrate buccal tablets in five strengths following the end of a

30-month stay. However, it is enjoined from launching the equivalentsto Cephalon’s Fentora analgesic until a Delaware district court rulesin its patent litigation with the originator.

As the first filer against two method-of-use patents protectingFentora until 26 March 2019 (Generics bulletin, 2 May 2008, page14), Watson believes it is entitled to 180-day exclusivity. However, theUS Food and Drug Administration (FDA) will not decide on exclusivityuntil another abbreviated new drug application (ANDA) is eligiblefor final approval. Fentora has annual US sales of US$179 million.

Just over a year ago, Teva’s Barr settled its patent litigation withCephalon. Barr gained rights to launch a rival to Fentora from October2018, or on the same day as market entry of another generic, subject tofirst-filer exclusivity (Generics bulletin, 27 November 2009, page 18).

Last year, Cephalon filed two citizen petitions, asking the FDA toreject Watson’s ANDA because the generic version contained anothersalt. It also demanded additional pharmacokinetic parameters. Butthe FDA rejected both petitions, stating that the originator had not“submitted sufficient evidence establishing that the Watson productcontains an additional salt form of fentanyl, fentanyl starch glycolate”and insisted that the agency’s existing pharmacokinetic standardswere sufficient to establish bioequivalence. G

PRODUCT NEWS


ANALGESICS

Watson has to waitfor buccal fentanyl

Hexal has extended its omeprazole-based Omep range in Germanywith Omep Plus combination packs also containing amoxicillin

and clarithromycin. The combination of a proton-pump inhibitor withtwo antibiotic agents offers a discount of up to 29% to Nycomed’sZacPac, which combines the antibiotics with pantoprazole. Hexalstressed that the competing treatments for helicobacter pylori gastricinfections shared identical indications.

Each blister pack of Omep Plus contains 14 omeprazole 20mgcapsules, 14 amoxicillin 1,000mg tablets and 14 clarithromycin 500mgtablets. The firm also recently introduced esomeprazole 20mg and40mg capsules under the Esomep brand name.

The Omep line extension came shortly after Hexal had expanded itsimmunology offering with leflunomide 10mg and 20mg tabletsequivalent to Sanofi-Aventis’Arava treatment for rheumatoid arthritis.The Sandoz subsidiary has also introduced perindopril/indapamide 4mg/1.25mg tablets with the same indications as Servier’s BiPreterax Nantihypertensive. Hexal also claims its recently-launched acarbosetablets offer a discount of up to 28% over Bayer’s Glucobay original.

Meanwhile, Germany’s federal institute for drugs and medicaldevices, BfArM, has set up a ‘flying team’ to cope with the anticipatedhigh number of generic dossiers for zolendronic acid 4mg/5mlconcentrate or powder and solvent once data exclusivity for Novartis’Zometa original expires on 20 March this year. G

GASTROINTESTINAL DRUGS/ANTIBIOTICS

Hexal expands itsGerman Omep range

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Glenmark has been told to pay damages of US$16.0 million to AbbottLaboratories for infringing a US patent protecting the brand

company’s Tarka (trandolapril/verapamil). The Indian firm launcheda generic version of the combination antihypertensive ‘at-risk’ last yearafter 30-month stays on final approval ended. A New York district-courtjury found that Glenmark had not demonstrated that US patent5,721,244 – which protects Tarka until 24 February 2015 – was invalidfor obviousness or obviousness-type double-patenting. Abbott’sdamages comprise US$15.2 million for lost profits and US$0.80million for price erosion.

The US Food and Drug Administration (FDA) had approvedGlenmark’s trandolapril/verapamil 2mg/180mg, 2mg/240mg, and4mg/240mg extended-release tablets in May 2010, followed in Augustlast year by the 1mg/240mg version.

In June 2010, New Jersey district Judge Dennis Cavanaugh refusedto grant Abbott and its licensing partner Sanofi-Aventis a temporaryrestraining order and preliminary injunction against Glenmark, rulingthat the generics firm had “raised a substantial question concerning thevalidity” of the ‘244 patent (Generics bulletin, 18 June 2010, page 19).Glenmark had argued that the prior-art US patent 5,089,910 had alreadydisclosed oral combinations of ACE-inhibitors and calcium antagonistsclaimed by the ‘244 patent. The Indian firm launched its generic soonafter with 180-day exclusivity. G

PRODUCT NEWS


ANTIHYPERTENSIVES

Glenmark must payfor ‘at risk’ launch

Parexel will assist Merck & Co in developing its biosimilars portfolioafter the two companies struck a deal for the contract research

organisation to provide Merck’s BioVentures division with globaldevelopment services for certain biosimilar candidates. Merck saidParexel would supply a “broad range of regulatory-strategy and clinical-development planning capabilities” to develop biosimilars across varioustherapeutic areas. Neither the molecules covered nor the financialterms of the deal were disclosed.

Parexel’s chairman and chief executive officer, Josef vonRickenbach, said the company was committed to using its “extensive,industry-leading experience with biosimilar development” to help Merckadvance its biosimilars portfolio. “We truly understand the scientificcomplexities and regulatory pathways involved,” he claimed.

The agreement allows Merck’s BioVentures division to establisha dedicated unit within Parexel. Michael Kamarck, president of MerckBioVentures, said Parexel had “the expertise and resources to conductclinical development of our diverse portfolio of candidates to allowtimely delivery of products to the marketplace”. Two years ago, Merckannounced that it would invest US$1.5 billion by 2015 in developingbiosimilars and ‘biobetters’ (Generics bulletin, 16 January 2009, page1). A few weeks later, the brand firm paid US$130 million for Insmed’sbiogenerics pipeline and manufacturing facility in Boulder, Colorado(Generics bulletin, 6 March 2009, page 17). G

BIOGENERICS

Parexel helps Merckdevelop biosimilars

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The maximum US prescription dose of acetaminophen – paracetamolin other markets – has been reduced by the Food and Drug

Administration (FDA) to 325mg. The agency said the move would“provide an increased safety margin to help prevent liver damage,[which is] a serious public health problem”.

All prescription acetaminophen products must also carry a boxedwarning – the strongest warning required by the FDA – highlightingthat acetaminophen overdose may cause liver failure. And a warningthat highlights the potential for allergic reactions must also be addedto the labels of these prescription products. The measures will be phasedin over the next three years, giving manufacturers until 14 January2014 to comply with the FDA’s requirements.

However, non-prescription products containing the active ingredient– such as McNeil’s Tylenol – are not affected by the measures. TheFDA said it was continuing to evaluate ways of reducing liver injuryfrom OTC acetaminophen products and was working to address therecommendations of its advisory committee.

Asked whether similar moves were likely in Europe, a spokespersonfor the European Medicines Agency (EMA) told Generics bulletinthe agency’s pharmacovigilance working party had been working withmember states to determine if any action was needed. “The safety ofparacetamol is under constant monitoring throughout Europe and isregularly reviewed by the working party,” the spokesperson added.The amount of paracetamol per dose in prescription-only combinationmedicines was not harmonised in the European Union, she noted, andparacetamol-based medicines were authorised at member-state level.

Sandra Kweder, deputy director of the FDA’s Office of New Drugs,said there was no immediate danger to patients who took combinationacetaminophen products, but that the risk of liver injury occurred whenpatients taking multiple products exceeded the current maximum doseof 4,000mg every 24 hours. In 2009, three FDA advisory committeesvoted narrowly in favour of banning prescription acetaminophencombination products altogether in the US (Generics bulletin, 1August 2009, page 18).

The committee members were almost unanimous in supportingboxed warnings should the products continue to be marketed.

In response to the FDA’s announcement, Covidien – which claimsto be the only North American manufacturer of acetaminophen – saidthat all of the combination prescription acetaminophen medicines itproduced were already available in 325mg formulations. The USfirm does not anticipate the measures affecting its 2011 results. G

PRODUCT NEWS


ANALGESICS

FDA limits strengthof US acetaminophen

Acino is to start supplying a generic version of Mundipharma’sPalladon SR (hydromorphone) in Germany after receiving a

marketing authorisation from the country’s federal institute for drugsand medical devices (BfArM) for 2mg, 4mg, 8mg, 16mg and 24mgcapsules. The Swiss company said it had already concluded two supplycontracts for the opioid painkiller and was in advanced negotiationswith two further marketing partners.

Acino estimates annual sales for the product at around C5 million(US$6.7 million). It said hydromorphone would complement its otheranalgesics, which include buprenorphine, fentanyl and oxycodone. G

ANALGESICS

Acino has German painkiller

PHARMAC, New Zealand’s pharmaceutical management agency, hasbegun funding Dr Reddy’s generic version of GlaxoSmithKline’sZofran (ondansetron) tablets and orodispersible tablets in 4mg and8mg strengths. Dr Reddy’s ondansetron tablets have already beenlisted in the agency’s pharmaceutical schedules and will have solesupply status between 1 May 2011 and July 2013. Its orodispersibletablets will be listed from 1 March and will have sole supply statusbetween 1 August 2011 and July 2013.

GENERIS has launched the cholesterol-lowering agent fluvastatinin Portugal. It is the firm’s 159th generics launch.

STRIDES ARCOLAB has been granted tentative approval by theUS Food and Drug Administration (FDA) for injectable adenosine3mg/ml packaged in 12mg/4ml single-dose vials. The Indiancompany said it would launch the product under its partnership withSagent Pharmaceuticals once the patents protecting the productexpired. Strides also received FDA approval for injectable lidocainein 5mg/ml and 10mg/ml multi-dose vials. The company plans tolaunch the products, along with single-use vials in the same strengths,and also 20mg/ml single-use vials, in the near future.

HIKMA has secured clearance to launch oxaliplatin 5mg/mlconcentrate in Germany under the Riboxatin brand name. Theauthorisation covers 10ml, 20ml and 40ml vials.

LUPIN has received final approval from the US Food and DrugAdministration (FDA) for a generic version of GlaxoSmithKline’sRelafen (nabumetone) 500mg and 750mg tablets. Annual US salesof the arthritis treatment nabumetone were US$66.8 million for theyear ended September 2010, Lupin said.

GENMED, a US and Dutch-based generics company, has announcedthat it will enter the European market with the launch of paracetamol500mg tablets in the third quarter of 2011. The company said it hadobtained licences to distribute the product in Belgium, France,Germany, Ireland, Luxembourg, the Netherlands and the UnitedKingdom. It has entered into a five-year contract with an Irishmultinational distributor that supplies more than 1,200 pharmacies.

IGI LABORATORIES has submitted its second abbreviated newdrug application (ANDA) to the US Food and Drug Administration(FDA). The company’s president and chief executive officer, CharlieMoore, said the firm was “focused on the task of building a portfolioof topical drug products”.

THE LSHTM – London School of Hygiene and Tropical Medicine –insists there is not enough evidence to recommend the widespreaduse of statins in people with no previous history of heart disease.“Given that low cholesterol has been shown to increase the risk ofdeath from other causes, statins may do more harm than good insome patients,” the LSHTM said in summarising a systematic reviewof data from 14 trials.

HOSPIRA has stopped producing Pentothal (sodium thiopental)due to concerns over the use of the product in capital punishment inthe US. Italy’s authorities had asked Hospira to control the product –which is manufactured at the company’s Italian plant – and preventit from being used for this purpose. However, the company said itcould not prevent the product from being diverted for use incapital punishment and could not risk being held liable by theItalian authorities. Hospira had never condoned this use, thecompany added. G

IN BRIEF

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PRODUCT NEWS


Caraco has convinced a Michigan district court judge that a key USmethod-of-use patent protecting Novo Nordisk’s Prandin

(repaglinide) and PrandiMet (repaglinide/metformin) diabetes brandsis invalid and unenforceable. The originator said it was “evaluating itsbest options” for appealing the ruling which invalidates the onlypatent listed against the two brands in the Orange Book maintained bythe US Food and Drug Administration (FDA).

As Generics bulletin went to press, Caraco had not commentedon the decision, obtained final FDA approval or disclosed launch plans.“At present, it is unclear whether or when a generic version of Prandinor PrandiMet will be available in the US market,” Novo Nordisk stated,adding that US sales of the two brands amounted to US$134 millionin the first nine months of 2010.

Delivering his verdict on a legal battle that had been running formore than five years (Generics bulletin, 20 May 2005, page 14),Judge Avern Cohn said US patent 6,677,358 – which covers thecombined use of repaglinide and metformin, and expires on 12 June2018 – was invalid because of obviousness. Furthermore, he ruled,the patent was unenforceable due to inequitable conduct.

“A person of ordinary skill in the art, as of the critical [priority]date, would have found it obvious to try the combination of metforminwith repaglinide as a potential treatment for type-2 diabetes,” Cohnstated. “Whether measured against the teaching/suggestion/motivationtest, or the obvious-to-try test, the record contains an abundance ofclear and convincing evidence establishing a strong prima facie caseof obviousness,” he added.

Cohn was unconvinced by Novo Nordisk’s arguments that theresults of the combination were unexpected. He also dismissed theoriginator’s claims of commercial success, pointing out that “onlyabout 0.5% of non-insulin-dependent diabetes mellitus (NIDDM)patient prescriptions for oral anti-diabetes drugs are for the claimedrepaglinide/metformin combination”.

Addressing the issue of inequitable conduct, Cohn said NovoNordisk’s attorney Richard Bork had “misrepresented and withheldhighly material information with intent to deceive the examiner”.Therefore, the ‘358 patent was unenforceable.

While the ‘358 patent claims only repaglinide used in combinationwith metformin, Novo Nordisk had used it to protect its repaglinide-onlyPrandin brand by incorrectly giving it a ‘patent code’ in the OrangeBook describing “a method for improving glycemic control in adultswith type-2 diabetes mellitus”. Last year, the US Court of Appeals forthe Federal Circuit narrowly voted to uphold an earlier ruling that Caracohad no statutory basis to force Novo Nordisk to correct the incorrect‘358 patent code (Generics bulletin, 3 September 2010, page 19). G

DIABETES DRUGS

Caraco clears pathfor repaglinide in US

Synthon has successfully concluded marketing-authorisationprocedures for exemestane 25mg tablets in major European Union

(EU) markets. Approval for its equivalent to Pfizer’s Aromasin breast-cancer treatment complements the authorisations for the aromatase-inhibitors anastrozole and letrozole that the Dutch firm already holds.Quoting IMS Health data for the year ended September 2010, Synthonsaid European exemestane sales were C173 million (US$227 million). G

ONCOLOGY DRUGS

Synthon gets EU exemestane

Apotex’ launch of lovastatin tablets in its home market in March 1997has returned to haunt the Canadian company after a federal court

found that the generic version of Mevacor infringed a process patentheld by Merck & Co.

Merck’s Canadian patent 1,161,380 – which expired on 31 January2001 – describes a process for lovastatin using the micro-organismaspergillus terreus. Merck claimed Apotex’ tablets used aninfringing active pharmaceutical ingredient (API) made in China byQingyuan Blue Treasure, and that the Canadian firm’s own non-infringing lovastatin was ‘salted’ with the infringing version. Apotexdenied the allegations and argued that the ‘380 patent was invalid.

Judge Judith Snider said she was satisfied DNA tests on a batch ofAPI made by Apotex in Winnipeg, Canada, infringed the ‘380 patent.And while tests on Blue Treasure samples were less conclusive, “theremaining evidence presented by Merck with respect to the Blue Treasurelovastatin strongly supports the conclusion that there was infringement”.

Having dismissed Apotex’ invalidity arguments that the ‘380patent’s claims were overly broad and lacked utility, Snider said Merckwas entitled to damages for all Apo-lovastatin made from a single APIbatch made in Canada, as well as 294 batches made by Blue Treasure. G

CHOLESTEROL-LOWERING DRUGS

Lovastatin returns tohurt Apotex Canada

Stada has launched a generic version of Janssen Cilag’s Durogesic(fentanyl) transdermal patches in Spain. The company will market

the opioid analgesic in 12µg/h, 25µg/h, 50µg/h, 75µg/h and 100µg/hstrengths. Packs of five matrix patches are priced between C7.06(US$9.57) for the 12µg/h strength and C58.84 for the 100µg/h version.G

ANALGESICS

Stada Spain offers fentanyl

Lupin has responded to Teva’s claims that it is entitled to 180-dayUS market exclusivity for a generic version of Viiv Healthcare’s

Combivir (lamivudine/zidovudine) 150mg/300mg tablets by attackingthe Israeli company for filing a “sham” abbreviated new drugapplication (ANDA) with the US Food and Drug Administration (FDA).

Teva was the first company to file an ANDA containing aparagraph IV certification against US patent 5,859,021, which expireson 15 May 2012. However, it did not at the time challenge the later-expiring US patent 5,905,082, which protects the antiretroviral branduntil 18 November 2016.

Addressing Teva’s response to Lupin’s citizen petition to the FDA– which was filed last year (Generics bulletin, 14 January 2011, page23) – the Indian firm points out that the FDA could not have approvedthe Israeli company’s ANDA before the ‘021 patent expired. Teva’scertification was therefore “a paragraph III certification for all legal andpractical purposes” and “a textbook example of a sham”, Lupin argues.

The Indian firm is also seeking exclusivity for generic Combivir.It filed an ANDA containing paragraph IV challenges to both patentsin January 2008. Teva did not amend its ANDA to contain a challengeto the ‘082 patent until October that year. G

ANTIRETROVIRALS

Lupin rebuts Teva on Combivir

Gen 1_2_11 Pgs.10-17.qxd 25/1/11 07:02 Page 7


PARAGRAPH IV WATCH

Thomson Reuters draws on strategic intelligence and competitive analysis information on the US genericsindustry to create Newport Premium™, the critical product-targeting and global business-development systemfrom the industry authority on the global generics market.

For further details contact Benjamin Burck, Thomson Reuters API Intelligence, 215 Commercial Street, Portland, Maine 04101, USA.Tel: +1 207 871 9700 x35. Fax: +1 207 871 9800. E-mail: [email protected]. Website: scientific.thomsonreuters.com/newport.

KEY DETAILS: SILENORBrand: Silenor

Active ingredient: doxepin hydrochloride

Delivery form: 3mg and 6mg tablets

Brand owner: Somaxon

Annual US brand sales: Launched September 2010

First paragraph IV filing 16 September 2010accepted by FDA:

Known paragraph IV filers: Actavis, Mylan, Par

Patents at issue – expiry dates: 6,211,229 – 17 February 2020

District court location: New JerseyLitigation references: Somaxon vs Actavis et al

1:10-cv-01100

Other FDA Orange Book 5,502,047 – 26 March 2013patents with expiry dates: Six other patents – 9 January 2015

Figure 1: Key details of paragraph IV challenges to Somaxon’s Silenor (doxepin)insomnia remedy in the US (Source – Thomson Reuters)

Brand Active ingredient NCE expiry date

Vyvanse lisdexamfetamine 23 February 2012

Amturnide aliskiren/amlodipine/HCTZ 5 March 2012

Tekamlo aliskiren/amlodipine 5 March 2012

Tekturna aliskiren 5 March 2012

Tekturna HCT aliskiren/HCTZ 5 March 2012

Valturna aliskiren/valsartan 5 March 2012

Tykerb lapatinib 13 March 2012

Altabax retapamulin 12 April 2012

Neupro (discont.) rotigotine 9 May 2012

Torisel temsirolimus 30 May 2012

Letairis ambrisentan 15 June 2012

FORTHCOMING NCE EXPIRIES

One strategy that innovators have used to counter weak pipelinesof novel drugs has been to develop new indications and

formulations for older compounds. Recent paragraph IV challengesin the US – such as those to Shire’s Intuniv (guanfacine) extended-release tablets (Generics bulletin, 28 May 2010, page 20) – haveshown one problem with this strategy, namely the lack of new chemicalentity (NCE) exclusivity. This exclusivity precludes submissions ofabbreviated new drug applications (ANDAs) that include paragraph IVcertifications for four years from the date of the original drug’s approval.

Somaxon Pharmaceutical’s Silenor (doxepin hydrochloride) tabletsare another dramatic example of how aggressively generics companiesare targeting products and how the lack of NCE exclusivity can reducethe time between new drug application (NDA) approval and thesubmission of generic challenges.

Silenor tablets are a low-dose formulation of the tricyclicantidepressant doxepin that is indicated for sleep-maintenance insomnia.While they do not qualify for NCE protection, they are subject to a new-product exclusivity that bars ANDA approvals until March 17, 2013,three years from the date of approval for Somaxon’s NDA.

However, as Thomson Reuters points out, even that period ofprotection is effectively reduced because although the US Food andDrug Administration (FDA) approved Silenor in March 2010, theinsomnia treatment’s commercial launch was delayed until Septemberlast year. On 7 September 2010, Somaxon announced the commercialavailability of the product. Full-scale promotion and marketing – inpartnership with Procter & Gamble – began on 20 September.

Although existing sales of doxepin hydrochloride products werequite modest – IMS Health reports US sales of US$14.2 million forthe 12 months ended June 2010 – generics firms were clearly watchingSilenor’s progress and ready to act when the opportunity arose.

“The FDA reports the first submission of an ANDA containing aparagraph IV certification for a generic version of Silenor on 16September 2010, just over a week after Somaxon announced thecommercial availability of the product and four days before the start ofpromotion of the NDA product,” Thomson Reuters highlighted.

Somaxon received paragraph IV notification letters from Actavisand Mylan on 3 November last year and filed suit against them in aDelaware district court on 15 December (see Figure 1). This actiontriggered 30-month stays on ANDA approval until early May 2013, lessthan two months after Silenor’s new-product exclusivity ends. On 23December, the originator received notice of Par’s ANDA. “Presumablya suit against Par will be filed shortly,” Thomson Reuters commented.

According to Somaxon, paragraph IV certifications were submittedby three ANDA filers to seven of the eight formulation or method-of-use patents listed against Silenor in the FDA’s Orange Book. However,the suit against Actavis and Mylan alleges infringement only of USpatent 6,211,229, which concerns the treatment of transient andshort-term insomnia and expires on 17 February 2020. Accordingto the Orange Book, six patents covering the drug product expireon 9 January 2015, while another patent covering the treatment ofinsomnia expires on 26 March 2013.

As Figure 2 shows, five-year NCE exclusivity for several significantbrands – including an array of aliskiren-based products – ends in thefirst half of 2012. As the FDA is permitted under US law to accept

Firms are awake to Silenor opportunity

ANDAs containing paragraph IV certifications one year beforeNCE exclusivity for the reference drug expires, generics firms haveseveral targets at which to take aim over the next few months.

The FDA’s decision to grant NCE exclusivity to Shire’s Vyvanse(lisdexamfetamine) attention deficit hyperactivity disorder (ADHD)drug until February 2012 was recently upheld by the Court of Appealsfor the District of Columbia. This followed a challenge by Actavis(Generics bulletin, 26 March 2010, page 18). G

Figure 2: Brands listed in the US Food and Drug Administration’s Orange Bookwith new chemical entity (NCE) exclusivities that are scheduled to expire in thefirst half of 2012 (Source – Thomson Reuters)

Gen 1_2_11 Pgs.10-17.qxd 25/1/11 07:02 Page 8

India’s Cipla has developed and manufactured a ‘polypill’ that willbe used in what is the first clinical trial of such a cardiovascular

product to be given to participants only on the basis of their age.Comprising four components, the daily polypill is anticipated to

prevent more than two-thirds of heart attacks and strokes, based on theeffect of each component in isolation. Three off-patent antihypertensives– losartan, hydrochlorothiazide and amlodipine – are included at halftheir standard doses; while off-patent simvastatin is present to reducecholesterol. This combination should maximise the polypill’s efficacyin preventing cardiovascular disease while minimising its side effects.

The only criterion for the 100 or so participants in the randomisedcrossover trial is that they should be aged over 50. Their starting blood-pressure or cholesterol levels will not be a selection factor used byresearchers at the Wolfson Institute of Preventive Medicine at QueenMary College, University of London.

The crossover trial – in which participants will take a placebo for12 weeks and the polypill for 12 weeks, without knowing which one theyare taking in each 12-week period – will last for 24 weeks. It will befollowed up by a two-year open-label trial with all of the participants.

David Wald, one of the researchers conducting the trial, said: “Thepolypill has the potential to be a daily preventive method against heartattacks and strokes. This trial is a step towards making access to thepolypill a reality.” Noting that the trial would assess the acceptabilityand efficacy of the polypill, Wald added that the combination – losartan25mg, hydrochlorothiazide 12.5mg, amlodipine 2.5mg and simvastatin40mg – had already been given to patients as individual tablets.

Claims for such a polypill were originally propounded by ProfessorsNicholas Wald and Malcolm Law at the Wolfson Institute about sevenyears ago. Their research indicated that daily dosing with a similarpolypill to that now being put on trial would dramatically reducecardiovascular problems in the over 55s. In a paper published in 2003by the British Medical Journal, they maintained that such a polypillcontaining six components – low-dose aspirin and folic acid were theother two – would prevent 88% of heart attacks and 80% of strokesif taken every day by people over the age of 55 or with existingcardiovascular disease. “About one in three people would directlybenefit,” they said, “each on average gaining 11-12 years of life withouta heart attack or stroke – or 20 years in those aged 55-64.”

Less than 10% of people were expected to have any adverse-effectsymptoms, mostly due to the presence of aspirin. Speaking to Genericsbulletin, Wald said aspirin had been omitted from the current polypillbecause of the risk of bleeding. “We wanted to make it as safe and aswell-tolerated as possible,” he said, adding that without the aspirin hewas expecting the polypill to prevent between 70% and 75% of heartattacks and strokes. Folic acid had been removed, he noted, for regulatoryreasons. Uncertainty over the efficacy of the component in isolationcould have led to difficulties in future justifying its inclusion.

Dr Reddy’s supplied a polypill combining aspirin, a statin and twoantihypertensives for a trial by the University of Auckland, NewZealand that was started about four years ago (Generics bulletin,12 January 2007, page 16). A few months later, India’s Torrent claimedit had introduced the world’s first polypill in its home market as acapsule combining aspirin, atorvastatin and ramipril, that was soldwith a metoprolol tablet (Generics bulletin, 11 May 2007, page 16).Cadila’s Polycap capsule – ramipril 5mg, aspirin 100mg, atenolol50mg, thiazide 12.5mg and simvastatin 20mg – has since been studiedin India (Generics bulletin, 17 April 2009, page 15). G

PRODUCT NEWS


CLINICAL TRIALS

Cipla makes polypillfor unique research

Gen 1_2_11 Pgs.10-17.qxd 25/1/11 07:02 Page 9

EVENTS


14-15 February

■ PharMeetLisbon, PortugalThis event will offer opportunities tonetwork as well as to strike licensingdeals for a wide range of products,including biosimilars.

Contact: PharMeet.Tel: +34 91 637 0660.E-mail: [email protected]: www.pharmeet.com.

16-18 February

■ GPhA Annual MeetingOrlando, USAThis three-day meeting of the US GenericPharmaceutical Association (GPhA) willdiscuss strategic issues, as well as providenetworking opportunities.

Contact: GPhA.Tel: +1 202 249 7100.E-mail: [email protected]: www.gphaonline.org.

17-18 February

■ Pharmaceutical RegulatoryAffairs in the Middle EastLondon, UKCovering countries including Egypt,Israel and Jordan, this two-day event willprovide an overview of the regulatoryenvironment.

Contact: Management Forum.Tel: +44 1483 730071.E-mail: [email protected]: www.management-forum.co.uk.

22-25 February

■ World Generic MedicinesCongress EuropeLondon, UKThis four-day event will providenetworking opportunities and includespre- and post-conference workshops.Topics to be covered will includesustainability and biosimilars.

Contact: Sabrina Khamissa, HNC.Tel: +44 207 608 7055.

E-mail: [email protected]: www.healthnetworkcommunications.com/2011/genericsuk.

28 February – 1 March

■ EuroPLX 45Lisbon, PortugalThis two-day meeting provides a forumfor companies to discuss licensing,marketing and distribution opportunitiesfor patented drugs, generics, OTCmedicines and nutraceuticals.

Contact: RauCon.Tel: +49 6222 9807 0.E-mail: [email protected]: www.europlx.com.

2 & 3-4 March

■ Generics andBiosimilars AsiaSingaporeThis two-day event will look at topicsincluding the outlook for the off-patentdrugs industry, regulatory issues andpricing strategies, collaborations andstrategic alliances, and biosimilars.

Contact: IQPC.Tel: +65 6722 9388.E-mail: [email protected]: www.genericsbiosimilarsasia.com.

18 March

■ 7th EGA Legal Affairs ForumBrussels, BelgiumThis one-day event organised by theEuropean Generic medicines Association(EGA) will cover patent issues and willalso provide networking opportunities.

Contact: Cristina Romagnoli, GPA Conferences.Tel: + 377 93 501 348.E-mail: [email protected] online at www.gpaconferences.com.

23-24 March

■ PharmaSource 2011Berlin, GermanyThis two-day event will consider trends in the

marketplace and global sourcing strategies.

Contact: UBM Conferences.Tel: +44 207 921 8039.E-mail: [email protected]: www.pharma-source.org.

28-30 March

■ DIA 23rd Annual EuroMeetingGeneva, SwitzerlandKeynote speaker at this event coveringpatient safety, counterfeiting, global drugdevelopment and biologicals will beEuropean health commissioner John Dalli.

Contact: Drug Information Association (DIA).Tel: +41 61 225 5151.E-mail: [email protected]: www.diahome.org.

31 March – 1 April

■ 1st Regional RegulatoryWorkshop – ElectronicSubmissionsKranjska Gora, SloveniaThis is a two-day workshop which willfocus on issues including regulations onelectronic submissions in the EuropeanUnion, new validation criteria and thecurrent status of acceptance with nationalcompetent authorities.

Contact: Nanokinetik.Tel: +386 41 278 003.E-mail: [email protected]: www.nanokinetik.com.

14-15 April

■ 9th EGA InternationalSymposium on BiosimilarsLondon, UKThis two-day conference will look at theemerging biosimilars landscape in theAsia-Pacific market, availability and patientaccess, and monoclonal antibodies.

Contact: Cristina Romagnoli, GPA Conferences.Tel: + 377 93 501 348.E-mail: [email protected] online at www.gpaconferences.com.

11-12 May

■ Generics, Super-Generics& Patent StrategiesLondon, UKTopics covered at this two-day event willinclude the global generic market, regulatoryand licensing issues in the European Union,emerging markets and patent strategies.

Contact: SMi Group.Tel: +44 207 827 6000.E-mail: [email protected]: www.smi-online.co.uk.

FFEEBBRRUUAARRYY

MMAARRCCHH

AAPPRRIILL

1-3 November

■ 14th IGPA Annual ConferenceCape Town, South AfricaThis three-day conference is being organised by South Africa’s NationalAssociation of Pharmaceutical Manufacturers (NAPM) and is the global event of theworldwide generics industry. It is the annual joint meeting of the Canadian, European,Indian, Japanese, South African and US generics industry associations, the CGPA, EGA, IPA,JGA, NAPM and GPhA. Speakers will include chief executive officers of the world’s leadinggenerics companies, as well as acknowledged experts in identifying market opportunities.

Contact: The Conference Company. Tel: +27 31 303 9852. E-mail: [email protected] online at www.igpacapetown2011.com.

MMAAYY

Gen 1_2_11 Pg.18.qxd 25/1/11 07:03 Page 2

PRICE WATCH ............ UK


Actavis made sure of making an impact on day one of risedronate’s16 December 2010 generic launch in the UK by offering a special

introductory price of just £2.37 (US$3.77) for the four-tablet versionof the osteoporosis treatment’s weekly 35mg strength.

This not only undercut the brand’s trade price by almost 90%,but was also totally out of line with Teva’s opening gambit of £11.47,which was nearly five-times higher.

WaveData noted that Sandoz had waited until 1 January 2011before making a market entrance. However, the newcomer gave itsrisedronate 35mg product a trade price of £11.45, which matchedTeva’s in all but a couple of pence.

Mylan said it had launched on day one both 28-tablet packs ofrisedronate 5mg as well as four-tablet packs of risedronate 35mg –two of the standard sizes of the brand original – and invited potentialcustomers to contact it for prices. Its equivalent 35mg price on 1January was £6.69, while the 5mg pack was £6.30. Procter & Gamble’sActonel is also available as 28-tablet packs of risedronate 30mg, butno generics prices have been recorded by WaveData.

Charles Joynson, WaveData’s managing director, said that the lowestrecorded price offered to independent pharmacists and dispensingdoctors had been £1.99 for packs of four risedronate 35mg tablets. Thisfigure had come from a wholesaler and represented a 90% discount onthe equivalent trade price for the brand.

As Figure 1 shows, the average daily trade price for the producthad fallen to about £3.00 by mid-January. This represented a price fallof about 84% within a month of generic launch.

Meanwhile, generic pramipexole was launched on the same dayas risedronate in the UK. All four strengths of the Parkinson’s diseasetreatment were launched on day one by Actavis and Teva, the UK’sleading players, although this time their prices varied only by a matterof pence. Actavis noted that Mirapexin/Sifrol sales in the EuropeanUnion totalled C339 million (US$446 million) in the year ended 30September 2010 (Generics bulletin, 14 January 2011, page 17).

Boehringer Ingelheim’s Mirapexin has a UK trade price of £9.55for a 30-tablet pack of the 88µg strength. Teva offered a 40% discounton day one with a trade price of £5.73, but Actavis settled on £5.63,which was 41% less than the equivalent brand price (see Figure 2).

An identical day-one pricing approach was taken by the twocompanies for the other three 180µg, 350µg and 700µg strengths in30-tablet packs, with Actavis consistently undercutting its rival by thenarrowest of margins. Actavis changed its tactics on 1 January thisyear, however, by cutting its prices on all four strengths such that itwas offering a 53% discount to the brand. Its 88µg price, for example,was reduced from £5.63 to £4.50. Teva, meanwhile, continued to holdfirm with a 40% reduction (see Figures 3 and 4).

Within a month of launch, the average generic price of pramipexole88µg had sunk to £4.24 from a brand price of £9.55 for 30-tablet packs,representing a discount of 56%. Average discounts for the other threestrengths were similar at between 55% and 58%. The lowest prices,however, offered at least a 76% discount, with the 700µg strengthproviding the highest 81% discount on the brand price. G

Risedronate receives a low-cost launch

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Long-term product price trends or other price analyses are available.

Please specify the product and period of time you would like toinvestigate and email your request to [email protected].

■ For further information see www.bppi.co.uk.Alternatively, contact Charles Joynson atWaveData Limited, UK. Tel: +44 (0)1702 425125.E-mail: [email protected].

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Thanks to various media stories, including thosecovering the Chinese heparin scare, many peoplein the US believe that Chinese finished-dose

medicines are proliferating in the country’spharmaceutical market. But nothing could be furtherfrom the truth, according to Kate Kuhrt, director ofgenerics and API intelligence at Thomson Reuters.

“Currently, very few finished-dose prescriptiondrugs that have been manufactured in China are beingbrought legally into the US,” she insists. “ZhejiangHuahai is one of the few companies in mainland Chinawhose finished-dose facility has been FDA approved.Huahai manufactures products such as benazepril forthe US market, both for sale under Huahai’s own labeland for Ranbaxy. While Chinese companies themselveshave filed abbreviated new drug applications (ANDAs)with the US Food and Drug Administration (FDA), nonehave been approved so far.”

Kuhrt points to several misapprehensions, not leastthat if Chinese active ingredients end up in finished doseproducts in the US, then the finished dose must becoming from China too, or that if unregulated productssuch as fish oil are entering the US from China, thenregulated prescription drugs must be coming into thecountry as well. “People also assume that if counterfeitdrugs are being made in China, then it must be a sourceof legal drugs as well.”

Only three Chinese companies hold ANDAs withfinal approval, she explains, and these have not beendeveloped in-house, but have been acquired fromgenerics firms with a broad US presence. ZhejiangHuahai – through Huahai US – has acquired sixANDAs from Actavis, Kali, KV and Par, although it alsohas a tentative approval for an ANDA for nevirapine200mg tablets under the President’s Emergency Planfor AIDS Relief (PEPFAR).

Beijing Pharma – through Beijing Double Crane –has approved ANDAs for two ex-Ranbaxy products;while Yabao Pharma – Beijing Yabao – ownsdiscontinued ANDAs for two products acquired fromIvax and Par. “We expect the manufacturing for many

of these ANDAs will be transferred to China at somepoint,” Kuhrt comments, “to take advantage of lowermanufacturing costs. However this could take sometime.” With the huge backlog of ANDAs awaitingreview, she adds, the FDA is in no hurry to look at thesupplemental ANDAs required for site transfers withoutgood reason, which saving some money is not.

Kuhrt says it remains to be seen if many Chinesefirms will pursue the route being trodden by Indiancompanies, many of which have grown from beingdomestic producers of active pharmaceutical ingredients(APIs), to supplying APIs and finished-dosages toregulated markets, to offering contract research andmanufacturing services (CRAMS) and developing noveldrug forms and even new chemical entities.

“We anticipate the strongest Chinese companies willexpand into making finished-dosage forms for regulatedmarkets sooner or later. But given the vast internalmarket and the high additional costs associated withsupplying to regulated markets,” she adds, “we anticipatethat many Chinese companies will decide that it’s moreprofitable to focus on the rapidly-growing local market.”Kuhrt notes, however, that China already leads India forsome products. These include fermentation-based andsteroid APIs, as well as intermediates and base chemicals.

Expenses are rising fast for Chinese firms, she says,thanks to increasing regulatory oversight, both of goodmanufacturing practice and of environmental compliance,as well as to higher energy and labour costs. “If the costdifferential decreases or disappears altogether,” Kuhrtremarks, “companies in regulated markets will sourcesome of their products from closer to home.”

Kuhrt says that today there are less than 50 ChineseAPI producers that Thomson Reuters would class as‘established’ – having supplied a number of products toregulated markets for some years – or ‘less established’,having only some experience in regulated markets.Less established companies from China outnumber the

MANUFACTURING


API and generics

intelligence expert,

Thomson Reuters’

Kate Kuhrt, outlines

to Mike Rice the

latest trends in

product supply.

India and China forge aheadwhile Europe plays catch-up

USA144

India66China

48

Italy34

Japan18

Spain16

Germany14

Others92

Figure 1: Established and less established API manufacturers onThomson Reuters’ database as of 14 January 2011. Establishedcompanies have years of experience with a number of productsin regulated markets, while less established firms only havesome experience (Source – Thomson Reuters)

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Figure 2: Total number of final approvals of abbreviated new drug applications (ANDAs) by the US Foodand Drug Administration (FDA) for Indian companies in the years shown (Source – Thomson Reuters)

Kate Kuhrt

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Gen 1_2_11 Pgs.20-22.qxd 25/1/11 07:20 Page 2

established companies by three to one.Thomson Reuters is currently tracking over 2,300

API producers worldwide in over 60 countries. Of theseonly about 400, or less than 20% of the total, are classedas established or less established, and of those 400,less than 40% are classified under the former heading.

Figure 1 shows that India and China together haveabout a quarter of the world’s established and lessestablished API players, but the US has a third of them.Fewer than a fifth of the 144 US players, however, areestablished, while over 100 of them are classified asless established because they have limited productlines. Kuhrt also observes that only about 160 of theworldwide total of 400 firms are pure API players.

While the total number of established or lessestablished Chinese companies has doubled over thepast five years, Kuhrt observes, others in the ‘potentialfuture’ category have risen faster, more than doublingfrom about 70 in 2006. In total, there are 150 or soChinese companies, she estimates, that have aspirationsto get involved in regulated markets. This is more thanhalf the total of ‘potential future’ players worldwide,which only numbers just over 300. “As these Chinesecompanies invest in their facilities and people, and gainexperience from working with regulated market players,they will move up to the less established and even to theestablished category over the next decade,” she maintains.

By comparison, India has 66 companies ranked asestablished or less established, up from 37 five yearsago. While this represents rapid progress in the faceof consolidation – Kuhrt points out that Matrix andRanbaxy have been excluded from the figures sincebecoming part of Mylan and Daiichi Sankyo – growthin ‘potential future’ players has lagged behind that ofChina. India now has just under 100 such contenders,but this compares with 70 five years ago.

However, Kuhrt points out the “almost exponential”increase in Indian companies’ANDA approvals over thepast decade, while the number of ANDA filers hasalso increased dramatically (see Figure 2). “In the caseof Indian companies,” she says, “we expect to seecontinued development of low-cost, high-qualityfinished products and value-added CRAMS capabilities.”

Rely on Chinese intermediatesAt the same time, however, Indian players will place

greater reliance on supplies of advanced intermediatesfrom China, which will do nothing to halt the continualrise in Indian API costs, Kuhrt observes.

She cannot see API manufacturing for regulatedmarkets moving to a second wave of emerging-marketcountries, she says, although she notes that someEuropean API firms have pursued joint ventures or builtfacilities to circumvent patents and reduce costs.“Emerging markets outside of India or China do notcurrently have a critical mass of manufacturing oravailable talent to be able to compete with India orChina,” she believes. Moreover, cost is only one of themany criteria that generics companies use to makesourcing decisions. “While many former long-termrelationships may have been thrown out in pursuit oflower costs, strategic long-term relationships are beingemphasised again,” maintains Kuhrt.

Brazil, for example, has only one locally-ownedless established API producer, according to ThomsonReuters’ classification, and four potential future

candidates. Russia has no established firms and just onewith future potential to become a regulated-marketsupplier. Local firms with no record, capability orinterest in supplying APIs to regulated markets number31 in Brazil, while Russia has 43. Altogether, there aremore than 1,500 companies of this type globally.

But while Kuhrt cannot see API suppliersestablishing themselves in emerging market countriesoutside of India and China, she can detect a resurgenceof producers in Italy and other European countries.

“With increased focus again on long-termrelationships and quality, European API manufacturersare in a good position to compete against India andChina,” she comments. “The mood among EuropeanAPI producers seems quite positive.” Not that it is allgood news in Europe, she adds, as the industry issuffering from excess capacity. “We expect more industryconsolidation,” Kuhrt comments.

Producers in Italy, Europe’s leader in terms ofestablished firms, were hamstrung by the country’sintroduction of supplementary protection certificates(SPCs) – patent-term extensions – in 1991, she believes.“You cannot overstate the damage SPCs did to producingAPIs in Italy,” she says. “For years, Italian API makerswere excluded from producing many ingredients thatwere already off-patent in other countries.”

Asked whether API manufacturing would havemoved to India and China anyway due to the costadvantages, Kuhrt says yes, absolutely. “But Europe’s

MANUFACTURING

There are 150 or

so Chinese companies

that have aspirations

to get involved in

regulated markets


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Figure 3: Numbers of Type II drug master files (DMFs) submitted to the US Food and Drug Admistration(FDA) by Chinese, Indian and Italian companies over the past decade (Source – Thomson Reuters)

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Figure 4: Numbers of inspections by the US Food and Drug Adminstration (FDA) of Chinese, Indianand Italian API manufacturers over the past decade (Source – Thomson Reuters)

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Gen 1_2_11 Pgs.20-22.qxd 25/1/11 07:20 Page 3

restrictive rules, combined with the increasinglycompetitive generics market in the US, speeded upthe rate aggressive generics firms sourced from India.”

A measure of Italy’s inability to match India, andlatterly China, can be gauged by the numbers of drugmaster file (DMF) submissions in the US made by thecountries over the past decade (see Figure 3). “Since2004, Chinese companies have consistently filed moreDMFs than their Italian counterparts,” observes Kuhrt,who adds that filing a DMF does not necessarily meanthat you are supplying the product to the US market.

A more meaningful measure of US supply, shenotes, is the number of FDA inspections of API plants“since you can’t supply API to the US market withoutfirst being inspected”. As Figure 4 shows, Indiancompanies come out on top. Chinese firms, however,have consistently received more inspections thanItalian API producers in recent years. The US leads theoverall list, but Italy is still ahead of China taking thepast decade as a whole (see Figure 5).

Despite Italy’s recent woes, Kuhrt sees a brighterfuture for Europe. Post-2015, she says, the majority ofAPIs coming off-patent will be small-volume products.“European API manufacturers with strong technologicalcapabilities in niche areas will be in a position to profitfrom this opportunity,” she believes. “They will benefitfrom more focus on reliability and quality in Europeand the US, as well as in markets like Brazil.”

Opportunities for European API players exist withinpeptides, controlled substances and biopharmaceuticals,notes Kuhrt, who says they are also taking a close lookat innovative and economical technologies, such asmicro-reactors. “Some European API manufacturers aretaking their lead from Indian firms,” she adds, “and areforward-integrating into finished-dosage forms.”

Moving into finished-dosage forms, European APIplayers will meet some Chinese firms going the sameway. “There are some good facilities in China that willbe able to compete with regulated-market players evenif the cost advantage disappears,” says Kuhrt. “And wesee no reason why the strongest should not soon besupplying finished-dosage forms to the US market,as many people assume they are already doing.” G

MANUFACTURING


Figure 5: Numbers of inspections of API manufacturers worldwideby the US Food and Drug Administration (FDA) during 2009, andin the decade since 2001 (Source – Thomson Reuters)

Location Inspections2009 2001-2010*

US 66 500India 47 171Italy 18 136China 31 127Germany 11 79Japan 12 67France 14 59Spain 8 47UK 5 47Switzerland 4 39Ireland 6 31Others 39 252Total 261 1,555* January to September 2010 onlyOpportunities for

European API players

exist within peptides,

controlled substances

and biopharmaceuticals

Gen 1_2_11 Pgs.20-22.qxd 25/1/11 07:20 Page 4

Lupin has appointed Ewan Livesey as senior vice-president ofcorporate development in Europe and country manager for

Switzerland. Livesey took up his post at Lupin Atlantis Holdings inSchaffhausen near Zürich, Switzerland, in January.

A qualified solicitor, Livesey began his career at UK law firmRoiter Zucker before spending more than 10 years as vice-presidentof legal affairs at Ivax Europe. In 2006, he became Glenmark’sexecutive vice-president of corporate development in Europe, a positionhe held until last year. Before joining Lupin, Livesey acted as abusiness development consultant at Creo Pharma.

PEOPLE

23bulletin1 February 2011

APPOINTMENTS

Livesey joins Lupin’sunit in Switzerland

DIPHARMA – the Italian active pharmaceutical ingredient (API)manufacturer – has named Stefan Peterli as sales director. Thecompany said Peterli – who has worked for more than 10 years in salesand business-development roles at Siegfried and API developer Lonza –would focus on expanding its customer base in the generics marketas well as the custom-synthesis segment. “We have never really pushedto acquire business in custom synthesis because we were focusedmostly on developing APIs for the generics market,” Dipharma noted.

PAR PHARMACEUTICAL said John MacPhee had resigned aspresident of the firm’s Strativa brands unit on 31 January to pursueother interests. Patrick LePore – the US firm’s chairman, chiefexecutive and president – is heading Strativa on an interim basis.

MOMENTA PHARMACEUTICALS has appointed Young Kwon asvice-president of business development. Kwon was previously seniordirector of business development at Biogen Idec. Craig Wheeler,Momenta’s chief executive officer, said Kwon would help the firmadvance its biogenerics portfolio and evaluate collaborationssimilar to its deal with Sandoz for a rival to Sanofi-Aventis’ Lovenox(enoxaparin) brand (Generics bulletin, 6 August 2010, page 1).

GPhA – the US Generic Pharmaceutical Association – has lost itssenior vice-president of government affairs after Bill Head left to takeup a similar role at the Consumer Healthcare Products Association.

IN BRIEF

Gen 1_2_11 Pg.23.qxd 25/1/11 07:13 Page 3

Perrigo pays US$540mn to purchase Paddock · Perrigo has signed a definitive agreement to buy privately-owned US generics firm Paddock Laboratories for US$540 million in cash. The

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