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Bulletin Publishing Group is a division of OTC Publications Ltd Registered Office: 4 Poplar Road, Dorridge, Solihull B93 8DB, UK. Registered in England No 2765878 Gen 21/3/14 Pg. 1_Gen 18/11/05 Pg. 1 17/03/2014 19:47 Page 1

21 March 2014

COMPANY NEWS 2 Council fits missing part Alvotech finesses its biotech production 2 Sun facility suffers an FDAimportalert 3 Lannett pursues buys as sales shoot ahead 4 Hikma commits to its US Generics unit 5 into patent courtpuzzle Aspen wants partner to push into Japan 6 legal compromise reached by the Council of the European Union (EU) is “the last ScinoPharm benefits from 7 focus on Japan Amissing part forthe establishment of Europe-wide patent protection” through aUnified Patent Court, the European Commissionhas claimed. Council ministers have endorsed a Endo to acquire‘twoorthree’ during 2014 8 compromise agreement on the Commission’sproposals forupdating existing rules on the Siegfried is seeking moretargets to buy 9 jurisdictionofcourts and recognition of judgements. “By making changes to the rules on Rising’sUSlaunches driveAceto’sgrowth 10 recognition of judgements, we aretaking afurther step on the way to the new Unified Patent Court beginning its work,”claimed EU Commissioners Michel Barnier and Viviane Reding. MARKET NEWS 11 The European Parliament nowneeds to vote in favour during aplenary session, “which is expected at the latest in April”, according to the Commission. Meanwhile, the Commission FDAasks forinput on research priorities 11 is encouraging participating EU member states to ratify the Unified Patent Court Agreement Patent reviewstudy shelved 12 “as quickly as possible” and to complete preparatory work for the court to start operating. in Australia At present, 25 EU member states have signed up to aunitary patent package that will allow FDAlabel rule hit by broad-based attack 13 parties to obtain European patents that can be litigated through the Unified Patent Court. Italy India issues guidance on 15 and Spain opted out, while Croatia has yet to opt in following its EU accession last year. patent exclusions Aimed at creating aunified court to decide patent disputes throughout the EU, the agreement relies on the EU’sBrussels IRegulation to determine the court’sinternationaljurisdiction. PRODUCT NEWS 16 Therefore, the Commission proposed amending the Brussels IRegulation to clarifyrelations between the court, member states and litigating parties. TWi defeats Par on US megestrol patent 16 Apreparatory committee charged with bringing the court into being sees early 2015 as “a realistic target date” for operations to start with adequate facilities, trained judges and an Te va offers US rivals to 17 electronic filing and case-management system. Patent holders will be able to opt out in favour Xeloda and Evista of national patent litigation. A16th version of draft rules of procedure for the court has just Patadaypatent falls to Canada’sCobalt 18 been unveiled by the preparatory committee. Among several alterations,this clarifies Firms finish US fight on 19 procedures for opting out of hearings before the unified court. G Tracleer samples Natco claims victory 21 on Indian Copaxone US Celebrex ruling opens door FEATURES 24 keyUSpatent protecting Pfizer’sCelebrex(celecoxib) blockbuster until December next Communication is keyto24 Ayear is invalid, aVirginia district court judge has ruled. The summary judgement opens the deliver on GDUFAgoals wayfor generics firms to secure approvalfor,and to launch, the arthritis drug once six-month More efficient communication between the paediatricextensions to twoother patents expire in May this year.Pfizer –which reported US US Food and Drug Administration (FDA) Celebrexsales ahead by 11% to US$1.93 billion last year –said it would appeal. and industry,aswell as within the regulator Judge Arenda Wright Allen granted summary judgement to Actavis, Apotex, Lupin, Mylan itself, will be crucial to fulfilling the promise and Teva,declaring that Pfizer’sreissued US method-of-use patent RE44,048 wasinvalid. Pfizer, of the country’sgenerics user-fee programme. she said, “could not use the reissue process to correct its failure to file adivisional application”. David Wallace reports. Furthermore, Allen added, Pfizer had deliberately filed acontinuation-in-part, not adivisional application, of an earlier patent to maximise its exclusivity for Celebrex. “Because intentional REGULARS acts are not correctable via reissue, the court finds that the ‘048 patent violates the reissue statute as amatter of law, and is invalid.”And as the ‘048 patent could not be considered divisional, Pipeline Watch – Relenza and Reyataz 20 it wasalso invalid due to obviousness-type double patenting in light of earlier patents. Events – Our regular listing 22 The ruling comes 12 months after the US Patent and Trademark Office (PTO) reissued Price Watch UK – Our in-depth 23 the ‘048 patent, and Pfizer sued the generics firms for alleged infringement. look at pricing trends in the UK Actavis said it “may be entitled to 180 days of generic market exclusivity,orshared People – Parpicks Coughlin 27 exclusivity” pending final approvalfor its 50mg, 100mg, 200mg and 400mg capsules, which the for operations post firm expects upon expiry of paediatric extensions to US patents 5,466,823 and 5,563,165 on 30 May this year.Mylan expects to share exclusivity on the three highest strengths. G Gen 21/3/14 Pgs. 2-10_Layout 1 17/03/2014 19:48 Page 2

COMPANY NEWS

STRATEGICALLIANCES MANUFACTURING/BIOLOGICALDRUGS Amneal partners on Alvotech finesses its developing its APIs biotech production

mneal has formed an alliance with Intrexon, asynthetic biology lvogen’snewly-formed biosimilars affiliate, Alvotech, has formed Aspecialist based in Maryland, US, to “develop an improved Aamanufacturing partnership with California-based Finesse production process for acomplexactive pharmaceutical ingredient Solutions. The deal will give Alvotech access to “world-class, scalable, (API)”. The agreement between the twofirms will leverage Intrexon’s flexible and cost-efficient manufacturing and laboratory technology proprietary UltraVector development platform –aswell as the firm’s through Finesse’sturnkey SmartFactory good manufacturing practice suite of other synthetic biology technologies –with the aim of reducing (GMP) manufacturing platform suite”. the cost of producing the API. “This partnership allows us to leverage Finesse’ssingle-use bio- “Intrexon has an impressive track record of developing the full manufacturing automation platform, combining best-of-breed bioprocess potential of synthetic biology.This is an exciting newpropositionfor equipment from upstream through downstream,”commented Alvotech’s the expansion of our generic pharmaceutical development capabilities,” chief executive officer,Andreas Herrmann. The deal gave Alvotech said Amneal’schairman and co-chief executive officer,Chintu Patel. “much-needed additional manufacturing capacity and scale-up The twofirms would look to explore similar opportunitiesinthe capabilities”, he said, adding that the first manufacturing suite would future, noted Intrexon, which said the alliance could “drive acomplex, be “in place by the end of 2015”. multistep chemical process towards anew era of more affordable Alvotech recently started building abiologics development and drugs produced through biology-enabled production methods”. manufacturing centre in Reykjavik, Iceland, that it plans to open in early In amove that expands its presence in Europe, Intrexon has just 2016. The firm is investing US$250 million in developing aportfolio of acquired laboratories located in Budapest, Hungary,from biocatalysts monoclonal antibodies (Generics bulletin,6December 2013, page 27). G specialist Codexis. “The acquisition will expand Intrexon’sstrain- and protein-development capabilities, as well as strengthen fermentation- IN BRIEF process optimisation and scale-up,”commented the US-based company. Robert Walsh, president of Intrexon’sIndustrial Products division, UNILIFE –the US-based injectabledelivery systems specialist –has said incorporating the Budapest team would “afford Intrexon greater secured a US$60 million loan from investment firm OrbiMed. G flexibility in existing collaborations, including with Amneal”. G

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COMPANY NEWS

BUSINESS STRATEGY MANUFACTURING Japan’s Nichi-Iko is Sun facility suffers seeking aUSpartner an FDA importalert

apanese generics player Nichi-IkoPharmaceutical is looking for un Pharmaceutical’sactive pharmaceutical ingredients(APIs) Jan American partner for marketing generics, low-molecular weight Sand finished-dose cephalosporins facility in Karkhadi, near products and biosimilars in the US. To assist its push into the US, the Gujarat, India, has been hit by an import alert issued by the US Food Japanese firm has established awholly-owned local subsidiary called and Drug Administration (FDA). This followed an inspection at the NIXS in Wilmington, Delaware, that is headed by Taizan Kawakami. plant that revealed current good current manufacturing practice Expanding beyond its Japanese base is akey facet of Nichi-Iko’s (cGMP) deficiencies. ‘Pyramid’ business plan “aimed at becoming one of the top-10 generic “The companyremains fully committed to compliance and has pharmaceutical makers in the world”. already initiated several corrective steps to address the observations Having set up arepresentative office in Bangkok, Thailand, ayear made by the FDA,”the Indian firm commented. ago, the Japanese firm has researched “the business environment in Thailand” and decided to set up alegal entity called Nichi-IkoThailand Maintains annual sales forecast under the leadershipofHaruhikoHirata. Describing the Karkhadi plant’scontribution to group turnover By switching from arepresentative office to alocal corporation as “negligible”, the Indian firm reiterated its forecast of 29% sales in Bangkok, Nichi-Ikobelievesthe local organisation will achieve growth to around Rs147 billion (US$2.40 billion) in its financial year “a higher levelofefficiency”. “By preparing such astructure,”the ending 31 March 2014 (Generics bulletin,7March 2014, page 9). Japanese companystated, “our products can in future be distributed The Karkhadi plant is Sun’sonly combined API and finished- not only in Thailand, butinsouth-east Asia as well.” dose manufacturing facility in India. The company’smanufacturing Product filings are already underway in Thailand –where Nichi-Iko capacities in the country comprise afurther nine plants, of which last year formed an alliance with local firm Biolab to support its five manufacture finished-dose formulations, while the rest only regulatory,repackaging and marketing operations –aswell as in Hong produce APIs. However, Sun also possesses FDA-approvedAPI Kong and Malaysia. The Japanese companyintends to “establishthe and finished-dose manufacturing facilities in Haifa, Israel, as well Nichi-Ikobrand in Asia” by capitalisingon“the strong image of as in Tiszavasvari, Hungary. G safety that comes with being Made in Japan”. Nichi-Iko’sPyramid business plan unveiled twoyears ago targets becoming atop-10 global generics player by increasing the group’s DIVESTMENTS turnoverfrom ¥93.9 billion (US$924 million) in its financial year ended March 2013 to ¥130 billion by March 2016. To reach that goal, Nichi-Ikowill need to achieve lowdouble-digit sales growth each year. Orchid can sell to Hospira Over the same period, the firm expects to improve its operating rchid Pharma can finally push ahead with the planned sale to profit from ¥8.23 billion to ¥14.3 billion, representing acompound OHospira of its penicillin and penem active pharmaceutical annual growth rate (CAGR) of slightly over20%. ingredients (APIs) manufacturing site in Aurangabad, India, along In its domestic market –where Nichi-Ikoformed agenerics joint with an associated development facility near Chennai. The US$200 venture with Sanofifour years ago –the Japanese companyisaiming million deal wasfirst agreed 18 months ago (Generics bulletin,14 for avalue market share in March 2016 of 15.5% of alocal generics September 2012, page 3). market that it believeswill be valued at just over¥1.00 trillion. That Agroup overseeing Orchid’sdebt restructuring package has issued would equate to around 11.3% of Japan’spharmaceutical market by aletter of approvalfor ascheme that will see the Indian firm use value, and 30.0% by volume. Rs6.81 billion (US$112 million) of the proceeds from the sale to pay Developing oncology drugs and biosimilars –aswell as creditors. Another slice of the proceeds will be carved out to serve differentiated, value-added products –iscentral to Nichi-Iko’sbusiness Orchid’sworking-capital requirements. G plan. The companyisalready developing arivaltoRemicade (infliximab)through an alliance with Sanofi, and it is also planning clinical trials for rituximab and trastuzumab. MANUFACTURING/STRATEGICALLIANCES The firm’ssmall-molecule pipeline includes rivals to Valtrex (valaciclovir) and Livalo (pitavastatin) this year (see page 21), followed in the year to March 2015 by generic versions of Blopress (candesartan) Lillyinvests in Chinese site and Diovan(valsartan). li Lilly plans to invest between US$60-US$70 million in its Chinese Nichi-Ikoisalso investing in upgrading and expanding its Egenerics partner Novast Laboratories to expand the latter’s production facilities in Japan, while exploring options to manufacture manufacturing and development capacities in Nantong, China. overseas. By bringing more production in-house, the Japanese firm The US companytwo years ago invested US$20 million in Novast expects to reduce its cost of goods. G –inwhich it already held astake–tohelp build aportfolio of Lilly- branded generic medicines in China (Generics bulletin,29June 2012, IN BRIEF page 2). That deal included acommitment to expand Novast’s manufacturing capacity in Nantong. TEVA has agreed to pay US$27.6 million to settle US allegations that The firms’ expansion plans will see the construction by the end its Ivax affiliate paid aChicago doctor to prescribe the anti-psychotic of 2015 of a24,000sq mfacility located near existing operations in agent clozapine to thousandsofMedicare and Medicaid patients. G Nantong that will add 2.2 billion standard and sustained-release oral- solid doses to Novast’sannual output. G

21 March 2014 GENERICS bulletin 3 Gen 21/3/14 Pgs. 2-10_Layout 1 17/03/2014 19:49 Page 4

COMPANY NEWS

BUSINESS STRATEGY/ANNUAL RESULTS BUSINESS STRATEGY/SECOND-QUARTERRESULTS IGI Labs secures first Lannett pursuesbuys ANDA approval in US as sales shoot ahead

GI Laboratories says it has reached “a turning point” in transforming annett is assessing potential takeovercandidates as it grows both Iitself from acontract manufacturer into atopical generics player Lits sales and profits strongly.Inthe US generics specialist’sfinancial with the approvalofits first abbreviated newdrug application(ANDA). second quarter ended 31 December 2013, Lannett benefitted from The approvalisfor lidocaine 4% topical solution, for which the firm price increasestolift its turnoverby84% to US$67.3 million (see submitted its ANDAinMay 2012. Figure 1) and improve its operating profit markedly to US$25.4 With companies including Hospira, Roxane and Wockhardt holding million, compared to US$4.7 million in the prior-year quarter. similar approvals for alternativestoFresenius Kabi’sXylocaine topical “Wecontinue to evaluate several potential acquisitioncandidates,” anaesthetic, IGI said the US market for lidocaine 4% solution was stated president and chief executive officer Arthur Bedrosian, adding worth around US$1.8 million per year. that the firm waslooking at both products and companies. Lannett “Although this particular drug is the smallest opportunity in our pipeline,”commented IGI’spresident and chief executive officer, Product Second-quarter sales Change Proportion of Jason Grenfell-Gardner,“it is an important milestone for demonstrating type (US$ millions) (%) total (%) IGI’scapabilities.”“With 13 further applications pending, and at least Thyroid deficiency26.2 +81 39 nine more filings planned this year,IGI will continue to execute its research and development plan as part of our goal of being aleading Cardiovascular 16.9 +133 25 player in the generic topical pharmaceutical market,”hepledged. Pain management 6.8 +60 10 Last year,IGI slightly reduced its research and development Antibiotics 4.3 +301 6 investment to US$2.74 million as it filed six ANDAs. The company Others 13.0 +37 19 plans to at least double that spending this year to support aminimum Lannett 67.3 +84 100 of 10 ANDAsubmissions as it increasesits turnoverby40-45%. The lower research and development expenditure helped to reduce Figure1:Breakdown by product type of Lannett’s sales in its financial second to US$0.08 million IGI’soperating loss on aturnoverthat doubled quarter ended 31 December 2013 (Source –Lannett) to US$18.2 million. The sales figure included US$7.4 million from four products in eight presentations sold under the IGI label –three begantrading on the NewYork Stock Exchange at the end of last year, authorised generics of MediSynalar (fluocinolone), plus the econazole and it recently raised more than US$70 million through ashare offering. nitrate 1% cream that the firm acquired from Prasco and launched Price increases –especially for levothyroxine and the during the third quarter (Generics bulletin,3May 2013, page 9).G cardiovascular drug digoxin –contributed US$25.5 million to Lannett’s overall US$30.8million sales gain. Higher volumes added the rest. IN BRIEF Having increased its research and development spending by 62% to US$5.79 million in its second quarter,the US firm ended the period with STADA expects to improve its 2013 earnings before interest,tax, 17 applications pending at the US Food and Drug Administration (FDA). depreciation and amortisation (EBITDA) by 18% to C384 million Lannett has raised its sales forecast for its financial year ending (US$526 million) on group turnoverupbyatenth to C2.01 billion.G June 2014 by 12% to US$275-US$285 million, while it has lifted its gross margin outlook by four percentage-points to 61-63%. G

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4 GENERICS bulletin 21 March 2014 Gen 21/3/14 Pgs. 2-10_Layout 1 17/03/2014 19:49 Page 5

COMPANY NEWS

BUSINESS STRATEGY/ANNUAL RESULTS Hikma commits to its US Generics unit

ikma Pharmaceuticals has committed to remaining asignificant Business Annual sales Change Operating Hplayer in the US oral-dose and topical generics markets. Having Segment (US$ millions) (%) margin (%) considered “strategic options” for its US Generics business segment in the wake of compliance problems at its solid-dose facility in Branded 554 +5 22.4 Eatontown, NewJersey(Generics bulletin,23November 2012, page 3), US 363 +23 – the Jordanian group is nowlooking for ways to expand the business. MENA92-4– “Our Eatontown facility underwent extensive remediation work Europe 81 +4 – in 2013 and wasre-inspected by the US Food and Drug Administration (FDA) in February 2014,”Hikma stated. “The inspection went well, Injectables 536 +14 28.9 and we are awaiting the FDA’sformal feedback on the regulatory US Generics 268 +158 47.4 status of the facility.” Other 7+17 –* Chief executive officer Said Darwazah told investors the FDA auditors had been in the Eatontown plant for three to four weeks and Hikma 1,365 +23 25.8** had “left with one minor Form 483 observation”. He expressed optimism *operating loss of US$9 million that awarning letter issued 18 months ago would be lifted (Generics ** includes unallocated corporate expenses of US$45 million bulletin,23November 2012, page 3). “Having spent considerable time on the remediation of our Figure1:Breakdown by business segment of Hikma Pharmaceuticals’ sales and Eatontown facility and reviewed the strategic potential of our Generics operating margin in 2013 (Source –Hikma) business,”Darwazah stated, “we believe there is an increasing number Noting that the Injectables segment had started rolling out the of attractivemarket opportunities, and it is our intention to pursue West-Ward International brand in the MENAregion, beginning in these.”Astrengthened US business-development team is looking for Saudi Arabia, Darwazah stated: “Wesee opportunities to build a “further product acquisitions” to supplement its initial pushes into presence in other markets, such as Egypt and Morocco. We are non-injectable niches such as dermatology and transdermal patches. assessing medium-term opportunities to establish local manufacturing Strong sales of the antibiotic doxycyline amid market shortages facilities in keyMENAmarkets, such as Algeria and Egypt.” were largely responsible for the non-injectable US Generics segment’s Just overhalf of 2013 European Injectables sales –upby4% turnovermore than doubling to US$268 million last year (see Figure to US$81 million –came from Germany, where Hikma sevenyears 1). While Hikma supplied 34 US Generics products from its facilities ago bought the Ribosepharm and Thymoorganoncology operations in the Middle East and North Africa (MENA) region last year,italso (Generics bulletin,27April 2007, page 5). Italy and Portugal accounted re-introduced 10 drugs from the Eatontown site during 2013, with for most of the rest. Launching17injectablesinEurope helped to offset 15 more to followthis year. double-digit price erosion, while the companysigned five newcontract- manufacturing agreements last year. US Generics segment returntoprofit Darwazah said Hikma’sglobal Injectables segment had reduced Having made an operating loss in 2012 (Generics bulletin,22 its overheads in absolute terms last year.Combined with the impact March 2013, page 7), the US Generics segment bounced back to post of recent launches and US price increases, this pushed up the segment’s an operating profit of US$127 million last year,evenincluding US$39 operating margin by 4.2 points to 28.9%. million of non-recurring remediation and other costs. This performance The firm recently installed ahigh-speed vial line in the US, and gave the business an operating margin of 47.4%. asimilar line will be in place in Portugal by the second half of this The Generics segment accounted for afifth of group turnover year.Around the same time, adedicated development centre in Portugal that advanced by 23% to US$1.37 billion. will be completed, while aPortuguese bag line is set to be operational Just overtwo-thirds of global Injectables turnoverthat moved next year.Atits US Cherry Hill site, Hikma is installing apre-filled ahead by 14% to US$536 million came from the US, with the MENA syringes line to capitalise on an agreement with drug-delivery specialist region contributing 17% and Europe 15%. Unilife. The firm’sfirst pre-filled syringes submissions will be made “Weare focusing on opportunities in the large and growing US this year,ahead of planned launches in late 2015 or early 2016. generic injectables market valued at around US$7.6 billion,”stated Upgrading and expanding MENAfacilities accounted for US$33 Darwazah. The firm’sUSInjectables turnoverclimbed by 23% to million of the group’sUS$59 million capital expenditure last year as US$363 million last year as securing several price increases augmented sales by Hikma’sBranded segment in the region increased by 5% as the positive effects of product acquisitions and sevenlaunches. reported –and by 8% on aconstant-currencybasis –toUS$554 million. Five US injectables approvals and 26 regulatory submissions Acquiring Egypt’sEPCI early last year (Generics bulletin,1 during 2013 left 60 dossiers pending US approval. The group submitted February 2013, page 3) gave Hikma adedicated facility for oral files to reactivate nine dormant injectable products. cephalosporins, while the group formed ajoint venture with Midroc Darwazah observed that Hikma’sWest-Ward operation ranked in Ethiopia (Generics bulletin,4October 2013, page 3). “Receiving third by volume in the US generic injectables market –behind Hospira our first approvals of locally-manufactured penicillin products in Algeria and Fresenius Kabi’sAPP –but waseighth by value. However, he will provide acompetitive advantage going forward,”claimed Darwazah. noted, West-Ward had during 2013 improvedits value share by 0.8 In Morocco, Hikma has begun to secure approvals for its owndrugs percentage-points to 4.2%. amid a“challenging regulatory environment”. “Weare looking at the Injectables sales in the MENAregion fell by 4% to US$92 million potential for local manufacturing in Iraq,”Darwazah revealed, adding as Hikma avoided lower-margin tender sales and shifted its focus from that the group wascontinuing to consider ways to enter Russia. anti-infectivestochronic conditions. More than half of the segment’s This year Hikma expects to achieve group turnovergrowth of 5%. sales in the region were generated in Algeria and Saudi Arabia, with An Injectables sales rise of over20% and aconstant-currencyBranded another quarter of turnovercoming from Jordan and Sudan. gain of around atenth should offset lower US doxycycline sales. G

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COMPANY NEWS

BUSINESS STRATEGY/HALF-YEAR RESULTS Aspen wants partner to push into Japan

spen Pharmacare intends to be trading in Japan by the end of this Region Half-year sales Change Operating Ayear.“Preference is being giventoajoint-venture partnership,” (ZAR millions) (%) margin (%) the South African group revealed, adding that it wasalso exploring ways to establish footholds in Indonesia and Thailand. Asia Pacific 4,291 +27 21.3 “Our regional leadership team is placing significant focus on the Pharma 3,203 +7 – development of the business in Asia, with Japan having been identified Consumer 634 +14 – as an area for specific attention,”stated chief executive officer Stephen South Africa 3,837 +8 22.1 Saad. At present, he said, Aspen wasnot looking to establish pharma operations in China or India. Latin America 1,202 +60 – Acknowledging that Japan wasa“challenging market” with “a lot Rest of world 2,206 +147 – of red tape”, Aspen said it had registered alocal operating entity and International 3,408 +94 27.3 wasapplying for abusiness licence. At present, the group has two Sub-Saharan Africa 1,394 +41 13.2 employees in place in Japan, and it is “looking for keystaff” to capitalise on the market-entry opportunities –especially in the hospitals Eliminations -954 +37 – sector –afforded by its recent acquisitions of branded portfolios from Aspen 11,976 +33 24.0 GlaxoSmithKline (GSK) and Merck &Co. Noting that Japan’s pharma market was“shifting towards generics”, Saad recognised Figure1:Breakdown by region of Aspen Pharmacare’s sales and operating margin that local bioequivalence and other regulatory requirements meant in the six months ended 31 December 2013 (Source -Aspen) it could cost US$1 million to register aproduct locally. Through local distributors, Aspen increased its Japanese sales by Aspen’sAsia-Pacific operating profit failed to keep pace with sales, 19% to around ZAR75 million (US$7.0 million) in the six months rising by just 5% to ZAR916 million. This cut its operating margin ended 31 December 2013. Japan accounted for around aquarter of by 4.5 percentage-points to 21.3%, due in part to the Australianpricing the South African group’sAsia turnoverofaround ZAR300 million and margin pressures. To improve its Australian cost of goods, the firm in its financial half-year. is transferring production from Australia to its plant in Port Elizabeth, Asian markets represented only around 7% of Aspen’sAsia-Pacific South Africa. Having agreed to sell its facility in Croydon, Australia, turnoverthat increasedby27% to ZAR4.29 billion in the six-month for A$10 million (US$9.0 million) later this year,Aspen intends to close period (see Figure 1). The Asia-Pacific region made up around athird its Baulkham Hills site near Sydneyduring the second half of 2014. of Aspen’sgroup sales that advanced by 33% to ZAR12.0billion. The South African group’sdomestic sales increasedby8%to “Aspen’snewly-established businesses in the Philippines, ZAR3.84 billion. That total comprised Pharmaceutical sales that rose Malaysia and Taiwan made impressive advances, albeit offalow base,” by 7% to ZAR3.20 billion, despite an 11% decline to ZAR525 million Saad commented. Sales in the Philippines shot up by 71% as the firm in turnoverfrom antiretroviral tenders, plus Consumer turnoverthat started up an OTCteam. OTCproducts also drove turnovergrowth movedahead by 14% to ZAR634 million. “Aspen grewahead of the of afifth in Taiwan, while expanding the Malaysian operation’s market in all segments of the private sector,” Saad pointed out. salesforce to 17 representativeshelped to generate a30% sales rise. However, lower antiretroviral prices and asignificantly weaker “The largest contributor in the Asia-Pacific territory,Australia, rand contributed to Aspen’sSouth Africanoperating margin declining faces challenges in the absence of market growth drivers and the by almost four percentage-points to 22.1%. ongoing mandated price-reduction programme,” Saad stated, adding Just overhalf of turnoverinSub-Saharan Africa –upby41% to that Aspen’sAustralianmanagement team wasfocusing on “performance ZAR1.39 billion –was generated in West Africa, where Aspen Nigeria optimisation and reductions in the cost of goods”. “Nearly one in started trading in April 2013 by launching an OTCportfolio and infant five prescriptions generated in Australia is for an Aspen-distributed formulas. In East Africa, Saad said the group had successfully shifted product,”Saad stated, adding that this amounted to more than 100 its Tanzanian Shelys operation from focusing on the public to the private million packs per year. sector.Aspen, he added, would focus on organic growth in the region In Australia –where Aspen claims to be local generics market due to the time required to improve quality issues at acquired companies. leader with a16% value share, including products promoted for third International sales that almost doubledtoZAR3.41 billion included parties –Saad said the positive impact of patent expirations was aZAR1.20 billion contribution from Latin American markets. A being negated by average retail discounts that had risen to 46%, and recently-acquired infant formula business contributed nearly half of “excessive discounting” of 85% to 95% on blockbuster molecules. turnoverthat reached ZAR789 million in Spanish Latin America,where He blamed such discounting largely on “Indian firms frustrated by “Mexico and Venezuela were strong performers”. Aspen’sBrazilian their inability to break into the market” due to the close ties between sales movedahead by 9% to ZAR413 million despite supply disruptions. established generics players and alimited number of local distributors. Saad said Aspen’sposition in Latin America had been strengthened Nevertheless, the companyincreased sales from its ‘base’ business by acquiring baskets of branded products from GSK and Merck. “These in Australia and NewZealand by 6% to ZAR2.67 billion. Aportfolio transactions have enabled Aspen to establish its ownbusiness units of “classic brands” such as Lamictal(lamotrigine), Valtrex(valaciclovir) in Russia,”hepointed out, adding that the former GSK anticoagulants and Zyban (bupropion)acquired from GSK contributed ZAR348 had giventhe South African group adirect presence in countries million, while taking overthe S-26 infant-formula brand from Nestlé such as the Czech Republic, Hungary,Poland and Ukraine. in April last year added ZAR444 million. These gains helped to offset Adeal for Merck’sDutch active pharmaceutical ingredients(APIs) lower turnoverfrom off-patent brands and authorised generics such business wascompleted on 1October last year,while at the end of as Zyprexa (olanzapine) and weaker contract-manufacturing revenues. 2013 Aspen gained 11 brands from Merck and anticoagulants such The recent deal to sell the Australian operation’sHerron OTCrange as Arixtra (fondaparinux) and Fraxiparine (nadroparin) from GSK to Perrigo would allowAspen to focus on core operations (see page 19). (Generics bulletin,6December 2013, page 7). G

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COMPANY NEWS

PRELIMINARYRESULTS ANNUAL RESULTS Private Par expands ScinoPharmbenefits ahead of JHP move from focus on Japan

ar Pharmaceutical achievedsales growth of almost 5% to US$1.10 cinoPharm said it doubled its turnoverinJapan last year.The Pbillion last year,according to preliminary figures unveiled in a STaiwanese active pharmaceutical ingredients (APIs) producer opened corporate presentation. The privately-owned US company–which last an office in ToykoinJuly last year “to more effectively capture apart month completed aUS$490 million takeoverofinjectablesspecialist of Japan’semerging generics market”. JHP –will unveil its audited 2013 results to investors later this month. At present, ScinoPharm supplies bulk drugs including the cancer With estimated sales last year of US$198 million, Par’sgeneric treatments gemcitabine and irinotecan to Japanese customers. version of AstraZeneca’sEntocort EC (budesonide) enteric-coated On aglobal basis, the firm’sturnoverfrom the colorectal-cancer capsules accounted for almost afifth of the group’sturnover. drug irinotecanalmost trebled, while sales of the breast-cancer treatment The US firm’sexclusive generic rivaltoGlaxoSmithKline’s exemestane “benefitted from adedicated production line used exclusively Rythmol SR (propafenone)extended-release capsules contributed sales for manufacturing steroids, which wascompleted at the end of 2012”. of just overUS$70 million, while another US$56.7 million came from “Generic drug sales have remained buoyant,”commented the the company’salternative to AstraZeneca’sToprol XL (metoprolol) Taiwanese producer as it reported group turnoverahead by 11% to extended-release tablets. NT$5.09 billion (US$168 million). Oncology molecules accounted At the end of last year,Par had 73 abbreviated newdrug applications for 57% of that total, and central nervous system agents another 39%. (ANDAs) pending approval, of which it believes27are confirmed Generic bulk drugs made up just under three-quarters of group turnover, first-to-file opportunities. and contract manufacturing of novelmolecules the other 28%. The Having in November 2011 paid US$410 million for US-based Taiwanese producer generated just overhalf of its group turnoverin controlled-release specialist Anchen, Parafew months later spent North America, while another fifth came from European customers. US$37 million on Indian generics developer Edict. Its US$2.2 billion ScinoPharm’s2013 operating profit grewinline with sales, buy-out by private-equity group TPG in 2012 wasswiftly followed by improving by 11% to NT$1.40 billion. its paying US$110 million for 14 drugs that Actavis and Watson were At the end of last year,the Taiwanese firm completed construction forced to divest as acondition of merging. As aprivate company, Par of its ScinoPharm Changshu facility in China. The site currently holds has agreed to acquire Indian bulk-drugs developer Nuray Chemicals. G permits to produce three bulk cancer drugs and one antiviral agent. G

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COMPANY NEWS

BUSINESS STRATEGY/ANNUAL RESULTS IN BRIEF INVENTIV HEALTH CLINICAL has teamed up with Proteomics Endo to acquire‘two International to offer an array of biosimilar development services. The twofirms said Proteomics’ expertise in structural characterisation and quality-control testing would complement InVentiv’s or three’ during 2014 bioanalytical capabilities. ORION reported sales of off-patent generic and OTCSpecialty ndo Health Solutions expects to complete “at least twoorthree Products ahead by 5% to C385 million (US$537 million) last year. Etransactions” this year and remains keen to bolster its semi-solids That increase came despite afall of two-fifths to C10 million in sales portfolio, the firm’spresident and chief executive officer,RajivDeSilva, of generic entacapone. Specialty Products accounted for the majority has insisted. “Weare looking for areas that stay away from typical of the Finnish group’sdomestic human pharmaceuticals turnoverthat oral solid-dosage forms,”DeSilvasaid, adding that the companywas improvedby7%to C255 million, as well as the bulk of human seeking areas of “niche benefit –either in terms of difficult formulations pharmaceuticals sales in Eastern Europe and Russia that climbed by or fewer competitors”. Noting that the firm was“actively” looking at 18% to C74 million. Orion’sFermion active pharmaceutical ingredients “small-to-medium” deals in the region of US$250-US$500 million, (APIs) division advanced its third-party sales by almost athird to De Silvasaid that acquisitions remained “an important component of C64 million. Group turnovergrewbynearly 3% to C1.01 billion, but building the business long-term”. Orion anticipates generic competition in Europe this year to its key The firm last month completed through its Qualitest generics Stalevo (entacapone/levodopa/carbidopa)Parkinson’sdisease drug, division the US$225 million purchase of US-based Boca Pharmacal for which European data exclusivity expired in October 2013 that wasfirst announced last year (Generics bulletin,6September (Generics bulletin,18October 2013, page 20). 2013, page 3). The Boca operations would nowbeintegrated into Qualitest –along with anyadditional assets that expanded the firm’s GENERA said launching four molecules in sevenpresentations generics presence in the US –under areporting segment that would through its Genera Lijekovihuman medicines division helped the be known as ‘Generic Pharmaceuticals US’, De Silvanoted. Croatian life-sciences group to increase its turnoverlast year by And more recently –inline with De Silva’sassertion that Endo 8.4% to CrK199 million (US$36.2 million).During 2013, Genera would look at deals “of anysize that will create value for shareholders” – Lijekoviobtained approvals for 10 molecules in 18 presentations the US companywrapped up its acquisition of Paladin Labs for US$2.7 from Croatia’sHalmed medicines agency. billion. De Silvanoted that while Paladin would continue to operate in Canada under its ownname, “further expanding [Paladin’s] international RECORDATI increased its turnoverby13.7% to C942 million footprint, particularly in Latin America, is akey strategic imperative”. (US$1.31billion) last year,while a17.0% rise in operating profit Generic competition faced by Endo to its Lidoderm (lidocaine) to C195 million produced an operating margin of 20.8%,even and Opana ER (oxymorphone) brands resulted in sales through its after an C8.0 million provision for salesforce restructuring in Endo Pharmaceuticals brands division dropping by 17% to US$1.39 France. During the year,the Italian group –which plans to exceed a billon in 2013 (see Figure 1). The US firm is “considering multiple turnoverof C1.0 billion this year –spent C89.5 million on buying options” for the Lidoderm brand –which contributed almost aquarter Spanish urology and gynaecology firm Casen Fleet, and C22.6 of group sales –following Actavis’ generic launch in September million on obtaining a67% stakeinTunisia’sOpalia Pharma. (Generics bulletin,20September 2013, page 7). These options, De Silva said, included introducing an authorised generic. ASCENDIS HEALTH said its Pharma-Med prescription drugs and Meanwhile, several recent generic launches accountedfor about medical devices division contributed ZAR70.4 million (US$6.58 half of the reported 15% turnoverrise to US$731 million by Endo’s million) of group turnoverthat morethan doubled to ZAR662 Qualitest division. But the Endo Pharmaceuticals brands decline, million in the six months ended 31 December 2013. The South African coupled with turnoverfrom the group’sAmerican Medical Systems healthcaregroup –which listed on the JohannesburgStock Exchange (AMS) business dropping by 2% to US$492 million, pushed group (JSE) in November last year –expects in the medium term for its turnoverdownby7%toUS$2.62 billion. Pharma-Med and Consumer Brands OTCdivisions to each contribute Costs of just overUS$1 billion related to litigation and asset two-fifths of its turnover, with the other fifth coming from its impairment charges –which included aUS$495 million impairment Phyto-Vet agriculture and veterinary unit. The firm’srecent ZAR300 charge related to goodwill attributable to Endo’sacquisition of AMS – million acquisition of medical devices firm Surgical Innovations is resulted in the group posting an operating loss of US$426 million. G currently being integrated into the Pharma-Med division.

Annual sales Change Proportion of STRIDES ARCOLAB reported standalone group turnoverthat (US$ millions) (%) total (%) rose by 13% to Rs8.07 billion (US$132 million) in the 12 months ended 31 December 2013. Excluding the cash receivedaspart of Lidoderm 603 -36 23 the US$1.85 billion deal to sell its Agila Specialties injectables Opana ER 228 -24 9 division to Mylan (Generics bulletin,8March 2013, page 1) Voltaren Gel 171 +45 6 Strides’ operating profit inched forward by 4% to Rs799 million. Other brands* 393 +25 15 The Indian firm –which has 18 abbreviated newdrug applications Endo Pharmaceuticals 1,394 -17 53 (ANDAs) pendingUSapproval–has shifted its financial year from Qualitest 731 +15 28 January-December to April-March. AMS 492 -2 19 NIPPON CHEMIPHAR said weak sales to third parties and a Endo 2,617 -7 100 sluggish performance from recent launches reduced its generics sales by 1.4% to ¥18.2 billion (US$179 million) in the nine months ended *includes US$63 million of royalties 31 December 2013. Group turnoverfell by 2.4% to ¥24.3 billion. G Figure1:Breakdown of Endo Health Solutions’ sales in 2013 (Source –Endo)

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COMPANY NEWS

ANNUAL RESULTS BUSINESS STRATEGY/ANNUAL RESULTS Hypermarcas finds Siegfriedisseeking better productivity moretargets to buy

olling out alean manufacturing programme at its production iegfried is “scanning the horizon for interesting acquisition RcomplexinAnápolis, Brazil, helped local group Hypermarcas to Sopportunities” after it last year finished integrating the US injectables improve the gross margin of its Pharma division by almost two producer Alliance Medical Products (AMP) that it acquired in June percentage-points to 76.7% last year on sales that advanced by 12.2% 2012. The Swiss group believesthere are “some interesting targets to BRL2.33 billion (US$983 million). The Brazilian group has started available” to push ahead with forward integration, while it is “keeping transferring to Anápolis “all the remaining drug-productionlines still its eyes open on consolidation” to achieve critical mass. running in Rio de Janeiro”. Although the Swiss group increased its turnoverby2.0% as Hypermarcas attributed the double-digit Pharma sales growth to reported –and by 3.1% on aconstant-currencybasis –toSFr375 “expansion in generics and branded generics”. Orlistat and oxymetazoline million (US$430 million), Siegfried’ssales would have declined by were among 13 unbranded generics launches last year,while additions 1.9% without the full-yearimpact of the AMP deal. to the group’sbranded generics portfolio included Magnostase 2mg Chief executive officer Rudolf Hankoinsisted reaching sales of (loperamide)and Timosopt (timolol/dorzolamide). SFr500-600 million in the contract-manufacturing organisation (CMO) The Pharma division accounted for 54.7% of Hypermarcas’ group market was“absolutely within reach for Siegfried”. The group, he said, turnoverthat increasedbyalmost atenth to BRL4.26 billion as wasfocusing on “achieving criticalmass and expanding our technology”. Consumer sales grewby7.4% (see Figure 1). G Adding AMP’ssteriles business was“astep in that direction”, he added. AMP –which met the group’s“sales and profitability expectations” Division Annual sales Change Gross –isnow led by Darrin Schellin after the departure of AMP’sfounder (BRL millions) (%) margin (%) Juan Valdes. In future, the California-based business will trade under Pharma 2,329 +12.2 76.7 the Siegfried brand. Consumer 1,930 +7.4 49.9 IncludingAMP,Siegfried increased the turnoverfrom its Drug Products reporting group by 3.4% –and by 4.9% on aconstant currency Hypermarcas 4,259 +9.9 64.5 basis –toSFr101 million. “In response to high demand and equipment utilisation,”the group commented, “we have expanded capacity [with Figure1:Breakdown by division of Hypermarcas’ sales and gross margin in 2013 asolid-dose blister line] in Malta and increasedstafflevels.” (Source –Hypermarcas) In May this year,the Swiss contract developer and manufacturer also expects to produce the first validation batches at the facility it is building in Nantong, China. This will “first and foremost allowusto ANNUAL RESULTS scale up business in off-patent active pharmaceutical ingredients (APIs)”. Commercialproductionisscheduled to begin in the fourth Exports push Podravka ahead quarter of this year at the site on the Yangtze river, north-west of xports rising by almost atenth helped to push Podravka’sBelupo Shanghai (Generics bulletin,20September 2013, page 6). EPharmaceuticals sales up by 3% to CrK853 million (US$153 “The basic building structures are nowinplace and equipment million) in 2013. This growth –which waslargely due to increases installation has started this year,” Siegfried stated, noting that the in Russia, as well as Bosnia and Herzegovina –more than offset a Nantong plant would have atotal capacity of 300cu m. Another 100cu m 2% drop in the Croatian firm’sdomestic market, where falling prices of reactor volume will be available at the API and intermediates factory outweighed rising volumes. that the group is building in Zofingen, Switzerland, to the same design Viewed by product group, prescription-drug sales rose by 3% on to simplify product transfers. higher turnovers of central nervous system (CNS), dermatologyand TurnoverbySiegfried’sDrug Substances product group ahead immunomodulatingdrugs. Sales of OTCmedicines increased by 4%. by 1.4% –and by 2.5% on aconstant-currencybasis –toSFr274 Pharmaceuticals accounted for just under aquarter of the Croatian million (see Figure 1) comprised SFr182 million from exclusive- food and drinks producer’sgroup turnoverthat stalled at CrK3.63 synthesis sales and SFr92 million of turnoverfrom Siegfried’sown billion last year.But even though Pharmaceuticals earnings before portfolio of controlledsubstances. The group said its sales growth had interest and tax (EBIT) stagnated at CrK117 million, the business been limited by anegative SFr8 million impact from lower prices for made up nearly nine-tenths of the group EBIT of CrK131 million. rawheparin that were passed on to an exclusive-synthesis customer. The Croatian group is investing CrK390 million overthe next three Better facility utilisation and the addition of sterile filling helped years in building twoBelupo facilities for solid, semi-solid and liquid Siegfried to more than double its earnings before interest and tax drugs. Podravka expects production to start early in 2017 (Generics (EBIT) to SFr40.8 million. The group’sEBIT margin improvedby bulletin,10January 2014, page 5). G six percentage-points to 10.9%. G

IN BRIEF Product Annual sales Change Proportion of group (SFr millions) (%) total (%) JUBILANT LIFE SCIENCES said price declines almost wiped out strong volume demand for solid-dose formulations and initial Drug Substances 274 +1.4 73 supplies to the Commonwealth of Independent States (CIS) as its Drug Products 101 +3.4 27 Pharmaceuticals sales rose by 2% to Rs6.75 billion (US$111 million) Siegfried 375 +2.0 100 in its financial third quarter ended 31 December2013. G Figure1:Breakdown by product group of Siegfried’s sales in 2013 (Source –Siegfried)

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COMPANY NEWS

BUSINESS STRATEGY/ANNUAL RESULTS SECOND-QUARTERRESULTS Akornisanticipating Rising’s US launches bearing fruit in India drive Aceto’s growth

korn has filed its first product –the injectableParkinson’sdisease aunching nine products through its Rising Pharmaceuticals Atreatment Cogentin (benzatropine) that it licenses from Lundbeck – Lsubsidiary during its previous financial year contributed to Aceto from one of the four facilities the firm has operating in India. The US raising its Human Health segment turnoverbyathird to US$39.8 companylast year said it believeddoing so would trigger aUSFood million in the group’sfinancial second quarter ended 31 December and Drug Administration (FDA) inspection of the plant, as none of 2013. On top of the Rising generic launches, Aceto said it had during the four currently hold US agencyapproval. “Because this is asite the quarter benefitted from expanding its nutritionalproducts business transfer of an approvednew drug application (NDA),”Akorn in the US and Germany. This more than offset slides in the firm’s commented, “we anticipate the FDAwill inspect the facility in the Pharmaceutical Ingredients and Performance Chemicals businesses, as next six to eight months.” group turnoverinched ahead by 2.2% to US$117 million (see Figure 1). By that time, Akorn –which said it had strengthenedits quality An almost three percentage-point rise in Human Health’sgross oversight in India in compliancewith the FDAand “other international margin to 32.7% helped Aceto to improve its group gross margin by regulatory agencies” –expects to have filed products from each of five points to 23.2%. The group’soperating profit jumped by over the remaining three facilities. The US companyacquired the Indian three-fifths to US$10.7 million. G facilities, of which three were still under construction, and aportfolio of nearly 300 products from Indian firm Kilitch Drugs for US$52 Second-quarter sales Change Gross million three years ago (Generics bulletin,14October 2011, page 5). (US$ millions) (%) margin (%) Aseries of significant product launches in late 2012 and early Human Health 39.8 +33.4 32.7 2013 helped Akorn to increase its group turnoverbyjust under a Pharmaceutical Ingredients 37.5 -5.8 20.7 quarter to US$318 million last year. Performance Chemicals 39.2 -11.5 15.8 Progesterone capsules and atetanus/diphtheria vaccine accounted for more than half of areported 38% sales increase to US$180 million Aceto 116.5 +2.2 23.2 by Akorn’sHospital Drugs &Injectablesbusiness segment. Striking aUS$52.8 million deal with Merck &Cofor the US Figure1:Breakdown by business segment of Aceto’s sales in its financial rights to Cosoptand Cosopt PR eyedrop brands containingdorzolamide second quarter ended 31 December 2013 (Source –Aceto) and timolol –aswell as the originator’sAzaSite (azithromycin) conjunctivitis treatment (Generics bulletin,6December 2013, page 24) ANNUAL RESULTS –contributed about afifth of a10% increase in Ophthalmicsturnover to US$115 million as sales of the OTCdry-eye remedy TheraTears also improved. Revenues from providing contract services edged up Infusion sale depletes Claris to US$23.6 million. elling amajority stakeinits infusion business in India and other Agreater proportionofdrugs made by third parties or subject to Semerging markets to Japanese firms Otsuka and Mitsui midway profit-sharing agreementsreduced the Hospital Drugs &Injectables through last year caused Claris Lifesciences’ group net sales to drop segment’sgross margin by just oversix percentage-points to 58.2% by 14% to Rs6.58 billion (US$108 million) in 2013. The joint-venture (see Figure 1). As aresult, Akorn’sgroup gross margin weakened by deal –which cost the twoJapanese firms atotal of Rs10.5 billion –left nearly four points to 54.1%. Claris holding only a20% stakeinthe business (Generics bulletin, Nevertheless, the US firm improvedits operating profit by 28% 9August 2013, page 8). The Indian firm’spre-tax profit slipped by to US$88.2 million, even after raising its research and development overafifth to Rs1.07 billion. spending by aquarter to US$19.9 million. In the US, Claris has filed 35 abbreviated newdrug applications In 2013, Akorn filed 12 abbreviated newdrug applications (ANDAs) with the US Food and Drug Administration (FDA). It is (ANDAs) with the FDA, taking its total pendingwith the agencyto65. awaiting approvalfor 22 of these, while the firm is “working towards” Four of those ANDAs hold tentative US approvals, and have amarket filing at least 15 ANDAs ayear overthe next three years. G value of approximately US$550 million, according to IMS Health data. Assuming that its proposed US$640 million takeoverofHi-Tech Pharmacal closes on 1April, Akorn anticipates group sales in the region ANNUAL RESULTS of US$540-US$560 million in 2014. This forecast assumes that Akorn’s Nembutal (pentobarbital) injectable brand avoids generic competition. G DSM Sinochem edges ahead Business Annual sales Change Gross SM Sinochem Pharmaceuticals improvedits turnoverby1%to segment (US$ millions) (%) margin (%) DC184 million (US$253 million) in 2013 as adverse exchange-rate shifts almost negated organic sales growth of 7%. “Sales were flat and Hospital Drugs/Injectables 180 +38 58.2 profitabilitystill too low,”the Dutch parent group noted as the business Ophthalmics 115 +10 55.4 posted an C8million loss at earnings before interest and tax (EBIT) level. Contract services 24 +4 16.8 DSM nowreports its Pharmaceutical Products contract- Akorn318 +24 54.1 development and contract-manufacturing business as adiscontinued operation after it merged with JLL/Patheon in aUS$2.65 billion Figure1:Breakdown by business segment of Akorn’s sales and gross margin in transaction to create privately-owned DPx Holdings. DSM owns 2013 (Source –Akorn) 49% of the venture. G

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MARKET NEWS

PRICING&REIMBURSEMENT REGULATORY AFFAIRS Germany counts up FDA asksfor input its contractssavings on researchpriorities

egotiating supply contracts for medicines, especiallythose covered nput from industry stakeholders on the US Food and Drug Nby reference prices, savedGermany’s132 statutory health insurance IAdministration’s(FDA’s) regulatory science priorities for generics funds around C2.8 billion (US$3.9 billion) last year,according to is being sought by the agencyatapublic meeting at the FDA’sWhite preliminary figures releasedbythe country’sMinistry of Health. Oak campus in Maryland, US, on 16 May. The C2.8 billion figure represented an increase of 36%, or C760 “FDAisseeking this input,”the agencyexplained, “as it fulfills million, overthe C2.1 billion of savings achievedin2012. its statutory requirement under the Generic Drug User Fee Amendments Without these savings achievedthrough tenders, the ministry (GDUFA) of 2012 to develop an annual list of regulatory science observed, the funds’ reported 2.4% increase in medicines spending initiativesspecific to generic drugs.” last year would have been twice as high. It noted that the AOKgroup Information from the meeting will be used in developing a of regional funds that has led the wayinaggressive tendering – regulatory science plan for the year ending 30 September 2015. typically offering sole-supply contracts for off-patent molecules –had Meanwhile, the FDAhas confirmed that research has started as been particularly successful in cutting its spending. part of external studies of generics under the regulatory science Last year,the AOKfunds achievedafunding surplus of C977 programme.Around US$20 million of funding has been allocated to million, the figures indicate, forming the bulk of an overall C1.2 billion various non-agencybodies –including universities and hospitals–to surplus for all statutory funds. carry out the research. “Over the past fewmonths, grants have been Nevertheless, Germany’slower house of parliament, the Bundestag, awarded and research is beginning,”the FDAsaid, noting that this on 20 February passed apackage of cost-cutting measures that include researchhad followed the public meeting on regulatory science aprice freeze for most medicines until the end of 2017 and arise in a priorities for generics held by the agencyinJune 2013 (Generics mandatory clawback from 6% to 7%. However, off-patent,multisource bulletin,17May 2013, page 13). medicines were exempted from these provisions (Generics bulletin, “These grants are part of the GDUFAcommitmentsand are from 7March 2014, page 1). GDUFAfee money,”the agencystated, noting that the research would The legislative package also entrusts Germany’sfederal joint “provide newtools for FDAtoevaluate generic drug equivalence committee, the G-BA, with drawing up alist of drugs that are excluded and for industry to efficiently develop newgeneric products”. from automatic generic substitution. G Certain studies will coverproduct categories, such as research on treatments delivered by metered-dose inhalers, orally-inhaled drugs, topicals and transdermals, solid-dose drugs or suspension nasal products MARKET RESEARCH for local action. Others focus on specific molecules,including bioequivalence studies for generic bupropion, stabilityresearch for Canada cutsspending growth fluticasonepropionate capsules, studies of mesalamine pharmacokinetics, and an evaluation of the effects of switching between branded and ncreasing the use of generics and slashing their prices led Canada’s generic tacrolimus in high-risk transplant recipients. G Ioverall spendingonprescription drugs to advance by just 2.3% to C$29.3 billion (US$26.4 billion) in 2013, according to areport by the Canadian Institute for Health Information (CIHI). This annual INTELLECTUAL PROPERTY growth rate was“the second-lowest in more than 20 years”, the market researcher pointed out. Europe’s pharmafilings fall The decline in spending growth was“due in large part to patent expiries for commonly-usedchemicals after 2007”, the CIHI said. For atent filings for pharmaceuticals submitted to the European Patent example, the organisation noted, public spending on statins had POffice (EPO) declined by 14% to 5,396 last year.Biotechnology “declined by an average annual rate of 7.0% between 2007 and 2012”. applications were 4% lower at 5,381. Total patent filings increased by “The impact of the entry of lower-cost generic products wasfurther 2.8% to around 266,000, according to the EPO’s2013 annual report. amplified with the implementation of generic pricing policies by public Almost two-thirds of all patent applications came from “large drug programmesoverthe past five years,”the CIHI observed. Along companies”. Germany’sBayer ranked 16th by the number of filings with with these provincial initiatives, Canada decided ayear ago to set the 850, ahead of DSM and Johnson &Johnson in joint 23rd with 659 national prices of six widely-used generics at 18% of their brand prices. applications each. Sanofimade 651 applications, ranking it 25th, while “Generic drugs account for almost three-quarters of use, butless Roche was28th with 594. Merck KGaA was44th and Novartis 49th. than half of spending in public drug programmes,”the CIHI observed. G The EPO granted arecord 66,700 patents, an increase of 1.6%. G

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21 March 2014 GENERICS bulletin 11 Gen 21/3/14 Pgs. 11-15_Layout 1 17/03/2014 19:50 Page 4

MARKET NEWS

TRADE AGREEMENTS INTELLECTUAL PROPERTY UNITAID voicesfears Patent reviewstudy over US’ TPPAterms shelvedinAustralia

Sproposals for measures to be included in aTrans-Pacific ustralia’s newLiberal-National coalition government has no plans UPartnership Agreement (TPPA) would “impose ahigher levelof Ato release afinal report on areviewofpharmaceutical patents for protection for intellectual-property rights than is required”,thereby which draft recommendations were released almost ayear ago. “As damaging access to generics in developing countries, according to an the Pharmaceutical Patents reviewwas commissioned by the previous analysis by the World Health Organization’sUNITAID affiliate. government and conducted by an independent panel, the government Highlighting several measures included in leaked US proposals – is not obliged to release the report,”Minister for Industry Ian Macfarlane “widely considered to be the basic negotiating text for the TPPA” – stated in awritten parliamentary answer. that go beyond the levels of protection required by the World Trade Responding to aquery posed by Labor member of parliament Organization’s(WTO’s) agreement on trade-related aspects of (MP) Melissa Parke, Macfarlane said the newgovernment wasnot intellectual-property rights (TRIPS), UNITAID says such TRIPS-plus considering the panel’srecommendations made in the draft report, nor provisions “delay generic market entry and competition”. As such, making plans to release afinal report. theyrun counter to UNITAID’sefforts to “increasethe affordability Among the panel’sdraft recommendations were reducing patent- of, and access to, medicines”. term extensions and providing “negotiated incentives” for parties that “There are also serious concerns,”UNITAID adds, “that proposed successfully challenged patents (Generics bulletin,19April 2013, provisions relating to financing and/or reimbursement of medicines – page 21). The draft reviewhad also recommended amending Australia’s as well as to investment –will have adverse implications for access Patents Act –sothat carving out patented indications did not amount to medicines and the protection of public health in general.” to infringement if “reasonable steps” were taken to avoid off-label use – The analysis suggests governments should adopt “a positive as well as creating aregister linking related patents to approveddrugs. agenda” of balancing trade interests with public-health goals. Existing Meanwhile, Australia’sGeneric Medicines Industry Association free-trade agreements, it says, should be examined to assess the impact (GMiA) has reiterated its opposition to further price cuts for generics. on access to affordable medicines of measures such as data exclusivity Chairman Mark Crotty called on the government to avoid the and patent-term extensions. “irreversible damage” to the country’s generics industry that would In asection on patents, the analysis finds the US proposal “appears come from lower prices, insisting that the Pharmaceutical Benefits to weigh heavily in favour of patent applicants by requiring lower levels Scheme (PBS) wasalready “delivering more savings than expected”. G of disclosure,lower standards of patentability,nopre-grant opposition proceedings and multiple opportunitiestoamend patent applications”. In particular,UNITAID is concerned that the text suggested by the REGULATORY AFFAIRS US would require newforms, uses and methods of use to be patentable, thereby stopping signatories from adopting anti-evergreening standards India collaborates with FDA such as those in place in Argentina and India. Furthermore, weakened requirementstodisclose the ‘best mode’ of practising apatented mproving communication between drugs regulators in India and the invention would hinder generics companies’ ability to replicate drugs. IUS is the goal of a‘statement of intent’ signed by regulatory agencies Allowing five-year patent extensions would, it argues, endanger in the twocountries, according to US Food and Drug Administration the benefits of generic competition that had seen the annual cost of (FDA) Commissioner Margaret Hamburg. Following her visit to India treatment with first-line triple-combination antiretrovirals tumble from in February (Generics bulletin,14February 2014, page 10), Hamburg US$10,439 to US$350. Furthermore, the analysis warns, the US said regulators in the twocountries planned to “strengthenour efforts proposal appears to prevent the use of Bolar early-working provisions to collectively work together so that we can help ensure that the to gain marketing authorisations in other countries. products being exported from India are safe and of high quality”. Aproposed TPPAintellectual-property chapter includes plans Some had questioned whether Hamburg’svisit to India had been for data exclusivity –including a‘placeholder’for biologicals –and “part of an effort to ‘target’ Indian companies”, she acknowledged. patent linkage. “Data exclusivity is widely considered to be aTRIPS-plus But Hamburginsisted that “this is not about targeting anyone country”, measure that has anegative impact on access to medicines,”UNITAID declaring that all FDAactions taken against Indian manufacturers observes, citing experiences in Guatemala and Jordan. Unlikeearlier were simply the result of the US regulatory framework. G trade agreements, “the TPPAproposal instead requires that the period of exclusivity should start from the point at which the medicine is registered in the country concerned”. REGULATORY AFFAIRS Requiring TPPAcountries –such as Australia, Chile, Japan, Malaysia, Mexico, Peru and Vietnam –toimplement patent-linkage systems would provide “another avenue for preventing the launch of EMA eyes afee rise in April generic medicines”,UNITAID cautions. uropean centralised fees for applicants and marketing-authorisation The analysis also discusses howtrademark and copyright rules might Eholders will rise by around 1.5% when newfees come into effect prevent generics firms from replicating an original drug’sappearance from 1April, according to the European Medicines Agency(EMA). or labelling. Information provided in infringement suits “could be used “The final adjustment is not yet known,”the EMA stated, noting to harass or intimidate other players in the supply and distribution chain”, that the European Commission was“currently in the process of while seized generics could be destroyed and “debilitating financial adopting aregulation adjusting the fees payable to the agencyinline damages sought”. “Just one case of infringement under the US’ proposals with the 2013 inflation rate”. Full details of the revised fees will be could potentially bankrupt ageneric competitor,” it warns. G published at the end of March. G

12 GENERICS bulletin 21 March 2014 Gen 21/3/14 Pgs. 11-15_Layout 1 17/03/2014 19:50 Page 5

MARKET NEWS

PRICING&REIMBURSEMENT/BIOLOGICALDRUGS REGULATORY AFFAIRS Spanish firms warn FDA label rule hit by over pricing policy broad-based attack

iosimilars must not be subjected to the same Spanish reference- roposals by the US Food and Drug Administration (FDA) to change Bpricing system as small-molecule generics if potential savings Plabelling requirements for generics would “have achilling effect” of C1.50 billion (US$2.05 billion) by 2020 are to be achieved, Spain’s on the generics industry and should be reconsidered, according to a generic medicines industry association, Aeseg, has told health ministers letter sent by more than twenty US healthcare industry groups to FDA during aclosed-door meeting. Aesegalso called on ministers to Commissioner Margaret Hamburg. Noting that the proposed rule – “develop an information policyand training” to tackle unfounded requiring generics firms to update safety information using the same misgivings about biosimilars among healthcare professionals. ‘changes being effected’ (CBE) process as originators –“could result Representing the European Generic medicines Association (EGA), in multiple versions of labels for the same medicine”, the letter claims which collaborated in the meeting, Hospira’sPaul Greenland stressed this would “create uncertaintythroughout the drug supply chain” and that the cost of developing biosimilars –and theyway theywere used lead to higher prices. by healthcareprofessionals –was very different to small-molecule “The FDAand others need to fully explore the potential unintended generics. Therefore, he argued, pricing and reimbursement systems consequences that the rule may have on patient access and national must be tailored to biosimilars’ unique characteristics. healthcarecosts,”the letter urges, adding that “permitting label changes To that end, Aesegplans to establish an annual forum in Spain for generic drugs without FDAapprovalcounters 30 years of law to inform healthcare professionals and authorities about biosimilars. requiring generic and brand medicines to have the same labels”. The first will takepart during the EGA’s 20th annual meeting in However, the letter –which is also backed by retailers including Madrid on 25-27 June this year. Walmart and Rite Aid –insists that “simple changes” to the proposed Meanwhile, astudy by Madrid’sUNED University has found rule could “achieve all of FDA’sobjectivesrelated to efficient “a clear communication strategy” in online media aimed at discrediting communication of important safety information”. generics through misinformation. The research–published in the The US Generic Pharmaceutical Association (GPhA) said the Qualitative Social Work journal –isaimed at helping healthcare social letter indicated that “groups from every part of the healthcare supply workers to reinforce the “social acceptability” of taking generics. G chain agree that the proposed rule raises serious questions about patient safety,cost and access”. The industry groups were joining with the GPhA to say “we can do better”, stated the association’spresident and REGULATORY AFFAIRS chief executive officer,Ralph Neas, insisting that the FDAshould “listen carefully to their concerns”. “Weare most concerned about the GPhA backs US budgetplans dangerous confusion that multiple labels would cause, and the increased costs of, and reduced access to, generic medicines for patients roposals to encouragegreater adoptionofgenerics by the US who need them most,”Neas emphasised. PMedicare health insurance programme and to reduce data Meanwhile, agroup of US Senators and Representatives–including exclusivity for originator biologics from 12 years to sevenhavebeen Representative Henry Waxman –has written to Hamburgtoexpress welcomed by the US Generic Pharmaceutical Association (GPhA). support for the proposed labelling rule. “The proposed rule is critically The plans –set out as part of the US budget for the country’s2015 important to ensure that the public is informed as soon as possible fiscal year –would “leverage the provenpower of generic medicines when newsafety information becomes available,”the letter states, “and to provide patients with the therapies theyneed while keeping the to ensure that labelling for aprescription drug remains up-to-date even nation’sbudget on target”, the GPhA said. when the branded drug is no longer being marketed or has not undergone However, the association said it “strongly opposes the budget’s alabelling update to reflect newly-discovered risks.” assumptions and methodology in estimating the impact of aban on “Some have expressed concern that allowing abbreviated newdrug patent settlements”. The budget document claims that the US could application (ANDA) holders to use the CBE process will impose undue save US$11.1 billion between 2015 and 2024 by “prohibiting brand costs on generic manufacturers, and therefore patients,”the and generic drug companies from delaying the availability of new Congressmen’sletter acknowledges. However, “this concern appears generic drugs and biologics”.But the GPhA insisted that “settlements unfounded”, it states, noting that generics firms are “already obligated result in early market entry for generic alternativesand thus save to monitor the safety of their products and recommend safety labelling billions of dollars”. improvements under current law”. The GPhA also said it opposed the extension of Medicaid rebates The proposed rule “simply builds on those existing reporting to the Medicare Part Dlow-income subsidy programme. “Imposing obligations to permit generic manufacturerstouse the CBE process rebates would likely have the unintended consequence of shifting to update their labelling information”, the letter insists. costs onto American consumers purchasing their care in the private Addressing the potential for inconsistent labels between different marketplace,”the association stated. versions of certain products, the letter asserts that it is “critical that Originator association the Biotechnology Industry Organization the principle of sameness in our generic drug system be preserved”. (BIO) criticised the budget proposals, insisting that manyofthe The proposed rule “includes important measures to address this provisions would “jeopardise the continued biotech research and concern”, the letter points out, “by providing that the ANDAholder development that is necessary to find cures and breakthrough medicines”. shall distribute its revised product labelling ‘on atemporary basis’ Noting that the 12-year data-exclusivity period had received while the FDAreviews the labelling change”. This process “strikes an “widespread bipartisan support”, BIO warned that “a reduction in this appropriate balance between ensuring that up-to-date safety information period will jeopardisethe careful balance established in the lawto is made available as quickly as possible, while promoting consistency reduce costs, expand access, and encourage continued innovation”. G in labelling”, it concludes. G

21 March 2014 GENERICS bulletin 13 NEW

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ToolboxA4leaflet-.indd 1 21/05/2013 10:54 Gen 21/3/14 Pgs. 11-15_Layout 1 17/03/2014 19:50 Page 7

MARKET NEWS

IN BRIEF INTELLECTUAL PROPERTY FDA –the US Food and Drug Administration –and the European Medicines Agency(EMA) have set up anew collaborative ‘cluster’ India issues guidance to focus on pharmacovigilance.This will provide “a forum for a more systematic and focused exchange of information on the safety of medicines”, the US agencystated. on patent exclusions MSF –lobbying group Médecins Sans Frontières–has criticised a report by University College London’s (UCL’s)School of Pharmacy nventions that are not patentable in India –including “mere discovery on the cost-effectiveness of medicines as “a Bayer and Novartis- Iof anew form of aknown substance which does not result in funded report which is part of awider campaign to increase drug enhancement of known efficacy, or mere discovery of anynew property prices across Europe”. “In calling on the UK’sNational Institute or newuse for aknown substance”, as outlined in Section 3(d) of the for health and Clinical Excellence (NICE) to abandonits narrow country’sPatents Act –are clarified in draft guidelines for examining focus on the National Health Service (NHS) budget,”MSF states, pharmaceutical patent applications that have just been released by “the report says that the only answer to innovation and newmedicines India’scontroller-general of patents, designs and trademarks. are ever-increasing prices. This is simply not true.” Noting that process, rather than product, patents had been available in India since 2005, the guidelines state: “Manyofthe issues related GHANA’s Ministry of Health has “pledged its support towards the to the product patenting in the field of pharmaceuticals are now feasibility study for the establishment of the Centrefor becoming clear through the decisions of the courts.”Therefore,they Bioequivalence and Bio-pharmaceutical Research (CBBR) in say,the examination guidelines reflecting such rulings will help to Ghana”. Alfred TiaSuguri, Ghana’sdeputy minister for health, said ensure “harmonious practice” among patent examiners. the study was“an effort to support local manufacturers of Section 3(d), the guidelines stress, “deserves special attention”. pharmaceuticals, importersand wholesalerstoimprove the quality India’sSupreme Court, it notes, had held that ‘efficacy’ in the context of their products”. of Section 3(d) should be understood as ‘therapeutic efficacy’. As some propertieswere inherent to specific forms –such as “solubilitytoa EUROPEAN draft guidelines on qualification and validation principles salt and hygroscopicitytoapolymorph” –such forms are not patentable of good manufacturing practice (GMP) have been published by unless they“differ significantly” in terms of therapeuticefficacy. the European Commission. Open for public consultation until May, As examples of applying Section 3(d), the guidelines cite the the guideline is expected to be published and adopted in its final Supreme Court’sruling that acrystalline salt form of imatinib failed form in October. the patentability test because “increased bioavailability alone may not necessarily lead to an enhancement of therapeuticefficacy” (Generics MHRA –the UK’sMedicines and Healthcare products Regulatory bulletin,5April 2013, page 1). But while asalt patent for Tykerb Agency–has been told by US Food and Drug Administration (FDA) (lapatinib)was ultimately found obvious by India’sIntellectual Property Commissioner Margaret Hamburgthat the global regulatory Appellate Board (IPAB), Section 3(d) wasnot abar to patentability in community must “work together to create astronger and safer system that case (Generics bulletin,6September 2013, page 22). of medical products” in the face of the increasing globalisation of the supply chain.The FDAmust have “more than just apresence Section 3(d) is controversial around the world”, Hamburgemphasised in aspeech addressing Section 3(d) has been at the centre of accusations from US industry the MHRA, insisting that the agencyhad to “engage internationally that India presents ahostile business environment for innovators. But with our counterpart regulatory authorities and with the industries such claims are overblown, according to Dilip Shah, chief executive we regulate in amultinationalfashion”. officer of the Vision Consulting Group. Writing an editorial in India’s Financial Express newspaper,Shah – FRENCH biotechnology industry association France Biotech has who is also secretary-general of the Indian Pharmaceutical Alliance announced its three main working areas for2014.The group’s industry association –said US pharma and biotech groups were guilty newly-elected president, Pierre-Olivier Goineau, said France Biotech of a“sweeping generalisation” in failing to recognise the extensive would focus on member services; promotional activities, including trade links and partnerships between the US and India, including in increasing the number of partnershipopportunities with ‘big pharma’ industries such as aerospace and telecommunications. companies; and interaction with government, including“improving “Since 2005,”Shah pointed out, “India has granted over1,500 relationships with academia and national research organisations”. patents for products and compositions to the top-nine global pharmaceutical companies alone.”When innovators objected to CANADA’s Chief Justice, Paul Crampton, has advised parties restrictionsonevergreening enshrinedinIndia’spatent laws, theywere, involved in litigation overthe validity of patents that certain details in fact, “complaining about the second or third patent for the same of any experimental testing conducted for the purposes of litigation product”, he said. should be conveyed to other parties “no later than twomonths before India’scompulsory-licensing regulations were “neither unusual thescheduled service of the expert reports”. “Unless aparty intending nor should be acause of concern”, Shah asserted, highlighting similar to rely on such experiments has so advised the other parties, the party provisions in western Europe. Only twoapplications for compulsory shall not, without leave of the court, lead evidence at the trial or licences had been made in India, and just one granted, he stressed. hearing as to anyexperimentsconducted by or for it for the purpose Movesbythe US Trade Representative (USTR) to start a of the litigation,”Crampton stated. ‘Special 301’ investigation into India’strade rules were unjustified, Shah argued. During arecent USTR hearing on Special 301 reviews, NHS –the UK’sNational Health Service –will raise its prescription the Pharmaceutical Research and Manufacturers of America (PhRMA) charge from £7.85 (US$13.03) to £8.05 from 1April 2014. “It is also highlighted India’sSection 3(d) as an example that “manyofour intended that the single charge will increase by 20 pence to £8.25 trading partners do not respect the value of innovative medicines”. in the following year,” the UK Department of Health stated. G The brand industry body similarly criticised Canada’sdoctrine on requiring patent utility to be proven. G

21 March 2014 GENERICS bulletin 15 Gen 21/3/14 Pgs. 16-21_Layout 1 18/03/2014 09:07 Page 2

PRODUCT NEWS

WEIGHT-LOSSTREATMENTS IN BRIEF DR REDDY’S has launched ageneric rivaltoBayer’s Avelox TWidefeats Par on (moxifloxacin)400mg tablets in the US following final approval from the US Food and Drug Administration (FDA). The Indian firm –which noted that the antibacterial agent would be available in bottles of 30 tablets –said the brand had US sales of around US megestrol patent US$195 million in 2013, according to IMS Health data.

US patent protecting ParPharmaceutical’sMegace ES (megestrol KISSEI PHARMACEUTICAL will begin developing a biosimilar Aacetate) brand until April 2024 is invalid due to obviousness in with fellowJapanese firm Alteogen after the twocompanies struck light of prior art, aMaryland district judge has determined. The victor, abusiness collaboration agreement.Kissei –which noted that the Taiwan’sTWi Pharmaceuticals, said it planned to launch the weight- deal would not impact its results for the company’sfinancial year loss treatment –potentiallywith 180-day generic market exclusivity ending 31 March 2014 –said the agreement would “further strengthen due to its paragraph IV patent challenge (Generics bulletin,2 its efforts into the biopharmaceuticals business”. September 2011, page 20) –upon final approvalfor its abbreviated newdrug application(ANDA). Parreported Megace ES sales last PAR has receivedfinal approvalfrom the US Food and Drug year of US$38.0 million. Administration (FDA) for its generic version of GlaxoSmithKline’s US patent 7,101,576 claims amethod of treating wasting –such Jalyn (dutasteride/tamsulosin)0.5mg/0.4mg capsules. as from anorexia or cachexia –inhumans by administering an oral suspension of megestrol acetate once daily.According to the litigants, SUVEN LIFE SCIENCES has struck adeal with Taro Pharmaceuticals such claims are embodied in the Megace ES nanoparticulate formulation. under which the US firm will gain the rights to market in Canada, Judge Catherine Blakenoted that the prior art at the April 2002 Mexico and the US Suven’s malathion 0.5% lotion. Taro will pay filing date of the ‘576 patent included the Megace OS micronised the Indian group royalties based on sales of the head-lice treatment, suspension that had been marketed for almost 10 years as ameans of with the deal between the twocompanies set to run until April 2028 increasing body mass in HIV/AIDS patients. As Megace OS had been “unless otherwise terminated”. administered daily in doses ranging between 40mg and 800mg, several claims of the ‘576 patent were obvious, she said. Furthermore, PFIZER has issued avoluntary recall for three lots of its venlafaxine nanoparticulate formulations of megestrol acetate had been expressly antidepressant extended-release capsules –two lots of its Effexor XR disclosed in prior-art patents. brand and abatch of its generic subsidiary Greenstone’sauthorised “The claimed pharmacokinetic parameters with respect to afood version –after apharmacist reported a Tikosyn (dofetilide)0.25mg effect are inherent properties of the obvious nanoparticulate formulation capsule present among abottle of the Effexor XR brand. Noting claimed by the ‘576 patent,”Blakeasserted, adding that such parameters that it had not receivedany other reports of the antiarrhythmic in did not render the formulation non-obvious. “TWihas demonstrated Effexor XR, the US firm said it had nevertheless recalled the lots that reducing particle size will improve bioavailability across all as a“precaution” as theywere packaged on the same line. administrations claimed in the invention, thus anyfood effect will inherently be reduced,”she added. MYLAN has in the US launched generic naloxone 0.4mg/ml for “Not only does the prior art disclose every element of the challenged injection upon receiving final approvalfrom the US Food and Drug claims,”Blakestated, “but it [also] discloses amotivation for aperson Administration (FDA). The US firm noted the treatment for opioid of ordinary skill in the art to combine the elements in the waydisclosed overdose wasdeemed by the agencytobeequivalent to Hospira’s by the ‘576 patent and to do so with areasonable likelihood of success.” reference-listed naloxone. Citing IMS Health data, Mylan said the Turning to whether it would have been obvious for askilled person 0.4mg/ml strength of naloxone had sales of US$12.3 million in 2013. to combine the prior art, Blakesaid: “TWiproveditwas known that Megace OS wasviscous and required more dosing, and that absorption KERN PHARMA has added desloratadine 0.5mg oral solution in levels varied greatly among patients. The court finds that both of these Spain as an antihistamine for children aged one year and above. problems provided sufficient motivation for aperson skilled in the art The firm also offers desloratadine 5mg tablets. to create amethod of treatment using nanoparticles.” G PERRIGO has launched in the US generic Neptazane (methazolamide)tablets. The glaucoma treatment waspart of a basket of ophthalmics that the US firm last year acquired from Fera ANTIBIOTICS Pharmaceuticals in adeal worth up to US$129 million (Generics bulletin,28June 2013, page 21). Methazolamide tablets had annual Apotex can claim on azithro US sales of approximately US$12 million, Perrigo noted. potexisentitled to claim compensation for lost sales caused by APfizer’sunsuccessful pursuit of patent-linkage litigation over TEVA has been granted final US approvals for its zolmitriptan 2.5mg azithromycin, Canada’sFederal Court of Appeal has ruled. The court and 5mg tablets by the US Food and Drug Administration (FDA). The rejected Pfizer’sappeal against alower court’sverdict. migraine treatment is equivalent to AstraZeneca’s Zomig brand. At the During Patented Medicines (Notice of Compliance)regulations same time, the Israeli group has launched Alexza Pharmaceuticals’ (PMNOC) litigation, Federal Judge James O’Reilly found that Pfizer Adasuve (loxapine)brand in the US. Teva last year struck alicence had failed to prove that Apotexhad infringed Canadian patent 1,314,876, and supply agreement with the originator for the 10mg powder for which expired on 23 March 2010. inhalation (Generics bulletin,17May 2013, page 14), which is Pfizer appealed on the grounds that O’Reilly had improperly relied indicated for the treatment of agitation associated with schizophrenia on evidence from Apotex’ expert that should not have been admitted. or bipolar Idisorder in adults. Alexza receivedUS$40 million upfront But the appeals judges pointed out that Pfizer had not taken numerous as part of last year’sagreement, with afurther US$195 million opportunitiestoobject to the expert’sevidence. Furthermore, theysaid, payable to the originator based on sales milestones. G that expert evidence formed only part of O’Reilly’sdeliberations. G

16 GENERICS bulletin 21 March 2014 Gen 21/3/14 Pgs. 16-21_Layout 1 17/03/2014 19:50 Page 3

PRODUCT NEWS

BIOLOGICALDRUGS ONCOLOGY DRUGS Japan’s Kayaku sits Teva offers US rivals on infliximab brink to Xeloda and Evista

apan’sNippon Kayaku believesitcould by the end of March receive eva has launched ageneric version of Roche’sXeloda (capecitabine) Japprovalfor biosimilarinfliximabfrom the country’sPMDA Tcancer treatment in the US. And the Israeli firm’srivaltoEli Lilly’s agency. The Japanese companyhas licensed local marketing rights to Evista (raloxifene) osteoporosis drug is set to start shipping to US the CT-P13 monoclonal antibody from South Korea’sCelltrion. customers by early April. Kayaku’stie-up with Celltrion also covers the CT-P6 trastuzumab Having obtained US Food and Drug Administration (FDA) approval biosimilarthat is currently“in preparation” for Phase Iclinical trials. for its capecitabine 150mg and 500mg tablets last year,Teva has now The South Korean companyrecently secured approvalinits domestic introduced its rivaltoXeloda under the terms of apatent-litigation market for its follow-on Herzuma brand of trastuzumab. settlement with the originator.Noting that it had been the first firm “Herzuma is expected to be in the market within the first half of to obtain approvalfor acapecitabine abbreviated newdrug application this year,after the completionofadministrative procedures, including (ANDA), Teva said Xeloda –which enjoys US patent protection until notification to the Ministry of Health and Welfare,”Celltrion stated. 14 June this year –had US sales of US$754 million last year. Noting that the Korean trastuzumabmarket wasworth around US$80 Approvalfor Teva’s raloxifene 60mg tablets came after several of million per year,Celltrion said it had “conducted global clinical trials Lilly’sEvista patents expired on 2March 2014. By virtue of having involving 558 patients –starting from August 2009 and lasting until submitted paragraph IV challenges to four Evista patents that each December 2011 –in18countries and 115 sites”. expire on 10 March 2017 –none of which prompted court action by Lilly that would have triggered a30-month stay on final ANDA Launched filgrastim last year approval–Teva is eligible for 180-day generic market exclusivity Having secured PMDAapprovalatthe end of February 2013 for running from the launch date. the follow-on filgrastim that it co-developed with Teva (Generics Meanwhile, the FDAhas said Teva’s Barr “may be eligible for bulletin,22March 2013, page 17), Kayaku introduced the biosimilar 180 days of generic-drug exclusivity” for the alternative to Actavis’ granulocyte-colonystimulating factor (G-CSF) in Japan in late-May Oxytrol (oxybutynin) 3.9mg/day extended-release film that the agency last year.Fuji Pharma and Mochida had obtained similar filgrastim has just approvedasthe first generic version. Litigation in aDelaware approvals in late-2012 (Generics bulletin,14December 2012, page 17). district court overeight Oxytrol patents –two of which expire on 26 Introducing its Filgrastim BS biosimilar –along with ageneric April 2015, and the other six on 26 April 2020 –has been dismissed. tegafur/gimeracil/oteracil combination in June, and generic imatinib Teva has secured tentative FDAapprovalfor valsartan/amlodipine in December –helped Kayaku to increase its Pharmaceuticals sales tablets in four strengths. The agency’sOrange Book lists patents by 1.8% to ¥39.1 billion (US$379 million) in the nine months ended protecting Novartis’ Exforge antihypertensiveuntil July 2019, while December 2013. Generic cancer drugs such as anastrozole, carboplatin Parholds 180-day exclusivity for three of the four strengths for which and paclitaxel accounted for ¥16.3 billion of that total. G Teva got tentative approval. G

OPIOID ANALGESICS ONCOLOGY DRUGS DEA mulls hydrocodone rule Sun faces doxorubicin attack ydrocodone could be movedfrom schedule III to schedule II of he US Food and Drug Administration (FDA) should withdrawthe Hthe US Controlled Substances Act under proposals published by Tdesignation of Sun Pharma’sdoxorubicin liposome injectableas the country’sDrug EnforcementAdministration (DEA). The proposed the reference listed drug (RLD) for its product group, according to rule –published by the DEA in the US Federal Register –isopen for acitizen petition submitted by lawfirm Greenblum &Bernstein. public comment until 27 April. Last year,Sun’sversion of the oncology drug receivedFDA “The Controlled Substances Act places substances with accepted approvalasageneric rivaltoJanssen’sDoxil brand (Generics bulletin, medical uses into one of four schedules, with the most potentially 15 February 2013, page 15), as part of efforts to reduce shortages of harmful and abusable medications being placed in schedule II,”the DEA the ovarian-cancer treatment. The approvalcame as part of a“priority said, adding that hydrocodone combinations “have ahigh potential reviewsystem” used by the FDA’sOffice of Generic Drugs (OGD) to for abuse that may lead to severe psychological or physical dependence”. “expedite the reviewofgeneric applications to help alleviate shortages”. “In 2013, the US Food and Drug Administration (FDA) held a Previously,the FDAhad authorised Sun to import the Indian firm’s public advisory committee meeting on the matter,and the committee Lipodox brand of doxorubicin through the firm’sUSdistributor,Caraco voted to recommend rescheduling hydrocodone combination products (Generics bulletin,9March 2012, page 19). from schedule III to schedule II by avote of 19 to 10,”the DEA added. Acknowleding that “compliance issues in manufacturing Doxil” Meanwhile, Purdue Pharma has announced that aPhase III study had resulted in shortages, the petition concedes that this had led the of an “investigational extended-release formulation of hydrocodone” FDAto‘de-designate’ Doxil as the RLD and designate Sun’sversion had met its primary endpoints. The formulation “incorporates abuse- as the RLD in place of the brand. However, the petition insists, “FDA’s deterrent propertiesintended to makethe tablets more difficult to action raises serious safety issues, because proving bioequivalence manipulate for the purposes of misuse and abuse by various routes of to Sun’sproduct –which wasnever subject to the full array of clinical administration such as snorting and intravenous injection”, the firm trials required for newdrug application(NDA) approval–does not stated, adding that it intended to submit the analgesic to the FDAas demonstratebioequivalence to Doxil, which wassubjected to the full anew drug application (NDA) later this year. G array of such clinical trials”. G

21 March 2014 GENERICS bulletin 17 Gen 21/3/14 Pgs. 16-21_Layout 1 17/03/2014 19:50 Page 4

PRODUCT NEWS

IMMUNOSUPPRESSANTS OPHTHALMIC DRUGS Sandoz is awarded Pataday patent falls NZ tacrolimus deal to Canada’s Cobalt

andoz will be the sole subsidised supplier for tacrolimus 0.5mg, ctavis’ Cobalt Pharmaceuticals affiliate in Canada should not be S1mg and 5mg capsules under adeal agreed with NewZealand’s Abarred from obtaining aNotice of Compliance (NOC), or marketing pharmaceutical management agency, Pharmac. From 1November 2014, authorisation, for ageneric version of Alcon’sPataday (olopatadine) Janssen-Cilag’sPrograf brand will be delisted from the pharmaceutical 0.2% eyedrops until after akey patent expires in 2022, Federal Judge schedule, leaving Sandoz’ version of the immunosuppressantasthe Mary Gleason has ruled. only listed tacrolimus until at least 31 October 2018. Under Canada’sPM(NOC) patent-linkage system, Cobalt had Sandoz had previously reached aprovisional sole-supply agreement challenged both unexpired patents –Canadian patents 2,195,094 and with Pharmac to run from 1September 2013 to 31 August 2017 2,447,924 –listed against the anti-inflammatory agent in the country’s (Generics bulletin,11January 2013, page 14). However, the agency patent register.But Alcon –having seen its ‘094 patent ruled obvious revised its proposal after considering “a number of responses” raising in acase it had previously brought against Apotex–sought abar on questions overthe bioequivalence of Sandoz’ version with Prograf, Cobalt receiving an NOC solely on the basis of twoclaims in the ‘924 as well as concerns overthe risk of “inadvertent switching” between patent, which expires on 19 June 2022. Prograf and Sandoz’ generic during the transition period (Generics bulletin,14February 2014, page 16). Utility not demonstrated To be approvedbylocal medicines agencyMedsafe, Sandoz’ Gleason accepted Cobalt’sposition that the promised utility of generic tacrolimus had been required to demonstrate“tighter the ‘924 patent –that the excipient polyvinylpyrrolidone (PVP) would bioequivalence margins than normally required for generic medicines”, enhance the physical stability of olopatadine solutions –was “neither Pharmac insisted. However, the agencyacknowledged that switching demonstrated nor soundly predicted by Alcon”. patients would require “careful monitoring”,citing the “narrow “The patent discloses no basis for predicting that the entire range therapeutic index” of tacrolimus. Pharmacists will get aswitching fee. of molecular weights of PVP claimed in Claim 2will have aphysically According to the agreement, Sandoz’ tacrolimus 0.5mg capsules stabilising effect on 0.2% olopatadine solutions,”Gleason stated. will have aprice and subsidy of NZ$85.60 (US$72.46) for 100 capsules, Similarly,she said, Alcon’sexperimentsdid not support the ranges of while the same pack size of 1mg capsules will have areimbursement molecular weights disclosed in Claim 7ofthe ‘924 patent. price of NZ$171.20. Fora50-capsule pack of the 5mg strength, the “AsIhavealready found that the ‘924 patent fails to meet the price will be NZ$428.00. promises advanced by the asserted claims,”Gleason continued, “it follows Separately,Pharmac has invited firms to submit by 1April proposals that the claims are drafted more broadly than is warranted.” G to supply erythropoietin in NewZealand. The agencynoted that Janssen-Cilag’sEprex(erythropoietin alpha) and Roche’sNeoRecormon (erythropoietin beta) were currently listed at prices between NZ$48.68 ANTIFUNGALS/ANTIBIOTICS for asix-syringe pack of Eprex1,000IU syringes and NZ$395.18 for six-count packs of Eprexand NeoRecormon in 10,000IU strengths. Mylan enters Indian segment Meanwhile, Pharmac has announced sole-supply deals running until June 2017 as part of tender awards following proposals submitted ylan is aiming for astakeinIndia’sUS$2.6 billion critical-care late last year.Douglas has wondeals for its Ibiamox (amoxycillin) Mmarket by launching its ownoperations in the country.The US injectable vials in 250mg, 500mg and 1g strengths from November, firm’sCritical Care segment –which it recentlysignalled its intention while the firm’sFlucloxin (flucloxacillin) injectable in the same to line up alongside existing antiretroviral, oncology and women’s-care strengths will be subsidised from October.Actavis’ bendrofluazide portfolios (Generics bulletin,7March 2014, page 3) –will focus on 2.5mg and 5mg tablets, bicalutamide 50mg tablets, brimonidine 0.2% antibiotics, anticoagulants and antifungals. eyedrops, norfloxacin 400mg tablets and timolol 0.25% and 0.5% eye Noting that the antifungal injectable AmBisome (amphotericin B) drops will also be reimbursed from October. licensed from Gilead would be one of the first critical-care products Apotex’ clarithromycin 250mg and 500mg tablets and doxazosin on offer,Mylan’spresident RajivMalik added that the firm would also 2mg and 4mg tablets –aswell as Sandoz’ benzylpenicillin 600mg introduce “several more high-growth critical-care products, including vials and Dr Reddy’sterbinafine 250mg tablets –will also have sole high-end antibiotics, in the near future”. subsidised-supply status from the start of October until June 2017. Mylan’srecent deal with Gilead also confers Indian marketing Mylan’sdoxycycline 100mg tablets and metoclopramide 10mg tablets and distribution rights for the antiretroviral brands Viread (tenofovir), will also be reimbursed from October,while subsidies for the Truvada (tenofovir/emtricitabine) and Stribild (tenofovir/emtricitabine/ firm’sbetahistine 16mg tablets and prochlorperazine 5mg tablets elvitegravir) and builds on the twofirms’ existing alliance for generic will start in July this year. G HIV treatments (Generics bulletin,14February 2014, page 13). G IN BRIEF IN BRIEF AMGEN expects to begin marketing the first of its current pipeline of SAGENT has recalledtwo batches of zoledronic acid 5mg/100ml six biosimilars in 2017. “Our biosimilar unit continues to makegood for injection in the US “due to apotential lack of container integrity”. progress,”said Sean Harper,the firm’svice-president of research The recall wasinitiated “due to the discovery of four leaking premix and development, noting that “enrollment has commenced” in a bags detected during an investigation conducted in response to a Phase III study for arivaltoGenentech’sAvastin (bevacizumab). G product complaint”,Sagent said. G

18 GENERICS bulletin 21 March 2014 Gen 21/3/14 Pgs. 16-21_Layout 1 17/03/2014 19:50 Page 5

PRODUCT NEWS

OTCMEDICINES CARDIOVASCULAR DRUGS Perrigo pays Aspen Firms finish US fight for an OTC portfolio on Tracleer samples

errigo has paid Aspen US$51 million in cash for abasket of OTC Sgenerics players including Apotexand Boehringer Ingelheim’s Pproducts marketed in Australia and NewZealand. The products – URoxane have settled litigation against Switzerland’sActelion over including the Herron range of analgesics, vitamins and supplements – whether the originator is obliged to provide samples of its Tracleer generate annual sales of around US$20 million. (bosentan)cardiovascular brand to enable generics firms to conduct Joe Papa, Perrigo’schairman, president and chief executive officer, bioequivalence testing. said the deal enhanced the company’spresence in Australia by No details of the settlement were disclosed in the order of dismissal “broadening our product offering and increasing our relevance with signed by NewJerseyDistrict Judge Noel Hillman, butthe case can be mass-market retail customers”. The deal also fitted with Perrigo’s reopened until the end of April “if the settlement is not consummated”. strategy of expanding internationally its Consumer Healthcare business. Around 18 months ago (Generics bulletin,1October 2012, page Perrigo’sConsumer Healthcarebusiness entered Australia in 2010 17), Actelion sued Apotexand Roxane in aNew Jerseydistrict court, when it acquired local store-brand firm Orion Laboratoriesfor about seeking adeclaratory judgement that it had no obligation to provide US$48 million in cash (Generics bulletin,26March 2010, page 2). The the Tracleer samples that the generics firms were demanding. Actavis, firm’sAustralianoperation currentlyoffers arange of store-brand Johnson Mattheyand Zydus Cadila were later added as defendants. OTCmedicines and the MediHealth “generic value brand”. It also Due to the potential for Tracleer to cause serious liverdamage, the has acontract-manufacturing deal with Johnson &Johnson. US Food and Drug Administration (FDA) required Actelion to adopt a The company’sAustralianbusiness is expected to generate sales of risk evaluation and mitigation strategy (REMS) for the treatment for around US$35 million in the year ended July 2014, led by its prescription pulmonary arterial hypertension. The originator argued that its legal and hospital offerings in areas such as hormones and anti-infectives. obligation to comply with the REMS programme prevented it from Separately,Perrigo has returned responsibility for developing the supplying samples. In anycase, the Swiss firm insisted, it had “the ELND005 (scyllo-inositol) candidate for Alzheimer’sdisease, bipolar right not to deal with, or assist, arival”. disorder and Down’ssyndrome to its partner,Transition Therapeutics. Last year,Hillman rejected Actelion’spetition for adeclaratory Perrigo will also pay US$15 million for 2.26 million of Transition’s judgement and ordered that the case proceed to the discovery stage. shares, and will be eligible for royalties and milestone payments. G At the same time, he permitted both the US Generic Pharmaceutical Association (GPhA) and the US Federal Trade Commission (FTC) to participate in the case. In its motion to participate as an amicus curiae,the FTC had argued that originatorsmust not use REMS programmestoimpede generic competition (Generics bulletin,22 March 2013, page 9). G

CHEMOTHERAPY DRUGS Australia expandsPBS entries lphapharm’stemozolomide capsules have been added to Australia’s APharmaceutical Benefits Schedule (PBS) from the start of March in 5mg, 20mg, 100mg, 140mg and 250mg strengths. At the same time, Aspen’sAldiq (imiquimod) 5% cream has also been listed. Aurobindo has secured PBS listings for lisinopril tablets in 5mg, 10mg and 20mg strengths, as well as pantoprazole 40mg tablets sold as Topra. Meanwhile, Eris has listed anastrozole1mg tablets and bicalutamide 50mg tablets under the respective Azastrole and Bicalox brands, as well as Rispernia (risperidone) tablets in 500µg, 1mg, 2mg, 3mg and 4mg strengths. Norac Pharma’sClavam(amoxicillin/clavulanic acid) 875mg/ 125mg combination tablets have also been added to the PBS, while Actavis is nowmarketing its sertraline 50mg and 100mg tablets under its companyname rather than as Sertraline-GA. Meanwhile, Australia’sDepartment of Health has announced that from 1April it will implement “a newstreamlined process to reduce the time taken to list medicines on the PBS and improve access to medicines”. “A keycomponent of this measure will be the cessation of the operations of the Pharmaceutical Benefits Pricing Authority (PBPA),” the Department stated, adding that the change will “further streamline PBS listing processes by allowing agreement on price to be reached in shorter timeframes following apositive recommendation from the Pharmaceutical Benefits Advisory Committee (PBAC)”. G

21 March 2014 GENERICS bulletin 19 Gen 21/3/14 Pgs. 16-21_Layout 1 18/03/2014 09:09 Page 6

PIPELINE WATCH Twoantivirals lose protection in Europe

he start of 2014 has seen the expiry of certainEuropean protection potential returns for generic developers are limited in scope. Tperiods for twoantiviral agents –GlaxoSmithKline’sRelenza During March, data exclusivity ended for Reyataz (see Figure 2). (zanamivir) flu brand and Bristol-Myers Squibb’s Reyataz (atazanavir) However, notes Ark, the antiretroviral enjoys patent protection until HIV/AIDS treatment. Supplementary protection certificates (SPCs) “at least April 2017”. Noting that Aurobindo, Emcure, Matrix and protecting Relenza recently expired in most European Union (EU) Teva have already obtained tentative US approvals for atazanavir, it member states (see Figure 1). These had been based on European believesgeneric competition will be fierce upon EU patent expiry. patent EP0,526,543, or national equivalents. Similar SPC periods in March also brings the end of the Swiss SPC for GlaxoSmithKline’s Switzerland, Cyprus and Portugal extend protection until June blockbuster Seretide (fluticasone/salmeterol).Most European SPCs 2014, December 2015 and July 2016, respectively. for the respiratory combination already expired in September last year While zanamivir molecule patents and data-exclusivity periods (Generics bulletin,20September 2013, page 20). G have expired across Europe, notes Ark Patent Intelligence, no generic marketing authorisations have been granted. This, the company believes, could be due to the difficulties of developing the drug as Data exclusivity expiries in February/March an inhalation powder and working around protectionfor the powder’s INN Country/Region Diskhaler delivery device. Giventhat Relenza has been overshadowed commercially by Roche’sTamiflu (oseltamivir) oral alternative,the February Choriogonadotropin alfaSwitzerland SPC expiries in February/March Febuxostat US Sevelamer Switzerland INN Country March February Ambrisentan Canada* Alemtuzumab Austria, Belgium, France, Germany, Atazanavir European Union Greece, Italy,Luxembourg, Netherlands, Cefditoren Belgium, France, Germany, Italy, Spain, Sweden, UK Luxembourg, Netherlands, Sweden, UK Candesartan Latvia Colesevelam European Union Daclizumab Belgium, Greece, Sweden Dabigatran Turkey Irbesartan/ Switzerland Eberconazole Belguim, France, Germany, Italy, Hydrochlorothiazide Luxembourg, Netherlands, Sweden, UK Eculizumab Australia Sildenafil Cyprus Efalizumab Switzerland Temoporfin Belgium, France, Germany, Greece, Eplerenone Belgium, France, Germany, Italy, Italy,Luxembourg, Netherlands, Spain, Luxembourg, Netherlands, Sweden, UK Sweden, UK Etravirine Canada* Zanamivir Austria, Belgium, Denmark, Finland, Fulvestrant European Union France, Germany, Greece, Ireland, Italy, Gadoxetic acid Belgium, France, Germany, Italy, Luxembourg, Netherlands, Norway, Luxembourg, Netherlands, Sweden, UK Romania, Slovakia, Slovenia, Spain, Sweden, UK Gefitinib Switzerland Lanthanum carbonate Belgium, France, Germany, Italy March Luxembourg, Netherlands, Sweden, UK Actinobacillus Denmark, Germany* Lidocaine/Nifedipine Belgium, France, Germany, Italy pleuropneumonia antibody Luxembourg, Netherlands, Sweden, UK Artemether/Lumefantrine Sweden Methoxy polyethylene Canada* Dorzolamide/Timolol Cyprus glycol-epoetin beta Fluticasone/Salmeterol Switzerland Methylnaltrexone bromide Canada* Retapamulin Canada* Somatropin Italy,Spain *This will be followed by ano-marketing period of twoyears during which anotice of Temoporfin Ireland compliance will not be granted to ageneric manufacturer.Inaddition, afurther six months of data protection will be added to the eight-year term for studies of etravirine *indicates that the SPC remained an application at expiry,sonever entered into force and retapamulin in paediatric populations.

Figure1:Molecules for which supplementaryprotection certificates (SPCs) expire Figure2:Molecules for which data exclusivity expires in key markets during in key markets during Februaryand March 2014 (Source –Ark Patent Intelligence) Februaryand March 2014 (Source –Ark Patent Intelligence)

This monthly update of keypatent, SPC and data exclusivity data is extracted from Ark Patent Intelligence Expiry Database. Covering 50 countries and over1,600 INNs, Ark Expiry Database contains watertight data teamed with the ultimate in generic launch analysis. Forfurther information, visit www.arkpatentintelligence.com, or contact: Europe: +44 870 879 0081. North America: +1 704 665 1986. Or e-mail: [email protected].

20 GENERICS bulletin 21 March 2014 Gen 21/3/14 Pgs. 16-21_Layout 1 17/03/2014 19:50 Page 7

PRODUCT NEWS

CHOLESTEROL-LOWERINGDRUGS MULTIPLE-SCLEROSIS DRUGS Legal fightinJapan Natco claims victory over Livalo widens on Indian Copaxone

our more Japanese generics companies, including Nippon atco Pharma says the NewDelhi High Court has dismissed asuit FChemiphar and SawaiPharmaceutical, have been sued by Nissan Nbrought by Teva,along with the Israeli company’spartner Yeda, Chemical for allegedly infringing akey patent protecting the Livalo that alleged the Indian firm’sprocess for making arivaltoCopaxone (pitavastatin calcium) cholesterol-lowering agent marketed by the (glatiramer acetate) infringed Indian patent 190,759. originator’s partner,Kowa. “Wecontinue to believe that the sole Indian process patent is invalid, Suits brought in aTokyo district court against Nippon Chemiphar, as reinforced by the outcomes of numerous other legalproceedings,” Nissin Pharmaceutical and Yoshindo were followed ashort time later Natco stated. “Weare also pursuingother challenges against this patent.” by patent holder Nissan suing Sawaion4March in the same court. In the same court, Natco is seeking to invalidate the ‘759 patent, which is the Indian counterpart to US patent 5,800,808, one of five Already sued 10 firms US patents held to be invalid by the US Court of Appeals last year Nissan had already reacted to National Health Insurance (NHI) (Generics bulletin,9August 2013, page 1). The Indian firm plans price listings for generic pitavastatin secured on 13 December last year to sell arivaltoCopaxone in the US through its development and by suing late in 2013 agroup of sevengenerics players –Daito, Kaken, marketing partner Mylan. Kobayashi Kako, Meiji Seika, Mochida, Towa and Tsuruhara (Generics Natco said India’sPatent Office had refused twoother patent bulletin,10January 2014, page 19). Similar actions against Kotobuki, applications that would have covered copolymer-1 products. Nichi-Ikoand Sagami followed afew weeks later (Generics bulletin, Teva recently published astudy in online scientific journal Plos 3February 2014, page 17). One that purported to show“significant differences in biological and In each case, Nissan is seeking injunctive relief that would force immunological effects” between Copaxone and Natco’sglatiramer the generics firms to cease and desist marketing pitavastatin. The formulation (Generics bulletin,3February 2014, page 17). This, the originator claims the generics infringe its patented crystal form of Israeli companyargued, showed that generic versions of the multiple- the cholesterol-lowering active ingredient. G sclerosis drug should be subjected to clinical trials. G

ANTIBIOTICS PARKINSON’S DISEASEDRUGS Lupinhas sole US Ciprorival France adds to its répertoire upin will be eligible upon launch for 180 days of generic marketing rka’srivaltoBoehringer Ingelheim’sSifrol (pramipexole) brand Lexclusivity in the US for ciprofloxacin 250mg/5ml and 500mg/5ml Khas been added to France’s répertoire of generic equivalents. The oral suspension after receiving final approvalfrom the US Food and Slovenian firm’sversion of the Parkinson’s disease treatment –sold Drug Administration (FDA). The Indian firm –which plans to launch under the Oprymea name –isavailable as 0.26mg, 0.52mg, 1.05mg the antibiotic shortly –was the first to file with the FDAacomplete and 2.1mg prolonged-release tablets. abbreviated newdrug application(ANDA) containing aparagraph IV At the same time, Medac’sversion of Correvio’sAgrastat (tirofiban) certification for the generic rivaltoBayer Healthcare’sCipro, which last 50µg/ml solution has been listed on the répertoire,along with Mylan’s year achievedUSsales of US$8.6 million according to IMS Health data. rivaltoHRA Pharma’sNorlevo (levonorgestrel) 1.5mg tablets. Actavis’ Meanwhile, Lupin has also receivedfinal FDAapprovalfor its Arrowhas secured alisting for dexpanthenol 5% ointment against generic version of Aqua Pharmaceuticals’ Monodox (doxycycline) 50mg, Bayer’sBepanthen, while Natlip has had its carbimazole 5mg and 75mg and 100mg capsules. Only Ranbaxy holds afurther approved 20mg tablets included in groups with Amdipharm’sNeo-Mercazole ANDAfor the 75mg strength, while Lupin would compete upon as the reference brand. launch with Actavis, Parand Ranbaxy for both the lower and higher GlaxoSmithKline’sNiquitin (nicotine) 2mg sugar-free tablets strengths. The brand had US sales of US$181 million in 2013, have also been added to the répertoire as areference brand. Johnson according to IMS Health data. G &Johnson has listed ageneric rival. G

GASTROENTEROLOGICALDRUGS IMMUNOSUPPRESSANTS PRAC restricts domperidone Infa tacrolimus kit has patent oncerns raised about domperidone’seffect on the heart have taly’sInfaGroup has receivedanotice of allowance for aUSpatent Cresulted in the European Medicines Agency’s(EMA’s) Icovering an intravenous administration kit that contains aholding Pharmacovigilance Risk Assessment Committee (PRAC) recommending solution and a5mg-10mg vial of tacrolimus. The newpatent follows newguidelines for the nausea and vomiting treatment throughout the 2012 issuance of Infa’sUSpatent 8,182,449, which covers a the European Union (EU). similar intravenous administration kit containing apre-filled Newmeasures include reducing the recommended dose and syringe of the immunosuppressant. duration of treatment, as well as removing its indication as atreatment “The issuance of this additional patent in 2014 further validates for heartburn and bloating. “The recommended dose should be reduced the innovative nature of Infagroup,”insisted the Italianfirm’svice- to 10mg up to three-times daily,” the PRACstated. G president of corporate business development, Paolo Magri. G

21 March 2014 GENERICS bulletin 21 Gen 21/3/14 Pg. 22_Layout 1 17/03/2014 19:51 Page 2

EVENTS

APRIL 19-21 November 2014 2-3April ■ 17th IGPAAnnual Conference ■ World Generic Medicines Miami,USA Congress Europe 2014 This three-day event is being organised by the US Generic Pharmaceutical Association (GPhA) and is the global event of the worldwide generics industry.Itisthe Barcelona, Spain annual joint meeting of the Canadian, European, Japanese, South African and US This four-day conference will be co-located generics industry associations, the CGPA, EGA, JGA, NAPM and GPhA. with the Biosimilar Drug Development Contact:Jennifer Nguyen, GPhA.Tel:+1202 249 7127. World event. The conference will look at E-mail: [email protected]. Website: www.gphaonline.org. topics including intellectual-property developments, commercial strategies and building market share, and will provide MAY business-development decision makers to global policyupdates. discuss and negotiate collaborative Contact:Health Network Communications. 20 &21-22 &23May agreements, in-licensing, marketing and Tel: +44 207 608 7055. ■ 5th Annual Biosimilars Asia distribution of patented medicines, E-mail: customerservices@healthnetwork generics, biosimilars, OTCproducts, Shanghai,China communications.com. medical devices and food supplements. Website: www.healthnetwork Looking at strategic challenges and communications.com. innovations in the development of Contact:Raucon. Tel: +49 6222 9807 0. biosimilars, this four-day event will be E-mail: [email protected]. 3-4April preceded and followed by workshops. Website: www.europlx.com. ■ 12th EGA International Keytopics to be covered will include regulatory updates. Biosimilar Medicines 25-27 June Contact:IBC Asia. Conference Tel: +65 6508 2401. ■ 20th EGA Annual Conference London, UK E-mail: [email protected]. Madrid,Spain This meeting is organised by the Website: www.biosimilarsasia.com. The EGA’s three-day annual conference will European Generic medicines Association look at topics including the current regulatory (EGA). The event will coverthe latest 27-28 May environment, markets, access to medicines industry developments and regulatory ■ Getting Approval of and the implementation of safety features. issues, such as global development and Generics in the EU &USA Contact:Lucia Romagnoli, GPAConferences. pharmacovigilance. Tel: +44 7562 876 873. Berlin,Germany Contact:Lucia Romagnoli, GPAConferences. E-mail: [email protected]. Tel: +44 7562 876 873. Topics covered at this two-day conference Register onlineatwww.egagenerics.comor E-mail: [email protected]. will include regulatory procedures in the www.gpaconferences.com/ega14.htm. Register onlineatwww.egagenerics.comor European Union, ANDAprocedures for www.gpaconferences.com/bios.htm. approvalinthe US, the Food and Drug 26-28 June Administration’s(FDA’s) user fee regulation –GDUFA–and its impact, ■ CPhI China 7-8April and eCTD submissions. Shanghai,China ■ Biosimilars &Biobetters USA Contact:Concept Heidelberg. Co-located with P-MEC, ICSE, New Jersey, USA Tel: +49 6221 8444 0. LABWorld, InnoPack and BioPh, this This conference will provide networking E-mail: [email protected]. three-day trade showwill provide an opportunities and will coverissues Website: www.gmp-compliance.org. insight into the latest industry trends with including innovation, legislation, over2,200 exhibitors. pharmacovigilance, intellectual property, JUNE Contact:UBM. biosimilar development and pricing. Tel: +31 204 099 544. Contact:SMi. 3-4June E-mail: [email protected]. Tel: +44 207 827 6000. Website: www.cphi.com/china. ■ GPhA CMC Workshop E-mail: [email protected]. Website: www.smi-online.co.uk. Maryland, USA This is atwo-day workshop which will SEPTEMBER provide information on chemistry, 25-26 September 28-29 April manufacturing and controls (CMC) ■ Paragraph IV Disputes regulatory requirements and meeting the ■ 2nd Annual Biosimilars Asia New Yo rk,USA challenges of first cycle approval. Singapore Focusing on litigation, legislation and Contact:GPhA. This is atwo-day meeting which will patent issues, this is atwo-day event which Tel: +1 202 249 7100. discuss topics including emerging will also offer aworking group on patent E-mail: [email protected]. markets, commercialising biosimilars, settlements. There will be speakers from Website: www.gphaonline.org. manufacturing and clinical trials. There industry associations and firms including will be case studies and information on Impax, Mylan, Novartis and Par. 23-24 June demonstrating biosimilarity. Contact:OxfordGlobal. Contact:American ConferenceInstitute. ■ EuroPLX 55 Tel: +1 212 352 3220. Tel: +65 657 02208. E-mail: [email protected]. Vienna, Austria E-mail: [email protected]. Website: www.hatch-waxmanevents.com. This meeting provides aforum for Website: www.biosimilarsasia-congress1.com.

22 GENERICS bulletin 21 March 2014 Gen 21/3/14 Pg. 23_Layout 1 17/03/2014 19:52 Page 3

PRICE WATCH ...... UK Unit-dose form commands better prices

ust oversix months ago on 5August 2013, Teva launched in the UK 105 J   Dorzolamide/timolol         Dorzolamide  eyedrops 2% asingle-dose generic version of Merck, Sharp &Dohme’sCosopt eyedrops 2%/0.5% dorzolamide/timolol 2%/0.5% preservative-free eyedrops. Standard 100   Dorzolamide/timolol      unit-dose generic versions of dorzolamide2%eye drops, with and without 0.5% eyedrops 2%/0.5% timolol, had already been on the UK market for more than three years, 95 having been introduced in March 2010. Unit-dose versions of Cosoptwere available when the standard 90 generics were launched. This meant the generics were competing 85 not only with the basic forms of Cosopt and Trusopt –the sister Price decay (%) dorzolamide-only brand from Merck, Sharp &Dohme –but also with 80 the preservative-free, unit-dosevariants as well. 

Premium prices for the unit-dose forms were being charged by 75 0123456 the originator.Cosopt’strade prices are the same today as theywere  when the generics were launched at £10.05 (US$16.67) for the standard Month form, but£28.59 for unit-doses. Last August, when the unit-dose generic Figure1:Monthly decay in the average trade prices for dorzolamide eye-drop formulations in the six months after generic launch (Source –WaveData) waslaunched, the lowest trade price in the market was£24.99, Dorzolamide/timolol representing just a12.5% discount on the brand price. In the same 120%120 Dorzolamide + Timolol 5ml % month, the trade prices for standard combination eye-drops had decayed eyedrops 2%/0.5% to an average of £2.95 and alowest price of £2.34, indicating a 100%100 DorzolamideDorzolamide 5ml % considerably better margin for suppliers on the unit-dose product. eyedrops 2% 80 However, the August 2013 prices for the standard form of the 80% Dorzolamide/timololDorzolamide +Timolol unit-dose 60 combination eyedrops had followed more than three years on the eyedrops 2%/0.5% 60%60 market. During that time, the product’saverage trade price had fallen to the point where it represented a70% generic discount to the brand. 40%40 Even just amonth after launch in March 2010, its trade price had Price decay (%) already dropped by 20% compared with the brand (see Figure 1). 20%20 Pharmacists too have benefitted from the generic launch of the 0%0

unit-dose product. This is because theyhavebeen reimbursed at 030 3 696 9 12 15 18 21 24 27 30 33 36 39 42 45 48 12 15 18 21 27 30 33 36 39 42 45 48 Cosopt’strade price, whereas theyonly received£3.26 last month for Month24 dispensing the standard form. The lowest price for the unit-dose Figure2:Monthly decay in the average trade prices for dorzolamide eye-drop combination reported to WaveData last month was£24.75, butthe formulations since generic launch (Source –WaveData) average price had movedupsince launch to £26.35, which represented AvAverageerage DrugDurg tariffTariff MinimumMinimum just an 8% generic discount to Cosopt’strade price. 77 WaveData’sCharles Joynson notes that the trade price of the unit- 6 dose product is decaying at aslower rate. “Our conclusion,”hesays, 6 “is that the greater the difference in character from the core original 55 product, then the longer it takes for other generic manufacturers to 44 introduce arival. This implies apremium price for the first to launch, 33 and amuch slower price-decay rate than for more common forms of Price (£) the product, and for generics in general.” 22 Figure 2also shows that there has been little difference between 11 the trade-price decay of dorzolamide and timolol in combination and 00 dorzolamide alone. Looking at the twoproducts individually,the lowest 0 1 2 3 10 11 12 13 14 v 1 v 1

trade price of dorzolamide was£1.17 last month, compared with an Feb-11

Feb-14

Nov-11

Aug-11

Feb-13

Feb-12

Feb-10

Nov-13

Aug-13

Nov-12

Aug-12

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May-13 May-12 Feb 10 AugMay-10 No Feb Aug 11Nov 1 Feb Aug 12No Feb Aug 13Nov 1 Feb average price of £1.86. Meanwhile, its Drug Tariff reimbursement May 10 May 11 May 12 May 13 Figure3:Monthly changes since launch in the trade and Drug Tariffreimbursement price was£2.31 (see Figure 3). When compared with Trusopt’strade prices for 5ml packs of dorzolamide 2% eye drops (Source –WaveData) price for the standard form of £6.33, these prices represent decays compared with the brand of 64% for the Tariff, 71% for the average Average DrugDrugTa tariffriff MinimumMinimum and 82% for the lowest price. 1212 Meanwhile, the equivalent decays for the standard combination 1010 of dorzolamide and timolol were 68%, 73% and 90% (see Figure 4). G 88

WANT MORE LIKE THIS? 66

Long-term product price trends or other price analyses are available. Price (£) 44 Please specify the product and period of time you would liketo investigate and email your request to [email protected]. 22 ■ Forfurther information see www.bppi.co.uk. 00 0 1 2 3 10 11 12 13 14 Alternatively,contact Charles Joynson at v 1 v 1 v 1 Feb-11 Nov-11 Aug-11 Feb-10 Feb-12 Feb-13 Feb-14 Nov-10 Nov-12 Nov-13 Aug-10 Aug-12 Aug-13 Feb 10 May-11 Feb Feb May-10 May-12 Feb May-13 Feb WaveData Limited, UK. Tel: +44 (0)1702 425125. May 10Aug No May 11Aug 11No May 12Aug 12No May 13Aug 13Nov 1 E-mail: [email protected]. Figure4:Monthly changes in the trade and Drug Tariffreimbursement prices for 60 unit-dose packs of dorzolamide/timolol 2%/0.5% eye drops (Source –WaveData)

21 March 2014 GENERICS bulletin 23 Gen 21/3/14 Pgs. 24-25_Layout 1 17/03/2014 19:52 Page 2

REGULATORY AFFAIRS Communication is keyto deliver on GDUFAgoals

Moreefficient hen the text of the US Generic Drug User Fee in the waythat the agencyoperates, according to Act (GDUFA) wasfinalised nearly twoyears Kathleen Uhl, acting director of the FDA’sOffice of communication Wago, the US Generic Pharmaceutical Generic Drugs (OGD). between the US Association (GPhA) hailed it as “the most important Addressing the GPhA’s annual meeting in Orlando, pharmaceutical legislation since the 1984 Hatch-Waxman Florida, at the end of February,she acknowledged that Food and Drug Act”. Now, almost 18 months since GDUFAcame into the FDAwould not succeed in improving the abbreviated force at the start of October 2012, the US generics newdrug application(ANDA) reviewprocess if it simply Administration (FDA) industry is beginning to see the fruits of the country’s channelled additional resources into procedures that were and industry, as well user-fee programme. carried out in the same wayastheywere before GDUFA. Areport recently published by the US Food and The user-fee programme wasa“major game- as within the Drug Administration (FDA) covering the first year of changer” that represented the “professionalisation of GDUFAindicates that the agency“met all GDUFA the generic drug programme”, Uhl stated, insisting that regulator itself, will programme commitments for the 2013 fiscal year” this would translatetoa“transformational change” for be crucial to fulfilling ended 30 September 2013. And in some cases –such both the FDAand industry.And improvements in as the requirement to appoint within the first year of communication –both between the regulator and the the promise of the GDUFAaquarter of the newstaffthat will be necessary generics industry,aswell as within the FDAand the country’sgenerics to implement the programme –the FDAevenexceeded OGD –were at the heart of this change. its requirements, with 31% of staffhired. One of the major steps already undertaken by the user-fee programme. However, as Figure 1shows, manyperformance FDAearlier this year had been to issue status updates metrics that will be used to gauge the agency’ssuccess for all ANDAs being reviewed by the agency, Uhl David Wallace reports. in meeting GDUFA’sgoals do not enter into force until explained, calling this a“one-time”activity that went the third year of the programme, beginning in October “above and beyond” the requirements of GDUFA. This this year.“Congress, FDAand industry recognised had required “substantialeffort” from OGD staffand had that implementing GDUFAwould require significant led to updates for more than 3,500 applications. resources, and therefore chose not to include specific As well as informing applicants of the current status early programme review-time goals,”the FDAexplains. of their applications, this process had revealed the “Instead, theyincluded agoal for the FDAtomaintain “chaos” of current information-technology(IT) levels of productivity similar to pre-GDUFAlevels in arrangements within the OGD, Uhl admitted. Problems the first twoyears of the programme.” included the general inflexibility of the IT network, Meeting the generics industry’s“huge expectations” along with inconsistent uses of certain terminology and of the requirements that will come into effect in “fragmented” data sources relating to various aspects GDUFA’sthird year will require substantial changes of applications. The OGD would thereforehaveto

FY 2013 FY 2014 FY 2015 FY 2016 FY 2017 Original abbreviated newdrug Expedite reviewofparagraph IV 60% in 15 months 75% in 15 months 90% in 10 months application (ANDA) ANDAs and maintain pre-GDUFAproductivity Tier 1first major amendment Maintain pre-GDUFA60% in 10 months 75% in 10 months 90% in 10 months productivity

Tier 1minor amendments (1st –3rd)Maintain pre-GDUFA60% in 3months* 75% in 3months* 90% in 3months* productivity

Tier 1minor amendments (4th –5th)Maintain pre-GDUFA60% in 6months* 75% in 6months* 90% in 6months* productivity

Tier 2amendment Maintain pre-GDUFA60% in 12 months 75% in 6months 90% in 12 months productivity

Prior approvalsupplements (PASs) Maintain pre-GDUFA60% in 6months* 75% in 6months* 90% in 6months* productivity

ANDAs, amendments and PASs in ––––Act on 90% by backlog as of 1October 2012 end of 2017

Controlled correspondences Maintain pre-GDUFA70% in 4months** 70% in 2months** 90% in 2months** levels

* 10 months if inspection required ** one additional month added to goal if clinical division input required

Figure1:FDA review performance goals under GDUFAfor the fiscal years ending 30 September 2013 to 30 September 2017 (Source –FDA)

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reorganise its IT systems into amore efficient, integrated FY 2013 FY 2014 FY 2015 FY 2016 FY 2017 platform,she declared. Reorganising the wayinwhich the OGD Hire and train newstaff25% 50% 25% –– communicated with ANDAapplicants wasalso an Type II DMF completeness Achieved– ––– important step in implementing GDUFA, Uhl believed. assessment –conduct and In the past, communications had often been piecemeal, publish list ad-hoc and labour-intensive,she pointed out, adding that theywere often inadequately documented and Enhanced refuse-to-receive Achieved– ––– inconsistent, with the potential for “differentiated standards for ANDAs and treatment” between different applicants. related submissions What wasneeded wasafair and consistent ANDAteleconference Maintain pre-GDUFAClose-out Close-out Close-out process, she stated, which would provide applicants requests levels 200 250 300 with asingle point of contact, rather than requiring them to communicate with multiple offices within the Type II DMF Maintain pre-GDUFA Limit one per DMF holder per month not OGD on different aspects of their applications. teleconference requests levels to exceed ANDAteleconference levels

EveryANDAhas project manager Risk-adjusted biennial Parity of Each ANDAwill therefore be assigned to a cGMP surveillance inspection inspections of generic API ____frequency regulatory project manager at the OGD who will between function as asingle, central point of contact for that and generic finished dosage foreign and domestic firms application. This approach –consistent with FDA form manufacturers practiceswithin other product centres –would help Figure2:Hiring, procedural and inspection performance goals under GDUFAfor the fiscal years streamline the ANDAreviewprocess, Uhl said, while ending 30 September 2013 to 30 September 2017 (Source –FDA) allowing the ANDAreviewers to concentrate on the process of reviewing rather than responding to queries. anyfacility inspections or changes to drug master The OGD’sintention is to respond to ANDAs with files (DMFs) wascrucial in ensuring that the ANDA single ‘complete response’ (CR) letters that are as process went smoothly,she indicated. comprehensive as possible, documenting anymajor and Moreover, Uhl recommended that applicants should minor deficiencies in the application which must be obtain afull DMF completeness assessment before remedied by the applicant.This will replace ongoing submitting ANDAs. DMFs should be submitted well feedback issued from separate OGD divisions as the in advance of the final application –around six months application is processed. earlier –toallowtime for applicants to respond to any Reviewers would “makeevery reasonable effort” problems with the DMF,she indicated. “Industryhas been given to use telephone information requests to address less In the first and second year of GDUFA, Uhl significant ‘easily-correctible deficiencies’, Uhl added, admitted, industry had been givena“free pass” in being a‘free pass’ in being able noting that this would allowreviewers to complete the able to submit DMFs along with related ANDAs. But ANDAreviewrather than delaying the process to correct in the third year and beyond, such ANDAs would to submit DMFs along such minor issues. probably be rejectedunder the OGD’srefuse-to-receive with related ANDAs. Furthermore, the OGD will also notify drug master standards, she anticipated. file (DMF) holders once anyANDAs referencing the Uhl also recommended that firms kept in close But in the third year and DMF are approvedortentatively approved. contact with the FDAiftheywere expecting approvals In tandem with these improvements to by acertain date. It might be useful to alert the agency beyond, such ANDAs communication on the part of the OGD, Uhl insisted, to such expectations around six months in advance, she will probably be rejected certain efforts would also have to be made by industry if suggested, as well as to makesure that the regulator had GDUFAwas to be asuccess. She advised generics firms access to anyrelevant legaldocuments or court findings. under the OGD’srefuse- to acquaint themselves fully with GDUFA, including “Paramount to meeting the [GDUFA] goals is the original agreement letter issued at the start of the improvedquality of applications and submissions,” to-receivestandards” user-fee programme.Aspart of efforts to “ease industry Uhl insisted, observing that in the past, industry’s familiarity with GDUFA”, the GPhA has launched a unofficial motto might have been ‘file first, develop website, GDUFAnow.org, that will act as a“digital later’. That had led to poor-quality applications, she said, library and online educational resource” for the user-fee with FDAreviewers effectively serving as consultants programme (Generics bulletin,7March 2014, page 14). to industry on product development. Communication within the supply chain wasalso “Easily avoidable, butcostly,errors can be important for generics firms, Uhl pointed out, urging minimised with clear guidance,”the FDApoints out in applicants to “demand accountability from your its GDUFAreport, indicating that within the first year contractors”, such as active pharmaceutical ingredient of the user-fee programme the agencypublished draft (API) manufacturers or suppliers. Keeping informed of guidance on refuse-to-receivestandards for ANDAs

Backlog as of First action receivedBacklog Expected Received 1October 2012 by 30 September 2013 clearance (%) Original ANDAs 850 992 ANDAs 2,866 868 30.3 DMF CAs 700 1,580 Controls 920 953 PASs 1,882 752 40.0 PASsupplements 576 265

Figure3:Progress made by the FDA towards addressing the backlog of ANDAs and prior-approval Figure4:Forecasted and actual applications received in the supplements (PASs) in the first year of GDUFAended 30 September 2013 (Source –FDA) first year of GDUFAended 30 September 2013 (Source –FDA)

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(Generics bulletin,18October 2013, page 11), as well as million of user-fee funding into additional testing studies completeness assessments (CAs) for type-II API DMFs. for generics under the GDUFAregulatory science “Both of these guidances are designed to help research programme (see page 11). These studies – sponsors increase the quality of their submissions, reduce which will be carried out by various non-agencybodies delays, and speed review,”the agencyindicates, adding including universities and hospitals–will “provide new that “additional efficiencyenhancements and goals will tools for the FDAtoevaluate generic-drug equivalence be phased in overthe next four years”. and for industry to effectively develop newgeneric As well as targets for completing ANDAreviews, products in all product categories”. “Over the past few the GDUFAgoals also include an expectation that the months, grants have been awarded and research is “As human generic user FDAwill by the end of September 2017 achieve “parity beginning,”the agencyconfirmed. of inspection frequencybetween foreign and domestic However, making inroads into clearing the backlog fees allowthe FDA firms” that manufacture final-dosage forms and APIs of ANDAs wasthe agency’smain priority in the first to increase inspection (see Figure 2). In the year ended 30 September 2013, year of GDUFA. “Giventhe substantial backlog, the the agencynoted, 82% of US final-dosage form facilities FDAfocused its reviewefforts in the 2013 financial capacity in subsequent had been inspected within the required two-year year on reducing the number of pending applications that inspection cycle, compared to 65% outside the US. For were receivedinprevious fiscal years,”the agencystates. years, the gap between domestic API producers, the figure was80%, Citing “significant progress” towards reducing the domestic and foreign compared to 67% for non-US suppliers of bulk drugs. applications backlog (see Figure 3), the FDAnotes that “Ashuman generic user fees allowthe FDAto first actions on ANDAs and prior-approvalsupplements inspection frequencies increase inspection capacity in subsequentyears,”the (PASs) could have included an approvalortentative agencystates, “the gapbetween domestic and foreign approval, acomplete response letter,arefusal to file should narrow” inspection frequencies should narrow.”Uhl said the or awithdrawalofthe application. agencywould “prioritise inspections of establishments Faced with an influx of applications during the first associated with ANDAs that are otherwise approvable year of GDUFAthat has largely been higher than or eligible for tentative approval”, adding that the expected (see Figure 4), the FDA’sperformance is sure regulator also planned to “makeinspection-classification to be closely monitored by the generics industry as the results and the date of the last facility inspection user-free programme approaches its crucial third year. available to the public and industry on the FDA’s “You have paid fees, and nowyou want and expect website”. The FDAalso intended to “develop a action,”Uhl acknowledged. Meanwhile, Ralph Neas – programme to utilise foreign inspection classifications president and chief executive officer of the GPhA –has when and where appropriate”, she indicated. pledged to “hold the agency’sfeet to the fire when it Meanwhile, the FDAisalso channelling US$20 comes to delivering on the GDUFAgoals”. G

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PEOPLE

APPOINTMENTS APPOINTMENTS Zipp openstime with Par picks Coughlin Lachman after Teva for operations post

ormer Barr and Teva executive Fran Zipp has accepted the ar Pharmaceutical has appointed former Glenmark executive Fposition of president at Lachman Consultant Services.She takes PTerrance Coughlin as its chief operating officer with effect from overfrom Roy Sturgeon,who has retiredbut continues to act as an 1April. Coughlin, 48, will receive an annual base salary of US$550,000, advisor to the US-based manufacturing consultancy. Responsible for plus benefits and bonuses. all consulting operations, Zipp reports to Lachman’schief executive Up to October last year,Coughlin served as president and officer, Paul Vogel. chief executive officer of Glenmark Generics in the US. He was Zipp previously served for more than five years as Teva’s replaced at Glenmark by former Bausch &Lomb executive Philip executive vice-president of global corporate quality,having held a Gioia (Generics bulletin,15November 2013, page 27). G similar position at Barr before its takeoverbythe Israeli group. Teva has appointed its chief business-process officer,Erez Israeli, as interim head of global quality. G APPOINTMENTS IN BRIEF Endo brings in scientist Hall CAMARGO –the US 505(b)(2) hybrid development specialist – ndo has appointed former Valeant and GlaxoSmithKline has appointed Olu Aloba as senior director of pharmaceutics to Eexecutive Susan Hall as chief scientific officer and global head oversee chemistry,manufacturing and controls (CMC) aspects of of research, development and quality.Hall –who is based at the development projects. Aloba joins from Warner Chilcott. analgesics specialist’snew global corporate headquartersinDublin, Ireland –replaces Ivan Gergel,who chose not to makethe move to AESEG –the Spanish generics association –has for the fourth time Ireland (Generics bulletin,7March 2014, page 30). re-elected Kern Pharma’schief executive officer, Raul Diaz-Varela, “Sue brings over30years of extensive multi-disciplinary and as its president for atwo-year spell. Ranbaxy’s Pere Lluis Sala and international expertise in drug development and lifecycle management Actavis’ Rodrigo Roman being replaced by Hospira’s Pablo de Mora across abroad range of therapeuticareas, along with extensive and Pensa’s Francisco Navarro were the only alterations to Aeseg’s experience in quality,” commented Endo’spresident and chief executive board of directors, as the association kept with Alter’s Antonio officer,RajivDeSilva. Alonso,Apotex’ Pablo Sancho,Cinfa’s Francisco Jose Aranda Hall –who has adegree in pharmacology from the UK’sUniversity and Lesvi’s Javier Mercade.Meanwhile, Normon’s Jesus Govantes, of Leeds and adoctorate in pharmacokinetics from the University of Mylan’s Javier Anitua,Sandoz’ Joaquin Rodrigo,Stada’s Mar Manchester –resigned as Valeant’sglobal head of research and Fabregas and Teva’s AdolfoHerrera also remain on the board. development last year following the firm’stakeoverofBausch &Lomb. However, she agreed to stay on to “ensure asmooth transition” and PERNIX THERAPEUTICS has named former Norwich Pharma to act as aconsultant on Valeant’sefinaconazole antifungal candidate. Services president Terence Novak as chief operating officer.Hewill As it integrated its US$8.7 billion Bausch &Lomb acquisition, report to Doug Drysdale, presidentand chief executive officer of the Valeant handed responsibility for research and development in US group that sold several of Cypress’and Macoven’sgenerics assets to various areas to each of its business unit heads. G Breckenridge last year (Generics bulletin,6September 2013, page 4).

FORMYCON has added former Sandoz US chief Bernhard Hampl RESHUFFLES to its advisory board. He joins former Sandoz colleague Gerhard Schaefer and newly-appointed Merck KGaA biosimilars head Trio to decide Actavis team Simon Sturge on the board of the German biosimilars developer. ctavis’ chairman and chief executive officer, Paul Bisaro,has been MYLAN said its chief accounting officer and corporate controller, Ajoined by his counterpart at Forest Labs, Brent Saunders,and Daniel Rizzo,would end his eight-year association with the US firm Actavis’ commercial and business-development chief, Siggi Olafsson, when he relinquishes his responsibilities on 1May this year. to form athree-member ‘office of the chairman’ overseeing plans to Meanwhile, Mylan’sboard of directors has nominated JoEllen Lyons integrate Forest into the group. Dillon as an independentdirector.Dillon –who is chief legalofficer “Paul, Brent and Siggi will work co-operatively to select the at 3D-printing group ExOne –will replace Mylan veteran Sonny combined company’sleadership from the ‘all-star team’ of exceptionally Todd if elected at the annual meeting of shareholders on 11 April. experienced and talented executiveswithin each company,”stated Actavis, which intends to close its US$25 billion purchase of Forest CFR PHARMACEUTICALS has creatednew chief executive officer by the middle of this year. positions for the firm’soperations in Latin America and South East Team leaders forming an ‘integration leadership group’ held an Asia. The Chilean company’spresident for Specialty Pharma, initial meeting on 27 February,charged with planning for integration Daniel Salvadori,will head CFR’soperations in Latin America, whilst ensuring that each firm meets its independent business while Thian Phin Chiew –who is currentlypresident of CFR’s objectives. The twofirms’ management teams have equal representation South East Asia business –will serveasthe chief executive in this group. officer in the latter region. G “Until close, Actavis and Forest will continuetooperate as separate companies, and as competitors,”the firms noted. G

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