3November 2017

COMPANY NEWS 2 Aristo buys Amneal in Nordics and Spain 2 Eight EU authorities are Biocadisgearing up to market in Europe 3 Sandoz enjoys Rixathon 4 and Erelzi start deemed equivalent to US Akorn Grand Avenue facility received 483s 5 WBA is set to shut 600 stores in the US 6 CVS and Anthem ally for a 7 ight European Union (EU) national authorities have been recognised as “capable of PBM deal in US Econducting inspections of manufacturing facilities that meet US Food and Drug Finnish price reform exacts toll on Orion 8 Administration (FDA)requirements” by the US agency, as part of agoodmanufacturing practice (GMP) mutual recognition deal struck by European and US regulators earlier this MARKET NEWS 10 year. Authorities in Austria, Croatia, France, Italy, Malta, Spain, Sweden and the UK were IndustryurgesactiononSPC waiver in EU 10 recognised under the agreement, in what the FDA called an “important milestone”. US attorneys aiming to 11 “Beginning 1November, we will take the unprecedented and significant step forward in widen suit’s scope realising the key benefits of the mutualrecognition agreement with our European counterparts EMA continuityplannot business as usual 12 in that we will now rely on the inspectional data obtained by theseeight regulatory agencies,” Commission admitstoPUMA plan failure 13 stated DaraCorrigan, the FDA’s acting deputy commissioner for global regulatory operations US$54bn in savings fromUSbiosimilars 14 and policy. “The progress made so far puts us on track to meet our goal of completing all 28 Health Canada plans labelling 15 capability assessments in the EU by July 2019.” fee overhaul Underthe terms of the agreement, the FDA was due to have completed an assessmentof “at least eight EU member states” by 1November, gradually expanding these assessments to PRODUCT NEWS 18 all member states by mid-2019(Generics bulletin,10March 2017, page 1).InJune2017, the Fluticasone is among new 18 European Commission determined that the FDA “has the capability, capacity and procedures FDA guidances in place to carry out GMP inspections at alevel equivalent to the EU”. Sandoz resubmits EU pegfilgrastim dossier 19 “The completion of these capability assessments enables the FDA and the EU to avoid Germany is missing biosimilars potential 20 duplication of drug inspections and allows regulators to devote more resources to other Biomm hits ablock on 21 manufacturing facilities in countries where there may be greater risk,” the FDA pointed out. Brazilian glargine “At atime in which medical product manufacturing is truly aglobal enterprise,” said FDA Mylan sued in the US over insulin glargine 22 Commissioner Scott Gottlieb, “there is much to be gained by partnering with regulatory counterparts to reduce duplicative efforts and maximise global resources while realising the Swiss court upholdsanSPC for Truvada 23 greatest bangfor our collectiveinspectional buck.” Through the partnership, Gottlieb said, “we US opioid crisis is anational emergency 24 can create greater efficiencies and better fulfill our public health goals”. G FEATURES 30 Impax and Amneal eye new 30 channels for US distribution Becoming aleader in alternative direct-to- Hikma is Company of the Year patient distribution is among the numerous benefits that Amneal and Impax expect to ikma was namedCompanyofthe Yearatthe Global Generics &Biosimilars Awards, heldon drive future growth as acombined company. H24 October in Frankfurt, Germany,byGenerics bulletin and co-hostedbyQuintilesIMS. Dean Rudge reports. Meanwhile, Accord Healthcare took home three prizes. The Intas subsidiary won the award for Acquisition of the Year, sponsored by Pharmawise, for its £603 million (US$791 million) REGULARS purchasefromTeva of the former Actavis business in the UK and Ireland that was completed Events – Our regular listing 8 at the start of this year (Generics bulletin,13January 2017, page 5). Accord was also given Price Watch UK – Our regular listing 10 the award for Patent Litigation of the Year for challenging Europeanpatent-protection for a People – GBMA seeks achief 32 high-concentration formulation of methotrexate, as well as winning the award for Business as Wood steps down Developmentofthe Year for developing lenalidomide tablets. Amneal picked up two awards –the Chartwell Pharmaceuticals-sponsored award for Company of theYear in the Americasregion and the Pharmacloud-backedaward for Leader of the Year, won by co-founders and co-chief executive officers Chintu and Chirag Patel – while Sandoz was recognised withboth the Regulatory Achievement of the Year award sponsored by Eignapharma, as well as with the Biosimilar Initiative of the Year award. Other awards See page 25 forcoverage of the event and winners sponsorsincluded Clarivate, Evapharma and International Health Partners, as well as mAbxience, Issue No.328 Panacea and Piramal. Next year, the Global Generics &Biosimilars Awards 2018–which are free to enter and attend –are due to take place on 9OctoberinMadrid, Spain. G

Gen 3-11-17 Pg.1.indd 1 01/11/2017 17:35 COMPANY NEWS

BUSINESSSTRATEGY MANUFACTURING Aristo buys Amneal Recipharm improves in Nordics and Spain serialisation abilities

ermany’s Aristo Pharma has struck adeal to acquire Amneal ecipharm has enhanced the serialisation capabilities of its site in GNordics and Amneal Spain. Theagreement follows Strides Shasun’s RLisbon,Portugal, ahead of looming US and European enforcement acquisition of Amneal Australia through the Indian firm’s Arrow deadlines.Notingthatthe Lisbonfacilitywas itssixth site to “become Pharmaceuticals unit (Generics bulletin,8September 2017, page 3) serialisation-ready for the US and European markets”, the Swedish and comesasAmneal prepares to integrate with Impaxfollowing the contract developer and manufacturer said it had added an “additional pair’s agreementtomerge (Generics bulletin,20October 2017,page1). four packaging lines to the company’s current serialisation capabilities”. “The acquisition of Amneal Nordics will provide Aristo with an Afurther seven lines would be added to the facility by June 2018, ideal platform for expanding its business into the Nordic countries,” Recipharm noted. the German firm declared. It has renamed the unit –which has its In February2016, Recipharmunveiled athree-year plan to invest headquarters in Copenhagen, Denmark–asAristo Pharma Nordic. C40 million (US$47.1 million) in serialisation technology and processes “At the sametime,” Aristo stated,“the company is expanding the to comply with the EuropeanUnion’s Falsified Medicines Directive. Aristo Pharma Iberia business in Spain byabout40additional active At the time, Recipharm said it would be “ready for US serialisation from ingredients”with the acquisition of Madrid-based Amneal Spain. November 2017, in line with the US Drug Supply Chain Security Act”. Synergies from the dealwouldalso be evident for Aristo UK, the Earlierthisyear, however,the US Food and Drug Administration firmnoted, with the UK operation gaining 20 newproducts. “Inaddition, (FDA) issued draft guidance for industry stating that manufacturers the acquisition contains extensive dossier rights,” Aristo said,“which would not face action from the agency for failing to comply with ‘track include the right to expand into other countries.” and trace’ productidentifier and verifier requirements for an additional “Following the creation of Aristo Pharma Iberia in 2013 and year beyond the current guideline (Generics bulletin,14July 2017, Aristo UK in 2016, the acquisition of Amneal Nordics and Spain is a page 10).Due to industry-wide readiness concerns, the FDA delayed further step on Aristo’s journey to become amajor generics player proceedings by ayear, pushing back the action date to 27 November 2018. in Europe.” The German firm previously took over UK-based CEB Pharma (Generics bulletin,10March 2017, page 5). ‘Preparing for along time’ Formed in 2008, Berlin-based Aristo offers awide array of “Recipharmrecognised the complexity of implementing serialisation generics, mature brands and herbal remedies that it produces through a at avery early stage,” insisted Staffan Widengren, Recipharm’s network of facilities, located primarily in Germany. The group –which director for corporate projects, “and so we have been preparing for the also operates aMedinsa solid-dose plant in Madrid, Spain –has new regulations in the US and Europe for along time now.” This capabilities thatinclude semi-solids, liquids and oral cephalosporins. G included forming aglobal alliance to “introduce new serialisation capabilities” with Italianfirms Marchesini and SEA Vision, and US- IN BRIEF based TraceLink in mid-2016 (Generics bulletin,8July 2016, page 4), as well as delivering its first serialised batch to Saudi Arabia earlier PANACEA BIOTEC has received a certificate of good manufacturing this year (Generics bulletin,28April 2017, page 4). practice (GMP) compliance from Ukraine’s medicines agency for its Recipharm said it had “already delivered over 1.3 million serialised Indian oral solid-dosage manufacturing facilityand oncologysite in and aggregated packs to markets such as China, South Korea, Saudi Baddi, Himachal Pradesh, following June inspections. Noting that Arabia and Turkey, where serialisation regulations are currently in Ukrainewas amemberofthe PharmaceuticalInspection Co-operation place”. Widengren, who alsoleads the global steering committee for Scheme (PIC/S), Panacea said the registration of 22 products that Recipharm’s serialisation project, observed that the Lisbon facility received manufacturing authorisations could now be “undertaken “brings us to over athird of the way through our implementation project”. in the 49 PIC/S countries on afast-track basis”. G The Swedish firm said its nextsitetobeequipped wouldbeafacility in Brescia, Italy, that would “supply serialisedproducts to the US”. G

Issue 328 l 3November 2017

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Terms &Conditions: See www.generics-bulletin.com/subscribe. [email protected] [email protected] While due care has been taken to ensurethe accuracy of information contained in this publication, the publisher makes no claim that it is free of error and disclaims any liability whatsoever for any decisions or actions taken as aresult of its contents. Assistant Editor: Dean Rudge Business Reporter: Grace Montgomery PublishedbyOTC Publications Ltd, 4Poplar Road, Dorridge, SolihullB93 8DB, UK. Tel: +44 (0) 1564 777550 Fax: +44 (0) 1564 777524 Company registered in England No 02765878. ©OTC Publications Ltd. All rights reserved. Generics bulletin® is registered as atrademark in the European Community. [email protected] [email protected] Printed by Warwick Printing Company Ltd. ISSN 1742-0784

2 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.2-15.indd 2 01/11/2017 17:31 COMPANY NEWS

BUSINESS STRATEGY SECOND-QUARTER RESULTS Biocad is gearing up Reddy’s waits for US to market in Europe launches to succeed

ussia’s Biocad is preparing to introduce in European markets its rReddy’sLaboratories says it expects to “see results”inthe coming Rroster of biosimilars, generics and innovative biological products, Dfinancial quarters from product launches in the US announced focusing on oncology drugsand autoimmune disease treatments. during the first six months of its current financial year ending March Takinginto accountthe European Medicines Agency’s (EMA’s) 2018, as asales slump in its key North America generic formulations centralisedprocedure for marketing authorisations, and thecorresponding business led the Indian firmtoagroupturnover decline in its financial “need for local clinical trials”, the Russian firm said it expected to begin secondquarter ended 30 September. receiving marketing authorisations for ‘biologic products’ in 2021. Launches so far thisyearincludeone of the first generic versions Biocad’s current portfolio of biosimilars includes its Acellbia of Merck &Co’s Vytorin (ezetimibe/simvastatin) tablets (Generics (rituximab)and Herticad (trastuzumab)products, which are marketed bulletin,5May 2017, page13), and agenericrival to The Medicines in Russiaand various emergingand developing countries. Moreover, Company’sAngiomax (bivalirudin). Moreover, the firm obtained a Biocad says the “last preparations” are underway for “conducting US approval for ageneric version of Janssen’s Doxil (doxorubicin) Phase III clinical trials of our adalimumab biosimilar” in Europe. liposome injection, the firm’s first complex depot injectable. “Sofar there are seven molecules in the European portfolio,” Biocad During the second quarter, Reddy’s began shipping in the US revealed,noting that these coveredtreatments for melanoma and breast, cefixime oralsuspension,bupropion extended-releaseand metaxalone stomach, kidney and lung cancer, as well as rheumatoid arthritis, tablets. Meanwhile, Reddy’s also introduced ageneric of Sanofi’s psoriasis and multiple sclerosis. “In addition, in 2021,” Biocad Renvela (sevelamer carbonate), although the Indian firm noted that forecasted, “generic oncology drugs–includingdocetaxel, paclitaxel, the product had been launched “post the cut-off date for revenue pemetrexed and irinotecan –willalso enter European countries.” recognition”,and so “no sales have beenrecorded during the quarter”. “Biocad is the only pharmaceutical company in Russia that is In its financial second quarter, Reddy’s Generics sales in North ready to provide dossiers for its medicines according to an International America slid by 11% to Rs14.3billion(US$221 million), with Conference on Harmonisation (ICH) common technical document Reddy’s pointing to continued high price erosion affecting key products (CTD) format in the shortest possible time,”insistedBiocad’s general such as azacitidine, esomeprazole and valganciclovir. As Figure 1 director, Dmitry Morozov. shows, North American sales accounted for two-fifthsofgroup turnover Earlier this year, Biocad unveiled plans to construct achemical that declined by 1% to Rs35.5 billion, with that region down five and biological products manufacturing facility in Turku, Finland, as percentage points year-on-yearasaproportion ofReddy’s totalturnover. part of broader plans to enter European markets via alocal partnership Saving Reddy’s from alarger turnover loss was double-digit that also covers drug development and fundamental sciences (Generics growth in the firm’s Emerging Markets Generics operation, driven bulletin,2June 2017, page 5). by growth of afifth to Rs3.2 billion in Russia, as well as arise of 36% Meanwhile, Biocad says it is continuing negotiationswith apartner to Rs2.42 billioninthe firm’s EuropeanGenerics operation. Reddy’s in Japan and is in discussions on “commercial terms and conditions said growth in Europe was “primarily driven by new launches and for the distribution of its products” in the market. The Russianfirm volume uptake in some of the key products”. addedthatitwas interested in licensinginnovativeproducts from “small In Europe,however, Reddy’s duringthe quarter had revoked the companies on mutuallyfavourable termsfor theRussian market”. G good manufacturing practice (GMP) certificate held at the firm’s Unit II formulations facility in Bachupally, India, by aGerman regulatory authority (Generics bulletin,1September 2017, page 7). STRATEGIC ALLIANCES Including an additional Rs454 million of ‘other income’, Reddy’s pre-tax profit rose by 3.2% to Rs4.09 billion, following adrop of 2.5% Cadila and Altus strike deal to Rs31.8 billion in total operating expenses. The firm said it would adila Pharmaceuticals has entered into aco-development and continue to focus on improving operational efficiencies. G Clicensing agreementwith Altus Formulation for the Quebec-based n [email protected] firm’sFlexitab formulation platform. AccordingtoAltus, the “innovative and commercially-validated” technology platform provides “novel, Second-quarter sales Change Proportion value-added lifecycle management opportunitiesthrough ‘Safer Use’ (Rs millions) (%) of total (%) breakable, extended-release tablets”. Flexitab tablets “maintain their North America 14,318 -11 40 drug-release profile when broken, and are alcohol insensitive”. India 6,370 +2 18 Under the terms of the arrangement, Cadila and Altus “will jointly Emerging markets* 5,506 +14 16 select key development targets benefiting from the Flexitab technology, Europe** 2,424 +36 7 and will co-develop and obtain marketing approvalfor these products in Global Generics 28,618 -1 81 various territories”. Products co-developed and commercialised under Pharma Services/APIs 5,654 -2 16 the agreement may be sub-licensed to third parties around the globe. Cadila’s chairman and managing director Rajiv Modi said the Proprietary Products/Other 1,188 +10 3 partnership allowedthe privately-held Indiancompany to leverage Altus’ Dr Reddy’s 35,460 -1 100 Flexitab technology, “ensuring cost-effectiveness and value-added *refers to Russia, other CIS countries, Romania and formulations for patients”. Damon Smith, chief executive officer of Rest of World markets including Venezuela Altus, said the firm “looked forward to co-developing and commercialising ** primarily Germany, the UK and out-licensing sales business arange of patent-protected and label-differentiated new products with Figure 1: Breakdown by region and business segment of Dr Reddy’s Laboratories’ Cadila that will bring significantvalue to both our companies”. G sales in its financial second quarter ended 30 September 2017 (Source –DrReddy’s)

3November 2017 GENERICS bulletin 3

Gen 3-11-17 Pgs.2-15.indd 3 01/11/2017 17:31 COMPANY NEWS

THIRD-QUARTER RESULTS Sandoz enjoys Rixathon and Erelzi start

wo biosimilars launched in Europe this summer following European TCommission approvals in June 2017 are “off to agood start”, Third-quartersales Reported Constant-currency (US$ millions) change (%) change(%) Sandoz and parent group Novartis have told investors. For their rival to Roche’s Rituxan/MabThera (rituximab) oncology Europe 1,233 +13 +8 therapy, “physiciansare willing to use Rixathon across indications”, US 798 -13 -13 the firms stated. The Commission’s approval for the Rixathon/Riximyo Asia, Africa, Australasia354 +4 +8 biosimilar covers all the same indications as granted for Rituxan/ Canada, Latin America 199 +16 +14 MabThera (Generics bulletin,23June 2017, page 11). Having alsoduring JunesecuredaCommissionauthorisation for Sandoz 2,584 +3 +1 its Erelzi (etanercept) alternative to Pfizer’s Enbrel anti-inflammatory Established Markets 1,881 -1 -3 agent (Generics bulletin,30June 2017, page 11), Sandoz selected Emerging Markets 703 +13 +12 Germany and the UK as lead markets for both biosimilars (Generics bulletin,7July 2017, page 13). Figure 2: Breakdown by region and market type of Sandoz’ sales in the third Commenting on Rixathon, Novartis’ chief executive officer Joe quarter of 2017 (Source –Novartis) Jimenez said the group had not expected moves by physicians in manufacturing ahead by 9% on aconstant-currency basis to US$292 Germany to switchentire patientpopulations across to the biosimilar. million. This came despite adecline in the US, “primarily due to “We are also getting quite positive feedback on Erelzi,” he stated. competitive pressures on Glatopa 20mgfromongoingmarket conversion Sandoz chief Richard Francis said the Rixathon launch had been to the 40mg version of the reference medicine”, Teva’s Copaxone, “very well accepted”, with entire accounts adopting the biosimilar that was compensated in part by continued growth from Zarxio across all indications. “We have had significant account wins in the (filgrastim-sndz) two years after its US market entry. UK for Erelzi,” he added. “We have currently about 2,600 patients Sandoz’ total US turnover tumbled by 13% to US$798 million queued up to actually get the drug.” in the three-month period, “driven by increased pricing pressure from In Septemberthisyear,Sandoz had itsRixathon dossier accepted competitioninretailgenericsand continued customer consolidation”. for review by the US Food and DrugAdministration(FDA) as arival Having identified “several negative-margin, limited growth to Rituxan (Generics bulletin,15September 2017, page 12). products that are no longer viable duetodouble-digit priceerosion in At around the sametime (Generics bulletin,22September 2017, the US generics market,” Sandoz has decided to move production at its page 13), Sandoz presenteddataatacongressofthe European Academy US facility in Broomfield, Colorado,toasite in Wilson, North Carolina. of Dermatology and Venereology (EADV) fromits 51-week ‘Adaccess’ But, as Figure 2shows, the firm’s other operating regions were adalimumab trial in 465 patients with moderate-to-severe chronic able to make up for the US pressures, as Sandoz’ reported 3% sales plaque psoriasis. The firm had its application for its GP2017 alternative rise to US$2.58 billionequated to 1%constant-currency growth. Volume to AbbVie’s Humira accepted for filing by the European Medicines growth of eight percentage points was largely wiped out by seven Agency (EMA) in May this year, at around the same time as Sandoz points of price erosion across the world. submitted its GP1111 infliximab to the EMA (see Figure 1). Constant-currency sales in Europe climbed by 8% to US$1.23 AUSfiling for adalimumab remains “on track” for submission billion, “driven by continuing stronggrowthinItaly, Russia,Switzerland by the end ofthis year,while Sandoz has justre-submitted its Zioxtenzo and Turkey”.Asimilar risetookSandoz’ sales in theAsia, Africaand pegfilgrastimcandidate to the EMA following its withdrawal at the start Australasia regiontoUS$354 million, whilea14% constant-currency of this year (see page 19). Asimilar US re-filing to addressconcerns rise to US$199 million in Canada and Latin America included Latin voiced by the FDA is scheduled for early 2019 after the company Americanturnoverupby12% to US$110million. increased the sample size of apharmacokinetic (PK) bridging study. On aglobalbasis, Retail Generics turnover was stableatUS$2.2 Thestrong start made by both Rixathon and Erelzi supported billion despite a13% decline in the US. Anti-Infectives sales up by double-digit European growth during the third quarter of this year by 3% to US$359 million comprised sales of finished products under Sandoz’ Biopharmaceuticals business segment, which recorded global the Sandoz name that rose by 7% to US$221 million, outweighing sales frombiosimilars, Glatopa (glatiramer acetate) 20mgand contract a3%drop to US$137 million in turnover from antibiotics supplied to third parties. Francis attributed a3.4 percentage- point improvement to 43.8% in Sandoz’ gross margin to acombination of focusing onthe most profitable geographic markets whilst rolling out higher-margin products such as biosimilars. “We havegrown our branded generics business more substantially than in the past,” he commented. Even with sales and marketing expenses higher by atenth to US$438 million, Sandoz was able to increase its operating profit by 10% to US$390 million, thereby raising the division’s operating margin by one percentage point to 15.1%. G Figure 1: Progress to date on Sandoz’ disclosed biosimilars pipeline as of 24 October 2017 (Source –Novartis) n [email protected]

4 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.2-15.indd 4 01/11/2017 17:31 COMPANY NEWS

MANUFACTURING BUSINESS STRATEGY Akorn Grand Avenue Concordia carries on facility receives 483s with debt restructure

korn’sGrand Avenue manufacturing facilityinDecatur,Illinois, oncordia International has filed for debt restructuring under the Ahas again fallen afoul of US Food and Drug Administration (FDA) CCanada Business Corporations Act (CBCA), as part of ongoing quality standards, with an inspection resulting in the agency issuing efforts to “protect our business, preserve our cash, and give us extra the US ophthalmics and injectablesspecialist with three ‘Form 483’ time to negotiate with lenders”. observations of current good manufacturing practice (cGMP) violations. The action was triggered by Concordia days before opting to use At the end of last year, Akorn announced that the facility had been a30-day ‘grace period’ to defer payment of approximatelyUS$26 cleared following an FDA re-inspection, after the agency previously million of interest on the firm’s US$735million unsecured notes. “The issued the firm with multiple Form 483 observations, including afailure deferral of the interest paymentdoes not resultinan‘event ofdefault’ to record or justify deviations from production and process-control untilthe expiry of the 30-daygrace period,”the firm saidatthe time. procedures (Generics bulletin,6January 2017, page 4). Concordia said it had chosen to initiate the debt restructuringto Other observations includedflaws in documenting batch-control “support its proposed recapitalisation transaction”, under which the and test results, and issues withbothclindamycin vials andephedrine firm is aiming to reduce its debts by more than US$2 billion, while ampoules (Generics bulletin,28October 2016, page 5). “significantly reducing” the company’s annual interest costs and Butfollowing an inspection at the end of April this year –around positioningthe business for “longer-term growth”. the time Fresenius Kabi announced aUS$4.75 billion deal to acquire Underlining that the CBCA was “not abankruptcy or insolvency Akorn (Generics bulletin,28April 2017,page 1) –deficiencieswere statute”, Concordia said its management team would “continue to lead again identified by theagency, including repeat observations. day-to-day operationsand operateits business as usual, while meeting As well as the use of inappropriate equipment for manufacturing, its commitment to employees, suppliers and customers”. processing, packing or holding of drug products, as well as cleaning, Earlier this year, Concordiaunveiled aseven-pillar growth strategy these deficiencies included, again, afailure to maintain written and named ‘Deliver’, as part of afive-yearplan to restore the company control procedures pertaining to quality. to growth (Generics bulletin,15September 2017, page 3). G Noting that he had observed “particles coming off the conveyor belt” that staged previously washed vials, an FDA inspector said the problem was not corrected, even after being brought to the attention of the vice-president of domestic sterile productsquality assurance. THIRD-QUARTER RESULTS Meanwhile, procedures designedtoprevent microbiological contaminationofdrug products“purporting to be sterile” did not include Abbott’s EPD sales increase “adequate validation of the sterilisation process”. bbott Pharmaceuticalsenjoyeddouble-digit growthfor the firm’s “Specifically, the firmhas failed to completeorinvalidated33% [of] AEstablished Pharmaceuticals Division (EPD) branded generics media fills attempted in [a] filling room since it has been converted operation, which includesthe US firm’sCFR andVeropharm businesses to an aseptic filling area,” commented the FDA inspector. in Latin America and Russiarespectively,inthe third quarter of this year. Fresenius Kabi is aiming to completeits acquisition of Akorn by The firm’s EPD saw sales increase by 15.7%, or 14.3% on a the end of this year (Generics bulletin,11August 2017, page 7). G ‘comparable operational’organicbasis,toUS$1.17billion, following a18.5% rise as reported to US$885 million in turnover from Key Emerging Markets, “led by strong growth across several countries, including double-digit growth in Brazil, Russia, India and China”. MANUFACTURING Sales in ‘other’ markets that rose by 7.6% as reported, or 4.0% on a comparable operational basis, added the remaining US$286 million. Cambrex expands its Iowa site “As expected, sales in India were positivelyimpactedbypurchasing ambrex has added“large-scalemanufacturing capacity” at its US patterns following the implementation of anew goods and services Cproduction facility in Charles City, Iowa, after completing an tax(GST)systemthat lowered second-quarter sales in thatcountry,” expansion. Located on a45-acresite, the facilitymanufactures awide commentedAbbott (Generics bulletin,28July 2017, page 2). “Total range of active pharmaceutical ingredients (APIs) and pharmaceutical EPD, Key EmergingMarkets and India salesgrowth increased double intermediates, including highly-potent molecules and controlled substances. digits with and without this impact.” The investment included installing 1,000- and 4,000-gallon glass- “It took awhile for analysts and investors to appreciate the lined reactors and ancillary equipment at the 700 sq mmulti-purpose uniqueness of our [EPD] strategy,” commented chairman and chief manufacturing facility, which opened in 2016. The bulk-drugsproducer executive officer Miles White. “And Ithink it sort of called out that noted that these reactors brought the current goodmanufacturing there is asegment of pharma that’s not commodity generic…that’s practice (cGMP) volume in the facility to 23,000 gallons, with total higher margin, highergrowth et cetera, in pretty key markets around capacity at the Charles City site “now approximately 107,000 gallons”. the world.Right now [EPD’s]our fastest growingbusiness, other than “This additional capacity enables us to take on new customer neuromodulation.” projects,” stated chief operating officer ShawnCavanagh,“as well as Abbott’sgroup sales jumped by 28.8% to US$6.83billion, following offering the flexibility for projects to be transferred in from other the firm’s acquisition of medical devices firm St. Jude Medical in early Cambrex sites as needed.” January. Meanwhile,the firm reported aUS$626 million group pre-tax Cambrex recently unveiled plans to invest US$24 million in a profit, representing an US$805 million swing from last year when highly-potent API manufacturing facility at the Charles City site, due Abbott was forced to make asignificant write-down in the value of to open in 2019 (Generics bulletin,1September 2017, page 10). G itsholding in Mylan (Generics bulletin,28October 2016, page 5). G

3November 2017 GENERICS bulletin 5

Gen 3-11-17 Pgs.2-15.indd 5 01/11/2017 17:31 COMPANY NEWS

BUSINESS STRATEGY/ANNUAL RESULTS IN BRIEF ENDO has divested privately-owned Mexican generics player Grupo WBA is set to shut Farmacéutico Somar to Advent Internationalfor apurchaseprice of around US$124 million,“after giving effect to estimated cash, debt and net working capital purchase price adjustments”. Endoacquired 600 stores in the US Somar in July 2014 (Generics bulletin,8August 2014, page 13). VITAL LABORATORIES has received a warning letter from the algreens Boots Alliance(WBA)isset to launchaUS$450 million US Food and Drug Administration (FDA) regarding active Wstore-optimisationprogramme in the US once its completesits pharmaceutical ingredients (APIs) at its Indian manufacturing facility purchase of 1,932 Rite Aid drugstores in the US. This will include in Vapi, Gujarat, following an inspectioninApril. Batch production closing around 600 stores. records “omitted signature fields to document whoperformed, directly Having secured antitrust clearance in Septembertostart acquiring supervised, and checked each critical step” in the manufacturing Rite Aid stores in aphased process running until spring next year process,while supervisors signed in place of operators because their (Generics bulletin,29September 2017,page 5), WBA has carried out “hands were dirty”, according to the letter. Aberrant analytical test a“complete review”ofits pro forma combined US store portfolio of results were ignored,whiledeficiencies werefoundinproductreviews. over 10,000 outlets to “determine the scope of aprogramme to optimise locations”. “This has resulted in our decision to close approximately TRACELINK saysmore than 100 contract manufacturingorganisations 600 stores and related assets over an 18-month period, beginning in (CMOs) are “fully configured” on the ‘TraceLink Life Sciences spring 2018,” explained chief financial officer George Fairweather. Cloud’ and are “ready to exchange serialisation data”. This includes While the store closures would incur cash costs of around US$450 Alpex, Central Pharma, Liconsa, Patheon and Recipharm. “An million, Fairweather noted, they would generate annual cost savings of additional 323 CMOs are currently in active testing on the TraceLink approximately US$300 million by the end of the group’s financial network and projectedtobeserialisation-ready in amatterofmonths,” year running until August 2020. the US-based group noted. Co-chief operating officer Alex Gourlaysaid “the vast majority” of closures would be of Rite Aid outlets that were located within amile BASF hasclosedits deal to sell its electrolytes manufacturing site of one of the group’s existing stores. The remaining 1,300orsoRite in Suzhou, China, to Shenzhen Capchem Technology. The divestiture Aid stores would, he pointed out, strengthen WBA’s retail footprint included aproduction site and the transfer of 69 employees to in the north-east and south of the US. Capchem. Separately,the German chemical producer has opened a production plant for biocatalyzed acrylamide at its site in Nanjing, Three years for integration China. Pointing out that the plant had acapacity of more than 50,000 Integratingand rebranding the acquired retail network is anticipated tons per year, BASF said the investment strengthened its ability to to span three years, resulting in acquisition-related costs of US$750 supply customers in Asia Pacific,especiallyinChina.“The construction million. WBA also plans to invest around US$500 million on “store of anew polyacrylamide production line is currently underway,and is conversions and related activities”, but expects to realise annual expected to go on stream in 2018,” BASF noted. synergies of over US$300 million within the next four years. As part of the deal, the remaining Rite Aid retail chain has an MCKESSON increased its turnover by 4% to US$52.1 billion in its option, exercisable until the end of May 2019, to become amember financial second quarter ended 30 September 2017. The company of WBA’sgroup purchasing organisation, WalgreensBoots Alliance highlighted its “organic growth across multiple business units, Development (WBAD), that is alsoset to tie up with ExpressScripts’ including the company’s strategic sourcing benefits through Econdisc sourcing unit. ClarusOne,alowersharecount and incremental profit contribution In its financialyear ended 31 August 2017, turnover by WBA’s from acquisitions”. North American distribution sales roseby5%– Retail Pharmacy USA division grew by 4.2% to US$87.3 billion. That both as reported and in constant currencies –toUS$43.5 billion. increase was responsible for areported 0.7% rise in group sales to US$118 billion (see Figure1). On aconstant-currency basis, the group’s CATALENT hascompleted its acquisition of Cook Pharmica for growth was 3.3%. WBA suffered a7.4%drop in group operating an undisclosed sum. The US-based firm said the purchase would profit to US$5.56 billion. strengthen its position as “a leader in biologics development and Negative exchange-rate shifts were responsible in part for a10.9% analytical services, manufacturing, and finished product supply”. turnover fall by WBA’s RetailPharmacy International division, which Catalent said it would create two drug-delivery units, one focusing operatesaround 4,700 storesacross eightcountries outside of the US. on biologics and specialty drugs, and one on oral formulations. Currency fluctuations also hit WBA’s global Pharmaceutical Wholesale business, which reported sales down by 6.1% to US$21.2 billion. G ASYMCHEM LABORATORIES’ active pharmaceutical ingredient n [email protected] (API) facility in Dunhua, China, has passed an inspection by Australia’s Therapeutic Goods Administration (TGA). Division Annual sales Change Operating (US$ millions) (%) margin (%) DSP –DSM Sinochem Pharmaceuticals –isaiming to reduce prescription drug counterfeiting through serialisation services, Retail USA 87,302 +4.2 4.8 including atrack and trace system. Acknowledgingupcoming global Retail International 11,813 -10.9 6.3 legislation on serialisation, the firm pointed out that regulations would Pharma Wholesale 21,188 -6.1 2.3 be effective in Europe from February 2019, preceded by Russia and the US. DSP –ajoint venture betweenDutchgroup DSM and Walgreens Boots 118,214* +0.7 4.6 China’sSinochem group–saiditwould offer an “on-boarding plan *includes US$2.09 billion of eliminated inter-divisional sales for its customers and supply-chain partners”. DSP aims to have its Figure 1: Breakdown by division of Walgreens Boots Alliance’s sales and operating full supply chain ready before the end of 2018. G margin in its financial year ended 31 August 2017 (Source –Walgreens Boots)

6 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.2-15.indd 6 01/11/2017 17:31 COMPANY NEWS

STRATEGIC ALLIANCES SECOND-QUARTER RESULTS CVS and Anthem ally Lupin’s US sales fall for aPBM deal in US again as others grow

major new player is set to enter the US pharmacy benefit manager ricing pressure in the US market continuedtodrag down Lupin’s A(PBM) market. Health insurer Anthem has teamed up with retailer PFormulations salesinNorth America in theIndian firm’s financial and PBM provider CVS Health to launch IngenioRx. The newly- second quarter ended 30 September 2017, with turnover down by created entity will start offering formulary and other services in 2020, almost athird to Rs13.6 billion (US$210 million) year-on-year. when Anthem’s contract with its current PBM, Express Scripts, expires. Describing the pricing pressure as “expected” the Indian firm Beginning on 1January 2020,afive-year agreement that Anthem nevertheless insisted that it had recorded “strong growth in all our has signed with CVS will see the latter provide prescription-fulfilment marketsbut for the US generic business”,astotal Formulations sales and claims-processing services to the new PBM. “IngenioRx will slid by 7.9% to Rs36.1 billion. Including active pharmaceutical combine itsmember and provider-engagementinitiatives and market- ingredients (APIs) sales that declined by 9.2% to Rs2.65billion,Lupin’s leading pricing with CVS’ expertise in point-of-sale engagement,” group turnover fell by 8.0% to Rs38.7 billion. the health insurance company commented. As Figure 1shows, Lupin enjoyed mid-teen level growth in its CVS maintained that assets such as itsextensive pharmacy chain key domestic and Asia-Pacific Formulations markets, while in its and its MinuteClinic walk-in centres would “allow the company to Europe, the Middle Eastand Africa (EMEA) operation, sales roseby applyits expertiseinpatientmessaging and engagement at the point- asimilar amount–17.1% –toRs2.76billion. Together these markets of-sale to support IngenioRx, broadening the scopeofclinical services accounted for more than half, or 53%, of Lupin’s group turnover. offered at the pharmacy counter to drive better outcomes”. As part of efforts to mitigate its sales decline in the US, Lupin Larry Merlo, president and chief executive officer of CVS, said recently completedaUS$150 milliondealfor gynaecology specialist the agreement“further validates the important role that CVS Health’s SymbiomixTherapeutics, bolstering its specialty offerings in the market integrated and innovative pharmacy care model plays in today’s health (Generics bulletin,20October 2017, page 3). This strategy was one system”, withnearly five million Americans visiting aCVS pharmacy component of agrowth plan laid out by the firm earlier this year, every day. Pointing out it expected to incur implementationcosts related includingfocusing on regulatory compliance andbuilding acomplex to the transition of members, “as is typical of any large, multi-year generics pipeline (Generics bulletin,11August 2017, page 7). contract”, CVSinsisted these costs were “expected to be immaterial”. Notingthat “we areontrack with our complex generic pipeline”, IngenioRx would “lower total healthcare costs”, Anthem asserted. Lupin also recently welcomed positive news concerning regulatory The new PBM was “expected to achieve greater than US$4 billion in compliance after receiving an establishment inspection report (EIR) gross savings annually” and would position Anthem to “take advantage closing out all outstanding inspections by the US Food and Drug of aunique opportunity to grow and diversify ourbusiness within our Administration (FDA) of the company’s formulations facility in existing footprint as well as nationally”. Aurangabad, India (Generics bulletin,1September 2017, page 11). However,the move has beenmet withresistance.The US Senior The Indian firm strengthened its US pipeline during the quarter Care Pharmacy Coalition (SCPC) argued that the alliance between by filing 10 abbreviated new drug applications (ANDAs), receiving Anthemand CVS “represents aperpetuation of the oligopolistic, anti- in turnnine approvals, including for generic Lidex (fluocinonide) and consumer shell game”. “By their very own design and intent, these Clobex (clobetasol). Lupin alsolaunched several generics, including relationships are ashell game premised upon keeping consumer, moxifloxacin and olmesartan medoxomil. lawmaker and regulator alike in the dark about virtuallyevery aspect Also during the quarter, Lupin brought in Alexion Pharmaceuticals of the mysterious ‘negotiations’ and ‘rebates’ we hear about, but never executive Jim Loerop as the firm’s chief corporate development officer, see,” insisted Alan Rosenbloom, president of SCPC. to drive the company’s global mergersand acquisitions and business Moreover, the SCPC pointed out that US Senate Committee on development functions(Generics bulletin,22September 2017, page 16). Health, Education, Labor and Pensions (HELP) chairman Lamar Including an additional Rs778 million of ‘other operating income’, Alexander and SenatorLisaMurkowski had “expressed frustration with Lupin’s operating profit fell by 17.2% to Rs8.53 billion, following the overly complex drug pricing system”. This included “bewilderment higher material and employeecosts. G about pricing determinations, systemic complexity and the ongoing n [email protected] mystery surrounding rebates”. Separately, CVS Health has introduced aPBM performance- Second-quarter sales Change Proportion based pharmacy network, anchored by CVS Pharmacyand Walgreens. (Rs millions) (%) of total (%) With 30,000 stores, the network also has up to 10,000 community- based independently-owned pharmaciesacrossthe US. “The network North America 13,611 -31.9 35 is designed not only to deliver unit cost savings, but also to improve India 11,593 +16.4 30 clinical outcomes that will lead to lower overall healthcare costs for Asia-Pacific 6,357 +15.2 16 CVS CaremarkPBM clients and their members,” CVSHealth stated. EMEA 2,758 +17.1 7 “Performance measures for participatingpharmacies will include Latin America 1,395 +41.5 4 demonstrated medication adherence for chronic conditions that are Rest of World 378 -4.5 1 impactful to client costs,” CVS Health noted, citing as examples Formulations 36,092 -7.9 93 hypertension, diabetes, respiratory conditions and behavioural health. APIs 2,650 -9.2 7 “Participating pharmacies are encouraged to implement their own Lupin 38,742 -8.0 100 proprietary programmes and workflow processes to enable them to deliver results related to the measures being tracked.” G Figure 1: Breakdown by region of Lupin’s sales in its financial second quarter n [email protected] ended 30 September 2017 (Source –Lupin)

3November 2017 GENERICS bulletin 7

Gen 3-11-17 Pgs.2-15.indd 7 01/11/2017 17:31 COMPANY NEWS

EVENTS – November 2017 –March 2018 RESULTS FORECAST/NINE-MONTH RESULTS 22 November Finnish price reform n 1st Value Added Medicines Conference Brussels, Belgium This event organised by Medicines for Europe will focus on exacts toll on Orion opportunities presented by medicines that are repositioned, reformulated or combined. rion expects that pricing reforms introduced at the start of this year Contact:Lucia Romagnoli. Tel: +44 7562 876 873. Oin the Finnish group’s domestic marketwill wipe around C15 million E-mail: [email protected]. Register online at (US$17 million) off its full-year turnover in 2017.“The effect is greater www.medicinesforeurope.com/events. than anticipated at the beginning of the year,” Orion admitted. 27-28November From the start of this year, Finland narrowed aprice difference ‘corridor’ within the country’s reference-price system. Whereas to n euroPLX 65 qualify for reimbursement drugs previously had to be priced within London, UK C1.50 of the cheapest productavailable for medicines costing less than This meeting provides an opportunity to discuss and negotiate C40.00 –and within C2.00 for more expensive drugs –the permitted agreements, development, in-licensing and marketing, promotion difference to the cheapest drug was narrowed to C0.50 (Generics and distribution. bulletin,24February 2017, page 10). Contact:RauCon. Tel: +49 6221 426296 0. The pricing pressure combined with supplyproblems through the E-mail: [email protected]. Website: www.europlx.com. groups local distributor, Oriola, to cause theFinnishgroup’sdomestic saleswithinits Specialty Products off-patent business segment to stall 24 January at C217 million in the first nine months of this year. n 11th Pharmacovigilance Conference But Specialty Products growth of almostafifth to C72 million in London, UK Scandinavia was aided by supplyingthe biosimilar Remsima (infliximab) This one-day Medicines for Europe conference will look at through anational tender in Norway (Generics bulletin,28July 2017, implementating pharmacovigilance legislation and current page 4). Orion –which has rightstoRemsimainNordiccountries and developments within the industry. Estonia under the terms of adeal with South Korea’s Celltrion–reported Contact:Lucia Romagnoli. Tel: +44 7562 876 873. total Remsima sales that increased by 44% to C44.6 million. E-mail: [email protected]. Register online at In Eastern Europe and Russia, Specialty Products turnover climbed www.medicinesforeurope.com/events. by 13% to C47 million, helping to push upthe segment’s total sales by 4% to C387 million. Specialty Products accounted for 48% of group 25-26January turnover that edged up by just over 1% to C804 million. n 17th Regulatory and Scientific Another5%came from third-party sales by the group’s Fermion Affairs Conference bulk-drugs unit thatrose by 23% to C40.5 million. That growthhelped to compensate for a3%slip to C261 million in turnoverfrom the group’s London, UK Proprietary Products unit that is continuing to rollout its budesonide/ This conference will follow the Pharmacovigilance event at the formoterol Easyhaler device in Europe. G same venue. There will be updates on regulatory developments and representatives from competent authorities in attendance. Contact:Lucia Romagnoli. Tel: +44 7562 876 873. E-mail: [email protected]. Register online at NINE-MONTH RESULTS www.medicinesforeurope.com/events.

Russia swells Podravka’s sales 12-14February xpanding its Russian productrangewith additions such as Vivaira n Access! 2018 –AAM Annual Meeting E(sildenafil) chewable tablets helped Podravka to increase its Florida, USA Prescription drugs turnover by 8.4% to CrK436 million (US$67.4 This Association for Accessible Medicines event will look at million) in the first nine months of this year. regulatory topics and the challenges facing the US generics industry. Including Non-Prescription sales that advanced by just over atenth Contact:Association for Accessible Medicines. Tel: +1 202 249 7100. to CRK72.3 million following OTC additions such as Naxil E-mail: [email protected]. Register online at (acetylcysteine) effervescent tablets, the Croatiangroup’s total www.accessiblemeds.org/events. Pharmaceuticalsturnoverincreased by 8.0% to CrK611 million. That equated to a5.9% rise at constant exchange rates. 1-2 March Russian growth lay behind a29.8% Pharmaceuticals rise to n 2nd OTC Innovation &Business CrK108million in Podravka’s EasternEuroperegion. Sales increased Development Conference by 3.1% to CrK452 million in the Croatian firm’sAdria region, which includes its domestic market, where the firm’s Belupo pharma unit in London, UK mid-Mayopened two plants for solid-dose and semi-solid drugs Organised jointly by the Pharmaceutical Licensing Group and following aCrK530 million investment. Pharmaceuticalssales in Central OTCToolbox, this event will focus exclusively on business Europeclimbed by 9.1%toCrK39.5million on turnovergrowth in development and innovation in the consumer healthcare/OTC Poland and the Czech Republic. market. The theme for this event is capitalising on change. Higher fixed costs associated with new facilities contributed to Contact:OTCToolbox. Tel: +44 121 314 8757. the Pharmaceuticals unit’soperating marginfalling by 3.8 percentage E-mail: [email protected]. points to 8.3%. Pharmaceuticals accounted for barely afifth of the Website: plg-group.com/events/3rd-otc-event. food and drinks group’ssales, butnearly half of its operating profit. G

8 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.2-15.indd 8 01/11/2017 17:31 Advertorial Feature

ANDA Arbitrage &the NewANDA Holder Program Fee Under GDUFA II By Kurt R. Karst –

The second iteration of the Generic Drug User Fee Amendments (A) IN GENERAL. –Aperson who fails to pay afee as required (“GDUFAII),whichiscontained in Title IIIofthe FDA Reauthorization under subsection (a)(5) by the date that is 20 calendar days after Act of 2017 (“FDARA”) (S. 934 and H.R. 2430) currently pending the due date, as specified in subparagraph (D) of such subsection, in Congress, will, if enacted, significantly change the current user shall be subject to the following: fee system and structure that have been in place the past five fiscal (i) The Secretary shall place the person on apublicly available arrears list. years under GDUFAI.Not only will FDA collect agreater amount of user fee funding each year ($493.6 million annually adjusted (ii) Any abbreviatednew drug application submittedbythe generic drugapplicantoranaffiliate of suchapplicant shall not be received, for inflation), but one fee type will be eliminated (i.e. the Prior within the meaning of section 505(j)(5)(A). Approval Supplement fee), while others fees would be modified (iii) All drugs marketed pursuant to any abbreviated new drug (e.g.anew Finished Dosage Form (“FDF”) facility fee for Contract application held by such applicant or an affiliate of such applicant Manufacturing Organizations (“CMO”)). GDUFA II will also shall be deemed misbranded under section 502(aa). introduce anew fee type –the ANDA Holder Program Fee –that will account for 35% of annual fee funding. The annual ANDA (B) APPLICATION OF PENALTIES. –The penalties under Holder Program Fee, along with the annual CMO FDF facility fee, subparagraph (A) shallapplyuntil thefee requiredunder subsection are proposedas“small businessconsiderations,” according to FDA. (a)(5) is paid. Under the GDUFA II fee structure, the ANDA Holder Program The ANDA fee schedule for Fiscal Year 2018 was just Fee is set up as follows: afirm and its affiliates will pay one program published by FDA on August 28th. For asmall or medium fee each fiscal year commensurate with the number of approved sized firm,the annual ANDA Holder ProgramFee is adecent ANDAs (both active and discontinued ANDAs) that the firm and amountofcash for some companies to lay out. And for those its affiliates collectively own. The program fee to be paid each year companies with amodest number of ANDAs,they’ll be laying depends on the number of ANDAs owned. Firms will not pay a out cash for drug products that they don’t currently market, per-ANDA fee. Instead, the program fee will be split into three because their ANDAs are in stasis, as identified in the tiers that represent different positions held by the firms and their Discontinued Drug ProductListsectionofthe Orange Book. affiliates within the market. Specifically, FDARA would amend the FDA will collect under the ANDA Holder Program Fee FDC Act to add Section §744B(b)(2)(E) to state: initiative as follows -companies in the small tier (1-5 ANDAs) (i) Thirty-five percent shall be derived from fees under subsection will pay $159,079; companies in the medium tier (6-19 (a)(5) (relating to generic drug applicant program fees). For purposes ANDAs) willpay $636,317;and companiesinthe large tier of this subparagraph, if aperson has affiliates, asingle program fee (> 20 ANDAs) will pay $1,590,792. For asmall tier company shall be assessedwith respect to that person, including its affiliates, this can be adramaticimpactintheirability to even retain and may be paid by that person or any one of its affiliates. The the assets they worked so hard to obtain! Secretary shall determine the fees as follows: Anew venture might offer some user fee relief and asolution to (I) If aperson (including its affiliates) owns at least one but not companies that have discontinued ANDAs for drug products not more than 5approved [ANDAs]onthe duedate for the fee under currently marketed. Acompany called ANDA Repository, LLC. thissubsection,the person(including its affiliates) shall be assessed ([email protected]) is offering what we can only characterize asmall business generic drug applicant program fee equal to one- as “ANDAarbitrage.” Imagine, if you will, aparkinglot. The owner of tenth of the large size operation genericdrugapplicant programfee. acar that is not being used on adaily basis needs aparking space for that car.Inexchange forthat parking space (and an annual fee)the (II)Ifaperson (including its affiliates) owns at least 6but not more car’s owner transfers title of the automobile to the parkinglot owner. than 19 approved [ANDAs]onthe due date for thefee underthis The old owner of the car can, with appropriate notice, take back subsection, the person (including its affiliates) shall be assessed amedium ownership when he decides that he wants to use the automobile size operation generic drug applicantprogram fee equal to two-fifths again. Provided the parkinglot owner has enough cars, this can be of the large size operation generic drug applicant program fee. abeneficial venture for all of the parties involved. (III) If aperson (including its affiliates) owns 20 or more approved In the imagery above, the automobileownerisanANDA sponsor, [ANDAs] on the due date for the fee under this subsection, the and the parking lot owner is ANDA Repository, LLC. When ANDA person (including its affiliates) shall be assessed alargesize operation Repository,LLC.obtainstitle to 20 or more ANDAs, then generic drug applicant program fee. thecompanywill be identified as a“large sizeoperation” and (ii) For purposes of this subparagraph,an[ANDA] shall bedeemed will pay afull generic drug applicant program fee regardless nottobeapproved if the applicanthas submittedawrittenrequest of how many additional ANDAs are owned.Inexchange for for withdrawal of approval of such [ANDA] by April 1ofthe itsservices, ANDA Repository,LLC. will charge an ANDA sponsor previous fiscal year. an annual fee, which would be significantly less than the ANDA HolderProgram Fee such ANDA sponsor would otherwise pay The statute (FDC Act 744B(g)(5)) would also be amended to as asmall or medium size operation. Not abad idea! Fees are include certain penalties for failure to pay the new ANDA Holder due by October 1st so please contact us at the email or phone Program Fee: below for more information.

For further information, contact ANDA Repository, LLC. Tel: +1 570 261 1901 Email: [email protected] Website: www.andarepository.com

3November 2017 GENERICS bulletin 9

Gen 3-11-17 Pgs.2-15.indd 9 01/11/2017 17:31 MARKET NEWS

INTELLECTUAL PROPERTY PRICING &REIMBURSEMENT Industry urges action APMGR attacks over on SPC waiver in EU clawback in Romania

egislative action must be taken by the European Commission to omania’s Prime Minister, Mihai Tudose, should dismiss the Lintroduce awaiver for generic manufacturing during the term of Rcountry’s health minister, Florian Bodog, local generics industry asupplementary protection certificate (SPC), off-patent association association APMGR hasurged, followingcontroversy over the country’s Medicines for Europe has urged in the wake of aconsultation on SPCs mandatory pharmaceutical clawback. launched by the Commission that is running until 4January 2018 In response to interview comments made by Bodog that the (Generics bulletin,20October2017, page 1). clawback had “not increased and has been kept to areasonable value”, “Medicines for Europe calls for aswift introduction of the SPC APMGR said the statement was “completelyfalse”. The clawback rate manufacturing waiver in European Union (EU) legislationand for a of 19.86% in the first quarter of 2017 had been more than four wide definition of Bolar,” the association stated, referring to the percentage points higher than the 15.62% rate in the first quarter of early-working exemption that already exists for research purposes. 2016, the association pointed out, whilethe 18.59% rateinthe second Citing areportpublished by the European Commission and compiled quarter of 2017 was almost three points higher than the 15.64% rate by Charles River Associates (CRA) on ‘Assessing the economicimpacts seen in the prior-year period. of changing exemption provisions during patent and SPC protection “To say that a20% turnover tax is reasonable shows contempt in Europe’(Generics bulletin,20October 2017, page 29), Medicines for the entire Romanian drug industry,” insisted APMGR executive for Europe director general Adrian van den Hoven said “the CRA study director Laurentiu Mihai. “Unfortunately, the authorities have not showsthe huge benefits that the SPC manufacturing waiver and Bolar even taken asingle measure to protect generic medicines,” he harmonisation offer Europe in terms of jobs, manufacturing and a complained, despite such drugs being used by poor and elderly patients, lower overall medicines bill”. “The Commissionmust now legislate often with chronic conditions. to make this areality,” he insisted. APMGR recently complained that prices being kept “artificially “The European Commission’s public consultation on the SPC low” in Romania could lead hundreds of generics to disappear from manufacturing waiver is essential for pharmaceutical manufacturing the market in the next year (Generics bulletin,20October 2017, in Europe,” Medicines for Europe emphasised. “The SPCmanufacturing page8). Morethan2,000generics have alreadydisappeared from the waiver will create thousands of high-skill jobsand open new opportunities market in recent years, the association claims. G for small- to medium-sized enterprises (SMEs) in Europe.” Moreover, “the waiver will ensure that Europe maintains its technological leadershipand capacity in the manufacturing and supply PRICE WATCH ...... UK of essential medicines and contribute to more competitiononmedicine costs”, the association underlined. Accordingtothe CRAreport, Medicinesfor Europe pointed out, Perindopril has concessions the SPC manufacturingwaiver would create between20,000 and 25,000 verage UK prices of perindopril tablets saw triple-digit rises additionalmanufacturing jobs in Europe by 2025. It would also increase Ain October,according to the latestfigures provided by WaveData. the net sales for the EU-based pharmaceutical industry by between Three strengths of the long-actingACE inhibitor –2mg, 4mg and C7.3 billion(US$8.5 billion) and C9.3 billion within the same period. 8mg –were among the top five biggestrises recorded by WaveData, An SPC manufacturingwaiver would also “ensure faster entry of based on averagescalculated on the basis of at least56data points. generic and biosimilar competition in the EU after SPC expiry, thus Comparing UK trade prices between the periods 1-30 September improving access for patients”, Medicines for Europe maintained, as 2017 and 1-31 October 2017, WaveData reported that 2mg well as enabling savings in pharmaceutical expenditure of between perindopril tablets in 30-count packs saw an average rise of 498% C1.6 billion and C3.1 billion “thanks to competition”. to £3.75 (US$4.95) as the cheapest availableofferalmostdoubled Furthermore, the association added, an SPC manufacturing waiver to £0.59. In response, the UK’s Department of Health (DoH) at together with abroader Bolar exemption would generate additional EU the end of October granted aconcession price for the2mg strength active pharmaceutical ingredient (API) salesofbetween C212million double the average price at £7.50. and C254 million by 2030, “creating an additional 2,000 jobs in that sector”. Perindopril 4mg tablets in the same pack size saw an average “The SPC compensates originator drugmanufacturers for regulatory price rise of 320% to £4.55 and received aconcession price from approvaldelays by extending their monopoly for up to five years after the DoH of £8.00, while the 8mg strength’s average rise of 227% patent expiry,” Medicines for Europe acknowledged. “Whilst our to £5.46 was met with aconcession of £8.50. industry does not challenge the principle of compensation for delays, Separately, amlodipine 5mg and 10mg tablets in 28-count the application of the SPC forces generic and biosimilar manufacturers packs saw average price rises of 238% to £2.08 and 161%to£1.78 to manufacture outside of Europe for export to countries without SPCs respectively. Concessions of £3.75 for the 5mg strengthand £3.99 or whose SPC expires earlier than in Europe.” “With the SPC for the 10mg strength weregranted. The DoH’s list of concessions manufacturing waiver, European medicine manufacturerswill be able included 40 molecules across more than 80 presentations. to re-invest in high-skill jobs in Europe,” the association noted. Meanwhile, aspirin 300mg tablets saw the steepestaverage “As proposed by the EuropeanCommission and confirmedin price decline of 57% to £0.86 for 32 tablets. G several studies,” Medicines for Europe concluded, “the SPC manufacturing waiver willnot affect originator drugmanufacturers as theywill continue Up to the minute live retail market pricing is available to benefit from the longest period of monopoly protection globally for the UK and Eire on Wavedata Live at wavedata.net. Alternatively, contact Charles Joynson at WaveData Limited, UK. for most drugs.” G Tel: +44 (0)1702 425125. E-mail: [email protected]. n [email protected]

10 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.2-15.indd 10 01/11/2017 17:31 MARKET NEWS

REGULATORY AFFAIRS LITIGATION WHO halts plans for US attorneys aiming abiological qualifier to widen suit’s scope

lans for aunique identifier code to be attached to biological US genericsantitrust lawsuit is set to expand to treble the number Pinternational non-proprietary names (INNs)have been put on hold Aof manufacturers cited to 18, raise the number of generic drugs by the World Health Organization (WHO), the global health bodyhas at issue from two to 15, and name as defendants two industry revealed in its latest publication of details of an expert consultation. executives –Mylan president Rajiv Malik and Emcure’s chiefexecutive In its report on the ‘expert consultation on improving access to officer and managing director, Satish Mehta. and use of similar biotherapeutic products’ –which took place on 2-3 May An initial complaintfiled in Connecticut that was recently transferred in Geneva, Switzerland –the WHO notes that “no consensus was to multi-district litigation in theEastern District of Pennsylvania cited reached on whether the WHO should continue with the biological six companies: Aurobindo, Citron, Heritage, Mayne, Mylanand Teva. qualifier (BQ)”. Therefore, “itshould be notedthat theWHO willnot In the case, attorneys-general alleged that the six firms entered into be proceeding with this at present”. illegal conspiracies to unreasonably restrain trade, artificially inflate Lastyear, the WHOunveiled its plansfor aBQcomprising four and manipulate prices and reduce prices in the US for two generics, random consonants and atwo-digit checksum (Generics bulletin,11 the delayed-release antibiotic doxycycline hyclate and the oral diabetes March 2016, page 6). However, the International Generics and Biosimilar treatment glyburide (Generics bulletin,6January 2017, page 1). Medicines Association (IGBA) warned that such amove would be The 46 attorneys-general are now seeking court permission to complicatedand confusing, while Europe’s Biosimilar Medicines Group expand the complaint to add another 12 companies as defendants:two (BMG) urged the WHO to implement amoratorium on the BQ scheme Actavis subsidiaries of Teva; Alkem’s Ascend; Apotex; Dr Reddy’s; (Generics bulletin,21October 2016, page 11). Glenmark; Lannett; Endo’s Par; Sandoz; Sun and Zydus Cadila, as Responding to the WHO’s decision to suspend plans for the well as Heritage’s Indian parent company, Emcure. initiative, the IGBA said it “welcomes the WHO decision to finally put Emcure’s Mehta and Mylan’s Malik are thefirst industry executives the BQ on hold”. The international generics and biosimilars association specifically named as defendants in the suit as having engaged in saidit“continues to promote worldwide the thoughtful and successful illegalconduct. “Considering the personalconduct of the individuals European Union (EU) system for track-and-trace,which ensures proper in furtheringthe price-fixingscheme, and the brazen and broad nature identificationthrough the product name –the trade name or the INN of the scheme, we believe suing individuals is justified and will send plus the manufacturer –and batch number”. apowerful message deterring this type of conduct,” remarked the During the consultation, the WHO noted, there had been attorneys-general, who noted that some states had policies not to sue “considerable discussion on the pros and cons of the BQ scheme”. individuals in antitrust cases, leaving them to be prosecuted by the Global brandindustry association theInternational Federation of US Department of Justice (DoJ) in criminal cases. Pharmaceutical Manufacturers and Associations (IFPMA) said it Mylan responded by insisting it had “deep faith in the integrity “strongly supports INN expert group recommendations on the use of a of its president, Rajiv Malik”. “We have been investigating these BQ for naming biological and biotechnological products”. Meanwhile, allegations thoroughly and have found no evidenceofprice-fixing on international biotech group the Biotechnology Innovation Organization the part of Mylan or its employees,” the company stated. (BIO) “commended theWHO on its BQ proposaland expressed their “The litigation thus far has centred on conspiracies in which support for development and implementationofnaming conventions Heritage Pharmaceuticals served as acentral player,” the attorneys- for biologics and biosimilars which allow traceability”. general commented. Two former Heritage executives, Jeffrey Glazer and Jason Malek, earlier this year pleaded guilty to criminal charges Patient body supportsBQ of conspiring to fixthe prices of generic doxycycline hyclate and TheInternational Alliance of Patients Organisations (IAPO)said glyburide in the US (Generics bulletin,20January 2017, page 16). it also “supports the currentBQproposal and suggested that BQ naming To those two drugs, the complaint adds 13 generics, including should apply to originators and biosimilars, which will allow tracing of doxycycline monohydrate and the glyburide/metformin combination. each product to its manufacturer”. Moreover, it claimed that the BQ Glipizide/metformin and fosinopril/hydrochlorthiazide are listed, as would “help patients worldwide enjoy the benefits of distinguishable are acetazolamide, leflunomide, meprobamate and nimodipine, plus naming, which will build patient and physician confidence”. nystatin,paromomycin,theophylline, verapamil and zoledronic acid. The WHO’s decision to not proceed with the BQ scheme came “Generic drug manufacturers argued publicly that significant despite “strong support for INN experts to promote BQ”, with claims price increases over the last several years were due to benign factors that “currently-available tools are not beingproperly used” to enable like industry consolidation,mandated plant closures or elimination traceability, thus indicating “a need to implement BQ”. of unprofitablegeneric product lines,” theattorneys-general observed. As well as announcing alack of consensus on the BQ scheme, Rather, they alleged, senior industry executives colluded both at the WHO said following the meeting that it would review and provide industry meetings andthrough e-mails,phone calls and textmessages clarification on 2009 guidelines on similar biotherapeutic products to inflate prices. “To avoid competing witheach other and avoid price “to reflect technological and analytical advances”. “It was suggested erosion,” they claimed, “the companies communicated with each other that the guidelines take intoaccountthe different needs for products, to determine and agree on how much market share and which customers such as product-specific guidelines for insulin,” the WHO noted. each companywas entitled to.” After the meeting, the WHO also noted that it would trial the Noting that the DoJ was in parallel conducting acriminal pre-qualification of two biosimilar molecules,rituximab and trastuzumab investigation,the attorneys-general said they would oppose movesby (Generics bulletin,12May 2017, page 13), in apilotprogramme that the DoJ that would delay discovery in the multi-district antitrust began in October (Generics bulletin,15September2017,page5). G litigation “for at least another six months”. G n [email protected] n [email protected]

3November 2017 GENERICS bulletin 11

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REGULATORY AFFAIRS REGULATORY AFFAIRS EMA continuity plan Originators lobby on not business as usual Ukrainian biosimilars

multi-phase business continuity plan (BCP) has been set out by six-point policy proposal aimed at improving the regulatory Athe European Medicines Agency (EMA) ahead of its relocation Aenvironment in Ukraine for biosimilarsaswell as original biological in the wake of the UK’s ‘Brexit’decision to leave the European Union drugs has been published by local brand industry body the Association (EU). However, implementing the BCPhad “consequences as regards of Pharmaceutical Research and Development (APRaD). “Fundamental to the current ‘business as usual’ operation of EMA”, the regulator warned. changes” to the Ukrainian regulatory system would “harmonise Endorsed by the management board at the EMA’sJunemeeting, Ukrainian legislation with the requirements of the European Union the BCP aims to “safeguard continuity of EMA’s operations to protect (EU)”, the APRaD said,providing “effective and optimal” treatment public health while the agency prepares for its relocation to anew host approaches for doctors and patients. city”. The agency saidthe plan was“an essentialtooltodeal with the Firstly, the proposals suggest that the local definitionofthe term uncertainty and workload implications”followingthe move, adding ‘biosimilar’ should be brought in line with EU legislation, “binding that it would be “continuously reviewed and adapted as necessary”. biosimilar registrability to the expirationdateofdata exclusivity” for “The first aim ofthe EMA Brexit preparednessBCP is to ensure the brand. Secondly, the APRaD proposes, automatic substitution that the necessary human resources are available to work on EMA of abiosimilar in place of abranded biologic “should be considered preparedness,”the regulator stated, “and subsequently, that activities unacceptable, as they are non-exchangeable unlike generic medicines”. with the highest priority will continue to operate ‘business as usual’, Decisions on substitution should, the third point of the proposal without interruption and to the same high standards.” Therefore, a advocates, be “basedonscientificdata”, should be “madeand controlled ‘phased approach’would be used to implement the plan,which includes by the attending physician after proper medical evaluation”, and should temporarily suspending or “scaling back” activities, starting with those be made with the awareness of the patient. “Appropriate directions” described as being the “lowest priority”.The EMA also outlined plans would need to be developed on this subject, the APRaD suggests. to “reallocate resources to its core activities if needed”. Mandatory tracking of trade names and batch numbers for “The plan prioritises tasks and activities and classifies them into pharmacovigilance purposes is urged as the fourth point. three categories, according to their impact on public health and the Biological drugs previously registered in Ukraine as generics agency’sability to function,” the agencystated. These distinct categories should, the fifth point argues,be“re-evaluatedand re-registered as had been identified by the EMA earlier this year, with ‘category 3’ biosimilars”. The APRaDsuggests using World Health Organization coveringthe lowest priority tasks, ‘category 2’ listing higher-priority (WHO) recommendations as the basis for this process, “including activities, and ‘category1’concerning highest priority tasks (Generics introducing the 12-month periodfor submissionofthe updated dossiers”. bulletin,11August 2017, page 13). Finally, on public procurement policies, the APRaD advocates “Freeing up” necessary resources “until the end of 2017” wasthe includingboth original biologics and biosimilarsinprocurement lists and first phase of the plan. Tasks would be temporarily “scaled back” or the national essential medicines list “by the trade name of such medicines”. suspended, firstly from ‘category 3’ and then from ‘category 2’, Referring to the use of originalbiologics and biosimilars as “more which divides activitiesinto two sub-divisions, the EMA explained. than amere issue ofeconomicalavailability of amedical treatment”, Lower-medium priorities under ‘category 2B’ would be looked at theAPRaD said that “side-by-sidemarket existence of several biosimilars first, followed by higher-medium priorities under ‘category 2A’. referring to one and the same original biological medicinal product Pointing out that the regulator had already since May started to can create achallenging environment for patients and physicians”. The scale back activities in ‘category 3’, the EMA said it would temporarily association said its proposals had been put forward “due to the importance, reduce audits, self-assessment activities and ‘transparency’ requests immediacy and insufficient regulation of the matter in Ukraine”. G for information. Meanwhile, activities concerningthe regulator’s integrated quality management system and meeting management enlargement would be provisionally suspended. Next,the focus will be on ‘category 2’ activities,includingreducing EDUCATIONAL CAMPAIGNS the developmentofnew external policiesand the revision of existing external policies and the EMA’s online programme. Temporarily UK promotes biosimilar trials suspended tasks cover the EMA’s e-submission project and the campaignhighlightingthe benefits of conducting biosimilartrials publication of clinical data. Awithin the UK’s National Health Service (NHS) has been launched Asecond phase would focus on freeing up additional resources by the country’s National Institute for Health Research (NIHR). for EMA preparedness for 2018 and 2019, as well as “ensuringthat Primarily using ‘talking head’ video clips in addition to written activities with the highest priority can continue in asituation where content, the ‘Focus on biosimilars’ campaign provides information for staff loss can no longer be compensatedthrough recruitment”. companies, health professionals, and patients and carers. Arange of ‘Category 3’ tasks would be further reduced, before moving to questions areanswered, including why firms shouldbring trialstothe ‘category 2’ activities, and “only in aworse case scenario, to UK,why professionalsshould support trials,and whypatients should certain ‘category 1’ activities”. consider taking part in trials or switchingprogrammes. “Although the de-prioritisation of activities under phase one is Observing that the “uptake and acceptance of biosimilars has rapidly mainly affecting internal governanceand support activities, with few accelerated across the NHS in recentyears”, the NIHR said the “clinical activities impacting on EMA partners and stakeholders,” the EMA evidence base is growing, benefits are beginning to be realised, and cost acknowledged, “thede-prioritisationofthe largemajority of activities savings arecoming to the fore”. “With the promise of asmaller price underphasetwo willimpact deliverables in the workprogramme.” G tag, biosimilars may well hold the key to ensuring the sustainability n [email protected] of our globally renowned public healthcare system,” the NIHR said. G

12 GENERICS bulletin 3November 2017

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VALUE ADDED MEDICINES PRICING &REIMBURSEMENT Commission admits FTC seeks feedback to PUMA plan failure on competition in US

ranting a10-year period of market exclusivity in theEuropean eedback on subjects including incentives for US generic entry, GUnion (EU) through apaediatric-use marketing authorisation Fanti-competitive strategies to reduce competition to off-patent drugs, (PUMA) aimed at stimulating the development of known molecules the role of intermediaries in the pharmaceutical supply chain and for children “has so far failed”,the European Commission has admitted. price-reduction proposals is being sought by the US Federal Trade Fulfilling its obligationtoreporttothe European Parliament and Commission (FTC),toaid discussions at aworkshopon8November. Council on the 10th anniversary of the EU’s Paediatric Regulation Taking place in Washington DC, the Commission will host the 1901/2006, the Commission observes that“to date,only three PUMAs workshop on ‘Understanding competition in prescription drug markets: have been granted”. “This is clearly below expectations,”itacknowledges. entry and supply chain dynamics’ (Generics bulletin,13October “While the European Medicines Agency (EMA) agreed more than 2017, page 7). Acting FTC chairman Maureen Ohlhausen and US 20 paediatric investigation plans (PIPs) with aview to submitting a Food and Drug Administration (FDA) Commissioner Scott Gottlieb PUMA,” the Commission continues, “it remains uncertain how many will give keynote addresses during the workshop, whichwill be free will everbecompletedand lead to commercialisation of anew product.” to attend, open to the public and webcast live. Moves by the Commission and the EMA in 2014 to clarify that An opening session willexplore factors that could preclude generic aPIP for aPUMA does not have to cover all age groups have, so far, marketentry after relevant patentshave expired, and discusses“price had alimited impact, the report recognises. “While this may allow and non-price factors that may influence entry in these markets”. A companies to focusresearchonthe mostprevalentpaediatricsubsets, second session will “evaluate intermediaries in the pharmaceutical it risks further reducingthe targetpopulationand potentialrevenues.” supply chain”, particularly pharmacy benefit managers (PBMs). A According to the Commission, the PUMAconcept struggles with thirdand final session covers group purchasingorganisations (GPOs), the same issues facing any scheme aimed at encouraging firms to including adiscussion concerning the “potential next steps to encourage repurpose known compounds. “Medicine developers fear that aPUMA entry and expand access through lower prices”. will not necessarily prevent physicians from continuing to use competitor Among the panellists will be members from generics industry products with the same active ingredient but authorised for other body the Association for Accessible Medicines (AAM), as well as the indicationsoff-label, at lower costs,nor [prevent] substitution for cheaper Health Transformation Alliance, US originator body PhRMA and the forms at the level of pharmacies,” it says. And national payers “are US Pharmaceutical Care Management Association (PCMA). generally hesitant to agree apremium price for such products”. The FTC is requesting comments on whether generic drug Acknowledging the limited evidence of just three PUMAs granted, manufacturers have sufficient incentives to enter off-patent markets the Commission saidthat while data “shows that the products authorised and whether policymakers “have arole in providing incentives to through PUMAs have received positive reimbursement decisions in encourage entry decisions that better align with the public interest”. several member states and represent good business cases, it may In addition, the Commissionisseeking inputonanti-competitive simply be the exception to the rule, partly supported by the specificities strategies and what more can be done to make generic entry more of the products rather than the PUMA concept alone”. “robust”. Comments on the benefits and costs of intermediaries in Such is the complexity of the factors influencing whether such prescription drug pricing hasalso been sought, as well as considering valueadded medicinesare commercially successful thatthey “can be how stakeholdersshould evaluate proposals to reduce drugprices and hardly addressed at EU level”, the Commission concludes. “They increase consumer access in prescription drug markets. G concern downstreamdecision-making at national level, which is outside the scope of EU law,” it admits, adding that “legislative incentives cannot compensate for economic success”. MARKET RESEARCH By contrast, the Commission’s report suggests, the Paediatric Regulation –which offers asix-month extension to supplementary Canada’s awareness improves protection certificates (SPCs) for completing aPIP,aswell as a two-year extension to 10-year orphan exclusivity for rare diseases – nowledge and awareness of biosimilars among prescribing physicians has had “a clear positive effect” in widening the range of medicines Khas improved in Canada between 2014 and 2017, according to the specificallydeveloped for children. latest survey by the originator-backed Alliance for Safe Biologic During the decade that the Regulationhas been in effect, “over 260 Medicines (ASBM). Of the 403 doctors spanning 13 therapeutic groups new medicinesfor use by children–new marketing authorisationsand surveyed by the ASBM, 28% said they were“veryfamiliar” with new indications –wereauthorised”, the Commission points out. “The biosimilars, compared to 10%respondingtoasimilarsurvey in 2014. number of agreed PIPs surpassed 1,000 in 2017, of which 131 were On biosimilar naming, ASBM said that more than two-thirds of completed at the end of 2016.” However, it adds, “figures suggest that, respondents “overwhelmingly support Health Canada implementing up to now, only 55% of the completedPIPsbenefited from areward”. distinguishable names,yet there was no consensus as to best method”. Estimating an averageresearch and development cost per PIP of Half favoured acompletely different non-proprietary name, while 31% C18.9 million (US$22.0 million), the Commissionmeasures theeconomic preferred adifferentiating prefix, 11% asuffix and 7% ashared value of the six-month SPC extension for eight selected products to international non-proprietary name (INN) with amanufacturercode. be C926 million. By 2019, the Commission intends to evaluate the Meanwhile, ASBM said, “54% believe abiosimilarwhich shares combined effects of the EU’s Paediatric and Orphan Regulations, an INN with its reference product implies the two are structurally informed by the recently launched review of the SPC regime (Generics identical, which is not the case”, while “63% believe abiosimilarwhich bulletin,20October 2017, page 1). G shares an INN with its reference product implies the two were approved n [email protected] for the same indications, which may or may not be the case”. G

3November 2017 GENERICS bulletin 13

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MARKET RESEARCH INTELLECTUAL PROPERTY US$54bn in savings Patent linkage forms from US biosimilars key priority in China

iosimilars could bring the US cost savings of US$54 billion over stablishing apatent-linkage system, implementing dataprotection Bthe next decade, accordingtoaRAND Corporation report. “We Eand awardingpatent-term restorations areamong the key priorities estimate that biosimilars will reduce direct spending on biologic drugs for strengthening intellectual-property protection in China as part of by US$54 billion from 2017 to 2026, or about 3% of total estimated reformstoimproveapproval processes for,and encourageinnovation biologic spending,” the RAND report states, acknowledging that the of, medicines in the country. final figure could fall between US$24 to US$150 billion. Requiringgenerics filers to address applicable patents as part of In aprevious review,RAND predictedthat US biosimilars would the application process would, Minister Bi Jingquan believed, enable save the countryUS$44 billion from 2014 to 2024 (Generics bulletin, patent disputes to be resolved during the drug-review process. “The 14 November 2014, page 26). RAND said the latest figure was around legal riskfor marketing generics will be lowered, and the patent holders’ 20% larger than previously suggested due to “improved analysis interests can be better protected,” he asserted. methods and rapid growth in spending for biologics overall”. The Alist of marketed drugs akin to the US Food and Drug researcher reviewed the sales historyofmore than100 biologic drugs Administration’s OrangeBookwouldinformphysiciansand pharmacists and analysed the performanceofSandoz’ Zarxio (filgrastim-sndz). on both reference drugs and their generic equivalents, he outlined. “Actual savings will hinge on industry and regulatory decisions, Bi noted that China had, when joining the World Trade Organization as well as potential policy changes to strengthen the biosimilar market,” (WTO), committed to providing protection for clinical-trial data. A RAND stated. “Payment arrangements, regulatory policies and pre-condition of restoring the patent term lost during the regulatory guidance, patient and prescriber acceptance of biosimilars, and other review was, he said, changing the requirement for generic approval issues will also influence the magnitude of potential savings.” Referring from clinical to bioequivalence trials, thereby “achieving abalance” to the Biosimilars Price Competitionand InnovationAct (BPCIA) of by cuttingthe cost of bringing generics to market. “We shall develop 2009 –which set out the US biosimilars framework –RAND described aplan as soon as possible and carry out apilot programme, after being this as a“faster andlesscostly” biologicspathwaythatalsopromoted authorised by the National People’s Congress,” he pledged. competition. The marketresearcher insistedthat as additionalbiosimilars Acknowledging the problem of China’s “under-development of are marketedinthe US,future research would “help us to assess whether generics”, Bi bemoaned the lack of domestic generics that were the BPCIA achieved competition and cost savings”. interchangeable with originator brands. “For the treatment of serious Moreover, RAND said that the “pervasive uncertainty” as to diseases,” he said, “we still heavily rely on imported drugs.” “whether the market will be sustainable and lead to cost savings”, presented two options for policymakers. One was to pursue current Domestic producers making ‘sub-standard drugs’ policies. “Increasing FDA and industry experience with approval Some domestic producers used “inferior materials” and turned requirements, precedent through early legal decisions, and evolving out “sub-standard drugs”, using manufacturing processes that could pricing and market-sharetrends,will eventually provide clarity on the have“aseriousimpact”onsafety and efficacy,Biadmitted. As potential stability of the US biosimilar market and the significance of biosimilars reasons for this problem he identified weak intellectual property, as to the healthcare system.” Alternatively, the reportsuggests, policymakers well as the lack of asystem of marketing-authorisation holders. could “intervene to helpsteer the US biosimilar marketmorequickly While aprocess to evaluate more consistently oral generics had to asustainable, competitive state”. G been “thoroughly implemented”, re-evaluatinggenericinjectables was scheduled to takeplaceover the next five to 10 years. “China’s Food and Drug Administration (CFDA) will clarify the method and timetable for injection re-evaluation as soon as possible,” Bi promised. PRICING &REIMBURSEMENT Another imminent task for the CFDA will be to implement a manufacturing verification system whereby all drug producers will US must consider differences have to provide details of theiractive pharmaceutical ingredients(APIs), olicymakers should consider the “differences inherent in the excipients, processes and other relevant information. Failure to provide Pbranded and generic prescriptiondrug markets”when considering such information could result in products being withdrawn from the public policy changes on drugpricing, theUSAssociation for Accessible market, Bi warned, adding that marketing-authorisationholders would Medicines (AAM) has insisted. The statement came as AAM president alsobelegally liable for the quality, safety andefficacy of their products. and chief executiveChip Davis addressed aUSSenate health, education, To combatthe threat of sub-standard and counterfeit medicines–as labour and pensions committee on the cost of prescription drugs. wellasproblems with “low-price tender drugs” –Chinese authorities Insistingthat the sustainability of acompetitive generics market intend to step up regulatory oversight, including through plans to was “in jeopardy”, Davis told the committee that “a failure of policy to “strengthen on-site inspection and quality sampling and testing”. Bi account for the unique challenges facing generic and biosimilar said creating a“professional inspector team” would be accelerated, medicines” was one of three factors threateningthe balance between while authorities would also focus on “capacity building” to establish innovation and access to generics, along with changing reimbursement amodern drug-review and inspection framework. frameworks and “the abuse of laws and regulations by bad actors”. Co-ordination and co-operation between different ministerial “Generic drug markets are fundamentallydifferentthan brands,” departmentsistobestrengthened, as is “learning and training”atthe Davisstated, citingdifferences in thesupply chain, rebate models and CFDA. The regulatory responsibilities of both central and local distribution channels. “It is critical that policymakers take steps to government would be clarified, Bi added, while clinical data generated ensure the continued supply of affordable FDA-approved generic abroad would be more readily acceptable. G medicines,” Davis concluded. G n [email protected]

14 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.2-15.indd 14 01/11/2017 17:31 MARKET NEWS

PRICING &REIMBURSEMENT EDUCATIONAL CAMPAIGNS Health Canada plans FDA to educate with labelling fee overhaul biosimilars campaign

new fee for generic labelling in Canada has been proposed as part neducational campaign about biosimilars has been launched by Aof alarger consultation on drugs and medical devicesopened by Athe US Food and Drug Administration (FDA), to give providers local agency Health Canada. Pointingout that the government had not a“better understanding” of the drugs and their approval process. updated its fees for drugs and medical devices since 2011, Health Notingthat the agency had “planned and researched extensively” Canada said although the regulator had “remained internationally prior to developing the materials, FDA Commissioner Scott Gottlieb competitive in meeting performance standards, costs have increased said that the FDA had “learned the specific areas that healthcare and taxpayers are assuming an increasing economic burden because providers had questions about”. This included gaining abetter of outdated fees charged to industry”. understanding of biosimilars as well as their approval process. Existing fees withinthe ‘human drug evaluation’ categorywould Educational materials developed by the agency includefactsheets “remain unchanged”, Health Canada proposed, although new fees and graphicsfor healthcare professionals,and resources for organisations would be created for ‘labelling only’ generic products and safety to usein“disseminating thisinformationtotheir interestedmembers”. supplemental new drug submissions. The materials, the FDA said, provided “basic definitions” of terms like Sponsors for generic products would havetwo filing options, the ‘biosimilar’,‘reference product’,and ‘interchangeable’. regulator noted, depending on the information submitted. ‘Labelling The resources also “describe the rigorous standards any biosimilar only’ submissions would relate to products with labels differing from must meet prior to approval,and explain how the FDA approval process that of the Canadian reference product (CRP) and/or for which a label review is required. Meanwhile, the newly-proposed fee category, ‘labelling only to be in line with the CRP’, would be relevant if no additional review was required. “The new categories will have aperformance standardof120 days, to be consistent with the level of effort,” Health Canada commented. ‘Labelling only’ fees are set to more than double from C$3,111 (US$2,416) to C$6,298, while feesfor labelling in line with the CRP is expected to drop from C$3,111 to C$2,626, the proposal outlines. According to Health Canada, acompanyin2017 paid C$89,080 for ahuman generic drug submission to Australia’s Therapeutic Goods Administration (TGA), C$269,794 to the European Medicines Agency (EMA),and C$88,298 to the US Food and Drug Administration (FDA). “Health Canada is proposing C$70,383,”the national authority noted. Turning to establishment licensing fees, Health Canada said activities included in the fees were “domestic and foreign building inspections and licensing/billing activities for active pharmaceutical works”. Understanding the process the agency used to evaluate biosimilars, ingredients (APIs), finished-dosage form drugs, veterinarydrugsand Gottlieb insisted, could “help providers and patients maximise the medical devices”. Health Canada is seeking feedbackonits proposals benefits from these products”. from stakeholders across the biotech, pharmaceutical,radiopharmaceutical, Furthermore, the resources provide “easily accessible information medical devices and veterinarydrug/natural healthproduct industries. about the data and information the FDA reviews to determine The deadline for comments is 4January 2018. G biosimilarity”, highlight information about the FDA’s Purple Book repositoryofbiological approval and exclusivity information, andalso give direction on how to find further materials. “Next, the FDA plans to embark on additional research with MARKET RESEARCH healthcare providers to learn more about the type of information Indian exports rise by afifth prescribers need to properly communicate with their patients about biosimilars,”Gottlieb stated. “An increaseinmarketcompetition, offered ndian exports of generics are “growing at around 22% per year”, by agrowing complement of biosimilars, may lead to meaningfully Iaccording to the latest data published by the India Brand Equity reducedcosts for both patients and our healthcare system,” he continued. Foundation(IBEF) and the country’sPharmaceuticals Export Promotion “As with the significant savings that we’ve seen through the Council (Pharmexcil). India accounted “for around20-22% of the world’s introduction of generic drugs in the US,” Gottlieb said, “biosimilars production, covering more than 60,000 brands and 60 therapeutic could also lead to substantial savings, thereby potentially improving classes”, the bodies stated, adding thattotal exports of pharmaceuticals – access and promoting better public health outcomes.” including active pharmaceutical ingredients (APIs), generics and Meanwhile, the FDA has released video presentations for industry, “alternative systems of medicine” –reached US$16.8 billion during explaining features of the reauthorised Generic Drug User Fee 2016-17, of which 34% was supplied to theUSand 15% to the European Amendments (GDUFA II) programme. Content includes “the new Union (EU). Thefigure was expected to reach US$20 billion by 2020. avenues of communications that are possible between generic drug “According to the analysis, India has provided up to 50% ofnew applicants and the agency, especially for the review of complexgeneric drug master files (DMFs) and between aquarter and athird of new products”, andthe shorter review goals available for applications that abbreviated new drug applications (ANDAs) each year for the past are public health priorities. G decade,” the IBEF and Pharmexcil said. G n [email protected]

3November 2017 GENERICS bulletin 15

Gen 3-11-17 Pgs.2-15.indd 15 01/11/2017 17:31 TILL NEXTNEXT TIME!TIME!

35 200+ 75 COMMERCIALM GENERIC PROJECTS PIPELINE NETWORKW IN PIPELINE ANDA‘S

28000 5 59% PASSSIONATE MANUFACTURING CAGR EMPLLOYEES AND R&D CENTERS SINCE 2009

Alvogen and Alvotech would liketothank youall forvisiting our booth at CPhl in Frankfurt this year. Whether it wastomeet our staff regarding acurrent project, inquire about our businesses or justhavealaughbycompeting in our formula simulatorchallenge,we‘rehappy youcameby. Our special congratulations go to Santiago from Medinexo who wonthe contestwith his outstanding driving skills and focus. This year‘s CPhlhas drawntoanend, but Alvogen will continue to drive change in our evolving industry and remain at the forefront of change with our approach to generics, over-the-counter and biosimilar products. See youinMadrid next year!

Thewinner,Santiago Diaz Mejia, took home the 1stprize, aMotion PRO II Formula Wheel. HereheiswithRobert Wessman CEO of Alvogen and Rasmus Rojkjaer CEO of Alvotech. Connect with Alvogen on www.alvogen.com TILL NEXTNEXT TIME!TIME!

35 200+ 75 COMMERCIALM GENERIC PROJECTS PIPELINE NETWORKW IN PIPELINE ANDA‘S

28000 5 59% PASSIONATES MANUFACTURING CAGR EMPLOYEESL AND R&D CENTERS SINCE 2009

Alvogen and Alvotech would liketothank youall forvisiting our booth at CPhl in Frankfurt this year. Whether it wastomeet our staff regarding acurrent project, inquire about our businesses or justhavealaughbycompeting in our formula simulatorchallenge,we‘rehappy youcameby. Our special congratulations go to Santiago from Medinexo who wonthe contestwith his outstanding driving skills and focus. This year‘s CPhlhas drawntoanend, but Alvogen will continue to drive change in our evolving industry and remain at the forefront of change with our approach to generics, over-the-counter and biosimilar products. See youinMadrid next year!

Thewinner,Santiago Diaz Mejia, took home the 1stprize, aMotion PRO II Formula Wheel. HereheiswithRobert Wessman CEO of Alvogen and Rasmus Rojkjaer CEO of Alvotech. Connect with Alvogen on www.alvogen.com PRODUCT NEWS

RESPIRATORY DRUGS IN BRIEF PERRIGO has received tentative approval from the US Food and Fluticasone is among Drug Administration(FDA) for ageneric version of Leo Pharma’s Picato (ingenol mebutate)0.015% gel, afterfiling aparagraphIV challenge last year (Generics bulletin,17June 2016, page 12).

new FDA guidances ACHIEVE LIFE SCIENCES has entered into an exclusive supply agreement with Sopharma for the manufacture of cytisine active luticasone propionate metered aerosol for inhalation, as well as a pharmaceutical ingredients (APIs)and finishedtablets. Throughthe Fpowder for inhalationformulation, are among 33 new product-specific deal, Sopharma willsupply cytisine to Achieve“for up to 20 years”. guidances published by the US Food and DrugAdministration (FDA) “describing the agency’s current thinking and expectations” on how GLENMARK has been granted finalapproval in the US for ageneric to develop “therapeutically-equivalent” generic drug products. rival to Merck, Sharp &Dohme’s (MSD’s) Emend (aprepitant) In addition to the new guidelines, the agency has also released 40mg, 80mg and 125mg capsules. Citing QuintilesIMS data, the 19 revised guidances,aspart of the FDA’sefforts “to further facilitate Indian firm observed thatthese strengths of Emend capsules achieved generic drugproduct availabilityand to assistthe generic pharmaceutical sales of US$64.9 million in the 12-month period ending August 2017. industry with identifying the most appropriate methodology for developing drugsand generatingevidence needed to support abbreviated AHF –the AIDS Healthcare Foundation –has called on Gilead new drug application (ANDA) approval”. Sciencestoreduce the price of its tenofovir-based drug regimens, To establish bioequivalence for fluticasone propionate metered including Truvada (tenofovir disoproxil fumarate/emtricitabine), aerosol for inhalation –the active ingredient in GlaxoSmithKline’s by “as much as 90%”. Pointingout that the firm had “made billions” (GSK’s) Flovent HFA inhaler–the FDA recommends in vitro studies off its tenofovirdrugs since the US Food and Drug Administration including single actuation content, aerodynamic particle-sizedistribution, (FDA) approved its Viread (tenofovir)inOctober 2001, AHF spray pattern, plume geometry and priming and repriming studies. claimed Gilead had “simultaneously sought to ‘evergreen’ and Meanwhile,the agency alsorecommendsthatapplicants conduct manipulate the patent extension process”. Under the terms of a afasted pharmacokinetic and comparative clinical endpoint bioequivalence patent-litigation settlement, Teva can launch generic tenofovir in study. And regarding the product device, the FDA advises sponsors to the US from 15 December this year. refer to draft guidance published about devices in January this year (Generics bulletin,20January 2017, page 6). ACETO’S Rising Pharmaceuticals subsidiary haslaunchedageneric On fluticasone propionate powder for inhalation, which references version of Pfizer’s Zoloft (sertraline)20mg/ml oral solution in the GSK’s Flovair Diskus, the FDA recommends sponsors also conduct US. According to QuintilesIMS data, US sales of sertraline 20mg/ml in vitro and in vivo studies, but on the former only lists single actuation oral solutionwere US$9.94 million for the year to June 2017. contentand aerodynamic particle-size distribution studies. Again,the FDA recommends afasted pharmacokineticand comparative clinical MIRACA LIFE SCIENCES has continued to “expand in clinical endpoint bioequivalence study. pathology” after its InformTx therapeutic drug monitoring (TDM) In addition to fluticasone propionate, another of GSK’s respiratory began the validation process for Merck, Sharp &Dohme’s Renflexis products is included on the FDA’s list of new guidances, salmeterol (infliximab-abda), abiosimilar of Remicade (infliximab).Since xinafoate,whichisthe activeingredientinthe UK-based originator’s launching the InformTx service in June 2016, Miraca pointed out Serevent inhaler. The FDA said it would consider comments on the it had “expanded its TDM testing to now eight biologic drugs that products’draftguidancebefore responding to aGSK citizen petition treat inflammatory bowel disease”. on establishing bioequivalence. Additional respiratory products on the agency’s list of guidances AUROBINDO has obtained final approval from the US Food and include mometasone furoate powder for inhalation and tiotropium Drug Administration (FDA) for its generic rival to Eli Lilly’s Effient bromide powder for inhalation. (prasugrel)5mg and 10mg tablets. The Indian company has also Meanwhile, other reference products cited as targets for generic receivedfinal approval in the US to manufacture ageneric version development include AmedraPharmaceuticals’Adrenaclick (epinephrine) of AstraZeneca’s Nexium 24HR (esomeprazole)delayed-release intramuscular injectable, Novartis’Afinitor (everolimus) tablets for 20mg capsules, to be launched immediately. suspension,AstraZeneca’s Lynparza (olaparib)capsulesand Mylan’s Astepro (azelastine hydrochloride) nasal spray. HIKMA’S US subsidiaryWest-WardPharmaceuticalshas launched These come alongside guidelines fordevelopinggeneric versions pantoprazole sodium for injection, available in a40mg dose. The of AstraZeneca’s Tagrisso (osimertinib mesylate) tablets, Valeant’s firm said it was“successfullyexecutingour injectables pipeline and Uceris (budesonide) rectalfoam and Shire’s Vyvanse (lisdexamfetamine leveraging the additional capacity we have been adding to our dimesylate) chewable tablets. Portuguese facility to support future growth”. Lisdexamfetaminedimesylate in capsule formulation is moreover among 19 revisedguidancedocuments,which also includes anumber STATIN prescribing evidence suggests overtreatment of low-risk of ophthalmic products such as brimonidine tartrate 0.1% and 0.2% groupsand undertreatment of high-riskgroups, according to astudy solution/drops, ciprofloxacin hydrochloride drops, diclofenacsodium published in the British Journal of General Practice.Inastudyof drops, ofloxacin drops and olopatadine hydrochloride drops. 1.4 million patients, “most patients at high risk of cardiovascular Meanwhile,companies looking to develop genericsofEli Lilly’s disease (CVD) were not initiated on statins”, while “one in six statin erectile dysfunctiontreatment Cialis(tadalafil)tablets –whichare set initiations weretolow-risk patients”. Furthermore, the study found to enter the US market in September 2018 under the terms of apatent- that after the UK’s National Institutefor Health and Care Excellence litigation settlement agreement agreed earlier this year (Generics (NICE) guidelines were updated in 2014 (Generics bulletin,7 bulletin,28July 2017, page 15) –can also now find the FDA’s March 2014, page 23), statin initiation rates declined in high-risk revised guidance on the molecule. G patients, but increased in intermediate-risk patients. G n [email protected]

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NEUTROPENIA TREATMENTS MULTIPLE SCLEROSIS DRUGS Sandoz resubmits EU UK revokesapatent pegfilgrastim dossier for glatiramerdosage

andoz’ Zioxtenzo(pegfilgrastim) biosimilar has been accepted for ylan and Synthon have seeninvalidated aUKdosage-regimen Sreview by the European Medicines Agency (EMA), less than a Mpatent protectingTeva’s Copaxone (glatirameracetate)40mg/ml year after concerns raised by the EMA’s committee for human formulation. The decision revokes the UK part of European patent medicinal products(CHMP) led the firm to withdraw its application. EP2,949,335 that Teva licenses on an exclusive basisfromYeda. The According to Sandoz, the firm’s comprehensive data package, ‘335 patent covers treating relapsingforms of multiple sclerosis through submitted as part of the marketing authorisation application (MAA), three subcutaneous injections of glatiramer acetate 40mg/ml every includes analytical, preclinical and clinical data, including Phase I seven days, with at least one day between each injection. pharmacokinetic and pharmacodynamicstudies in healthyvolunteers, Notingthat Mylan and Synthon wished to “clear the way”for the as well as Phase IIIsafety and efficacy data in breast-cancerpatients. 40mg formulationfor which they hadobtainedamarketingauthorisation Sandoz insists that its clinical development programme for the on 5October, Patents Court Judge Richard Arnold said infringement proposed biosimilar version of Amgen’s Neulasta (pegfilgrastim) was not disputed if the ‘335patent’s claims 1and 3were valid. “strongly demonstrates that the biosimilar pegfilgrastim matches the Among the key prior-art references relied upon by Mylan and reference medicine in terms of safety, efficacy and quality”. Synthon to challengethe ‘335 patent’s novelty was the Pinchasi At the beginning of this year, the CHMP adopted aprovisional international patent application filed by Teva and published in July opinionthat Zioxtenzo “couldnot have beenapproved as abiosimilar 2007. This disclosedthat “administration of glatiramer acetate at a of Neulasta”, leading Sandoztonotifythe committee that it wishedto dose of 40mg/day significantly improves efficacy, but does not have withdraw the application (Generics bulletin,3February 2017, page 11). acorresponding increase in adversereactions suffered by the patient”. The CHMP’s opinion was based on two “main” concerns: that It also discloses administering such doses “every other day”. Sandoz’ study results were not able to show that the concentrations Addressingobviousness, Arnold said “the sole difference between of pegfilgrastim in blood were the same after taking Zioxtenzo and Pinchasi and claim 1ofthe patent is that Pinchasi disclosesaregimen Neulasta;and that the biosimilar’s manufacturing site lacked acertificate of 40mg every-other-day while claim 1requires aregimen of 40mg of good manufacturing practice (GMP). three-times-a-week”. He agreed with Mylan and Synthon that a The CHMP, at that time, describedSandoz’study as “clearly under- thrice-weekly regimen was “nothing more than asmall and simple powered”, noting that the pegfilgrastim exposure in healthy subjects variation on Pinchasi’s teaching”, so the claimed dosage would have was “up to 36%” higherwith Zioxtenzo than EU-approved Neulasta. been “obvioustotry”. Similarly,the lower frequency of injection site Stressing thatitwas the “European market leader” forbiosimilar reactions (ISRs) covered by claim 3was also obvious. filgrastim –which the firm markets under the Zarzio name –Sandoz Whilehefound claims 1and 3tobenovel over Pinchasi,Arnold said it now had three biosimilars under EMA review. Pegfilgrastim noted that the UK’s SupremeCourt had recently introduced adoctrine joins Sandoz’ applicationsfor proposed versions of AbbVie’sHumira of equivalents in adisputebetweenActavis and Lilly overpemetrexed (adalimumab) and Janssen’s Remicade (infliximab). (Generics bulletin,14July2017, page 1).“If it is legally possible for Sandoz insisted that it was the “global leader in biosimilars”, with aclaimtobedeprived ofnovelty by virtueofthe doctrineofequivalents, five marketed worldwide, and a“leading global pipeline”. then claim 1lacks novelty over Pinchasi,” he stated, adding that Lastmonth, Cinfa Biotech had itspegfilgrastimbiosimilar MAA claim 3would also lack novelty. accepted for review by the EMA (Generics bulletin,13October 2017, Having refused to issue an ‘Arrow’ declaration of invalidity for page 15), joining filings submitted by firms including Coherus. A two pending divisional patent applications, Arnold notedthat the basic biosimilar alternative to the branded treatment for chemotherapy- low-molecular-weight glatiramer acetate patent EP0,762,888had induced neutropeniahas, however,proved ahurdlefor otherplayers, expired on 23 May 2015. Furthermore, the European Patent Office’s with EMA applications submittedbyBiocon and Mylan as well as (EPO’s) Technical Board of Appeal had recently revoked process GedeonRichter and Stada amongthose withdrawninthe last12months. patent EP2,361,924 in its entirety.AUK dispute over another process In late August this year, supplementary protection certificates patent, EP3,050,556, is scheduled for trial in April next year. (SPCs) shielding Neulasta in most European Union (EU) member Mylan saidthe UK victory would“further help pave the way”to states expired, based on Amgen’s European patent EP0,733,067, which launch glatiramer40mg/ml “in certain European markets”.InIreland, is entitled ‘N-terminally chemically modified protein compositions the genericsfirm said it had recently learned of an infringement action and methods’ (Generics bulletin,11August 2017, page 18). G brought by Teva in the country’s High Court, alleging that Mylan’s 40mg/ml injectable formulation infringes two European patents. Counterpart dosage-regimen patentsinthe US had beenheldinvalid by both aDelaware district court and the Patent Trial and Appeal Board DERMATOLOGY DRUGS within the US Patent and Trademark Office (USPTO), pointed out Mylan, which launched its three-times-a-week US rival to Copaxone Perrigo settles over Onexton in early October (Generics bulletin,13October 2017, page 14). G errigo has settled US litigation brought by Valeant and Dow PPharmaceuticals relating to Onexton (clindamycin phosphate/ IN BRIEF benzoyl peroxide) 1.2%/3.75% gel. As details of the settlement were “confidential”, no further information was disclosed. Accordingtothe TEVA has submitted a biologics license application (BLA) to the US Orange Book, fourUSpatents expiring in 2029 protect the treatment US Food and Drug Administration (FDA) for TEV-48125, the Israeli for acne vulgaris.Perrigo observed thattotal brandsalesfor the year firm’s fremanezumab investigational migraine treatment. G ended August 2017 were approximately US$120 million. G

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BIOLOGICAL DRUGS MIGRAINE DRUGS Germany is missing Sawai strikes deal for biosimilars potential zolmitriptan in Japan

iosimilars have captured slightly less than 4% by volume of the awai will manufacture and market Zomig (zolmitriptan) 2.5mg Boff-patent biologics market open to them in Germany during the Stablets –aswell as the Zomig Rapid Melt or RM orally-disintegrating first eight months of this year, according to Insight Healthdata provided version of the migrainetreatment –inJapan, after striking an exclusive by local industry association Pro Biosimilars. Measured by value at agreement with originator AstraZeneca. retail prices, biosimilars’ share of the off-patent market was 11.9%, due in “Under the termsofthe agreement, Sawai is expected to take over part to the presence of several relatively low-value mature brands. the manufacturing and marketing of the products in Japan by mid-2018 Taken as part of Germany’s total biologics market, including from AstraZeneca,” the Japanese company noted. patented originals,biosimilars hadjust a2.9% volume share with “The Rapid Melt or RM preparation is designed to melt quickly in 19.8 million defined daily doses (DDDs) sold in the January to August the mouth,” the firm noted, “due to the actions of disintegrating and period, as the total market amountedtojust almost 695 million DDDs. Of foaming agents within the product, taken with or without water.” G the total market, nearly 500 million DDDs were for off-patentbiologics. By value, biosimilars accounted for 5.2% of the total biologics market with retail sales of around C280 million (US$326 million). The sameshare at ex-factory prices translatedtosales of C214 million out ONCOLOGY DRUGS of atotal market worth C4.11 billion, of which C1.79billion, or 43.6%, was off-patent. Lannett settles over Thalomid “The enormous potential of biosimilars is not by any means being annett will be able to manufacture and market in the US arival to exhausted,” Pro Biosimilars commented. LCelgene’sThalomid (thalidomide) from 1August 2019, or earlier Etanercept biosimilars have steadily taken share since their market under certain circumstances, under the terms of apatent-litigation introduction just overayearago to generate ex-factory sales of C76.7 settlement and licensing deal thatthe generics firmhas struck with the million in the first eightmonths of this year. The biosimilars’ market originator. Other terms of the deal were not disclosed. share reached 26.5% by value and 30.8% by volume. “We believe our thalidomide will be the first entrant in the US By August, biosimilar sales of the rival to Pfizer’s Enbrel (etanercept) genericmarket,” said Lannett’schief executive officer, Arthur Bedrosian. were running at around C12 million from more than 300,000 DDDs Noting thatThalomid is subjecttoaRisk Evaluationand Mitigation per month in amarket that had expanded by around atenth over the Strategies (REMS) programme, as mandated by the US Food and Drug past year to around 900,000 DDDs per month. But anational 31.1% Administration(FDA),Lannett said it was seeking FDA approval for DDD share for biosimilars in August covered regional penetration rates its pending abbreviated new drug application (ANDA) covering 50mg, that rangedfrom just 14.8% in Thuringia to 63.8% in Westphalia-Lippe. 100mg, 150mg and 200mg thalidomide capsules. G Etanercept accounted for alittleover athird of all biosimilar sales in Germany (see Figure 1), while infliximab madeupmore thanaquarter with eight-month sales of C58.4 million. Biosimilar alternatives to Janssen’s Remicade (infliximab) captured 44.8% of ex-factory sales ATTENTION DEFICIT HYPERACTIVITY DISORDER DRUGS and 50.7% of DDDs in the eight-month period. With ex-factory sales of C36.2 million and C16.5 million respectively Actavis eyes an Adzenys entry in the January-August period, epoetin and filgrastimbiosimilarsheld eva’s Actavis has entered into aconfidentialsettlement and licensing value shares of just over athird and just under two-thirdsofthe total Tagreement withNeos Therapeutics to resolve all ongoinglitigation markets for each molecule. Their volume shares of those markets involving all four of Neos’ US patents protecting its Adzenys XR-ODT were 42.4% and 73.4% respectively. G (amphetamine) extended-release orally-disintegrating tabletsand Actavis’ n [email protected] abbreviated new drug application (ANDA) for ageneric version. Neos’ Adzenys is arival to Shire’s Adderall XR (amphetamine salts). Somatropin Under the agreement, Neos has granted Actavis the right to C13.7m manufacture and market its generic version of Adzenys beginning on Etanercept Filgrastim 1September2025, or “earlier under certain circumstances”. Reiterating C76.7m C16.5m that the settlement and licensing deal was “confidential”, Neos noted that the agreement was also“subject to submission to the US Federal Trade Commission(FTC) andthe US Department of Justice (DoJ)”. In Septemberlast year, Neos filedacomplaint against Actavis in Epoetin aDelaware district court, alleging infringement of Neos’ four Adzenys C36.2m US patents: 8,709,491; 8,840,924; 9,017,731; and 9,265,737. According to the Orange Book maintainedbythe US Food and Drug Administration Follitropin (FDA), the ‘924 patent expires in April 2026, while the three remaining C3.8m patents protect Adzenys until June 2032. Insulin glargine Neos launchedAdzenys, “the first and only extended-releaseorally- C9.2m Infliximab disintegrating tabletfor the treatmentofattentiondeficit hyperactivity C58.4m disorder(ADHD)” in the US in May 2016, after receiving approval via the Figure 1: Sales by molecule of biosimilars in Germany that totalled C214 million in 505(b)(2)hybrid pathway (Generics bulletin,5February2016, page 14). the first eight months of 2017 (Source –Insight Health/Pro Biosimilars) The firm recently got approval for an extended-release oral suspension.G

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DIABETES DRUGS/ONCOLOGY DRUGS HEPATITIS CDRUGS Biomm hits ablock Lobbying group files on Brazilian glargine sofosbuvir challenges

razilian insulins and biosimilarsspecialist Biomm says it has had ix ‘core’ sofosbuvir patents belonging to Gilead Sciences “do not Bamarketing authorisationapplication for Glargilin (insulin glargine) Smeetthe legal standards for noveltyand non-obviousness”, according rejected by Brazil’s medicines regulatory agency, Anvisa. Biomm to non-profit lobbying group Initiative for Medicines, Access & offered no comment on the grounds for rejection, but stressed that Knowledge (I-MAK), which has filed the “first-ever US patent challenges” Anvisa’s decision –which has now beenpublished in Brazil’sofficial against the hepatitis Ctreatment. journal –isopen to appeal. IMAK has filed an “unprecedented” set of inter partes review Anvisa’s rejection of Biomm’s alternative to Sanofi’s Lantus patent challenges with the US Patent and Trademark Office (USPTO), (insulin glargine) blockbuster comes shortly after the Brazilian company including for sofosbuvir’s compoundpatent,7,429,572,which expires bolstered its biosimilarpipelinebygaining exclusivesales and marketing in April 2025. Accordingtothe group, all 19 claims of the ‘572 patent rights in Brazil for the Herzuma (trastuzumab) biosimilardeveloped are unpatentable due to obviousness in light of two prior-art documents. by South Korea’s Celltrion. “The ‘572 patent claims pharmaceutical compounds that were CitingBiomm’sexpertise in both biopharmaceuticals and oncology, already published by the US government years before the patent owner Celltrion Healthcare’s presidentand chief executive officer, Man Hoon applied for the ‘572 patent,” I-MAK insists. “Other scientists also Kim, said the Brazilian firm would be able to offer anew treatment publicly identified the pharmaceutical compounds claimed by the ‘572 option to thousands of breast-cancer patients in Brazil. “Following patent before the patent owner applied for the ‘572 patent. Thus, its our success with the first infliximab and rituximab biosimilars in claims are invalid based on that prior art.” Europe that broadened access to moreeconomical life-saving treatments,” Meanwhile, I-MAK has filed challenges against sofosbuvir prodrug he commented, “we are confident that we will enjoy the same success patent 7,964,580 that expires in March 2029, additional prodrug patents through our partnership with Biomm in Brazil.” 8,735,372 and 8,334,270 that shield the molecule until March 2028, “Through this exclusive partnership,” stated Biomm’s chief and crystalline structures patents 8,633,309 and 9,284,342,whichexpire executive officer, Heraldo Marchezini, “we arealigned with our corporate in March 2029 and September 2030 respectively. mission ofoffering an affordable portfolio of quality biopharmaceuticals, Sofosbuvir is the active ingredient in Gilead’s flagship Sovaldi and to therebyoffertreatmenttoanincreasing numberofpeople.” G (sofosbuvir) and Harvoni (sofosbuvir/ledipasvir)brands, as well as the originator’s Epclusa (sofosbuvir/velpatasvir). In 2016, Harvoni sales in theUSwere US$4.9 billion, Sovaldi sales were US$1.9 billion,and Epclusa turnover was US$1.6 billion. ANTIBIOTICS “By reviewing evidence that the USPTO never considered, I-MAK Invanz process patent invalid has found that sofosbuvir was developed through obvious tweaks to existingcompounds and formulations commonly used in older HIV and US process patent covering astable formulation of Invanz cancer drugs,” insisted I-MAK. “If Gilead’s six core patents for A(ertapenem) is invalid due to obviousness, the US Court of Appeals sofosbuvir are ruled unmerited,UStaxpayers will save US$10billion, has affirmed in asplit decision. Merck &Cohad appealed against a and generics can get to market 14 years faster.” Delaware district court’s decision last year to invalidate 14 asserted “Every week, the US patent office grants 6,000 new patents,” claims in US patent 6,486,150 as obvious in light of prior-art references I-MAK claims, “and some of those are not merited. Pharmaceutical (Generics bulletin,21October 2016, page 12). corporations are over-patenting drugs even when thereisnonew science On appeal, Merck argued that the district court had erred in finding that justifies theirexclusivity and are stackingupasmanyunmerited obviousness in light of US patent 5,952,323 that expires next month patents as possible to prolong their monopolies and block cheaper and an Almarsson patentapplication because none of the manufacturing generics from entering the market.” steps described in the ‘150 patent were disclosedinthe prior art. “As voters demand that Congress take action to lower prescription Furthermore, the originator insisted, the prior art focused solely on drugprices,”I-MAK added, “Gilead Sciences has obtained unmerited degradation by dimerization, not hydrolysis, thereby teachingaway patents for hepatitis Cmedicine sofosbuvir, blocking millions in the from the claimed invention. US from affordable treatment.” Earlier this year, are-examination board within China’s patent No more than conventional steps office rejected Gilead’s appeal against a2015 decision to deny apatent Writing for the majority of the Court of Appeals panel, Judge on the prodrug of sofosbuvir, after I-MAK filed third-party observations Alan Lourie said that “Merck’s problem is that the purported ‘solution’ against aChinese patent application submitted by aGilead affiliate for minimising both degradation pathways constitutes nothing more (Generics bulletin,12May 2017, page 17). than conventional manufacturing steps that implement principles “Since 2006, I-MAK has challenged unmerited patents worldwide disclosed in the prior art”. winning over 80 percent of its cases,” the group claimed. “Challenging Armed with those prior-art references, askilled person would and winning cases on four HIV drugs alone has helped save over have arrived at the claimed invention “via routine experimentation”, US$500 million –money that can be reinvested to treat more than Lourie objected, adding that Merck’s evidenceofcommercial success one million people.” of the injectable antibiotic could not overcome the weight of prima According to Gilead,generics manufacturers may submit Sovaldi facie evidence proving obviousness. abbreviatednew drug applications (ANDAs) beginning in December In adissenting opinion, Judge Pauline Newman argued that this year, one year before the expiry of the brand’s new chemical secondary evidence such as copying and commercial success was entity (NCE) exclusivity period. G being under-valued. G n [email protected]

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DIABETES DRUGS IN BRIEF ENDO has sued theUSFood and DrugAdministration (FDA) in a Mylan sued in the US Columbia district court in abid to block bulk compounding of vasopressin.The firm,which markets the Vasostrict (vasopressin) injectable treatment for low blood pressure, believes that US Drug Quality and Security Act 2013 (DQSA) amendments require the over insulin glargine FDA to implement aregulatory framework for bulk compounding that protects public health. Separately,Endo recently obtained three ylan’s proposed 505(b)(2) hybrid versions of Sanofi’s insulin US patents that, like two existing listed patents, protect Vasostrict Mglargine-based Lantus and Lantus SoloStar brands infringe 18 until 30 January 2035. US patents assigned to theFrenchoriginator,according to alawsuit filed by Sanofi in aNew Jersey district court. EGIS hasacquired from AstraZeneca full rights in central and Sanofi’s complaint alleges infringement of 18 of the 19 patents eastern Europe, as well as the Commonwealth of Independent States listed against Lantus and Lantus SoloStar in the US Food and Drug (CIS), to the Sorbifer (ferrous sulfate)d rug for preventing and Administration’s(FDA’s) Orange Book, the latest of which, entitled treating anaemia. Since 1985, the Hungarian company has been “pen-type injector”, expires in March 2028, including asix-month producing, distributing and promoting in 18 countries the Sorbifer paediatric exclusivity period. brand that has since become its fifth-largest product with annual The Frenchoriginator revealed that it received Mylan’s new drug sales of around C20 million (US$23 million). application(NDA) with anotice letter–whichdisclosed that the generics firm’s application contained paragraph IV patentchallenge certifications AMERIGEN has linked up with India’s Biophore to develop and forthe patents-in-suit –inmid-September. As Generics bulletin went market a generic version of Valeant’s Cuprimine (penicillamine), to press, Mylan’sNDA had not receivedany form of FDA approval. as wellasotherpenicillinamine-based generics,for the US market. “Since receiving Mylan’s notice letter and the accompanying Amerigen, which will source active pharmaceutical ingredients offer of confidential access (OCA), Sanofi has negotiated in good (APIs) fromBiophore, said it had alreadyfiled an abbreviated new faith with Mylan to procure acopy of [the] NDA and relatedproduct drug application (ANDA) for ageneric rival to the Cuprimine information under restrictions as would apply had aprotective order chelating agent for treating Wilson’s disease. been issued,” Sanofi noted. “Sanofi timely responded to all correspondence with Mylan and sought to reach reasonable compromise with Mylan MAYNE PHARMA has been denied areview of adecision not to regarding its OCA. These negotiations have been unsuccessful.” place its oxycodone sustained-release tablets on the Australian Moreover, the complaint points out, Mylan in Junethis year also Register of Therapeutic Goods (ARTG). Australia’sAdministrative filed petitions with the US Patent and Trademark Office (USPTO) AppealsTribunal determined thatitlacked the jurisdiction to consider for inter partes review of two of the patents-in-suit, US patents new material cited by Mayne in an attempt to force alisting of its 7,476,652 and 7,713,930. For example, Mylan’s petition regarding generic version of the discontinued OxyContin AU analgesic. the ‘652 patent alleges “by apreponderance of evidence” that askilled Australia’s Therapeutic Goods Administration (TGA) had refused artisan would havehad reason to combine the Lantus label with prior to authorise Mayne’s version because it was not satisfied that art to reach the claimed invention. comparative testsconducted against adiscontinued Canadian reference Although none of the four Mylan businesses named by the product adequately demonstrated the generic’s safety and therapeutic originator in the suit are based in New Jersey, Sanofi –which has a equivalence. Separately, Mayne has received TGA approval for “principal place of business” in local Bridgewater through its Sanofi US Monurol (fosfomycintrometamol)3ggranules and has launched affiliate –insists in its complaint that “the venue is proper”. “Mylan Urorec (silodosin)8mg capsules in Australia. Inc. and the other Mylan defendants have aregular and established placeofbusiness in this district because they operate as ‘One Mylan’ MYLAN has failed to persuade aDelaware district court to adopt with Mylan Specialty and other Mylan subsidiaries in New Jersey.” its preferred construction of several terms contained in US patent At the end of last year, Eli Lilly and Boehringer Ingelheim’s 8,946,292 that protects until March 2027 the Dyloject (diclofenac Basaglar (insulin glargine) 505(b)(2) hybrid became the first follow-on sodium)injectable marketed by Pfizer’s Hospira under licence from insulin glargine available in the US, under the terms of apatent- Javelin. The court preferred Javelin’s proposed construction of the litigation settlement deal struck with Sanofi in October 2015 (Generics terms‘about 82% of maximum observabletotal pain relief’,‘visual bulletin,6January 2017, page 18). analog scale’ and ‘total pain relief’. Furthermore, Merck &Co. and SamsungBioepis earlier this year received tentative FDA approval for their Lusduna Nexvue (insulin ACCORD HEALTHCARE has secured clearance in Germany to glargine) injectable follow-on hybrid 505(b)(2) version of Lantus. market adenosine in 6mg/2ml and 30ml/10ml ampoules. However,Merck and Samsung mayhave to wait untilearly2019 to receive final approval for the diabetes treatment owing to ongoing AMNEAL has filed acitizen petition urging the US Food and Drug patent-infringement litigation with the French originator (Generics Administration (FDA) not to approve any generics of Eli Lilly’s bulletin,28July 2017, page 1). Sanofi has lawsuits against Merck in Forteo (teriparatide)t hat contain asynthetically derived active both Delaware and New Jersey district courts. ingredient. Only abbreviated new drug applications (ANDAs) based Around ayear ago, Mylan and its development partner Biocon on recombinant human parathyroid hormone will be truly equivalent had theirmarketing authorisation application (MAA) for abiosimilar to the original, Amnealargues. Synthetic peptidesshould be submitted version of Lantus accepted for review by the European Medicines as hybrid 505(b)(2) applications, the US firm insists. Agency (EMA).The firms’filingincluded“analytical,functional and pre-clinical data, as well as results from the pharmacokinetics and CIPLA AND IMPAX have followed Aurobindoand Dr Reddy’s in confirmatory efficacy/safety global clinical trial in type 2diabetes obtaining US approval for, and launching,generics of Sanofi’s Renvela patients”comparingthe biosimilar against Lantus (Generics bulletin, (sevelamer carbonate)800mg tablets. Annual US brand sales of 11 November 2016, page 15). G Renvela are around US$1.85 billion, Cipla and Impax noted. G n [email protected]

22 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.18-32.indd 22 01/11/2017 17:33 PRODUCT NEWS

ANTIRETROVIRALS CONTRACEPTIVES Swiss court upholds US NuvaRing ruling an SPC for Truvada is reversed on appeal

witzerland’s federal patent court has rejected an attempt by Teva’s US district court improperly relied on hindsight in deciding that SMepha Pharma to invalidate alocal supplementary protection Aasserted claims in akey US patent shielding Merck &Co’s certificate (SPC) protecting Gilead Sciences’ Truvada (tenofovir NuvaRing (ethinylestradiol/etonogestrel) contraceptive vaginal ring disoproxil fumarate/emtricitabine) combination antiretroviral. But a were obvious in lightofpriorart,aUSCourt of Appeals has decided, Danish court has refused to grant Gilead an injunction to blockAccord’s handing an unfavourable decision to abbreviated newdrug application tenofovir/emtricitabine combination on the basis of asimilar SPC. (ANDA) filer Warner Chilcott. Mepha argued unsuccessfully that Swiss SPC C00915894/01 – Reversing the districtcourt’s decision, the panelofthree appeals based on European patent EP0,915,894 thatexpired on 25 July 2017 – court judges also remanded proceedings back to the lower court for wasinvalid because the Truvada combination was not “protectedby further action. Warner Chilcott –now part of Teva –had previously abasic patent in force”, as required by Article 3(a) of the European conceded that its ANDA product would infringe US patent 5,989,581 – Union’s (EU’s)SPC Regulation 469/2009. Swisscourts,Mepha said, the sole US patent listed in theUSFood and Drug Administration’s should follow EU law and jurisprudenceindetermining SPC validity. (FDA’s) Orange Book protecting NuvaRing –were the patent valid. In particular, Mepha insisted that the Swiss court should align with In August last year, Delaware District Judge Gregory Sleet had the Court of Justice of the EU’s (CJEU’s) jurisprudence, especially ruled thatitwould havebeen obvious to apersonofordinary skill to its landmark Medeva ruling from2011,which stated thatArticle 3(a) have modified aprior art document –InternationalPatentApplication must be interpreted as precluding “granting asupplementary protection WO 97/02015 (PCT ‘015) –toarrive at the ‘581 patent, which certificaterelating to activeingredients which are not specified in the shields NuvaRing until 8April next year. wording of the claims of the basic patent relied on in support of the According to the appeals court, inventors had previously struggled application for such acertificate”. to create adevice that released both progestogenic and oestrogenic compounds –inthis case etonogestrel (ETO) and ethinylestradiol Patent claims ‘other therapeutic ingredients’ (EE) –atastable rate, with earlier prior art designs combining ETO Claim 27 of the ‘894 patent covers tenofovir disoproxil, including and EE in asingle compartment that were however unabletoproperly its fumarate salt, “together with apharmaceutically acceptablecarrier controlreleases foreach compound simultaneously.“The‘581patent and optionally other therapeutic ingredients”. purports to solve this problem byproviding avaginalring made of a Since afederal court ‘Fosinopril’ruling from July 1998, Swiss polymer that is supersaturated with ETO,” the appeals court noted. courts have used an ‘infringement test’todetermine SPC validity. This “Like the ‘581 patent,” it added, “PCT ‘015 also discloses a requires that the product protected by an SPC is covered by the basic vaginal ring that prevents contraception by releasing ETO and EE. patent, butnot that the productcovered by the SPC be specificallynamed PCT ‘015, however, relies on atwo-compartment design, in which in the basicpatent, thus allowing SPCs forcombinations such as Truvada. afirst compartment includes ETO only, and asecond compartment “Thejurisprudence of thefederal court’s Fosinopril ruling on the includes ETO and EE.” infringement test is clear and unmistakeable,and has stood unchallenged In his ruling, Sleet found that it would have been obvious to for decades,” the patent court asserted.“Medeva seems to set an modify the two-compartment ringsothat“pharmaceutically required” additional –albeit negatively formulated –condition to the infringement amounts of both ETO and EE were delivered from one compartment. “The test,” the Swiss courtobserved. While the CJEU had been strivingto district court also found that PCT ’015 discloses target release rates create harmonisationonSPCs withinthe EU to avoidbarriers to free for ETO and EE, and that ‘it would have been obvious for aperson movement of medicines, “Switzerland is not part of the EU’s internal of skill to derive the claimed ratios of progestin and oestrogen’ from market,” the patent court stated. “The Medeva arguments about the the target release rates,” the appeals court noted. internal market therefore are not transferable to Switzerland.” Both conclusions were however rejected on appeal. In reaching Pointing outthat the SPC harmonisation in the EU was largely the first conclusion, the district court had, the appeals court found, basedona“parallel harmonisation of marketing authorisations”, the improperly “relied on hindsight”, aviewpoint underscored by the prior court said Switzerland had “an autonomous licensing procedure”that art’s criticism of one-compartment vaginal rings.“PCT ‘015 expressly resulted in different scope and duration of marketing authorisations. statesthat one-compartment rings are undesirable because it is difficult “Following the Medeva ruling would neither lead to SPCs in the EU to control the release rates for both compounds.” and Switzerland being essentially the same, nor to arecognisably better “Because PCT ‘015 criticises the use of one compartment to free circulation of medicinal products,” it concluded. deliver bothcompounds,”itruled, “the person of ordinary skill would Furthermore, the Swisscourt commented, the disparate language not be motivated to modify ‘015 to make aone-compartment ring.” used in post-Medeva rulings in theEU, as wellasrecent CJEU referrals, Meanwhile, the appeals court also rejected Warner Chilcott’s showed that “the Medeva decision has not clarified the situation so argument that it would have been obvious to calculate the relative much as caused uncertainty”. concentrations for each compound based on disclosures in the prior art, Meanwhile, Denmark’s Maritime and Commercial High Court as the district court had ruled. “PCT ‘015 warns that release rates for refused to grant an injunctiononthe grounds thatclaim 27 of the ‘894 single compartment rings are difficult to control,” the appeals court patent did not comply with Article 3(a) of the EU’s SPC Regulation by commented. “Indeed, PCT ‘015 explains that its design can achieve specifying emtricitabine either by name, chemicalstructureorfunctional consistent release rates because there are two compartments.” definition.Thus, local SPCCR2005 00032couldnot serve as abasis Therefore,itconcluded, an ordinaryartisan would not discard the to bar from the Danish marketAccord’semtricitabine/tenofovir disoproxil two-compartment design “but still expect the ring to deliver a 200mg/245mg coated tablets, the court stated, awarding costs to Accord.G controlled dose of both compounds”. G n [email protected] n [email protected]

3November 2017 GENERICS bulletin 23

Gen 3-11-17 Pgs.18-32.indd 23 01/11/2017 17:33 PRODUCT NEWS

OPIOID-DEPENDENCE DRUGS GASTROINTESTINAL DRUGS US opioid crisis is a Celltrion and Pfizer national emergency stress switching data

SPresident Donald Trump has officially declared the country’s elltrion’s CT-P13 biosimilar rivalmatched the efficacy and safety Uopioid crisis anational public health emergency under federal law, Cof Janssen’s Remicade (infliximab) in aswitching study conducted after adetermination was signed by acting secretary of health and in Crohn’s disease patients, the South Korean company has told a human services Eric Hargan. meeting of European gastroenterologists. Pointing out that nearly US$1 billion in grants for addiction Presenting data from arandomised Phase III trial that was jointly prevention and treatment were alreadybeing distributed, Trumpalso funded by its US marketing partner Pfizer, Celltrion told the 25th stated that the federal government would potentially “bring major United European Gastroenterology (UEG) Week that 166 out of 220 lawsuits against bad actors”. Moreover, the National Institute of Health patients across 16 countries had completed the study to 54 weeks. At had “taken the first steps of an ambitious public-private partnership week 30, around half of the patients in each double-blindgroup were with pharmaceutical companies to develop non-addictive painkillers switched to the alternative treatment. and new treatments for addiction and overdose”, as well as workingon “Efficacy, pharmacokinetics (PK) and safety were comparable an advertising campaign to prevent opioid uptake, especially in children. among all treatment groups up to week 30,” Celltrion stated, adding Trump also outlined actions made by the US Food and Drug that several disease-activity and quality-of-life metrics showed similar Administration (FDA), such as requiring drug companies that results in each group at week 54. “The safety profiles among all manufactureprescription opioids to provide more training to prescribers. treatmentgroups –including adverse reactions, seriousadverse events, AddressingTrump’s“importanteffortstoaddressthe opioid crisis”, infectionsand immunogenicity –were similar throughout the one-year FDA Commissioner Scott Gottlieb said that the agency was “committed treatment period,” the South Korean developer added. to taking additionalsteps” under the new declaration. “The FDA has During UEG Week, Celltrion also presented PK data from an avital role to play in curbing new addiction,” he commented. initial open-labelstudy of asubcutaneousform of CT-P13inhealthy Afocus forthe agencywould beon“promoting the development volunteers.Suchanadministration route was “found to be feasible in of opioids that are harder to manipulate and abuse, and non-opioid terms of bioavailability and safetyprofile,and couldprovidepatients pain treatments”,Gottlieb noted. Further actions included “supporting with amore convenient and accessible treatment option,” the firm said. important efforts to increase the use of and access to the potentially Pfizer –which markets CT-P13 in the US under the Inflectra life-saving antidote naloxone”, and “encouraging the safe adoption and (infliximab-dyyb) brand name –stressed the biosimilar’s comparable morewidespread use of FDA-approved medically-assisted treatments efficacy,safety and tolerability over a24-week period after switching. to help combat addiction”. The firm said the results added to a“considerable body of evidence, The agency also plans to work with federal and international including real-world studies and the Nor-Switch trial”. G partners to “stop the flow of heroin and extremely potent, and often deadly, synthetic drugs like illicitly-made fentanyl”. “One area we’ve committed to exploring further is how opioid drug products are packaged,stored, and ultimately –when no longer GASTROINTESTINAL DRUGS needed –discarded,” Gottlieb continued. “It’s possible that adefined, short-term supply of medication could be packaged in amanner that Canada denies Apotex appeal limits thenumber of pills dispensed.” Other packaging innovations potex has failed to convince the Supreme Court of Canada to could make it easier to track the number of doses that have been taken, Aorderare-hearing of aruling that AstraZeneca’sCanadian patent he suggested, while other optionscould workto“improve storageand 2,139,653 is not invalidfor want of utility.The ‘653 claims optically encourage prompt disposaltoreducethe available supply and reduce pure salts of the proton-pump inhibitor esomeprazole. the risk for third-party access”. Technologies could allow healthcare In alandmark decision handeddown earlier this year, the Supreme providers, pharmacists or family members to monitor patient use of Court had overturned previous findings that the ‘653 patent was invalid prescription opioids, Gottlieb added. because it unjustifiably promised aspecific utility –the so-called The FDA has announced atwo-day public workshop on opioid ‘promise doctrine’ (Generics bulletin,7July 2017, page 1). Rather, the packaging, storage and disposal options, to be held at its campus in Supreme Court said, courtsshould considerwhether identified subject Silver Spring, Maryland, on 11-12 December. Aiming to cover three matter in the patent is useful, adding that“ascintilla of utility will do”. G areas, the workshop willdefine the “specific problems that thesetypes of packaging and disposal solutions can help address”, as well as defining the “guiding principles thatthe scientific community should consider in designing product features that achieve these possible GASTROINTESTINAL DRUGS solutions”. Alast point focuses on defining the “typesofdataneeded to evaluate how these solutions are working”. Two toss out Delzicol case In July, Gottlieb outlined the agency’s latest actions on the opioid ylan and Teva have obtained summary judgements of non- addictioncrisis, including benefit-riskassessment in thepre- and post- Minfringement for US patent 6,649,180 that protects until April market setting, provider education, and steps to reduce overall exposure 2020 Allergan’sDelzicol(mesalamine)capsules for ulcerative colitis. to these drugs(Generics bulletin,28 July 2017, page18). This followed Eastern Texas District Judge Rodney Gilstrapnoted that the judgements ameeting on whether opioidmedications with abuse-deterrent properties “may allow the Food and Drug Administration (FDA) to lift the regulatory were “having their intended impact on limiting abuse” (Generics 30-month stay” on generic approval for Mylan and Teva. Gilstrap bulletin,23June 2017, page 13). G found no errorwithamagistrate’sconstruction of ‘gelling agent’ to mean n [email protected] a‘substance that gels the film composition’ which is not water. G

24 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.18-32.indd 24 01/11/2017 17:33

AWARD WINNERS

Award: Company of the Year Award: Company of the Year, Americas Sponsor: QuintilesIMS Sponsor: Chartwell Pharmaceuticals Winner: Hikma Pharmaceuticals Winner: Amneal Pharmaceuticals

Award: Company of the Year, Asia-Pacific Award: Company of the Year, EMEA Sponsor: Evapharma Sponsor: Panacea Winner: Aurobindo Winner: Medis

Award: Acquisition of the Year Award: Leader of the Year Sponsor: Pharmawise Sponsor: Pharmacloud Winner: Accord Healthcare Winner: Amneal Pharmaceuticals SAVE THE DATE ... The Global Generics &Biosimilars Awards 2018 will take place on Tuesday 9October 2018 and be held in Madrid, Spain.

26 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.18-32.indd 26 01/11/2017 17:33 AWARD WINNERS

Award: Innovation of the Year Award: Business Development of the Year Sponsor: Piramal Pharma Solutions Sponsor: James Dudley Management Winner: Chemo Group Winner: Accord Healthcare

Award: API Supplier of the Year Award: Biosimilar Initiative of the Year Sponsor: Clarivate Analytics Sponsor: Generics bulletin Winner: Laurus Labs Winner: Sandoz

Award: Regulatory Achievement of the Year Award: Patent Litigation of the Year Sponsor: Eignapharma Sponsor: QuintilesIMS Winner: Sandoz Winner: Accord Healthcare

Award: Industry Partner of the Year Award: CorporateSocial Responsibility (CSR) Initiative of the Year Sponsor: mAbxience Sponsor: International Health Partners (IHP) Winner: Piramal Pharma Solutions Winner: Alvogen

3November 2017 GENERICS bulletin 27

Gen 3-11-17 Pgs.18-32.indd 27 01/11/2017 17:33 AWARDS

7

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28 GENERICS bulletin 3November 2017

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Bulletin Publishing Group, OTC Publications Ltd, 4 Poplar Road, Dorridge, Solihull B93 8DB, UK. (Tel: +44 (0)1564 777550; Fax: +44 (0)1564 777524). Registered in England No. 2765878. VAT GB 608 0432 69 MERGERS &ACQUISITIONS Amneal and Impax eye new channels forUSdistribution

Becoming a leader in littleunder two month sago, PaulBisaro, Impax modelfor certaingenerics,under whichAmneal could Laboratories’ president and chiefexecutive officer, bypass payers and create a direct relationship with patients. alternative, direct-to- A expressed his belief thatmanufacturersinthe US “In the past we’ve thought mostly about our patient distribution is were likely to explore relationships with consumer- customers as being the wholesalers, retailers and the focused operators, against the backdrop of customer mail-order companies,” Bisaro acknowledged. “And I among the numerous consolidation in the market that has created just three think we as agenerics industry need to start thinking key buying groups for retail generics. about our customers as patients, and find ways to be benefits that Amneal “I think we areatthe cusp ofatime whenwewill more connectedtothose patients. That is going to be one and Impax expect to start seeing new distribution channels coming to fruition, of the ways that we address some of the challenges that just because of the dynamics of the industry,” Bisaro this industry is facing.” drive future growth as told investors (Generics bulletin,22September 2017, “The great news about new Amnealiswenow have page 4). “And we now liveinanenvironment and time the resources to be able to do that,” he insisted, “and not acombined company. where companies like Amazon, Federal Express and just from aproduct perspective, but from afinancial Dean Rudge reports. UPS, who have direct access to consumers, will find perspective. So that’s what makes me so excited about away to participate in the channel.” this transaction, and why Ithink we can be successful By using “anAmazonordirect-to-patientmodel”, in what is clearly achallenging industry right now.” Bisaro opined,Impaxcould “sellour productatprobably With the combination forecasting asales compound the same margin, or maybe at even aslightly higher annual growthrate (CAGR) of around12% overthe margin, because we are now cutting our way around next three years, the “challenging” nature of the industry all the people who had to take apiece of the pie”. was high on investors’ listofqueries as they faced both Such strategies are now high on Bisaro’s agenda management teams. “I think it’s fair to say investors moving forward, following Impax’ agreement with are alittle bit gun-shy about signing up for revenue Amneal Pharmaceuticals to mergeinto anew publicly- growth in the generics business, let alonedouble-digit traded company. The all-share transaction, which is growth,” one analyst commented. expected to close in the first half of next year, is set to Underits sales forecast, the new firm expects pro create the fifth-largest generics business by sales in forma sales to rise fromapproximately US$1.75-US$1.85 the US (Generics bulletin,20October 2017, page 1). billion this year to around US$2.6 billion in 2020. Alongside Impax’ chief financial officer Bryan Acknowledging the intensity of pricing pressure Reasons, and Amneal’s foundersand co-chief executive facing manufacturers in the US market, Reasons said officers, Chirag Patel and Chintu Patel, Bisaro told that thecombinationhad factored in base price erosion investors that the new company would havethe “scale of around 8.5-10%, “if there were no other competitive and flexibility to be creative in all commercial strategies reasons to model something differently”. “We have one in the evolving generics industry”. of the nicest housesinthe neighbourhood, Bisaro said, Describing product distribution as a“challenge” “and whatweneed to do is improve the neighbourhood.” the industry was currently facing, Bisaro raised the To achieve the double-digit sales growth,Amneal possibility of the new Amneal Pharmaceuticals company and Impax aim to capitalisesales on the combination’s adopting a‘cash-pay’ direct-to-patient distribution “significantly expanded generics portfolio”, covering “just

Other Injectables Other Injectables Transdermals 3% 14% Transdermals 2% 23% 2% 5% Nasal sprays Nasal sprays 1% 2% Topicals 7% Inhalation 6%

Extended- Topicals release 5% tablets Extended- 15% release tablets 5% Immediate- Oral liquids release Immediate- 7% Oral liquids tablets release tablets 14% 21% 37% Capsules/soft gels Capsules/soft gels 14% 16%

Figure 1: Breakdown by product type of Amneal’s and Impax’ Figure 2: Breakdown by product type of Amneal’s and Impax’ combined pipeline of approximately 150 abbreviated new drug combined development pipeline of approximately 165 products application (ANDA) filings (Source –Amneal/Impax) (Source –Amneal/Impax)

30 GENERICS bulletin 3November 2017

Gen 3-11-17 Pgs.18-32.indd 30 01/11/2017 17:33 MERGERS &ACQUISITIONS about every dosageformavailable”, as well as execute to adeveloper,” Bisaro underlined. “We have plenty on on its “exceptional generics pipeline”. our plate right now, with very complex molecules, According to Chirag Patel, the combination’s peptides and difficultprojects.” Impax’ chief noted that portfolio willnumber approximately165 marketed generic the new company would “figure out apath later if we product ‘families’ in the US, of which around half want to get into manufacturing biosimilars”. hold either the number one or two position by sales. Supporting the firms’ portfolio and pipeline ambitions Meanwhile, Patelstressed, all of Amneal’s products is the combination’s “fully diversified, cost-efficient” were manufactured in-house, meaning that no profits global manufacturing and research and development derived were shared with partners. network. “We have aconsistent track record [of quality], “I don’t think we’ll be rationalising our portfolio with 59 successful FDA inspections across the in the generics space,” Bisaro said in response to an manufacturing network,” Chintu Patel pointed out. investor query. “However, we’ll certainly continue to Across the US and Europe, the combination will monitor products where they fall belowdirect costs.” boast oral-solid manufacturing facilities in Hayward, Meanwhile, the combination’s pipeline will be California, and Brookhaven and Hauppauge, New York; composed ofapproximately150 abbreviated new drug liquid and topicals facilities in Branchburg and Piscataway, applications (ANDAs) pending US Food and Drug New Jersey, as well as transdermal capabilities at the Administration (FDA) approval,aswell as 165 projects Piscataway facility; and the capability to manufacture currently under development. respiratory products at afacility in Cashel, Ireland. Of these approximate315 pipeline assets, roughly Outside of the US and Europe, the firms will have 50% are defined as ‘high-value’ opportunities by the sterile, aseptic and oral-solid dosage facilities in merger partners, representing projects that are exclusive Ahmedabad and Hyderabad, India, as well as active first-to-file, first-to-file,first-to-marketor“otherhigh- pharmaceutical ingredient (API) manufacturing in Vizag value opportunities with zero to three competitors”. and Dehej, India. Of the firms’ global manufacturing As Figure1shows, just lessthantwo-fifths of the footprint, seven facilitieshad research and development 150 pending ANDAs reference immediate-release tablet centres co-located within, Chintu Patel pointed out. formulations.Extended-release tablet formulations make Moving forward, the combination is mulling the up another 15% of ANDA filings, capsulesorsoft-gel idea of bringing in-house Impax’ current roster of products and injectables each comprise 14%, and oral products currently manufactured by contract liquids and topicals another 7% each. manufacturers, in an effort to drive further efficiencies, “Amneal overinvested Amongthe combination’s leading ANDAs currently and improve the combined company’s gross margins. pending FDA approval are rivals to Teva’s Copaxone Quizzed on whether the firms had any plans to in research and (glatiramer acetate), Shire’s Lialda (mesalamine) and consolidatethe combined manufacturing network,Bisaro Jazz Pharmaceuticals’ Xyrem (sodium oxybate). said adecision had not been made.“As it evolves, we development, and new Moreover, Impax has just launched generic rivals to will keep you guys informed,” he said. But, Bisaro Amneal is going to enjoy Sanofi’s Renvela (sevelamer carbonate) immediately opined,the combination currently had “plentyofcapacity upon obtaining FDA approval (see page 22). to manufacture products that are filed, as well as the the fruits of that” Concerning the development pipeline, Chintu Patel products that are in the pipeline.” pointed out that “the future of our generics franchise In addition to these strategic benefits, the firms also is more heavily weightedtowardscomplex products,such feel the combination will be “financially compelling”, as injectables, topicals and transdermal and respiratory with the new company projected to generate annual products”. As Figure 2shows,injectables comprise just cost savings of US$200million within three years. under aquarter of development assets, while transdermal The combined synergies would be in addition to products and inhaledproducts also representagreater those achieved from Impax’ existing ‘cost improvement proportion compared with filed ANDAs. plan’, throughwhich the US-based firm has announced And, Patel added, becoming apublicly-traded US$135 million worth of savingsover the last 18 months, company meant investors couldhope “to see manymore according to Reasons (Generics bulletin,1September products from our pipeline” moving forward. 2017, page 7). Impax’ cost savings were now starting “Amneal overinvestedinresearch and development to “kick in”, Reasons said, and would be more tangible in the first 10 years of its life, and new Amneal is going in the remainder of this year and into 2018. to enjoy the fruits of that,” Bisaro insisted. “I can’t Together, these cost savings will help the firms guarantee that all of these products will not have achieve their goal of reporting adjusted pro forma additionalcompetition, but Iamconfident thatwewill earnings before interest, tax, depreciation and amortisation havealimitednumber of competitorsinsomeofthese (EBITDA) of approximately US$1.1 billion in 2020, projects. We have alot of shotsongoal.” up from approximately US$600-US$650 million in In addition to capturing value from its own pipeline, 2017, representing aCAGR of around 22%. the combination also aims to derive value through its Commenting further on the double-digit sales and nascent biosimilars pipeline, in conjunction with Amneal’s earnings guidance over the next three years, Bisaro partner Adello Biologics. The combination will hold observed that the “law of large numbers is in our favour commercial rights in the US to both Adello’s Neupogen right now”. “We are asmall company that is growing, (filgrastim) and Neulasta (pegfilgrastim) biosimilars. which is why we feel very comfortable about double- Amneal noted that the Neupogenbiosimilar had digit growth,” he insisted. been filed with the FDA, while the Neulasta biosimilar– “As we get out five-to-seven years, we have to for which approval has so far proved elusive for several recognise that the growth profile of our generics business biosimilars developers –would be filed in “early 2018”. is going to slow down, and so we need to deploy our “With respect to biosimilarsgoingforward, we see capital in away thatgives us adjacenciesthat allow us ourselves as moreofacommercialpartner, as opposed to grow beyond thoseyears at thisfast rate.” G

3November 2017 GENERICS bulletin 31

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RESIGNATIONS APPOINTMENTS GBMA seeks achief Teva’s Schultz plans as Wood steps down to start global review

ustralia’s Generic and BiosimilarMedicinesAssociation (GBMA) eva has announced that its new president and chief executive Ais looking to recruit anew chief executive officer (CEO), after Tofficer (CEO), Kåre Schultz,has begun his tenure as leader of the the incumbent, Belinda Wood,announced plans to standdown from Israeli firm and as amember of its board from 1November. Former the post in February 2018. Lundbeck chief Schultz was announced as the successor to interim Having served as CEO of the GBMA since 2014, Wood had been chief Yitzhak Peterburg in September (Generics bulletin,15 “pivotal in the signing of, and subsequent extension to, the strategic September 2017, page 1), ending asearchthat began when Erez agreement with government”, the association said, referring to the Vigodman resigned “by mutual agreement” at the start of February five-year deal struck in 2015 (Generics bulletin,5June 2015, page 14) (Generics bulletin,10February 2017, page 1). that was extended by two years earlier in 2017 (Generics bulletin, “I am looking forward to getting to work as Teva’s CEO alongside 26 May 2017, page 1). The GBMA’s “enhanced reputation with the Teva team,” Schultz stated. “I look forward to travelling throughout government” had enabled the associationto“have a‘seat at the table’ Teva’s global operations and reviewing the opportunities we have to for ongoing policy discussions”, the group stated. better serve patients and healthcare systems in each of our markets.” “It has been an honour to lead GBMA as its CEO for the past three Schultz said his focus would be on “strengthening Teva’s business years,” Wood said. “When Itook the role, my focus was to deliver and enhancing our leadership in specialty and generic medicines to certainty for the generic and biosimilar medicines industry, to increase deliver sustained shareholder value creation”. the use of affordable medicines and to secure apredictable market Schultz joining the company was “the start of anew chapter at access pathway for biosimilars. Having achieved these goals, and Teva”, said board chairman Sol Barer.With “extensive global securing and extending the strategic agreementwith government, the pharmaceutical experience and astrong track record in corporate time is right for me to look for the next opportunity, knowing Ileave turnarounds, as well as in driving growth and leading international the GBMA well-placed for the future.” expansion”, Schultz would help “position Teva for long-term success”, Wood’s successor as CEO of the GBMA will be asked to “lead Barer said. Teva suffered aUS$5.74 billion operatingloss in the second the association through its next phase in implementing the key elements quarter of 2017,due to weakness in US generics that led to aUS$6.1 of the extended strategic agreement”. G billiongoodwillimpairment(Generics bulletin,11August2017, page1).G

FOR 2017NEW MAIL ORDER AND INTERNET PHARMACY IN EUROPE 2017 RESIGNATIONS REAPING THE BENEFITS OF Slegers steps down at Stada AN OMNICHANNEL PRESENCE tada has announced that Luc Slegers is stepping down as manager Sof Stada Europe and retiring after 26 years with the company. AStudy Of Mail Order “With the new majority owners Cinven and Bain Capital as well as And Internet Pharmacy the new chief executive officer Claudio Albrecht,Stadaisvery well- In 17 European Countries positioned,” Slegers stated. “I see tremendous opportunities for growth in segments wherewewere previously limited due to financialresources.” Plus Key Learnings Executive board chairman and chief executive Albrecht was From The US And China nominated to replace Engelbert Coster Tjeenk Willink earlier this year following Stada’s takeover by Bain Capital and Cinven (Generics This expanded fourth edition of Mail bulletin,8September 2017, page 1). He said Slegers “leaves behind Order and Internet Pharmacy in afoundation that we can use to build Stada into an even more important Europe shows how e-commerce is and bigger player in the generics and OTC businesses”. reshaping the pharmacy landscape Meanwhile, Stada has named FrankStaud as itsexecutive vice- and playing a key role in president of corporate communications, branding and sponsoring. As the omnichannel strategies well as being responsible for “the image of the Stada brand”,hewill also manage the group’s communication activities, includingcorporate of leading healthcare retailers. and product communication, change communication, external and internalcommunications, branding,and sponsorship. Staud will report Mail Order and Internet Pharmacy in Europe directly to Albrecht. covers: Austria, Belgium, China, Czech “Stada currently finds itself in the midst of the biggest transformation Republic, Denmark, Finland, France, phase in its history.Outstanding internaland external communication Germany, Hungary, Italy, Netherlands, is thereforeofutmostimportance,”Albrechtpointedout. “I am therefore Norway, Poland, Slovak Republic, Spain, extremely pleased that we have been able to attract Frank Staud, a Sweden, Switzerland, the UK and the US. proven expert, for this important task –someone who is aspecialist in change communication.”Staud –who “has more than 20 years of ® experience” in communications –previously servedasexecutive vice- Available to download at ® JAMES DUDLEY president of corporate communications at Actavis, where Albrecht www.james-dudley.co.uk MANAGEMENT was formerly chief executive. G

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