Mylan claims victory on US and Irish Copaxone · 2017. 12. 5. · DeputyEditor:DavidWallace...

15 December 2017

Mylan claims victory onUS and Irish Copaxone

COMPANY NEWS 2New Harbor assumes 2LGM Pharma control

Authorised generics interest Aspen Japan 2

PMC buys Isochem to boost 3pharma push

Sandoz commits to competing in the US 3

Saneca sees Russia as a route to growth 4

Shredded documents 5at issue for Glenmark

WBA grabs stake in Chinese 5GuoDa chain

MARKET NEWS 6Industry airs concern over 6ANDA guidance

UK urged to address 7shortages and prices

FDA comes good on reviews 7at first cycle

ICH adopts guideline on 8multi-region trials

Canada price body to relax reporting rules 8

PRODUCT NEWS 9IGBA asks FDA for increased flexibility 9

Teva prevails in US 9Namenda XR appeal

Mylan petitions FDA on Advair standards11

Unipharma launches 11French levothyroxine

NZ awards Apotex a solo 12gabapentin deal

Romania eyes Roche on 13erlotinib exclusion

Teva offers services to support sildenafil 13

Sandoz’ rituximab is 15approved in Australia

Coherus claims win on US pegfilgrastim 15

REGULARS

Events – Our regular listing 6

Pipeline Watch – Rosuvastatin, retigabine10

Price Watch UK – Our regular listing 14

People – Obituary: Olainfarm’s 16Valerijs Maligins

Issue No.334

Teva has dismissed US patent litigation against Mylan over two patents protecting theIsraeli firm’s Copaxone (glatiramer acetate) 40mg/ml, following a claim-construction

decision in Mylan’s favour. At the same time, Teva has agreed to withdraw counterpartIrish patents from proceedings recently filed against Mylan in Ireland.

Noting that the US litigation involved two non-Orange Book patents – US patents 9,155,775and 9,763,993, relating to the final sterile filtration step in the manufacturing process forglatiramer acetate – Mylan confirmed that “Teva dropped litigation on these patents after theUS District Court for the district of Delaware issued a decision adopting Mylan’s interpretationof the patent’s claims”. “In addition, Teva has agreed to withdraw the Irish equivalent to thesepatents from the recently-filed proceeding in Ireland,” submitted by the firm in October.

After these dismissals, Mylan observed, “Teva’s only remaining patent challenges in theUS and Ireland against Mylan’s glatiramer acetate 40mg/ml relate to the three-times-a-weekdosing regimen, which Mylan has already successfully invalidated at the US District Court forDelaware, the US Patent Trial and Appeal Board (PTAB), and the UK’s High Court of Justice”,where it was found that the thrice-weekly formulation was “obvious to try” (Generics bulletin,3 November 2017, page 19). However, Teva is appealing against these decisions. A hearingon Teva’s Irish injunction request has been scheduled for January.

Earlier this year, Mylan launched generic versions of both the lower Copaxone 20mg/mlstrength and the higher 40mg/ml version following US Food and Drug Administration (FDA)approval (Generics bulletin, 6 October 2017, page 1). Teva warned that Mylan could face“significant damages” given that the launch took place while appeals and ongoing litigation werestill pending (Generics bulletin, 13 October 2017, page 14).

Sandoz also markets a 20mg/ml version of glatiramer in the US through a partnership withMomenta, but the pair were told earlier this year that a 40mg/ml version could not be approvedin the US until deficiencies are resolved at a US plant operated by fill-finish manufacturingpartner Pfizer (Generics bulletin, 24 February 2017, page 1). G

Notice gives no validity to SPCsEnd of procedure notices issued as part of decentralised marketing-authorisation applications

in Europe do not convey validity on supplementary protection certificates (SPCs), accordingto a ruling handed down by the Court of Justice of the European Union (CJEU). Rather, the courtsaid in a dispute over Merck, Sharp & Dohme’s (MSD’s) Atozet (ezetimibe/atorvastatin), avalid national marketing authorisation is required at the time of filing for an SPC.

On 10 September 2014, the reference member state (RMS) in a decentralised procedure,Germany, issued an end of procedure notice for the Atozet combination cholesterol-loweringagent. Two days later, on 12 September, MSD applied for an SPC in the UK, accompanied bya copy of the end of procedure notice issued in Germany. But the UK’s Intellectual PropertyOffice (UKIPO) a week later rejected the application because MSD did not hold a valid UKmarketing authorisation. The UK’s Patents Court referred the dispute to the CJEU.

According to the CJEU, an end of procedure notice “represents an intermediate stage inthe decentralised procedure” and does not have the same legal effect as a valid marketingauthorisation, so could not be used as the basis to obtain an SPC. Furthermore, the Europeancourt stated, the absence of a marketing authorisation “does not constitute an irregularity” thatcould be corrected under Article 10(3) of the SPC Regulation 469/2009/EC. G

2 GENERICS bulletin 15 December 2017

COMPANY NEWS

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Issue 334 l 15 December 2017

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Active pharmaceutical ingredient (API) distributor LGM Pharma nowforms part of private-equity firm New Harbor Capital’s healthcare

portfolio after the Chicago-based investor completed a majority equityinvestment in the bulk-drugs specialist for an undisclosed fee.

With a headquarters in Nashville, Tennessee – supported by amarketing and administration office in Boca Raton, Florida, a business-development unit in New York and a warehouse in Erlanger, Kentucky –LGM describes itself as specialising in “streamlining the API supplychain throughout all development stages while providing completetechnical capabilities and expert regulatory support”.

“Some of the APIs that we supply are manufactured via non-infringing processes which would be suitable for paragraph IV [patent]challenges and/or early launches in regulated markets,” highlightedLGM, which – according to New Harbor – achieved a turnovercompound annual growth rate (CAGR) of 12% in the three years priorto being acquired.

Founded in 2005, the company claims to serve “many activecustomers across biotech, generic pharma, contract manufacturing,specialty pharma, contract development and manufacturing organisations(CDMOs), academic institutes, compounding and pharmaceuticalmanufacturing industries”, as well as to support all stages of drugdevelopment and commercialisation by supplying a wide range of APIs,drug master file (DMF) documentation and other services.

“With the healthcare network, strategic vision and capital thatNew Harbor brings to LGM, we look forward to expanding our serviceofferings while continuing to invest in the substantial growth of ourcompany,” commented LGM’s chief operating officer Mendy Schurder,who co-founded the distributor with commercial director Gideon Schurder.

With over US$400 million of capital under management, NewHarbor invests in “lower middle-market” companies that operate inthe healthcare, educational and business services arenas. Its broadhealthcare interests cover psychiatry, pain-management specialists,primary care and veterinary compounding.

Explaining its move for LGM, the private-equity firm said it was“pursuing pharmaceutical and pharma services investments, with anemphasis on companies that add value to the prescription medicationsupply chain”. Among New Harbor’s plans to capitalise on its investmentare increasing LGM’s business-development capabilities and pursuing“complementary acquisitions to enhance core offerings”. G

MERGERS & ACQUISITIONS

New Harbor assumesLGM Pharma control

Aspen Japan – the local operation of South Africa’s AspenPharmacare – says “various parties” are in discussions with the

firm to “broaden the basket” of the firm’s authorised generics, “andmake Aspen Japan their go-to partner” for such products in the market.

Pointing to its current strategy for authorised generics frommultinational companies, Aspen highlighted valaciclovir tablets andgranules. For the tablet formulation of its authorised generic ofGlaxoSmithKline’s (GSK’s) Valtrex original, Aspen said it had, afterlaunching in July last year, achieved the number one position in apool of 32 competitors, with an 18.5% market share.

Meanwhile, Aspen has also achieved the number one position forthe granule formulation, obtaining a market share of greater than aquarter out of four rivals, after introducing the product last September.

And for sumatriptan succinate, which Aspen Japan launched inJanuary this year, the company currently places second out of 10competitors, with a 12.6% market share.

Aspen began operating in Japan from the third quarter of 2015,after signing an agreement with GSK in 2014 to invest ¥2.5 billion(US$22.2 million) into a new Japanese business – 75% from Aspen,and 25% from GSK. Under the agreement, Aspen said it wouldtransfer to Aspen Japan all products currently marketed or distributedon its behalf in Japan, as well as rights to all future products that itacquires or licenses in the country.

Meanwhile, GSK agreed to provide a portfolio of certain off-patent, mature brands in addition to authorised generics of the originator’sbrands upon loss of exclusivity (Generics bulletin, 17 October 2014,page 7). For these products, the Japanese firm said it had achieved“proven success” with GSK.

Aspen Japan’s retail sales to customers in its financial yearended 30 June 2017 totalled ¥19.3 billion, including ¥5.88 billion from‘existing global brands’ and ¥1.14 billion from ‘licensed products’.Recently, Aspen Japan announced that it had “inherited” themanufacturing and marketing approval for the UK-based originator’sArixtra (fondaparinux) subcutaneous injectable anticoagulant.

Noting that Aspen was attracted to the Asia region due to its“emerging middle class”, as well as the loyalty displayed by Asianpatients to off-patent brands, the South African firm said it would aimto offer a ‘pan-Asia’ solution to its partners, attesting that “we areattracting more opportunities as a one-stop shop”. G

BUSINESS STRATEGY

Authorised genericsinterest Aspen Japan

3GENERICS bulletin

COMPANY NEWS

15 December 2017

US-based chemicals and plastics company PMC Group has furtheredits strategic goal of becoming “a major market player in providing

cost-effective generic drugs and drug intermediates to the globalmarket” by acquiring the pharma business of French bulk-drugsproducer Isochem for an undisclosed fee. The transaction comes lessthan two months after PMC bought Indian pharma company YegnaManojavam (YM) Drugs and Chemicals, a deal that marked the startof PMC’s “journey toward building a global pharmaceutical business”(Generics bulletin, 17 November 2017, page 6).

Through its French affiliate, PMC says it is acquiring in Isochem“a fully integrated business comprised of research, product/processdevelopment, regulatory approvals, pilot-scale and full plant-scaleproduction of drug intermediates and active pharma ingredients (APIs)for major pharmaceutical companies worldwide”. The French firm, itinsists, is able to serve the needs of clients operating in therapeuticcategories including oncology, cardiovascular, infectious diseases,gastrointestinal, neurology and rare diseases.

The deal includes facilities at three sites within around 100kmof Paris, France – Gennevilliers, Pithiviers and Vert-Le-Petit – thathave a combined footprint of around 16 hectares. The three productionsites – all of which have been certified for current good manufacturingpractice (cGMP) by the US Food and Drug Administration (FDA), andtogether employ over 230 staff – will operate under the ‘PMC IsochemSAS’ banner as a wholly-owned subsidiary of PMC Group France.

Isochem – which was acquired by Germany’s Aurelius group in2010 – says it generates around three-quarters of its turnover frompharmaceuticals, 15% from cosmetics and a tenth from other finechemicals. The European Union (EU) and the US each make up about45% of turnover.

Noting that the move for Isochem came shortly after its takeoverof Hyderabad-based fluoroquinolone producer YM, PMC Group’sexecutive vice-president Raj Chakrabarti insisted that the firm was now“in a solid position to serve all the regulated pharma markets aroundthe world with cost-effective offerings of proprietary drugs, drugintermediates, and custom drug research and manufacturing servicesfor a wide range of disease categories”. G


PMC buys Isochemto boost pharma push

Sandoz has no intention of exiting the US generics arena entirely,a company spokesperson told Generics bulletin in response to a

media report suggesting parent group Novartis was looking at “offloadingits generic pills business in the US as the market continues to decline”.

“We are continually reviewing our portfolio and are confidentthat our focus on value-added products will drive sustainable profitablegrowth in the long term. In response to high pricing pressure, we arecurrently optimising our US portfolio,” the spokesperson stated.

“This includes divesting/discontinuing certain non-core productsand focusing investment on strategic areas that will drive growth andincrease access. While we continue to optimise our portfolio, it isclear that the US market is a very important market for Sandoz andwill continue to be so in the future,” he insisted.

Citing an analyst’s report, media reports had suggested that JoeJimenez, chief executive officer of parent group Novartis, and hisimminent successor Vas Narasimhan, had indicated that the group wasexamining options for Sandoz’ US solid-dose operation, including aspin-off. Previous media rumours had suggested that Novartis wasconsidering whether to divest the US generic dermatology businessthat Sandoz had acquired by paying US$1.525 billion for Fougerafive years ago (Generics bulletin, 18 May 2012, page 1).

Stressing that headlines suggesting a full spin-off of the USoperation were “misleading”, the Sandoz spokesperson declined tocomment on specific parts of Sandoz’ US business. However, he saidthe division was working on rationalising its US portfolio to eliminatenon-core and unprofitable products.

Sandoz had, he pointed out, already taken action to streamlineits US manufacturing footprint by announcing plans to shift productionfrom a facility at Broomfield, Colorado, to a site in Wilson, NorthCarolina. The decision to close the Broomfield plant came after Sandozidentified “several negative-margin, limited-growth products that areno longer viable due to double-digit price erosion in the US genericsmarket” (Generics bulletin, 3 November 2017, page 4).

The US remains Sandoz’ largest single market. In the third quarterof this year, sales of retail generics in the US tumbled by 13%, matchinga similar fall in total US turnover to US$798 million, “driven byincreased pricing pressure from competition in retail generics andcontinued customer consolidation”. The US accounted for 31% ofSandoz’ total turnover in the quarter that rose by 3% as reported, andby 1% on a constant-currency basis, to US$2.58 billion.

Amid the severe pricing pressure in the US, Novartis had reviseddownward its full-year global sales guidance for Sandoz to “broadlyin line with prior year to a slight decrease”. G

BUSINESS STRATEGY

Sandoz commits tocompeting in the US

Deficiencies observed by the US Food and Drug Administration(FDA) at Dr Reddy’s Bachupally facility in Hyderabad, India,

have been resolved after the agency issued an establishment inspectionreport (EIR) closing out the audit of the plant. Earlier this year, theFDA inspection resulted in 11 ‘Form 483’ observations that theIndian firm said were “mostly procedural in nature, reflecting the needto improve people capabilities and strengthen documentation andlaboratory systems” (Generics bulletin, 5 May 2017, page 3).

The FDA’s resolution of the deficiencies observed at Bachupallycomes shortly after German regulators allowed the firm to resumeproduction for European Union (EU) markets at its sterile injectablesfacility in Duvvada, India (Generics bulletin, 8 December 2017, page 2).An EIR was also recently received from the FDA relating to the Duvvadasite, but Dr Reddy’s noted that the agency has not yet formally closedthe inspection (Generics bulletin, 1 December 2017, page 4). G

MANUFACTURING

FDA certifies a Reddy’s plant

Biocon has received almost unanimous shareholder approval in apostal ballot to transfer its biosimilars operation as a “going concern”

to a wholly-owned subsidiary of the Indian group. The transfer by wayof a ‘slump sale’ will be to the firm’s Biocon Biologics India subsidiary.

The Indian company markets several follow-on biologics in itsdomestic market and has a global strategic alliance with Mylan.

Biocon did not explain its rationale, but media reports have suggestedit may facilitate a stock exchange listing for the biologics business. G

BUSINESS STRATEGY

Biocon can shift biosimilars


COMPANY NEWS

Making products for its partners to market in Russia is “an importantpart of the growth strategy” for Saneca Pharma, the contract

development and manufacturing organisation (CDMO) believes. Thecompany’s facility in Hlohovec, north-east of Bratislava, Slovakia, wasearlier this year approved by Russian regulators to supply film-coatedtablets, hard and soft-gel capsules, liquids for topical use, and semi-solids such as ointments (Generics bulletin, 26 May 2017, page 4).

Chief executive officer Anthony Sheehan told Generics bulletinthat the good manufacturing practice (GMP) inspection by Russianauthorities had been triggered by a regulatory filing made by a client.

Acknowledging the Russian government’s ‘Pharma2020’ goal ofincreasing domestic production of medicines, especially of thosedeemed to be essential drugs, Sheehan insisted that ample opportunitiesremained for CDMOs to import into the country. “An important segmentof our customer base will be European companies looking to importinto Russia,” he predicted.

As part of that strategy, Saneca last year struck a five-year deal tomake more than 20 branded generics for Xantis Pharma, the Swiss-based company founded by a group of former Actavis executives thatis building a portfolio of branded generics and OTC products in EasternEurope, including in Russia and the Commonwealth of IndependentStates (Generics bulletin, 5 August 2016, page 2).

Beyond Russia, Sheehan said Saneca had secured “several newcustomers during 2017 in the ‘DACH’ region – Germany, Austria andSwitzerland – France, Belgium, Netherlands and Luxembourg (Benelux)and Ukraine. Furthermore, he said the company was “working ondevelopment projects for customers in France, England and Poland,so the quantity and quality of customers continues to grow for Saneca”.

Discussing Saneca’s technical capabilities, Sheehan said thecompany was working on maximising the return on the investment ithad made in controlled-release pellet manufacturing, such as through acontract the firm had secured with Italy’s Menarini (Generics bulletin,25 November 2016, page 6). Effervescent tablets, liquids, hard andsoft-gelatin capsules also remained areas of interest, he added.

Having filed two European certificates of suitability (CEPs) during2017, Saneca was growing its bulk opiates business in Europe, Sheehanrevealed. “We are looking for partners with which to forward integratein this area in Europe,” he said, pointing out that in the US – whereabuse-deterrent technologies were of greater market importance – thecompany had a strategic alliance with AMRI.

Sheehan said Saneca was targeting three to four regulatory filingsfor active pharmaceutical ingredients (APIs) per year, having recentlyinstalled a kilo-lab at Hlohovec to enable it to scale-up bulk drugs on asmaller scale, thereby minimising raw-material costs during development.

Having expanded in part through acquisition, the Slovakiancompany – which acquired the Hlohovec site from Sanofi’s Zentivafive years ago (Generics bulletin, 14 December 2012, page 3) – wascurrently aiming to consolidate and was “not actively looking” fortakeover targets, Sheehan said, noting the need to continuously upgradeequipment and to invest in serialisation technologies.

Relying on organic growth to achieve Saneca’s stated target ofreaching a turnover of C100 million (US$117 million) by 2021 wouldbe “challenging”, Sheehan admitted. However, he said, acting as areliable, single-source site for around 15-20 core finished-dosecustomers should enable the firm to keep expanding. “We know whowe are,” he stated. “We do not need hundreds of key accounts.” Gn [email protected]

BUSINESS STRATEGY

Saneca sees Russiaas a route to growth

PANACEA BIOTEC has had its credit rating downgraded byIndia’s Credit Analysis & Research (CARE) in light of the firm’srecent financial performance. The Indian company – which recentlyteamed up with Apotex to launch prasugrel in the US, and has alsojust had a filing for generic Abraxane (paclitaxel) albumin-boundparticles suspension accepted for filing by the US Food and DrugAdministration (FDA) – acknowledged that its ‘CARE D’ creditrating “indicates that instruments with this rating are in default orare expected to be in default soon”. Due to “cash-flow challenges”,Panacea said it was facing delays in meeting instalments on a loan.

PHARMAFORCE – the privately-held contract development andmanufacturing organisation (CDMO) – is investing US$145 millionin expanding two US facilities near Columbus, Ohio, according toa local economic development body. “Construction and remodellingwill commence in 2018,” the Columbus 2020 body said, noting thatPharmaForce would add around 13,000 sq m by building outmanufacturing and warehousing operations at its New Albany site,while adding 170 sq m to a plant in Hilliard would accompanyinvestment in new equipment.

ASCENDIS HEALTH has agreed to pay ZAR396 million (US$28.9million) plus a deferred, performance-related sum, for veterinaryproduct supplier Kyron. The South African group – which alsomarkets human generic and OTC drugs – said the deal wouldcomplement the recent purchase of Cipla’s animal-health businessby its Ascendis Phyto-Vet division. Separately, Ascendis has decidedto “raise equity to repay a portion of the company’s medium-termdebt obligations” ahead of a deferred payment of C90 million(US$106 million) becoming due on 25 August 2019 to the vendorsof Cypriot generics developer Remedica. That obligation has nowbeen reduced to C86.2 million in return for accelerated payments.

FRESENIUS KABI has opened an extension at its production plantin Mihla, Germany, following a C10 million (US$12 million)investment. In a new 1,000 sq m hall, employees will make injection-moulded components for pharmaceutical containers, infusion portsystems and medical disposables. The firm has also expanded itswarehouse at Mihla to hold 2,000 pallets.

STRIDES SHASUN has completed its Rs5.00 billion (US$76.8million) divestment of its Indian branded generics business toEris Lifesciences. Strides said selling the portfolio of more than 130brands in India, which generated annual sales of Rs1.81 billion,would enable it to “focus more sharply on larger regulated markets”.Eris said the deal would strengthen its presence in India’s marketsfor central nervous system drugs and gastrointestinal therapies.

CORNING says it is creating 185 jobs through an investment in itsCorning Valor Glass packaging system that it says “dramaticallyreduces particle contamination, breaks and cracks while significantlyincreasing throughput”. The funding for its innovation anddevelopment centres in Big Flats and Sullivan Park, New York,form part of a US$500 million investment programme announcedby the US group in July this year.

CAMARGO – the 505(b)(2) hybrid regulatory pathway consultancy –has during December been holding meetings in India, Japan,South Korea and Taiwan “in response to strong interest from Asianpharmaceutical companies seeking access to the US markets”.

ANUH PHARMA raised its turnover by 9% to Rs580 million(US$9.00 million) in the three months ended 30 September 2017.G

IN BRIEF

5GENERICS bulletin15 December 2017

COMPANY NEWS

Shredded quality documents that were not logged for disposal,warehouse employees being able to create, access and delete quality

documents, and problems with hold-time studies are among thedeficiencies outlined in a list of seven ‘Form 483’ observations releasedby the US Food and Drug Administration (FDA) following a Novemberinspection of Glenmark Pharmaceuticals’ oral solids, semi-solids andliquids facility in Baddi, India.

The heavily redacted Form 483 says that auditors found remnantsof quality documents within a shredder in the plant’s regulatory affairsstaff room, even though these papers did not appear in the logbookfor shredding as required by the firm’s operating procedures.

Noting that a warehouse employee was able to access and altera wide range of documents on the quality department’s network drives,the FDA observed that documents deleted from drives were not movedto a recycling bin, but were rather deleted permanently from servers.

“There are no written procedures for production and process controlsdesigned to assure that the drug products have the identity, strength,quality and purity they purport or are represented to possess,” theagency complained, highlighting several issues around hold-time studiesand samples. Furthermore, complaint records – due to problems suchas the grittiness of an undisclosed cream – were “deficient in that theydo not include the findings of the investigation and follow-up”.

Upon recently disclosing the seven Form 483 observations(Generics bulletin, 8 December 2017, page 3), Glenmark said it wouldshortly be “providing a comprehensive response” on the facility, whichcurrently contributes around a tenth of its US sales. G

MANUFACTURING

Shredded documentsat issue for Glenmark

Walgreens Boots Alliance (WBA) is poised to expand in China’sretail pharmacy market by snapping up a minority stake in the

country’s GuoDa national drugstore chain. Under the terms of a publictender process, WBA will pay China National Accord Medicinesalmost CNY2.77 billion (US$416 million) to take a 40% stake in itssubsidiary Sinopharm Holding GuoDa Drugstores. The transaction issubject to antitrust approval and other closing conditions.

Headquartered in Shanghai, GuoDa operates more than 3,500retail pharmacies in 70 cities across China, employing almost 20,000people. The chain was established in March 2004 as the retail pharmacyplatform of the China National Pharmaceutical Group Corporation(CNPGC), and was last year consolidated into China National AccordMedicines, which is also known as Sinopharm Accord.

“After over 10 years of rapid growth,” the partners proclaimed,“GuoDa has developed national coverage across 19 provinces,autonomous regions and municipalities.”

Describing GuoDa as “China’s leading pharmacy chain”, WBA’sexecutive vice-chairman and chief executive officer, Stefano Pessina,insisted that the retailing and wholesaling giant could, as a strategicinvestor in the Chinese chain, “positively contribute to GuoDa’scontinued successful development with our global pharmacy expertise”.“We have had a presence in China for around 10 years, and we areexcited about the opportunity to further invest in the country’s fast-growing retail pharmacy sector,” he added.

“In line with CNPGC’s strategy to further grow the state-ownedpharmaceutical and healthcare business,” WBA stated, “GuoDa aimsto take advantage of the unprecedented opportunities created by theChinese healthcare reform to further expand nationwide.” As Chinaincreasingly shifted from a hospital-led healthcare model towardsincreasing the “importance of the pharmacy channel”, WBA said itwas well positioned to support the chain’s growth ambitions. G


WBA grabs stake inChinese GuoDa chain

An inspection by the US Food and Drug Administration (FDA) ofShilpa Medicare’s formulations facility situated in a special

economic zone (SEZ) in Jadcherla near Hyderabad, India, has resultedin 10 ‘Form 483’ observations of deficiencies.

The Indian bulk-drugs specialist said that seven of the observationscited following the audit of the Jedcherla finished-dose plant required“improvement in procedures and practices”. The others coveredanalytical specifications, test procedures and method validation”.

Spread over a plot of more than 36,000 sq m, the Jedcherla plantconsists of six blocks covering 13,876 sq m that are dedicated to “contractmanufacturing and dosage developments”. Alongside developmentand pilot-level capabilities, on a commercial scale the facility has twotablet lines and another for capsules, while a separate injectables blockcan produce lyophilised vials and pre-filled syringes.

Shilpa – which saw its turnover slip by 0.4% to Rs3.83 billion(US$59.3 million) in the six months ended 30 September 2017 – alsohas Indian formulations facilities in Shadnagar and Hyderabad, thelatter specialising in orodispersible thin films. Three active pharmaceuticalingredient (API) units in Raichur, India, are complemented by the firm’sLoba Feinchemie organic compounds site near Vienna, Austria. G

MANUFACTURING

Shilpa gets 10 observationsClaris has reached a settlement with Baxter over manufacturing

deficiencies identified at a Claris manufacturing facility inAhmedabad, India, immediately before the closure of Baxter’s US$625million deal to acquire Claris’ global generic injectables business(Generics bulletin, 6 January 2017, page 3).

Noting that the US Food and Drug Administration (FDA) hadperformed an unannounced inspection of the Ahmedabad site on 27July 2017 – “the closing date of the Baxter sale” (Generics bulletin,28 July 2017, page 17) – Claris said this inspection led to observations“for which certain costs, corrective measures and other items will beincurred, as Baxter integrates Claris Injectables into its quality systems”.Claris had therefore “been in discussions with Baxter to settle allpotential claims against the company”, including these costs.

While financial terms of the settlement were not disclosed, Clarissaid it had “reached a settlement with Baxter to settle all potentialclaims against the company and its subsidiaries”. Under the terms ofthe deal, “after the completion of certain pre-requisites, the escrow andcertain other amounts related to contingencies will be paid to Baxterin exchange for the release from all potential claims against the companyand its subsidiaries under the Baxter sale”.

When the acquisition was first announced, Baxter said it plannedto “build upon Claris Injectables’ existing footprint” by addingtechnologies and making investments to expand the firm’s research anddevelopment pipeline and manufacturing capacity. Baxter said itexpected to have around 50 molecules in the US market by 2020. G

MANUFACTURING

Claris has Baxter settlement


MARKET NEWS

24 Januaryn 11th Pharmacovigilance Conference

London, UKThis one-day Medicines for Europe conference will lookat implementing pharmacovigilance legislation and currentdevelopments within the industry.

Contact: Lucia Romagnoli. Tel: +44 7562 876 873.E-mail: [email protected]. Register online atwww.medicinesforeurope.com/events.

25-26 Januaryn 17th Regulatory and Scientific

Affairs ConferenceLondon, UKThis conference will follow the Pharmacovigilance event at thesame venue. There will be updates on regulatory developmentsand representatives from competent authorities in attendance.


12-14 Februaryn Access! 2018 – AAM Annual Meeting

Orlando, USAThis event, organised by the Association for AccessibleMedicines, will look at regulatory topics and the challengesfacing the US generics industry.

Contact: Association for Accessible Medicines. Tel: +1 202 249 7100.E-mail: [email protected]. Register online atwww.accessiblemeds.org/events.

1-2 Marchn 2nd OTC Innovation & Business

Development ConferenceLondon, UKOrganised jointly by the Pharmaceutical Licensing Group andOTCToolbox, this event will focus exclusively on businessdevelopment and innovation in the consumer healthcare/OTCmarket. The theme for this event is capitalising on change.

Contact: OTCToolbox. Tel: +44 121 314 8757.E-mail: [email protected]: www.plg-group.com/events/3rd-otc-event.

25 Apriln 14th Legal Affairs Conference

London, UKThis one-day conference organised by Medicines for Europe willcover legal and intellectual-property developments regardinggenerics and biosimilars.


EVENTS – January – April 2018

SAVE THE DATE...Tuesday 9 October 2018, Madrid, Spain

Draft guidance published by the US Food and Drug Administration(FDA) on amendments to abbreviated new drug applications

(ANDAs) raises “concerns” for industry and also potentially representsa “unilateral renegotiation” of the commitment letter already agreedunder the Generic Drug User Fee Amendments (GDUFA), accordingto comments on the document submitted by the US Association forAccessible Medicines (AAM).

First published in October, the guidance on ANDA amendmentsunder the second iteration of the user-fee programme – ‘GDUFA II’ –covers minor and major amendment categories, and explains howadjustments to ANDA and prior approval supplement (PAS) submissionsmay affect an application’s review goal dates (Generics bulletin,13 October 2017, page 5).

But the AAM said it had “concerns about some of the examplesthat are proposed for classification as major”. Additionally, “we havesome concerns regarding the examples of the process that the FDA willemploy to prioritise unsolicited amendments, and in a few areas, werecommend clarification”. And the AAM also recommended that theguidance “specifically provide applicants the opportunity to explainwhy an amendment should not be categorised as a major”.

While the AAM agreed with certain examples of majoramendments given in the text of the guidance, it said it disagreed thatsome of the examples in the document’s appendix were “appropriatelycharacterised as major amendments”.

“We are also particularly concerned that all deficiencies regardingfacilities will be classified as major,” the AAM noted. “Some deficienciesassociated with facilities could and can be readily corrected withoutrequiring the FDA to conduct an extensive review of a submission,”the association argued, “and historically, submissions in response tothese deficiencies have been considered minor amendments – forexample, if an alternate facility not used in the manufacture of theANDA batches is removed due to compliance issues.”

“Therefore,” the AAM urged, “the FDA should provide examplesof deficiencies in this category that will be considered major – andother examples, such as those provided here, of deficiencies that willbe considered minor amendments, as they have been in the past.”

As well as asking for clarification of certain phrases and examplesincluded in the guidance, the AAM warned that the document’s assertionthat it will ultimately replace previous 2001 guidance on major andminor classification determinations would contradict the GDUFA IIcommitment letter, which “expressly directs” the FDA to makedeterminations based on the 2001 document. “If this were to occur,it would be a unilateral renegotiation of the agreed-to commitmentletter,” the AAM insisted.

Nevertheless, the association believes there are “areas where theFDA and industry can further collaborate to better define the bestprocess to appropriately classify major and minor deficiencies so asnot to impede or delay access to critical, more affordable genericdrug products”.

Separate comments on the guidance submitted by Teva also suggestthat facility deficiencies should not be automatically characterised asmajor, and labels as “concerning” the perceived ambiguity within thedocument over changes to ANDAs submitted after tentative approval,suggesting that this could delay approval dates. Apotex asks for greaterclarity in several areas, while Sanofi observes that the term “priorityreview” is “repeated in the guideline but not defined”. Gn [email protected]

REGULATORY AFFAIRS

Industry airs concernover ANDA guidance


MARKET NEWS

Shortages and price hikes for generics in the UK must be addressedurgently by the UK’s Department of Health (DoH), local pharmacists

body the Pharmaceutical Services Negotiating Committee (PSNC) hasurged. Noting that it had pressed the DoH to respond to a series ofprice rises in November – requesting that the DoH agree to a total of97 reimbursement price concessions for the month – the PSNC saidcontinuing shortages were exacerbating the problem.

Earlier this year, the PSNC noted that UK contractors were suffering“very great difficulties” in sourcing “a large number of products”following manufacturing issues that had been identified at facilitiesoperated by Bristol Laboratories and Dr Reddy’s (Generics bulletin,29 September 2017, page 3).

This led “an extraordinary number of price concessions” to begranted in September, with further “urgent intervention” urged by thePSNC the following month (Generics bulletin, 20 October 2017, page 12).

Price concessions granted by the DoH only apply to the monthfor which they are granted, meaning that the PSNC is required to applyor re-apply for concessions on a monthly basis.

“We are receiving unprecedented numbers of calls from communitypharmacy teams who cannot get hold of certain medicines that patientsneed, despite their best efforts,” said Mike Dent, director of pharmacyfunding at the PSNC, “or who are having to pay prices many timesmore than the National Health Service (NHS) reimbursement price.”

“This has been going on for many months,” Dent emphasised.“When we request price concessions, the DoH always makes its owninquiries following reports from us.” This, he explained, was “tovalidate the availability and prices around the country”.

Some concessions receivedOffering an update on the price concessions granted so far by the

DoH for November, the PSNC said that after “repeated pressure fromthe PSNC to the DoH”, it had received “a list of proposed concessionprices for 52 of the 67 outstanding requests for November concessions”.“We are, as is normal, considering the proposals and will respond tothe DoH as soon as possible... so they can be considered alongsideNovember’s payment in the usual way,” the PSNC noted.

This update on the ongoing negotiations between the PSNC andthe DoH had been offered “in view of the extreme pressures at presentand the concerns of all [pharmacy] contractors about November”, thePSNC explained. “We are also in dialogue about concession pricesfor December,” the Committee confirmed. The PSNC said it would“make applications for December as usual and continue to press forsettlement of the backlog for November”.

“PSNC is continuing to work to ensure that the DoH understandsthe problems and risks if pharmacies are not able to obtain medicinesfor patients in a timely manner,” the PSNC stated, “and to press forbetter systems to address the impact of high price rises.”

“We have made the DoH aware of the hardship the situation isimposing on contractors,” the PSNC insisted, “coming as it does ontop of the recent funding cuts” – referring to cuts to funding for UKpharmacists for 2016-17 and 2017-18 that were upheld by the UK HighCourt earlier this year, despite PSNC opposition (Generics bulletin,26 May 2017, page 10) – “and ultimately of the risks for patientswho may struggle to access vital medicines.”

The PSNC has asked its members to continue reporting genericsupply and pricing issues as it pursues its negotiations with the DoH.Gn [email protected]

PRICING & REIMBURSEMENT

UK urged to addressshortages and prices

The US Food and Drug Administration (FDA) more than doubledthe record for its rate of first-cycle generic drug approvals as a

proportion of total abbreviated new drug application (ANDA) approvalsduring October, according to the latest monthly performance metricsthat have just been published by the agency.

Of the 87 ANDAs that received final approval in October, 26 wonapproval in the first review cycle. FDA Commissioner Scott Gottliebnoted that this was an “all time record high of 29.9% first-cycleapprovals”, more than doubling the previous record of 14.3%.

Meanwhile, 14.3% of ANDAs – or two of 14 – were grantedtentative approval at the first hurdle by the agency during October.

The FDA’s Generic Drugs Program published the figures as partof commitments outlined in the second iteration of the Generic DrugUser Fee Amendments (GDUFA II), which was signed into law on18 August, and implemented from 1 October (Generics bulletin, 1September 2017, page 1).

In March this year, Janet Woodcock, director of the FDA’s Centerfor Drug Evaluation and Research (CDER), told a House sub-committeeon health that only 9% of ANDAs were approved after the first reviewcycle, as part of discussions ahead of GDUFA II (Generics bulletin, 10March 2017, page 11). However, she said, this was a vast improvementover a rate of less than 1% before the first iteration of GDUFA wasimplemented in 2012.

“Historically, it has taken on average about four review cycles toapprove an ANDA as a result of deficiencies by generic drug sponsorsin submitting complete applications,” Woodcock observed at the time.

Industry bodies including the US Association for AccessibleMedicines (AAM) previously described increasing the proportion ofANDAs approved after the first cycle of review by the FDA as a“key goal for both industry and the agency”.

Responding to the 29.9% first-cycle approval record, the AAMcommended the FDA and said lower barriers to entry would equalmore competition and greater access to patients. “Policymakers mustalso focus on barriers to access like intellectual-property abuse andbuyer consolidation,” the AAM urged.

Initial data for November shows a record 107 ANDA authorisations,comprising 84 final and 23 tentative approvals (see Figure 1). However,the number of complete responses in November – 240 – was significantlylower than the 325 issued by the agency in October this year. G

REGULATORY AFFAIRS

FDA comes good onreviews at first cycle

Figure 1: The number of final and tentative approvals for abbreviated new drugapplications (ANDAs) granted in 2017 to date (Source – FDA)

120

100

80

60

40

20

0

Num

ber

of

AN

DA

s

Final approvals Tentative approvals

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov

2017

5161 62

57

7788

6860

70

87 84

14

1119

9

1912

1417

12

14 23


MARKET NEWS

The International Council for Harmonisation (ICH) has realised plansto adopt a final guideline on the planning and design of ‘multi-

regional clinical trials’ (MRCTs), after formally putting into place its“major” ‘E17’ guideline during its November meeting in Geneva,Switzerland, in aid of efforts to reduce the “unnecessary” duplicationof clinical studies.

Pointing to the “increasing globalisation of medicines development”,the ICH said it was intended that the E17 guideline would “facilitatethe acceptability of MRCTs as part of global regulatory submissionsin ICH and non-ICH regions, as well as making it easier to seekapprovals of global trials”. Members of the ICH Assembly first endorsedthe guideline during the ICH’s June 2016 meeting in Lisbon, Portugal(Generics bulletin, 22 July 2016, page 7).

The ICH noted that “facilitating the conduct and acceptability ofMRCTs is expected to have a direct public health benefit”, in particularby encouraging more predictability around the approval of trials andthe use of clinical trial data from a greater variety of countries andregions. “It is hoped that this will decrease the delay in marketingauthorisation often caused by requirements to conduct trials in localpopulations,” the ICH said, “and promote earlier access to innovativemedicines. Avoidance of duplicative regional or national trials willalso avoid unnecessary trial subjects’ exposure.”

Meanwhile, the ICH said it had also reached an agreement to begin anextended 12-month public consultation on its draft ‘Q12’ guidelineon ‘technical and regulatory considerations for pharmaceutical productlifecycle management’, after the ICH Assembly adopted draft guidelines.

With a goal of managing post-approval chemistry, manufacturingand controls (CMC) changes for all drugs more efficiently, the Q12guideline was first endorsed by the ICH’s Steering Committee inSeptember 2014 (Generics bulletin, 5 December 2014, page 21).

The ICH also noted that its Assembly had approved Singapore’sHealth Sciences Authority (HSA) as a new regulatory member, andColombia’s National Food and Drug Surveillance Institute (Invima)and the Bill & Melinda Gates Foundation as new observers. Withthese new parties, there are now 15 members and 24 observers. G

REGULATORY AFFAIRS

ICH adopts guidelineon multi-region trials

Pricing information on ‘patented generic’ drugs – such as complexgenerics or biosimilars – need only be filed with Canada’s Patented

Medicine Prices Review Board (PMPRB) if requested by the board,the country’s government has recommended in its proposed amendmentsto the Patented Medicines Regulations. Representing the “first majorupdate to the regulations in more than 20 years”, the suggested changeshave been published in the Canada Gazette, Part I.

Included in the proposed regulations are new pricing informationreporting requirements, with one element focusing on reducing thereporting obligations for patented veterinary, OTC and generic medicines.“As these products pose a lower risk of asserting market power andcharging excessive prices,” Health Canada noted, “this reduction wouldenable the PMPRB to focus on medicines at higher risk of excessivepricing.” The PMPRB does not regulate prices for non-patented generics.

Currently, the regulations only require patented veterinary andOTC medicines that do not contain a controlled substance or are not aradiopharmaceutical or biologic – as per the Food and Drugs Act andthe Food and Drug Regulations – to report price and sales informationto the PMPRB on a complaints basis. Proposed amendments wouldfurther reduce reporting obligations for these medicines so that suchinformation would only be required on request by the PMPRB forall patented veterinary and OTC medicines, and also for generics.

“Patentees of generic medicines typically face greater competition,and the risk of excessive pricing is generally not cause for concern,”Health Canada explained. “These proposed amendments are intendedto spare patentees unnecessary reporting regulatory burden for medicinesthat pose a lower risk of excessive pricing.”

Generics industry representatives supported the proposals, accordingto Health Canada. “They recommended this amendment be extendedto include other complex forms of generics that do not receive adeclaration of equivalence from Health Canada, such as biosimilarsand generics with complex ingredients and formulations,” the agencynoted. However, nurses’ associations were not supportive of exemptingpatented generics from systematic reporting requirements.

“While other products such as biosimilars and other patentedgeneric medicines that are not authorised for sale by way of anabbreviated new drug submission (ANDS) were considered,” HealthCanada said, “these products and their risk of excessive pricing couldnot be adequately defined.”

Out of the 1,359 medicine products in the patented generic, OTC andveterinary category, Health Canada observed, 96 are currently requiredto file information with the PMPRB. “Given that the Federal Court ofAppeal only recently clarified and upheld the PMPRB’s jurisdictionover these medicines, the compliance for reporting of these medicineshas not historically been considered by the PMPRB,” it pointed out.

Health Canada said that there would be a “potential [qualitative]impact on wholesalers, distributors, pharmacies and generic medicinemanufacturers, whose mark-ups and prices are often expressed as apercentage of patented medicines prices”.

Noting that the consultation period on the proposed revisions wouldrun until 14 February, Health Canada said it had built on an initialconsultation from May, which had included ‘engagement sessions’.While insurers had been “in favour of reducing regulatory burden forpatented generics medicines”, they had suggested the PMPRB “stillrequest price and sales information for patented generic medicinesat risk of higher prices”. Gn [email protected]

REGULATORY AFFAIRS

Canada price body torelax reporting rules

Australia, Canada, Singapore and Switzerland (ACSS) are nowinviting expressions of interest to participate in a generics work-

sharing trial through their regulatory consortium. Australia’s TherapeuticGoods Administration (TGA) is leading communications.

Describing the potential advantages of a co-ordinated assessmentof generic applications in about five months through the trial, the fourACSS agencies said “very short timelines for the assessment ofapplications have been suggested for this pilot in order to rapidly gainexperience on the potential opportunities associated with the work-sharing trial and to encourage participation by applicants”. Suchexperience would, they added, “inform internal procedure on theeffective use of foreign assessment reports as well as collaborativework with international regulatory partners”.

To assist participants, the four agencies have released an updatedquestion-and-answer document on the work-sharing trial that describesthe procedure and clarifies that all dosage forms are eligible. G

REGULATORY AFFAIRS

ACSS opens up work-sharing


PRODUCT NEWS

ADelaware district court was correct to find key claims in six USpatents protecting Allergan’s Namenda XR (memantine) extended-

release capsules were invalid based on indefiniteness, the US Courtof Appeals has determined in a ruling in favour of Teva.

After Teva had in December 2013 filed an abbreviated new drugapplication (ANDA) including paragraph IV challenges to six patentslisted against Namenda XR, Allergan’s Forest sued for infringementin the Delaware court. During a claim-construction hearing, the districtcourt determined that key patent claims – which related to changes inmemantine concentration in the blood for extended- and immediate-release formulations – were invalid as indefinite.

On appeal, Forest argued that the Delaware court had erred inconstruing the claims to require that the concentration profiles of bothextended- and immediate-release formulations be derived frommeasurements in human pharmacokinetic (PK) studies. But the Courtof Appeals found that it was “unreasonable” to read claim languageas requiring a PK study only for the extended-release version of theAlzheimer’s disease treatment.

Forest barred from switching argumentNoting that Forest had in the district court “argued repeatedly

that it would be improper” to read into the claims a requirement forboth extended- and immediate-release profiles to be measured in thesame study, the Court of Appeals cited “interest in judicial efficiency”in barring the originator from arguing the opposite on appeal.

In a concurring opinion, appeals judge Alan Lourie maintainedthat “claiming a result without reciting what materials produce thatresult is the epitome of an indefinite claim”.

While Teva does not currently hold ANDA approval for memantineextended-release capsules, several other firms – Amneal, Anchen,Apotex and Lupin, as well as Mylan, Sun and Zydus Cadila – haveapprovals for generic alternatives to Namenda XR, which generatedUS sales of US$241 million for Allergan in the first six months ofthis year. The originator has reached litigation settlements with severalANDA filers that include US market entry dates from January 2020.G

ALZHEIMER’S DISEASE DRUGS

Teva prevails in USNamenda XR appeal

Teva’s German affiliate, Ratiopharm, is pledging to make pre-exposureprophylaxis (PrEP) HIV drugs “accessible across the board” by

slashing the cost of emtricitabine/tenofovir combinations.Although the antiretroviral combination had been shown to be

effective in preventing HIV infections, Ratiopharm noted that Germany’shealth insurance funds did not currently reimburse the drug as aprophylactic. This led patients to pick up the full C800 (US$939) permonth cost of Gilead’s Truvada original, or pay C600 for the first genericto market. “A truly low-cost alternative is only available through a pilotproject running through a few selected pharmacies,” the firm observed.

But from this month, Ratiopharm is making a month’s supply of30 tablets available from all German pharmacies at a retail price ofC69.90. “This price cut not only makes PrEP more affordable forself-payers, it also at the same time considerably reduces costs for thestatutory health insurance funds,” which has also launched an educationalcampaign based around its website www.sex-on-prep.de. G

HIV DRUGS

Ratiopharm cuts PrEP prices

Greater flexibility on alternative and scientifically justified strategiesis needed in the draft guidance on statistical approaches to evaluating

analytical similarity of biosimilars that the US Food and DrugAdministration (FDA) released for comment earlier this year (Genericsbulletin, 29 September 2017, page 15), according to the InternationalGeneric and Biosimilar medicines Association (IGBA).

Furthermore, the IGBA insists in its comments, limiting analyticalsimilarity assessments to US-licensed reference products is “overlyrestrictive”. Rather, the industry body suggests, a revised guidanceshould “include the option to combine US and non-US licensedreference/comparator products in situations when the sponsor can provideevidence”, such as bridging data or publicly-available information. This,it says, would “support the current practices of global developmentof biosimilar medicines”.

Arguing that the draft guidance is “written in a highly prescriptivemanner”, the IGBA’s chair, Ingrid Schwarzenberger, proposes thatwording be altered so that biosimilar sponsors can “select and scientificallyjustify” alternative approaches to statistical testing. Additionally, shesuggests, the draft should be clarified so the purpose of statisticalapproaches is to “serve as supportive tools in data interpretation”, ratherthan, as the current text reads, to provide “a high degree of confidence”.

Along with the US Association for Accessible Medicines (AAM)and its Biosimilars Council, the IGBA appreciates the FDA’s statementin lines 157-161 of the draft that it is possible to combine data frombiosimilar lots made using “different processes and/or at differentscales” in the analytical similarity exercise. The AAM and BiosimilarsCouncil, however, would like greater clarity on how such an approachfits in with the International Council for Harmonisation (ICH) guidelineQ5E on comparability of biological products subject to changes inmanufacturing process.

The industry associations are also aligned in highlighting concernsabout how biosimilar approvals could be hampered by the FDA’sproposed approach to ‘Tier 1’ equivalence testing “for quality attributeswith the highest risk ranking”, typically involving assays that evaluateclinically relevant mechanism of action.

“Currently,” points out the AAM, “there are no guidelines thatrequire consistency in means of quality attributes. “The draft guidanceshould state that alternative statistical approaches are acceptable inthe event that the mean of a given quality attribute of the referenceproduct changes over time,” it asserts. Observing that the FDA’sproposed approach for Tier 1 attributes is to test whether the means fora certain quality attribute of a biosimilar matches that of the referencedrug, the IGBA warns that “a designed or random change in the meanof the reference product” could defeat biosimilar developmentprojects, potentially by originators “deliberately changing the mean”.

From the perspective of originators, the US BiotechnologyInnovation Organization (BIO) stressed the need for discussions betweensponsors and the FDA early in the biosimilar development phase to“avoid misinterpretations of expectations”. Echoing the IGBA’s andAAM’s stances, BIO said the draft guidance failed to directly acknowledgethat the reference product’s “quality-attribute levels may fluctuate orchange at any time during, or even after, the proposed biosimilarproduct’s development”.

Furthermore, the originators’ body agreed, “Tier 1 equivalencetesting may not be appropriate”. “We request clarification from theagency that this guidance does not apply post-approval,” it added.Gn [email protected]

BIOLOGICAL DRUGS

IGBA asks FDA forincreased flexibility


PIPELINE WATCH

Figure 1: Molecules for which supplementary protection certificates (SPCs)expire in certain markets in December 2017 (Source – Ark Patent Intelligence)

Figure 2: Molecules for which data exclusivity expires in certain markets duringDecember 2017 (Source – Ark Patent Intelligence)

This monthly update of key patent, SPC and data exclusivity data is extracted from IQVIA’s Ark Patent Intelligence Expiry Database.Covering 130 countries and over 3,000 INNs, Ark Expiry Database contains watertight data teamedwith the ultimate in generic launch analysis.For further information, visit www.arkpatentintelligence.comor e-mail: [email protected].

December brings the end of supplementary protection certificate(SPC) monopolies in several European Union (EU) member states

for both AstraZeneca’s Crestor (rosuvastatin calcium) cholesterol-lowering agent and GlaxoSmithKline’s (GSK’s) Trobalt (retigabine)anticonvulsant treatment for epilepsy.

Towards the end of this month, six-month paediatric extensionsto Crestor SPCs that are based on European compound patentEP0,521,471 will come to an end in Austria, Belgium, Cyprus, Denmark,France, Germany, Hungary and Italy, as well as in Luxembourg, theNetherlands, Portugal, Spain, Sweden and the UK (see Figure 1).

Even in the first nine months of this year, AstraZeneca blamed“the increasing presence of generic medicines” for European salesof the cholesterol-lowering blockbuster falling by 22% to US$514million. Global Crestor sales slid by more than a third to US$1.77billion as US turnover tumbled by 78% to US$246 million followingthe market entry of several generics in July 2016 (Generics bulletin,29 July 2016, page 12). Crestor is also coming under increased genericcompetition in Japan (Generics bulletin, 24 November 2017, page 11).

Earlier in December, GSK’s Trobalt tablets loses SPC monopoliesin Austria, Belgium, Denmark, France, Germany, Greece, Ireland,Italy, as well as in Luxembourg, the Netherlands, Portugal, Spain,Sweden, Switzerland and the UK.

Trobalt already withdrawn in UKHowever, observes IQVIA – which maintains the Ark Patent

Intelligence database of SPC and data exclusivity periods on a globalbasis – the impact of the loss of protection for GSK’s retigabine 50mg,100mg, 200mg, 300mg and 400mg tablets has already been mitigatedby the originator’s decision to withdraw the epilepsy treatment in theUK from June 2017 due to the “very limited usage of the medicineand the continued decline in new patient initiation”.

A six-month paediatric SPC extension for Bristol-Myers Squibb’sOrencia (abatacept) also runs out in December across several EUmember states. Those SPCs are based on European patent EP0,606,217.

Turning to data exclusivity, IQVIA notes that BioMarin’s Firdapse(amifampridine) loses eight-year EU exclusivity during December.However, the only approved drug for symptomatic treatment ofLambert-Eaton myasthenic syndrome (LEMS) will benefit from twoyears of market exclusivity in the EU through to 2019. IQVIA has alsoidentified European patent EP1,358,159 as a potential barrier to tartrateor phosphate forms of the orphan drug.

In the US, Takeda’s Iclusig (ponatinib) loses its New ChemicalEntity (NCE) exclusivity this month. The Japanese group generatedUS sales of the leukaemia brand totalling US$40 million in its financialfirst quarter ended 30 June 2017, rising to US$42 million in the threemonths ended 30 September.

“Generic approval of Firdapse in the US may be delayed as longas December 2019 because of orphan-drug exclusivity, and marketentry could be delayed until December 2026 due to Orange Book-listed patents,” IQVIA points out. G

Abatacept* Austria, Belgium, Denmark, Finland, France, Germany,Greece, Italy, Ireland, Luxembourg, Netherlands,Spain, Sweden, UK

Icatibant Latvia

Retigabine Austria, Belgium, Denmark, France, Germany, Greece,Italy, Ireland, Luxembourg, Netherlands, Portugal,Spain, Sweden, Switzerland, UK

Rosuvastatin* Austria, Belgium, Cyprus, Denmark, France, Germany,Hungary, Italy, Luxembourg, Netherlands, Portugal,Spain, Sweden, UK

* expiry of paediatric extension

Amifampridine* European Union

Apixaban** Canada

Apixaban US

Azilsartan medoxomil Turkey

Bedaquiline US

Catridecacog† US

Crofelemer US

Diquafosol South Korea

Dronedarone†† European Union

Eribulin** Canada

Ferumoxytol** Canada

Fidaxomicin Turkey

Indacaterol** Canada

Indacaterol†† European Union

Lomitapide US

Pasireotide US

Plerixafor** Canada

Ponatinib US

Prucalopride** Canada

Ranibizumab China

Teduglutide US* Orphan drug exclusivity** This will be followed by a no-marketing period of two years during

which a notice of compliance will not be granted to a generic manufacturer.† This will be followed by a no-marketing period of eight years during

which approval will not be granted to a biosimilar manufacturer† † This will be followed by two years of market exclusivity, where a

generic will not be placed on the market

SPC expiries in December

INN Country

Data exclusivity expiries in December

INN Country

Rosuvastatin and retigabine reach EU end


PRODUCT NEWS

Unipharma has introduced into French pharmacies this month the firstgeneric of levothyroxine, against the backdrop of ongoing controversy

involving the Levothyrox original marketed by Germany’s Merck.Earlier this year, a reformulated version of Merck’s Levothyrox –

in which the excipient lactose had been replaced by anhydrous citricacid for greater batch consistency – was linked with adverse effectsby certain patients (Generics bulletin, 29 September 2017, page 8).

Announcing the introduction of Unipharma’s Thyrofix version oflevothyroxine – which does not include anhydrous citric acid as anexcipient – French medicines agency ANSM pointed out that the launchformed part of “the expansion of the offer of medicines” for patientswith thyroid problems. A factsheet setting out all available levothyroxine-based medicines in France has been published by the agency.

Unipharma’s Thyrofix tablets – already marketed in Greeceand the Netherlands – are available in France in 25µg, 50µg, 75µgand 100µg strengths, in packs of 30 or 100 tablets, having been approvedby ANSM in September. They are the only levothyroxine-basedmedicine characterised by the agency as a generic drug.

Also available in France is Merck’s reformulated Levothyrox, aswell as its Euthyrox version of levothyroxine that is equivalent to theearlier lactose formulation and has been marketed by the originator in“limited quantities” since the start of October. ANSM stressed that nonew treatment should be initiated with Euthyrox, emphasising thetemporary availability of the drug.

Meanwhile, Sanofi is offering an L-Thyroxin Henning scoredtablet that has been available since mid-October. And Serb is marketingL-Thyroxine Serb, a 150µg/ml oral solution in a 15ml bottle that hasbeen on the market since 2008. G

THYROID TREATMENTS

Unipharma launchesFrench levothyroxine

Amultiple-batch study design approach to demonstrate pharmacokinetic(PK) bioequivalence (BE) for US generics of GlaxoSmithKline’s

Advair Diskus (fluticasone/salmeterol) is “ultimately unnecessary”, andraises “critical questions” under the US Food and Drug Administration’s(FDA’s) “well-established” single-batch test versus reference studydesign, Mylan has argued in a citizen petition filed with the agency.

Mylan’s petition refers to a physicians’ abstract and podiumpresentation “exploring a multiple-batch PK BE study with a very largenumber of test and reference product batches as a way of demonstratingPK BE between a proposed generic and Advair Diskus”.

In contrast, the FDA’s current Advair bioequivalence guidelines –published more than four years ago (Generics bulletin, 20 September2013, page 1) – provide for a “single-batch PK BE study based onthe comparison of one batch of test and reference product”, Mylanpoints out. “These batches must be representative of the products basedon careful in vitro analysis of product characteristics, particularly thosethat are shown to be critical determinants of product performancein vivo,” the US firm explains.

Mylan is asking the agency to “refrain from approving anyabbreviated new drug application (ANDA) that relies on multiple-batchPK BE study designs unless, after conducting an appropriately rigorousreview under the established standards for establishing BE, generally,and for [Advair] specifically, the FDA concludes that such a studydesign is valid and will ensure a therapeutically equivalent product.”

Highlighting the case of rival Sandoz, Mylan said the Novartisoperation “appears to be having difficulty establishing BE of its proposedproduct and the reference-listed drug (RLD), at least at the lowest100µg/50µg strength, and appears to be considering a multiple-batchapproach to demonstrating BE, presumably for this strength alone”.

In October last year, Sandoz had petitioned the agency to refrainfrom approving Advair ANDA products based solely on the FDA’s2013 guidance, after raising concerns that filed ANDAs, includingthat by Mylan, as well as by Hikma, might fail to contain “accurateand generalisable” evidence of PK BE for the lowest 100µg/50µg Advairstrength (Generics bulletin, 28 October 2016, page 14).

As a result of the degree of batch-to-batch variability, Sandoz hadargued, “targeted study-design requirements” were needed to accuratelydemonstrate PK BE for the lowest strength. The FDA later deniedSandoz’ petition.

Urging the FDA to “exercise caution” toward “any approach…that proposes a new BE methodology in circumstances in which thesponsor was apparently unable to achieve acceptable BE results withthe recommended methodology”, Mylan said it was concerned thatapplicants might be attempting to rely on such “novel, unprecedented”PK BE study designs, such as the multiple-batch study design, becausethey had not “adequately performed the necessary development workto understand the RLD product and the proposed generic”.

In late March, Mylan received an FDA complete response letterinforming the firm that its Wixela Inhub proposed alternative to Advairwas not yet ready for approval (Generics bulletin, 7 April 2017, page 1).Sandoz, meanwhile, had its ANDA accepted for filing by the FDA inmid-June, with the firm stating it was “confident in our applicationand data” (Generics bulletin, 23 June 2017, page 1).

Sandwiched in between these two dates was a complete responseletter issued by the FDA to Hikma and partner Vectura for thefirms’ VR315 fluticasone/salmeterol candidate, in May. Gn [email protected]

RESPIRATORY DRUGS

Mylan petitions FDAon Advair standards

Sanofi has secured final approval from the US Food and DrugAdministration (FDA) for Admelog, “the first follow-on insulin

lispro” in the US. The approval for the short-acting 100 unit per 1 mlformulation that is similar to Eli Lilly’s Humalog came through theFDA’s 505(b)(2) hybrid pathway, supported by two Phase III trials.

“Admelog will be available in both vials and the SoloStar pen,which is the most-used disposable insulin pen platform in the US,”stated Sanofi, owner of the blockbuster Lantus (insulin glargine) brand.“Complementing our existing insulin portfolio, Admelog will offer amore affordable option for those who require control of their blood-sugar levels at mealtime.”

Earlier this year, the FDA had granted Admelog tentative approval.At the time, the agency explained that it could not yet grant finalapproval because a statutory 45-day period in which Lilly could securea 30-month stay on final approval by suing for patent infringement hadnot yet expired (Generics bulletin, 8 September 2017, page 17). Sanofisubsequently said it anticipated final approval shortly, but did not expectto achieve “significant coverage” for the brand in 2018 because payercontracts for next year were largely in place already (Generics bulletin,10 November 2017, page 8). Lilly reported US Humalog sales ofUS$1.25 billion in the first nine months of 2017.

The European Commission approved a similar product under itsbiosimilars pathway as Insulin Lispro Sanofi in July this year. G

DIABETES DRUGS

FDA approves Sanofi’s Admelog


PRODUCT NEWS

Apotex has been granted a sole-supply deal for gabapentin capsulesby New Zealand’s Pharmaceutical Management Agency, Pharmac.

From 1 June 2018, Apo-Gabapentin will be funded via a sole-supplyarrangement in both hospital and community settings. Packs of 100Apo-Gabapentin 100mg capsules will have a price and subsidy ofNZ$2.65 (US$1.84), while the same pack size for the 300mg strengthcapsules will have a price of NZ$4.07 and the 400mg form NZ$5.64.

In the community pharmacy setting, other versions of gabapentin –including Arrow-Gabapentin, Pfizer’s Neurontin and Alphapharm’sNupentin – will be reference-priced to these prices from 1 August 2018,and from 1 November 2018 they will be delisted, leaving Apo-Gabapentinas the sole fully-funded version until 30 June 2021. In hospitals, theother versions will be delisted from 1 August 2018.

Meanwhile, Pfizer has been granted a similar deal for its genericversion of the firm’s own Lyrica (pregabalin). From 1 May, Pfizer’sown-branded pregabalin capsules will be listed via a sole-supplyarrangement in both hospital and community settings, with a price andsubsidy of NZ$2.25 for 56-count packs of 25mg capsules; NZ$2.65for the same pack size of the 75mg strength; NZ$4.01 for 150mgcapsules; and NZ$7.38 for the 300mg presentation. Pfizer’s deal willalso run until 30 June 2021. G

EPILEPSY DRUGS

NZ awards Apotex asolo gabapentin deal

Apan-European centralised marketing authorisation for Biopartners’somatropin has ceased to be valid because the Swiss company

never brought the once-weekly human growth hormone to market. Anexemption granted for Somatropin Biopartners by the EuropeanCommission to the European Union’s (EU’s) Article 14(4) ‘sunsetclause’ – which causes marketing authorisations to lapse if the productis not marketed in any of the EU member states within three years ofapproval – has now expired. The European Medicines Agency (EMA)said Biopartners had “confirmed that the product had not been marketedas they were unable to supply it” after approval in August 2013. G

GROWTH HORMONES

Sun sets on somatropin in EU

Celltrion has welcomed independent data on the safety and tolerabilityof rapid infusion of its Truxima (rituximab) biosimilar presented

during the annual meeting of the American Society of Hematology(ASH). The data from the UK’s University College London HospitalsNHS Foundation Trust (UCLH) shows that Truxima, also known asCT-P10, was “well-tolerated across all patient groups” and that patientscould safely be switched from the MabThera reference brand to thebiosimilar “without reverting to slower infusion rates”.

Having in May 2017 switched all its patients from MabThera tothe Truxima biosimilar marketed by Napp, UCLH maintained thatfindings from its rapid infusion study “should help to increase physicianconfidence and facilitate the introduction of CT-P10 at centres prescribingrituximab across the UK and beyond”. Celltrion also used the ASHmeeting to present pharmacokinetic data for its rituximab biosimilar. G

ONCOLOGY DRUGS

Celltrion cites UK infusion data

AMNEAL is set to launch the “only generic injectable oftriamcinolone” in the US after receiving approval for a rival toApothecon’s Kenalog-40 (triamcinolone acetonide) 40mg/mlinjectable suspension. The US firm said the anti-inflammatory agent –which would be “available direct and through wholesalers anddistributors” – would be sold in 1ml single-dose vials, as well asin 5ml and 10ml multiple-dose vials.

DAIICHI-SANKYO has launched in Japan a generic version of AsahiKasei’s Famvir (famciclovir) 250mg and 500mg tablets. At thesame time, the company also introduced a generic alternative toAstraZeneca’s Crestor OD (rosuvastatin) orodispersible tablets,available in 2.5mg and 5mg strengths. Fellow Japanese firm NipponChemiphar also announced plans to launch rosuvastatin in bothstandard and orodispersible tablet formats during December, followingsimilar recent announcements from Nichi-Iko, Sawai and Towa(Generics bulletin, 24 November 2017, page 11). These three firms,along with Nippon Chemiphar, also intend to introduce irbesartanand olmesartan this month.

TEVA’S data from its pivotal Phase III Halo study evaluating theefficacy, safety and tolerability of two subcutaneous dose regimensof fremanezumab for the treatment of chronic migraine has beenpublished online by the New England Journal of Medicine. Thearticle reports results of a randomised, double-blind, parallel-groupstudy that evaluated monthly and quarterly doses of fremanezumabversus placebo for the preventive treatment of chronic migraine in1,130 patients. Teva said that these findings, along with episodicmigraine data from the Halo study, were included in the biologicslicense application recently submitted to the US Food and DrugAdministration (Generics bulletin, 3 November 2017, page 19).

UPSHER-SMITH has launched in the US Klor-Con (potassiumchloride) 20mEq powder for oral solution, following approval bythe US Food and Drug Administration (FDA). The company notedthat Sandoz would continue to operate as the firm’s “licensedmarketer and distributor in the US for the balance of the Klor-Conline of potassium products”.

HETERO is set to sell Oasmia Pharmaceutical’s Paclical (paclitaxel)after the latter received marketing approval for the oncology drug inKazakhstan. Named ‘Apealea’ in Europe, the treatment for epithelialovarian cancer is due for launch “during the first half of 2018”.

ALEMBIC has obtained US approval for a generic alternative toAllergan’s Enablex (darifenacin) extended-release tablets, availablein 7.5mg and 15mg strengths. Citing data from Iqvia, Alembicestimated a US market size of US$64 million in 2016.

IMPAX has received tentative approval from the US Food and DrugAdministration (FDA) for a generic version of GlaxoSmithKline’sCoreg CR (carvedilol) extended-release capsules, available in 10mg,20mg, 40mg and 80mg strengths. The US firm noted that itsabbreviated new drug application (ANDA) for the hypertensiontreatment would be eligible for final approval upon marketingexclusivity expiry on 7 May 2018.

SANDOZ has received approval from the US Food and DrugAdministration (FDA) for its generic rival to United Therapeutics’Remodulin (treprostinil). In late 2015, through a litigation settlementwith the originator, Sandoz secured rights to launch its generic versionof the injectable treatment for pulmonary arterial hypertension on26 June 2018 (Generics bulletin, 23 October 2015, page 27). G

IN BRIEF


PRODUCT NEWS

Anti-competitive behaviour aimed at excluding generic competitorsto Tarceva (erlotinib) from the Romanian market as well as distorting

wholesale prices for oncology medicines is the subject of a two-prongedinvestigation into Roche that has just been launched by Romania’sCompetition Council.

“One investigation targets possible anti-competitive behaviourconsisting of the fact that Roche Romania, in relation to a distributor,has wholesale prices higher than the prices offered by Roche Romaniain the context of tender procedures for the supply of medicines tohospitals,” the Competition Council explained.

“The second investigation relates to acts of Roche Romania whichhave the effect of excluding from the market the generic – cheaper –version of the innovative drug Tarceva.” Erlotinib, the CompetitionCouncil noted, was included in Romania’s prescribed medicines list.

“Dawn raids were carried out at the premises of Roche Romania,”the regulator revealed, “and the documents gathered are underassessment.” These raids had been authorised by the Bucharest Courtof Appeal, and were an “important step” that was “justified by the needto obtain all the information and documents necessary to clarify thepossible anti-competitive prices analysed”, the Competition Council said.

Carrying out the investigations into Roche did not represent “aprior decision concerning the company’s involvement in an anti-competitive practice”, the regulator emphasised.

Roche confirmed to Generics bulletin that the Competition Councilhad on 21 November “performed an unannounced inspection at theheadquarters of Roche Romania as part of an analysis related to possibleabuse of dominant position”. The Swiss originator said its Romanianaffiliate had “made available all information required so far by theinspectors of the Competition Council” and insisted that it wouldcontinue to collaborate fully during the investigation.

“The inspection by the Competition Council is part of the currentpractice of the institution and does not indicate in itself a breach of theapplicable competition legislation by the company,” the originatorstressed. “Roche Romania remains firmly committed to observing allnational and European applicable legislation in terms of competition.”

Noting that its investigations followed a sector inquiry into theRomanian pharmaceutical market that was finalised this year, theCompetition Council said it had found more broadly that “genericdrugs, although cheaper than their innovative alternatives, fail tocapture a significant market share”.

“In the study,” the watchdog explained, “the Competition Councilanalysed the marketing and promotional activities carried out inconnection with the sale of medicines and found a possible correlationbetween the marketing activities of the innovative drug companies andthe low penetration rate of generic medicines.”

“Intense” promotional activities by innovators had influenceddoctors to recommend that patients ask for brand drugs in 57% ofcases, the Competition Council found, despite national requirementsthat medicines be prescribed by international non-proprietary name(INN) aside from “exceptional justified cases”.

Local generics industry association APMGR has long lobbied againstRomania’s mandatory pharmaceutical clawback tax that the groupbelieves discriminates against generics disproportionately, discouragingcompetition and leading manufacturers to exit the market. It also saysprices in Romania are being kept “artificially low” (Generics bulletin,3 November 2017, page 10). Gn [email protected]

ONCOLOGY DRUGS

Romania eyes Rocheon erlotinib exclusion

Teva has accompanied its launch of a US rival to Pfizer’s Viagra(sildenafil) tablets with a range of “wraparound services to improve

patient access”. The generic will compete with a brand that had annualUS sales of around US$1.4 billion according to Iqvia, as well as anauthorised generic that has just been launched by Pfizer.

The Israeli firm launched its version of the erectile-dysfunctiondrug as expected through a patent-litigation settlement struck withthe originator at the end of 2013, after which Teva secured the firstgeneric sildenafil approval from the US Food and Drug Administration(FDA) in early 2016 (Generics bulletin, 18 March 2016, page 15).

Pfizer has also entered into settlement agreements with othergenerics firms – including Apotex, Hetero and Mylan, as well as Teva’sActavis – the full details of which were not disclosed.

“The launch of Teva’s sildenafil tablets brings an affordablegeneric treatment option to the estimated 18 million men in the USwho are diagnosed with erectile dysfunction,” stated Teva’s commercialvice-president for North America, Brendan O’Grady. “Our team hasmade it a priority to ensure that patients are able to access this medicine,through both traditional and more innovative channels.”

A dedicated website – tevasildenafil.com – includes informationon how patients can “order medicine online and have it shipped directlyto them, as well as how to obtain it through traditional retail channels”.

Teva’s ‘wraparound services’ also include a sildenafil tabletssavings card that will enable “people who meet certain requirements”to participate in a programme that allows them to pay “as little asUS$0 out-of-pocket with a maximum benefit of up to US$100 per fill,for up to six sildenafil tablets prescriptions”. G

ERECTILE-DYSFUNCTION DRUGS

Teva offers servicesto support sildenafil

Sandoz’ Zioxtenzo (pegfilgrastim) biosimilar matched thepharmacokinetics (PK), pharmacodynamics (PD), safety and

immunogenicity of Amgen’s Neulasta in a Phase I study conducted inhealthy volunteers, according to data presented during the 2017 SanAntonio Breast Cancer Symposium that Sandoz insisted “add to thetotality of evidence supporting our proposed biosimilar pegfilgrastim”.

Participants were randomised to receive a single 6mg subcutaneousinjection of biosimilar pegfilgrastim or reference medicine on day one.After dosing, the participants underwent a four-week assessment periodfollowed by an eight-week wash-out period, before crossing over toreceive the other medicine, and were assessed for a further four weeks.

“The results demonstrated that Sandoz’ proposed biosimilarpegfilgrastim matched the reference medicine in the PK and PDcomparisons as primary endpoints, in terms of absolute neutrophil countand maximum serum concentration of study medication afteradministration,” Sandoz observed. Secondary endpoints of safety andimmunogenicity were comparable between both groups, the firm added.

Sandoz pointed out that Zioxtenzo was currently under review bythe European Medicines Agency (EMA), for use in the same indicationas Neulasta. The agency accepted Zioxtenzo for review at the end ofOctober (Generics bulletin, 3 November 2017, page 19), less than ayear after concerns raised by the EMA’s committee for human medicinalproducts (CHMP) led the firm to withdraw its application (Genericsbulletin, 3 February 2017, page 11). G

NEUTROPENIA TREATMENTS

Sandoz has pegfilgrastim data


PRICE WATCH.....UK

Figure 1 (above): Comparison between the periods 1-31 October 2017 and 1-30November 2017 of UK trade prices of the most recently-launched generics listed incategory M of the Drug Tariff of pharmacy-reimbursement prices. Averages calculatedfrom at least 17 data points. Figure 2 (top right) and Figure 3 (centre right): Biggestaverage trade-price changes between 1-31 October 2017 and 1-30 November 2017.Averages calculated from at least 16 data points. Figure 4 (bottom right): Rankingof fastest-moving products subject to the most price offers made to independent UKpharmacists (one strength per ingredient; offers recorded by 30 November). Data forFigures 2, 3 and 4 from a basket of about 750 commonly-dispensed generics. Recently-launched products in Figure 1 excluded from Figures 2 and 3 (Source – WaveData).

Aripiprazole tabs 10mg 28 £1.12 +26 £4.44 +34Benzydamine 0.15% 300ml £4.69 ±0 £5.35 -1Carbimazole tabs 5mg 100 £35.99 -4 £39.74 -6Celecoxib caps 200mg 30 £0.81 -6 £1.32 +2Cilostazol tabs 100mg 56 £3.15 ±0 £4.09 +4Cyclizine tabs 50mg 100 £5.40 +1 £6.82 +2Desogestrel tabs 75µg 84 £1.96 -2 £2.66 -12Duloxetine caps 30mg 28 £2.95 +18 £6.70 -17Entacapone tabs 200mg 30 £2.30 -21 £3.39 -3Eplerenone tabs 25mg 28 £4.10 ±0 £33.06 +111Escitalopram tabs 10mg 28 £0.37 ±0 £0.81 -2Frovatriptan tabs 2.5mg 6 £6.60 +1 £8.00 -1Memantine tabs 10mg 28 £0.59 +7 £0.95 -5Montelukast tabs 10mg 28 £0.73 ±0 £1.12 ±0Nefopam tabs 30mg 90 £13.50 -14 £19.02 -7Nortriptyline tabs 10mg 100 £4.49 -10 £9.99 -17Olmesartan tabs 10mg 28 £0.89 ±0 £1.36 -20Pregabalin caps 150mg 56 £3.25 -17 £7.62 -16Raloxifene tabs 60mg 28 £1.55 -33 £2.81 -4Rasagiline tabs 1mg 28 £1.40 -5 £6.52 -6Rizatriptan tabs 10mg 3 £7.49 +14 £11.65 +5Sevelamer tabs 800mg 180 £21.50 ±0 £30.55 +1Sildenafil tabs 100mg 4 £0.24 ±0 £0.43 +8Telmisartan tabs 80mg 28 £0.88 -4 £1.55 +4Zonisamide caps 100mg 56 £5.50 -8 £16.44 -9

Atorvastatin tabs 20mg 28 146 100 115Lansoprazole caps 30mg 28 129 111 114Sertraline tabs 50mg 28 131 97 110Fluoxetine caps 20mg 30 119 98 106Gabapentin caps 300mg 100 113 127 104Simvastatin tabs 40mg 28 127 116 103Citalopram tabs 10mg 28 102 99 102Omeprazole caps 20mg 28 149 103 101Quetiapine tabs 25mg 60 82 96 95Ramipril caps 10mg 28 93 91 92

Glimepiride tabs 4mg 30 £0.59 ±0 £5.58 +336Glimepiride tabs 3mg 30 £0.52 ±0 £4.28 +320Glimepiride tabs 2mg 30 £0.39 ±0 £3.07 +234Glimepiride tabs 1mg 30 £0.39 +77 £2.20 +178Bicalutamide tabs 50mg 28 £1.34 ±0 £4.76 +162Losartan tabs 100mg 28 £0.94 +6 £2.47 +79

Naproxen tabs 250mg 28 £0.33 -3 £0.49 -53Amlodipine tabs 10mg 28 £1.29 -1 £1.86 -30Olanzapine O/d tabs 20mg 28 £6.45 +17 £31.06 -28Amlodipine tabs 5mg 28 £1.20 -8 £1.75 -27Quetiapine tabs 25mg 60 £6.20 -43 £13.66 -26Olanzapine O/d tabs 15mg 28 £5.75 +64 £22.78 -25

Up to the minute live retail market pricing is available for the UK and Eire on Wavedata Live at wavedata.net.

Alternatively, contact Charles Joynson at WaveData Limited, UK.Tel: +44 (0)1702 425125. E-mail: [email protected].

RECENT LAUNCHESProduct/Strength/Pack size Lowest Change AverageChange

price (%) price (%)

BIGGEST RISERSProduct/Strength/Pack size Lowest Change AverageChange

price (%) price (%)

BIGGEST FALLERSProduct/Strength/Pack size Lowest Change AverageChange

price (%) price (%)

FAST MOVERSPrice offers as at 30 November 2017

Product/Strength/Pack size September October November

WANT MORE LIKE THIS?

Eplerenone 25mg tablets saw their average UK trade price more thandouble in November, having previously experienced the same rise

in October, according to the latest figures provided by WaveData.The category M cardiovascular treatment saw its average price

grow by 111% to £33.06 (US$44.25) in November, despite the lowestavailable offer remaining unchanged at £4.10 (see Figure 1). In October,the presentation had experienced an identical average price rise of111% to £15.65 (Generics bulletin, 17 November 2017, page 10).

Among the ‘biggest risers’ seen in Figure 2, glimepiride tabletsdominated, with 30-count packs of four strengths – 1mg, 2mg, 3mgand 4mg – accounting for the top four average price rises seen inNovember. The highest strength saw the steepest rise of 336% to £5.58,while the lowest strength experienced the slightest increase of the fourpresentations with a rise of 178% to £2.20. The cheapest available

offers for every strength except the 1mg tablets were unchanged.The rises come as the UK’s Pharmaceutical Services Negotiating

Committee (PSNC) continues to put pressure on the country’s Departmentof Health (DoH) to agree to almost 100 price concessions to adjustreimbursement prices for November (see page 7).

As Figure 3 shows, some declines were also seen in November.Naproxen 250mg tablets in 28-count packs saw their average pricemore than halve to £0.49 despite the cheapest available offer slippingby just 3% to £0.33. And amlodipine 10mg tablets in the same packsize experienced an average drop of three-tenths to £1.86, while thelowest price was almost unmoved at £1.29.

Meanwhile, atorvastatin and lansoprazole continued to featurehighly among our ‘fast movers’ representing the products with thehighest number of offers in the marketplace (see Figure 4). G

Eplerenone doubles for the second month


PRODUCT NEWS

Marketing authorisation applications (MAAs) for biosimilar versionsof Amgen’s Neulasta (pegfilgrastim) and Genentech’s Herceptin

(trastuzumab) were among new applications accepted for review bythe European Medicines Agency (EMA’s) committee for humanmedicinal products (CHMP) through to the end of November.

From the end of October to the end of November, the number ofbiosimilar pegfilgrastim applications with the CHMP increased fromfour to six, while the number of biosimilar trastuzumab applicationsrose from three to four, the EMA’s latest figures show.

Mylan and Biocon recently announced that the EMA had acceptedfor review the firms’ biosimilar pegfilgrastim and trastuzumabcandidates (Generics bulletin, 8 December 2017, page 11). Bothapplications were previously withdrawn in the wake of issues identifiedby French regulators at Biocon’s biological drug-product manufacturingfacility in Bommasandra, India (Generics bulletin, 14 July 2017, page 3).

Other recent biosimilar pegfilgrastim applications accepted forreview include applications filed by Cinfa Biotech and Sandoz, thelatter also being a resubmission (Generics bulletin, 13 October 2017,page 15; 3 November 2017, page 19). USV is said to have filed.

Last month, Samsung Bioepis received from the EuropeanCommission the first MAA approval for a biosimilar trastuzumab, withits Ontruzant for which it has licensed marketing rights to Merck,Sharp & Dohme (MSD). The approval followed a positive CHMPopinion in September (Generics bulletin, 24 November 2017, page 13).

Meanwhile, the number of applications under review for a biosimilarversion of AbbVie’s Humira (adalimumab) rose from two to three.In November, Boehringer Ingelheim’s Cyltezo biosimilar was approved,joining Amgen’s Amgevita/Solymbic and Samsung Bioepis’ Imraldi(Generics bulletin, 17 November 2017, page 15). G

NEUTROPENIA TREATMENTS/BREAST CANCER TREATMENTS

EU biosimilar filings increase

France’s medicines agency, ANSM, has added Sandoz’ methylphenidate18mg, 36mg and 54mg prolonged-release tablets to the country’s

répertoire of generic equivalents, with Janssen’s Concerta as thereference brand for all three newly-created generic groups.

At the same time, EG Labo’s generic amlodipine/valsartan tabletsin 5mg/80mg and 5mg/160mg strengths have been listed againstNovartis’ Dafiro. Accord and Medichem’s versions of Merck, Sharpand Dohme’s (MSD’s) Cubicin (daptomycin) powder for solution havealso been added in 350mg and 500mg strengths, along with Bailleul’srival to Effik’s Lomexin (fenticonazole) 2% cream.

Accord’s equivalent to Mylan’s Rythmol (propafenone) 300mgtablets has also been listed on the répertoire. Lucane Pharma’scarglumic acid 200mg tablets have been added in a new group withOrphan Europe’s Carbaglu as the reference brand, while Teva’s versionof Bayer’s Levitra (vardenafil) tablets have been included in 5mg,10mg and 20mg strengths. G

ATTENTION DEFICIT HYPERACTIVITY DISORDER DRUGS

France lists rivals to Concerta

Coherus BioSciences has claimed a victory in US litigation withAmgen over pegfilgrastim, after Coherus convinced a US magistrate

judge to recommend dismissing the originator’s complaint againstthe biosimilars specialist.

Earlier this year, Amgen had sought a declaratory judgement froma Delaware district court that Coherus’ proposed biosimilar of Neulastainfringes US patent 8,273,707, which expires in 2024. Coherus hadsubmitted its application for the biosimilar last year (Generics bulletin,26 August 2016, page 17) before receiving a complete response letterfrom the US Food and Drug Administration (FDA) on the applicationearlier this year (Generics bulletin, 16 June 2017, page 9).

“On 7 December,” Coherus revealed in a US Securities andExchange Commission (SEC) filing, “the US Magistrate Judge issuedunder seal a report and recommendation to the district court,recommending that the district court grant, with prejudice, the company’spending motion to dismiss Amgen’s complaint for failure to state aclaim pursuant to Federal Rule of Civil Procedure 12(b)(6).”

Coherus said it “expects the district court to issue a publicly-available version of the magistrate judge’s report and recommendationwithin approximately two weeks”. Subsequently, and “subject to furtherbriefing by the parties on the matter in the coming weeks”, Coherusnoted that it “expects the district court to decide in the first quarter of2018 whether to adopt the magistrate judge’s recommendation”.

Coherus president and chief executive officer Denny Lanfearrecently revealed that the firm had made “excellent progress on thecomplete response letter issues”. Pointing out that the FDA had requesteda re-analysis of a subset of subject samples with a revised immunogenicityassay, Lanfear said Coherus had now “successfully completedvalidation” and believed the results were consistent with the FDA’srequest (Generics bulletin, 24 November 2017, page 14).

Meanwhile, Coherus had also enjoyed “very good success” withthe second part of the complete response letter, which related to chemistry,manufacturing and controls issues. Lanfear said the firm was “confidentin our approach to these issues, and plan to validate such with theagency in upcoming discussions”. G

ONCOLOGY DRUGS

Coherus claims winon US pegfilgrastim

Sandoz has secured approvals on the Australian Register of TherapeuticGoods (ARTG) for the country’s first biosimilar alternatives

to Roche’s MabThera (rituximab) oncology and arthritis treatment.Sandoz said it was working towards reimbursement.

Australia’s Therapeutic Goods Administration (TGA) hasauthorised Sandoz’ Riximyo (rituximab) 100mg/10ml and 500mg/50mlvials for treating non-Hodgkin’s lymphoma and chronic lymphocyticleukaemia in oncology settings, as well as for treating rheumatoidarthritis, granulomatosis with polyangiitis and microscopic polyangiitis.

The 100mg strength is authorised in packs of two or three vials ofconcentrate for intravenous infusion, while the 500mg concentratecomes as one or two 50ml vials. All have a shelf life of 36 months.

In the European Union (EU) – where Sandoz secured centralisedmarketing authorisations for rituximab under the Riximyo and Rixathonbrand names in mid-June this year (Generics bulletin, 23 June 2017,page 11) – Novartis’ generics and biosimilars division recently extendedthe shelf life of its rituximab finished product after dilution orreconstitution, “supported by real-time data”. An unopened vial has ashelf life of three years, or 36 months, according to the current label,while chemical and physical stability has been demonstrated forRiximyo for 30 days at 2°C-8°C when diluted in 0.9% sodium chloridesolution, and for 24 hours when diluted in 5% glucose solution. G

ONCOLOGY DRUGS/ARTHRITIS TREATMENTS

Sandoz’ rituximab isapproved in Australia


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OVER 20 COUNTRIES AND 300GRAPHS, TABLES & FIGURES

Romanian generics industry association APMGR has congratulatedits chief executive officer, Laurentiu Mihai, on being named as

the president of local health insurer CNAS. Adrian Grecu, presidentof APMGR, said Mihai had promoted access to medicines and hadhelped create a “predictable and sustainable business environment”during his six-year tenure as the association’s chief executive.

At CNAS, Grecu said, Mihai would use his “vast experience inhealth management and detailed knowledge of the problems andchallenges of the Romanian healthcare system” to focus the insurer’sefforts on reforming and modernising the country’s medicines framework.

During a recent meeting with Romanian health minister FlorianBodog, Mihai set out the “immediate objectives” of the CNAS, includingincreasing access of insured patients to treatments, building a dialoguewith family doctors to identify ways in which to optimise their workingconditions, and finalising a draft framework contract for healthcareprofessionals for 2018. Bodog insisted Mihai would treat the role ofCNAS president with the “utmost responsibility”.

Mihai recently led lobbying by APMGR to have Bodog removedfrom office. This was due to the health minister’s “completely false”statement that the country’s mandatory pharmaceutical clawback tax –much lamented by the association as disproportionate and inhibitiveof generic competition – had “not increased and has been kept to areasonable value” (Generics bulletin, 3 November 2017, page 10). G

APPOINTMENTS

Mihai leaves APMGRfor Romanian insurer

Olainfarm has announced the death of its chairman, ValerijsMaligins, at the age of 52. Following the firm’s privatisation in

1997, Maligins was named chairman. Under his management andbenefiting from his “more than 25 years of experience in managerialpositions in the chemical and pharmaceutical industry”, Olainfarm said,the firm became “one of the most valuable companies in Latvia, reachingthe level of C100 million (US$118 million) in its revenues, and sellingits products to more than 50 countries”.

Following the announcement, board member Salvis Lapinsrevoked previously-announced plans to resign by 12 January 2018,with the approval of the company’s supervisory council.

Lapins joined Olainfarm in 2006, and as well as being a boardmember, serves as director of the firm’s investment and communicationdepartment. With “almost 20 years in pharmaceuticals and banking”,he was previously chief financial officer of Forma Tres and chiefexecutive officer of Balartis.

Emphasising his “very strong ties with Olainfarm”, Lapins insistedthey had “matured during more than a decade, during which we hadour reasons for celebrations and we have coped with quite a few crises”.“The loss of Mr Maligins has upset our personnel, shareholders andpartners very heavily,” he commented. “I think that my duty now isto use my experience and wisdom learned from Valerijs to help thework of his life to overcome these uneasy times.” G

OBITUARIES

Obituary: Olainfarm’sValerijs Maligins

ICH – the International Council for Harmonisation (ICH) – hasre-elected the European Commission’s Lenita Lindström-Gommersas chair and Japan’s Toshiyoshi Tominaga as vice-chair untilNovember 2019. Sophie Sommerer had been unanimously appointedchair of ICH’s MedDRA management committee, to serve untilNovember 2018. MedDRA is an ICH standardised dictionary ofmedical terminology.

BBCIC – the Biologics and Biosimilars Collective IntelligenceConsortium – has named Charles Barr as its chief science officer.Noting that Barr’s “extensive research experience crosses industry,academia and medicine”, the BBCIC said his “prior leadership roleshave centred on both clinical trial and observational research projects”.

ASPEN said its independent non-executive director, MaureenManyama, “will no longer be standing for re-election” after “retiringby rotation” at the firm’s annual general meeting on 7 December.

INTREXON has announced three “key executive promotions” as itaims for a “more streamlined senior management structure”. ThomasBostick, who has been with Intrexon since 2016 as senior vice-president of the environment sector, has been named chief operatingofficer, replacing Andrew Last. Meanwhile, Nir Nimrodi has beenappointed as chief business officer. He “served in multiple rolessince joining the company in 2014, including most recently as seniorvice-president and head of corporate development”. Helen Sabzevarihas been named president of Intrexon’s wholly-owned subsidiaryPrecigen. All three will report to chairman and chief executiveofficer Randal Kirk. G

IN BRIEF

Mylan claims victory on US and Irish Copaxone · 2017. 12. 5. · DeputyEditor:DavidWallace...

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