Gen 6-7-18 Pgs.1-20...in central and eastern Europe (CEE); and Shanghai Henlius Biotech will allow Accord to sell its trastuzumab in more than 70 countries around the globe. MylanwillhaverightstosellLupin’sproposedetanercept–whichcompletedPhaseIII

6 July 2018

Biosimilar deals forgea trio of partnershipsAflurry of activity in the biosimilar licensing arena has resulted in three new

partnerships being struck. Lupin and Mylan have entered a deal for Mylan to sellthe Indian firm’s etanercept candidate in various worldwide territories; Prestige Biopharmaand Alvogen have agreed a licensing and supply arrangement on Prestige’s trastuzumabin central and eastern Europe (CEE); and Shanghai Henlius Biotech will allow Accordto sell its trastuzumab in more than 70 countries around the globe.

Mylan will have rights to sell Lupin’s proposed etanercept – which completed Phase IIItrials in February (Generics bulletin, 16 February 2018, page 15) and has so far been filedwith the European Medicines Agency (EMA) – in Europe, Australia, New Zealand, LatinAmerica, Africa and “most markets throughout Asia”. In return, Lupin will receive an upfrontpayment of US$15 million along with commercial milestones and an equal share of net profits.Biocon – which is also partnering with Mylan on biosimilars, including etanercept – clarifiedthat it “retains its economic interest in this arrangement” under the terms of its deal with Mylanand would “benefit from the opportunity to accelerate commercialisation of this product”,similar to its statement when Mylan partnered with Fujifilm Kyowa Kirin Biologics onadalimumab, another Biocon partnership product (Generics bulletin, 20 April 2018, page 13).

Prestige’s deal with Alvogen gives the Iceland-based firm “exclusive rights to commercialiseHervelous (trastuzumab) in all of its CEE markets, leveraging the company’s strong sales andmarketing capabilities and experience in successfully bringing new biosimilars to market”.Prestige will be responsible for developing and registering the product with the EMA – which,along with a US Food and Drug Administration (FDA) filing, is expected in 2019, afterPhase III trials are complete – as well as supplying the biosimilar from its plant in Osong, Korea.

And Accord’s agreement with Henlius will give the Intas subsidiary exclusive rights tomarket Henlius’ HLX02 trastuzumab candidate “in the territory covering 53 countriesincluding UK and France in Europe, 17 countries including Saudi Arabia and the UnitedArab Emirates in the Middle East and North Africa (MENA), and some Commonwealth ofIndependent States (CIS)”. HLX02 has passed Phase I trials and is in global, multi-centrePhase III clinical trials. G

COMPANY NEWS 3

Bain Capital will buy all 3of DSM Sinochem

Samsung deal costs Biogen US$700m 3

Hikma’s West-Ward gets 4re-branded in US

Chemiphar’s Vietnam plant to 4ship this year

Advent firms up deal for Sanofi in Europe 5

Grindeks secures deal for 5HBM in Slovakia

Jacobson to acquire and expand pipeline 7

Lannett has a plan to restructure 7Cody Labs

MARKET NEWS 8

Pressure mounts for UK clarity on Brexit 8

Biosimilar switch guide launched in EU 9

WHO plots shake-up of 10CPP certification

EC experts consider 10repurposing proposal

EMA and FDA add to 12collaboration on GMP

PRODUCT NEWS 13

FTC told to examine 13biologic pay-for-delay

Sawai introduces in Japan seven generics13

Court stings AbbVie with 15an AndroGel fine

Truvada SPC survives Swiss 15appeal decision

Aurobindo offers US 16atazanavir, ertapenem

Amgen’s infliximab may exceed Remicade 17

Nevirapine is hit by cutting 17in Australia

Lannett fails a second time 18on Zomig in US

REGULARS

Events – Conferences and meetings 12

Price Watch UK – Basket Index 17

People – Concordia reshuffles 20as debt plan proceeds

Issue No.361

Sandoz evaluates US enoxaparinSandoz is weighing the future of its US rival to Sanofi’s Lovenox (enoxaparin), after

choosing to withdraw its current version of the injectable anticoagulant from the US market.A formal discontinuation notice published by the US Food and Drug Administration (FDA)on 2 July – relating to the Novartis subsidiary’s enoxaparin in 30mg/0.3ml, 40mg/0.4ml,60mg/0.6ml, 80mg/0.8ml, 100mg/ml, 120mg/0.8ml and 150mg/ml presentations – indicatesthat “Sandoz has made a business decision to permanently discontinue this product”.

“Sandoz will be discontinuing drug product manufacturing of our enoxaparin injectionproduct at the currently approved supplier while evaluating tech-transfer options to a new, lower-cost supplier,” a spokesperson for the company told Generics bulletin. Currently, Sandoz’ USenoxaparin is manufactured at Baxter’s site in Bloomington, Indiana. Other current US competitorson the seven strengths being discontinued include Amphastar and Teva. A 300mg/3mlpresentation – for which Sandoz currently markets the only FDA-approved generic – was notincluded in the notice. Launched in July 2010 upon FDA approval (Generics bulletin, 6August 2010, page 1), Sandoz’ enoxaparin in 2011 became the company’s first product toachieve annual sales in excess of US$1 billion (Generics bulletin, 3 February 2012, page 5). G

Gen 6-7-18 Pgs.1-20.indd 1 04/07/2018 14:33

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3GENERICS bulletin6 July 2018

COMPANY NEWSBUSINESS STRATEGY/STRATEGIC ALLIANCES

Samsung deal costsBiogen US$700mnBiogen has exercised its option to increase its ownership stake in

Samsung Bioepis – its joint venture with Samsung BioLogics –from 5.4% to around 49.9%, at a cost of “approximately US$700million”, subject to closing conditions. The exact share purchaseprice for the transaction – which is expected to close in the secondhalf of 2018 – “will depend on the timing of the closing and foreigncurrency exchange rates at that time”, Biogen observed.

Under the terms of Biogen and Samsung BioLogics’ joint ventureagreement in 2012, Biogen had the right to execute a ‘call’ optionto increase its stake to give it control of “50% minus 0.5 shares” inSamsung Bioepis, compared to Samsung BioLogics’ “50% plus 0.5shares”. Biogen had earlier this year indicated that the move waslikely (Generics bulletin, 4 May 2018, page 3) before confirming inlate May that it intended to execute the option by the end of June(Generics bulletin, 25 May 2018, page 3).

“It will take about two to three months for the completion of formalprocedures, including those related to international transfer and depositof funds and merger control approvals,” Samsung said at the time.

While Samsung BioLogics will retain a slim majority stake inSamsung Bioepis, the framework for the joint venture requires a 52%majority for all actions taken by shareholder vote, meaning that theventure will be jointly managed by the two firms. The board of directorswill be split into two groups and a representative director nominated.

“We are very pleased with the progress made to date at SamsungBioepis,” said Biogen chief executive officer Michel Vounatsos, “andbelieve exercising this option is an opportunity to create meaningfulvalue for our shareholders.” The transaction “allows us to increaseour ownership share in a leading biosimilar company at what webelieve are attractive terms”, he added. “We look forward to buildingan important relationship with Samsung BioLogics.”

The move comes as Samsung BioLogics is being investigatedby Korea’s Financial Supervisory Service (FSS) over allegationsthat the firm breached accounting rules when it changed methods ofaccounting for its interest in Samsung Bioepis (Generics bulletin,11 May 2018, page 3). G

DIVESTMENTS

Novartis plans Alcon spin-offNovartis plans to seek shareholder approval for a “100% spin-off

of the Alcon eyecare devices business” into a separately-tradedstandalone company by the end of the first half of 2019, in line withNovartis’ strategy of “focusing as a medicines company”. The moveraises the share of Novartis’ group turnover generated by its Sandozdivision from a fifth to almost a quarter.

Novartis fully acquired Alcon in 2011, with the firm’s Falcongenerics operation integrated into Sandoz (Generics bulletin, 6 May2011, page 5). Having in 2016 transferred Alcon’s ophthalmicpharmaceuticals to Novartis’ Innovative Medicines division, thestandalone Alcon would become a “world-leading eyecare devicescompany” with around US$7 billion in 2017 sales, Novartis said. Alconchief executive Mike Ball has been named chairman-designate, withchief operating officer David Endicott promoted to replace Ball.

Separately, Novartis has announced a share buyback of up toUS$5 billion that will be executed by the end of 2019. G

MERGERS & ACQUISITIONS

Bain Capital will buyall of DSM SinochemDSM and Sinochem have agreed to sell their DSM Sinochem

Pharmaceuticals (DSP) 50-50 joint venture to private-equityinvestors Bain Capital, after the firms signed a definitive acquisitionagreement. “DSM will receive around C250 million (US$290 million)for its equity stake,” the Dutch firm revealed, “excluding an earn-out – estimated at around C50 million – and transaction costs.” Thedeal is expected to be completed in the fourth quarter of 2018, subjectto customary regulatory approvals and consultations.

Bain Capital – which also acquired a controlling stake in Stadawith its partner Cinven last year (Generics bulletin, 1 September2017, page 3) – described DSP as “the global leader in sustainableantibiotics, next-generation statins and antifungals”, with an“international reputation for high-quality products and reliability”.Noting that the intermediates, active pharmaceutical ingredients (APIs)and finished-dosage forms producer “has manufacturing sites andsales offices in China, India, the Netherlands, Spain, the US andMexico, with approximately 2,000 employees”, Bain cited the firm’s“long history of technical innovation”.

In 2017, DSP increased its sales by 2% to C440 million, indicatingat the time that it had delivered “strong growth over the year as itssustainability-driven antibiotics platforms are increasingly valued bythe market” (Generics bulletin, 16 March 2018, page 6). On anadjusted basis, the joint venture’s earnings before interest, tax,depreciation and amortisation (EBITDA) margin improved by aroundthree percentage points to 17% in 2017. And more recently, DSPonce again pointed to “increased recognition of its best-in-classmanufacturing activities” as it raised its first-quarter turnover by atenth to C121 million (Generics bulletin, 25 May 2018, page 7).

DSP chief executive Karl Rotthier said DSM and Sinochem hadbeen “great supporters of our vision to be the global leader in genericpharmaceuticals”, adding that Bain Capital would be “the ideal partnerto drive DSP into its next stage of global development, given its deephealthcare expertise and operational skills across its worldwide team”.

Setting out Bain Capital’s vision for the business, managingdirector Benjamin Kunstler said “we believe that DSP has tremendouspotential to grow organically and through acquisitions, thanks to itsstrong production technology, product quality and its focus onproviding pharmaceutical customers with reliable solutions to theirincreasingly complex supply chains”. G

MERGERS & ACQUISTIONS

CVC funds control RecordatiAcontrolling stake in Recordati will be acquired by funds led by

CVC Capital Partners under the terms of a C3.03 billion (US$3.52billion) transaction agreed by CVC with FIMEI, which owns anapproximately 51.8% stake in the Italian company. The figure – whichimplies a price of C28.00 per share – will be payable as C2.3 billionin cash and C750 million in subordinated long-term debt securities.The transaction is expected to close in the fourth quarter of 2018.

Recordati had sales of C1.29 billion in 2017. Of 2018 first-quarterpharma sales of C357 million, 21.4% came from Italy, 9.6% Franceand 9.4% Germany, with Russia, the Ukraine and other Commonwealthof Independent States (CIS) countries contributing 9.0%. The USaccounted for 7.4%, Turkey 6.4% and Spain 5.9%. G

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4 GENERICS bulletin 6 July 2018

COMPANY NEWS

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Issue 361 l 6 July 2018

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BUSINESS STRATEGY

Hikma’s West-Wardgets re-branded in USHikma’s West-Ward Pharmaceuticals affiliate in the US will now

operate as Hikma, as part of a “global rebranding effort” that isbringing all Hikma’s subsidiary corporate brands under a “refreshedHikma group brand, which includes a new positioning and visualidentity”. “Other US subsidiaries will also have similar name changes toalign with the new Hikma brand,” the Jordanian company noted.

Having been acquired by Hikma “more than 20 years ago”, West-Ward became “a leading provider of quality oral, liquid, inhalant andinjectable branded and non-branded generic medicines in the US”.

As well as marking Hikma’s 40th anniversary, the name change isalso “the beginning of a new chapter in the company’s history”. “Inan increasingly global world,” stated Brian Hoffman, president of thefirm’s US Generics business, “it is important that our employees, aswell as our customers and partners, can benefit from the synergiesand efficiencies of Hikma operating all operations under one brand.”

Seamless transition to HikmaDan Motto, the company’s executive vice-president of commercial

development strategy for the US Injectables business, added: “For ourUS customers and partners, the transition to Hikma will be seamless,with no change to our strong portfolio of products.” He added, “mosttouchpoints in the US will now bear the new Hikma logo, includingour building signage, our company collateral, and our website.”

Hikma’s redesigned logo and visual identity was first unveiledby the firm in mid-March, when Hikma revealed its new globalslogan, “Better Health. Within Reach. Every Day” (Generics bulletin,23 March 2018, page 14). “The new logo is a wordmark with the nameof the company in precisely drawn and spaced lettering, punctuatedat the end with a full stop that conveys certainty and confidence, aswell as a nod to the digital age,” Hikma explained. “The coral colouris connected to the legacy red of the original Hikma group logo, butre-interpreted in a contemporary hue.” Lower-case letters “makethe brand friendly and approachable”, Hikma believes.

“Our updated product packaging and labelling will be rolled outover the next 12 to 18 months, with our priority being to maintainconsistent supply and patient safety,” Motto stated. The firm notedthe US brand launch coincided with the European launch, meaningthat the “new logo and new design system are live across mobile,social and web properties in all of the Hikma group’s markets”. G

MANUFACTURING/ANNUAL RESULTS

Chemiphar’s Vietnamplant to ship this yearNippon Chemiphar says its Vietnamese manufacturing plant will

become operational in the second half of 2018, with plans tocommence exports to Japan before December. “Currently, trialmanufacturing and various drug applications have been submitted forapproval,” the firm noted. The 10,000 sq m facility, known as NipponChemiphar Vietnam, will mainly produce generic drugs and proprietaryproducts, and is set to manufacture 600 million pills per year.

Chemiphar reiterated its previous goal to “secure our presencein the generics business”, largely focusing these efforts in Asia(Generics bulletin, 6 October 2017, page 19). The Japanese firmhowever acknowledged that domestic market growth had slowed dueto National Health Insurance (NHI) price reductions and “increasinglyfierce price competition”, including from authorised generics.

Pledging to “strengthen the entire [generics] supply chain”,Chemiphar said it would review development and sales strategies, andreduce costs by “promoting switching to high-quality and inexpensiveactive pharmaceutical ingredients (APIs)”. Furthermore, the firmplans to develop value-added generics and to seek product acquisitions.

During the company’s financial year that ended 31 March 2018,Chemiphar’s group turnover fell by 1.0% to ¥35.3 billion (US$321million). Generics sales rising by 3.1% to ¥30.1 billion were boostedby improved amlodipine turnover, despite sales drops for severaldrugs including lansoprazole, donepezil, rabeprazole and limaprost.Proprietary brands sales slid by over a tenth to ¥2.04 billion.

An “increase in upfront strategic expenses, such as trial costsahead of the commencement of commercial production” at NipponChemiphar Vietnam, along with “increased research and development(R&D) expenses for new and generic drugs”, led the firm to reportselling, general and administrative costs that were 4.1% higher at ¥13.9billion. Operating income slumped by over a third to ¥1.85 billion.

In its current financial year, Chemiphar expects both groupturnover and generics sales to increase by 0.5% to ¥35.5 billion andby 0.1% to ¥30.2 billion respectively. Total turnover will be improvedby new sales channels and product launches such as lanthanumcarbonate and nalfurafine, the firm forecasts, despite the NHI pricerevisions causing a 14% decline. The company anticipates operatingprofit to fall by over two-fifths to ¥1.10 billion, due to commercialproduction start-up costs at Nippon Chemiphar Vietnam of around¥400 million, and a rise of over ¥300 million in R&D expenses. G

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COMPANY NEWSMERGERS & ACQUISITIONS

Advent firms up dealfor Sanofi in EuropeAdvent International and Sanofi have struck a final deal for the

private-equity investment group to acquire Sanofi’s Europeangenerics business, Zentiva, through a share purchase agreementworth C1.9 billion (US$2.2 billion). The deal comes after thecompletion of exclusive negotiations that were announced by the twocompanies in mid-April (Generics bulletin, 20 April 2018, page 1).

“The signing of this share purchase agreement marks a criticalstep on the way to the closing of the deal and the transfer of theZentiva business to Advent,” Sanofi said. This was “anticipated duringthe course of the fourth quarter of 2018”, the French company noted,observing that the transaction “remains subject to the approval ofthe competent regulatory authorities”.

Zentiva – which has its headquarters in Prague, the CzechRepublic – is one of the largest generics players in Europe, selling in25 European countries while producing and distributing more than350 million packs annually. The purchase price is around 2.5-timesSanofi’s European Generics sales in 2017, which fell by 4.9% atconstant exchange-rates to C760 million. ‘Eurasian’ countries suchas Russia, Ukraine, Georgia, Belarus, Armenia and Turkey do notfall under the European Generics segment as defined by Sanofi.

When negotiations were first announced, US-based buy-outspecialist Advent pledged to support the Zentiva management teamby investing in the company’s operations, production facilities andresearch and development pipeline, noting that it would “workcollaboratively” with Sanofi to form a new independent operation.

Having first acquired Zentiva in 2009 (Generics bulletin, 13February 2009, page 1), Sanofi built up a considerable genericspresence in Central and Eastern Europe, complementing its existingWestern European footprint that largely fell under the Winthrop label.Adding Switzerland’s Helvepharm the same year helped to bolsterSanofi’s generics business in Europe.

However, since late 2015 Sanofi has been openly exploringoptions for the European Generics business, pointing to a changingEuropean generics market that would require “different skills anddifferent products, specifically differentiated generics and biosimilars,in order to grow” (Generics bulletin, 20 November 2015, page 3).The French firm ultimately confirmed in late 2016 that the unit wouldbe divested within two years. G

MERGERS & ACQUISITIONS/BUSINESS STRATEGY

Amazon purchases PillPackAmazon has signed a deal to acquire for an undisclosed fee PillPack,

a US online pharmacy that “delivers medications in pre-sorteddose packaging, co-ordinates refills and renewals, and makes sureshipments are sent on time”. The agreement – which is subject toregulatory approvals and other customary closing conditions – isexpected to close by the end of 2018.

Describing PillPack as being “designed to provide the best possiblecustomer experience in the US for people who take multiple dailyprescriptions”, Amazon highlighted the firm’s “combination of deeppharmacy experience and a focus on technology”. The deal followsAmazon appointing Atul Gawande as chief executive of the healthcarecompany it recently formed with Berkshire Hathaway and JPMorganChase (Generics bulletin, 29 June 2018, page 16). G

MANUFACTURING

Two firms are warned by FDAChina’s Henan Lihua Pharmaceutical and France’s Biologique

Recherche have each been hit with warning letters from the USFood and Drug Administration (FDA) regarding their manufacturingfacilities. Inspections at the sites unearthed “significant deviations”from current good manufacturing practice (cGMP).

After an audit at Henan’s two plants in Henan, China, in December2017, the FDA observed “numerous blank batch-manufacturingrecords in an open cabinet in your manufacturing workshop office”,including “multiple blank product-release forms marked with a redquality-assurance release stamp as ‘permitted to leave the factory’”.

Two record-issuance stamps for batch and page number were“uncontrolled”, the FDA continued, with Henan’s quality unit failingto “control these records to assure that information entered on theseforms is accurate and reliable”. Furthermore, an instrument used forstability testing for multiple active pharmaceutical ingredients (APIs)was subsequently used to perform in-process analytical testing. TheFDA placed the company on import alert in March 2018.

An inspection at Biologique Recherche’s site in Suresnes, France,in September last year found that an undisclosed OTC drug wasreleased “without adequate testing for the identity and strength of theactive ingredients”. The firm also failed to test incoming raw materials,instead relying on certificates of analysis from unqualified suppliers.

Written procedures were not established for “numerous functionsof the quality unit”, including for conducting annual product qualityreviews, and investigating deviations and out-of-specification results.“You did not have adequate stability data to demonstrate that thechemical and microbiological properties of your drug products remainacceptable throughout their labelled expiry period,” the FDA added.Biologique Recherche was placed on import alert in January 2018. G

MERGERS & ACQUISITIONS

Grindeks secures dealfor HBM in SlovakiaLatvia’s Grindeks has completed its C18.2 million (US$21.2 million)

acquisition of Slovakian contract manufacturing business HBMPharma, after paying in full under the terms of the agreement. Notingthat the “core business” of HBM was pharmaceuticals manufacturing,Grindeks said it had “conducted a long-term agreement” with thecompany to produce injectables.

HBM makes the following sterile liquids in injectable ampoules:fentanyl, furosemide, magnesium sulphate, metamizole, mildronate,morphine, oxytocin and piracetam. The firm also produces film- andsugar-coated tablets, such as amisulpride, escitalopram, itopride, andpentoxifylline, along with perindopril, propafenone, quetiapine andsildenafil. Observing that the company had the capacity to produce80 million ampoules and 400 million tablets, HBM noted that itachieves over C25 million in sales annually.

Having been acquired in July 2005 by Sanitas – a Lithuaniancompany that was later taken over by Valeant (Generics bulletin,2 September 2011, page 12) – HBM was then bought by Latvia’sLiplats 2000 five years later (Generics bulletin, 6 August 2010,page 4). In 2012, Grindeks entered into a purchase agreement forthe firm, which prior to February 2010 was called Hoechst-Biotika.

Grindeks now has four subsidiaries, Kalceks and Namu inLatvia, HBM in Slovakia and Tallinn Pharmaceutical in Estonia. G

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Gen 6-7-18 Pgs.1-20.indd 6 04/07/2018 14:33


COMPANY NEWSBUSINESS STRATEGY/ANNUAL RESULTS

Jacobson to acquireand expand pipelineHong Kong’s Jacobson Pharma has committed to “invest in

expanding our generic drug and proprietary medicine productportfolio and pipelines”, as well as outlining plans to “integrate ouroperational capabilities and explore opportunities through in-licensing,strategic alliances and acquisitions”, including on biosimilars.

“We are committed to expanding our regional platform, buildingon our commercial strengths, maximising our ability to invest inopportunities, and retaining the best talent in the industry,” the firmstated. Outlining its “strategic priorities”, Jacobson revealed that itaims to bolster its biosimilars portfolio by “building up commercialcapabilities” and being “the partner of choice for in-licensing orbusiness representation in Asia”.

In December 2017, Jacobson entered into a licensing frameworkagreement with Shanghai Fosun’s subsidiary, Shanghai Henlius Biotech,for exclusive rights to develop and market biosimilar trastuzumab in itsdomestic market and Macau. The deal included “a right of firstnegotiation” to sell the monoclonal antibody in “certain emerging marketswithin the Association of South-East Asian Nations (ASEAN) region”.

Jacobson also signed an in-licensing agreement for a specialtyantiviral drug for manufacturing and exclusive distribution rights inHong Kong and other Asian countries such as Cambodia, Malaysia,Myanmar, the Philippines, Thailand and Vietnam. No further detailsof the agreement were disclosed.

In the firm’s financial year ended 31 March 2018, sales of genericdrugs increased by 7.4% to HK$1.18 billion (US$150 million), ofwhich public- and private-sector turnover rose by 7.9% and 7.2%respectively. “The group saw solid sales growth for its central nervoussystem (CNS) and respiratory categories at 20.5% and 36.0%respectively,” Jacobson observed, noting that there was a “strongperformance” in its CNS drug segment, including for amisulpride,zolpidem and risperidone. Losartan and gliclazide achieved “robustsales growth”.

Furthermore, the company secured new tenders for genericzolpidem, amisulpride, risperidone and lamivudine tablets, along withursodeoxycholic acid capsules. Jacobson’s ophthalmic preparationsand dermatological products “also posted an encouraging growth, of14.9% and 20.0% respectively, in the public sector”.

Reporting group sales that advanced by almost a quarter toHK$1.55 billion, the firm achieved a gross profit that was 10.9%higher at HK$618 million. G

BUSINESS STRATEGY

Lannett has a plan torestructure Cody LabsLannett has announced a restructuring and cost-reduction plan for

its Cody Laboratories active pharmaceutical ingredients (APIs)manufacturing subsidiary, in response to what it describes as thechanging regulatory and competitive landscape for pain-managementAPIs, with the loss of around 50 jobs.

The US firm will discontinue the manufacture of “less profitableAPI products”. Cody’s current portfolio includes cocaine hydrochloride,methylphenidate hydrochloride, hydrocodone bitartrate, hydromorphonehydrochloride and morphine sulfate. Furthermore, Lannett will“rationalise” Cody’s API product development program. The firmnotes lisdexamfetamine dimesylate as an in-development API asset.

As part of a three-prong strategy, the US firm intends to transferproduction of finished-dosage liquid pharmaceutical products to itsmanufacturing facility in Carmel, New York, which Lannett pickedup through its June 2015 acquisition of Silarx Pharmaceuticals.

Noting the scheme was expected to generate annualised costsavings of approximately US$10 million and be “substantiallycompleted” by this December, Lannett estimated that it would incurcosts of approximately US$5 million to implement the plan, “comprisedprimarily of severance and employee-related costs”. “In addition,”Lannett said, “the company may incur non-cash impairment chargesrelated to Cody’s facility, equipment and other plant-related assets.”

At the beginning of last year, Lannett had announced a US$50million expansion plan to develop Cody’s operations, with the aimof “significantly increasing” production of APIs and strengthening itsvertical integration efforts for pain-management products.

But this scheme was frozen earlier this year, with Lannett optingto focus on “nearer-term opportunities” (Generics bulletin, 11 May2018, page 5). Tim Crew, Lannett’s chief executive officer, said thechanged regulatory and competitive landscape for pain-managementAPIs had extended Cody’s “timeline to profitability and caused usto revise our plan for this business”.

“We determined the substantial continuing investment to attainthe size and scale necessary to become a broad competitive force inthat space was inconsistent with our renewed focus on our corebusiness, where we see a great deal more near-term opportunities togrow high-value assets,” Crew commented. Nevertheless, he said,Cody continued to offer “intriguing vertical integration opportunities”.

Lannett had also “begun evaluating strategic alternatives to unlockeven more value from Cody”, Crew said, without explaining further. G

MANUFACTURING

Mylan to improve MorgantownMylan has “committed to a robust improvement plan” as part of

its response to a 32-page ‘Form 483’ issued by the US Food andDrug Administration (FDA) to highlight observations and deficienciesat the firm’s flagship facility in Morgantown, US. The company hasfull confidence in the quality, safety and efficacy of the site’s products.

Among the 13 observations listed in the Form 483 are issues withquality-control procedures, equipment cleaning and maintenance,laboratory controls and reviews of batch failures. “There are no writtenprocedures for production and process controls designed to assure thatthe drug products have the identity, strength, quality and purity theypurport or are represented to possess,” one observation reads. G

MANUFACTURING

Dr Reddy’s clears API hurdleDr Reddy’s Laboratories says it has received an establishment

inspection report (EIR) from the US Food and Drug Administration(FDA) following recent inspections of two active pharmaceuticalingredient (API) plants in the Indian state of Telangana.

Earlier this year, the Indian company disclosed that its ‘HyderabadPlant 1’ facility in Jinnaram Mandal had received four ‘Form 483’observations from the FDA, while the US agency had issued fiveForm 483 observations, “related to procedures and facility maintenance”,against its ‘Hyderabad Plant 3’ site in Bollaram (Generics bulletin,23 March 2018, page 4). At that time, Reddy’s pledged to addressthe issues “comprehensively within the stipulated time”. G

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MARKET NEWS

ONLY THREE European Union (EU) member states have a specificdefinition of a supply disruption or shortage in their nationallegislation, according to a questionnaire distributed by the EuropeanCommission. Responding to the survey on national measures forimplementing Article 81 of Directive 2001/83/EC – which requiresmarketing authorisation holders (MAHs) and distributors to“ensure appropriate and continued supplies” – Denmark, Germany,Spain and Sweden reported having definitions or classifications intheir internal procedures. In Hungary, Latvia, the Netherlands andPortugal, definitions were implied in obligations to notify authoritiesof shortages, while in Slovakia, a methodology for determiningwhether sufficient stock was on hand served a similar purpose.

FDA – the US Food and Drug Administration – would hand overits responsibility for food safety to the US Department of Agricultureunder a reform plan put forward by the executive office of theUS President. The FDA – which would be renamed as the FederalDrug Administration – would focus on drugs, devices, biologics,tobacco, dietary supplements and cosmetics.

EMA – the European Medicines Agency – has amended itsquality review of documents (QRD) general principles on thesummary of product characteristics (SmPC) for generic, hybridand biosimilar medicines. An added section states that indicationsapplied for should be reflected in section 4.1 of the SmPC as perthose of the reference drug with the same strength and pharmaceuticalform. Any additional strengths and forms that are suitable for certainpatient sub-groups, such as oral solutions for children, should bementioned in section 4.2.

ACCC – the Australian Competition & Consumer Commission –has sought High Court special leave to appeal against a recent FederalCourt dismissal of allegations that Pfizer abused its marketpower to deter generic competition to its Lipitor (atorvastatin)cholesterol-lowering brand. The antitrust watchdog in late May failedin its appeal against an earlier finding that Pfizer was not guilty ofoffering anti-competitive inducements to Australian pharmaciststo stock up on the originator’s own generic version of Lipitor aheadof patent expiry (Generics bulletin, 1 June 2018, page 13).

CJEU – the Court of Justice for the European Union – has ruledthat specific mechanisms laid down for EU accession countriesmust be interpreted as allowing holders of supplementary protectioncertificates (SPCs) issued in non-accession member states to opposeparallel imports from accession states where it was not possibleto obtain equivalent protection. Pfizer had sought the ruling toblock parallel imports of Enbrel (etanercept) from countries suchas Estonia and Latvia into Germany by Denmark’s Orifarm.

MEDSAFE – New Zealand’s medicines and medical devices safetyauthority – has opened a consultation on a “major revision” to itsclinical trials guideline. The update reflects a shift from self-certification of clinical-trial sites to a notification procedure, aswell as a move from paper to online applications.

HPRA – Ireland’s Health Products Regulatory Authority – hasupdated its guide to interchangeable medicines. This followsclarification from the country’s Department of Health thatdemonstrating bioequivalence is not required under the Health(Pricing and Supply of Medical Goods) Act of 2013 that introducedgeneric substitution and reference pricing. Meanwhile, the HPRAhas just closed a consultation on a “multi-stakeholder approach tohandling medicines shortages”. G

IN BRIEFREGULATORY AFFAIRS

Pressure mounts forUK clarity on BrexitClarity is urgently needed on arrangements for the pharmaceutical

industry after the UK leaves the European Union (EU), accordingto the Association of the British Pharmaceutical Industry (ABPI)and the UK BioIndustry Association (BIA).

Commenting on ‘Brexit’ negotiations after the latest EU Councilmeeting, ABPI chief executive Mike Thompson and BIA chiefexecutive Steve Bates released a joint statement highlighting that “weare now fewer than nine months away from the day the UK leavesthe EU, and as it stands we still do not have a deal on the futurerelationship or any certainty on the conditions our companies areexpected to operate under come 29 March 2019”.

“Every month,” Thompson and Bates pointed out, “45 millionpacks of medicines move from the UK to the EU and 37 million comeback the other way.” Emphasising the importance of clarity overfuture arrangements, they observed that “the health of millions of EUand UK patients are dependent on our industry’s ability to movemedicines and vaccines across borders without delay or interruption”.

Recently, the British Generic Manufacturers Association (BGMA)insisted that “in order to maintain stability of supply, it is paramountmanufacturers are given assurances over the next three years whereverpossible”. “Nothing should be put in place which disrupts gettingmedicines to the right patient at the right time,” cautioned theassociation’s director general Warwick Smith (Generics bulletin,29 June 2018, page 5).

Simon Stevens, chief executive officer of National Health Service(NHS) England, noted in a recent interview that there was now“significant planning going on around all the scenarios”, includingthe possibility that the UK will leave the EU with no agreed dealbetween the two parties. “Nobody is pretending this is a desirablesituation,” he acknowledged, “but if that’s where we get to then it willnot have been unforeseen.”

“There is immediate planning which the health department, withother parts of government, are undertaking around securing medicinessupply and equipment under different scenarios,” Stevens revealed,including “extensive work” in conjunction with pharmaceuticalcompanies and the life sciences industry. “That will obviously crystallisewhen it’s clear later this autumn what the UK’s position will be.”

“Nobody is in any doubt,” Stevens emphasised, “that top of thelist in terms of ensuring continued supplies for all the things that weneed in this country, right at the top of the list, has got to be thosemedical supplies.”

Separately, revised Brexit guidance has just been published by theEuropean Medicines Agency (EMA), including updates to a question-and-answer document and to practical guidance for industry.

Updates to the question-and-answer document include urginggeneric and hybrid applicants to take into account at the time ofsubmission the requirement to refer to an EU reference product.However, “generic/hybrid marketing authorisations granted before30 March 2019 referring to a reference product authorised by theUK remain valid”. Meanwhile, multi-country packs that include theUK “may have to adapt their packaging” as multi-country packsincluding a non-EU country “will normally not be possible”.

Within the revised practical guidance are new sections dealingwith contact points at the EMA for Brexit-related activities, as wellas what to consider when changing a pharmacovigilance master file(PSMF) location from the UK to the EU. Gn [email protected]

Gen 6-7-18 Pgs.1-20.indd 8 04/07/2018 14:33


MARKET NEWS

Abiosimilar switching guide for nurses in Europe has been publishedby the European Organisation for Specialised Nurses (ESNO) to

facilitate interactions with patients switching between similarbiological medicines and to contribute to the safe use of biosimilars.

Supported by off-patent industry association Medicines for Europeand brand body EFPIA, the initiative “focuses on tools for nurses tobetter inform and communicate on biological and biosimilar medicinesto patients”. Throughout the 48-page guide, ESNO illustrates itspoints with case studies, questions-and-answers and flowcharts.

Developed by the organisation “based on similar initiatives acrossEurope where switching programs are already in place”, the guide“builds on existing European Commission guidelines for the healthcareprofessional community by specifically addressing the role ofspecialised nurse interactions with patients during the switch process”.

The European Commission revised a patient question-and-answerdocument on biosimilars early last year (Generics bulletin, 27 January2017, page 10). Shortly after, the Commission – in collaboration withthe European Medicines Agency (EMA) – released an informationguide for healthcare professionals entitled ‘Biosimilars in the EuropeanUnion’ (Generics bulletin, 12 May 2017, page 1).

Stating that switching needs “good management”, ESNO’sexecutive director Ber Oomen says that nurses “play a critical role incommunicating with patients and providing support and reassurance,before, during and after the switch”. “It is a process that requirestime, patience and care,” he maintains. “Patients need to know thattheir healthcare professionals understand the reasoning behind theswitch and are confident that it is the right thing to do. This guideaims to achieve that.”

Defines specific featuresThe first section begins by defining biosimilars, detailing their

“specific features”, such as being highly similar to the referencemedicine with no clinically meaningful differences, and having thesame strict standards of quality, safety and efficacy. Questions coveredin this section include: “Why are you changing my current treatmentto a biosimilar medicine?” and “How do you know it’s as good as theoriginal medicine?”, along with queries over safety and extrapolation.

Next, the guide describes switching, substitution andinterchangeability. “For a nurse, it is important to understand thatthere is no such thing as a ‘one size fits all’ approach for the use ofbiosimilars,” ESNO asserts, pointing out that “different countries havetheir own policies and regulations, and this can vary between regions”.

A chapter on the benefits of biosimilars discusses improvedaccess to drugs through increased competition in the market and thusmore choice for prescribers and patients. It also states that biosimilarscan be more cost-effective than reference drugs, which could savemoney on healthcare budgets. Such savings could be used to expandhospital teams, get access to more hours for specialist nurses, or offerbetter training for non-specialist healthcare professionals, ESNO adds.

The York Teaching Hospital Foundation Trust in the UK switched

from the reference infliximab to a biosimilar alternative in September2015, saving around £450,000 (US$588,335) in the first year.

Looking at how “changing guidelines can affect biosimilar use”,the guide notes that in Sweden, before biosimilar versions of Amgen’sNeupogen (filgrastim) were launched, the originator drug could onlybe administered to patients after the consent of three physicians.“Because of the reduction of the treatment costs due to biosimilarcompetition, the authorities relaxed the restrictions on prescribing,requiring consent from only one physician,” it observes. “This resultedin a 500% increased use of biosimilar filgrastim.”

A section on switching emphasises the nurse’s role in “buildingpatients’ confidence and commitment to the switch”, a process thatis described in eight steps. Beginning with ‘contact’, the nurse mustprovide clear information about biosimilars to create ‘awareness’.Showing examples, answering questions and dealing with challengesforms the ‘understanding’ phase, while ‘positive perception’ reinforcesthe benefits of the change.

‘Experimentation’ means talking through the processes ofadministration and showing the patients the biosimilars, leading themto begin the treatment in the ‘adoption’ phase. Following up anyquestions after the switch and reinforcing previous steps is referredto as ‘institutionalisation’, while finally, ‘internalisation’ involvescontinuing to reassure patients, working to counter any negativethoughts, and monitoring adherence and compliance as the biosimilartreatment becomes routine.

“To avoid confusion, the team of nurses and other healthcareprofessionals should have a consistent explanation that is used by all,”the guide insists. Contending that “communication with patientsthroughout the process is vital”, it says that support should also addressissues such as pharmacovigilance, adverse events and productcomplaints. Flowcharts provided could act as a reference point fornurses in dealing with the following scenarios: introducing biosimilars,implementing switches, and for follow-ups and support.

Acknowledging that switching medication “can be challenging”for patients, the guide offers sample responses to those who arereluctant to change. Questions tackled in this section include: “Canthe biosimilar have a different packaging or delivery system?”, “MightI have to change medicine again?” and “What should I do if I thinkthe biosimilar is causing side effects?”

On pharmacovigilance, ESNO highlights the importance ofsafety monitoring, including “product and batch traceability duringdaily use and at all levels in the supply chain”, and also monitoringand reporting suspected adverse drug reactions.

Along with a glossary, the final section also features a list ofbiosimilar medicines approved in Europe as of 30 May 2018, alongwith those currently in development as of 8 December last year.‘Additional supporting information’ provides examples of real-worlddata and clinical trials, as well as highlighting examples of nationalpolicies on introducing and substituting biosimilars. Gn [email protected]

REGULATORY AFFAIRS

Biosimilar switch guide launched in EU

FDA – the US Food and Drug Administration – has issued guidancefor industry on assessing biosimilar user fees under the seconditeration of the Biosimilar User Fee Amendments (BsUFA II). Theguide covers the types of development, application and programfees under BsUFA II, the process for making payments and theconsequences for failing to pay fees, as well as fee waivers. G

IN BRIEFBEMVO – Belgium’s medicines verification organisation – is nowconnected to the pan-European EMVO hub for verifying uniqueproduct identifiers required by the European Union’s FalsifiedMedicines Directive. With Croatia, Cyprus, Estonia, Finland,Luxembourg and Norway also having recently connected, Hungary,Latvia, Portugal and Slovakia are scheduled to join up during July.G

IN BRIEF

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MARKET NEWSREGULATORY AFFAIRS

WHO plots shake-upof CPP certificationRapid globalisation of the pharmaceutical manufacturing sector,

along with changes in the make-up of regulators and procurementbodies, have prompted the World Health Organization (WHO) toconsult over revising the scheme through which it issues certificatesof a pharmaceutical product (CPP). Comments are due by 30 August,after which the WHO will present its plans to the 18th InternationalConference of Drug Regulatory Authorities (ICDRA) on 3-7 Septemberand to its own expert committee on specifications for pharmaceuticalpreparations (ECSPP) in late October.

Acting on the ECSPP’s recommendation, the WHO intends toimprove its voluntary certification scheme on the quality ofpharmaceutical products moving into international commerce thatincludes CPPs, statements of marketing authorisation status and batchcertificates. The last revision took place in 1997.

Among the planned changes are clarifying that “CPPs shouldnot be requested in countries that have the capability to conduct fullquality, safety and efficacy (QSE) reviews unless they have a rationaleto request one”. However, the WHO cites two examples that justifyrequesting a CPP: where a competent authority that conducted QSEreviews does not disclose the product registry information or disclosesthe list only in its local language; and where a CPP can facilitate afast-track approval by the requesting authority.

Model templates for CPPs should be revised so a proposed tradename in the importing country can be stated, the WHO proposes.Importing countries should not require legalisation of certificates, suchas through additional stamps, it says, while certifying authoritiesshould follow a “standard timeframe, ideally within 30 working days”.

The WHO also plans to add an indicator for a country possessingan “effective marketing authorisation system” compliance with itsown global benchmarking tool (GBT) at ‘maturity level 3’. It alsoplans to require memberships of certificate-issuing countries to berenewed every five years, and to change the wording of the schemeso that regional organisations such as the European Union canformally participate. Certificates should, “as a minimum”, includeinformation on manufacturers responsible for making dosage formsand finished batches, as well as packaging and labelling. G

REGULATORY AFFAIRS

ICH members add agenciesThree regulatory agencies – China’s CFDA, Singapore’s HSA and

South Korea’s MFDS – have swelled the ranks of the managementcommittee of the International Council for Harmonisation (ICH). Theregulators took up their role at the same time as US biotech groupBIO and off-patent body the International Generic and BiosimilarMedicines Association (IGBA) joined the committee as “one of theremaining steps of implementing the 2015 reforms of ICH” (Genericsbulletin, 15 June 2018, page 1).

Among other decisions taken during the ICH Assembly held inKobe, Japan, during June was to approve Chinese Taipei’s TFDAagency as a new regulatory member, along with Armenia’s SCDMTE,Malaysia’s NPRA, Moldova’s MMDA and Turkey’s TITCK asobservers. There are now 16 ICH members and 27 observers.

During the Kobe meeting, the ICH finalised six guidancedocuments and adopted two draft guidelines. G

REGULATORY AFFAIRS

EC experts considerrepurposing proposalAEuropean Commission expert group on Safe and Timely Access

to Medicines for Patients (STAMP) is considering an industrydraft proposal for a framework to help repurpose off-patent moleculesfor new uses. In particular, the STAMP experts are evaluating whetherto run a pilot of the proposed scheme.

A joint proposal by off-patent industry association Medicinesfor Europe and its patented brands counterpart EFPIA describes howa ‘champion’ – defined as a person, academic unit, learned society,research fund or company other than a marketing-authorisation holder(MAH) seeking a new extension as part of its lifecycle-managementstrategy – could put forward a repurposing proposal for regulatoryevaluation. Based on guidance provided by regulators, this wouldbe in the form of a standard package including: information on thecompound and the specific product if it already exists; the proposedrepurposing to prevent, treat or diagnose a particular condition; anda description of new and existing supporting in vitro, in vivo andclinical data to support a new indication.

Regulators and competent authorities such as the EuropeanMedicines Agency (EMA) would then notify affected MAHs of therepurposing proposal as they start to evaluate the standard packageof evidence. Highlighting the need for a repurposing proceduralguidance around issues such as workload and scientific advice, theindustry bodies suggested a standardised evaluation. This would bebased on existing Commission and EMA guidelines, outlining thescientific rationale for repurposing, the status of proposed indicationin terms of unmet need and patient population, and the suitability ofthe data for various regulatory procedures, such as variations, orphandesignations and paediatric use marketing authorisations (PUMAs).

Positive evaluation placed in pool“If the regulatory evaluation is positive,” Medicines for Europe

and EFPIA proposed, “it is placed in a ‘repurposing data pool’ tobe picked up by the applicable MAH(s). The intention is not to resubmitdata by each MAH, but rather to refer to the positive recommendationissued by the authorities.” This, they suggested, would open up thepossibility of the champion partnering with MAHs or other partiesinterested in repurposing molecules.

“Additionally,” the industry partners stressed, “specific considerationof appropriate incentives and the impact on pricing is needed.” Forexample, they said, free scientific advice in the course of the repurposingpathway and/or decreased and waived fees for variations could spurparties to conduct further work on finding new indications for knownsubstances. But payers and health authorities must be dissuaded fromencouraging off-label use on economic grounds.

Furthermore, a repurposing fund could support projects acceptedin the pool, the industry bodies advocate, citing the example of a UKproposal to enable companies to recoup investments through researchand development tax credits. “One advantage is that this type ofincentive would certainly support small to medium-sized enterprises(SMEs) and companies with limited capital risk upfront.”

Should the assessing regulatory agency take a negative view of thepackage, the reason for that finding would also be put into the repurposingdata pool “to inform stakeholders of the shortcomings or other reasonswhy the opportunity should not be pursued”. Indicating through thedata pool that a repurposing proposal had been rejected for a lack ofplausibility “can help to stop existing off-label use”, they argued. Gn [email protected]

Gen 6-7-18 Pgs.1-20.indd 10 04/07/2018 14:33

Recognisinnng the best in the globalgenerics aaand biosimilarsss industries

Cocktail Reception &Awards Presentation

Tuesday 9 October 2018Palacio Municipal de CongresosMadrid, Spain

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Gen 6-7-18 Pgs.1-20.indd 11 04/07/2018 14:33


MARKET NEWS

5-7 Septembern GRx+Biosims

Maryland, USAThis three-day event, organised by the Association for AccessibleMedicines, combines previous conferences – Fall TechnicalConference, Leading on Biosimilars and the CMC Workshop –to bring updates on topics such as regulatory and best practiceswithin the generics and biosimilars industries.

Contact: Association for Accessible Medicines. Tel: +1 202 249 7138.E-mail: [email protected]. Website: www.accessiblemeds.org.

26-27 Septembern Biosimilars & Biobetters 2018

London, UKTopics covered at this two-day conference will include sustainability,patient access, launching biosimilars in Europe, and clinical trials.There will be case studies and speakers from companies includingLupin, Mylan and Sandoz.

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

9-11 Octobern CPhI Worldwide

Madrid, SpainCPhI Worldwide offers an exhibition and networking opportunities.Running alongside this event will be the ICSE, InnoPack, P-MECand Finished Dosage Formulation exhibitions.

Contact: UBM Information. Tel: +31 20 708 1637.E-mail: [email protected]. Website www.cphi.com.

29-30 Octobern World Biosimilar Congress

Basel, SwitzerlandThere will be networking receptions and lunches, an exhibitionand a conference included in this event.

Contact: Terrapinn. Tel: +44 207 092 1257.E-mail: [email protected]. Website www.terrapinn.com.

21 Novembern 2nd Value Added Medicines Conference

Brussels, BelgiumOrganised by Medicines for Europe, this one-day event will look atopportunities presented by value added medicines across the industry.

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

26-27 Novembern EuroPLX 68

Noordwijk, The NetherlandsThis two-day meeting provides an opportunity to discuss andnegotiate agreements, development, in-licensing, marketing,promotion and distribution.

Contact: RauCon. Tel: +49 6221 426296 0.E-mail: [email protected]. Website: www.europlx.com.

EVENTS – September – November

9 October 2018Palacio Municipal de Congresos,

Madrid, Spain

Sponsor, Enter,Join us!

[email protected]

Call: +44 1564 777550

REGULATORY AFFAIRS

EMA and FDA add tocollaboration on GMPFurther collaboration on generics has been set out by the European

Union (EU) and US after a bilateral meeting between the EuropeanMedicines Agency (EMA) and the US Food and Drug Administration(FDA) in late June. “The opportunity was taken to better understandthe fundamentals of legal, regulatory and scientific requirements forapproving generic and hybrid applications on both sides,” the EMAnoted, “and to identify possible ways of streamlining the scientificrequirements for such approvals with a particular focus on complexgenerics for the FDA and hybrids for the EU.” Possible next stepsinclude “the continued access for companies to EMA-FDA parallelscientific advice and further collaboration between regulators onthe product-specific guidelines they develop”.

At the same time, the EU and US confirmed that their mutual-recognition agreement on good manufacturing practice (GMP)inspections – struck in early 2017 (Generics bulletin, 10 March 2017,page 1) – remained “on track” to be operational in all EU memberstates by 15 July 2019. The FDA recently brought to 14 the numberof EU countries accepted by the US under the deal (Generics bulletin,15 June 2018, page 9). “The two parties committed to continue towork closely at a technical level,” the EMA said, “to further streamlinethe process, measure progress made, and monitor closely theimplementation of the mutual-recognition agreement.” G

REGULATORY AFFAIRS

FDA updates off-patent listAtotal of 11 products are included in an appendix to a US Food

and Drug Administration (FDA) ‘list of off-patent, off-exclusivitydrugs without an approved generic’ that details molecules for whichgenerics have become available in the US since the last time theagency updated the list in December 2017.

Among the products removed from the list, and included in theappendix, are injectable baclofen and capreomycin sulfate followingFDA approvals obtained by Mylan. Shanghai Hengrui’s first-timeapproval for a generic of Suprane prompted the removal of desfluraneliquid to the appendix, with Taro’s clearance for dapsone gel havinga similar effect.

Par and Teva launches reduce listPar’s approval for generic Biltricide (praziquantel) tablets late

last year prompted another appendix entry, as did Teva’s approval,and immediate launch, of generic Syprine (trientine) 250mg capsules(Generics bulletin, 16 February 2018, page 14). Other entries ontothe appendix are: cyclophosphamide capsules; fluoxetine tablets;methadone for injection, potassium chloride for solution; andtiagabine tablets.

The main list – which the FDA has committed to updatingevery six months – is split into two parts. The first contains dozensof formulations and combinations for which the FDA believes itcould “immediately accept an abbreviated new drug application(ANDA) without prior discussion”. The second part lists many moreproducts for which the FDA acknowledges that “ANDA developmentor approval may raise potential legal, regulatory or scientific issuesthat should be addressed with the agency prior to consideringsubmission of an ANDA”. G

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PRODUCT NEWS

OPIOID-DEPENDENCE THERAPIES

Reddy’s Suboxone still heldAUS district court has extended briefly a temporary restraining

order against Dr Reddy’s Laboratories barring the Indian firmfrom marketing its generic of Indivior’s Suboxone (buprenorphine/naloxone) sublingual film formulation.

In response to the Indian firm launching its generic productat-risk immediately following US Food and Drug Administration(FDA) approval, New Jersey District Judge Kevin McNulty lastmonth granted originator Indivior’s request for a temporary restrainingorder compelling Reddy’s to cease launch activities (Genericsbulletin, 22 June 2018, page 11).

The temporary restraining order remains in place while McNultyconsiders Indivior’s pending motion for a preliminary injunction thatwould keep the bar on Reddy’s launch until the outcome of litigationover US Suboxone patent 9,931,305. A ‘show cause’ hearing on themotion was held on 28 June.

“The judge has heard the matter,” Reddy’s confirmed in a brieffiling with the Bombay Stock Exchange (BSE), “and extended thetemporary restraining order for a further period of 14 days pendinghis decision.” G

ANAPHYLAXIS DRUGS

Sandoz bags US epinephrineSandoz has acquired exclusive distribution and commercialisation

rights in the US to Adamis Pharamceuticals’ Symjepi (epinephrine)subcutaneous injectable, a non-substitutable alternative to Mylan’sEpiPen anaphylaxis treatment. The deal covers both an approved0.3mg strength as well as a 0.15mg version that is pending US Foodand Drug Administration (FDA) approval, while Sandoz also has “firstright of negotiation” to acquire commercial rights outside of the US.

Under the terms of the deal, Sandoz has agreed to pay California-based Adamis an undisclosed upfront fee, as well as potentialperformance-based milestones payments, in exchange for commercialrights to Symjepi. Sandoz and Adamis will equally share net profits.

“Symjepi is an affordable alternative treatment for patients whoare at increased risk for anaphylaxis,” commented Sandoz’ USpresident, Carol Lynch. “As one of the largest pharmaceuticalcompanies in the US, Sandoz has the right capabilities to support broadpatient access to Symjepi.”

Actavis had previously agreed US commercial terms for Adamis’epinephrine disposable pre-filled syringes, but terminated the agreementafter the developer received a complete response letter (CRL) fromthe FDA in mid-2016 (Generics bulletin, 29 July 2016, page 10).Adamis resubmitted through the FDA’s 505(b)(2) hybrid new drugapplication (NDA) pathway towards the end of 2016, and obtainedapproval for the 0.3mg strength around 12 months ago (Genericsbulletin, 23 June 2017, page 12).

“We believe the financial terms of this agreement have the potentialto bring meaningful recurring revenue to Adamis,” commentedpresident and chief executive officer Dennis Carlo, “and we lookforward to growing, and possibly expanding, this partnership withSandoz based on the future success of Symjepi in the market.” G

HYPERPHOSPHATAEMIA DRUGS/EPILEPSY DRUGS

Sawai introduces inJapan seven genericsSawai has introduced seven generic drugs in Japan, six of which

the firm recently cited as anticipated entries during June on thecountry’s National Health Insurance (NHI) reimbursement list (Genericsbulletin, 25 May 2018, page 11). Noting that there were 17 strengthsavailable across the seven generics launches, Sawai observed that thefirm’s product line “now includes 302 compounds with 738 strengths”.

Among the six heralded launches are generics of Bayer’s Fosrenol(lanthanum carbonate), a treatment for hyperphosphataemia in agranules formulation, GlaxoSmithKline’s Lamictal (lamotrigine)tablets for treating epilepsy and bipolar disorder, and Roche’s Tamiflu(oseltamivir) antiviral in both capsule and dry syrup forms. Furthermore,Sawai listed and has launched alternatives to Aimix (irbesartan/amlodipine), Remitch (nalfurafine) and Talion (bepotastine) tablets.

In addition, Sawai has introduced a generic version of Bonoteo/Recalbon (minodronic acid), a treatment for osteoporosis that isavailable in tablet form, which was not mentioned in the Japanesecompany’s previous list of planned launches.

Separately, Sawai has started to manufacture and marketAstraZeneca’s Zomig (zolmitriptan) 2.5mg tablets – as well as theZomig Rapid Melt 5mg version of the migraine treatment – in Japan,after concluding its exclusive agreement with the originator that wasstruck in October (Generics bulletin, 3 November 2017, page 20). G

BIOLOGICAL DRUGS

FTC told to examinebiologic pay-for-delayThe US Federal Trade Commission (FTC) should “examine

whether makers of biologic medicines are using strategies like‘pay for delay’ to hinder or delay biosimilars from entering the market”,according to an open letter from US Senators Chuck Grassley andAmy Klobuchar to the US antitrust regulator.

“In light of the importance of biosimilar competition to drivedown prices and improve the quality of life for American patients,”Grassley and Klobuchar write, “we urge the FTC to examine globalpatent settlements relating to biosimilars to ensure they are not inviolation of antitrust laws”.

Noting that “biologics are a fast-growing class of medicines thatare often more expensive than traditional pharmaceutical products”,the Senators suggested that “the use of ‘pay for delay’ deals – thepractice of brand-name and generic drug companies using pay-offagreements to delay the introduction of cheaper substitutes – and otheranti-competitive tactics for biologics could make some criticalprescriptions unaffordable for patients”.

In particular, the letter highlights global settlement deals struckby AbbVie with both Amgen and Samsung Bioepis over Humira(adalimumab) in late September 2017 (Generics bulletin, 6 October2017, page 1) and April 2018 (Generics bulletin, 13 April 2018,page 13) respectively. “Under the agreements, Amgen and Samsungwill not launch their products in the US until 2023, but both companieswill be able to launch their biosimilars into the European market inOctober 2018,” the Senators observe.

“While such terms in patent-settlement agreements may not alwaysbe inappropriate,” the letter acknowledges, “the incentives for partiesto delay biosimilar entry are present, and biologic markets could besusceptible to patent-settlement abuse.”

“Without biosimilar competition,” Grassley and Klobuchar caution,“US patients and payers will likely see additional price increases onbiologics in the years to come.” G

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15GENERICS bulletin

PRODUCT NEWS

6 July 2018

HIV/AIDS DRUGS

Truvada SPC survivesSwiss appeal decisionTeva’s Mepha Pharma has failed to convince Switzerland’s Federal

Supreme Court to overturn a Patent Court ruling from last yearthat upheld the validity of a local supplementary protection certificate(SPC) for Gilead’s Truvada (tenofovir disoproxil fumarate/emtricitabine)combination antiretroviral that came into effect upon patent expiryon 25 July 2017 (Generics bulletin, 3 November 2017, page 23).

But the Supreme Court differed from the Patent Court on thequestion of whether Switzerland should abandon its traditional‘infringement test’ for determining whether SPCs were valid as coveredby the scope of a basic patent in favour of the disclosure test – wherebythe active ingredient or ingredients must be disclosed or specified inthe claims of the basic patent – currently favoured by the Court ofJustice for the European Union (CJEU).

In denying Mepha’s revocation action, the Patent Court had lastyear argued that the CJEU’s landmark Medeva decision from 2011,requiring SPCs to relate to active ingredients covered by the wordingof the basic patent’s claims, “has not clarified the situation so muchas caused uncertainty”.

CJEU case law ‘not clear’Acknowledging that Switzerland had adopted SPCs from EU law,

the Supreme Court said it had to examine “whether the currentestablished case law of the CJEU, which differs in particular withregard to SPCs for combination products, justifies a change in Swisspractice”. “The fact that CJEU case law is not clear in every detail,as the lower court pointed out, does not change the fact that a changeof practice to adopt the European concept of the so-called disclosuretest seems appropriate,” the Supreme Court stated. “If the basic patentspecifies only one of two active ingredients, a product cannot becovered by an SPC if it comprises two active substances.”

Thus, the court said, the question was whether CJEU case lawjustified revoking a Swiss SPC that had legitimately been granted inaccordance with prevailing law at the time. “In principle,” it determined,“legally-binding administrative decisions cannot be reconsidered orrevised due to a change in case law.”

Such final decisions, it added, could only be altered if not to doso would contravene the principle of equity or to do so would servean “important public interest”. But no major public interest would beserved, the court said, by retrospectively applying changed case lawto SPCs that had already been legitimately granted. Thus, the TruvadaSPC issued in August 2008 remained valid. G

HORMONE REPLACEMENT THERAPIES

Court stings AbbViewith an AndroGel fineAUS district court has ordered AbbVie and partner Besins Healthcare

to repay consumers US$448 million, plus interest, for using‘sham litigation’ to unlawfully delay generic competition to AbbVie’sAndroGel (testosterone) 1% gel brand, in the largest monetary awardever in a litigated US Federal Trade Commission (FTC) antitrust case.

The FTC filed suit against AbbVie and Besins in a Pennsylvaniadistrict court in September 2014, alleging violation of section 5(a) ofthe FTC Act, amounting to unfair or deceptive acts or practices in oraffecting commerce (Generics bulletin, 19 September 2014, page 12).

In September last year, the court ruled that ‘sham’ infringementlawsuits filed by AbbVie – over US patent 6,503,894, which protectsAndroGel 1% until 6 January 2020 – against abbreviated new drugapplication (ANDA) filers Teva and Perrigo were ‘objectivelybaseless’ and entered summary judgement in favour of the FTC.

Judge Harvey Bartle now weighed whether AbbVie and Besins‘subjectively intended’ to file such lawsuits, as well as whether thefirms possessed monopoly power in the market. To prove its case, theFTC had to prevail on all three issues. A previous FTC allegation thatAbbVie and Teva had entered into an unlawful ‘pay-for-delay’ dealdelaying generic competition was dismissed by the court in May 2015.

In a 102-page ruling, Bartle determined that “the FTC had proventhat AbbVie and Besins had a “dominant share” of the market fortransdermal testosterone replacement therapies (TTRTs), and that“significant barriers existed for entry into that market”.

The Commission had also established “the actual market reality”that AbbVie and Besins “possessed monopoly power and illegallyand wilfully maintained that monopoly power through the filing ofsham litigation”, Bartle found. “This sham litigation delayed the entryof much less expensive competitive generic products into the TTRTmarket to the detriment of consumers and protected the defendantsagainst loss of hundreds of millions of dollars in sales and profits.”

The court was also persuaded by evidence presented by theCommission that the filing of the sham lawsuits and the resulting delayin generic entry for AndroGel 1% “increased defendants’ profits onnot only AndroGel 1%”, but also on AbbVie’s newer, lower volumeAndroGel 1.62% formulation. “Androgel 1% and AndroGel 1.62%compete within the TTRT market, both with each other as well aswith all other TTRTs,” it observed.

A disgorgement of US$1.35 billion had been sought by the FTC,based on a world where Teva would have entered the market with aBX-rated, non-substitutable generic product in June 2012. But Bartlefound the FTC had not proven this would have occurred, given otherfactors barring the launch. However, he agreed in awarding theUS$448 million figure that Perrigo would have entered the marketin June 2013, around 18 months earlier than Perrigo’s actual marketentry in December 2014, but for sham litigation on the ‘894 patent.

He split the liability for both the award and the pre-judgementinterest between AbbVie and ‘894 patent owner Besins according totheir royalty rates for AndroGel, which for Besins was 8% throughthe end of March 2015, and 5% thereafter.

However, Bartle rejected the FTC’s request for injunctive relief“that in its view would prevent or deter defendants from engaging insimilar misconduct in the future”. “The FTC has presented no evidencethat defendants are currently violating antitrust laws or about to violateantitrust laws,” Bartle said. “We are also concerned that the injunctionsought by the FTC is overbroad and punitive in nature.” Gn [email protected]

GOUT TREATMENTS

Endo launches a Colcrys AGEndo has realised plans to launch an authorised generic of Takeda’s

Colcrys (colchicine) 0.6mg tablets through its Par Pharmaceuticalsubsidiary, under a prior US supply and distribution agreementinvolving the Endo Ventures affiliate.

In May this year, Endo’s president and chief executive officer,Paul Campanelli, told investors the firm was looking forward tolaunching the authorised generic gout treatment (Generics bulletin,18 May 2018, page 5). In Endo’s pipeline of upcoming generic USlaunches, the firm also has the Mitigare (colchicine) 505(b)(2) hybridversion of Colcrys developed by Hikma. G

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PRODUCT NEWS

ACELRX has obtained approval from the European Commissionfor its Dzuveo (sufentanil) 30µg sublingual tablets that are indicatedfor managing acute moderate to severe pain. This follows a positiveopinion on the analgesic adopted in late April by the committee forhuman medicinal products (CHMP) within the European MedicinesAgency (EMA) for the hybrid version of Akorn’s Sufenta injectablethat was submitted by FGK Representative Service. AcelRx alreadyoffers Zalviso (sufentanil) 15µg sublingual tablets in Europe throughits marketing partner Grünenthal. In the US, California’s AcelRx hasan assigned prescription drug user fee act (PDUFA) action date of3 November 2018 for the 30µg strength under the Dsuvia brand name.

INDIVIOR has filed with Australia’s Therapeutic Goods Administration(TGA) for approval of its Sublocade (buprenorphine) extended-release treatment for opioid dependence. The UK-based firm madesimilar submissions for the subcutaneous formulation in the USin November 2017 and in Canada in April this year.

ORAMED says it has enrolled its first patient in a glucose clampstudy for its ORMD-0801 oral insulin capsule candidate. Havingalready completed several Phase II trials under an investigational newdrug (IND) application with the US Food and Drug Administration(FDA), Oramed described the glucose clamp technique as being “thepremier standard for pharmacodynamic studies in diabetes drugdevelopment” as well as “a requirement of the FDA”. The firm plans toenrol patients aged 18 to 70 years with HbA1c levels of 10% or belowto characterise exposure-response profiles of type-1 diabetes patients.

PULMATRIX has announced positive top-line results from thefirst two sections of a three-part Phase I clinical trial of its Pulmazole(itraconazole) formulation of the antifungal that uses its iSpersepatented dry-powder delivery technology. Pulmazole was “welltolerated across all doses tested in all cohorts”, the respiratoryspecialist noted. Furthermore, daily inhalation of its itraconazolereformulation at doses ranging between 10mg and 35mg “suggestthat total systemic exposure over 24 hours is approximately 100-to 400-fold lower than what would be expected followingadministration of 200mg of oral Sporanox”, Janssen’s oral original.“These results support the potential of Pulmazole to improve thesafety profile of oral Sporanox,” Pulmatrix said of its study in 58healthy adult patients. The third part of the Phase I study will beconducted in adults with mild to moderate, stable asthma, withstudy visits and analysis of preliminary data already underway.

MUNDIPHARMA has launched Zubsolv (buprenorphine/naloxone)sublingual tablets in the European Union (EU) in a choice of upto six strengths. This has triggered a milestone payment of C3 million(US$3 million) to the firm’s Swedish development partner for theopioid-dependence treatment, Orexo.

SUNOVION has had its new drug application (NDA) for its APL-130277 apomorphine sublingual film accepted for review by theUS Food and Drug Administration (FDA). The expected prescriptiondrug user fee act (PDUFA) action date for the “fast-acting,on-demand treatment” for Parkinson’s disease is 29 January 2019.

NORAMCO has entered into a letter of intent to exclusively supplyRespireRx with bulk dronabinol for development firstly as a gelcapsule in sesame oil, and secondly as a modified formulation “withenhanced pharmaceutical properties”. RespireRx intends to marketthe synthetic cannabinoid – which is currently indicated for treatinganorexia, nausea and vomiting – as a treatment for obstructivesleep apnea. G

VALUE ADDED MEDICINES IN BRIEFHIV/AIDS DRUGS/ANTIBIOTICS

Aurobindo offers USatazanavir, ertapenemAurobindo Pharma has introduced atazanavir sulfate 100mg, 150mg,

200mg and 300mg capsules in the US immediately upon approvalfrom the US Food and Drug Administration (FDA). And the Indiancompany intends to follow up this month by launching its newlyapproved ertapenem 1g vials for injection that it is making at itsAuronext Pharma penem injectables facility in Bhiwadi, India.

Citing Iqvia data for the 12 months ended April 2018,Aurobindo said atazanavir capsules had annual US sales of US$324million. Other than Bristol-Myers Squibb’s (BMS’) Reyataz original –for which the 100mg strength was discontinued for reasons otherthan safety and efficacy – only Teva holds approval for a genericversion of the antiretroviral HIV treatment. The Israeli companyannounced an “exclusive launch” with 180-day generic marketexclusivity six months ago, marking the introduction of its fifthgeneric HIV treatment in the US (Generics bulletin, 12 January 2018,page 17). This followed settlement of Teva’s patent litigation withBMS over US patent 6,087,383 for which a six-month paediatricextension ends on 21 June 2019.

By contrast, Aurobindo – which secured tentative FDA approvalfor its atazanavir capsules in early 2014 under the US President’sEmergency Plan for AIDS Relief (PEPFAR) – elected not to challengethe ‘383 patent. Announcing its atazanavir launch, the Indian firmsaid it held 339 final and 32 tentative abbreviated new drug application(ANDA) approvals.

A day earlier, Aurobindo had said it would during July launchits generic version of Merck & Co’s Invanz (ertapenem) 1g vials intoa US market valued at US$387 million in the year to April 2018. Theonly other generic approval for the injectable antibiotic is held byACS Dobfar following FDA clearance earlier this year (Genericsbulletin, 27 April 2018, page 10).

In a split decision last year, the US Court of Appeals affirmedthat US process patent 6,486,150 covering a stable formulation ofInvanz was invalid due to obviousness (Generics bulletin, 3 November2017, page 21).

Separately, Aurobindo has just been sued by Astellas after filingan ANDA for generic Vesicare (solifenacin succinate) that the Japaneseoriginator says infringes its US patent 6,017,927 protecting theoveractive bladder tablets until 19 May 2019, including six monthsof paediatric exclusivity. Astellas has filed a similar suit in the sameDelaware district court against Cipla.

According to Astellas’ suit against Aurobindo, the Indian firm’sparagraph IV certification asserts that the claims of the ‘927 patent areinvalid. The originator also notes that Aurobindo holds a drug masterfile (DMF) for bulk solifenacin succinate and alleges that an ANDAfiling notification sent by the generic firm on 11 May was “not aneffective notification” because it purported to come from a Delawarecorporation, Aurobindo Pharmaceuticals Inc, that does not exist. G

EMA’s – the European Medicines Agency’s – committee for humanmedicinal products (CHMP) is evaluating one application for acentralised marketing authorisation in the European Union (EU) forbiosimilar etanercept. Furthermore, single applications for genericcabazitaxel, febuxostat and ioflupane 123I are also being consideredby the agency, along with two for ambrisentan. G

IN BRIEF

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PRODUCT NEWS

Up to the minute live retail market pricing is available for the UK and Eireon Wavedata Live at wavedata.net.Alternatively, contact Charles Joynson at WaveData Limited, UK.Tel: +44 (0)1702 425125. E-mail: [email protected].

Price WatchIndex

PharmacyProfit Index61.7 43.8

Monthly change ±0 Monthly change -0.2

June 2018 June 2018

June 2018 was a month of relative stability for UK pharmacistsin terms of their profit margin, according to WaveData.

With a reimbursement price for our representative basket ofgenerics that again was only a couple of pounds lower than theprevious month – £2,051.78 (US$2,700.58), compared to £2,053.75in May (Generics bulletin, 8 June 2018, page 15) – the basketprice was similarly unmoved at £1,314.51. This resulted in apharmacy profit that was just £2.71 lower at £737.27.

Based on the Index values of 100 that were set in March 2016,this meant that the Pharmacy Profit Index dropped by just 0.2Index points to 43.8, compared to 44.0 in June. Meanwhile, thePrice Watch Index was completely unmoved at 61.7. G

The Price Watch Index is based on the actual average trade price according to WaveData of a representativebasket of 20 popular generic products in March 2016, when the Index was 100. The basket reflects recentofficial prescribing data for England and Wales and represents what an average pharmacy would pay forthe products, which were selected as being the top cash generators within pharmacy. The Pharmacy ProfitIndex is calculated on the same basis by applying Drug Tariff reimbursement prices to the basket.

June 2018

PRICE WATCH ....... UK

Basket Price Reimbursement Price Pharmacy Profit£1,314.51 £2,051.78 £737.27

ARTHRITIS DRUGS

Amgen’s infliximabmay exceed RemicadeAmgen’s ABP 710 infliximab biosimilar candidate may offer

superior efficacy to its Remicade reference drug, results from aPhase III clinical trial in patents with moderate to severe rheumatoidarthritis suggest. However, Amgen – which is working towardsregulatory submissions – believes the study shows “no clinicallymeaningful differences” between its biosimilar and Remicade, while“the totality of the evidence we have generated supports ABP 710as highly similar to the reference product”.

A double-blind Phase III trial, in which 558 arthritis patientsin North America and Europe were randomised equally to an ABP710 or Remicade group, used as its primary endpoint an assessmentof response difference measured by 20% improvement in AmericanCollege of Rheumatology criteria (ACR20) at week 22.

“The primary endpoint of ACR20 had a pre-specified equivalencemargin of +/- 15%, and the observed upper end of the confidenceinterval was 15.96%,” Amgen revealed, adding that secondary endpointsof 50% and 70% improvements – ACR50 and ACR70 – “trended inthe same direction as ACR20”. A disease activity score 28-jointcount C reactive protein (DAS28-CRP) difference in mean changefrom baseline was “close to zero”.

“The results confirm non-inferiority compared to infliximab, butcould not rule out superiority based on its primary efficacy endpoint,”explained the biologics specialist, which pointed out that “overall,the safety profile and immunogenicity were comparable betweenABP 710 and infliximab”. G

ANTICOAGULANTS

Teva obtains a French listingTeva Santé has secured an entry in France’s répertoire of substitutable

generic medicines for its prasugrel 10mg scored tablets as analternative to Daiichi Sankyo’s Efient original. The répertoire entrynotes that Teva’s generic uses sucrose as an “excipient with a notableeffect”, as opposed to the anti-platelet original’s use of lactose.

France’s national medicines agency, ANSM, has also createda group for dextromethorphan 1.5mg/ml liquid, placing Biogaran’ssugar-free solution alongside Elerte’s Tussidane reference brand. G

ANTIRETROVIRALS

Nevirapine is hit bycutting in AustraliaReimbursement prices for drugs including the antiretroviral

nevirapine, the diuretic furosemide and the antiemetic granisetronin Australia are set to be reduced by more than a third from 1 Octoberthis year under the country’s price-disclose scheme. Final ex-factoryprices payable under Australia’s Pharmaceutical Benefits Scheme(PBS) are scheduled to be published in mid-September.

Indicative prices just published by the PBS propose a 34.9%ex-factory cut for nevirapine 200mg standard and 400mg extended-release tablets to A$102.33 (US$75.70) per pharmaceutical item from1 October, based on a weighted average disclosed price (WADP) withoriginator brand data removed. At the same time, reimbursement pricesfor furosemide 20mg/2ml for injection and granisetron 3mg/3mlconcentrate for injection will decline by 38.5% and 35.4% respectively.

Other products facing PBS price reductions of around a thirdinclude bleomycin powder for injection and bosentan tablets. Cuts ofmore than a quarter are lined up for medicines such as dorzolamideeye drops, imatinib tablets and capsules, nicorandil tablets, pemetrexedpowder for infusion and ursodeoxycholic acid capsules. Dozens ofother drugs – among them capecitabine, entecavir, infliximab,oxycodone and pregabalin – will experience double-digit price drops.

From 1 July, Australia’s PBS lists Sandoz’ buprenorphine 5µg,10µg, 15µg and 20µg per hour patches, with the 15µg strength beingthe only listed alternative to Mundipharma’s Norspan original.Novartis’ generics division has also secured PBS entries for metformin1g tablets as well as for moxonidine 200µg and 400µg tablets, whilePharmacor got a listing for ezetimibe 10mg tablets.

Mylan and its local Alphapharm affiliate have obtained PBSlistings for acamprosate calcium 333mg enteric tablets, along withentries for ondansetron 4mg and 8mg as both standard and orally-disintegrating tablets. But Mylan faces competition to its EpiPen(adrenaline) anaphylaxis treatments in Australia after Link MedicalProducts secured PBS entries for its Emerade 150µg/0.15ml and300µg/0.3ml auto-injectors. Australia’s Pharmaceutical BenefitsAdvisory Committee (PBAC) had during its meeting in March thisyear recommended that Link’s devices be added to the PBS “toaddress the current supply-shortage issue of adrenaline products”.

At the same meeting, the PBAC updated its position on biosimilar‘a flagging’, or pharmacy substitution, to reflect experience over thepast three years. Advice will take account of “supportive data” onswitching, as well as “practical considerations” such as strengths andpack sizes. However, “parallel processing” of reimbursement evaluationswith regulatory processes of biosimilars by Australia’s TherapeuticGoods Administration (TGA) “should not be made available”. G

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PRODUCT NEWSMIGRAINE TREATMENTS

Lannett fails a secondtime on Zomig in USTwo US patents shielding Impax’ Zomig (zolmitriptan) nasal spray

are not invalid, a US Court of Appeals has affirmed, upholdingan unfavourable lower court ruling against abbreviated new drugapplication (ANDA) filer Lannett.

The US player had appealed against Delaware District JudgeRichard Andrews’ finding that US formulation patents 6,750,237 and7,220,767 were not invalid on the grounds of obviousness oranticipation (Generics bulletin, 7 April 2017, page 14). Both patentsexpire on 28 May 2021, including six months of paediatric exclusivity.

Impax licenses exclusive commercial rights to the migraineremedy, including tablet and orally-disintegrating tablet formulations,from AstraZeneca under the terms of an agreement signed in 2012.The originator was also a plaintiff in the litigation.

As part of his non-obviousness conclusion, Andrews in Marchlast year found prior art taught away from formulating zolmitriptan forintranasal formulation, “because zolmitriptan was known to be active,not by itself, but through its more potent metabolite, 183C91”.

Prior art at the time, notably the Chauveau pair of documentsreferenced by Lannett, also failed to teach that zolmitriptan by itself,as contrasted with its metabolite, would have been effective, Andrewsfound. Meanwhile a skilled artisan “would not have been motivatedto make with a reasonable expectation of success nasal formulationsof zolmitriptan”. Andrews had acknowledged the “question ofobviousness” was a “close one”, before ultimately determining thatLannett “had failed to meet its burden of proving invalidity by clearand convincing evidence”. He also awarded injunctive relief to Impaxand AstraZeneca until patent expiry.

On appeal, Lannett contended that Andrews had erred in concludingthat the claims at issue would not have been obvious “based on anerroneous finding that the prior art taught away from nasal formulations”.

Having dropped its anticipation argument, Lannett insisted thecourt had “improperly disregarded express teachings in the prior art”,while Andrews had also erred in finding that the 2012 agreementsupported its conclusion of non-obviousness. “All of the claims atissue rise and fall together with the issue of whether it would havebeen obvious to make zolmitriptan into a nasal spray,” the appealscourt summarised.

Discussing Lannett’s appeal, the appeals court first rejected thecompany’s assertion that prior art expressly disclosed nasal formulationsof zolmitriptan. As a whole, it found, Chauveau was “not aboutintranasal formulations of zolmitriptan, which is barely mentioned”.

Concerning Lannett’s argument the district court reached alegally erroneous conclusion of non-obviousness, the appeals courtagreed the case was “close”. “But,” it said, “we defer to the districtcourt in its fact findings, including what Chauveau discloses and thestate of the prior art as a whole.”

The appeals court was “especially persuaded” by the testimony ofImpax and AstraZeneca’s expert, on which the district court relied,“who opined that it would have been ‘absolutely counterintuitive’ tomake an intranasal formulation of zolmitriptan, given that its activityprimarily came from its metabolite”.

“We find no reversible error in the district court’s decision thatLannett failed to prove invalidity of the asserted claims by clear andconvincing evidence,” the appeals court concluded. Impax’ parentAmneal noted Lannett now had 30 days to submit a petition for apanel rehearing and/or for rehearing en banc. Gn [email protected]

STADA ARZNEIMITTEL has expanded its OTC products offeringby acquiring, for an undisclosed fee, rights in the Europe, MiddleEast and Africa (EMEA) region to Johnson & Johnson’s Nizoral(ketoconazole) anti-dandruff shampoo. Noting that the antifungalshampoo was the clear market leader with EMEA sales of aroundC33 million (US$38 million) last year, the German group said morethan half of that total came from Russia, Italy, the UK, Poland andthe Middle East. The deal includes the Nizoral umbrella brand,as well as the local brands Nizoril, Nizorelle, Terzolin, Fungarest,Ketoderm, Oranozol and Triatop. In Denmark and Italy, Stadahas also gained rights to Nizoral cream for skin infections. “Togetherwith head-lice treatment Hedrin (dimeticone),” commented chiefexecutive officer Claudio Albrecht, “Nizoral solidifies our competencein the hair and scalp product segment.”

TELIGENT has obtained its seventh abbreviated new drug application(ANDA) approval to date this year with US clearance for lidocaine/prilocaine 2.5%/2.5% cream equivalent to Actavis’ Emla. Thegenerics specialist intends to launch the local anaesthetic duringthe third quarter of this year.

UNICHEM LABORATORIES will be able to launch a genericversion of Eli Lilly’s Cialis (tadalafil) from 26 March 2019 underthe terms of a US patent-litigation settlement. The Indian firm willpay Lilly a royalty of 5% on net sales up to the expiry of US patent6,943,166 on 26 April 2020.

WAVERLEY PHARMA has filed abbreviated new drug applications(ANDAs) “for two high-value anti-cancer generic drugs” coveredby a licensing and development deal struck with India’s RelianceLife Sciences around a year ago. Canada’s Waverley holdsexclusive rights to the drugs in the US and Canada, was well as inthe European Union (EU) other than in the UK, where it has non-exclusive rights and recently acquired capecitabine and temozolomidegenerics (Generics bulletin, 29 June 2018, page 3).

STRIDES SHASUN has secured World Health Organization (WHO)pre-qualification for its artesunate 100mg rectal suppositories.Achieved with support from the Medicines for Malaria Venture(MVV) and funding from Unitaid, the pre-qualification enables theIndian firm to supply the malaria treatment to developing countrieswith donor funding.

AMGEN has been sued by Genentech for allegedly infringing morethan three dozen US patents protecting the the firm’s Herceptin(trastuzumab) breast-cancer treatment. Having announced in late-Julylast year that it had filed its ABP 980 trastuzumab candidate with theUS Food and Drug Administration (FDA), Amgen entered into a‘patent dance’ exchange of information about manufacturing processesand intellectual property with Genentech. As part of that exchange,Amgen gave Genentech 180-day notice of commercial marketing on15 May 2018, opening the door for a potential launch from late October.Of the 37 asserted patents, 20 relate to cell culture, purification andantibody manufacturing. According to the suit filed in a Delawaredistrict court, one patent – US patent 6,407,213 – “claims the Herceptinantibody itself”, while three each relate to combination chemotherapy,acidic variants, HER2 diagnostics and combining trastuzumabwith Perjeta (pertuzumab).

CIPLA has received final US Food and Drug Administration (FDA)approval for and launched its generic rival to Pharmacia andUpjohn’s Depo-Testosterone (testosterone cypionate) 100mg/mland 200mg/ml injectable. G

IN BRIEF

Gen 6-7-18 Pgs.1-20.indd 18 04/07/2018 14:33

A New ANDA Holder Program Fee Approach Under GDUFA II

The new ANDA Holder Program Fee under GDUFA II is now in place! A firm and its affiliates pay one program feeeach fiscal year commensurate with the number of approved ANDAs (both active and discontinued ANDAs)that the firmand its affiliates collectively own. The program fee is split into three tiers that represent the numberof approved ANDAs held by the firms and their affiliates within the Orange Book.

The ANDA fee schedule for Fiscal Year 2018 was published by FDA on August 28th, 2017. The annual ANDAHolder Program Fee represents significant funds for some companies. And for those companies with a modestnumber of ANDAs, they’ll be laying out cash for drug products that they don’t currently market or are identifiedin the Discontinued Drug Product List section of the Orange Book. And YES, discontinued ANDAs are stillconsidered approved ANDAs for user fee purposes unless the approval is withdrawn.

In addition, a one-time marketing status report was required to be submitted to the FDA by Wednesday,February 14, 2018, identifying the submission as “MARKETING STATUS REPORT / ONE-TIME UPDATE.” Whilethere is no guidance as to what happens to the ANDAs identified as “not marketed”, one scenario may bethey will be either moved to discontinued status or have approval withdrawn.

FDA collects fees under the ANDA Holder Program initiative as of each October 1 as follows: small tier (1-5ANDAs) companies pay $159,079; medium tier (6-19 ANDAs) companies pay $636,317; and large tier (greaterthan 20 ANDAs) companies pay $1,590,792. For a small or medium-tier company this can be a dramaticimpact in their ability to even retain the assets they worked so hard to obtain! And Fiscal Year 2019 fee rates,which will be published later this year, seem likely to rise.

What is the penalty for not paying the program fee? There are three effects if an applicant fails to pay theprogram fee: (1) If the program fee is not paid within 20 calendar days after the due date, the parent companywill be placed on a publicly available arrears list. (2) Any ANDA submitted by the applicant or its affiliateswill not be received. (3) All drugs marketed pursuant to any abbreviated new drug application held by suchapplicant or an affiliate of such applicant shall be deemed misbranded.

For the second year a company called ANDA Repository, LLC. has successfully offered significant user feerelief and a solution for companies that have discontinued ANDAs, and for drug products not currently marketed.Imagine, a parking lot. The owner of a car that is not being used on a daily basis needs a parking space forthat car. In exchange for that parking space (and an annual fee) the car’s owner transfers title of the car to theparking lot owner. The former owner of the car can, with appropriate notice, take back ownership when he/she decides they want to use the car again. Since the parking lot owner has enough cars, this has proven to bea beneficial venture for all of the parties involved, and the cars are kept safe and secure.

In the example above, the car owner is an ANDA sponsor, and the parking lot owner is ANDA Repository, LLC.In exchange for its services, ANDA Repository, LLC. charges an ANDA sponsor an annual fee, which is significantlyless than the ANDA Holder Program Fee such ANDA sponsor would otherwise pay as a small or medium sizefirm. There is NO need to pay excessive fees, or to withdraw your valued assets due to short-term marketconditions, capacity constraints, API supplier issues, etc.!

Alternatively if your choice is to WITHDRAW the ANDA we may be interested in purchasing it from you!

Phone: +1-570-261-1901 Email: [email protected]

… Important Time-Sensitive Material – A Must Read ….

The FY2019 GDUFA Generic Drug Applicant Program Feeis due October 1st so please contact us soon!

Gen 6-7-18 Pgs.1-20.indd 19 04/07/2018 14:33


PEOPLEAPPOINTMENTS

Ascendis’ Sonnekushas South Africa roleAscendis has announced the appointment of Marnus Sonnekus as

interim chief operating officer for the South Africa region, citinghis “strong background in private equity, management consulting andaccounting, including eight years with global management consultancyMcKinsey & Company”.

Following the retirement in June of Cliff Sampson, managingdirector of the group’s South African operations, the firm had “decidedto appoint an interim chief operating officer to lead the local business”,noted chief executive officer Thomas Thomsen.

“Our leadership structure will be finalised once the strategicreview has been completed, and any potential changes to the operatingmodel or group structure have been adopted,” Thomsen added, referringto the business review initiated earlier this year, shortly after he wasappointed as chief executive (Generics bulletin, 6 April 2018, page 6).

Follows consolidation planAs part of the strategic review, Ascendis recently set out plans to

consolidate its pharmaceutical manufacturing facilities in Gauteng,South Africa, as well as to sell its South African production plant inIsando, Johannesburg. A manufacturing site in Wynberg, also inJohannesburg, “will be retained, and management expects to generatecost savings and manufacturing synergies” (Generics bulletin, 29June 2018, page 4). G

XELLIA has appointed Matthew Anderson as chief financialofficer (CFO), taking over from interim CFO Otto Rasmussen.The Danish firm said former PharMedium Healthcare CFO Andersonjoined Xellia “at an exciting time, as we are preparing to launchour pipeline of value-added anti-infective drug products intothe US institutional market” as well as “considerably expandingour North American commercial organisation with a new officeplanned in Chicago”.

DSM SINOCHEM’s board chairman, Feng Zhibin, will leave therole after resigning from his role as vice-president of Sinochemgroup “for personal reasons, to pursue a career path outside thecompany”. A successor on DSM Sinochem’s board will be announced“in due time”. The announcement came shortly before private-equity firm Bain Capital agreed to acquire the antibiotics and statinsjoint venture (see page 3).

JHL BIOTECH has named Ellis Chu as chief financial officer ofthe Taiwanese firm. “With biosimilars taking off in Asia, I amexcited to join JHL,” former venture capitalist Chu said, addingthat “several of our drugs [are] entering late-stage clinical trialsthis year and next”.

DR REDDY’S director Hans Peter Hasler has resigned from theIndian firm’s board. This was after he “decided to actively engagein a business opportunity which could pose a potential conflict ofinterest vis-à-vis his position as a director of Dr Reddy’s”.

WEST PHARMACEUTICAL SERVICES has appointed BernardBirkett as senior vice-president, chief financial officer and treasurer.G

IN BRIEF

MANAGEMENT RESHUFFLES

Concordia reshufflesas debt plan proceedsConcordia has named Graeme Duncan as its permanent chief

executive officer as part of a management reshuffle to create a“truly unified executive leadership team”, as the firm continues topursue a recapitalisation transaction to manage its debt and interest costs.

Duncan – who was formerly president of Concordia’s Internationalsegment, and had earlier this year set out plans to leave the company(Generics bulletin, 16 March 2018, page 16) – was made interimchief executive officer at the start of May, as part of a previousreshuffle, following the departure of his predecessor Allan Oberman“to pursue other opportunities”. Also during that reshuffle, formerAmdipharm Mercury (AMCo) executive Guy Clark returned to theConcordia group to become chief corporate development officer,replacing Sarwar Islam (Generics bulletin, 11 May 2018, page 16).

“Looking forward,” Duncan said, “we are excited about our newleadership structure, which consists of a talented and experiencedteam that is now well-placed to capitalise on the opportunities aheadof us.” This team includes former vice-president of global pharmaceuticaloperations, Karl Belk, who has been promoted to chief operationsofficer of Concordia.

At the same time, Adeel Ahmad has been appointed as Concordia’schief financial officer, having previously served in the chief financialofficer role for the firm’s International segment. He replaces DavidPrice, who will “continue to support the recapitalisation process thathe has led, through to conclusion” before leaving Concordia on 31 July.

Simon Tucker has been promoted to president of Concordia’sInternational segment, where he will “oversee the management ofConcordia’s North America segment and its rest-of-world territories”,although the firm’s Photofrin photodynamic therapy for treatingcancer will continue to be managed separately. Sanjeeth Pai, presidentof Concordia North America, will step down from the position andleave the company on 31 August.

Finally, Paul Burden has been promoted from his current roleas managing director for UK and Ireland to become president ofConcordia’s UK and Ireland division.

Concordia’s latest management reshuffle comes as the Canadianfirm has just obtained a final court order from the Ontario SuperiorCourt of Justice approving a plan of arrangement set out under theCanada Business Corporations Act (CBCA) that will allow it toimplement a recapitalisation transaction to manage its debt and interestcosts by raising just over US$586 million.

Under the terms of the transaction – which has already beenapproved by 100% of debtholders and 87.37% of shareholders at ameeting in June (Generics bulletin, 22 June 2018, page 4) –debtholders will be issued new shares, while a ‘share consolidation’will significantly dilute existing shares “on the basis of one commonshare for every 300 existing common shares”.

“It is expected that the recapitalisation transaction will becompleted on or about 31 July 2018,” Concordia said, “subject to thesatisfaction or waiver of all other conditions to the plan of arrangement.”Calling the transaction “a major milestone in the company’s history”,Duncan said the firm was “grateful to all of our stakeholders forsupporting our recapitalisation transaction, and we are workingdiligently to complete the transaction”.

“On behalf of our board,” said Duncan, “we thank all of ouremployees, including those who are moving on from Concordia, fortheir unwavering commitment and effort through this process.”n [email protected]

Gen 6-7-18 Pgs.1-20.indd 20 04/07/2018 14:33

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Gen 6-7-18 Pgs.1-20...in central and eastern Europe (CEE); and Shanghai Henlius Biotech will allow Accord to sell its trastuzumab in more than 70 countries around the globe. MylanwillhaverightstosellLupin’sproposedetanercept–whichcompletedPhaseIII