21 September 2018

FDA guides on changesin the wake of valsartanDraft guidance on post-approval changes to active pharmaceutical ingredient (API) drug

master files (DMFs) and the obligations of abbreviated new drug application (ANDA)holders that reference them – addressing how risks of changes to the drug substanceshould be assessed, as well as providing recommendations on required documentation tosupport changes to the drug substance and drug product – has been published by theUS Food and Drug Administration (FDA), with a 60-day comment period.

FDA Commissioner Scott Gottlieb said the policy would “guide drug makers looking tomake changes to drug substance manufacturing processes during the post-approval period”,in particular to “ensure quality, safety, and reduce the risk that impurities can be introducedinto the manufacturing process”. Gottlieb’s comments follow the discovery of impurities invalsartan API from certain manufacturers, leading to investigations and recalls across the globe(Generics bulletin, 13 July 2018, page 1).

“As part of the reauthorisation of the Generic Drug User Fee Amendments (GDUFA II),the FDA committed to issuing a guidance on post-approval changes to API DMFs, also knownas type-II DMFs, and submission mechanisms for ANDA holders who reference such DMFs,”the agency explained. The guidance covers five key areas: facility, scale and equipmentchanges; specification changes to starting materials, raw materials, intermediates, and theunfinished and final drug substance; synthetic manufacturing process changes; changes in thesource of drug substance; and a change to the container closure system of the drug substance.Complex active ingredients are not covered by the document.

While any modification to drug-substance manufacturing carries some risk of an adverseimpact on quality, “late-stage changes in the drug substance manufacturing process are generallyviewed as more likely to have an adverse impact on the quality of the drug substance and,consequently, on the drug product”, the guidance states. “The responsibility for reporting thetypes of changes described in this guidance could lie with a single party or with several parties,depending on whether the drug substance synthesis or processing is described in an applicationor in one or more master files.” When a master file holder makes a manufacturing processchange, this should be described in an amendment to the master file, while the applicationholder should provide notification of the change in a supplement or annual report. G

Celltrion carves out US rituximabCelltrion will seek approval for only three indications of the eight covered by Biogen and

Genentech’s Rituxan (rituximab) brand when the Korean firm’s CT-P10 proposed biosimilaris discussed at a US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee(ODAC) meeting on 10 October. Celltrion said it had submitted CT-P10 for three non-Hodgkin’slymphoma (NHL) indications – but not for a fourth Rituxan NHL indication and three otherindications, including rheumatoid arthritis and granulomatosis – “due to the current intellectualproperty and exclusivity landscape”.

An FDA warning letter against Celltrion’s manufacturing facility in Incheon, Korea, ledthe firm to receive a complete response letter (CRL) for CT-P10 earlier this year (Genericsbulletin, 13 April 2018, page 1). The facility recently received a ‘Form 483’ listing eightobservations of deficiencies following a reinspection, months after Celltrion had resubmittedCT-P10 for evaluation (Generics bulletin, 10 August 2018, page 3).

Teva has the US marketing rights for the biosimilar monoclonal antibody (mAb), under alicensing agreement struck with Celltrion in October 2016. G

COMPANY NEWS 3

Biocad and Shanghai to 3build site in China

Sun acquires a stake 3in Israel’s Tarsius

Pfenex takes commercial leap 3

Indonesia’s Kalbe eyes 4unbranded rise

Teva Germany strikes supply 4deal with funds

Aspen eyes launch of new 5HPC formulation

Lupin’s Nagpur facility clears 5FDA inspection

Aceto amends credit and 6delays reporting

Aetos and Pall form 6a bio pact

MARKET NEWS 7

Shortages legislation is 7lauded in Australia

WHO road map draws welcome 7and criticism

Single-winner tenders 10threaten the future

PRODUCT NEWS 11

Sandoz has stipulated 11over Enbrel patents

US appeals upholds over 11Ampyra patents

Boehringer’s Cyltezo is an 12equal to Humira

EPO upholds patent on 13Gilead’s Sovaldi

Teva holds off launch 13until Reddy’s decision

REGULARS

Events – Our regular listing 6Price Watch UK – Our regular listing 15People – Frost among 10 to be 16charged on fraud plot

Issue No.369

Gen 21-9-18 Pgs.1-16.indd 1 17/09/2018 15:02

A New ANDA Holder Program Fee Approach Under GDUFA IIFeesThe ANDA Holder Program fee schedule for Fiscal Year 2019 was just published by FDA and fees increased by17% from last year. Fees due to the FDA by October 1, 2018 are as follows:

This is a significant expense for many firms. Those with amodest number of ANDAs will again be paying substantialsums for drug products they don’t currently market or that are identified as Discontinued in the Orange Book. Fora small or medium-tier company this can be a dramatic hurdle to retain the assets they worked so hard to own. And,yes, discontinued ANDAs are still considered approved ANDAs for user fee purposes unless the approval is withdrawn.

In addition, a one-timemarketing status report was required to be submitted to the FDA earlier in 2018, identifyingthe submission as “MARKETING STATUS REPORT / ONE-TIME UPDATE.” While there has been no guidance asto what happens to the ANDAs identified as “not marketed”, one scenario may be they will be either movedto discontinued status or have their approval withdrawn.

PenaltiesWhat is the penalty for not paying the program fee?1) If the fee is not paid within 20 calendar days after the due date, the parent company will 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 such applicant or an affiliate

of such applicant shall be deemed misbranded.

A SolutionFor the second year, ANDA Repository, LLC. offers significant user fee relief and a solution for companies thathave discontinued ANDAs or drug products not currently marketed. Like with a parking lot, car owners needspace for their cars, whether in use or not. Only here, in exchange for the space (and a fee) car owners transferstitle of the car to the parking lot owner. The former car owners can, with appropriate notice, resume ownershipwhen they choose to use the car again. Since the parking lot owner has enough cars, this venture benefits forall the parties involved, and the cars remain safe and secure.

In the example above, the car owner is an ANDA owner, and the parking lot owner is ANDA Repository, LLCwhichcharges ANDA owners an annual fee that is significantly less than the ANDA Holder Fee that the FDA charges smallor medium sized firms.

There is NO need to pay excessive fees or be forced to withdraw your valued assetsdue to short-termmarket conditions, capacity constraints, API supplier issues, etc.!

Alternatively, if your choice is toWITHDRAWyour ANDAs, wemay be interested in purchasing them!

URGENT – FY2019 GDUFA Fees JustAnnounced... Increased by 17%

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

Tier ANDAS Owned FeeSmall 1-5 $186,217Medium 6-19 $744,867Large 20 or more $1,862,167

Phone: +1-570-261-1901 Email: info@andarepository.com

Gen 21-9-18 Pgs.1-16.indd 2 17/09/2018 15:02

3GENERICS bulletin21 September 2018

COMPANY NEWS

BUSINESS STRATEGY

Pfenex takes commercial leapPfenex is ramping up its preparations for commercial activity,

appointing Shawn Scranton to join its management team as chiefoperating officer from 1 October. The move comes as the US biosimilarsand hybrid specialist is preparing to file with the US Food and DrugAdministration (FDA) for its lead candidate, its PF708 equivalent toEli Lilly’s Forteo (teriparatide) osteoporosis blockbuster.

“As our operations have evolved through the advancement of ourclinical pipeline and Pfenex is working towards its first new drugapplication (NDA) submission,” outlined chief executive officerEef Schimmelpennink, “we are increasing our focus on the approvaland commercialisation of our existing pipeline, as well as explorationof new pipeline and technology opportunities.”

Scranton would, he said, “support this transition to a commercial-stage biotech company”, offering “more than 20 years of experiencein the biopharmaceutical industry” including in portfolio strategy,research, development and commercial roles.

Scranton was most recently chief scientific officer at SentynlTherapeutics, which was acquired by Zydus Cadila last year (Genericsbulletin, 27 January 2017, page 4). “I am excited to join the Pfenexteam at this important time in the company’s development,” he stated.

Despite plans to file teriparatide through the FDA’s hybrid 505(b)(2)pathway slipping from the third quarter to the fourth quarter of thisyear, Pfenex still believes it may be able to enter the market in thethird quarter of next year through its marketing partnership withAlvogen (Generics bulletin, 15 June 2018, page 12).

Recently, Pfenex’ chief medical and scientific officer Hubert Chenresigned from his post, although he will continue to support the firmin an advisory capacity (Generics bulletin, 31 August 2018, page 24). G

MERGERS & ACQUISITIONS/MANUFACTURING

Sun acquires a stakein Israeli firm TarsiusSun Pharma says that one of its wholly-owned subsidiaries has

agreed to acquire an 18.75% stake in Israeli eyecare start-upTarsius Pharma for US$3 million. Founded in February 2016 by itschief executive officer, Daphne Haim-Langford, Tarsius is an early-stage research and development company that focuses on developingdrug candidates in the field of ophthalmology, including a biomimeticcandidate for treating uveitis. It did not register any sales last year.

Noting that “no governmental or regulatory approvals are required”,Sun stated that the cash deal for 345,622 shares was scheduled toclose immediately.

Meanwhile, the Indian firm has responded to media reportsconcerning its local plant in Mohali, Punjab, clarifying that the USFood and Drug Administration (FDA) initiated an inspection at thesite on 10 September. Sun said the audit “is ongoing”.

The Mohali facility, a former Ranbaxy plant that Sun obtainedthrough its US$4 billion takeover of the firm, was placed under animport alert in September 2013, following FDA inspections thatidentified “significant current good manufacturing practice (cGMP)violations” (Generics bulletin, 20 September 2013, page 3). In March2017, the import ban was lifted and the site’s ‘official action indicated’status was removed (Generics bulletin, 24 March 2017, page 3), afteran FDA audit in November 2016 determined that the plant “appearsto be in compliance with cGMP”. G

STRATEGIC ALLIANCES/MANUFACTURING

Biocad and Shanghaito build site in ChinaRussia’s Biocad has signed a memorandum of understanding with

Shanghai Pharmaceuticals Holding (SPH) to produce, develop,register and market several monoclonal antibodies (mAbs) in China.This will include building a biologics drug-substance manufacturingsite in China. Construction of the jointly-owned production facilitiesfor mAb active pharmaceutical ingredients (APIs) in China is set to“start as early as 2019”.

Biocad said two joint ventures would be established “with themain purpose of development, manufacturing, authorisation andmarketing of at least six of Biocad’s products used in advanced therapyof cancer and autoimmune diseases”. This includes treatments forchronic lymphatic leukaemia, colorectal cancer, lung cancer, breastcancer, psoriasis and ankylosing spondylitis. SPH revealed that thisportfolio comprises “four heavyweight biosimilars” as well as twoof the Russian firm’s innovative biologics.

“We believe that transferring Biocad’s technologies to a jointly-owned manufacturing facility in China will boost our pharmaceuticalexports,” stated Dmitry Morozov, the Russian biotech firm’s founderand chief executive officer. “It will also allow our Chinese partnersto acquire the platform and valuable experience that is necessary formanufacturing other mAb-based biological therapeutics.”

Morozov said this “first massive Russian-Chinese co-operationproject in the pharmaceutical industry” would support Biocad’s goalof expanding internationally.

Jun Zhou, chairman of SPH – which claims to be “the largestmedicine importer and third-largest pharmaceutical distributor inChina” with a turnover last year of RMB131 billion (US$19.1 billion) –described the deal as “a strategic step forward in our transformationinto a branded pharmaceutical manufacturer and a modern healthcareservices provider with international competitiveness”.

In particular, Zhou said the agreement would help the genericsand novel drugs producer to refine the strategic plan for its manufacturingsegment that centred on making anti-tumour biopharmaceuticals. SPHpointed out that “currently, there are not too many biopharmaceuticalcompanies capable of achieving actual commercial operation in China”.Biocad’s history of marketing biologics in Russia and other marketswould, it added, “exert a positive influence on China”. G

MANUFACTURING

Asymchem’s site cleared by USAsymchem’s ‘Tianjin 2’ multi-purpose development and commercial-

production active pharmaceutical ingredient (API) site in Tianjin,China, has passed a US Food and Drug Administration (FDA)re-inspection in July with no ‘Form 483’ observations.

The China-based contract development and manufacturingorganisation (CDMO) for APIs pointed out that a 2014 inspection atthe plant had also resulted in zero Form 483 observations. To “keep upwith increasing demand”, Asymchem is expanding the Tianjin 2 siteto include peptide manufacturing capabilities and to increase low-volumeAPI manufacturing capacity. Both will be operational “by late 2018”.

Audits at Asymchem’s ‘Dunhua 1’ and ‘Fuxin 1’ facilities – inMarch 2017 and March 2018 respectively – also concluded with nodeficiencies. The company said its carbapenem production capacity wasset to expand in April 2019 with the opening of its ‘Dunhua 2’ site. G

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4 GENERICS bulletin 21 September 2018

COMPANY NEWS

aidan.fry@generics-bulletin.com

Issue 369 l 21 September 2018

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Published by OTC Publications Ltd, 4 Poplar Road, Dorridge, Solihull B93 8DB, UK.Tel: +44 (0) 1564 777550 Fax: +44 (0) 1564 777524Company registered in England No 02765878.© OTC Publications Ltd. All rights reserved.Generics bulletin® is registered as a trademark in the European Community.Printed by Warwick Printing Company Ltd. ISSN 1742-0784

BUSINESS STRATEGY/FIRST-HALF RESULTS

Indonesia’s Kalbeeyes unbranded riseIncreasing its participation in the unbranded generics sector is one

of two key strategic initiatives that Indonesian producer Kalbe intendsto pursue to expand its Prescription Pharmaceuticals business. Theother is strengthening the company’s position in specialty products.

Supported by a “dedicated unbranded generics plant”, Kalbe isselecting “focused categories to achieve scale” as it seeks to penetratefurther into the international non-proprietary name (INN) sector ofthe market. In the specialty oncology arena, the firm has been operatingits own factory since 2014 and has alliances in place with multinationalplayers including Intas, Nippon Kayaku and Sun Pharma. The firmhas also opened its Kalbio Global Medika biosimilars facility.

Citing Iqvia data for 2016, Kalbe said unbranded drugs made upalmost a fifth of Indonesia’s prescription pharmaceuticals market

that, in turn, accounted for 62% of a total pharmaceuticals market,including OTC products, that was valued at Rp67.2 trillion (US$4.52billion) following compound annual growth of 8.9% since 2012.

In the first half of this year, unbranded generics constituted 18%,or around Rp450 billion, of Kalbe’s total Prescription Pharmaceuticalssales that advanced by 2.7% to Rp2.49 trillion (see Figure 1). Brandedgenerics were responsible for 54% of the segment’s turnover, withthe other 28% coming from in-licensed drugs.

Kalbe – which claims to control around a tenth of the localprescription market, making it the market leader – said it wasexperiencing “increasing price competition following national healthinsurance implementation”. The firm said a 1.2 percentage-point declinein the Prescription unit’s gross margin to 55.4% was due mainly to achange in product mix and the depreciation of the Indonesian rupiah. Gn aidan.fry@generics-bulletin.com

Business segment First-half sales(Rp billions)

Change(%)

Grossmargin (%)

Distribution & Logistics 3,056 +4.7 30.5

Nutritionals 2,995 +3.4 55.8

Prescription Pharma 2,487 +2.7 55.4

Consumer Health 1,842 +0.7 54.9

Kalbe 10,381 +3.1 48.1

Figure 1: Breakdown by business segment of Kalbe’s sales and gross margin inthe first half of 2018 (Source – Kalbe)

BUSINESS STRATEGY

Teva Germany strikessupply deal with fundsTeva’s German operation has reached an agreement to supply

generic drugs marketed under the Teva, AbZ and Ratiopharmlabels to the LM+ group of four private health insurance funds. Thepartners did not disclose any details of the range of products coveredby the “comprehensive co-operation contract”.

“This co-operation will reduce our expenditure on medicines andthe resulting savings will benefit privately-insured members,” commentedthe LM+ joint venture between the Barmenia, Gothaer, Hallesche andSignal Iduna funds. “In the private health insurance sector, it is amajor aim for us to offer our customers high-quality medicines atlow prices,” commented Thomas Soltau, managing director of LM+.

Following a recent wave of consolidation, Teva Germany nowmarkets all of its generic, branded prescription and OTC medicinesout of the former Ratiopharm headquarters in Ulm. G

MERGERS & ACQUISITIONS

Cambrex completes on HaloCambrex has completed its US$425 million acquisition of contract

development and manufacturing organisation (CDMO) HaloPharma that it initially announced in late July this year (Genericsbulletin, 3 August 2018, page 5).

Halo’s US facility in Whippany, New Jersey, and its Canadiansite in Mirabel, Québec, would, Cambrex said, “provide formulationdevelopment, and clinical and commercial manufacturing services,specialising in oral solids, liquids and creams [as well as] sterile and non-sterile ointments. The facilities’ core competencies include developingand manufacturing highly complex and difficult-to-produce formulations,products for paediatric indications and controlled substances.”

Comprising around 40,000 sq m of space in total, the Whippanyand Mirabel sites “have capacity for mid-term growth”, accordingto Cambrex. The deal will include the transfer of around 450 Halostaff members.

Cambrex’ president and chief executive officer Steve Klosk saidthe deal “diversifies Cambrex’ business, expands our customer base,and broadens our small-molecule funnel beyond our existing APIoffering in the innovator, generic and controlled-substance categories”.G

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5GENERICS bulletin21 September 2018

COMPANY NEWSMANUFACTURING

Lupin’s Nagpur facilityclears FDA inspectionLupin says its oral solid dosages facility in Nagpur, India, has

successfully passed a US Food and Drug Administration (FDA)audit without any observations. “This inspection was a product-specificpre-approval inspection,” the Indian company commented.

The Nagpur oral-solids site had only recently received anestablishment inspection report (EIR) from the FDA following asuccessful inspection by the agency earlier this year (Generics bulletin,7 September 2018, page 9). Lupin’s managing director Nilesh Guptadescribed that clearance as “a positive development as we continueour journey to meet and exceed international regulatory standards”.

Nagpur – which “also houses Lupin’s state-of-the-art injectablemanufacturing facility” – is the Indian group’s newest formulationssite. Having started constructing the plant in a special economic zone(SEZ) located in central India around six years ago (Generics bulletin,4 May 2012, page 4), Lupin officially inaugurated the 60,000 sq mfacility in August 2013 with a view to serving markets including the US.

The FDA recently observed one “procedural deficiency” duringa current good manufacturing practice (cGMP) inspection of Lupin’sbulk-drugs plant in Tarapur, India, that was linked to ‘sartan’antihypertensives (Generics bulletin, 14 September 2018, page 4).G

BUSINESS STRATEGY/ANNUAL RESULTS

Aspen eyes launch ofnew HPC formulationAspen Pharmacare intends to launch a preservative-free formulation

of the firm’s generic hydroxyprogesterone caproate (HPC)injectable in the US “in the next four-to-five months”, following therecent successful review of its dossier by the US Food and DrugAdministration (FDA). Disclosing the news to investors as Aspenpresented full-year results for its financial year ended 30 June 2018,group chief executive officer Stephen Saad noted that the launch hadformed part of a two-pronged strategy for HPC. However, the firstpart, adding an undisclosed indication to the firm’s existing HPCproduct, had recently been denied by the FDA, he revealed.

With HPC sales in the US “absent” during Aspen’s 2017/18financial year after the company changed its distribution partner,Aspen’s Regional Brands turnover in developed markets outside ofAustralia and New Zealand fell by 28% at constant exchange rates(CER) to ZAR794 million (US$53.6 million). Nevertheless, Aspen’stotal Regional Brands sales increased by 5% on the same basis toZAR14.3 billion, and by 2% as reported (see Figure 1).

Aspen’s South African Regional Brands sales climbed by 12%at CER to ZAR7.17 billion, driven by double-digit growth for bothprescription and OTC products. Amid recent calls by industry for anincrease above the 1.26% granted for the country’s single exit price(SEP), Saad said that with “wild movements in exchange rates andconsumer price index (CPI) there’s no way a 1% increase is going toleave you in a situation where you’re going to come out all right”.“It’s something we’ve engaged on with the regulators,” Saad disclosed.

Elsewhere, Aspen’s Australasian Regional Brands sales movedahead by 2% at CER to ZAR3.60 billion, with Saad reflecting onpricing pressures in Australia and warning of more to follow. And inAsia, sales jumped by 27% to ZAR628 million in constant currencies,“driven by Japan, particularly around authorised generics”.

Group sales increased by 5% at CER, and 3% as reported, toZAR42.6 billion, with a stronger rand in the second half resulting inreported second half sales decreasing by ZAR1.3 billion compared tothe first half. Operating profit increased by 11% to ZAR9.24 billion.

Aspen’s full-year sales report came as the firm agreed to sell itsglobal Nutritionals business for C740 million (US$866 million), inorder to focus on the firm’s core anaesthetics, thrombosis and highpotency & cytotoxic portfolios. “Generic products contribute lessthan 15% to the group’s pharma revenue today and our strategicfocus is on building our specialty portfolio,” Aspen said. Gn dean.rudge@generics-bulletin.com

Business segment Annual sales(ZAR millions)

Change(%)

Proportionof total (%)

Regional Brands 14,336 +2 34

Anaesthetics 8,332 +18 19

Thrombotics 6,430 +14 15

High-potency/cytotoxics 4,172 -11 10

Commercial Pharma 33,270 +6 78

APIs 4,591 +4 11

Finished-dose 1,644 -23 4

Manufacturing 6,235 -5 15

Nutritionals 3,091 -4 7

Aspen Pharmacare 42,596 +3 100

Figure 1: Breakdown by business segment of Aspen Pharmacare’s sales in itsfinancial year ended 30 June 2018 (Source – Aspen)

MANUFACTURING

Lernapharm has FDA warningLernapharm has received a warning letter from the US Food and

Drug Administration (FDA) for its manufacturing facility inQuébec, Canada. Following an inspection at the site in December lastyear, the agency identified “significant violations” of current goodmanufacturing practice (cGMP) concerning finished-dosage forms.The site was placed under import alert on 24 April 2018.

The FDA said that Lernapharm failed to test the sterility offinished-product batches of an undisclosed drug, and instead relied onthe use of a biological indicator organism. “You reprocessed multiplebatches of drug products which purport to be sterile, that did not meetprocess parameters or quality attributes,” the agency detailed. “In oneinstance, you reprocessed a lot after five biological indicator stripswere found with microbial growth.”

According to the FDA, Lernapharm also failed to conductthorough investigations into customer complaints for an undisclosedsterile drug product. In October 2017, Lernapharm received complaints“due to a significant number” of leaking seals, with an investigationconcluding that these leaked “due to pinholes in the package caused bydebris that had accumulated on the sealing of the packaging machine”.

“You did not evaluate all potential causes for customer complaintsor extend the investigation to other potentially affected batches andother products,” the FDA stated. The firm also determined that 18 otherbatches could have been affected by debris on the sealing, but noinformation was provided regarding investigations into these.

Sterile products were manufactured in “areas of insufficient controland air classification”, the FDA discovered, deeming these conditions“inadequate to protect the drug and its container-closure systems duringdrug production”. Also environmental monitoring was insufficient toevaluate whether a manufacturing environment is operating in a stateof control.” the FDA stated. “You have minimal information on theidentity of micro-organisms in your environment.” G

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6 GENERICS bulletin 21 September 2018

COMPANY NEWS

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: cphicustomerservice@ubm.com. Website www.cphi.com.

22-23 Octobern Next Steps: Manufacturing &

Quality WorkshopMaryland, USAThis event, organised by the Association of Accessible Medicines(AAM), will provide information on manufacturing and qualitycomponents of generics and biosimilars businesses.

Contact: AAM. Tel: +1 202 249 7127.E-mail: jennifer.soup@accessiblemeds.org. Website www.accessiblemeds.org.

24-26 Octobern 21st APIC/CEFIC European Conference

Budapest, HungaryThis conference will discuss the latest developments in the fieldof GMP and regulatory compliance.

Contact: Concept Heidelberg. Tel: +49 6221 84 44-0.E-mail: info@concept-heidelberg.de. Website www.api-conference.org.

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: issa.mauthoor@terrapinn.com. 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: events@medicinesforeurope.com. Register online atwww.medicinesforeurope.com/events.

26-27 Novembern EuroPLX 68

Athens, GreeceThis 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: meetyou@europlx.com. Website: www.europlx.com.

EVENTS – October – November

9 October 2018

Join us!

awards@generics-bulletin.com www.generics-bulletin.comCall: +44 1564 777550

Palacio Municipal de Congresos,Madrid, Spain

BUSINESS STRATEGY

Aceto amends creditand delays reportingAceto has restructured its finances following negotiations with

lenders, securing a waiver for defaulting on key financial ratiosfor its financial fourth quarter ended 30 June 2018 and for all fourquarters of its current financial year ending 30 June 2019. At thesame time, the US firm has delayed filing its annual results from mid-to late-September.

“The amendment provides for a waiver of any event of defaulton the total net leverage ratio, senior secured net leverage ratio anddebt service coverage ratio financial covenants,” Aceto explained.It also “allows for greater capital expenditures and investments, placeslimitations on the payment of quarterly dividends, increases the interestrate payable on all loans under the amended and restated credit agreement,and requires the company to maintain minimum liquidity levels”.

The developments come after Aceto earlier this year revealed thatit was weighing “a range of strategic alternatives” – including breakingup the company or merging with another firm – as it grappled with“persistent adverse conditions in the generics market” (Genericsbulletin, 27 April 2018, page 3).

Shortly after, Aceto cited “a decline in actual and forecastedrevenue and earnings” due to these persistent adverse conditions – aswell as compliance issues with products it previously purchased fromLucid – as the reason for registering for an impairment charge ofUS$256 million relating to its Rising Pharmaceuticals generics business,leading the firm to a US$259 million operating loss in its financialthird quarter (Generics bulletin, 11 May 2018, page 7).

In the wake of these developments, former vice-chairman AlanLevin was chosen to become non-executive chairman from 1 July,succeeding Albert Eilender (Generics bulletin, 15 June 2018, page 16).This came after Aceto had also appointed a new interim chief financialofficer, Rebecca Roof, to replace Edward Borkowski earlier in the year.

Meanwhile, Aceto said that its decision to delay filing its resultsfor the financial year ended 30 June 2018 had been made after itrealised that “additional analysis would be required to determine ifit would be appropriate to record an additional valuation allowancefor the fiscal year” with respect to net deferred tax assets.

Having originally planned to report its results on 12 September,Aceto filed with the US Securities and Exchange Commission (SEC)for a 15-day extension. “The analysis remains ongoing,” it noted,“and the company expects to file its annual report on 28 September”. G

MANUFACTURING/STRATEGIC ALLIANCES

Aetos and Pall form a bio pactOffering “manufacturing solutions to the global biosimilars market”

is the goal of a strategic partnership formed by US-based companiesAetos Biologics and Pall Biotech. Aetos will provide “high-quality,high-titre cell lines and scalable manufacturing processes”, whilefiltration, separation and purification specialist Pall will contribute“next-generation bioprocess equipment”, such as its Allegro STRsingle-use stirred tank bioreactor and a range of consumables.

“By aligning Pall Biotech equipment, including bioreactors,mixing and storage, and downstream technologies with Aetos Biologics’cell lines and manufacturing processes,” the partners claimed,“customers benefit from access to integrated solutions for expeditedbiosimilars development.” G

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7GENERICS bulletin21 September 2018

MARKET NEWSDRUG SHORTAGES

Shortages legislationis lauded in AustraliaLegislation passed by Australia’s government aimed at better

informing patients about medicines shortages has been applaudedby the country’s Generic and Biosimilar Medicines Association(GBMA). Under the new law – which will come into effect from 1January 2019 – shortages of ‘important’ medicines must be reported“as soon as they occur”, while the removal of any critical drug fromthe market must be notified to the Department of Health “at least12 months in advance, or as soon as possible”.

“A shortage that will severely impact on patients must be notifiedto the Therapeutic Goods Administration (TGA) as soon as possible,”the Department of Health said, “and no later than two working daysafter the medicine company knows or should know of the shortage.”

“Mandatory reporting will apply to all prescription medicines aswell as other medicines which are vital for public health, such asEpiPen (epinephrine) and inhalers,” the Department of Health outlined,noting that Australia was earlier this year hit by EpiPen shortagesthat were not reported to the TGA in advance. “Tough penalties willapply to companies that do not comply with these new laws, includingfines of up to A$210,000 (US$149,000) for each infringement andthe possibility of further court action.”

Under the legislation, a critical medicine is deemed to be inshortage “if there is not enough, or likely will not be enough, for allpatients in Australia who take it or may need to take it, at any timein the next six months”. Firms must also notify the Department ofHealth shortages that will not have a severe impact on patients, within10 working days.

Welcoming the legislation, the GBMA noted that it had been“working closely with the government and stakeholders to harnesssupport for the passage of this important legislation”, includingalongside brand industry body Medicines Australia, the AustralianSelf-Medication Industry, and other pharmacy and healthcare groups.

GBMA chair Sylvain Vigneault said that medicines shortages were“a global challenge”, adding that Australia was “showing leadership onsuch a complex issue”. “Now industry, community pharmacy, hospitalsand the government will collaborate more effectively to ensure informationabout the supply of vital medicines reaches those who need it.” G

REGULATORY AFFAIRS

Seek study funding, FDA toldPatient and physician access to interchangeable biosimilars in the

US would be enhanced by shifting the onus to conduct the necessarystudies away from biosimilar developers, the National Association ofChain Drug Stores (NACDS) told the US Food and Drug Administration(FDA) during an agency hearing on biologic competition and innovation.

Michelle Cope, the NACDS’ director of federal and state publicpolicy, argued that it would not always be cost-effective for biosimilarsponsors to conduct the studies needed to secure an interchangeabilitydesignation from the agency. “We encourage the FDA to work withCongress and the Agency for Healthcare Research and Quality (AHRQ)to explore new opportunities to facilitate the studies,” she said.

“The FDA could achieve this,” Cope suggested, “by securingfederal funding for interchangeability studies of approved biologicsor by accepting studies performed by health systems or other privateentities that demonstrate interchangeability.” G

PRICING & REIMBURSEMENT

WHO road map drawswelcome and criticismHumanitarian groups and charities have welcomed a World Health

Organization (WHO) draft road map on access to medicines andvaccines between 2019 and 2023. But such advocacy groups havestrongly criticised several aspects of the ‘zero draft’ document.

In a section on ‘fair pricing’, the zero draft – released forconsultation to member states at a stakeholders’ meeting on 10September – pledges WHO “support for implementation of financingpolicies and policies to reduce out-of-pocket payments, includingthe adoption of generics and biosimilars in selection, procurementand use of medicines”. This is the only mention of generics orbiosimilars in the 31-page document.

Oxfam responded by telling the WHO that “new work onbiosimilar medicines needs to be prioritised”. The charity formed partof a coalition of advocacy groups that called on the WHO secretariatto develop by the end of 2020 a best-practices manual on controllingand remedying excessive drug pricing. “The manual should compileexpertise on various legal and technical aspects of excessive pricing,including the context-specific methodologies employed by memberstates for determining if prices are excessive, and the mechanismsto remedy and control pricing abuses,” the groups insisted.

They also argued that drug and vaccine prices must be delinkedfrom research and development costs, and proposed “granting ofcompulsory licenses and/or the use of competition law” to addressexcessive prices. Doctors group Medécins Sans Frontières (MSF)maintained that a better definition of fair pricing “requires managementof exclusive rights to avoid undue or abusive monopolies, and farmore transparency” and demanded “additional investment” in theWHO’s pre-qualification program.

Addressing the road map’s supply chain, MSF insisted that the“WHO should reject the vertical supply-chain model driven bypharmaceutical corporations”. Global originators’ body IFPMAcountered that access challenges could best be addressed through“provision of incentives through intellectual-property protection,together with health systems strengthening, supply-chain management,regulatory capacity building, strengthening primary healthcare andtimely diagnosis”. G

REGULATORY AFFAIRS

FDA guides on analysis dataGuidance on technical specifications for comparative clinical

endpoint bioequivalence study analysis datasets for abbreviatednew drug applications (ANDAs) has been published by the US Foodand Drug Administration (FDA). It covers recommendations on howsuch data, including skin adhesion and irritation/sensitisation studydata for ANDAs, should be submitted to the agency.

“By providing extensive technical details and example data tables,”the FDA stated, “this guidance may help generic drug applicants todesign better studies, capture critical data and submit their resultsas part of a complete ANDA.”

Detailed data specifications are provided for adhesion studies andirritation/sensitisation studies for transdermal delivery systems (TDS)and topical patches, and also for comparative clinical endpointbioequivalence studies using endpoints such as lesion count, 100%clearance of all actinic keratosis lesions and total nasal symptom score. G

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10 GENERICS bulletin 21 September 2018

MARKET NEWS

Figure 1: Sales volumes evolution across seven biologic molecules subject to competition, in selected European countries (Source – Iqvia)

Tender systems that award the total market volume for a moleculeto a single competitor are one of two “recent dynamics in the

biosimilars market” that pose a danger to the sustainability of thesector in Europe. The other is payer-driven switching between products,according to an ‘Advancing biosimilar sustainability in Europe’ reportcommissioned by Pfizer from the Iqvia Institute.

“Although single-winner tenders were found to achieve greatestprice reduction on biologic molecules when biosimilar competitionexists, they were also found not to support long-term sustainabilityas they disrupt market forces and competition by excluding non-winner manufacturers from the market for the duration of the tendercontract,” the report finds.

“Additional evidence suggests single-winner tenders do not alwaysoptimise savings, since physicians can still use non-preferred productat a higher price; whereas multi-winner tenders offer price reductionson all contracted products. They also eliminate the incentive forbiosimilar manufacturers to innovate in areas to support patients andproviders when they select on price only,” states the ‘multi-stakeholderassessment’, which looked at experiences with a set of seven molecules“with different purchasing and use characteristics” that were launchedbetween 2013 and 2017 – enoxaparin sodium, etanercept, follitropinalfa, infliximab, insulin glargine, insulin lispro and rituximab – acrossseven countries “with differing approaches to biosimilar utilisation”:Denmark, France, Germany, Italy, the Netherlands, Norway and Spain.

In the report that aims to identify best practices that can beleveraged to support long-term sustainability in Europe, Iqvia observesthat, while its analysis shows single-winner tenders generally achievethe greatest price discounts upon biosimilar competition, “there isadditional evidence from other data sources to show that multiple-winner tenders may result in lower average net molecule costs perdefined daily dose (DDD) for a region overall”.

In support of that assertion, the report cites hospital data fromSweden’s E-hälsomyndigheten agency that shows county councilsachieving average net costs for infliximab up to 40% or more lowerwhen awarding contracts to two or more suppliers rather to a singletender winner. By naming multiple suppliers, Iqvia points out, payersand healthcare providers can achieve savings through price reductions

obtained on all contracted products, “often including the originator”,rather than on just one product. Furthermore, “tenders with multiplewinners offer the option of supply alternatives in case of distributionor stocking issues”.

However, the analysis acknowledges, “use of national tendersleads to faster and higher biosimilar penetration” than in countries suchas France, Germany, Italy, the Netherlands and Spain where suchsystems are not in place. Such rapid uptake is particularly marked incountries like Denmark and Norway that run “single tenders with singlewinners”. As evidence, the report contrasts experiences in Denmark –where biosimilar infliximab had monopolised the market, and biosimilaretanercept had reached an 88% market share through single-winnernational tenders – with biosimilar shares of just 48.6% for infliximaband 10.7% for etanercept in France under multiple-winner, sub-nationalprocurement processes.

As Figure 1 shows, Denmark and Norway are the two of the sevenstudied markets in which biosimilar launches have hugely acceleratedthe growth in volume utilisation of molecules now subject to competition.

“Payer-driven switch, especially if enforced through negativephysician incentives, provides a means to manage healthcare budgetsin the short term, but jeopardises sustainability by disrupting marketforces and bringing uncertainty to manufacturers of whether they willbe locked out from selling product in a market for a duration of time,”the Pfizer-funded report maintains. Such substitution withoutinvolving the prescriber also took the choice of product out of thehands of doctors and recued patients’ involvement in their treatment.

“Potential enforcement of medicine switching policies by payers inthe future, either via binding guidelines or negative incentives tophysicians such as financial penalties, remains an element of criticalimportance for the long-term outlook of sustainability,” it cautions.

In general, the report – which observes that “no critical issues onbiosimilar safety, quality and supply have been identified” – identifiesfive key policy areas influencing sustainability: access to biologicalmedicines; regulatory environment and clinical guidelines; productsafety, quality and supply; direct and indirect incentives; and competitivepressure, including pricing dynamics and purchasing mechanisms. Gn aidan.fry@generics-bulletin.com

MARKET RESEARCH

Single-winner tenders threaten the future

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11GENERICS bulletin21 September 2018

PRODUCT NEWS

ONCOLOGY DRUGS

EMA is assessing an erlotinibThe European Medicines Agency’s (EMA’s) committee for human

medicinal products (CHMP) received a solitary application fora centralised marketing authorisation in the European Union (EU) forgeneric Tarceva (erlotinib), according to the committee’s September2018 update. At the same time, the committee received new applicationsfor two generic antibiotic drugs: tigecycline and tobramycin.

And according to the CHMP, from the end of July to the end ofAugust, the number of biosimilar rituximab dossiers being evaluatedby the committee increased from one to two. G

CARDIOVASCULAR DRUGS

Mylan comes first with esmololMylan says it has introduced in the US the first generic version of

Baxter’s Brevibloc (esmolol hydrochloride) in sodium chlorideinjectable treatment for tachycardia and hypertension. The US-basedfirm is offering 2,500mg/250ml and 2,000mg/100ml single-dose plasticbags to its institutional customers after its abbreviated new drugapplication (ANDA) was approved by the US Food and DrugAdministration (FDA).

The FDA’s approval letter issued in June this year noted thatBaxter’s Brevibloc and Brevibloc Double Strength pre-mixed injectionin plastic container benefitted from protection from US patents6,310,094 and 6,528,540, both of which expire on 12 July 2021 aftersix-month paediatric exclusivity periods. With infringement litigationover the ‘094 and ‘540 patents having been dismissed, the FDAconcluded that Mylan had forfeited its eligibility for 180-day genericmarket exclusivity because the firm had not secured tentative approvalfor its ANDA within 30 months of filing.

Quoting Iqvia data for the 12 months ended 30 June 2018, Mylansaid US sales of esmolol 10mg/ml and 20mg/ml single-dose plasticbags totalled US$126 million. G

AUTOIMMUNE DISEASES TREATMENTS

Sandoz has stipulatedover Enbrel patentsSandoz has stipulated to its abbreviated biologics license application

(aBLA) for Erelzi (etanercept-szzs) infringing certain claims ofUS patents 8,063,182 and 8,163,522 just ahead of trial getting underwayin a New Jersey district court in the Novartis division’s dispute withAmgen and Roche over Enbrel (etanercept). Sandoz secured approvalfor Erelzi from the FDA at the end of August 2016 (Generics bulletin,9 September 2016, page 1), but the company has not yet launchedthe arthritis and inflammatory conditions drug.

Court filings reveal that Sandoz’ stipulation on the ‘522 patent –one of two ‘Roche’ patents on which the originators sued, along with‘psoriasis’ patents 7,915,225; 8,119,605; and 8,722,631 – followeddistrict judge Claire Cecchi’s decision in August this year that thedisputed term in the ‘522 patent ‘wherein the polynucleotide encodesa protein consisting of’ must be construed as meaning ‘wherein thepolynucleotide contains the genetic information for a protein consisting of’.

In late-January this year, Sandoz asked the FDA to delete Erelzi’sapproved indications for psoriatic arthritis and plaque psoriasis. G

MULTIPLE-SCLEROSIS DRUGS

US appeals upholdsover Ampyra patentsAUS district court decision that opened the door for generic

competition to Acorda Therapeutics’ Ampyra (dalfampridine)10mg extended-release tablets by invalidating four patents shieldingthe treatment for multiple sclerosis has been upheld by a US Courtof Appeals. The 2-1 split decision, with a dissenting opinion fromJudge Pauline Newman, favours abbreviated new drug application(ANDA) filers Hikma, Mylan and Teva. “We are reviewing the decisionand will consider future options, including the possibility of a furtherappeal,” Ron Cohen, Acorda’s president and chief executive officer,said in response to the decision.

As Generics bulletin went to press, the three ANDA filers – Hikmathrough its Roxane affiliate – held tentative approvals from the USFood and Drug Administration (FDA) for their applications, alongsideMicro Labs and Sun Pharma. Actavis, itself now a part of Teva,holds a final approval, in addition to Accord, Alkem and Aurobindo.

In August, with the April 2017 district court decision having gonein their favour, Hikma and Teva had signed confidential “interimagreements” with Acorda that would run until the appeals court ruling(Generics bulletin, 10 August 2018, page 14). Meanwhile, Mylanreached a settlement agreement with the originator providing formarket entry with its generic Ampyra product “sometime in 2025or earlier under certain circumstances”.

Acorda had, shortly before that settlement, warned that “multiplegeneric-drug manufacturers may decide to launch at-risk genericversions” after its US patent 5,540,938 – owned by Elan and licensedto Acorda – expired on 30 July and an appeals court refused to issuean injunction (Generics bulletin, 3 August 2018, page 17).

The appeals court’s decision came after Delaware District JudgeLeonard Stark ruled that the four patents at-issue with expiry datesranging from January 2025 to May 2027 – 8,663,685; 8,007,826;8,440,703; and 8,354,437 – were invalid as obvious (Generics bulletin,7 April 2017, page 11). The patents generally claim the administrationof a medication containing the active ingredient 4-aminopyridine(4-AP) to improve walking in individuals with multiple sclerosis.

But Stark observed that this was “not to say that there is nosignificant evidence of non-obviousness”. Pointing to Acorda’s “credible”testimony, Stark had said: “In the end, there is evidence on both sidesof the parties’ dispute, and this was an eminently ‘triable case’.”

On appeal, Acorda argued that the district court had erred becausea person of skill would not have had a motivation to combine the priorart to arrive at the invention, and a reasonable expectation of successin doing so, and that claim limitations relating to pharmacokineticswere not inherent in the claimed invention, as the district courtdetermined, and therefore were not obvious.

Moreover, the originator asserted, the district court had “improperly”applied a categorical rule that the “blocking” Elan patent “negates anyfindings in favour of Acorda on the objective indicia of commercialsuccess, failure of others, and long felt but unmet need”. All threechallenges were rejected by Judges Timothy Dyk and Richard Taranto.

In her dissenting opinion, Newman wrote that obviousness of thefour patents was “not established by clear and convincing evidence”.“The prior art did not provide a suggestion to select the specific elementsand limitations of the Acorda formulation, and did not suggest that suchselection and combination would have a reasonable expectation ofsuccess in relieving the walking impairment of multiple sclerosis,”Newman concluded. Gn dean.rudge@generics-bulletin.com

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12 GENERICS bulletin 21 September 2018

PRODUCT NEWS

TEVA has secured US Food and Drug Administration (FDA) approvalfor a new vial presentation and an indication in paediatric patientsaged one month and older for its Granix (tbo-filgrastim) neutropeniatreatment. Complementing existing pre-filled syringe presentationsof the granulocyte colony-stimulating factor (G-CSF), the single-dosevials will be available in 300µg/1ml and 480µg/1.6ml versions.

AMILORIDE in a nasal-spray formulation could be used to treatcertain types of anxiety as well as pain, according to a studyconducted by Canada’s Centre for Addiction and Mental Health(CAMH). The blood-pressure drug “reduced the physical respiratorysigns of anxiety and pain in a pre-clinical model of illness”.

XSPRAY PHARMA has announced “positive data from a clinicalbioequivalence study” for its HyNap-Dasa (dasatinib) lead productcandidate. The Swedish company said the Phase I study testedin 16 healthy subjects the bioavailability of “two different tabletformulations of HyNap-Dasa” in comparison with Bristol Myers-Squibb’s Sprycel treatment for chronic myeloid leukaemia. “Theplanned studies required to take HyNap-Dasa to final registrationstudies will now be performed as planned,” stated the Stockholm-based firm, which plans to launch its first product in the US by 2021.

XELLIA PHARMACEUTICALS has formed a global strategicpartnership with German biotech company Leukocare to “discoverinnovative and superior formulations” that will help Denmark’s Xelliato develop a “pipeline of value-added antibiotic and antifungalproducts”. Munich-based Leukocare will apply its proprietaryStabilizing and Protecting Solutions (SPS) formulation technology todiscover and develop “novel liquid formulations” of anti-infectives inreturn for fees, funding and royalties. The deal supports Xellia’s strategyof “transitioning lyophilised products into liquid formulations”.

MUNDIPHARMA has made its Flutiform K-haler (fluticasone/formoterol) 50µg/5µg and 125µg/5µg aerosol inhaler available inUK for adults and children aged 12 years and older with asthma.Using the same formulation of the firm’s Flutiform pressurisedmetered-dose inhaler (pMDI), the newcomer features a “breath-triggered aerosol device utilising a patented ‘kinked’ k-valve”designed to make it easier for patients to use the inhaler properly.Further launches in Europe are scheduled.

ITF PHARMA – the US subsidiary of Italy’s Italfarmaco – hasobtained US Food and Drug Administration (FDA) approval for itsTiglutik (riluzole) oral suspension for treating amyotrophic lateralsclerosis (ALS). “Tiglutik is the first and only easy-to-swallowthickened riluzole liquid for ALS and is administered twice-dailyvia an oral syringe,” claimed ITF, which secured approval via anFDA fast-track designation as an orphan drug.

LUYE PHARMA has moved its LY01005 injectable goserelinacetate extended-release microspheres into Phase III clinical trialsfor prostate cancer in China. The oncology drug is already undergoingPhase I clinical trials in the US as part of a hybrid 505(b)(2) program.

SUN PHARMA has introduced in the US its Kapspargo Sprinkle(metoprolol succinate) 25mg, 50mg, 100mg and 200mg extended-release capsules for treating hypertension, angina pectoris and heartfailure. The Indian company said its extended-release coated pellets –which are covered by US patents 9,504,655 and 9,700,530 expiringon 9 July 2035 – “may be sprinkled over soft food, or administeredvia a nasogastric tube, to facilitate long-term, once-daily administration,particularly for patients who have difficulty swallowing”. G

VALUE ADDED MEDICINES IN BRIEF

OPIOID-DEPENDENCE TREATMENTS

Teva’s Zubsolv win reversedTeva’s Actavis has lost on appeal in US patent-infringement

proceedings over Orexo’s Zubsolv (buprenorphine/naloxone)1.4mg/0.36mg and 5.7mg/1.4mg sublingual tablets. The US Court ofAppeals has reversed a Delaware district court’s decision to invalidatea key formulation patent shielding the brand until September 2032.The appeals court has remanded the case for further proceedings.

“Obviousness was not proved by clear and convincing evidence,”it found, concluding that US patent 8,940,330 “provides a significantimprovement” over the prior art. The Swedish originator said it wouldnow request the Delaware district court to issue a judgement that Actavis’generic Zubsolv products infringe the patent and will not be approvedby the US Food and Drug Administration (FDA) until expiry in 2032.

Actavis did not appeal against Delaware District Judge SueRobinson’s November 2016 decision that US patent method-of-use8,454,996 – which expires in September 2019 – was valid and infringedby Actavis’ generic (Generics bulletin, 25 November 2016, page 13).G

GASTROINTESTINAL DRUGS

Actavis finds a Xifaxan dateTeva’s Actavis will be able to offer a generic alternative to Bausch

Health’s Xifaxan (rifaximin) 550mg tablets in the US around twoyears before the longest-lasting US patent protecting the gastrointestinaldrug expires. Under the terms of a patent-litigation settlement thatends proceedings in a Delaware district court, Actavis can market,without royalties, its own approved generic of Xifaxan 550mg from1 January 2028. Alternatively, from the same date, the generics firmcan license restricted supplies of an authorised generic.

If another generic rifaximin product is approved in US and entersthe market, Actavis will be able to launch before 1 January 2028.

Bausch, which markets the irritable bowel syndrome treatmentthrough its Salix subsidiary under licence from Alfasigma, said “finalpatent expiry on Xifaxan 550mg tablets is late 2029”. However, theOrange Book maintained by the US Food and Drug Administration(FDA) lists against the brand, in addition to several 2029 patents,US patent 9,421,195 that has an expiry date of 10 March 2030. G

ARTHRITIS DRUGS

Boehringer’s Cyltezois an equal to HumiraBoehringer Ingelhiem’s Cyltezo (adalimumab-adbm) is equivalent

to reference brand Humira “with no clinically meaningful differencesin efficacy, safety and immunogenicity in people with moderate-to-severe chronic plaque psoriasis” according to Phase III study.

Citing 16-week data from the randomised study – which treated318 moderate-to-severe chronic plaque psoriasis patients with Cyltezoor Humira – Boehringer said that the primary endpoint, of a 75%reduction in psoriasis area and severity index (PASI) at week 16, wasmet. Further 24-week data “are expected to be presented next year”.

Cyltezo was approved by the US Food and Drug Administration(FDA) at the end of August 2017 (Generics bulletin, 1 September2017, page 1) and by the European Medicines Agency (EMA) inNovember that year (Generics bulletin, 17 November 2017, page 15). G

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13GENERICS bulletin21 September 2018

PRODUCT NEWS

Tuesday, 9 October 2018Palacio Municipal de Congresos,

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ONCOLOGY DRUGS

Riximyo gets an AusPARAustralia’s Therapeutic Goods Administration (TGA) has released

an Australian public assessment report, or AusPAR, for Sandoz’Riximyo (rituximab) biosimilar. The 100mg/10ml and 500mg/50mlsingle-use vials were entered onto the Australian Register of TherapeuticGoods (ARTG) on 30 November last year as an alternative to Roche’sMabThera (Generics bulletin, 15 December 2017, page 15).

With Riximyo poised to obtain reimbursement status throughAustralia’s Pharmaceutical Benefits Scheme (PBS), Roche in Junethis year obtained an injunction barring Sandoz from launching therituximab biosimilar in Australia until 11 August 2019, the earliestexpiry date of four asserted method-of-use patents (Genericsbulletin, 22 June 2018, page 13). G

OPIOID-DEPENDENCE TREATMENTS

Teva holds off launchuntil Reddy’s decisionTeva has agreed to eschew market entry for the firm’s recently

approved alternative to Indivior’s Suboxone (buprenorphine/naloxone) sublingual film, until certain legal matters putting the brakeson Dr Reddy’s Laboratories’ generic Suboxone product are resolved.

“This agreement will prevent Teva from selling, offering to sell,or import its buprenorphine/naloxone sublingual film product untilthe earlier of a US Court of Appeals decision lifting the preliminaryinjunction against Dr Reddy’s, and the outcome of filed litigationagainst Dr Reddy’s related to US [Suboxone] patents 9,931,305,9,855,221 and 9,687,454,” the originator explained.

Oral arguments will be heard during the first week of Octoberin Reddy’s appeal against the US district court order, with an appealscourt having earlier granted Reddy’s “emergency motions” for anexpedited appeal against the preliminary injunction (Generics bulletin,27 July 2018, page 15). A decision is expected in early November.

Teva’s Cassipa (buprenorphine/naloxone) 16mg/4mg sublingualfilm is a new dosage strength of the opioid dependence therapy,approved through the US Food and Drug Administration’s (FDA’s)505(b)(2) hybrid new drug application (NDA) pathway relying, in part,on the agency’s finding of safety and effectiveness for Suboxonesublingual film to support approval.

Reddy’s had launched the company’s Suboxone sublingual filmgeneric ‘at-risk’ immediately upon receiving FDA approval earlierthis year. But a US district court soon granted Indivior a temporaryrestraining order compelling Reddy’s to immediately cease launchactivities, due to ongoing litigation over the ‘305 patent (Genericsbulletin, 22 June 2018, page 11).

The originator then obtained a preliminary injunction against theIndian firm from a US district court, which Reddy’s failed to havestayed by the US Court of Appeals pending a ruling on its appealagainst the injunction (Generics bulletin, 3 August 2018, page 12). G

INVESTIGATIONS

Aspen updates price probesAspen Pharma has confirmed that separate investigations by the

European Commission and the UK’s Competition and MarketsAuthority (CMA) into the firm’s pricing practices for certain productsare ongoing. Possible outcomes, including whether the bodies willformally open cases, are however unknown “at this stage”.

The Commission is examining whether Aspen “abused a dominantmarket position in breach of European Union (EU) antitrust rules” forfive mature oncology brands, while the CMA is looking into allegedanti-competitive conduct in relation to Aspen’s supply of fludrocortisoneacetate 0.1mg tablets (Generics bulletin, 19 May 2017, page 12; 20October 2017, page 6). A CMA investigation into dexamethasone 2mgtablets, launched at the same time, has since been dropped.

In relation to the former, Aspen said the Commission’s decision“whether to formally open a case is likely only to be made during thefirst quarter of 2019 after conclusion of its investigation”, noting thatitself and its advisors were “fully co-operating” with the EU body.And regarding the CMA investigation, Aspen said a decision was“likely to be made by November 2018”, when it concludes. “A highlevel of co-operation and diligence is being afforded to the investigationteam by Aspen.” G

HEPATITIS C TREATMENTS

EPO upholds patenton Gilead’s SovaldiAkey European patent protecting Gilead’s sofosbuvir until at least

April 2024 has been upheld by the European Patent Office (EPO)in opposition proceedings. “Account being taken of the amendmentsmade by the patent proprietor during the opposition proceedings, thepatent and the invention to which it relates are found to meet therequirement of European Patent Convention Article 101(3)(a) EPC,”the EPO stated following a hearing on European patent EP2,604,620.

Granted in 2016, the ‘620 patent is entitled ‘Modified fluorinatednucleoside analogues’. Applications for supplementary protectioncertificate (SPCs) extensions for up to five years are pending inseveral European Union (EU) member states. Opponents includingMédecins Sans Frontières (MSF) and the European Public HealthAlliance (EPHA) cited numerous prior-art references.

Responding to the EPO’s decisions, MSF said it “allows Gilead toretain a patent on a pharmaceutically-inactive component that appearsin the body during the synthesis of sofosbuvir”.

“This decision is a clear illustration of how multinationalpharmaceutical corporations like Gilead abuse the patent system so theycan shut out any competition and continue unfettered to charge exorbitantprices,” argued Gaëlle Krikorian, head of policy for MSF’s accesscampaign. “We will appeal the decision.” G

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15GENERICS bulletin

PRICE WATCH.....UK

21 September 2018

Figure 1 (above): Comparison between the periods 1-31 July 2018 and 1-31 August2018 of UK trade prices of the most recently-launched generics listed in category Mof the Drug Tariff of pharmacy-reimbursement prices. Averages calculated from atleast 21 data points. Figure 2 (top right) and Figure 3 (centre right): Biggest averagetrade-price changes between 1-31 July 2018 and 1-31 August 2018. Averagescalculated from at least 20 data points. Figure 4 (bottom right): Ranking of fastest-moving products subject to the most price offers made to independent UK pharmacists(one strength per ingredient; offers recorded by 31 August). Data for Figures 2, 3 and4 from a basket of about 750 commonly-dispensed generics. Recently- launchedproducts in Figure 1 excluded from Figures 2 and 3 (Source – WaveData).

Aripiprazole tabs 10mg 28 £1.25 +23 £2.32 -3Carbimazole tabs 5mg 100 £23.61 -6 £29.75 -2Celecoxib caps 200mg 30 £0.81 +8 £1.12 -7Cilostazol tabs 100mg 56 £3.33 ±0 £5.23 +26Duloxetine caps 30mg 28 £1.00 -16 £1.99 -28Eplerenone tabs 25mg 28 £3.20 -2 £5.32 -18Escitalopram tabs 10mg 28 £0.44 -2 £0.80 +5Etoricoxib tabs 90mg 28 £2.13 +1 £3.40 +1Frovatriptan tabs 2.5mg 6 £2.75 -4 £5.48 -5Memantine tabs 10mg 28 £0.54 -2 £0.81 +3Montelukast tabs 10mg 28 £0.60 +5 £0.87 +1Nefopam tabs 30mg 90 £5.50 -8 £10.44 -9Nortriptyline tabs 10mg 100 £1.32 +10 £5.48 -12Olmesartan tabs 10mg 28 £0.75 ±0 £1.39 +4Pregabalin caps 150mg 56 £2.30 +7 £4.04 +2Raloxifene tabs 60mg 28 £2.26 -1 £2.81 -5Rasagiline tabs 1mg 28 £1.10 -4 £2.19 -11Rizatriptan tabs 10mg 3 £4.55 -4 £6.40 -7Rosuvastatin tabs 5mg 28 £0.77 ±0 £1.22 -10Sevelamer tabs 800mg 180 £22.20 +1 £27.17 +3Sildenafil tabs 100mg 4 £0.23 ±0 £0.39 -7Tadalafil tabs 10mg 4 £0.99 -10 £1.55 -7Telmisartan tabs 80mg 28 £0.88 +9 £1.19 -1Travoprost drops 40µg/ml 2.5ml £2.50 -8 £4.37 -10Zonisamide caps 100mg 56 £3.59 ±0 £6.91 -6

Atorvastatin tabs 20mg 28 145 126 121Omeprazole caps 20mg 28 128 128 116Lansoprazole caps 30mg 28 121 118 113Simvastatin tabs 40mg 28 132 117 108Ramipril caps 2.5mg 28 101 94 104Fluoxetine caps 20mg 30 121 108 101Citalopram tabs 20mg 28 91 85 95Amitriptyline tabs 10mg 28 113 103 94Bisoprolol fumarate tabs 2.5mg 28 106 104 91Tamsulosin MR caps 400µg 30 87 83 88

Propranolol tabs 80mg 56 £0.80 ±0 £4.21 +234Risperidone tabs 2mg 60 £1.02 +17 £3.67 +158Risperidone tabs 1mg 60 £0.49 +11 £2.96 +157Losartan tabs 25mg 28 £0.24 ±0 £0.88 +138Risperidone tabs 0.5mg 20 £0.21 -19 £1.63 +123Nebivolol tabs 5mg 28 £1.10 +86 £4.51 +112

Olanzapine tabs 7.5mg 56 £1.21 -51 £6.95 -52Terbinafine tabs 250mg 28 £1.69 -11 £4.69 -41Pioglitazone tabs 45mg 28 £1.25 -29 £3.49 -36Quetiapine tabs 100mg 60 £3.08 ±0 £6.25 -36Olanzapine tabs 15mg 28 £1.25 +29 £4.18 -34Olanzapine tabs 20mg 28 £1.59 +36 £5.53 -33

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

Alternatively, contact Charles Joynson at WaveData Limited, UK.Tel: +44 (0)1702 425125. E-mail: cjoynson@wavedata.co.uk.

RECENT LAUNCHESProduct/Strength/Pack size Lowest Change AverageChange

price (%) price (%)

BIGGEST RISERSProduct/Strength/Pack size Lowest Change AverageChange

price (%) price (%)

BIGGEST FALLERSProduct/Strength/Pack size Lowest Change AverageChange

price (%) price (%)

FAST MOVERSPrice offers as at 31 August 2018

Product/Strength/Pack size June July August

WANT MORE LIKE THIS?

Double-digit shifts for average trade prices of generics wereobserved in both directions among recently-launched UK

presentations in August, according to the latest figures from WaveData.While 56-count packs of cilostazol 100mg tablets saw their

average price rise by more than a quarter to £5.23 (US$6.77) – despitethe lowest available offer in the market remaining constant at £3.33– other molecules saw movement in the opposite direction.

Duloxetine 30mg tablets in packs of 28 saw the most pronouncedaverage decline among our recent launches (see Figure 1), with anaverage drop of 28% to £1.99. This was accompanied by eplerenone25mg tablets that saw an 18% fall in their average price to £5.32, aswell as nortriptyline, rasagiline and rosuvastatin tablets that experienceddeclines of at least a tenth, as did travoprost drops.

Significant rises for molecules such as risperidone saw some

presentations double or even treble in price (see Figure 2), provokingthe Department of Health and Social Care (DHSC) to grant priceconcessions in August for more than 20 molecules across over 50presentations (Generics bulletin, 7 September 2018, page 17). However,the concessions list did not feature losartan, despite 28-tablet packs ofthe 25mg strength seeing a 138% rise in their average price to £0.88.

Meanwhile, several presentations of olanzapine featured amongthe biggest fallers in Figure 3, with the average price of olanzapine7.5mg tablets more than halving to £6.95, and 28-count packs ofother strengths experiencing declines of more than a third.

Once again, statins and proton-pump inhibitors dominated thefast movers in Figure 4, with atorvastatin, omeprazole, lansoprazoleand simvastatin taking the top four spots among those molecules withthe most price offers in the marketplace. G

Sharp UK movements are seen in August

Gen 21-9-18 Pgs.1-16.indd 15 17/09/2018 15:02

16 GENERICS bulletin 21 September 2018

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LITIGATION

Frost among 10 to becharged on fraud plotThe billionaire former chairman of Teva, Phillip Frost, is among

a group of 10 individuals and “10 associated entities” to have beencharged by the US Securities and Exchange Commission (SEC) forhis part in an alleged stock manipulation scheme, a claim disputed byFrost’s current company and co-defendant in the suit, Opko Health.

According to the SEC’s complaint filed in a Southern District ofNew York court, Frost participated in two of three “long-runningfraudulent schemes that generated over US$27 million from unlawfulstock sales and caused significant harm to retail investors, who wereleft holding virtually worthless stock” in three public companies.

These were “classic pump-and-dump schemes”, the SEC says,taking place from 2013 to 2018 by a group of “prolific South Florida-based micro-cap fraudsters led by Barry Honig”.

Opko, for which Frost has been chief executive officer andchairman since March 2007, insisted that the suit contained “seriousfactual inaccuracies”. “Had the SEC followed its own standardprocedures, Opko and Dr Frost would gladly have provided informationthat would have answered a number of the SEC’s apparent questions,and filing of this lawsuit against them could have been avoided,” theMiami-based company stated.

Opko and octogenarian Frost were also “confident that once aproper investigation is completed and the facts of the case have beenfully disclosed, the matter will be resolved favourably for them”. G

GERREISHEIMER has appointed Dietmar Siemssen as chiefexecutive officer (CEO). Taking the role from 1 November, Siemssen,most recently CEO of automotive supplier Stabilus, replacesChristian Fischer, who resigned with immediate effect at the startof the year “due to personal reasons” (Generics bulletin, 16 February2018, page 16). Prior to joining Stabilus in 2011, Siemssen “servedfor 19 years in various senior management positions at Continentalin Germany and abroad, including in Asia”. Separately, the Germanpackaging specialist’s chief financial officer Rainer Beaujean hasinformed the advisory board that he will not serve the additionalthree-year term of office offered to him by the board. “I havedecided to take on new professional challenges,” he stated. “It goeswithout saying that I will fulfil all obligations under my contractuntil the end of April.”

AMERISOURCEBERGEN has named executive vice-president andgroup president of global commercialisation services and animalhealth James Cleary as the company’s chief financial officer (CFO),after Tim Guttman announced his retirement from the role. Steppingdown on 9 November, Guttman – who served a 16-year tenure atthe firm – “will continue in an advisory capacity further into fiscalyear 2019 to ensure a smooth transition”. Joining the firm in 2002as vice-president and corporate controller, he went on to his currentrole as CFO and executive vice-president in 2012.

CITOXLAB has chosen former head of Synexus ChristopheBerthoux to become chief executive officer of its European operations.The contract research organisation for non-clinical research saidthe appointment of Berthoux “will further drive current and futuredevelopment of Citoxlab’s European sites, which are alreadyexperiencing strong growth”.

UPM PHARMACEUTICALS – a contract development andmanufacturing organisation focused on oral solid and semi-soliddrug dosage forms – has appointed Chi-Chang Wung as directorof analytical development. Bringing “more than 20 years of experiencein analytical development, pharmaceutical development, qualityoperations and certified management consultant (CMC) consulting”to UPM, Wung previously held senior analytical-development andquality-control positions at Alkermes, SIGA Technologies andAsymchem Laboratories.

ETHYPHARM has selected Emmanuel Schmidt as chief financialofficer (CFO) and senior vice-president. He will report to presidentand chief executive officer Hugues Lecat. Schmidt has two decadesof experience serving as CFO for “major international groups”,including eight years at Pierre Fabre’s Pharma division, and since2010 he held the role at the Star’s Service Group.

CATALYST PHARMACEUTICALS has named Stanley Iyadurai asvice-president of clinical development, where he will be responsiblefor leading the firm’s clinical development efforts including directing,planning and executing clinical activities, and analysing andinterpreting clinical-trial results. Iyadurai will report to Catalyst’schief medical officer and head of regulatory affairs, Gary Ingenito.The US-based biopharmaceutical firm – which is developing ageneric version of Lundbeck’s Sabril (vigabatrin) – recently expandedits commercial leadership team, appointing Jason James as seniorvice-president of commercial operations and analytics and JeffDel Carmen as senior vice-president of sales and marketing. KevinRohrbach was named as senior director of patient engagement/advocacy, while Maria Pandolfo was appointed as senior directorof patient services. G

IN BRIEF

Gen 21-9-18 Pgs.1-16.indd 16 17/09/2018 15:02