mylan and biocon are refused on us neulasta · 3.10.2017 · ectd reg ops to-do list end of nees...

13 October 2017

Mylan and Biocon arerefused on US Neulasta

The newly-elected president of Medicines for Europe, Fresenius Kabi’s Marc-Alexander Mahl,has launched an ‘Access to Medicines: Better Care for More Patients’ campaign. This callson health ministers to “fully embrace generic, biosimilar and value-added medicines to improvethe sustainability of healthcare systems across Europe”, building on the European Union’s (EU’s)health council conclusions from June last year (Generics bulletin, 24 June 2016, page 5).

Mahl – who is beginning a two-year stint as Medicines for Europe’s president, having takenover from Mylan’s Jacek Glinka – said the access campaign would “provide compelling dataand proposals to help policy-makers and stakeholders improve access to medicines”. In particular,it would assist policy-makers in encouraging competition “in complex, specialty medicinemarkets where there are tremendous opportunities to increase access, spend resources moreefficiently and improve overall care for patients”.

Executive vice-president of Fresenius Kabi’s Generic Drugs business unit, Mahl – who alsochaired Medicines for Europe’s Hospital sector – insisted that the “simple and obvious way”to relieve pressure on healthcare budgets in Europe was “to promote generic, biosimilar andvalue-added medicines use by patients, medical professionals and pharmacists”. G

Mahl heads Medicines for Europe

COMPANY NEWS 3Canada’s Jean Coutu is acquired by Metro 3Beximco will control 3Bangladesh’s NuvistaBiocad falls short in US 4antitrust dispute

MARKET NEWS 5Europe trumps US on 5naming of biosimilarsFDA issues guidance in line with GDUFA II 5Switzerland seeking input on extensions 6No more benefit seen for 6switching studiesIreland is missing out 7on etanercept savingsFTC hosts workshop over US competition 7JAMA letter says less lawsuits to lift savings 8EMA seeks temporary staff 9ahead of moveOGD raises approval rate by 1017% in FY17

PRODUCT NEWS 12Synthon has EU nod for glatiramer 40mg 12Lilly’s Alimta patent 12withstands challengeBreckenridge obtains five 13Nostrum ANDAsNetherlands revokes 13rituximab use patentTeva warns Mylan of glatiramer damages14MPP and Gilead add bictegravir 15to allianceCinfa’s pegfilgrastim filing accepted in EU15Mylan gets first with US 17moxifloxacin bagsKabi finds way around Italian Alimta patent17Actavis fails in its US attack over Noxafil 18

FEATURES 22Eagle signs Japanese deal 22as part of global ambition

REGULARSEvents – Our regular listing 8Price Watch UK – Our regular listing 16Pipeline Watch – Myfortic 21People – Kaundinya expands 24his role at Momenta

Issue No.326

Final approval for a biosimilar version of Amgen’s Neulasta (pegfilgrastim) blockbustercontinues to elude developers in the US, with Mylan and its partner Biocon receiving acomplete response letter (CRL) from the US Food and Drug Administration (FDA)informing the firms that Mylan’s biologics license application (BLA) is not yet ready forapproval. “We are committed to working with the agency to resolve the issues stated inthe CRL expeditiously,” Mylan and Biocon stated.

Responding to Generics bulletin enquiries, the firms revealed that the CRL related to apending update of the application with certain chemistry, manufacturing and controls (CMC) datafrom “facility requalification activities post recent plant modifications”. In August, FDA inspectorsidentified 10 ‘Form 483’ observations of current good manufacturing practice (cGMP) deficienciesat Biocon’s biological drug-product facility in Bommasandra, India, adding to deficienciespreviously identified by European regulators.

The firms underlined that the CRL for Mylan’s MYL-1401H biosimilar pegfilgrastimapplication “did not raise any questions on biosimilarity, pharmacokinetic/pharmacodynamicdata, clinical data or immunogenicity”, while it moreover was not expected to “impact thecommercial launch timing of biosimilar pegfilgrastim in the US”.

This disclosure come after Amgen last month sued Mylan in a Pennsylvania district courtfor alleged infringement of two US patents protecting Neulasta, US patents 8,273,707 and9,643,997, which claim methods of purifying proteins. Both patents were previously includedin exchanges under the US Biologics Price Competition and Innovation Act (BPCIA) withMylan, which was also accused by Amgen of providing inadequate details of its manufacturingprocess (Generics bulletin, 29 September 2017, page 12).

The latest CRL for biosimilar pegfilgrastim comes four months after US-based developerCoherus BioSciences received one for the company’s CHS-1701 pegfilgrastim biosimilar (Genericsbulletin, 16 June 2017, page 9). Previously, around 15 months ago, Sandoz’ LA-EP2006pegfilgrastim was the subject of a CRL (Generics bulletin, 22 July 2016, page 9), whileprivately-held Apotex has had its biosimilar pegfilgrastim candidate, Lapelga, sitting withthe US agency since December 2014. G

eCTD Reg Ops To-Do List

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3GENERICS bulletin13 October 2017

COMPANY NEWS

Medicure has opted to cash in on its staggered acquisition of amajority stake in US-based active pharmaceutical ingredient (API)services provider Apicore after selling its interests in the company toan undisclosed pharma company for approximately US$105 million.

“These funds to be received by the company are after payment ofall transaction costs, the cashing in of Apicore employee stock options,the redemption of the remaining shares of Apicore not owned byMedicure and other adjustments,” Medicure disclosed. “Over the next18 months, additional payments may be payable under the agreement,in the form of contingent payments, including an earn-out paymentbased on the achievement of certain financial results by Apicorefollowing closing and other customary adjustments.”

Having initially taken a minority 6.09% interest in Apicore throughan agreement signed in July 2014, Medicure increased its stake to60.0% on a fully-diluted basis through a US$33.25 million dealannounced in November last year (Generics bulletin, 25 November2016, page 3). Medicure’s majority stake was further increased inJuly – to approximately 98%, or 94% on a fully-diluted basis – througha US$24.5 million deal (Generics bulletin, 28 July 2017, page 3).

Albert Friesen, Medicure’s president and chief executive officer,said the firm would use proceeds to pay debt and associated pre-payment fees, as well as to pursue the acquisition of commercialcardiovascular products and advance the company’s pipeline. G

DIVESTMENTS

Medicure sells Apicore unit

Jean Coutu, the Canadian pharmacy group that includes the Pro Docgenerics subsidiary, has agreed to be acquired by local grocery anddrugstore giant Metro in a C$4.5 billion (US$3.6 billion) transaction.The C$24.50 per share deal – that was finalised following a letter ofintent signed by Jean Coutu and Metro in August, and is expected toclose in the first half of 2018 – will consist of consideration that is75% cash and 25% Metro common shares.

Following the closure of the deal, Metro’s existing pharmacydistribution and franchising activities will be combined with those ofthe Jean Coutu group, which will operate as a stand-alone division ofMetro with its own management team led by Jean Coutu’s currentpresident and chief executive officer, François Coutu.

The combined business will have an overall network of morethan 1,300 stores in Canada, with estimated proforma sales of C$15.9billion – of which a quarter stem from the pharmacy division –generating earnings before interest, tax, depreciation and amortisation(EBITDA) of around C$1.33 billion. Synergies of around C$75 millionare expected within three years.

“The strategic and commercial fit between the two companies andtheir retail networks represents an opportunity for continued growth,”said François Coutu. The move would “consolidate our position as theleading destination for professional services, health, beauty andwellness”, he insisted.

“Bringing together our two highly-respected and longstandingQuebec brands represents an exciting milestone in the history of theJean Coutu group,” said group chairman Jean Coutu. “I am confidentthat this combination will ensure the safeguard of our entrepreneurialvision... as well as enable us to pursue our growth plan”. G

MERGERS & ACQUISITIONS

Canada’s Jean Coutuis acquired by Metro

Beximco Pharmaceuticals is set to acquire an 85.2% majority stakein Nuvista Pharma for an undisclosed fee, after entering into anon-binding memorandum of understanding with the hormone andsteroid drug specialist. The proposed acquisition – which is subject todue diligence, negotiation and a definitive sales and purchase agreement –is due for completion by the end of December.

Fellow Bangladeshi firm Nuvista – formerly part of Organon –has a local branded pharmaceuticals manufacturing facility in Tongi,Dhaka, and also has a “long-term manufacturing and marketingcollaboration with Merck Sharp & Dohme (MSD)”.

Due to the terms of the deal, Beximco reiterated that there was “noguarantee that the proposed acquisition will complete at this stage”.However, it said that if finalised, the acquisition was likely to be a“substantial transaction” to be satisfied in cash, and would “acceleraterevenue growth and improve the earning potential for Beximco”.

“We believe that this proposed acquisition, whilst relatively smallcompared to Beximco Pharma, will serve as a strong foundation forsustainable growth in the future, as well as being the first in ourcompany’s history,” said managing director Nazmul Hassan. “In ourview, Nuvista is a good strategic fit for Beximco Pharma as their strongposition in hormones and steroids, with a unique portfolio of 50generics, complements our existing product range.” G

MERGERS & ACQUISITIONS

Beximco will controlBangladesh’s Nuvista

Dasan E&T has received a warning letter from the US Food andDrug Administration (FDA) for its Gimpo finished-dose formulationsfacility in Kyonggi-do, South Korea, following an inspection by theagency in January.

According to the FDA, Dasan released products – including anundisclosed cream lot – “without testing each active ingredient foridentity and strength”. In response, the company told the regulator itwould “test the…labelling ingredients and [drug] content in the finalproduct test”. But this response was “inadequate”, the agency decided,as “the procedure you provided lacks specific details”.

Furthermore, Dasan did not validate manufacturing processes foran undisclosed drug or perform qualification studies, and lacked anongoing programme for monitoring process control. The company also“failed to demonstrate that the microbial limits test method is suitableto detect micro-organisms in the presence of your drug product”.

“Your firm failed to analyse glycerin raw material from yoursupplier prior to the quality unit releasing the glycerin for use in drugproduct manufacturing,” the FDA added.

Noting that glycerin was “an ingredient in multiple drug products”manufactured by Dasan, the agency said the firm “did not test each lotto determine if diethylene glycol (DEG) or ethylene glycol (EG) waspresent”. DEG contamination, the FDA pointed out, had “resulted invarious lethal poisoning incidents” worldwide.

Moreover, referring to Dasan’s initial response in February, theFDA said the company had “submitted a number of inadequateprocedures” to the agency. “None of these procedures had sufficientdocumentation control and oversight,” the FDA wrote, citing a lack ofdates, version control numbers, and evidence of quality-control unitreview and approval. G

MANUFACTURING

Dasan is hit by FDA warning

4 GENERICS bulletin 13 October 2017

COMPANY NEWS

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Issue 326 l 13 October 2017

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Russian biologics developer Biocad lacks standing to bring anantitrust complaint against Roche in the US, a New York districtjudge has ruled. Biocad had sued Roche in June last year, alleging ahost of anti-competitive conduct that was intended to prevent the Russianfirm entering the US market with oncology biosimilars (Genericsbulletin, 24 June 2016, page 11).

According to Biocad’s complaint, Roche acted illegally in Russiaby: engaging in “predatory pricing” by cutting prices by between72% and 84%; selling products at a loss through local distributorR-Pharm; bribing doctors and pharmacists; limiting access to samplesneeded to develop biosimilars; bundling Herceptin (trastuzumab) withPerjeta (pertuzumab); misrepresenting the availability of Avastin(bevacizumab) in Russia; and packaging Herceptin so that much ofthe drug was discarded.

But New York District Judge Richard Sullivan found that Biocadhad “failed to plead an antitrust injury, because the foreign locus of[its] claims place them outside the reach of US antitrust law”. Thealleged practices that had caused Biocad harm had almost entirelytaken place outside of the US, he pointed out.

Sullivan was also unmoved by Biocad’s insistence that it waspreparing to offer biosimilar rivals to Avastin, Herceptin and Rituxan(rituximab) in the US, having opened a US subsidiary and taken stepstowards meeting US Food and Drug Administration (FDA) standardsfor current good manufacturing practice (cGMP).

“Plaintiff [Biocad] has not merely failed to allege that it filed forFDA approval – it has failed to supply any facts whatsoever regardingthe FDA approval process for its biosimilars,” Sullivan objected. “Theplaintiff makes no allegation that any of [Roche’s] anti-competitiveconduct has prevented it from applying for FDA approval, and in factprovides no explanation for its failure to take any steps toward applyingfor FDA approval to sell its biosimilars in the US.”

In particular, Biocad had failed to provide information about“whether it has begun conducting clinical trials, its expected FDAapplication date, whether it has begun preparing an application, whetherit has contacted the FDA [and] whether it has ever obtained approvalfor other biosimilar drugs from the FDA”.

Sullivan added that closing Biocad’s case had not affected Roche’smotion to apply sanctions against the Russian firm (Generics bulletin,24 March 2017, page 11). G

BUSINESS STRATEGY

Biocad falls short inUS antitrust dispute

ONCOBIOLOGICS has received written notification from the USNasdaq stock exchange that the pure-play biosimilars developer is“not in compliance with the rules for continued listing”, as it didnot hold an annual meeting of shareholders within 12 months of thecompany’s fiscal year end. “The company will have 45 calendardays from the date of the notification to submit a plan to regaincompliance, and if Nasdaq accepts, Nasdaq can grant an exceptionof up to 180 calendar days from fiscal year end, or until 29 March2018 to regain compliance,” Oncobiologics noted. “If Nasdaq doesnot accept the company’s plan, the company may…request a hearingto remain on the Nasdaq global market.” Oncobiologics was told byNasdaq in July that the firm did not meet the minimum US$50.0million market value of listed securities to maintain continuedlisting (Generics bulletin, 14 July 2017, page 4).

AVARA PHARMACEUTICAL SERVICES has entered a deal withAstraZeneca to acquire the UK brand company’s manufacturingand distribution facility in Reims, France. With this addition, Avarapointed out that it now had eight sites, including three in the US andseparate sites in Puerto Rico, the UK, Ireland and Italy. Chairmanand chief executive officer Timothy Tyson said the acquisition was“another important component of our strategic plan that furtherexpands our services” in contract development and manufacturing.

FOSUN PHARMA has completed its deal to acquire a majoritystake in Indian generic injectables specialist Gland Pharma. TheChinese company signed a definitive agreement last year for an86% stake in Gland for up to US$1.26 billion (Generics bulletin,5 August 2016, page 1), which was modified recently to a 74%shareholding (Generics bulletin, 22 September 2017, page 2). Inacquiring the majority stake, Fosun will pay “no more than US$1.09billion, including paying no more than US$25 million contingentconsideration for Gland’s enoxaparin sales in the US”.

SIEGFRIED says the RAG-Stiftung Beteiligungsgesellschaft nowholds a 9.8% stake in the Swiss bulk-drugs and finished-dose producer.The government-backed investment foundation has exercised anoption to covert a SFr60 million (US$61.2 million) bond issued in2015 into shares in the Swiss group. The conversion will be satisfiedout of the country’s treasury shares. Siegfried’s chief executiveofficer, Rudolf Hanko, said the move demonstrated the trust thatits “stable partner” had in the group’s future.

SHARON BIO-MEDICINE has secured a 90-day extension tocomplete an insolvency resolution process. G

IN BRIEF


MARKET NEWS

European conventions of applying the same international non-proprietary name (INN) to biosimilars as to their reference productsare superior to the “inconsistent naming decisions” and discriminatorysuffixes being employed in the US, according to the InternationalGeneric and Biosimilar medicines Association (IGBA).

In a slide deck posted on its website, the IGBA lays out its positionon regional developments in naming for biological therapies, includingbiosimilars, in the European Union (EU), the US, Canada and Australia.

“Tracking and tracing can be ensured with a proper identificationthrough product name and batch number,” the IGBA insists. Applyingsuffixes – such as through the World Health Organization’s (WHO’s)biological qualifier (BQ) scheme – is “not a viable option to improvepharmacovigilance activities”.

“The EU has implemented a thoughtful and successful system fortrack and trace of all medicines,” the global body commends. Adoptinga guideline to enhance pharmacovigilance by requiring the productname and batch number to be included in adverse event reporting, andin all product packaging throughout the supply chain, has enhancedpharmacovigilance, it observes.

“Data from the EudraVigilance database suggests continuousrobust levels of product identification of biologicals from clinicalpractice,” the IGBA continues. An ongoing European Medicines Agency(EMA) study of adverse-event reporting revealed an overall 95.5%identifiability of classes of biologics for which biosimilars have beenapproved, proving that biologics sharing the same INN was no barrierto effective pharmacovigilance.

By contrast, the guide on non-proprietary naming of biologicalproducts issued by the US Food and Drug Administration (FDA) earlythis year – which requires a random four-letter suffix to be added tothe INN or core name of all newly- and previously-licensed biologics(Generics bulletin, 20 January 2017, page 5) – had been appliedinconsistently. While all seven approved biosimilars had been givena four-letter suffix, not one of the 11 originator biologics approvedsince January 2017 had such a suffix.

“This can only be interpreted as discriminative towards biosimilarmedicines,” the IGBA objects, pointing out that such an “imbalance”between original and biosimilar medicines – both subject to stringentFDA approval standards – “cannot effectively ‘improve’ the USpharmacovigilance system”. “There is no data available that demonstratesthat added suffixes in the US will improve the US pharmacovigilancesystem,” the association stresses.

While Health Canada continues to use the same INN for biosimilarsand their reference products, the regulatory agency is following closelyglobal naming developments, including practices in the neighbouringUS, the IGBA notes. “As a priority for 2017/18,” it observes, “HealthCanada plans to consult with stakeholders on the development of adomestic naming policy.” Maintaining the status quo of employingthe same INN is set to be one of the options under consideration.

Responding to a similar naming consultation run by Australia’sTherapeutic Goods Administration (TGA), the IGBA recently suggestedimproving the status quo by making it mandatory to include productnames and batch numbers in both adverse-event reporting systemsand educational measures (Generics bulletin, 29 September 2017,page 6). Implementing a track-and-trace barcode along the lines ofthose to be used in the EU from February 2019 was supported, butonly with a transition period “of at least three years”. Gn [email protected]

REGULATORY AFFAIRS

Europe trumps US onnaming of biosimilars

Two draft guidance documents on abbreviated new drug application(ANDA) submissions have been published by the US Food andDrug Administration (FDA). One is a question-and-answer documenton refuse-to-receive (RTR) standards, and the other is a guide onamendments to ANDAs under the renewed Generic Drug User FeeAmendments (GDUFA II) programme.

As well as covering the ANDA filing process, the RTR standardsquestion-and-answer document also provides information on respondingto deficiencies and RTR determinations. Deficiencies relating to drugmaster file (DMF) reviews, product quality, bioequivalence and clinicalstudies, as well as general deficiencies, are tackled in the guidance.

The guide on amendments under GDUFA II covers minor andmajor amendment categories, and explains how adjustments to ANDAand prior approval supplement (PAS) submissions may affect anapplication’s review goal dates. The document also describes how theFDA should review amendments submitted to ANDAs and PASs receivedprior to 1 October 2017, the GDUFA II review goals’ effective date.

Meanwhile, the FDA has also published updates to two finalguidances to “reflect GDUFA II commitments and performance goals”.A final version of ‘ANDA submissions – prior approval supplementsunder GDUFA’ specifically explains how the GDUFA II performancereview goals apply to standard and priority PASs that require aninspection, ones for which an inspection is not required, and alsoPAS amendments. The guidance was finalised late last year (Genericsbulletin, 21 October 2016, page 7), following a draft documentpublished in 2014 (Generics bulletin, 8 August 2014, page 16).

A final guide on ‘Completeness assessments for type II activepharmaceutical ingredients (API) DMFs under GDUFA II’ publishedin February 2016 (Generics bulletin, 19 February 2016, page 10) hasalso been updated to reflect GDUFA II’s goal of the FDA reviewing90% of Type II DMFs with 60 days of receipt of fee payment.

Separately, the FDA has published two new manuals of policiesand procedures (MAPPs) entitled ‘Receiving and processing a requestfor voluntary withdrawal of an approved ANDA’ and ‘CommunicatingANDA review status updates with industry’. The first outlinesinformation on the receipt, review and processing of a withdrawalrequest submitted by an ANDA holder to the FDA’s Office of GenericDrugs (OGD), while the second addresses issues such as informationrequests and mid-review cycle meetings.

These follow two draft guidances recently released by the FDA oncomplex generics (Generics bulletin, 6 October 2017, page 1). Adocument providing information on formal meetings between the FDAand ANDA applicants aims to “allow for more efficient generic drugdevelopment, review and approval pathways” through “enhancedcommunication”. A second guide helps applicants determine whensubmitting ANDAs for peptides would be appropriate, covering fivemolecules: glucagon, liraglutide, nesiritide, teriparatide and teduglutide.

Revealing that the FDA would soon release “other importantpolicies aimed at spurring competition to generic drugs”, CommissionerScott Gottlieb insisted that “better guidance isn’t the only answer”.“Some drugs lack generic competition because they cannot be measuredthrough traditional in vivo bioequivalence methods, and there’s noefficient and convincing bioequivalence test method available,” hestated. Such products would require “more extensive clinical-endpointtesting”, he pointed out, which would be “burdensome and discouragegeneric product development”. Gn [email protected]

REGULATORY AFFAIRS

FDA issues guidancein line with GDUFA II


MARKET NEWS

Interested parties have until 20 October to comment on proposals tointroduce six-month paediatric extensions to supplementary protectioncertificates (SPCs) in Switzerland.

A proposed amendment to Switzerland’s patents act that has beenapproved by the Swiss parliament foresees both six-month extensionsto SPCs that have already been granted and new standalone paediatricSPCs that are linked directly to the terms of a patent and are also validfor six months. The Swiss confederation noted that the plannedpaediatric SPC – which is only available where no standard SPC hasbeen granted – was a “newly created protective right that does notexist in other countries”.

“There are major gaps in provision in the area of medicines forchildren,” the confederations justice and police department maintained.“To encourage research and development into medicines that aretested and licensed especially for children, the patents act is to beamended within the framework of a revision of healthcare legislation.”

However, the date of its entry into force through the revision toSwitzerland’s Therapeutic Products Act has not yet been determined.

To qualify for a paediatric extension, applicants will have toconduct clinical studies in children that comply with a paediatricinvestigation plan (PIP). The results of such studies will have to bemade public in information on the authorised medicine. The deadlinefor applying for such extensions will be no later than six months afterthe first authorisation in the European Economic Area (EEA).

Draft legislation allows any person to apply to the country’s federalinstitute of intellectual property, the IGE, for a paediatric extensionto be revoked. Only one standalone paediatric extension is permittedper product, but multiple patent holders may apply. Fees are payablefor both forms of paediatric extension.

Discussions on following the European Union’s (EU’s) exampleon offering paediatric extensions in Switzerland started several yearsago. In March last year, the country’s parliament included changesto the patents act in its planned revision of the Therapeutic ProductsAct, and instructed the IGE to draw up the necessary implementingorders. A consultation on the plans was launched in late June this year,covering the Swiss cantons, political parties, intellectual-propertybodies and industry associations. G

INTELLECTUAL PROPERTY

Switzerland seekinginput on extensions

The US Association for Accessible Medicines (AAM) has appealedagainst a ruling by a Maryland district court that a local law intendedto combat “price-gouging” for off-patent drugs can come into effect.

Through its appeal to the US Court of Appeals for the FourthCircuit, the AAM is attempting to overturn a denial by MarylandDistrict Judge Marvin Garbis of a preliminary injunction to halt theimplementation of Maryland House Bill HB631 with effect from 1October (Generics bulletin, 14 July 2017, page 7).

While Garvis dismissed the AAM’s argument that HB631 violateda ‘dormant commerce clause’ by discriminating against interstate trade,he found that the association had “presented a plausible claim” thatthe law was impermissibly vague in defining price-gouging as “anunconscionable increase” in price that is “excessive” and “not justified”.Thus, he said, the vagueness challenge could proceed. G

PRICING & REIMBURSEMENT

AAM appeals on Maryland law

REGULATORY AFFAIRS

No more benefit seenfor switching studies

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Figure 1: Share of etanercept market enjoyed by Benepali in Denmark, Norwayand Sweden between March 2016 and August 2017 (Source – Steinar Madsen)

Further switching studies for biosimilars are “unnecessary”, medicaldirector of the Norwegian Medicines Agency Steinar Madsen hasinsisted. Addressing delegates to SMI’s 8th annual conference onBiosimilars and Biobetters 2017, held in London, UK, at the endof September, Madsen noted that previous studies had shown thatswitching was “safe in the following situations: from originator tobiosimilar; from biosimilar to biosimilar based on the reference product;and from biosimilar to originator”. Further switching studies, hecontended, were “a waste of time and resources, because they are nevergoing to give any interesting results”.

In October 2016, Norway’s Nor-Switch study concluded thatswitching from Janssen’s Remicade (infliximab) to Celltrion’s ‘CT-P13’Inflectra biosimilar was not inferior to continued treatment with Remicade(Generics bulletin, 21 October 2016, page 1). Data from 481 patientstreated at 40 centres and followed for 52 weeks showed similar outcomes,using disease-worsening as the primary endpoint.

Examining biosimilar market shares in Scandinavia, Madsenpointed out that biosimilar infliximab in Norway had captured 75.7% ofthe market 18 months after launch, while in Denmark it had hit 97.2%at the 17-month mark, after reaching 90% just five months after launch.Meanwhile, infliximab in Sweden had captured just over a third ofthe market, or 36.5%, after 17 months.

Turning to etanercept, Madsen noted that Biogen’s Benepalialternative to Pfizer’s Enbrel had by August this year taken over four-fifths of the market – 84.9% – in Norway, 18 months after launch. Thiswas just behind the “extremely efficient” Denmark, which accountedfor 87.1% after 17 months (see Figure 1). Meanwhile, Madsen saidthat market share in Sweden, at 72.1% after 18 months, was “improving”.

Biosimilar etanercept had not been launched in Finland, Madsencontended, because the country had “a system that is killing competition ”.

Moreover, Madsen maintained that biosimilar companies “musthave an aggressive price policy”, and stated that the purchasing system“should be based on competition, not regulation”. He also said nationaltenders were “efficient”, and proposed that “restrictions on retroactiveprice-matching and bundling should be in place”. Gn [email protected]


MARKET NEWS

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Ireland is failing to capitalise on savings available from biosimilars,especially Biogen’s Benepali (etanercept), according to the primary-care spokesperson of the Fianna Fáil opposition party, John Brassil.

During a questions to the Taoiseach session, Brassil asked whyIreland’s Health Services Executive (HSE) was directing doctors toprescribe Pfizer’s Enbrel reference brand when Biogen offered adiscount of C101 (US$118), or 11%, on a month’s supply, amountingto potential annual savings of nearly C17 million.

“There are 11 biosimilar drugs available in Ireland at the minute,and all are on the non-interchangeable list, meaning that doctors andconsultants cannot decide to prescribe them,” asserted Brassil, whois a community pharmacist by profession. “A simple change in policywould radically cut the cost to the HSE.”

A consultation period on developing a national biosimilars policyhas just closed (Generics bulletin, 6 October 2017, page 6). Aconsultation paper invited views on both physician-led switching andpharmacist-led substitution for biological medicines, alongside otherpotential measures to increase biosimilar uptake (Generics bulletin,1 September 2017, page 19). However, originators’ body the IrishPharmaceutical Healthcare Association (IPHA) described pharmacist-led substitution as “neither needed nor appropriate”, as the decision onwhich biological drug a patient should be given should always be takenby the prescribing physician, in consultation with the patient. G

GOVERNMENT POLICIES

Ireland is missing outon etanercept savings

Barriers to generic and biosimilar market entry will be examinedduring a workshop on ‘Understanding competition in prescriptiondrug markets: entry and supply-chain dynamics’ that the US FederalTrade Commission (FTC) will host on 8 November in Washington DC.

Acting FTC chairman Maureen Ohlhausen and US Food and DrugAdministration (FDA) Commissioner Scott Gottlieb will give keynoteaddresses during the workshop, which will be free to attend, open tothe public and webcast live.

An initial session will “explore generic drug markets”, includingfactors that could preclude market entry after relevant patents haveexpired. “Panellists will discuss price and non-price factors that mayinfluence entry in these markets,” the FTC stated.

A second session will “evaluate intermediaries in the pharmaceuticalsupply chain”, particularly pharmacy benefit managers (PBMs) andgroup purchasing organisations (GPOs), as well as their contractualrelationships with manufacturers and insurance-plan sponsors.

Pointing out that generics had saved Americans more than US$1.67trillion over the past decade (Generics bulletin, 16 June 2017, page 5),Ohlhausen said it was critical to address barriers to competition afterpatent expiry “in light of concerns about rising drug prices”. “One ofmy highest priorities as FDA Commissioner is to increase competitionin the market for prescription drugs and facilitate entry of lower-costalternatives, like generics,” commented Gottlieb. G

PRICING & REIMBURSEMENT

FTC hosts workshopover US competition


MARKET NEWS

24-26 Octobern CPhI Worldwide

Frankfurt, GermanyCPhI Worldwide is an exhibition and networking opportunity thatwill be preceded by the Pre-Connect Congress, which will look atthe latest developments in the pharma industry.

Contact: UBM Information. Tel: +31 207 08 1637.E-mail: [email protected]. Website: www.cphi.com.

25-27 Octobern 20th APIC/CEFIC API Conference

Berlin, GermanyThis conference will discuss the latest developments in the area ofGMP and regulatory compliance.

Contact: Concept Heidelberg. Tel: +49 6221 84 440.E-mail: [email protected]. Website: www.api-conference.org.

6-8 Novembern AAM Fall Technical Conference

Maryland, USAThis conference will cover regulatory issues with speakers fromthe industry and the US Food and Drug Administration.

Contact: AAM. Tel: +1 202 249 7100.E-mail: [email protected]. Website: www.accessiblemeds.org.

22 Novembern 1st Value Added Medicines Conference

Brussels, BelgiumThis is a new one-day conference organised by Medicines for Europe.The focus of the event is to look at the opportunities presented bymedicines that are repositioned, reformulated or combined.

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

27-28 Novembern euroPLX 65

London, UKThis meeting provides an opportunity to discuss and negotiateagreements, development, in-licensing and marketing, promotionand distribution.

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

EVENTS – October, November

24 October 2017 – Frankfurt, GermanyT: +44 1564 777 550 E: [email protected]

W: www.generics-bulletin.com

31 October – 1 Novembern World Biosimilar Congress Europe

Basel, SwitzerlandThis conference will look at issues including market accessstrategies, commercial challenges, follow-on biologics,regulatory guidelines, and biosimilar and biobetter development.

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

Spain’s biosimilars industry association, BioSim, has reached anagreement with local medical colleges body, Organización MédicaColegial (OMC), on developing jointly a training programme for doctors.

Sponsored by Biosim, the programme is to offer a “structured,didactic and eminently practical reference” for Spanish doctors onbiosimilars. An online ‘What physicians should know about biosimilars’course is aimed at being a “point of first reference” for doctors.

The two partners will also work on developing a conference thatwill cover “ethical and legal aspects” of biological medicines, with agoal of strengthening the existing consensus on factors affectingprescriptions of biological drugs.

Spanish generics industry association Aeseg marked the 20thanniversary of the first generic launch in the country by pointing outthat around 430 active ingredients in more than 8,000 presentations arenow available as generics in Spain. The cost of treating a patient withsimvastatin was 23-times lower now than 20 years ago, Aeseg noted. G

EDUCATIONAL CAMPAIGNS

Biosim strikes training deal

Reducing US patent litigation “may lead to larger cost savings inbiologic products”, according to a letter published in the Journalof the American Medical Association (JAMA). Entitled ‘Challengesto biosimilar substitution’, the letter is a response to a JAMA studyon ‘Obstacles to the adoption of biosimilars for chronic diseases’,which suggested that biosimilars were “unlikely to yield widelyexpected cost savings” (Generics bulletin, 12 May 2017, page 8).

Authors of the letter, academics Brian Chen, Tony Yang andCharles Bennett, pointed out that they agreed with the cost-savingsstatement made by Aaron Hakim and Joseph Ross, writers of theobstacles report. Proffering a potential explanation, Chen, Yang andBassett said: “The frequency and complexity of biosimilar-relatedpatent litigation have thus far resulted in too few marketed biosimilars.”

Noting that only two of the five biosimilars approved by the USFood and Drug Administration (FDA) were currently commerciallyavailable, the letter observed that launching two other biosimilars wouldrisk patent litigation and damages. “This lack of competition will likelyprevent substantial price decreases for biologics and biosimilars,”they stated. “Balancing intellectual-property protection against timelycommercial launches to increase price competition is important.”

Referring to the US Supreme Court’s decision in June to remove amandatory six-month launch notice after biosimilar approval (Genericsbulletin, 16 June 2017, page 1), the letter insisted that “if Congressadopted parts of the Hatch-Waxman Act, patent-dispute resolutioncould not be used to delay biosimilar market entry”.

In response, Hakim and Ross said: “We agree with the concernthat an ambiguous and convoluted patent-dispute resolution processcould unnecessarily delay market entry of biosimilars, thereby limitingprice competition and reducing biosimilar cost savings.” This “potentialobstacle”, they said, applied to all biosimilars, “whether they treatacute or chronic conditions”.

But in clarifying parts of the US Biologics Price Competition andInnovation Act (BPCIA), the Supreme Court’s decision “may amplifythe appeal of the biosimilar approval pathway for manufacturers”,Hakim and Ross believed. G

LITIGATION/INTELLECTUAL PROPERTY

JAMA letter says lesslawsuits to lift savings


MARKET NEWS

A£31.8 million (US$41.9 million) tender has been launched bythe European Medicines Agency (EMA) to recruit temporarystaff ahead of its relocation in the wake of the UK’s ‘Brexit’ decisionto leave the European Union (EU).

Spread across four years, the tender comprises six separatecontracting lots, with the contract for each lot to be signed “with amaximum of five companies”. Staff requirements include generaladministrative and maintenance staff; conference organisers; ITadministrators, developers and support staff; scientific administrativestaff; employees with a legal, auditing and policy background; andcommunication specialists. The values of each contracting lot rangefrom £1.3 million to £8.8 million, over the four years.

Tender bids – which must be submitted by 6 November aheadof being opened on 10 November – must be valid for a period ofnine months following the submission date.

The tender followed the publication by the EMA of a staff retentionsurvey that raised “serious concerns” over the agency’s relocation(Generics bulletin, 6 October 2017, page 9). It illustrated likely staffretention levels for each of the 19 cities bidding to host the agencyof between 6% and 81%, but did not identify which candidate citiescorresponded to which retention rates.

However, “in order to complete the picture and set the recordstraight”, the agency has now published in full the information itsubmitted to the European Commission in support of its assessmentof the 19 bids. The EMA said this decision came “following the recentpublication of isolated pieces of information circulating in the press”.

Two annexes published by the EMA evaluate the 19 bids. Thefirst annex relates to the technical assessment of the proposed buildingor buildings to house the EMA. The second consists of a reviewcarried out by the agency of information related to other criteria,including accessibility of the location, existence of adequate educationfacilities, appropriate access to the labour market, social security andmedical care, and business continuity (see Figure 1).

In evaluating the bids, the EMA assigned each city one of fourratings for each criterion. The highest rating was a determination thatmoving to the city would meet EMA requirements for a given criterion,and ensure that the agency is operational on time. The next-highestrating indicated that the city would meet EMA requirements but wouldraise concerns that the EMA would not be operational on time.

The two lower ratings indicate that the city only partially meetsEMA requirements and raises “major concerns” regarding EMAbusiness continuity; and that the city does not meet EMA requirementsand does not ensure EMA business continuity. Detailed commentson each city were provided within the annexes.

Four cities – Dublin, Ireland; Porto, Portugal; Vienna, Austria;and Warsaw, Poland – included multiple premises as part of theirbids, leading to some mixed verdicts, with different ratings for somecriteria applied to each of the individual premises.

Reflecting on the EMA’s comments on the member state bids,the agency’s deputy director Noël Wathion said “the accessibility ofthe new premises for delegates and experts, and staff retention, arekey to ensuring the agency remains operational and able to deliver onits mission after its relocation”. This needed to be supported by adequatepremises and facilities, he stressed.

Meanwhile, Yann Le Cam, patient representative on the EMAboard, said the decision where to locate the EMA as of March 2019“should not be based on what the EMA would bring to the new hostcountry, but on whether the new host country has what it takes topreserve the value the EMA brings to patients in the EU”. “The capacityof the new host city to retain current staff and attract new people at

the same level of quality is key for this.”The EMA’s board said that it had initiated an early discussion on

the implications for 2018’s draft budget and 2019’s preliminary draftbudget of “the challenges the EMA will face over the next few years”.“While no firm predictions can be made until the new location of theagency is known,” the EMA said – following a vote that is due totake place on 20 November – “the EMA is anticipating staff losseswhich will not only challenge the agency’s operability, but could alsoresult in a major deficit in its budget.”

“If operations are delayed or have to stop because of massivestaff losses, the agency could experience a dramatic drop in fee income,”the EMA acknowledged, “which would in turn result in reducedpayments to the national competent authorities.” Furthermore, “thefinancial consequences would be further exacerbated by the cost ofreplacing staff”, the EMA said, suggesting that “such shortfall wouldneed to be made up from the EU budget”. Gn [email protected]

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Figure 1: Selected criteria evaluated by the EMA for each of the 19 cities biddingto host the agency (Source – EMA)

REGULATORY AFFAIRS

EMA seeks temporary staff ahead of move


MARKET NEWS

The number of final approvals for abbreviated new drug applications(ANDAs) issued by the Office of Generic Drugs (OGD) withinthe US Food and Drug Administration (FDA) increased by just over17% in its 2017 financial year ended September 2017 to 763 approvals.

An average of just over two ANDA approvals every day resultedin at least 50 approvals per month, with a high point of 88 authorisationsachieved in June 2017.

The OGD approved 112 more ANDAs in the 12 months toSeptember 2017 than it did in its 2016 financial year ended September2016 (Generics bulletin, 11 November 2016, page 10). However, thenumber of tentative approvals granted slipped by 10 to 174. The totalof complete responses issued by the OGD was also lower, at 1,603versus 1,725 in the previous 12-month period.

As Figure 1 shows, the OGD gradually picked up the pace of bothfinal and tentative ANDA approvals during the five-year scope of thefirst iteration of the Generic Drug User Fee Amendments (GDUFAI) that began on 1 October 2012. During that period, the OGD hasrestructured and hired more staff, including ANDA reviewers.

While the FDA has not yet revealed its annual data for the numberof ANDAs withdrawn or subject to ‘refuse to receive’ (RTR) notifications,both metrics look likely to fall, based on data covering the first 11 monthsof the 2017 financial year.

However, while the OGD has stepped up the speed of its approvals,its workload has increased at an even faster pace. Having received852 ANDAs in its 2016 financial year ended September 2016, theOGD experienced a 52% leap in receipts in the 12 months endedSeptember 2017 as 1,292 ANDAs were filed.

Those submissions also tended to come in spurts, with four months –October and December 2016, as well as March and September 2017 –producing three-digit numbers of ANDA filings. Indeed, Septemberthis year saw a mammoth 202 submissions, presumably as companiesrushed to get their dossiers into the OGD before ANDA filing feesclimbed by more than US$100,000 to US$171,823 under the seconditeration of GDUFA that kicked in from 1 October this year (Genericsbulletin, 8 September 2017, page 9).

The September 2017 number of ANDA filings was the highestseen since an enormous wave of 635 in June 2014, ahead of stricterstability requirements being implemented by the FDA. Gn [email protected]

REGULATORY AFFAIRS

OGD raises approvalrate by 17% in FY17

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Figure 1: The number of final and tentative abbreviated new drug application (ANDA)approvals granted by the Office of Generic Drugs within the US Food and DrugAdministration in its financial years ended September 2013 to 2017 (Source – FDA)

NHS – the UK’s National Health Service – says it has saved£130 million (US$171 million) over three years by implementingelectronic prescriptions that allow general practitioners to sendprescriptions directly to pharmacies. Furthermore, by cutting thetime and frequency needed to dispense and collect prescriptions, theelectronic system has saved prescribers £327 million, dispensersnearly £60 million and patients almost £75 million.

INDIA’S GOVERNMENT has, for the first time, published apharmacovigilance guidance for marketing-authorisation holders.Six modules cover: pharmacovigilance system master files; collection,processing and reporting of individual case-safety reports; preparingand submitting periodic safety update reports; quality-managementsystems; audits and inspections; and submitting risk-management plans.

THE EUROPEAN COMMISSION has adopted two legal acts on goodmanufacturing practice (GMP). The first, Commission Directive2017/1572, is an implementing directive that sets out GMP principlesand guidelines where manufacturing or import is subject to amanufacturing or import. The second is a delegated regulation coveringGMP and inspections for investigational medicines.

CASE STUDIES of acyclovir and metronidazole will feature duringa workshop on developing topical dermatological generics that theUS Food and Drug Administration (FDA) is hosting on 20 October.Other issues covered during the workshop at the agency’s WhiteOak campus include in vivo dermal open-flow microperfusion andin vitro bioequivalence data.

US SENATOR Claire McCaskill has introduced a bill, S.1948, toabrogate the sovereign immunity of Native American tribes as adefence in inter partes reviews of patents. Allergan recently transferredits patent rights in Restasis (ciclosporin) ophthalmic emulsion tothe Saint Regis Mohawk Tribe, thereby potentially exempting thepatents from inter partes review by the US Patent and TrademarkOffice (Generics bulletin, 6 October 2017, page 17).

INTERPOL says it seized “25 million illicit and counterfeit medicines”worth more than US$51 million and made around 400 arreststhrough the latest wave of its international Operation Pangeaanti-counterfeiting initiative.

ABPI – the Association of the British Pharmaceutical Industry –has decided not to appeal against an administrative court ruling thatdenied a judicial review of new rules on evaluating and fundingmedicines. The brand body had sought a review of plans by the UK’sNational Institute for Health and Care Excellence (NICE) for a £20million (US$26 million) budget cap on new medicines (Genericsbulletin, 28 July 2017, page 13).

IRAN, MEXICO AND TURKEY – through their respective IFDA,Cofepris and TMMDA regulatory agencies – will from 1 January2018 accede to the Pharmaceutical Inspection Co-operationScheme (PIC/S). Regulatory agencies from Russia and Saudi Arabiahave applied for PIC/S pre-accession.

LEADING US GENERICS PLAYERS have succeeded in dismissinga price-fixing lawsuit brought by a health insurance plan in aPennsylvania district court. Judge Anita Brody dismissed claimsthat the companies had deliberately inflated their average wholesaleprices (AWPs), finding that the Plumbers health plan had no groundsto allege negligent misrepresentation, unfair trade practices andunjust enrichment. G

IN BRIEF


Advertorial Feature

The second iteration of the Generic Drug User Fee Amendments(“GDUFA II), which is contained in Title III of the FDA ReauthorizationAct of 2017 (“FDARA”) (S. 934 and H.R. 2430) currently pendingin Congress, will, if enacted, significantly change the current userfee system and structure that have been in place the past five fiscalyears under GDUFA I. Not only will FDA collect a greater amountof user fee funding each year ($493.6 million annually adjusted

for inflation), but one fee type will be eliminated (i.e. the PriorApproval Supplement fee), while others fees would be modified(e.g. a new Finished Dosage Form (“FDF”) facility fee for ContractManufacturing Organizations (“CMO”)). GDUFA II will alsointroduce a new fee type – the ANDA Holder Program Fee – thatwill account for 35% of annual fee funding. The annual ANDAHolder Program Fee, along with the annual CMO FDF facility fee,are proposed as “small business considerations,” according to FDA.

Under the GDUFA II fee structure, the ANDA Holder ProgramFee is set up as follows: a firm and its affiliates will pay one programfee each fiscal year commensurate with the number of approvedANDAs (both active and discontinued ANDAs) that the firm andits affiliates collectively own. The program fee to be paid each yeardepends on the number of ANDAs owned. Firms will not pay aper-ANDA fee. Instead, the program fee will be split into threetiers that represent different positions held by the firms and theiraffiliates within the market. Specifically, FDARA would amend theFDC Act to add Section § 744B(b)(2)(E) to state:

(i) Thirty-five percent shall be derived from fees under subsection(a)(5) (relating to generic drug applicant program fees). For purposesof this subparagraph, if a person has affiliates, a single program feeshall be assessed with respect to that person, including its affiliates,and may be paid by that person or any one of its affiliates. TheSecretary shall determine the fees as follows:

(I) If a person (including its affiliates) owns at least one but notmore than 5 approved [ANDAs] on the due date for the fee underthis subsection, the person (including its affiliates) shall be assesseda small business generic drug applicant program fee equal to one-tenth of the large size operation generic drug applicant program fee.

(II) If a person (including its affiliates) owns at least 6 but not morethan 19 approved [ANDAs] on the due date for the fee under thissubsection, the person (including its affiliates) shall be assessed a mediumsize operation generic drug applicant program fee equal to two-fifthsof the large size operation generic drug applicant program fee.

(III) If a person (including its affiliates) owns 20 or more approved[ANDAs] on the due date for the fee under this subsection, theperson (including its affiliates) shall be assessed a large size operationgeneric drug applicant program fee.

(ii) For purposes of this subparagraph, an [ANDA] shall be deemednot to be approved if the applicant has submitted a written requestfor withdrawal of approval of such [ANDA] by April 1 of theprevious fiscal year.

The statute (FDC Act 744B(g)(5)) would also be amended toinclude certain penalties for failure to pay the new ANDA HolderProgram Fee:

(A) IN GENERAL. – A person who fails to pay a fee as requiredunder subsection (a)(5) by the date that is 20 calendar days afterthe due date, as specified in subparagraph (D) of such subsection,shall be subject to the following:

(i) The Secretary shall place the person on a publicly available arrears list.

(ii) Any abbreviated new drug application submitted by the genericdrug applicant or an affiliate of such applicant shall not be received,within the meaning of section 505(j)(5)(A).

(iii) All drugs marketed pursuant to any abbreviated new drugapplication held by such applicant or an affiliate of such applicantshall be deemed misbranded under section 502(aa).

(B) APPLICATION OF PENALTIES. – The penalties undersubparagraph (A) shall apply until the fee required under subsection(a)(5) is paid.

The ANDA fee schedule for Fiscal Year 2018 was justpublished by FDA on August 28th. For a small or mediumsized firm, the annual ANDA Holder Program Fee is a decentamount of cash for some companies to lay out. And for thosecompanies with a modest number of ANDAs, they’ll be layingout cash for drug products that they don’t currently market,because their ANDAs are in stasis, as identified in theDiscontinued Drug Product List section of the Orange Book.

FDA will collect under the ANDA Holder Program Feeinitiative as follows - companies in the small tier (1-5 ANDAs)will pay $159,079; companies in the medium tier (6-19ANDAs) will pay $636,317; and companies in the large tier(> 20 ANDAs) will pay $1,590,792. For a small tier companythis can be a dramatic impact in their ability to even retainthe assets they worked so hard to obtain!

A new venture might offer some user fee relief and a solution tocompanies that have discontinued ANDAs for drug products notcurrently marketed. A company called ANDA Repository, LLC.([email protected]) is offering what we can only characterizeas “ANDA arbitrage.” Imagine, if you will, a parking lot. The owner ofa 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) thecar’s owner transfers title of the automobile to the parking lot owner.The old owner of the car can, with appropriate notice, take backownership when he decides that he wants to use the automobileagain. Provided the parking lot owner has enough cars, this can bea beneficial venture for all of the parties involved.

In the imagery above, the automobile owner is an ANDA sponsor,and the parking lot owner is ANDA Repository, LLC. When ANDARepository, LLC. obtains title to 20 or more ANDAs, thenthe company will be identified as a “large size operation” andwill pay a full generic drug applicant program fee regardlessof how many additional ANDAs are owned. In exchange forits services, ANDA Repository, LLC. will charge an ANDA sponsoran annual fee, which would be significantly less than the ANDAHolder Program Fee such ANDA sponsor would otherwise payas a small or medium size operation. Not a bad idea! Fees aredue by October 1st so please contact us at the email or phonebelow for more information.

ANDA Arbitrage & the New ANDA Holder Program Fee Under GDUFA IIBy Kurt R. Karst –

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


PRODUCT NEWS

Synthon’s generic rival to Copaxone (glatiramer) 40mg/ml has beenapproved in Europe via the decentralised procedure, marking theregion’s first approved equivalent to the thrice-weekly higher strengthof the multiple sclerosis drug. Synthon obtained approval for the20mg/ml strength in 2016 (Generics bulletin, 15 April 2016, page 1).

Noting that the approvals had been obtained in all 27 EuropeanUnion (EU)/European Economic Area (EEA) member states involvedin the procedures, Synthon said “granting of national marketingauthorisations will follow in the near future”.

Synthon recently celebrated the revocation by the European PatentOffice (EPO) of Teva’s European patent EP2,361,924, claiming anallegedly improved process for the synthesis of glatiramer acetate, thusclearing the way for the firm’s 20mg/ml generic (Generics bulletin,22 September 2017, page 11). However, at the time, a Tevaspokesperson emphasised to Generics bulletin that “Copaxone 40mgcontinues to be covered under separate patent[s]”.

Synthon was also partially successful in a recent attack on the Dutchpart of European dosing patent EP2,405,749. While a motion for adeclaratory judgement of invalidity was denied, patent owner Yeda –which licenses the patent to Teva – disclaimed the patent in theNetherlands (Generics bulletin, 6 October 2017, page 17).

Mylan – which has just launched both a 20mg/ml and 40mg/mlversions of glatiramer acetate in the US (see page 12) – is Synthon’sdistribution and supply partner, with exclusive rights in 17 territories.These include Belgium, Cyprus, Denmark and Finland, as well asFrance, Germany, Greece and Ireland. Also covered by Mylan’sexclusive distribution deal are Italy, Malta, the Netherlands, Norwayand Portugal, along with Spain, Sweden, Switzerland and the UK.

Alvogen also has marketing rights for Synthon’s generic glatiramerin certain European countries. The Icelandic firm’s vice-president forcentral and eastern Europe, Hacho Hatchikian, said the approval was“another significant milestone for our company” that “reinforces ourproven capabilities in bringing complex and difficult-to-manufactureproducts to market ahead of the competition”. Alvogen markets itsglatiramer 20mg/ml under the brand name Remurel, which will alsobe used for the 40mg/ml strength. G

MULTIPLE SCLEROSIS DRUGS

Synthon has EU nodfor glatiramer 40mg

The largest generics companies in the world are among thosecontinuing to be frustrated in their endeavours to bring a genericversion of Eli Lilly’s Alimta (pemetrexed disodium) injectable to theUS market ahead of patent expiry in May 2022.

The Patent Trial and Appeal Board (PTAB) within the US Patentand Trademark Office (USPTO) has rejected challenges brought by amultitude of generics companies, including Teva, Sandoz and Mylan,against the originator’s US vitamin-dosing regimen patent, findingthat the firms had failed to show “by a preponderance of the evidence”that 22 claims of the patent were invalid as unpatentable.

In total 19 petitioners had sought to obtain an unpatentable decisionconcerning Lilly’s US patent 7,772,209, which expires on 24 May 2022,including a six-month period of paediatric exclusivity. The patent ismoreover the only remaining listed against the chemotherapy agentin the US Food and Drug Administration’s (FDA’s) Orange Book.

Inter partes review proceedings had been initiated by Sandoz andNeptune Generics, with twelve more petitioners eventually joiningSandoz’ petition and five more joining Neptune’s.

Novartis’ Sandoz was joined by two Apotex businesses, EmcurePharmaceuticals and two of its Heritage Pharma operations, threeGlenmark businesses and Mylan, as well as Teva, Fresenius Kabi andWockhardt. Meanwhile, two Apotex businesses, as well as Teva, Kabiand Wockhardt, joined Neptune’s petition.

Both groups of petitioners had contended that claims 1-22 of the‘209 patent were rendered obvious by a collection of prior-artdocuments, but were unable to prove this allegation by a preponderanceof evidence before the PTAB. Lilly’s ‘209 patent specifically coversa method of administering pemetrexed with the requirement that aphysician co-administers vitamin B12, and instructs the patient toobtain and take folic acid to reduce the toxicity caused by pemetrexed.

The patent has also proven a stubborn hurdle for abbreviated newdrug application (ANDA) filers in US patent-litigation court proceedings.In early 2014, the patent survived an obviousness attack brought byKabi and Teva in an Indiana district court, before the same court thefollowing year found that Teva’s proposed generic product would alsoinduce infringement of the patent (Generics bulletin, 4 April 2014,page 11; 11 September 2015, page 18).

At the beginning of this year, a US Court of Appeals concludedthat neither decision had been reached in error concerning Teva’sproduct, following appeal proceedings launched by the Israeli firm(Generics bulletin, 20 January 2017, page 11).

Several companies, including Teva itself, Dr Reddy’s and Pfizer’sHospira, as well as Eagle Pharmaceuticals, are moreover developingalternative Alimta formulations through the FDA’s 505(b)(2) hybridnew drug application (NDA) pathway. Eagle has a target action dateunder the US Prescription Drug User Fee Act (PDUFA) for its‘differentiated’ product later this month, on 30 October (see page 22).

Decreased demand driven by competitive pressure led sales ofAlimta in the US to fall by 9% to US$502 million in the first sixmonths of this year, while global sales slid by 13% to US$1.02 billiondriven by factors including a “loss of exclusivity in several countries”.In July, the UK’s Supreme Court found that Actavis’ Armisarte(pemetrexed diacid) – launched at risk two years ago – directly andindirectly infringe the French, Italian, Spanish and UK designationsof a Lilly European patent that expires in June 2021 (Genericsbulletin, 14 July 2017, page 1). Gn [email protected]

ONCOLOGY DRUGS

Lilly’s Alimta patentwithstands challenge

Saudi Arabia’s Tabuk Pharmaceutical Manufacturing is allying withSelectchemie to market the Swiss firm’s caspofungin antifungalinjectable in markets including the Middle East and North Africa (MENA).

Under the firms’ agreement, Selectchemie has granted Tabuk alicence to register, market and sell the antifungal in Saudi Arabia, theGulf countries, North Africa and the rest of the Middle East.

“We are excited about this major partnership collaboration withSelectchemie,” commented Tabuk’s senior vice-president of businessdevelopment, Rana Azzam. “Caspofungin [for] injection is a hard-to-develop and lifesaving product. This partnership will provide anopportunity for both companies to leverage their combined strength.”

Tabuk’s agreement comes shortly after it agreed to sell to Acinothree currently-marketed cardiovascular products in Saudi Arabia, theGulf countries and the MENA region, excluding Morocco, Sudanand Algeria (Generics bulletin, 6 October 2017, page 4). G

ANTIFUNGALS

Tabuk signs caspofungin deal


PRODUCT NEWS

Breckenridge Pharmaceutical has acquired from Nostrum Laboratoriesfive US abbreviated new drug applications (ANDAs), with a total“generic market value” of US$305 million, according to Breckenridge,which cited QuintilesIMS data from July.

Three of the ANDAs have already been approved by the US Foodand Drug Administration (FDA) and are central nervous system productsindicated for the treatment of attention deficit disorders and narcolepsyattention deficit disorders in “various dosage forms”. Breckenridgewill sell these products under the privately-held firm’s own label.

Noting that the remaining two ANDAs were filed and pendingwith the FDA, Breckenridge stated that these products had anticipatedapproval dates “within the next 12 months”. “The parties have enteredinto a separate agreement whereby Nostrum will remain the exclusivemanufacturer for certain assets,” Breckenridge added, although nofurther details were given.

Privately-owned distributor Breckenridge recently entered intoan agreement with Canada’s Impopharma to exclusively market inthe US an undisclosed “generic version of a leading corticosteroidproduct with sales in excess of US$25 million” (Generics bulletin,6 October 2017, page 16). And earlier this year, Breckenridge strucka deal with South Korea’s Sam Chun Dang Pharm (SCD) to developand market at least seven ANDAs in the US (Generics bulletin, 7July 2017, page 13). G

CENTRAL NERVOUS SYSTEM DRUGS

Breckenridge obtainsfive Nostrum ANDAs

Celltrion has convinced a court in the Netherlands to declare thelocal part of European method-of-use patent EP1,951,304 as lackingnovelty in light of prior art. Entitled ‘Method for treating joint damage’,the ‘304 patent covers methods for using rituximab to treat rheumatoidarthritis in specific patient populations. It was granted in October2014, having been filed on 14 November 2006 by Roche and Biogen,and claims priority from two US patents with filing dates of 15November 2005 and 6 November 2006 respectively.

Citing as prior art a Keystone study presented during a EuropeanLeague against Rheumatism (Eular) congress held on 21 June 2006,Celltrion successfully argued that the patent was not entitled to prioritybecause the patent’s inventors had not effectively transferred their priorityrights to Roche and Biogen under terms of an ‘employee proprietaryinformation and inventions and dispute-resolution agreement’.

Having ruled out an automatic transfer of priority rights that werenot specifically covered by the agreement, the court found that theappropriate priority date for the ‘304 patent was 6 November 2006,thereby rendering the Keystone reference novelty-destroying prior art.

In reaching its decision, the court in The Hague took note ofopposition procedures against the ‘304 patent pending before theEuropean Patent Office (EPO) – with oral arguments scheduled for27 June 2018 – as well as similar actions that were underway inGermany, Ireland, Italy and the UK. G

ARTHRITIS DRUGS

Netherlands revokesrituximab use patent


PRODUCT NEWS

Mylan could face “significant damages” following its launch of aUS rival to Teva’s Copaxone (glatiramer acetate) 40mg/ml, theIsraeli firm has warned. At the same time, Mylan launched a genericversion of the 20mg/ml strength of the multiple sclerosis drug, followingUS Food and Drug Administration (FDA) approval (Generics bulletin,6 October 2017, page 1).

“Any launch by Mylan of a generic version of Copaxone 40mg/mlprior to final resolution of the pending patent appeals and other patentlitigation should be considered an ‘at-risk’ launch,” Teva insisted, “whichcould subject Mylan to significant damages among other remedies.”

Two Teva appeals over Copaxone 40mg/ml are pending beforethe US Court of Appeals for the Federal Circuit. In the first, Teva isappealing against an inter partes review finding from just over a yearago that all claims of three Copaxone patents – US patents 8,232,250,8,399,413 and 8,969,302 – were unpatentable (Generics bulletin, 9September 2016, page 16). In the second appeal, Teva is appealing aDelaware district court ruling from early this year in which certainclaims of four Copaxone patents – the ‘250, ‘413 and ‘302 patentsas well as US patent 9,155,776 – were declared invalid for obviousness(Generics bulletin, 3 February 2017, page 1).

“The two appeals have been fully briefed and await the schedulingof oral arguments,” Teva pointed out. Moreover, “in additional litigation,Teva has brought suit against five abbreviated new drug application(ANDA) filers, including Mylan, for infringement of a patent coveringa manufacturing process for glatiramer acetate”, referring to USpatent 9,155,775 (Generics bulletin, 27 January 2017, page 9).

“We have planned for the eventual introduction of a genericcompetitor to glatiramer acetate,” observed Yitzhak Peterburg, Teva’sinterim president and chief executive officer. Peterburg – who is dueimminently to be replaced on a permanent basis by Kåre Schultz(Generics bulletin, 15 September 2017, page 1) – said Teva was“confident in patient and physician loyalty to Copaxone due to itsrecognised efficacy, safety and tolerability profile”.

Pledging to “continue to support the product”, Peterburg said that“as we are closing the third quarter, it is too soon to officially commenton any change to our full-year business outlook”. Further details ofthe financial impact of Mylan’s glatiramer launches would be providedin early November, Teva promised.

Citing annual US Copaxone 40mg/ml sales of US$3.64 billion,Mylan chief executive Heather Bresch said the launch was a “significantmilestone” for the firm that reinforced its “proven capabilities inbringing complex and difficult-to manufacture products to market”.The company’s application included “rigorous side-by-side analyses,including characterisation data”, while the firm has also launched a‘Mylan MS Advocate’ patient-support service to assist multiplesclerosis sufferers treated with Mylan’s glatiramer product.

As one of the first paragraph IV filers on the 40mg strength, Mylansaid it “may be eligible for 180 days of generic drug exclusivity”, althoughit acknowledged that “the FDA has not made a formal determinationon exclusivity at this time”.

Copaxone 20mg/ml had annual US brand sales of US$700 million,Mylan noted. The lower strength already faces competition from Sandozand Momenta’s Glatopa 20mg. However, Sandoz and Momenta were toldearlier this year that their 40mg version cannot be approved untildeficiencies are resolved at a US plant operated by fill-finish manufacturingpartner Pfizer (Generics bulletin, 24 February 2017, page 1). Gn [email protected]

MULTIPLE SCLEROSIS DRUGS

Teva warns Mylan ofglatiramer damages

JCR PHARMACEUTICALS – the Japanese recombinant DNAspecialist – has submitted to the country’s Ministry of Health, Welfareand Labour an application for marketing approval for the firm’sJR-051 proposed biosimilar version of Sanofi’s Fabrazyme(agalsidase beta), which is used to treat Fabry disease. “The clinicalpharmacokinetics study conducted in February 2015 demonstratedbioequivalence of JR-051,” JCR commented, “and the Phase II/IIIclinical trial with Fabry patients initiated in May 2015 generatedresults that demonstrated equivalence in efficacy and safety of JR-051compared with the innovator product.”

LANNETT is “closing in on a record year for product approvals, with11 received thus far in calendar 2017”, according to chief executiveofficer, Arthur Bedrosian, after the firm obtained US Food andDrug Administration (FDA) approval for prescription-only and OTCformulations of lansoprazole delayed-release capsules. Lannettsaid it would launch the OTC lansoprazole alternative to Prevacid24HR “sometime in the future” through its Silarx business aspart of plans to develop a “fuller line of OTC products”. The USfirm has also recently picked up US approvals for oxycodone/acetaminophen 5mg/325mg and 10mg/325mg tablets, as well asfor dexmethylphenidate 2.5mg, 5mg and 10mg tablets.

INTAS PHARMACEUTICALS is aiming to make bevacizumabmore accessible to cancer patients in India after ‘bringing downthe cost’ of its version of Genentech’s Avastin by 60% comparedto the “currently available options” in the country. “Intas’ bevacizumabtherapy is priced at Rs39,995 ‘(US$611.34) for the dose strengthof a 400mg variant,” the Indian firm noted. “The drug has beenavailable in India since 2004 but the cost has been so prohibitivethat clinicians have been able to give this drug to very feweligible patients.”

EMA – the European Medicines Agency – is now reviewing threeapplications for biosimilar version of Amgen’s Neulasta (pegfilgrastim)after receiving one new application as of the beginning of October(see page 15), according to an update on applications for new humanmedicines under evaluation by the regulator’s committee for humanmedicinal products (CHMP). Meanwhile, the agency has also receivedan application for generic buprenorphine, the active ingredientin Indivior’s Subutex opioid-dependence treatment.

ARECOR – the therapeutic protein and peptide specialist – is set tolicense worldwide its ‘Arestat’ proprietary formulation technologyfor developing “differentiated biosimilars” to an undisclosed globalpharmaceutical and healthcare company after the latter exercised anoption. Under the terms of the agreement, Arecor will receive paymentson relevant development milestones and royalties on sales, in returnfor supplying its technology and expertise to develop “superiorformulations of certain biosimilar products”. “This is the first licenceconversion resulting from the multi-product research agreemententered into by both parties at the end of 2015,” Arecor noted.

CSPC PHARMACEUTICAL has together with two partners beensued by DSM Sinochem Pharmaceuticals (DSP) for allegedlyinfringing the Dutch part of the originator’s European patentEP1,610,766. The patent describes and claims amoxicillin trihydrate“having a low free water content and processes for the manufacturethereof”. “DSP seeks compensation for damages and a permanentinjunction to prevent the infringing manufacture, use, importationand sale of CSPC’s amoxicillin active pharmaceutical ingredient(API), and/or any drug product that utilises the active pharmaceutical,in the Netherlands,” the Dutch firm noted. G

IN BRIEF


PRODUCT NEWS

WINNER

The Medicines Patent Pool (MPP) has broadened its relationshipwith Gilead Sciences by signing a new licence with the originatorcovering the originator’s bictegravir that is currently pending approvalas part of a once-daily single-tablet HIV regimen.

The arrangement for bictegravir allows manufacturers to developand sell generic bictegravir-containing medicines in 116 low- andmiddle-income countries, “where more than 30 million people live withHIV”. This is contingent on Gilead obtaining a US approval for itsnovel bictegravir/emtricitabine/tenofovir alafenamide product, which thefirm submitted to the US Food and Drug Administration (FDA) in June.

“The new amendment permits manufacturers located in India,China and South Africa to manufacture bictegravir in such countries andsell products containing the compounds in 116 countries, including74 middle-income nations,” the MPP confirmed.

Meanwhile, the MPP and Gilead have expanded the geographicalscope of licences on other HIV medicines, enabling generic medicinescontaining tenofovir alafenamide, cobicistat and tenofovir disoproxilfumarate to be supplied to Belarus, the Philippines, Malaysia and Ukraine.

Having first allied in 2011, the MPP and Gilead said a series ofamendments to their initial partnership now meant it covered five Gileadcompounds – tenofovir disoproxil fumarate, elvitegravir, cobicistat,emtricitabine and tenofovir alafenamide – through agreements struckwith 13 generics companies. G

ANTIRETROVIRALS

MPP and Gilead addbictegravir to alliance

Cinfa Biotech has had its marketing authorisation application forB12019, its proposed biosimilar version of Amgen’s Neulasta(pegfilgrastim), accepted for review by the European Medicines Agency(EMA). The Spanish firm said that its B12019 application was supportedby a “comprehensive set of biosimilarity data from analytical, biofunctionaland clinical studies” comparing Cinfa’s biosimilar to Neulasta.

The data – which forms part of an EMA-advised clinicaldevelopment programme and includes a pivotal and a supportiveclinical study – was presented by Cinfa to the European Society forMedical Oncology (ESMO) 2017 Congress held in Madrid, Spain, inSeptember (Generics bulletin, 15 September 2017, page 14).

The pivotal clinical trial comprised a pharmacokinetic andpharmacodynamic study comparing B12019 against Neulasta in 172healthy volunteers, while the support study examined immunogenicityand pharmacodynamic comparability of Cinfa’s biosimilar and Amgen’soriginal product in 96 healthy volunteers. Positive data from the studieswere initially disclosed in July last year and May this year, respectively(Generics bulletin, 8 July 2016, page 11; 26 May 2017, page 12).

“We are pleased that the EMA has initiated the review of themarketing authorisation application of B12019,” stated Cinfa Biotechmanaging director Ruediger Jankowsky. Noting that the developmenttook “just four years”, he said this “confirms our highly efficientdevelopment approach”. G

CHEMOTHERAPY DRUGS

Cinfa’s pegfilgrastimfiling accepted in EU


PRICE WATCH.....UK

Figure 1 (above): Comparison between the periods 1-31 August 2017 and 1-30September 2017 of UK trade prices of the most recently-launched generics listed incategory M of the Drug Tariff of pharmacy-reimbursement prices. Averages calculatedfrom at least 34 data points. Figure 2 (top right) and Figure 3 (centre right): Biggestaverage trade-price changes between 1-31 August 2017 and 1-30 September 2017.Averages calculated from at least 17 data points. Figure 4 (bottom right): Ranking offastest-moving products subject to the most price offers made to independent UKpharmacists (one strength per ingredient; offers recorded by 30 September). Data forFigures 2, 3 and 4 from a basket of about 750 commonly-dispensed generics. Recently-launched products in Figure 1 excluded from Figures 2 and 3 (Source – WaveData).

Aripiprazole tabs 10mg 28 £0.78 ±0 £1.15 ±0Benzydamine 0.15% 300ml £4.85 +1 £5.46 +2Carbimazole tabs 5mg 100 £38.50 -1 £42.88 -3Celecoxib caps 200mg 30 £0.85 ±0 £1.32 +6Cilostazol tabs 100mg 56 £3.15 ±0 £3.68 +1Cyclizine tabs 50mg 100 £5.49 ±0 £7.26 +8Desogestrel tabs 75µg 84 £1.54 +19 £2.53 +18Duloxetine caps 30mg 28 £1.65 +42 £4.76 +72Entacapone tabs 200mg 30 £2.92 +9 £3.59 -2Eplerenone tabs 25mg 28 £3.56 ±0 £7.42 +63Escitalopram tabs 10mg 28 £0.37 ±6 £0.85 +12Frovatriptan tabs 2.5mg 6 £6.82 -7 £8.66 +2Memantine tabs 10mg 28 £0.59 +5 £1.07 +27Montelukast tabs 10mg 28 £0.75 ±0 £1.13 +10Nefopam tabs 30mg 90 £16.99 -4 £24.64 -2Nortriptyline tabs 10mg 100 £6.55 +3 £14.85 +6Pregabalin caps 150mg 56 £6.29 +88 £15.38 +3Rabeprazole tabs 10mg 28 £0.65 -3 £1.03 +26Raloxifene tabs 60mg 28 £2.26 +10 £2.90 +4Rasagiline tabs 1mg 28 £1.99 +262 £9.26 -10Rizatriptan tabs 10mg 3 £7.59 +1 £11.03 +12Sevelamer tabs 800mg 180 £22.99 -6 £30.64 +3Sildenafil tabs 100mg 4 £0.24 ±0 £0.43 +16Telmisartan tabs 80mg 28 £0.79 -9 £1.23 -1Zonisamide caps 100mg 56 £7.25 +1 £22.69 +5

Omeprazole caps 20mg 28 138 147 136Atorvastatin tabs 20mg 28 131 125 134Lansoprazole caps 30mg 28 138 130 122Sertraline tabs 50mg 28 128 113 120Simvastatin tabs 40mg 28 131 128 120Fluoxetine caps 20mg 30 127 103 112Bisoprolol fumarate tabs 2.5mg 28 116 103 109Simvastatin tabs 20mg 28 107 109 108Ramipril caps 2.5mg 28 119 104 107Paracetamol caplets 500mg 100 121 107 107

Chlorpromazine tabs 25mg 28 £1.62 +49 £26.29 +2,055Chlorpromazine tabs 50mg 28 £1.39 +30 £25.12 +1,910Chlorpromazine tabs 100mg 28 £1.65 +32 £26.31 +1,779Amlodipine tabs 5mg 28 £0.23 +53 £2.36 +1,080Amlodipine tabs 10mg 28 £0.27 +59 £2.35 +922Amiloride tabs 5mg 28 £0.42 ±0 £6.18 +636

Paracetamol tabs 500mg 100 £0.37 -8 £0.65 -43Quinapril tabs 20mg 28 £1.45 ±0 £2.72 -36Co-amilofruse tabs 5mg/40mg 28 £0.84 -6 £1.24 -33Quinapril tabs 40mg 28 £1.74 ±0 £3.11 -22Sumatriptan tabs 50mg 6 £12.95 -30 £19.57 -16Ferrous sulphate tabs 200mg 1,000£23.99 ±0 £39.85 -14

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

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

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