29 September 2017 Canada, Mexico and US unite over NAFTA goals P fizer’s Hospira has been ordered to pay Amgen US$70.0 million in damages after a US district court found that Hospira’s proposed epoetin alfa biosimilar infringed claims in a US patent shielding Epogen (epoetin alfa). Following a jury trial, Delaware District Court jurors found that Amgen had proven by a “preponderance of evidence” that Hospira’s biosimilar product infringed process claims 24 and 27 of US patent 5,856,298 when 21 batches of Hospira’s erythropoietin drug substance were manufactured over the course of 2013-2015. Hospira had denied the allegation, claiming that the lots were shielded by US ‘safe harbour’ provisions and the ‘298 patent claims were anticipated by, and obvious in light of, prior art. But jurors found that ‘safe harbour’ provisions did not protect 14 of Hospira’s erythropoietin batches concerning the ‘298 patent, and also that Hospira had not proven that the patent was invalid on either basis. However, jurors found, the originator failed to prove by the same standard that Hospira infringed any of seven cell or process claims of the other patent in suit, US patent 5,756,349, when Hospira manufactured 11 batches of erythropoietin between 2013 and 2015. G Hospira faces US EPO damages COMPANY NEWS 2 Fresenius Kabi starts Melrose Park project 2 Gufic plans to widen 2 horizons for exports Bristol and Reddy’s hamper UK sourcing 3 Rivopharm acquires in Europe from Teva 3 Teva adjusts its loans with 4 lenders’ support Walgreens Boots will purchase 5 for Rite Aid Catalent to buy Cook 5 in a US$950mn deal MARKET NEWS 6 Committee unable to predict 6 UPC start date Require batch numbers IGBA 6 advises Australia French doctors seek clarity on substitution 8 Canadian body wants improved incentives 8 AAM-backed report 9 reveals CMS savings Portugal sets 30-day price decision limit 9 Rituximab is setting records in Germany 10 IGBA to present case 10 during FDA workshop PRODUCT NEWS 12 Canada applies utility 12 ruling to Sprycel case Samsung Bioepis gets 13 adalimumab in Korea Pfizer accuses J&J of blocking US Inflectra 13 Amneal and Apotex are beaten on Livalo 14 Mylan links on HIV with Russia’s Rostec 15 FDA publishes guide on 15 judging similarity German oncologists should study process 16 Mylan and Aurobindo 16 sign price agreement Strides supplies Par with soft-gels in US 17 Australian order halts 17 Precedex alternative FEATURES 18 QuintilesIMS sees US savings 18 REGULARS Price Watch UK – Our regular listing 10 Events – Our regular listing 14 People – Lannett’s Bedrosian 20 to step down as chief Issue No.324 L eaders of groups representing the generics industry in Canada, Mexico and the US have united to set out their priorities for the renegotiation of the North American Free Trade Agreement (NAFTA) between the three signatories, in a letter to the chief NAFTA negotiators of all three countries. Jim Keon, president of the Canadian Generic Pharmaceutical Association (CGPA) stood alongside his counterpart Rafael Maciel Martinez at the Mexican Association of Generic Medicines (AMEGI) and Chip Davis, president and chief executive of the US Association for Accessible Medicines (AAM), in insisting that it is “essential that the balance between innovation and affordability of medicines is maintained”. “In particular”, the letter states, “we believe that including a new provision in NAFTA to mandate biologic drug exclusivity – above and beyond the protections already provided by voluminous patents – will harm the growing biosimilar industry which aims to provide price competition to the most expensive biological drugs and allow patients to benefit from affordable biologic medicines. Keon said the CGPA was “concerned by reports that the US plans to table extensive intellectual-property provisions in the NAFTA negotiations, including 12 years of data exclusivity for biologic drugs and further extensions of patent terms”. To enhance NAFTA’s intellectual-property framework, the letter urges, signatories should “require a research – Bolar – exception to facilitate timely access to generic and biosimilar competition once patents have expired”, thus allowing generics and biosimilars to be developed during the patent term. NAFTA should also “require patent transparency, such as the disclosure of the ‘best mode’ for carrying out an invention, as part of a patent application”, as well as introducing “a public registry for all patents and exclusivities granted to a drug”. And initial generic and biosimilar competition could be enhanced by “requiring an incentive to challenge patent and exclusivities for reference drugs and granting a reward to those that do so”. An updated NAFTA could also “streamline the regulatory process”, the letter suggests, through “regulatory harmonisation and recognition where appropriate”. In particular, the letter urges a mutual-recognition deal on inspections between Canada and the US similar to that reached between the US and European Union (Generics bulletin, 10 March 2017, page 1). Addressing regulatory approval backlogs for generics was also a priority, “with special emphasis on expediting the approval of first generics”. G
Transcript
29 September 2017
Canada, Mexico and USunite over NAFTA goals
Pfizer’s Hospira has been ordered to pay Amgen US$70.0 million in damages after a USdistrict court found that Hospira’s proposed epoetin alfa biosimilar infringed claims in a US
patent shielding Epogen (epoetin alfa). Following a jury trial, Delaware District Court jurorsfound that Amgen had proven by a “preponderance of evidence” that Hospira’s biosimilarproduct infringed process claims 24 and 27 of US patent 5,856,298 when 21 batches of Hospira’serythropoietin drug substance were manufactured over the course of 2013-2015.
Hospira had denied the allegation, claiming that the lots were shielded by US ‘safe harbour’provisions and the ‘298 patent claims were anticipated by, and obvious in light of, prior art.But jurors found that ‘safe harbour’ provisions did not protect 14 of Hospira’s erythropoietinbatches concerning the ‘298 patent, and also that Hospira had not proven that the patent wasinvalid on either basis. However, jurors found, the originator failed to prove by the same standardthat Hospira infringed any of seven cell or process claims of the other patent in suit, US patent5,756,349, when Hospira manufactured 11 batches of erythropoietin between 2013 and 2015. G
Hospira faces US EPO damages
COMPANY NEWS 2Fresenius Kabi starts Melrose Park project 2Gufic plans to widen 2horizons for exportsBristol and Reddy’s hamper UK sourcing 3Rivopharm acquires in Europe from Teva 3Teva adjusts its loans with 4lenders’ supportWalgreens Boots will purchase 5for Rite AidCatalent to buy Cook 5in a US$950mn deal
MARKET NEWS 6Committee unable to predict 6UPC start dateRequire batch numbers IGBA 6advises AustraliaFrench doctors seek clarity on substitution 8Canadian body wants improved incentives 8AAM-backed report 9reveals CMS savingsPortugal sets 30-day price decision limit 9Rituximab is setting records in Germany 10IGBA to present case 10during FDA workshop
PRODUCT NEWS 12Canada applies utility 12ruling to Sprycel caseSamsung Bioepis gets 13adalimumab in KoreaPfizer accuses J&J of blocking US Inflectra13Amneal and Apotex are beaten on Livalo 14Mylan links on HIV with Russia’s Rostec 15FDA publishes guide on 15judging similarityGerman oncologists should study process 16Mylan and Aurobindo 16sign price agreementStrides supplies Par with soft-gels in US 17Australian order halts 17Precedex alternative
FEATURES 18QuintilesIMS sees US savings 18
REGULARSPrice Watch UK – Our regular listing 10Events – Our regular listing 14People – Lannett’s Bedrosian 20to step down as chief
Issue No.324
Leaders of groups representing the generics industry in Canada, Mexico and the US haveunited to set out their priorities for the renegotiation of the North American Free Trade
Agreement (NAFTA) between the three signatories, in a letter to the chief NAFTA negotiatorsof all three countries. Jim Keon, president of the Canadian Generic PharmaceuticalAssociation (CGPA) stood alongside his counterpart Rafael Maciel Martinez at the MexicanAssociation of Generic Medicines (AMEGI) and Chip Davis, president and chief executiveof the US Association for Accessible Medicines (AAM), in insisting that it is “essentialthat the balance between innovation and affordability of medicines is maintained”.
“In particular”, the letter states, “we believe that including a new provision in NAFTA tomandate biologic drug exclusivity – above and beyond the protections already provided byvoluminous patents – will harm the growing biosimilar industry which aims to provide pricecompetition to the most expensive biological drugs and allow patients to benefit from affordablebiologic medicines. Keon said the CGPA was “concerned by reports that the US plans to tableextensive intellectual-property provisions in the NAFTA negotiations, including 12 years ofdata exclusivity for biologic drugs and further extensions of patent terms”.
To enhance NAFTA’s intellectual-property framework, the letter urges, signatories should“require a research – Bolar – exception to facilitate timely access to generic and biosimilarcompetition once patents have expired”, thus allowing generics and biosimilars to be developedduring the patent term. NAFTA should also “require patent transparency, such as the disclosureof the ‘best mode’ for carrying out an invention, as part of a patent application”, as well asintroducing “a public registry for all patents and exclusivities granted to a drug”. And initialgeneric and biosimilar competition could be enhanced by “requiring an incentive to challengepatent and exclusivities for reference drugs and granting a reward to those that do so”.
An updated NAFTA could also “streamline the regulatory process”, the letter suggests,through “regulatory harmonisation and recognition where appropriate”. In particular, the letterurges a mutual-recognition deal on inspections between Canada and the US similar to that reachedbetween the US and European Union (Generics bulletin, 10 March 2017, page 1). Addressingregulatory approval backlogs for generics was also a priority, “with special emphasis onexpediting the approval of first generics”. G
2 GENERICS bulletin 29 September 2017
COMPANY NEWS
Gufic Biosciences is “augmenting its global focus by deepeningits presence in priority markets”, according to comments made
by the Indian active pharmaceutical ingredient (API), lyophilisedinjectables and herbals specialist in its latest annual report. Thesemarkets include “India, Germany, Switzerland, South Africa, Russiaand Europe”, as well as “key countries within emerging markets”.
“To widen its reach and meet the healthcare needs of peoplethroughout the world,” commented chairman and managing directorJayesh Choksi, “Gufic continues to enter into licensing agreementswith both Indian and international companies.”
Gufic – which had annual sales of Rs2.59 billion (US$40.4 million)in its most recent financial year – “expects that the healthcare marketin Africa – Kenya, Nigeria, Tanzania, Egypt and Francophone states –south-east Asia, South Africa, Australia, Canada and the Middle Eastwill mature a lot”. Aside from generics, Gufic also foresees that “amarket will open for high-end lifesaving products, which is a greatopportunity to be targeted”, in particular in the field of injectables.
However, future export growth “is expected to be led by increasinggeneric penetration in the regulated markets like Europe, the UK,Canada, Australia, Brazil, Russia and South Africa”, Gufic said. Thiswould come “on the back of enhanced focus on niche and complexproduct segments, targeting molecules where patents are expiringand enabling licensing agreements”. G
BUSINESS STRATEGY
Gufic plans to widenhorizons for exports
Fresenius Kabi has broken ground at its planned US$250 millionUS manufacturing ‘campus’ in Melrose Park, Illinois.
In August last year, the German firm announced plans to “transform”the existing former APP Pharmaceuticals generic sterile injectablessite through a decade-long expansion project (Generics bulletin, 26August 2016, page 6). Scheduled for completion in 2026, the expansionproject will lead to “hundreds of high-paying manufacturing andconstruction jobs in the Melrose Park region”, according to Kabi.
Noting that the current Melrose Park site manufactured injectablesused in hospitals and clinics throughout the US, Kabi said the expansionwould create “multiple new buildings connected to the existingmanufacturing site”. These, the firm added, “will feature fully automatedaseptic filling lines using state-of-the-art isolator technology, expandedlyophilisation capabilities, formulation areas, a dedicated warehousefor raw materials and components, and an administration building withconference centre, laboratories, office space and cafeteria”.
“[The expansion] comes following an extensive intergovernmentalagreement worked out last year that provided for tax incentives andland-use controls,” revealed Kabi, which operates additional USmanufacturing sites in Grand Island, New York, as well as in NorthCarolina and Pennsylvania.
Since announcing the Melrose Park expansion scheme, Kabi hassigned a US$4.75 billion agreement to acquire US-based Akorn. G
MANUFACTURING
Fresenius Kabi startsMelrose Park project
3GENERICS bulletin29 September 2017
COMPANY NEWS
Switzerland’s Rivopharm believes itself and its subsidiaries acrossEurope have been transformed into a “more substantial player in
the generics market” after obtaining the green light from the EuropeanCommission for the firm’s acquisition of multiple baskets of productsfrom Teva and Actavis.
Linked to divestments stemming from Teva’s acquisition ofAllergan’s Actavis generics business – which was completed on 2August 2016 – the baskets of 77 total products comprise generics aswell as branded OTC products, covering a number of undisclosedEuropean Union (EU) markets.
Rivopharm said itself and Teva had agreed not to disclose thecommercial and financial terms of the agreement, but noted that, withgreater than 400 stock-keeping units (SKUs), the portfolio was likelyto add more than C20 million (US$23.8 million) to Rivopharm’s sales.
Noting that the portfolio spanned multiple dosage forms and“complements our presence in niche and non-niche areas”, leading to“greater operational efficiencies”, the Swiss firm revealed the majorityof the products would be transferred into Rivopharm’s local commercialand manufacturing plant in Manno.
“The transaction is in line with Rivopharm’s goal of increasingits territorial presence, maintaining its commitment to delivering highstands in both service and products to its customers and adhering to itsstatus as a premier Ticino-based company providing ‘Swiss PharmaSolutions’,” Rivopharm commented.
Meanwhile, in accordance with the transaction, Rivopharm expectsto increase its current workforce by more than 15% for its next financialyear, representing a “significant increase of personnel in differentareas across the company”. G
MERGERS & ACQUISITIONS
Rivopharm acquiresin Europe from Teva
UK contractors are suffering “very great difficulties” in sourcing “alarge number of products” following manufacturing issues identified
at facilities operated by Bristol Laboratories and Dr Reddy’s, accordingto the UK’s Pharmaceutical Services Negotiating Committee (PSNC).
In August, good manufacturing practice (GMP) deficiencies wereidentified at Dr Reddy’s Unit II formulations facility in Bachupally,India, following an inspection by the Bavarian medicines inspectorate(Generics bulletin, 1 September 2017, page 7).
Critical quality issues and five ‘major’ deficiencies were citedby the authority, relating to non-sterile products as well as primaryand secondary packaging and quality-control testing.
“Pending revocation of the non-compliance notification,” Dr Reddy’sconfirmed, “the plant will not be able to make any further dispatch tothe European Union (EU) until the next inspection, to be initiated byan invitation from [Dr Reddy’s German affiliate] Betapharm.”
Also last month, the UK’s Medicines and Healthcare ProductsRegulatory Agency (MHRA) found Bristol Laboratories’ sites in Lutonand Peterlee, UK, did not comply with GMP. This followed inspectionsconducted in April and July this year that uncovered problems with dataand analytical records (Generics bulletin, 8 September 2017, page 10).
The MHRA’s inspection in Luton identified “two criticaldeficiencies relating to the integrity and recording of GMP criticaldata and with the ongoing stability monitoring programme”. The site’sGMP certificate was withdrawn as a result.
“A statement of non-compliance and restricted GMP certificatewill be issued,” the MHRA stated, “to permit continued manufactureand testing of products considered to be medically critical or to ensurecontinuity of supply, as determined by the national competent authority”.However, no batches of non-critical product may be supplied to EUmarkets while the statement of non-compliance remains in force.
“Both shortage and pricing issues” were playing a part in the supplyissues being experienced by UK contractors, the PSNC said, addingthat this was “having a huge impact on workload and a catastrophicimpact on cash flow” for UK pharmacists.
“We are in urgent discussions with the Department of Health (DoH)regarding price concessions and wider concerns about the numerousmarket issues that pharmacy contractors and teams are facing,” thePSNC stated, “and are seeking immediate action to offer some relief forcontractors.” It asked pharmacists to “continue to report generic issues”.
PSNC member and independent community pharmacy contractorMark Burdon said the issues were “having a serious impact on all ofour abilities to deliver medicines to patients”. “Factors such as theremoval of regulatory lag and the increasing use of branded genericsby clinical commissioning groups (CCGs) are combining to cause realproblems with supply and prices,” he added, urging “action to ensurethe resilience of the supply chain”.
Meanwhile, Dr Reddy’s has also announced that its UK activepharmaceutical ingredient (API) plant in Mirfield, West Yorkshire,has received three ‘Form 483’ observations following an inspectionby the US Food and Drug Administration (FDA). The Indian firmsaid it was “addressing” the observations.
Dr Reddy’s also announced that the technology development centreat its custom pharmaceutical services facility in Hyderabad, India, haspassed an FDA inspection with “zero observations”, while anestablishment inspection report (EIR) has been issued closing out aninspection of the firm’s formulations plant in Srikakulam, India. Gn [email protected]
MANUFACTURING
Bristol and Reddy’shamper UK sourcing
Vivimed’s Uquifa active pharmaceutical ingredients (APIs) divisionintends to invest in “capacity augmentation and organic growth”,
as well as to reduce its debt and optimise its capital structure, afterVivimed signed definitive agreements to bring in US$42.5 million offunding from healthcare investment specialist OrbiMed Asia.
Uquifa – which operates three US-audited sites in Spain andMexico – contributes around three-fifths of Vivimed’s Rs15 billion(US$228 million) group turnover and most of the Indian firm’s earningsbefore interest, tax, depreciation and amortisation (EBITDA), havingdoubled its EBITDA margin to around 17-18% since its acquisitionby Vivimed in 2011. “The growth in the business has been driven bya ramp up in contract development and manufacturing organisation(CDMO) business, better product mix and higher market shares in thegenerics portfolio,” commented the Indian group, which has just setup a wholly-owned subsidiary in Mauritius.
“Uquifa, today, is a significant part of Vivimed’s presence in thepharmaceuticals business and is poised to grow well ahead of theindustry on the back of our strategic initiatives and investmentscommitted,” managing director Santosh Varalwar insisted. “Even aswe have seen a scale-up in the sales and profitability metrics from thispart of the business in the recent past,” he added, “we are confidentthat high-value opportunities in our targeted segments of the marketwill drive the future.” G
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Teva says it now has greater flexibility in its financial leverage ratioagreements after completing amendments to its credit facilities, as
part of the Israeli firm’s strategy to better manage its capital structure.As of 30 June this year, the Israeli firm’s aggregate principal
amount outstanding was approximately US$6.4 billion, comprisingUS$5.0 billion in US dollar term loans and US$1.4 billion in Japaneseyen term loans, while the group had US$4.5 billion available undera syndicated revolving line of credit. Teva’s total gross and net debtsstood at US$35.1 billion and US$34.3 billion respectively.
With annualised earnings before interest, tax, depreciation andamortisation (EBITDA) of US$7.5 billion at 30 June 2017, Teva’sgross and net debt to EBITDA leverage ratio was 4.6. Around 4% ofthe group’s debt was classified as short-term, while two-thirds of itstotal debt was denominated in US dollars, and a quarter in euros.
“The amended leverage ratio covenants in the credit agreementspermit a maximum leverage ratio of 5.0 times [EBITDA] through andincluding 31 December 2018, gradually declining to 3.5 times by 31December 2020,” the Israeli firm noted. “The amendments receivedthe support of lenders holding approximately 98% of the aggregateloans and undrawn commitments across the five credit facilities.”
Michael McClellan, Teva’s interim group chief financial officer,said the amendments showed a “strong support from our lending group”.“These amendments are an important part of Teva’s plan to obtainlonger-term flexibility with our credit facilities and manage Teva’scapital structure,” McClellan added.
Teva is currently in the process of divesting non-core assets topay down some of its sizeable debt, having recently agreed to sellfor US$1.1 billion the firm’s Paragard intrauterine copper contraceptiveand later agreed two separate deals to divest its remaining Women’sHealth assets for a combined US$1.38 billion (Generics bulletin, 15September 2017, page 4; 22 September 2017, page 1). The Israeli groupsaid proceeds from both transactions would be used to repay term-loan debt, in line with its pledge to generate net proceeds of at leastUS$2 billion by divesting non-core assets.
In August, Teva reported a US$5.74 billion group operating lossfor its financial second quarter ended 30 June 2017, due to a US$6.1billion impairment charge recorded by the firm’s US generics operationon the back of price erosion and decreased volumes (Generics bulletin,11 August 2017, page 1). G
BUSINESS STRATEGY
Teva adjusts its loanswith lenders’ support
LAURUS LABS has received an establishment inspection report(EIR) from the US Food and Drug Administration (FDA) for itsUnit II finished dosage formulations and active pharmaceuticalingredients (APIs) plant in Vishakhapatnam, India, following aninspection in May. Laurus’ Unit II site also completed a Germanauthority inspection for formulations, and its Units I and III – alsolocated in Vishakhapatnam – completed a World Health Organisation(WHO) audit with no critical or major observations.
HUMANWELL PURACAP PHARMACEUTICAL has announcedthat the US Food and Drug Administration (FDA) has completedan inspection of its soft-gelatin capsule manufacturing facilityin Wuhan, Hubei Province, China. No ‘Form 483’ observationswere issued during the inspection, which confirmed that the sitewas compliant with current good manufacturing practices (cGMP).As a result of the inspection, a pending abbreviated new drugapplication (ANDA) was recommended for approval.
RECIPHARM has entered into a collaboration with Roche and“signed a long-term manufacturing agreement” whereby the Swedishfirm will manufacture a range of solid-dose products. Recipharmwill also acquire a manufacturing facility in Leganés, Spain, whichproduces solid-dose products and currently employs 200 people.The deal is expected to close by the end of this year.
TEVA has entered into a partnership with US hospital group MountSinai Health System “to create scalable solutions to improve patientand health-system care for multiple chronic conditions”. Aimingto “gain new data and insights into interventions”, the firms notedthere would be a regional pilot programme at Mount Sinai’s ArnholdInstitute for Global Health in New York.
ALKEM LABORATORIES has received an inspection reportcontaining two ‘Form 483’ observations from the US Food andDrug Administration (FDA) following a recent inspection of thefirm’s manufacturing facility in Baddi, India. Alkem said it would“put together a detailed response with adequate corrective andpreventive measures to address the FDA observations, and the sameis proposed to be filed within the timeline stipulated by the FDA”.
ORCHID PHARMA says it has received an establishment inspectionreport (EIR) from the US Food and Drug Administration (FDA)following an inspection in May of the Indian firm’s activepharmaceutical ingredient (API) manufacturing facility located inAlathur, Tamil Nadu, India. G
IN BRIEF
5GENERICS bulletin29 September 2017
COMPANY NEWS
US-based Catalent says it will strengthen its position as a “leaderin the rapidly growing area of biologics development and analytical
services, manufacturing and finished-product supply” through a US$950million all-cash agreement to acquire Cook Pharmica, “an integratedprovider of drug-substance and drug-product manufacturing and relatedservices” based in Bloomington, Indiana.
Founded in 2004, privately-owned Cook Pharmica, part of theCook group, is a contract development and manufacturing organisationspecifically focused on the biologics space, with capabilities acrossbiologics development, clinical and commercial cell-culturemanufacturing, finished-dosage formulation manufacturing andpackaging, according to Catalent.
Moreover, the transaction will give Catalent access to CookPharmica’s 81,300 sq m development and manufacturing facility, alsoin Bloomington, Indiana, that has “extensive biomanufacturingcapacity and deep expertise in sterile formulation and fill-finishacross liquid and lyophilised vials, pre-filled syringes and cartridges”.
Catalent’s Catalent Biologics division operates severalcomplementary manufacturing sites, including a development andbiomanufacturing facility in Madison, Wisconsin, fill-finish servicesplants in Brussels, Belgium and Limoges, France, conjugationtechnology services in Emeryville, California, that uses Catalent’sproprietary ‘Smartag’ site-specific protein-modification and linkertechnologies, as well as a “network of biologics analytical locations”.
Commenting on the addition of Cook Pharmica’s manufacturingcapabilities, Catalent said they “perfectly augment Catalent’s expertisein cell-line engineering, bioconjugate development, analytical services,biomanufacturing, pre-filled syringe and blow-fill-seal technologies”.
Having turned over US$179 million in its most recent financialyear ended 30 June 2017, Cook Pharmica also employs more than750 staff, which will join Catalent’s 10,000-strong workforce at morethan 30 sites across five continents upon the transaction’s closure.
“The complementary biologics development, biomanufacturing,and fill-finish capabilities of Catalent and Cook Pharmica will providebiopharmaceutical firms with a single, integrated partner supportinga wide range of clinical and commercial needs,” commented JohnChiminski, Catalent’s chairman and chief executive officer. “We arevery excited to join forces with the talented Cook Pharmica team inBloomington and plan to invest aggressively there, in our rapidlyexpanding Madison facility, and in the rest of the Catalent Biologicsnetwork to build a true global leader in the biologics market, whichwill help us to improve the lives of patients around the world.”
Subject to customary closing conditions, including regulatoryauthority approvals, the transaction is scheduled to close by the endof 2017. Catalent will pay US$750 million upon the deal’s completion,and the remaining US$200 million in equal instalments on each ofthe deal’s next four anniversaries of closing. G
MERGERS & ACQUISITIONS
Catalent to buy Cookin a US$950mn deal
US drugstore chain Rite Aid now has an option to purchase genericssourced through an affiliate of Walgreens Boots Alliance (WBA)
“at a cost substantially equivalent to Walgreens for a period of 10 years”after the two firms received US antitrust clearance to complete arevised US$4.375 billion deal.
A Hart-Scott-Rodino US antitrust waiting period has now expired,allowing to go through a deal that sees WBA acquire less than halfof rival Rite Aid’s more than 4,500 stores. Wholesale and retail giantWBA is acquiring 1,932 Rite Aid stores – located primarily in north-eastern and southern US – along with three distribution centres andrelated inventory, on a cash-free, debt-free basis. Rite Aid also hasan option, exercisable until the end of May 2019, to become a memberof WBA’s group purchasing organisation, Walgreens Boots AllianceDevelopment (WBAD) that is also set to tie up with Express Scripts’Econdisc sourcing unit.
WBA – which expects to realise more than US$300 million inannual synergies within four years of closing, “derived primarily fromprocurement, cost savings and other operational matters” – said thissmaller transaction replaced the recently agreed US$5.175 billion dealfor a total of 2,186 stores, which was announced after its proposedUS$17.2 billion full takeover of Rite Aid collapsed amid competitionconcerns (Generics bulletin, 7 July 2017, page 4).
Rite Aid noted that, following discussions with the US FederalTrade Commission (FTC), it would retain around 250 more stores thanoriginally planned in the previous deal, a change reflected in thereduced transaction price.
Stating that the agreement had been approved by both firms’boards, WBA said it expected to begin store purchases in October andto complete the acquisition – “subject to other customary closingconditions” – in spring 2018. Acquired Rite Aid stores would be“converted to the Walgreens brand in carefully planned phases overtime”. The transition of the three distribution centres located in Dayville,Connecticut, in Philadelphia, Pennsylvania and in Spartanburg, SouthCarolina, to WBA “will not begin for at least 12 months”.
Stefano Pessina, WBA’s executive vice chairman and chiefexecutive officer, said approval of the revised deal marked a “significantmoment” for the company. “Combining Walgreens’ retail pharmacynetwork with a strong portfolio of Rite Aid locations is expected tohelp us achieve enhanced, sustainable growth,” Pessina insisted, “whileenabling us to broaden our reach and provide greater access to convenient,affordable care in more local neighbourhoods across the US.”
With over 13,200 stores in 11 countries at present, WBA alsoserves more than 230,000 pharmacies and other healthcare outletsthrough a network of nearly 400 distribution centres.
Following completion of the transaction, Rite Aid will operatearound 2,600 stores and six distribution centres, as well as itsEnvisionRx pharmacy benefit manager. G
MERGERS & ACQUISITIONS
Walgreens Boots willpurchase for Rite Aid
WUXI MEDICAL INSTRUMENT FACTORY has received a warningletter from the US Food and Drug Administration (FDA) for itsfinished-dose formulations facility in Jiangsu, China, following aninspection in March. Deviations included failures to establish writtenprocedures for production and process controls, and also to maintainadequate written records of major equipment maintenance. G
IN BRIEFCLARIS LIFESCIENCES has sold its 20% stake in its OtsukaPharmaceutical joint venture to its Japanese partner for US$20million, after agreeing to the deal in May (Generics bulletin, 12 May2017, page 6). Otsuka already owned 60%, and Mitsui 20%, of theinfusions venture that was formed in 2013 to target India and otheremerging markets (Generics bulletin, 11 January 2013, page 4). G
IN BRIEF
6 GENERICS bulletin 29 September 2017
MARKET NEWS
Mandating that batch numbers are included in reports of adversedrug reactions (ADRs) is a more effective means of strengthening
pharmacovigilance for biological medicines than adding a suffix tonon-proprietary names, the International Generic and Biosimilarmedicines Association (IGBA) has told Australia’s TherapeuticGoods Administration (TGA).
Responding to the TGA’s consultation on nomenclature ofbiological medicines, Ingrid Schwarzenberger – chair of the IGBA’sbiosimilars committee – said the industry body and its local affiliate,Australia’s GBMA, strongly supported reporting of unique productsnames combined with batch-specific details, but strongly opposedintroducing suffixes to names of biological drugs.
In its consultation paper, the TGA notes that its current adverseevent reporting system “gives prominence to reporting of a medicine’snon-proprietary name, with or without the trade name or batch number”.
For biological drugs, the agency observes, “concerns have beenraised that currently unknown adverse events may arise from switchingbetween reference medicine and biosimilar products”. While the TGAacknowledges that “to date, these concerns have largely not beenevident”, it is seeking feedback on how naming could influencepharmacovigilance, particularly against a backdrop of inconsistentpractices around the world.
The TGA lays out four options for naming biological drugs:maintaining the status quo of using the approved biological name,typically the international non-proprietary name, while relying on theproprietary trade name and Australian registration number (AUST R)to identify individual products; maintaining the status quo, but improvingpublic reporting of the trade name, AUST R and batch number, such asby educating healthcare professionals and mandating the trade name as afield in the online ADR reporting system; moving towards European-style barcodes; or introducing suffixes to the name of active ingredients,in line with US Food and Drug Administration (FDA) policies.
In its response, the IGBA argued that maintaining the status quoin Australia without improving ADR reporting would be “anunsatisfactory outcome”. But building on the status quo by improvingreporting would “enhance what is already in place without increasingregulatory burden or adversely impacting the government’s policy tosupport the increased uptake of biosimilar medicines”.
Setting as mandatory fields for online ADR reports details suchas trade name, AUST R and batch number would “enable track-and-tracing of any medicinal product,” the IGBA maintained. “There areno concerns that we are aware of that pharmacovigilance is impairedfor the many biological medicines that already share internationalnon-proprietary names,” Schwarzenberger stated.
In principle, Schwarzenberger continued, the IGBA supportsEuropean-style barcodes, not least because the TGA currently adoptsEuropean Medicines Agency (EMA) guidelines. However, she cautioned,“the medicine packaging requirements have only recently been updatedin Australia, and the cost of introducing another requirement cannot beignored.” Thus, a transition period “of at least three years” is needed.
By contrast, suffixes would “cause confusion among stakeholders”,“undermine the biosimilarity scientific concept” and create an“additional burden” for industry, healthcare providers and regulators.Adopting FDA-style suffixes that had not been shown to bring anypharmacovigilance benefit would “be inconsistent with the TGA’scurrent practice of harmonising with the EMA,” the IGBA added. Gn [email protected]
REGULATORY AFFAIRS
Require batch numbersIGBA advises Australia
Apreparatory committee for Europe’s unified patent court (UPC)admits “it is now difficult to predict any timeline” for the
system to start operating. Previously, committee chairman AlexanderRamsay had in late-June this year, expressed hopes that a period ofprovisional application could begin in “autumn 2017”, but admittedthat it was “difficult to maintain a definitive starting date” (Genericsbulletin, 7 July 2017, page 8).
The source of the delay is a case currently pending in Germany’sfederal constitutional court that challenges the basis for the Germanparliament passing a law on implementing the UPC agreement. “Thiswill cause delay to the German ratification of the UPC agreement andthe protocol on provisional application,” the committee acknowledged.“We are following the situation and will publish a further update whenadditional information is available.”
Otherwise, the preparatory committee insisted it had “been makinggood progress regarding the ratification of the UPC agreement”. “Wenow have 14 full ratifications and more in the pipeline, making itreasonable to expect that we will begin operations with closer to 20contracting states,” it stated, adding that it was “also very close to the13 required ratifications of the protocol on provisional application”.
As of 25 September, the Council of the European Council said ithad received notifications that the UPC agreement had been ratifiedby Austria, Belgium, Bulgaria, Denmark, Estonia, Finland and France,as well as by Italy, Lithuania, Luxembourg, Malta, the Netherlands,Portugal and Sweden. However, two of the three states that mustratify the agreement for it to take effect – France, Germany and theUK – have not yet done so.
The Council said the protocol on provisional application had, todate, been signed by 12 participating states: Bulgaria, Denmark, France,Germany, Greece and Hungary, and by Italy, Luxembourg, Romania,Slovenia, Sweden and the UK. G
INTELLECTUAL PROPERTY
Committee unable topredict UPC start date
Patient waiting rooms and airports, as well as broadcast and cablechannels, are among the media through which the US Food and
Drug Administration (FDA) is aiming to educate the US public aboutgeneric medicines.
The FDA’s 30-second public service announcement, aimed atconsumers and patients, features a cartoon character named Blue thatis feeling unwell and is prescribed a generic. A voiceover reassuresBlue that “generics and name-brand medications work the same”. Eventhough generics may look different to their reference brand, “FDAapproval is equally rigorous for generics to make sure they are as safeand effective as name brands”. The message ends with Blue savingmoney when picking up the prescribed generic and feeling better.
The agency – which is also targeting healthcare professionalsthrough print and online advertisements – said its new promotionaland educational materials aimed to “encourage communication betweenhealthcare providers and patients around generic drugs”.
Furthermore, the FDA has updated its ‘generic drug facts’ andquestions and answers pages on its website, including a new downloadablegeneric drug facts handout. “More educational materials are expectedlater in 2017-2018”, the agency promised. G
PROMOTIONAL CAMPAIGNS
FDA will target waiting rooms
8 GENERICS bulletin 29 September 2017
MARKET NEWS
French doctors’ association MG France has demanded “a clarificationof the French policy on generic medicines”, especially as it relates
to prescribers’ ability to mark a prescription as ‘non-substitutable’,thus preventing the pharmacist from dispensing a generic substitute.
Following a declaration by French health minister Agnès Buzynthat patients “should be able to choose the medicine best suited tothem” – in the wake of a crisis over adverse events linked with areformulated version of Merck’s Levothyrox (levothyroxine) – MGFrance said clarity was needed over individual responsibility forprescription medicines.
Insisting that its position was “overall favourable towards generics”,MG France said patients could not be told that they were able tochoose their medicine and prescribers asked to endorse this choice.“The responsibility of the choice can not be entrusted to the patient andthe physician blamed for validating this choice through his prescription.”
“MG France suggests that general practitioners should not use the‘non-substitutable’ label,” the association said, instead suggesting thatdoctors “advise patients to talk to their pharmacist, who has the rightto issue the brand if the patient asks for it”. The body concluded byurging the French authorities, “for the sake of clarity, to remove theconstraint of this added mention of ‘non-substitutable’, handwritten ornot, which places responsibility on the doctor for a choice that nowbelongs to the patient”.
Buzyn had made her comments as part of an ongoing crisisinvolving Levothyrox. A reformulated version of the drug marketed byMerck – in which the excipient lactose had been replaced by anhydrouscitric acid for greater batch consistency – had been linked with adverseeffects experienced by certain patients. European stocks of the earlierformulation have been obtained for use by affected patients, but Buzynemphasised that this was only a temporary measure. The “vast majorityof patients” were unaffected, she stated. G
REGULATORY AFFAIRS
French doctors seekclarity on substitution
Greater incentives are needed in Canada’s intellectual property (IP)regime to encourage generics and biosimilars firms to invest in
litigation to bring medicines to market more quickly, according to theCanadian Generic Pharmaceutical Association (CGPA). Speaking asthe country began its “provisional application” of the comprehensiveeconomic and trade agreement (CETA) with the European Union (EU)on 21 September, CGPA president Jim Keon also lamented theintroduction of two-year patent-term extensions for brands.
“Canada had high, internationally-competitive standards forpharmaceutical IP before the CETA negotiations commenced,” Keonstated, “with average market protection periods for brand-name drugsthat were equal to or longer than in other developed markets.Unfortunately, concessions were made in the CETA negotiations thatwill delay market entry of cost-saving generic and biosimilar prescriptionmedicines in Canada in the future.”
“A new pharmaceutical IP litigation system also comes into effecttoday,” Keon observed, referring to the revised framework designedto eliminate Canada’s dual litigation approach. “While that systemincludes several improvements, the CGPA remains concerned thatthere remains too much business risk and uncertainty and too fewincentives for generic and biosimilar medicines companies to invest inlitigation to bring new cost-saving medicines to the market,” he stated.
Warning of the “long-term negative impact” of CETA – includingincreased healthcare costs for provinces, employers and Canadianswho pay for medicines out-of-pocket – Keon said the changes wouldalso have “negative consequences for Canada’s lifesciences sector”.
Moreover, Keon stated, “as the generic and biosimilar medicinescompanies and pharmaceutical payers adapt to the CETA pharmaceuticalIP concessions, we are now concerned by reports that the US plans totable extensive intellectual property provisions in the North AmericanFree Trade Agreement (NAFTA) negotiations” (see front page). G
INTELLECTUAL PROPERTY
Canadian body wantsimproved incentives
Ensuring that “a broad assortment of medicines” is available frompharmacies must be the aim of long-term measures to avoid drug
shortages in Germany, the country’s pharmacists declared during theirrecent Expopharm day held in Düsseldorf, Germany.
Appealing for legislators to take into account “the numerous causesfor supply shortages”, a resolution passed by the country’s pharmacistscalled for “a rebate tender system with proportion, that does not haveas its sole focus the cheapest price, but also takes considerable accountof security of supply”. Legislation, they said, should prohibit tenderingfor certain critical drugs for serious and life-threatening conditions, aswell as for medicines with a narrow therapeutic index or few suppliers.
Bork Bretthauer, managing director of German industry associationPro Generika welcomed the resolution’s rejection of short-term,mandatory measures on shortages. Stressing that pricing and rebatepressures had played key roles in shortages of the oncology drug5-fluorouracil and the antibiotic piperacillin/tazobactam, Bretthauersaid such pressures could force suppliers out of the market. Amongreforms that could “get to the roots of the problem” should be ensuringtender contracts were awarded to more than one supplier per molecule,thereby spreading the responsibility to supply, he proposed. G
PRICING & REIMBURSEMENT
Germany must ensure varietyExpert judges are casting their votes to determine the winners of
all 14 categories in the Global Generics & Biosimilars Awards2017. The awards – which are free to attend – will be presented on24 October 2017 at the Frankfurt Marriot Hotel in Frankfurt, Germany.
Co-hosts QuintilesIMS will present awards for Company of theYear and Patent Litigation of the Year, while Panacea will sponsor theaward for Company of the Year in Europe, the Middle East and Africa(EMEA). Chartwell Pharma will support the award for Company ofthe Year in the Americas region, and Evapharm for Asia-Pacific.
International Health Partners (IHP) is supporting the award forCorporate Social Responsibility (CSR) Initiative of the Year, andJames Dudley Management for Business Development of the Year.
Clarivate Analytics will sponsor the award for Active PharmaceuticalIngredient (API) Supplier of the Year, while Pharmawise andPharmacloud will support the Acquisition and Leader of the Yearawards respectively. Eignapharma will lend its backing to the RegulatoryAchievement award and Piramal the Innovation award, with mAbxiencesponsoring the award for Industry Partner of the Year. Still availablefor sponsorship is the Biosimilar Initiative award. Gn To request tickets to attend, e-mail [email protected].
INDUSTRY AWARDS
Judges cast votes for Awards
9GENERICS bulletin29 September 2017
MARKET NEWS
Bethesda North Marriott Hotel andConference Center | North Bethesda, MDNovember 6-8, 2017
Join more than 700 generic industry professionals and attend this unique educational conference whereFDA and industry experts share experiences and knowledge about drug product research and developmentand ANDA application review. Hear presentations from key industry leaders, industry scientists, and agencyofficials on topics ranging from compliance and inspections to the impact and expectations of GDUFA IIcommitments for ANDA review timelines and first cycle approvals and much more.
Register online at www.accessiblemeds.org. For more information, contactJennifer Soup at [email protected] or +1(202)249-7127.
Register Now
Pricing and reimbursement decisions on both biosimilar and genericmedicines in Portugal must be taken within 30 calendar days, an
ordinance published in the country’s official gazette states. The Portaria270/2017 ordinance allows 75 days to decide on non-generic drugswhich have an international non-proprietary name (INN) or therapeuticindications that are already reimbursed, and 180 days for other drugs.
Once a biosimilar medicine in Portugal achieves a market shareof 5% or more, its reimbursement price will be limited to a maximumof 70% of the price of its reference biologic, under a legal decreepublished in the gazette. Decree-law 115/2017 defines new rules forPortugal’s national health technology assessment system, SiNATS,through which drugs and medical devices can qualify for reimbursementunder the country’s national health insurance scheme, the SNS.
Alongside homogenous groups of generics with the same activeingredient and delivery form that are used to draw up reference-pricegroups, the decree-law creates the same procedure for biosimilars.
Article 21 of the decree-law states that, for reimbursementpurposes, the maximum public retail price of biosimilars cannot, ingeneral, exceed 80% of the retail price of its reference biologicaldrug. However, once that biosimilar achieves at least 5% of itsmarket defined by international non-proprietary name, that limitdrops to 70%, requiring at least a 30% discount to the price of thereference brand. G
PRICING & REIMBURSEMENT
Portugal sets 30-dayprice decision limit
The US would save US$11.4 billion on healthcare spending over thenext decade were the US Centers for Medicare & Medicaid Services
(CMS) to revise its existing reimbursement policy for biosimilars byadopting unique Healthcare Common Procedure Coding System(HCPCS) billing and payment codes, according to an analysis findingendorsed by the US Association for Accessible Medicines (AAM).
In its ‘Fiscal Implications of Discrete Codes for Biosimilars’ report,The Moran Company – which works on projects related to Medicarepayment system rules – analyses the budgetary implications of areversal of the current CMS policy for HCPCS codes, or ‘J-codes’,which assigns the same J-code to all biosimilars approved for the samereference biologic for reimbursement purposes under Medicare Part B.
Citing total spending on Medicare Part B biologics at US$287billion over the next 10 fiscal years assuming no biosimilar entry,The Moran Company said adjusted net Medicare Part B share andpremium savings would be US$6.6 billion, while an additional US$4.8billion would be saved through interactions with Medicare Part C.
In a prior analysis report published in July 2015 The MoranCompany had warned that the current reimbursement policy couldsacrifice larger, long-term savings for Medicare for “potential short-term gains”. Moreover, it predicted, the policy would either causebiosimilars manufacturers to exit the market “over time” or not enterthe biosimilars market at all. G
PRICING & REIMBURSEMENT
AAM-backed reportreveals CMS savings
10 GENERICS bulletin 29 September 2017
MARKET NEWS
Up to the minute live retail market pricing is availablefor 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].
Concessions ramp up in UKPrice concessions offered by the UK’s Department of Health
(DoH) ramped up this month, with the list issued on 19September comprising over 30 different molecules across morethan 50 separate presentations. The concessions came as UKpharmacists experienced supply issues, in part due to manufacturingdeficiencies identified at major suppliers (see page 3).
Concession prices of £32.20 (US$43.41) and £35.00 continuedto be offered for chlorpromazine 25mg and 100mg tablets respectivelyfor 28-count packs, as average UK prices for the moleculeexperienced huge leaps compared to August, according to the latestfigures provided by WaveData.
Comparing UK trade prices between the periods 1-31 August2017 and 1-26 September 2017, WaveData reported that 28-countpacks of chlorpromazine 25mg tablets saw an average price riseof 2,005% to £25.77, exceeding the rate of 1,891% recorded earlierthis month (Generics bulletin, 22 September 2017, page 8). The100mg presentation saw its average rise by 1,742% to £25.90,while the 50mg strength in 28-tablet packs experienced an averageleap of 1,863% to £24.60, based on averages calculated from atleast 33 data points.
Average price declines were far less pronounced, with risedronatesodium 35mg tablets in packs of four registering the steepest averageprice drop recorded by WaveData: a 51% fall to £0.46. G
PRICE WATCH ....... UK
Rituximab is achieving the fastest penetration by value to date amongsecond-wave biosimilars in Germany, according to QuintilesIMS
data. Within just four months of market entry of Mundipharma’sTruxima (rituximab) rival to Roche’s MabThera/Rituxan, the biosimilarhas achieved a double-digit value share, the data shows.
Following European approval through an alliance with SouthKorea’s Celltrion, Mundipharma earlier this year started to roll outTruxima in countries including Germany and the UK (Genericsbulletin, 3 March 2017, page 1).
As Figure 1 shows, the initial market uptake of biosimilar rituximabin Germany has been slightly faster than that for infliximab in 2015, asthe pace of growth of the latter gradually tailed off. Etanercept, bycontrast, started more slowly, but maintained a steady rate of growthto surpass infliximab’s share within about 10 months of launch.
Presenting data on the biosimilars “second wave”, QuintilesIMS’spresident for Central Europe, Frank Wartenberg, noted that the rituximabbiosimilar’s market share of 8.5% of total treatment days with themolecule as of June 2017 was slightly ahead of the 7.6% share capturedin the other lead market, the UK. However, biosimilar etanercept andinfliximab are faring considerably better in the UK than in Germany.
“Biosimilar penetration within Europe lacks any uniform pattern,”Wartenberg commented. For example, while biosimilar infliximab hadconsistently captured double-digit volume shares – albeit ranging fromjust 31.4% in France as of June 2017 to almost total market dominancein Denmark, Finland, Norway and Poland – the spread for biosimilaretanercept was far wider. Whereas Biogen’s Benepali (etanercept)alternative to Pfizer’s Enbrel had by June this year taken over four-fifths of the market in Norway, the biosimilar’s share by treatmentdays was languishing at 4.3% in France and 2.9% in Spain.
With etanercept, trastuzumab, infliximab, rituximab, enoxaparin,and insulin glargine already off-patent in Europe – and to a large extentsubject to competition – EU losses of exclusivity were anticipated in2018 for Humira (adalimumab), for Avastin (bevacizumab) in 2019, forEylea (aflibercept) in 2021 and for Lucentis (ranibizumab) in 2022.
As of July 2017,Wartenberg said, QuintilesIMS had counted 75biosimilar projects in Phase III clinical trials globally, with another17 candidates in the pre-registration phase.
Noting that all biological drugs in Germany had shown double-digitgrowth to C13 billion (US$16 billion) in 2016, Wartenberg saidautoimmune and oncology therapies each accounted for just over afifth of Germany’s total biologics market. Gn [email protected]
Figure 1: Value market shares captured by biosimilars in Germany in the monthsafter their launch (Source – QuintilesIMS)
Nick Cappuccino of Dr Reddy’s will present the InternationalGeneric Biosimilar medicines Association’s (IGBA’s) perspective
during a workshop on ‘Leveraging quantitative methods and modellingto modernise generic drug development and review’ that the US Foodand Drug Administration (FDA) is hosting on 2-3 October.
Cappuccino is scheduled to speak directly after FDA CommissionerScott Gottlieb during a morning session that will focus in large part onInternational Conference for Harmonization (ICH) standards and reformsin the context of harmonising global regulation of generics. Otherspeakers on the same morning will include representatives from China’sFood and Drug Administration (CFDA), India’s Central Drugs StandardControl Organisation (CDSCO) and Mexico’s Cofepris regulatoryagency, as well as Anthony Fake from the World Health Organization(WHO). Topics covered during the workshop will include developingand reviewing complex and locally-acting products, narrow therapeuticindex and model-guided signal detection at a post-marketing stage.
Meanwhile, the FDA has acceded to requests from parties includingthe US Association for Accessible Medicines (AAM) and Teva to extendby 60 days a deadline for comments in the agency’s public docketFDA-2017-N-3615 on ‘Administering the Hatch-Waxman Amendments:Ensuring a balance between innovation and access’ (Generics bulletin,30 June 2017, page 5). The new deadline for comments on issues suchas exclusivity periods, patent listing and citizen petitions is 17 November.G
REGULATORY AFFAIRS
IGBA to present caseduring FDA workshop
11GENERICS bulletin29 September 2017
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
12 GENERICS bulletin 29 September 2017
PRODUCT NEWS
There is a “serious lack of new antibiotics under development tocombat the growing threat of antimicrobial resistance”, with most
pipeline products “short-term solutions” that are only “modificationsof existing classes”, the World Health Organization (WHO) has warned.
In a 48-page report analysing antibacterial clinical developmentpipelines, including tuberculosis, the WHO points out that only twonew antibiotics for the treatment of multi-drug-resistance tuberculosishave reached the market “in over 70 years”, while current researchand development investment in the disease is “seriously underfunded”and “at its lowest level since 2008”.
But while there are 51 new antibiotics and biologics in clinicaldevelopment to treat priority antibiotic-resistant pathogens, accordingto the WHO, only eight are classed by the international health bodyas innovative treatments that will “add value to the current antibiotictreatment arsenal”. Part of the problem, the WHO report states, lies witha “well-established market for efficacious generic substitutes”, leavingpharma companies with little incentive to invest in new treatment options.
The WHO has established a Global Antibiotic Research andDevelopment Partnership (GARDP) together with Drugs for NeglectedDiseases Initiative to “combat the threat” posed by the current lack ofnew antibiotic treatment options, fuelled by a C56 million (US$70.0million) pledge from six nations. G
ANTIBIOTICS
WHO warns of antibiotic crisis
LUPIN has received final approval from the US Food and DrugAdministration (FDA) for a generic version of Galderma’s Clobex(clobetasol propionate) 0.05% lotion. Teva’s Actavis, Sun’s Taroand Teligent hold similar approvals.
CYCLE PHARMACEUTICALS has selected Virtus Pharmaceuticalsas the importer and distributor for the ketorolac tromethamine30mg/ml injectable for which it has just secured US approval.UK-based Cycle partnered on development of the non-steroidalanti-inflammatory drug (NSAID) with India’s Caplin Point, whichis also manufacturing the analgesic. “This is the first abbreviatednew drug application (ANDA) that has been approved from ourinjectables site,” Caplin Point stated, adding that it intended to file30-35 ANDAs over the next three to four years.
ACCORD HEALTHCARE has bolstered its generics portfolio in theUK by introducing mycophenolic acid 180mg and 360mg gastro-resistant tablets. The tablets – which are used in combination withciclosporin and corticosteroids for acute transplant rejection inadults – are available in 120-count packs at list prices of £91.87(US$124.17) and £183.75.
PERRIGO now holds US approvals for all strengths of genericExalgo (hydromorphone) extended-release tablets after the USFood and Drug Administration (FDA) cleared the firm’s 32mgversion. Perrigo – which already holds approvals for 8mg, 12mgand 16mg extended-release tablets through its Paddock affiliate –said it would launch the highest strength imminently. Teva’s Actavisand Osmotica hold similar approvals for generics of Mallinckrodt’sopioid analgesic. Perrigo said annual US sales of Exalgo 32mgand its generic equivalents totalled around US$35 million in the12 months ended July 2017.
TEVA has re-introduced its generic equivalent to Pfizer’s Depo-Provera (medroxyprogesterone acetate) 150mg/ml suspensionfor injection in the US. The Israeli group holds the only approvalfor an alternative to the contraceptive brand.
AN OSLO DISTRICT COURT has invalidated Eli Lilly’s Norwegianpatent NO321,602 that protects its Cialis (tadalafil) erectile-dysfunction brand following an action brought by Actelion on thegrounds that the particle-size patent lacked an inventive step. A localsupplementary protection certificate based on the tadalafil moleculepatent NO306,465 expires on 12 November this year.
MYLAN has been sued by Amgen in a Pennsylvania district courtfor alleged infringement of two US patents protecting the originator’sNeulasta (pegfilgrastim). Amgen said it had included the asserted8,273,707 and 9,643,997 patents, which claim methods of purifyingproteins, in its exchanges with Mylan under the framework of theBiologics Price Competition and Innovation Act (BPCIA). Theoriginator also accused Mylan of having provided inadequate detailsof its manufacturing process. Mylan has also settled on confidentialterms its litigation in a Delaware district court with Indivior overSuboxone (buprenorphine/naloxone) sublingual film. Mylan wasamong several firms that Indivior had recently sued over its newly-issued US oral-film patent 9,687,454, along with Alvogen, Dr Reddy’s,Par and Teva/Actavis.
ZYDUS CADILA has received final approval from the US food andDrug Administration (FDA) for desoximetasone 0.25% ointmentand for labetalol 100mg, 200mg and 300mg tablets. Both drugs willbe made at facilities in Ahmendabad, India. G
IN BRIEF
Canada’s Federal Court of Appeal has applied the reasoning handeddown by the country’s Supreme Court in abolishing a controversial
patent ‘promise’ doctrine to overturn a lower court’s ruling in favourof Apotex. A patent protecting Bristol-Myers Squibb’s (BMS’) Sprycel(dasatanib) treatment for chronic myelogenous leukaemia (CML)until 12 April 2020 was valid, the appeals court said.
Earlier this year (Generics bulletin, 7 April 2017, page 12), FederalJudge Michael Manson denied BMS a prohibition against Apotex’obtaining a notice of compliance (NOC), or generic approval, fordasatinib tablets. He accepted Apotex’ arguments that a key claim inCanadian patent 2,366,932 failed to justify its promise of utility, whilethree claims in Canadian patent 2,519,898 – which expires in March2024 – were obvious.
However, with Apotex still awaiting an NOC, Canada’s SupremeCourt in a landmark decision on esomeprazole then decided that“the application of the promise doctrine is not the correct approachto determine whether a patent has sufficient utility”. Rather, courtsshould identify the claimed subject matter and determine whether thatinvention is useful, with “a scintilla of utility” being sufficient(Generics bulletin, 7 July 2017, page 1).
In light of the Supreme Court of Canada’s decision in Esomeprazole,”a panel of three appeals judges stated, “the federal court’s determinationregarding the lack of utility of claim 27 in the ‘932 patent cannotstand.” Claim 27 was “a bare composition claim for dasatinib” withoutits potential therapeutic uses, they pointed out, adding that evidenceof dasatinib inhibiting certain protein tyrosine kinases (PTKs) metthe minimum “scintilla of utility”.
However, the appeals panel found no reason to overturn Manson’sfinding that claims 1 and 3 of ‘898 patent were obvious. G
ONCOLOGY DRUGS
Canada applies utilityruling to Sprycel case
13GENERICS bulletin29 September 2017
PRODUCT NEWS
Johnson & Johnson (J&J) is using “improper exclusionary tactics”to unlawfully “maintain the dominance” of its flagship Remicade
(infliximab) original in the US at the expense of Pfizer’s Inflectra(infliximab-dyyb) biosimilar, according to a lawsuit filed by Pfizeragainst J&J in a US district court.
In a 49-page complaint filed in the US District Court for the EasternDistrict of Pennsylvania, Pfizer accuses the originator of denyingpatients access to therapeutic options, violating federal antitrust laws andundermining the principal goals of the US Biologics Price Competitionand Innovation Act (BPCIA) through “anticompetitive practices”.
Underlining that Inflectra was launched in November 2016 at awholesale acquisition cost (WAC) 15% lower than Remicade, Pfizerinsists: “Within weeks of Inflectra’s launch, J&J began to deploy whatit publicly has termed its ‘Biosimilar Readiness Plan’.”
Pfizer says the core features of J&J’s ‘plan’ are exclusionarycontracts that “foreclose Pfizer’s access to an overwhelming share ofconsumers”, coupled with “anticompetitive bundling and coerciverebate policies designed to block both insurers from reimbursing, andhospitals and clinics from purchasing, Inflectra or other biosimilarsof Remicade despite their lower pricing”.
Specifically, Pfizer alleges, J&J has induced insurers to enter intocontracts that require an “explicit commitment not to cover Inflectraat all, or to do so only in the rarest of circumstances”. “As a directresult of these exclusive dealing contractual commitments, Inflectrais either not listed on the insurance company’s medical policy or isdesignated reimbursable only in so-called ‘fail first’ cases,” Pfizer claims.
According to Pfizer, the “spurious nature” of J&J’s ‘fail first’restriction – which requires patients to fail on Remicade first beforea biosimilar infliximab can be reimbursed – is illustrated by “the factthat in early 2017, before J&J’s contracts took hold, the major insurerslisted Inflectra at parity with Remicade, indicating that they saw nomedical reason to favour one over the other”.
But, Pfizer claims, J&J has successfully coerced insurers intoaccepting exclusionary commitments by denying rebates to insurersthat decline its commitments for existing-patient Remicade demand.This economically ‘incontestable’ portion of the market is not arealistic candidate for biosimilar firms to compete for given existingRemicade patients’ unlikeliness to switch to a biosimilar once available.
“J&J bundles this economically ‘incontestable’ demand forRemicade with the portion of demand that is ‘contestable’ for biosimilarfirms – new patients starting therapy with infliximab – by threateningto deny rebates on all Remicade prescriptions if any infliximabbiosimilar prescriptions are reimbursed,” Pfizer alleges.
“Given the widespread gaps in Inflectra’s insurance coverageproviders have overwhelmingly chosen to stock only Remicade ratherthan deal with the risk of possible denials of coverage for Inflectra,”Pfizer states, noting that as a result of J&J’s alleged tactics Inflectrahad secured less than 4% of total infliximab unit sales in the US asof 1 September 2017. “If J&J’s conduct is allowed to continue, its‘Biosimilar Readiness Plan’ will become the playbook for biologicoriginator firms seeking to preserve their dominance in the face ofbiosimilar competition,” Pfizer believes.
In the 10 months since launch, Inflectra’s WAC has dropped to19% lower than Remicade, according to Pfizer, which also competeswith Merck’s Renflexis (infliximab-abda) that launched in July at a35% discount to Remicade (Generics bulletin, 28 July 2017, page 1).Gn [email protected]
AUTOIMMUNE DISEASES TREATMENTS
Pfizer accuses J&J ofblocking US Inflectra
Samsung Bioepis has obtained a marketing authorisation for its SB5adalimumab candidate from South Korea’s Ministry of Food and
Drug Safety (MFDS) under the brand name Hadlima. The approvedindications for the biosimilar Humira are for treating rheumatoidarthritis, juvenile idiopathic arthritis, axial spondyloarthritis, psoriaticarthritis, psoriasis, Crohn’s disease and ulcerative colitis.
In a filing submitted to the country’s Kospi stock exchange, parentgroup Samsung Biologics said “launch timing in Korea will bedetermined after expiration of Humira’s patent”.
The Korean approval for SB5 comes less than a month after theEuropean Commission granted Samsung Bioepis a pan-Europeancentralised marketing authorisation for adalimumab under the Imraldibrand name. At the time, the joint venture between Samsung Biologicsand Biogen said it would “continue to closely collaborate with Biogenin preparing for launch plans”, with Biogen to be responsible forcommercialisation in the European Union (EU).
Following the EU approval for Imraldi, a spokesperson for Biogentold Generics bulletin that “the product will not be available before thefourth quarter of 2018 or early 2019” (Generics bulletin, 1 September2017, page 21). Supplementary protection certificates (SPCs) linkedto the European adalimumab molecule patent EP0,929,578 are setto expire in mid-October next year.
Samsung Bioepis already holds approvals in both South Koreaand Europe for its SB2 infliximab and SB4 etanercept biosimilars. Thejoint venture has also received authorisations for etanercept in Australiaand Canada, as well as for infliximab in Australia and the US. G
ANTI-INFLAMMATORY DRUGS
Samsung Bioepis getsadalimumab in Korea
Three challengers to patents protecting Amgen’s Sensipar (cinacalcet)blockbuster treatment for secondary hyperparathyroidism in kidney
dialysis patients have settled litigation that had been brought by theoriginator in a Delaware district court.
In a consent judgement signed off by Delaware District JudgeGregory Sleet on 21 September, Breckenridge Pharmaceutical admittedthat Amgen’s US patent 9,375,405 – which expires on 22 September2026, and is entitled ‘Rapid dissolution formulation of calcium receptor-active compound’ – is enforceable, valid and infringed by its proposedgeneric cinacalcet tablets. “All other claims and demands for reliefprayed for by Amgen against the defendant in this action are deemedto be satisfied,” Sleet declared.
Settlement agreements reached recently between Amgen andgeneric challengers Apotex and Micro Labs remained under court sealas Generics bulletin went to press.
In litigation that has been consolidated by the Delaware court,Amgen is suing many of the world’s leading generics players overSensipar. Defendants include Ajanta, Amneal, Aurobindo, Cipla,Dr Reddy’s, Hetero and Mylan, as well as Piramal, Strides, Sun, Teva’sActavis/Watson and Zydus Cadila.
Amgen reported US sales of Sensipar – which is protected by twoother patents listed in the Orange Book maintained by the US Food andDrug Administration (FDA), US patent 6,011,068 expiring on 8 March2018 and 7,829,595 that runs until 22 September 2026 – that increasedby 13% to US$342 million in the second quarter of this year. G
KIDNEY DISEASE DRUGS
Three settle over US Sensipar
14 GENERICS bulletin 29 September 2017
PRODUCT NEWS
Amneal and Apotex have failed to convince a New York districtjudge that a US polymorph patent protecting Kowa’s Livalo
(pitavastatin calcium) tablets until 2 February 2024 is invalid due toanticipation and/or obviousness. Judge Paul Crotty also ruled thatApotex’ abbreviated new drug application (ANDA) infringed US patent8,557,993, with Amneal already having conceded that its genericsformulation infringed the patent.
Kowa had alleged that ANDAs filed by both Amneal and Apotexinfringed six key claims of the ‘993 patent, which is directed to newcrystalline forms of pitavastatin calcium, as well as to an amorphousform. Specifically, the Japanese originator argued that the genericproducts contained ‘Form A’, one of six polymorphs covered by thesix patent claims at issue. Amneal had stipulated that its version wasin Form A, and thus directly infringed the asserted claims of the‘993 patent, if valid. By contrast, Apotex insisted that the activepharmaceutical ingredient (API) in its ANDA product did not meetthe claim limitations of the ‘993 patent, and thus did not infringe.
Both Amneal and Apotex contended that the ‘993 patent wasinvalid due to inherent anticipation in light of a European patentapplication EP0,520,406A1 and/or was obvious in view of the priorart as of the patent’s priority date of 12 February 2003.
Addressing anticipation, Crotty said the generics companies hadnot proven that practising Example 3 of the European ‘406 application“necessarily and inevitably” results in Form A. Noting that the ‘406application did not describe any polymorphs of pitavastatin calcium,the judge observed that the US Patent and Trademark Office (USPTO)examiner had considered the ‘406 application during her prosecutionof the ‘993 patent.
Skilled person could produce several polymorphs“A person of skill in the art (POSA) following Example 3,
‘filling in’ and choosing the drying conditions from a ‘broad’ range ofoptions, could produce a pitavastatin calcium product with varyingwater contents and, possibly, varying polymorphic forms,” Crotty saidin ruling out inherent anticipation.
Turning to obviousness, Crotty noted that Amneal and Apotexhad asserted that a skilled person as of the ‘993 patent’s 2003 prioritydate would have been motivated to perform a ‘routine’ polymorphscreen on pitavastatin calcium and would have had a reasonableexpectation that the screen would have produced Form A as claimed bythe ‘993 patent. But the judge found that this argument was “driven byimpermissible hindsight”, as a skilled person performing such a screen“would not have been able to predict the results of the experiments,including whether a substance would be polymorphic”, and thus wouldnot have had a reasonable expectation of success in obtaining Form A.
And even if the ANDA filers had established a prima facie caseof obviousness, Crotty continued, secondary considerations – including“commercial success”, with Livalo achieving US sales of US$279 millionlast year – supported a finding that the ‘993 patent was not obvious.
On the question of whether Apotex’ ANDA infringed the ‘993patent, Crotty preferred the evidence of Kowa’s expert witnesses whotestified that the x-ray diffraction pattern of the API supplied to Apotexby MSN matched that of Form A.
Earlier this year, the same court upheld Kowa’s US Livalo patent5,856,336, which expires on 25 December 2020. Six generics developershave already reached litigation settlements with Kowa. Gn [email protected]
CHOLESTEROL-LOWERING DRUGS
Amneal and Apotexare beaten on Livalo
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Nacimbio, the immunology arm of Russia’s state-owned Rostecconglomerate, says it has entered into an agreement with the Indian
affiliate of Mylan to source active substances with which to produce“modern combined drugs for HIV treatment”.
Speaking at the Biotechmed-2017 conference held in Gelendzhik,Russia, Rostec’s head, Sergey Chemezov, said the state-ownedcorporation was aiming to reduce Russia’s reliance on imported finished-dosage forms. “We are developing our own drug-producing facilities,including in co-operation with renowned foreign pharmaceuticalcompanies that are ready to move their production capacities to Russia.”
Chemezov said the alliance with Mylan would provide Nacimbiowith “a supply of substances, transfer of technology and the productionof modern combination drugs for HIV treatment”. As a result, the costof antiretrovirals in the Russian market would “significantly decrease”.
Currently, Nacimbio supplies 17 vaccines under state contractswith Russia’s Ministry of Health, of which 14 are “completely Russian-made”. The company’s development strategy foresees producing by2025 around a fifth of local demand for treatments for HIV as wellas hepatitis B and C. Furthermore, the state-owned producer – whichincludes Sintez among its manufacturing assets – intends to meet alldemand in Russia for vaccines and blood plasma factors.
Separately, Nacimbio has struck a deal to export medicines toUzbekistan through an alliance with local player Uzmedexport. G
HIV DRUGS
Mylan links on HIVwith Russia’s Rostec
Draft guidance on “statistical approaches to evaluate analyticalsimilarity” for biosimilars has been published by the US Food and
Drug Administration (FDA). Open for comment for 60 days, thedocument sets out “general principles for evaluating analytical similarity”.
Insisting that “appropriate statistical analyses in the evaluation ofanalytical similarity can provide a high degree of confidence in theresults and reduce the potential for bias”, the document neverthelessacknowledges that “there are many challenges in designing the statisticalanalyses to be performed”. These include the possibility that there are“a limited number of reference product lots, and those obtained maybe the result of biased sampling, leading to imprecise and possiblyinaccurate estimates of the distributions of important quality attributes”.
There may also be a limited number of biosimilar lots “and theavailable lots may not reflect the true variability of biosimilar productmanufacturing”. And the “large number of potential quality attributesthat can be compared in an evaluation of analytical similarity” couldlead to “concluding incorrectly that a large number of truly highlysimilar products are not highly similar”.
To address these challenges, the agency recommends “a risk-based approach” consisting of several steps: determining characteristicquality attributes of a product; ranking them according to the risk ofclinical impact; and evaluating them according to “one of three tiersof statistical approaches” set out in detail by the document. G
BIOLOGICAL DRUGS
FDA publishes guideon judging similarity
29 September 2017
16 GENERICS bulletin 29 September 2017
PRODUCT NEWS
Oncologists and haematologists in Germany should ensure they arewell informed about the key concepts supporting biosimilarity,
according to a chapter included the latest ‘innovation report’ releasedby academics along with the country’s Techniker Krankenkassehealth insurance fund.
Pointing out that a wave of approvals for oncology biosimilarswas anticipated, the report’s authors – Professor Gerd Glaeske fromBremen university and Wolf-Dieter Ludwig, an oncologist who chairsthe German doctors’ medicines commission, the AkdÄ – argue thatstudying key concepts such as extrapolation of indications,interchangeability and immunogenicity is a “pre-requisite for makingevidence-based, appropriate and economic decisions on therapy”.
“Concerns and fears often voiced about biosimilars have to beaddressed through independent, understandable information for doctors,care providers and patients,” the authors insist.
“From a clinical perspective,” Glaeske and Ludwig maintain,“biosimilars are suitable alternatives to off-patent, costly referencemedicines.” “Many years of experience with biosimilars support theunproblematic interchangeability of reference drugs and biosimilars,”they state, adding that no data from clinical trials, registers or otherstudies give reason not to use biosimilars. “In Europe,” they point out,“not one market withdrawal of biosimilars has occurred on groundsof safety or insufficient efficacy.”
Particularly in the oncology arena, the authors recognise, questionshave been raised about extrapolation between localised and metastaticstages of cancer, as well as between adjuvant and neoadjuvant regimens.To combat such concerns, they say, specialists need to be better informedof how the same principle has been applied for years to ensure originalbiologics remain equally safe and effective after manufacturing changes.
Using biosimilars for oncology indications can “contribute toreducing healthcare spending and upholding the sustainability ofhealthcare systems”. This, the authors note, is particularly true afterthe entry earlier this year of Mundipharma’s Truxima (rituximab) intoa German market for the monoclonal antibody valued at aroundC287 million (US$342 million) last year.
Welcoming the inclusion of a chapter on biosimilars in the reportlargely dedicated to assessing the economic value of new medicines,German industry association Pro Biosimilars highlighted Ludwig’sstatement that “several studies have shown in the past few years thatswitching from the reference biologic to a less expensive biosimilaris possible without negative effects on efficacy or side effects”.
Selective contracts could improve biosimilars adoption, ProBiosimilars commented, while prescribing quotas could address widevariations in usage at a regional level.
Estimating savings for statutory health insurance funds of up toC500 million per year through greater use of biosimilars, Ludwig alsonoted that the AdkÄ had recently updated its guidelines on biosimilarsto give “clear recommendations for their rational use”. G
ONCOLOGY DRUGS
German oncologistsshould study process
Mylan and Aurobindo have joined forces with a host of charitableorganisations to facilitate the availability of the first “affordable”
generic dolutegravir-containing antiretroviral to public-sector purchasersin more than 90 low- and middle-income countries (LMICs), includingKenya and South Africa, through a “breakthrough pricing agreement”that is part of “global efforts to reach all 36.7 million people livingwith HIV with high-quality antiretroviral therapy”.
Priced at US$75 per person per year, Aurobindo’s and Mylan’sdolutegravir/lamivudine/tenofovir disoproxil fumarate once-a-dayfixed-dose combination 50mg/300mg/300mg generic tablets weredeveloped under license from originator Viiv Healthcare, innovatorof the Tivicay (dolutegravir) brand.
Global organisations behind the pricing agreement include theJoint United Nations Programme on HIV/AIDS (UNAIDS), theClinton Health Access Initiative (CHAI), the Bill & Melinda GatesFoundation (BMGF), Unitaid, the UK’s Department for InternationalDevelopment (DFID), the US President’s Emergency Plan For AIDSRelief (PEPFAR), the US Agency for International Development(USAID), as well as the Global Fund to Fight AIDS.
“Ministries of Health and programme managers should anticipatebeing able to order dolutegravir/lamivudine/tenofovir disoproxilfumarate in 2018 at around a projected average price of US$75 perpatient, per year,” the CHAI commented, noting that further pricingdetails were “available upon request” to Mylan or Aurobindo. “Theceiling price agreements apply to purchases for public-sector use in all92 countries covered under Viiv’s dolutegravir licensing agreement,representing over 90% of people in LMICs currently living with HIV.”
Both Aurobindo and Mylan have recently obtained tentative USFood and Drug Administration (FDA) approval for their new drugapplications (NDAs) under the PEPFAR programme. “UNAIDSestimates that in 2016, just over half – 19.5 million – of all people livingwith HIV had access to the lifesaving medicines,” the CHAI noted.
The CHAI added that in addition to “improving treatment qualityand retention”, “widespread use of dolutegravir is expected to lower thecost of first-line HIV treatment regimens while also reducing the needfor more expensive second- and third-line regimens”. The World HealthOrganization (WHO) had in July this year issued guidance to countries“on how to safely and rapidly transition to dolutegravir-basedantiretroviral treatment”, noted the CHAI, which added that the upperprice limit for the fixed-dose combination was expected to save publicsector purchasers up to US$1 billion over six years.
Commenting on the agreement, South Africa’s health minister,Aaron Motsoaledi, said the country would introduce the genericantiretroviral in April next year, with the launch set to save SouthAfrica “up to ZAR11.7 billion (US$883 million) over the next sixyears”. “The large volumes of antiretrovirals purchased by South Africawere used to leverage the decrease in pricing that will benefit allLMICs,” South Africa’s government claimed.
Meanwhile, Kenya’s health secretary Cleopa Mailu pointed toantiretroviral therapy guidelines introduced by Kenya in July last yearthat made provisions for use of “newer antiretroviral medicines such asdolutegravir”. “Research has shown that dolutegravir offers bettertolerability, fewer adverse drug reactions, fewer drug interactions, andhigher genetic barrier to resistance. It is with this in mind that, in Julythis year, Kenya approved its inclusion in the National AntiretroviralTherapy (ART) Program.” Gn [email protected]
ANTIRETROVIRALS
Mylan and Aurobindosign price agreement
GENORPH – the French generic orphan drugs specialist – hasreceived a positive opinion from the committee for human medicinalproducts (CHMP) within the European Medicines Agency (EMA) fora generic version of Actelion’s Zavesca (miglustat) 100mg capsulesfor treating Gaucher disease. G
IN BRIEF
17GENERICS bulletin29 September 2017
PRODUCT NEWS
Zolpidem Oro-Dispersible TabletBioequivalent to Stilnox® Sanofi France
Drug Delivery Solutions Pvt Ltd
Athena has an EU GMP approved facility forGranules, Tablets, Capsules & Sachet lines.
Strides Shasun is supplying the generic version of GlaxoSmithKline’sLovaza (omega-3 acid ethyl esters) soft-gel capsules for Endo’s
Par affiliate to market in the US. Having just secured approval fromthe US Food and Drug Administration (FDA), Strides is producingthe cholesterol-lowering capsules at its facility in Bangalore, India.
The Indian firm noted that Par – along with Teva – was one of thefirst firms to offer a generic version of Lovaza in a US market valuedat around US$300 million per year. Amneal and Apotex also holdgeneric approvals for the soft-gel capsules.
“We are delighted with this important product approval, whichcame through after a long approval cycle of almost 60 months, due tosignificant regulatory changes,” commented Strides’ managing director,Shashank Sinha. Late last year, the FDA amended its draft guidelineon establishing bioequivalence for omega-3-acid ethyl esters. Theagency recommends conducting one in vitro study using a quantitativecapsule rupture test or two in vivo studies in both fasting and fed subjects.
Separately, Strides has received its first FDA approval for anextended-release formulation. The Indian firm said it would launchimmediately its potassium citrate 5mEq, 10mEq and 15mEq extended-release tablets equivalent to Mission Pharmacal’s Urocit-K kidney-stone treatment. “Strides Shasun will be the second generics playerto commercialise the product,” the firm stated, adding that the USpotassium citrate market was around US$110 million per year. G
CHOLESTEROL-LOWERING DRUGS
Strides supplies Parwith soft-gels in US
InterPharma has been barred from making, marketing or supplyinggeneric dexmedetomidine for use in intensive care unit (ICU) sedation
in Australia. Pfizer and its Hospira affiliate, along with partner Orion,convinced Federal Court Judge Susan Kenny to issue a restrainingorder to stop sales of the generic sedative pending a hearing oninterlocutory relief scheduled for 23 November.
In issuing the order – which includes a demand that InterPharmarecall, purchase back or take other steps to recover all stocks of itsgeneric version of Hospira’s Precedex (dexmedetomidine) already intrade channels – Kenny noted that a hearing on an interlocutoryinjunction had originally been set to take place on 8 September. Whenthe court was forced to reschedule to 23 November, Hospira hadsought immediate relief, claiming that InterPharma had failed to giveundertakings not to offer or supply its generic before the hearing.
Hospira alleged that InterPharma’s generic version of Precedexwould infringe all claims of Australian patent 754,484 that coversusing dexmedetomidine for ICU sedation until it expires on 31 March2019. However, InterPharma – which acts as a local distributor forcompanies including Concordia and Wockhardt – countered that the‘484 patent was invalid due to lack of novelty and inventive step, aswell as for lack of fair basis and clarity.
Noting that marketing authorisations for dexmedetomidine thatInterPharma had obtained in July this year under the Ever Pharma labelhad included the patented ICU indication in labelling, Kenny saidHospira appeared to have “a prima facie case of infringement”. “Theevidence presently before the court does not permit assessment ofInterPharma’s case on invalidity,” she added.
Kenny concluded that the balance of convenience favouredgranting interim relief to Hospira. The ‘484 patent, she pointed out,had been “registered for some time without challenge”, with InterPharmahaving taken “no steps to clear the way” until commencing invalidityproceedings on 8 August this year.
And while there was evidence before the court that InterPharmahad sold its sedative to customers, the distributor’s marketing activitieshad prompted Hospira’s customers to seek new pricing deals. Allowingthe generic to remain in the market would force Hospira to cut itsprice or lose market share, leading to a “substantial financial loss” forwhich damages would be difficult to calculate. G
SEDATIVES
Australian order haltsPrecedex alternative
Amneal has settled its US patent litigation over AstraZeneca’sByetta (exenatide) on confidential terms. As part of the settlement
that has just received assent from Delaware District Judge GregorySleet, the generics firm has admitted both the invalidity and infringementof all eight patents listed against the twice-daily injectable diabetesbrand in the Orange Book maintained by the US Food and DrugAdministration (FDA).
However, the Orange Book shows, two of those patents havealready expired, and two more run out on 15 October this year. Anothertwo expire in January 2018, and the remaining two in January 2020.
In the first half of this year, AstraZeneca reported US Byetta salesdown by 35% to US$58 million as the originator switched its promotionalfocus to its once-weekly Bydureon (exenatide) formulation. G
DIABETES DRUGS
Amneal settles over Byetta
18 GENERICS bulletin
MARKET RESEARCH
QuintilesIMS sees US savings
29 September 2017
When the market opportunity offered by brandpatent expiries hit a high in 2012, there wasmuch talk of a ‘patent cliff’ after which the
value of targets for generics developers would rapidlydiminish. And in subsequent years, the savingsrepresented by losses of exclusivity (LOEs) in the USfell from US$32.6 billion in 2012 to US$20.6 billionin 2013 and just US$12.3 billion in 2014, includingboth small-molecule and biologic drugs.
But while the value of US losses of exclusivity wereonly barely higher in the two years after that – amountingto US$14.2 billion in 2015 and US$14.0 billion in2016 – the sharp increase forecasted by QuintilesIMSto US$22.0 billion in 2017 is just the start of a reversalthat will see the figure rise from now through to 2021.
“The total impact of patent expiries is expected to be50% higher in the next five years than in the last five,”QuintilesIMS states in its latest report, ‘Understandingthe Drivers of Drug Expenditure in the US’, citing atotal figure of US$140.4 billion from 2017 to 2021,compared to US$93.6 billion for the past five years(see Figure 1). “However, excluding biosimilars theimpact is expected to be US$102.9 billion, comparedto US$91.1 billion in the prior five years.”
“The impact of patent expiries has been relativelyunchanged for the past three years,” QuintilesIMSexplains, “but is expected to increase sharply in 2017and again in 2018”. Over the past five years, the reportnotes, “21 products lost exclusivity and had revenuesreduced by more than US$1 billion, with an aggregateimpact of US$67.2 billion.” These included blockbusterdrugs such as Lipitor (atorvastatin), Plavix (clopidogrel),Abilify (aripiprazole) and Singulair (montelukast), aswell as Cymbalta (duloxetine), Seroquel (quetiapine),Nexium (esomeprazole), Lexapro (escitalopram) andZyprexa (olanzapine).
Also cited by QuintilesIMS as being partlyresponsible for the loss of exclusivity figure over thepast five years are Actos (pioglitazone), Celebrex(celecoxib), Crestor (rosuvastatin), Diovan (valsartan)and Diovan HCT (valsartan/hydrochlorothiazide),along with Tricor (fenofibrate), Namenda (memantine),Geodon (ziprasidone), Provigil (modafinil), Eloxatin(oxaliplatin), Gleevec (imatinib) and Copaxone(glatiramer acetate) 20mg.
Noting that “the largest-selling branded medicine,Humira (adalimumab), is expected to face biosimilarcompetition in late 2018”, QuintilesIMS observes thatother biosimilars anticipated in 2018 or 2019 includerivals to Erbitux (cetuximab), Herceptin (trastuzumab)and Avastin (bevacizumab).
“Net revenue growth for prescription medicinesis projected to average 2-5% through 2021,” the reportoutlines, although it acknowledges that “price growthof existing products has been declining as protectedbrands price increases have slowed and been offset bythe impact of losses of exclusivity”.
As Figure 2 shows, “the impact on aggregatemanufacturer net revenues of patent expiries hasoutweighed the impact of manufacturer price increasesover the past six years”, due to “the significant reductionin the price of a medicine after loss of exclusivity andintroduction of competition”.
In calculating its estimates of net revenues,QuintilesIMS makes adjustments to the wholesaleacquisition cost (WAC) to reflect elements such as off-invoice discounts and rebates, or other price concessions.These adjustments differed for protected brands andgenerics (see Figure 3).
“Invoice-based pricing is derived from QuintilesIMSproprietary information gathered from wholesalers andcompany direct sales,” the market researcher explains.“For generic companies, a sample of five large genericcompanies’ generic portfolios were analysed inaggregate consistent with their US Securities andExchange Commission (SEC) filings, as specific genericproduct analyses are not possible.” G
Series3
100
80
60
40
20
0
Adj
ustm
ent
(%)
Protected brands Generics Total
WAC Invoice Net
100% 100% 100%
84%
56% 55%39%
74%53%
33%44%
30%
61%28%
47%
Figure 3: 2016 average net sales adjustment by product type (Source – QuintilesIMS)
US savings from patent
expiries are due to grow
by 50% over the next
five years, according
to QuintilesIMS.
David Wallace reports.
10
5
0
-5
-10
-152011 2012 2013 2014 2015 2016
CAGR 2010-2016
Impact of LOEon price
Total existingproduct price
Brand andgeneric price
+3.3%
-2.5%
-5.8%
Figure 2: Net price growth percentage contribution to overall sales growth for existing products notwithin 24 months of launch or off-patent in the US (Source – QuintilesIMS)
Series1 Series2Small molecules Biologics
2012 2013 2014 2015 2016 2017 2018 2019 2020 2021
-32.
1
-20.
5
-12.
1
-13.
4
-13.
1
-17.
8
-32.
0
-21.
8
-15.
2
-16.
0
-0.5
-0.1
-0.2
-0.8
-0.9
-4.2
-5.0 -9
.0
-10.
9 -8.5
-US$93.6 billion -US$140.4 billion
Figure 1: Actual and forecast lower brand spending in the US due to loss of exclusivity between2012 and 2021 (Source – QuintilesIMS)
20 GENERICS bulletin 29 September 2017
PEOPLE
Neogen is looking fora Licensing Manager
The ideal candidate will have several yearsexperience in out-licensing in Europe andpreferably other territories.Neogen’s headquarters are located inBelgium, but some flexibility is possiblefor the right candidate.We ask candidates to send their interestto our HR Manager, Marieke Houthuys [email protected] or +32 (0)2 526 64 10.
24th-26th OCTOBER 2017-FRANKFURT-Germany
Visit us at stand 90F80
Please visit our websitefor more information:
www.neogen.be
MALLINCKRODT has elected David Norton to its board of directors.Boasting “more than 30 years of experience in the biopharmaceuticalindustry” – including as Johnson & Johnson’s company groupchairman for global pharmaceuticals – Norton will serve as anindependent director on the board’s human resources and compensationcommittee, as well as its portfolio committee. Norton also currentlyserves as chairman of the board of directors for Vivus.
VIVIMED chief executive officer Pavan Kumar “will be transitioninginto an advisory position for Vivimed”, according to the Indiancompany. No further details of the development were given in theannouncement that followed a meeting of the firm’s board of directorsat the end of August.
TELIGENT has appointed Aetna’s general counsel, Thomas Sabatinoto its board of directors. Teligent president and chief executiveofficer Jason Grenfell-Gardner said Sabatino’s “extensiveexperience in the various aspects of the pharmaceutical industry,including experience in manufacturing, wholesale and retaildistribution, as well as his most recent experience on the payorside of the business, will be a valuable asset to Teligent”.
VANC says its directors received “overwhelming support” at itsannual general meeting in mid-September. Bob Rai, David Hall,Alan Arnstein and Sherif Guorgui were each re-elected “with eachreceiving over 98% of the votes cast at the meeting in their favour”.Rai – the Canadian firm’s chief executive officer – said the results“clearly affirm shareholders’ support of Vanc’s management andits strategy”. “With the overwhelming support of shareholders,”Rai added, “Vanc will continue to work towards becoming a healthsolutions provider for pharmacies.”
BMWP – the Biosimilar Medicinal Products Working Party for thecommittee for human medicinal products (CHMP) within theEuropean Medicines Agency (EMA) – has named Niklas Ekmanas vice-president for a three-year term. Ekman – a special researcherat the Finnish Medicines Agency, Fimea – serves on the BMWPunder chair Elena Wolff-Holz. Other members include Sean Barry,Marie-Christine Bielsky, Karen De Smet and Thijs Giezen, aswell as Nanna Aaby Kruse, Alexandre Moreau, Leon van Aertsand Martina Weise.
DOWDUPONT – the entity resulting from the merger of Dow Chemicaland DuPont that was completed at the end of August – has confirmedits 16-strong board of directors that includes eight directors eachfrom the former Dow and DuPont boards. DowDuPont – led bychief executive officer Ed Breen along with executive chairmanAndrew Liveris – said it was focusing on “finalising the organisationalstructures that will be the foundations of” the three independent,publicly-traded companies that are due to be spun out of the company.Three advisory committees have been established by the board to“generally oversee the establishment of” the Agriculture, MaterialsScience and Specialty Products divisions in preparation for theseparation. Pharmaceuticals are included in the latter segment.
CMA – the UK’s Competition and Markets Authority – has announcedthat its chair David Currie is to step down “in the coming months,once a successor is identified and in place”. “Handing over theorganisation’s leadership at this point will allow his successor toboth shape and deliver the organisation’s approach to Brexit,” theCMA stated. Currie said the UK’s decision to leave the EuropeanUnion (EU) was “likely to generate a big increase in the CMA’sworkload and its role in the world”. G
IN BRIEF
Lannett’s board of directors says chief executive officer ArthurBedrosian has “agreed to step down” upon the company appointing
his successor, after it unanimously approved plans to begin searchingfor a new company head and retained a “leading executive searchfirm to identify potential candidates to assume the role”.
“During the search process, Bedrosian will remain a member ofthe board of directors,” Lannett clarified. “Following the appointmentof a successor, it is expected that Bedrosian will remain with thecompany in a strategic advisory role, ensuring a seamless transition ofleadership responsibilities.” Thanking Bedrosian for his service toLannett, chairman Jeffrey Farber said the board’s search for Bedrosian’ssuccessor was “in the early stages”.
Chief executive officer of Lannett since January 2006, Bedrosianfirst became affiliated with the US generics specialist in February 2000when he joined the company’s board of directors. He resigned fromthe board early in 2002 to become Lannett’s vice-president of businessdevelopment before being appointed company president in May thatyear. Bedrosian was re-appointed to Lannett’s board in 2006.
News of the board’s decision to search for a new chief on 25September came three days after Bedrosian won a lawsuit he had filedagainst the US Internal Revenue Service (IRS), according to Lannett,after the IRS “claimed Bedrosian failed to properly and timely report aforeign bank account” he had opened in 1973. G
