eight eu authorities are deemed equivalent to us · “following the creation of aristo pharma...

3 November 2017

Eight EU authorities aredeemed equivalent to US

COMPANY NEWS 2Aristo buys Amneal in Nordics and Spain 2Biocad is gearing up to market in Europe 3Sandoz enjoys Rixathon 4and Erelzi startAkorn Grand Avenue facility received 483s 5WBA is set to shut 600 stores in the US 6CVS and Anthem ally for a 7PBM deal in USFinnish price reform exacts toll on Orion 8

MARKET NEWS 10Industry urges action on SPC waiver in EU 10US attorneys aiming to 11widen suit’s scopeEMA continuity plan not business as usual 12Commission admits to PUMA plan failure 13US$54bn in savings from US biosimilars 14Health Canada plans labelling 15fee overhaul

PRODUCT NEWS 18Fluticasone is among new 18FDA guidancesSandoz resubmits EU pegfilgrastim dossier 19Germany is missing biosimilars potential 20Biomm hits a block on 21Brazilian glargineMylan sued in the US over insulin glargine 22Swiss court upholds an SPC for Truvada 23US opioid crisis is a national emergency 24

FEATURES 30Impax and Amneal eye new 30channels for US distributionBecoming a leader in alternative direct-to-patient distribution is among the numerousbenefits that Amneal and Impax expect todrive future growth as a combined company.Dean Rudge reports.

REGULARSEvents – Our regular listing 8Price Watch UK – Our regular listing 10People – GBMA seeks a chief 32as Wood steps down

Issue No.328

Eight European Union (EU) national authorities have been recognised as “capable ofconducting inspections of manufacturing facilities that meet US Food and Drug

Administration (FDA) requirements” by the US agency, as part of a good manufacturingpractice (GMP) mutual recognition deal struck by European and US regulators earlier thisyear. Authorities in Austria, Croatia, France, Italy, Malta, Spain, Sweden and the UK wererecognised under the agreement, in what the FDA called an “important milestone”.

“Beginning 1 November, we will take the unprecedented and significant step forward inrealising the key benefits of the mutual recognition agreement with our European counterpartsin that we will now rely on the inspectional data obtained by these eight regulatory agencies,”stated Dara Corrigan, the FDA’s acting deputy commissioner for global regulatory operationsand policy. “The progress made so far puts us on track to meet our goal of completing all 28capability assessments in the EU by July 2019.”

Under the terms of the agreement, the FDA was due to have completed an assessment of“at least eight EU member states” by 1 November, gradually expanding these assessments toall member states by mid-2019 (Generics bulletin, 10 March 2017, page 1). In June 2017, theEuropean Commission determined that the FDA “has the capability, capacity and proceduresin place to carry out GMP inspections at a level equivalent to the EU”.

“The completion of these capability assessments enables the FDA and the EU to avoidduplication of drug inspections and allows regulators to devote more resources to othermanufacturing facilities in countries where there may be greater risk,” the FDA pointed out.“At a time in which medical product manufacturing is truly a global enterprise,” said FDACommissioner Scott Gottlieb, “there is much to be gained by partnering with regulatorycounterparts to reduce duplicative efforts and maximise global resources while realising thegreatest bang for our collective inspectional buck.” Through the partnership, Gottlieb said, “wecan create greater efficiencies and better fulfill our public health goals”. G

Hikma is Company of the YearHikma was named Company of the Year at the Global Generics & Biosimilars Awards, held on

24 October in Frankfurt, Germany, by Generics bulletin and co-hosted by QuintilesIMS.Meanwhile, Accord Healthcare took home three prizes. The Intas subsidiary won the award

for Acquisition of the Year, sponsored by Pharmawise, for its £603 million (US$791 million)purchase from Teva of the former Actavis business in the UK and Ireland that was completedat the start of this year (Generics bulletin, 13 January 2017, page 5). Accord was also giventhe award for Patent Litigation of the Year for challenging European patent-protection for ahigh-concentration formulation of methotrexate, as well as winning the award for BusinessDevelopment of the Year for developing lenalidomide tablets.

Amneal picked up two awards – the Chartwell Pharmaceuticals-sponsored award forCompany of the Year in the Americas region and the Pharmacloud-backed award for Leaderof the Year, won by co-founders and co-chief executive officers Chintu and Chirag Patel –while Sandoz was recognised with both the Regulatory Achievement of the Year award sponsoredby Eignapharma, as well as with the Biosimilar Initiative of the Year award. Other awardssponsors included Clarivate, Evapharma and International Health Partners, as well as mAbxience,Panacea and Piramal. Next year, the Global Generics & Biosimilars Awards 2018 – whichare free to enter and attend – are due to take place on 9 October in Madrid, Spain. G

See page 25 for coverage of the event and winners

Gen 3-11-17 Pg.1.indd 1 01/11/2017 17:35

2 GENERICS bulletin 3 November 2017

COMPANY NEWS

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Issue 328 l 3 November 2017

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Recipharm has enhanced the serialisation capabilities of its site inLisbon, Portugal, ahead of looming US and European enforcement

deadlines. Noting that the Lisbon facility was its sixth site to “becomeserialisation-ready for the US and European markets”, the Swedishcontract developer and manufacturer said it had added an “additionalfour packaging lines to the company’s current serialisation capabilities”.A further seven lines would be added to the facility by June 2018,Recipharm noted.

In February 2016, Recipharm unveiled a three-year plan to investC40 million (US$47.1 million) in serialisation technology and processesto comply with the European Union’s Falsified Medicines Directive.At the time, Recipharm said it would be “ready for US serialisation fromNovember 2017, in line with the US Drug Supply Chain Security Act”.

Earlier this year, however, the US Food and Drug Administration(FDA) issued draft guidance for industry stating that manufacturerswould not face action from the agency for failing to comply with ‘trackand trace’ product identifier and verifier requirements for an additionalyear beyond the current guideline (Generics bulletin, 14 July 2017,page 10). Due to industry-wide readiness concerns, the FDA delayedproceedings by a year, pushing back the action date to 27 November 2018.

‘Preparing for a long time’“Recipharm recognised the complexity of implementing serialisation

at a very early stage,” insisted Staffan Widengren, Recipharm’sdirector for corporate projects, “and so we have been preparing for thenew regulations in the US and Europe for a long time now.” Thisincluded forming a global alliance to “introduce new serialisationcapabilities” with Italian firms Marchesini and SEA Vision, and US-based TraceLink in mid-2016 (Generics bulletin, 8 July 2016, page 4),as well as delivering its first serialised batch to Saudi Arabia earlierthis year (Generics bulletin, 28 April 2017, page 4).

Recipharm said it had “already delivered over 1.3 million serialisedand aggregated packs to markets such as China, South Korea, SaudiArabia and Turkey, where serialisation regulations are currently inplace”. Widengren, who also leads the global steering committee forRecipharm’s serialisation project, observed that the Lisbon facility“brings us to over a third of the way through our implementation project”.The Swedish firm said its next site to be equipped would be a facilityin Brescia, Italy, that would “supply serialised products to the US”. G

MANUFACTURING

Recipharm improvesserialisation abilities

Germany’s Aristo Pharma has struck a deal to acquire AmnealNordics and Amneal Spain. The agreement follows Strides Shasun’s

acquisition of Amneal Australia through the Indian firm’s ArrowPharmaceuticals unit (Generics bulletin, 8 September 2017, page 3)and comes as Amneal prepares to integrate with Impax following thepair’s agreement to merge (Generics bulletin, 20 October 2017, page 1).

“The acquisition of Amneal Nordics will provide Aristo with anideal platform for expanding its business into the Nordic countries,”the German firm declared. It has renamed the unit – which has itsheadquarters in Copenhagen, Denmark – as Aristo Pharma Nordic.

“At the same time,” Aristo stated, “the company is expanding theAristo Pharma Iberia business in Spain by about 40 additional activeingredients” with the acquisition of Madrid-based Amneal Spain.

Synergies from the deal would also be evident for Aristo UK, thefirm noted, with the UK operation gaining 20 new products. “In addition,the acquisition contains extensive dossier rights,” Aristo said, “whichinclude the right to expand into other countries.”

“Following the creation of Aristo Pharma Iberia in 2013 andAristo UK in 2016, the acquisition of Amneal Nordics and Spain is afurther step on Aristo’s journey to become a major generics playerin Europe.” The German firm previously took over UK-based CEBPharma (Generics bulletin, 10 March 2017, page 5).

Formed in 2008, Berlin-based Aristo offers a wide array ofgenerics, mature brands and herbal remedies that it produces through anetwork of facilities, located primarily in Germany. The group – whichalso operates a Medinsa solid-dose plant in Madrid, Spain – hascapabilities that include semi-solids, liquids and oral cephalosporins. G

BUSINESS STRATEGY

Aristo buys Amnealin Nordics and Spain

PANACEA BIOTEC has received a certificate of good manufacturingpractice (GMP) compliance from Ukraine’s medicines agency for itsIndian oral solid-dosage manufacturing facility and oncology site inBaddi, Himachal Pradesh, following June inspections. Noting thatUkraine was a member of the Pharmaceutical Inspection Co-operationScheme (PIC/S), Panacea said the registration of 22 products thatreceived manufacturing authorisations could now be “undertakenin the 49 PIC/S countries on a fast-track basis”. G

IN BRIEF

Gen 3-11-17 Pgs.2-15.indd 2 01/11/2017 17:31

3GENERICS bulletin3 November 2017

COMPANY NEWS

Russia’s Biocad is preparing to introduce in European markets itsroster of biosimilars, generics and innovative biological products,

focusing on oncology drugs and autoimmune disease treatments.Taking into account the European Medicines Agency’s (EMA’s)

centralised procedure for marketing authorisations, and the corresponding“need for local clinical trials”, the Russian firm said it expected to beginreceiving marketing authorisations for ‘biologic products’ in 2021.

Biocad’s current portfolio of biosimilars includes its Acellbia(rituximab) and Herticad (trastuzumab) products, which are marketedin Russia and various emerging and developing countries. Moreover,Biocad says the “last preparations” are underway for “conductingPhase III clinical trials of our adalimumab biosimilar” in Europe.

“So far there are seven molecules in the European portfolio,” Biocadrevealed, noting that these covered treatments for melanoma and breast,stomach, kidney and lung cancer, as well as rheumatoid arthritis,psoriasis and multiple sclerosis. “In addition, in 2021,” Biocadforecasted, “generic oncology drugs – including docetaxel, paclitaxel,pemetrexed and irinotecan – will also enter European countries.”

“Biocad is the only pharmaceutical company in Russia that isready to provide dossiers for its medicines according to an InternationalConference on Harmonisation (ICH) common technical document(CTD) format in the shortest possible time,” insisted Biocad’s generaldirector, Dmitry Morozov.

Earlier this year, Biocad unveiled plans to construct a chemicaland biological products manufacturing facility in Turku, Finland, aspart of broader plans to enter European markets via a local partnershipthat also covers drug development and fundamental sciences (Genericsbulletin, 2 June 2017, page 5).

Meanwhile, Biocad says it is continuing negotiations with a partnerin Japan and is in discussions on “commercial terms and conditionsfor the distribution of its products” in the market. The Russian firmadded that it was interested in licensing innovative products from “smallcompanies on mutually favourable terms for the Russian market”. G

BUSINESS STRATEGY

Biocad is gearing upto market in Europe

Cadila Pharmaceuticals has entered into a co-development andlicensing agreement with Altus Formulation for the Quebec-based

firm’s Flexitab formulation platform. According to Altus, the “innovativeand commercially-validated” technology platform provides “novel,value-added lifecycle management opportunities through ‘Safer Use’breakable, extended-release tablets”. Flexitab tablets “maintain theirdrug-release profile when broken, and are alcohol insensitive”.

Under the terms of the arrangement, Cadila and Altus “will jointlyselect key development targets benefiting from the Flexitab technology,and will co-develop and obtain marketing approval for these products invarious territories”. Products co-developed and commercialised underthe agreement may be sub-licensed to third parties around the globe.

Cadila’s chairman and managing director Rajiv Modi said thepartnership allowed the privately-held Indian company to leverage Altus’Flexitab technology, “ensuring cost-effectiveness and value-addedformulations for patients”. Damon Smith, chief executive officer ofAltus, said the firm “looked forward to co-developing and commercialisinga range of patent-protected and label-differentiated new products withCadila that will bring significant value to both our companies”. G

STRATEGIC ALLIANCES

Cadila and Altus strike deal

Dr Reddy’s Laboratories says it expects to “see results” in the comingfinancial quarters from product launches in the US announced

during the first six months of its current financial year ending March2018, as a sales slump in its key North America generic formulationsbusiness led the Indian firm to a group turnover decline in its financialsecond quarter ended 30 September.

Launches so far this year include one of the first generic versionsof Merck & Co’s Vytorin (ezetimibe/simvastatin) tablets (Genericsbulletin, 5 May 2017, page 13), and a generic rival to The MedicinesCompany’s Angiomax (bivalirudin). Moreover, the firm obtained aUS approval for a generic version of Janssen’s Doxil (doxorubicin)liposome injection, the firm’s first complex depot injectable.

During the second quarter, Reddy’s began shipping in the UScefixime oral suspension, bupropion extended-release and metaxalonetablets. Meanwhile, Reddy’s also introduced a generic of Sanofi’sRenvela (sevelamer carbonate), although the Indian firm noted thatthe product had been launched “post the cut-off date for revenuerecognition”, and so “no sales have been recorded during the quarter”.

In its financial second quarter, Reddy’s Generics sales in NorthAmerica slid by 11% to Rs14.3 billion (US$221 million), withReddy’s pointing to continued high price erosion affecting key productssuch as azacitidine, esomeprazole and valganciclovir. As Figure 1shows, North American sales accounted for two-fifths of group turnoverthat declined by 1% to Rs35.5 billion, with that region down fivepercentage points year-on-year as a proportion of Reddy’s total turnover.

Saving Reddy’s from a larger turnover loss was double-digitgrowth in the firm’s Emerging Markets Generics operation, drivenby growth of a fifth to Rs3.2 billion in Russia, as well as a rise of 36%to Rs2.42 billion in the firm’s European Generics operation. Reddy’ssaid growth in Europe was “primarily driven by new launches andvolume uptake in some of the key products”.

In Europe, however, Reddy’s during the quarter had revoked thegood manufacturing practice (GMP) certificate held at the firm’sUnit II formulations facility in Bachupally, India, by a Germanregulatory authority (Generics bulletin, 1 September 2017, page 7).

Including an additional Rs454 million of ‘other income’, Reddy’spre-tax profit rose by 3.2% to Rs4.09 billion, following a drop of 2.5%to Rs31.8 billion in total operating expenses. The firm said it wouldcontinue to focus on improving operational efficiencies. Gn [email protected]

SECOND-QUARTER RESULTS

Reddy’s waits for USlaunches to succeed

Figure 1: Breakdown by region and business segment of Dr Reddy’s Laboratories’sales in its financial second quarter ended 30 September 2017 (Source – Dr Reddy’s)

North America 14,318 -11 40India 6,370 +2 18Emerging markets* 5,506 +14 16Europe** 2,424 +36 7Global Generics 28,618 -1 81

Pharma Services/APIs 5,654 -2 16

Proprietary Products/Other 1,188 +10 3

Dr Reddy’s 35,460 -1 100

* refers to Russia, other CIS countries, Romania andRest of World markets including Venezuela

** primarily Germany, the UK and out-licensing sales business

Second-quarter sales Change Proportion(Rs millions) (%) of total (%)

Gen 3-11-17 Pgs.2-15.indd 3 01/11/2017 17:31


COMPANY NEWS

Figure 1: Progress to date on Sandoz’ disclosed biosimilars pipeline as of 24 October 2017 (Source – Novartis)

Two biosimilars launched in Europe this summer following EuropeanCommission approvals in June 2017 are “off to a good start”,

Sandoz and parent group Novartis have told investors.For their rival to Roche’s Rituxan/MabThera (rituximab) oncology

therapy, “physicians are willing to use Rixathon across indications”,the firms stated. The Commission’s approval for the Rixathon/Riximyobiosimilar covers all the same indications as granted for Rituxan/MabThera (Generics bulletin, 23 June 2017, page 11).

Having also during June secured a Commission authorisation forits Erelzi (etanercept) alternative to Pfizer’s Enbrel anti-inflammatoryagent (Generics bulletin, 30 June 2017, page 11), Sandoz selectedGermany and the UK as lead markets for both biosimilars (Genericsbulletin, 7 July 2017, page 13).

Commenting on Rixathon, Novartis’ chief executive officer JoeJimenez said the group had not expected moves by physicians inGermany to switch entire patient populations across to the biosimilar.“We are also getting quite positive feedback on Erelzi,” he stated.

Sandoz chief Richard Francis said the Rixathon launch had been“very well accepted”, with entire accounts adopting the biosimilaracross all indications. “We have had significant account wins in theUK for Erelzi,” he added. “We have currently about 2,600 patientsqueued up to actually get the drug.”

In September this year, Sandoz had its Rixathon dossier acceptedfor review by the US Food and Drug Administration (FDA) as a rivalto Rituxan (Generics bulletin, 15 September 2017, page 12).

At around the same time (Generics bulletin, 22 September 2017,page 13), Sandoz presented data at a congress of the European Academyof Dermatology and Venereology (EADV) from its 51-week ‘Adaccess’adalimumab trial in 465 patients with moderate-to-severe chronicplaque psoriasis. The firm had its application for its GP2017 alternativeto AbbVie’s Humira accepted for filing by the European MedicinesAgency (EMA) in May this year, at around the same time as Sandozsubmitted its GP1111 infliximab to the EMA (see Figure 1).

A US filing for adalimumab remains “on track” for submissionby the end of this year, while Sandoz has just re-submitted its Zioxtenzopegfilgrastim candidate to the EMA following its withdrawal at the startof this year (see page 19). A similar US re-filing to address concernsvoiced by the FDA is scheduled for early 2019 after the companyincreased the sample size of a pharmacokinetic (PK) bridging study.

The strong start made by both Rixathon and Erelzi supporteddouble-digit European growth during the third quarter of this year bySandoz’ Biopharmaceuticals business segment, which recorded globalsales from biosimilars, Glatopa (glatiramer acetate) 20mg and contract

manufacturing ahead by 9% on a constant-currency basis to US$292million. This came despite a decline in the US, “primarily due tocompetitive pressures on Glatopa 20mg from ongoing market conversionto the 40mg version of the reference medicine”, Teva’s Copaxone,that was compensated in part by continued growth from Zarxio(filgrastim-sndz) two years after its US market entry.

Sandoz’ total US turnover tumbled by 13% to US$798 millionin the three-month period, “driven by increased pricing pressure fromcompetition in retail generics and continued customer consolidation”.

Having identified “several negative-margin, limited growthproducts that are no longer viable due to double-digit price erosion inthe US generics market,” Sandoz has decided to move production at itsUS facility in Broomfield, Colorado, to a site in Wilson, North Carolina.

But, as Figure 2 shows, the firm’s other operating regions wereable to make up for the US pressures, as Sandoz’ reported 3% salesrise to US$2.58 billion equated to 1% constant-currency growth. Volumegrowth of eight percentage points was largely wiped out by sevenpoints of price erosion across the world.

Constant-currency sales in Europe climbed by 8% to US$1.23billion, “driven by continuing strong growth in Italy, Russia, Switzerlandand Turkey”. A similar rise took Sandoz’ sales in the Asia, Africa andAustralasia region to US$354 million, while a 14% constant-currencyrise to US$199 million in Canada and Latin America included LatinAmerican turnover up by 12% to US$110 million.

On a global basis, Retail Generics turnover was stable at US$2.2billion despite a 13% decline in the US. Anti-Infectives sales up by3% to US$359 million comprised sales of finished products underthe Sandoz name that rose by 7% to US$221 million, outweighinga 3% drop to US$137 million in turnover from antibiotics supplied

to third parties.Francis attributed a 3.4 percentage-

point improvement to 43.8% in Sandoz’gross margin to a combination of focusingon the most profitable geographic marketswhilst rolling out higher-margin productssuch as biosimilars. “We have grown ourbranded generics business more substantiallythan in the past,” he commented.

Even with sales and marketingexpenses higher by a tenth to US$438million, Sandoz was able to increaseits operating profit by 10% to US$390million, thereby raising the division’soperating margin by one percentagepoint to 15.1%. Gn [email protected]

Europe 1,233 +13 +8US 798 -13 -13Asia, Africa, Australasia 354 +4 +8Canada, Latin America 199 +16 +14

Sandoz 2,584 +3 +1

Established Markets 1,881 -1 -3Emerging Markets 703 +13 +12

Figure 2: Breakdown by region and market type of Sandoz’ sales in the thirdquarter of 2017 (Source – Novartis)

Third-quarter sales Reported Constant-currency(US$ millions) change (%) change (%)

THIRD-QUARTER RESULTS

Sandoz enjoys Rixathon and Erelzi start

Gen 3-11-17 Pgs.2-15.indd 4 01/11/2017 17:31


COMPANY NEWS

Abbott Pharmaceuticals enjoyed double-digit growth for the firm’sEstablished Pharmaceuticals Division (EPD) branded generics

operation, which includes the US firm’s CFR and Veropharm businessesin Latin America and Russia respectively, in the third quarter of this year.

The firm’s EPD saw sales increase by 15.7%, or 14.3% on a‘comparable operational’ organic basis, to US$1.17 billion, followinga 18.5% rise as reported to US$885 million in turnover from KeyEmerging Markets, “led by strong growth across several countries,including double-digit growth in Brazil, Russia, India and China”.Sales in ‘other’ markets that rose by 7.6% as reported, or 4.0% on acomparable operational basis, added the remaining US$286 million.

“As expected, sales in India were positively impacted by purchasingpatterns following the implementation of a new goods and servicestax (GST) system that lowered second-quarter sales in that country,”commented Abbott (Generics bulletin, 28 July 2017, page 2). “TotalEPD, Key Emerging Markets and India sales growth increased doubledigits with and without this impact.”

“It took a while for analysts and investors to appreciate theuniqueness of our [EPD] strategy,” commented chairman and chiefexecutive officer Miles White. “And I think it sort of called out thatthere is a segment of pharma that’s not commodity generic…that’shigher margin, higher growth et cetera, in pretty key markets aroundthe world. Right now [EPD’s] our fastest growing business, other thanneuromodulation.”

Abbott’s group sales jumped by 28.8% to US$6.83 billion, followingthe firm’s acquisition of medical devices firm St. Jude Medical in earlyJanuary. Meanwhile, the firm reported a US$626 million group pre-taxprofit, representing an US$805 million swing from last year whenAbbott was forced to make a significant write-down in the value ofits holding in Mylan (Generics bulletin, 28 October 2016, page 5). G

THIRD-QUARTER RESULTS

Abbott’s EPD sales increase

Akorn’s Grand Avenue manufacturing facility in Decatur, Illinois,has again fallen afoul of US Food and Drug Administration (FDA)

quality standards, with an inspection resulting in the agency issuingthe US ophthalmics and injectables specialist with three ‘Form 483’observations of current good manufacturing practice (cGMP) violations.

At the end of last year, Akorn announced that the facility had beencleared following an FDA re-inspection, after the agency previouslyissued the firm with multiple Form 483 observations, including a failureto record or justify deviations from production and process-controlprocedures (Generics bulletin, 6 January 2017, page 4).

Other observations included flaws in documenting batch-controland test results, and issues with both clindamycin vials and ephedrineampoules (Generics bulletin, 28 October 2016, page 5).

But following an inspection at the end of April this year – aroundthe time Fresenius Kabi announced a US$4.75 billion deal to acquireAkorn (Generics bulletin, 28 April 2017, page 1) – deficiencies wereagain identified by the agency, including repeat observations.

As well as the use of inappropriate equipment for manufacturing,processing, packing or holding of drug products, as well as cleaning,these deficiencies included, again, a failure to maintain written andcontrol procedures pertaining to quality.

Noting that he had observed “particles coming off the conveyorbelt” that staged previously washed vials, an FDA inspector said theproblem was not corrected, even after being brought to the attentionof the vice-president of domestic sterile products quality assurance.

Meanwhile, procedures designed to prevent microbiologicalcontamination of drug products “purporting to be sterile” did not include“adequate validation of the sterilisation process”.

“Specifically, the firm has failed to complete or invalidated 33% [of]media fills attempted in [a] filling room since it has been convertedto an aseptic filling area,” commented the FDA inspector.

Fresenius Kabi is aiming to complete its acquisition of Akorn bythe end of this year (Generics bulletin, 11 August 2017, page 7). G

MANUFACTURING

Akorn Grand Avenuefacility receives 483s

Cambrex has added “large-scale manufacturing capacity” at its USproduction facility in Charles City, Iowa, after completing an

expansion. Located on a 45-acre site, the facility manufactures a widerange of active pharmaceutical ingredients (APIs) and pharmaceuticalintermediates, including highly-potent molecules and controlled substances.

The investment included installing 1,000- and 4,000-gallon glass-lined reactors and ancillary equipment at the 700 sq m multi-purposemanufacturing facility, which opened in 2016. The bulk-drugs producernoted that these reactors brought the current good manufacturingpractice (cGMP) volume in the facility to 23,000 gallons, with totalcapacity at the Charles City site “now approximately 107,000 gallons”.

“This additional capacity enables us to take on new customerprojects,” stated chief operating officer Shawn Cavanagh, “as well asoffering the flexibility for projects to be transferred in from otherCambrex sites as needed.”

Cambrex recently unveiled plans to invest US$24 million in ahighly-potent API manufacturing facility at the Charles City site, dueto open in 2019 (Generics bulletin, 1 September 2017, page 10). G

MANUFACTURING

Cambrex expands its Iowa site

Concordia International has filed for debt restructuring under theCanada Business Corporations Act (CBCA), as part of ongoing

efforts to “protect our business, preserve our cash, and give us extratime to negotiate with lenders”.

The action was triggered by Concordia days before opting to usea 30-day ‘grace period’ to defer payment of approximately US$26million of interest on the firm’s US$735 million unsecured notes. “Thedeferral of the interest payment does not result in an ‘event of default’until the expiry of the 30-day grace period,” the firm said at the time.

Concordia said it had chosen to initiate the debt restructuring to“support its proposed recapitalisation transaction”, under which thefirm is aiming to reduce its debts by more than US$2 billion, while“significantly reducing” the company’s annual interest costs andpositioning the business for “longer-term growth”.

Underlining that the CBCA was “not a bankruptcy or insolvencystatute”, Concordia said its management team would “continue to leadday-to-day operations and operate its business as usual, while meetingits commitment to employees, suppliers and customers”.

Earlier this year, Concordia unveiled a seven-pillar growth strategynamed ‘Deliver’, as part of a five-year plan to restore the companyto growth (Generics bulletin, 15 September 2017, page 3). G

BUSINESS STRATEGY

Concordia carries onwith debt restructure

Gen 3-11-17 Pgs.2-15.indd 5 01/11/2017 17:31


COMPANY NEWS

Walgreens Boots Alliance (WBA) is set to launch a US$450 millionstore-optimisation programme in the US once its completes its

purchase of 1,932 Rite Aid drugstores in the US. This will includeclosing around 600 stores.

Having secured antitrust clearance in September to start acquiringRite Aid stores in a phased process running until spring next year(Generics bulletin, 29 September 2017, page 5), WBA has carried outa “complete review” of its pro forma combined US store portfolio ofover 10,000 outlets to “determine the scope of a programme to optimiselocations”. “This has resulted in our decision to close approximately600 stores and related assets over an 18-month period, beginning inspring 2018,” explained chief financial officer George Fairweather.

While the store closures would incur cash costs of around US$450million, Fairweather noted, they would generate annual cost savings ofapproximately US$300 million by the end of the group’s financialyear running until August 2020.

Co-chief operating officer Alex Gourlay said “the vast majority”of closures would be of Rite Aid outlets that were located within a mileof one of the group’s existing stores. The remaining 1,300 or so RiteAid stores would, he pointed out, strengthen WBA’s retail footprintin the north-east and south of the US.

Three years for integrationIntegrating and rebranding the acquired retail network is anticipated

to span three years, resulting in acquisition-related costs of US$750million. WBA also plans to invest around US$500 million on “storeconversions and related activities”, but expects to realise annualsynergies of over US$300 million within the next four years.

As part of the deal, the remaining Rite Aid retail chain has anoption, 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.

In its financial year ended 31 August 2017, turnover by WBA’sRetail Pharmacy USA division grew by 4.2% to US$87.3 billion. Thatincrease was responsible for a reported 0.7% rise in group sales toUS$118 billion (see Figure 1). On a constant-currency basis, the group’sgrowth was 3.3%. WBA suffered a 7.4% drop in group operatingprofit to US$5.56 billion.

Negative exchange-rate shifts were responsible in part for a 10.9%turnover fall by WBA’s Retail Pharmacy International division, whichoperates around 4,700 stores across eight countries outside of the US.Currency fluctuations also hit WBA’s global Pharmaceutical Wholesalebusiness, which reported sales down by 6.1% to US$21.2 billion. Gn [email protected]

BUSINESS STRATEGY/ANNUAL RESULTS

WBA is set to shut600 stores in the US

Figure 1: Breakdown by division of Walgreens Boots Alliance’s sales and operatingmargin in its financial year ended 31 August 2017 (Source – Walgreens Boots)

Retail USA 87,302 +4.2 4.8

Retail International 11,813 -10.9 6.3

Pharma Wholesale 21,188 -6.1 2.3

Walgreens Boots 118,214* +0.7 4.6

* includes US$2.09 billion of eliminated inter-divisional sales

Division Annual sales Change Operating(US$ millions) (%) margin (%)

ENDO has divested privately-owned Mexican generics player GrupoFarmacéutico Somar to Advent International for a purchase priceof around US$124 million, “after giving effect to estimated cash, debtand net working capital purchase price adjustments”. Endo acquiredSomar in July 2014 (Generics bulletin, 8 August 2014, page 13).

VITAL LABORATORIES has received a warning letter from theUS Food and Drug Administration (FDA) regarding activepharmaceutical ingredients (APIs) at its Indian manufacturing facilityin Vapi, Gujarat, following an inspection in April. Batch productionrecords “omitted signature fields to document who performed, directlysupervised, and checked each critical step” in the manufacturingprocess, while supervisors signed in place of operators because their“hands were dirty”, according to the letter. Aberrant analytical testresults were ignored, while deficiencies were found in product reviews.

TRACELINK says more than 100 contract manufacturing organisations(CMOs) are “fully configured” on the ‘TraceLink Life SciencesCloud’ and are “ready to exchange serialisation data”. This includesAlpex, Central Pharma, Liconsa, Patheon and Recipharm. “Anadditional 323 CMOs are currently in active testing on the TraceLinknetwork and projected to be serialisation-ready in a matter of months,”the US-based group noted.

BASF has closed its deal to sell its electrolytes manufacturing sitein Suzhou, China, to Shenzhen Capchem Technology. The divestitureincluded a production site and the transfer of 69 employees toCapchem. Separately, the German chemical producer has opened aproduction plant for biocatalyzed acrylamide at its site in Nanjing,China. Pointing out that the plant had a capacity of more than 50,000tons per year, BASF said the investment strengthened its ability tosupply customers in Asia Pacific, especially in China. “The constructionof a new polyacrylamide production line is currently underway, and isexpected to go on stream in 2018,” BASF noted.

MCKESSON increased its turnover by 4% to US$52.1 billion in itsfinancial second quarter ended 30 September 2017. The companyhighlighted its “organic growth across multiple business units,including the company’s strategic sourcing benefits throughClarusOne, a lower share count and incremental profit contributionfrom acquisitions”. North American distribution sales rose by 5% –both as reported and in constant currencies – to US$43.5 billion.

CATALENT has completed its acquisition of Cook Pharmica foran undisclosed sum. The US-based firm said the purchase wouldstrengthen its position as “a leader in biologics development andanalytical services, manufacturing, and finished product supply”.Catalent said it would create two drug-delivery units, one focusingon biologics and specialty drugs, and one on oral formulations.

ASYMCHEM LABORATORIES’ active pharmaceutical ingredient(API) facility in Dunhua, China, has passed an inspection byAustralia’s Therapeutic Goods Administration (TGA).

DSP – DSM Sinochem Pharmaceuticals – is aiming to reduceprescription drug counterfeiting through serialisation services,including a track and trace system. Acknowledging upcoming globallegislation on serialisation, the firm pointed out that regulations wouldbe effective in Europe from February 2019, preceded by Russiaand the US. DSP – a joint venture between Dutch group DSM andChina’s Sinochem group – said it would offer an “on-boarding planfor its customers and supply-chain partners”. DSP aims to have itsfull supply chain ready before the end of 2018. G

IN BRIEF

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COMPANY NEWS

Pricing pressure in the US market continued to drag down Lupin’sFormulations sales in North America in the Indian firm’s financial

second quarter ended 30 September 2017, with turnover down byalmost a third to Rs13.6 billion (US$210 million) year-on-year.

Describing the pricing pressure as “expected” the Indian firmnevertheless insisted that it had recorded “strong growth in all ourmarkets but for the US generic business”, as total Formulations salesslid by 7.9% to Rs36.1 billion. Including active pharmaceuticalingredients (APIs) sales that declined by 9.2% to Rs2.65 billion, Lupin’sgroup turnover fell by 8.0% to Rs38.7 billion.

As Figure 1 shows, Lupin enjoyed mid-teen level growth in itskey domestic and Asia-Pacific Formulations markets, while in itsEurope, the Middle East and Africa (EMEA) operation, sales rose bya similar amount – 17.1% – to Rs2.76 billion. Together these marketsaccounted for more than half, or 53%, of Lupin’s group turnover.

As part of efforts to mitigate its sales decline in the US, Lupinrecently completed a US$150 million deal for gynaecology specialistSymbiomix Therapeutics, bolstering its specialty offerings in the market(Generics bulletin, 20 October 2017, page 3). This strategy was onecomponent of a growth plan laid out by the firm earlier this year,including focusing on regulatory compliance and building a complexgenerics pipeline (Generics bulletin, 11 August 2017, page 7).

Noting that “we are on track with our complex generic pipeline”,Lupin also recently welcomed positive news concerning regulatorycompliance after receiving an establishment inspection report (EIR)closing out all outstanding inspections by the US Food and DrugAdministration (FDA) of the company’s formulations facility inAurangabad, India (Generics bulletin, 1 September 2017, page 11).

The Indian firm strengthened its US pipeline during the quarterby filing 10 abbreviated new drug applications (ANDAs), receivingin turn nine approvals, including for generic Lidex (fluocinonide) andClobex (clobetasol). Lupin also launched several generics, includingmoxifloxacin and olmesartan medoxomil.

Also during the quarter, Lupin brought in Alexion Pharmaceuticalsexecutive Jim Loerop as the firm’s chief corporate development officer,to drive the company’s global mergers and acquisitions and businessdevelopment functions (Generics bulletin, 22 September 2017, page 16).

Including an additional Rs778 million of ‘other operating income’,Lupin’s operating profit fell by 17.2% to Rs8.53 billion, followinghigher material and employee costs. Gn [email protected]

SECOND-QUARTER RESULTS

Lupin’s US sales fallagain as others grow

Figure 1: Breakdown by region of Lupin’s sales in its financial second quarterended 30 September 2017 (Source – Lupin)

North America 13,611 -31.9 35India 11,593 +16.4 30Asia-Pacific 6,357 +15.2 16EMEA 2,758 +17.1 7Latin America 1,395 +41.5 4Rest of World 378 -4.5 1Formulations 36,092 -7.9 93

APIs 2,650 -9.2 7

Lupin 38,742 -8.0 100

Second-quarter sales Change Proportion(Rs millions) (%) of total (%)

Amajor new player is set to enter the US pharmacy benefit manager(PBM) market. Health insurer Anthem has teamed up with retailer

and PBM provider CVS Health to launch IngenioRx. The newly-created entity will start offering formulary and other services in 2020,when Anthem’s contract with its current PBM, Express Scripts, expires.

Beginning on 1 January 2020, a five-year agreement that Anthemhas signed with CVS will see the latter provide prescription-fulfilmentand claims-processing services to the new PBM. “IngenioRx willcombine its member and provider-engagement initiatives and market-leading pricing with CVS’ expertise in point-of-sale engagement,”the health insurance company commented.

CVS maintained that assets such as its extensive pharmacy chainand its MinuteClinic walk-in centres would “allow the company toapply its expertise in patient messaging and engagement at the point-of-sale to support IngenioRx, broadening the scope of clinical servicesoffered at the pharmacy counter to drive better outcomes”.

Larry Merlo, president and chief executive officer of CVS, saidthe agreement “further validates the important role that CVS Health’sintegrated and innovative pharmacy care model plays in today’s healthsystem”, with nearly five million Americans visiting a CVS pharmacyevery day. Pointing out it expected to incur implementation costs relatedto the transition of members, “as is typical of any large, multi-yearcontract”, CVS insisted these costs were “expected to be immaterial”.

IngenioRx would “lower total healthcare costs”, Anthem asserted.The new PBM was “expected to achieve greater than US$4 billion ingross savings annually” and would position Anthem to “take advantageof a unique opportunity to grow and diversify our business within ourexisting footprint as well as nationally”.

However, the move has been met with resistance. The US SeniorCare Pharmacy Coalition (SCPC) argued that the alliance betweenAnthem and CVS “represents a perpetuation of the oligopolistic, anti-consumer shell game”. “By their very own design and intent, theserelationships are a shell game premised upon keeping consumer,lawmaker and regulator alike in the dark about virtually every aspectof the mysterious ‘negotiations’ and ‘rebates’ we hear about, but neversee,” insisted Alan Rosenbloom, president of SCPC.

Moreover, the SCPC pointed out that US Senate Committee onHealth, Education, Labor and Pensions (HELP) chairman LamarAlexander and Senator Lisa Murkowski had “expressed frustration withthe overly complex drug pricing system”. This included “bewildermentabout pricing determinations, systemic complexity and the ongoingmystery surrounding rebates”.

Separately, CVS Health has introduced a PBM performance-based pharmacy network, anchored by CVS Pharmacy and Walgreens.With 30,000 stores, the network also has up to 10,000 community-based independently-owned pharmacies across the US. “The networkis designed not only to deliver unit cost savings, but also to improveclinical outcomes that will lead to lower overall healthcare costs forCVS Caremark PBM clients and their members,” CVS Health stated.

“Performance measures for participating pharmacies will includedemonstrated medication adherence for chronic conditions that areimpactful to client costs,” CVS Health noted, citing as exampleshypertension, diabetes, respiratory conditions and behavioural health.“Participating pharmacies are encouraged to implement their ownproprietary programmes and workflow processes to enable them todeliver results related to the measures being tracked.” Gn [email protected]

STRATEGIC ALLIANCES

CVS and Anthem allyfor a PBM deal in US

Gen 3-11-17 Pgs.2-15.indd 7 01/11/2017 17:31


COMPANY NEWS

22 Novembern 1st Value Added Medicines Conference

Brussels, BelgiumThis event organised by Medicines for Europe will focus onopportunities presented by medicines that are repositioned,reformulated or combined.

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

27-28 Novembern euroPLX 65

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

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

24 Januaryn 11th Pharmacovigilance Conference

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


25-26 Januaryn 17th Regulatory and Scientific

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


12-14 Februaryn Access! 2018 – AAM Annual Meeting

Florida, USAThis Association for Accessible Medicines event will look atregulatory topics and the challenges facing the US generics industry.

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

1-2 Marchn 2nd OTC Innovation & Business

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

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

EVENTS – November 2017 – March 2018

Orion expects that pricing reforms introduced at the start of this yearin the Finnish group’s domestic market will wipe around C15 million

(US$17 million) off its full-year turnover in 2017. “The effect is greaterthan anticipated at the beginning of the year,” Orion admitted.

From the start of this year, Finland narrowed a price difference‘corridor’ within the country’s reference-price system. Whereas toqualify for reimbursement drugs previously had to be priced withinC1.50 of the cheapest product available for medicines costing less thanC40.00 – and within C2.00 for more expensive drugs – the permitteddifference to the cheapest drug was narrowed to C0.50 (Genericsbulletin, 24 February 2017, page 10).

The pricing pressure combined with supply problems through thegroups local distributor, Oriola, to cause the Finnish group’s domesticsales within its Specialty Products off-patent business segment to stallat C217 million in the first nine months of this year.

But Specialty Products growth of almost a fifth to C72 million inScandinavia was aided by supplying the biosimilar Remsima (infliximab)through a national tender in Norway (Generics bulletin, 28 July 2017,page 4). Orion – which has rights to Remsima in Nordic countries andEstonia under the terms of a deal with South Korea’s Celltrion – reportedtotal Remsima sales that increased by 44% to C44.6 million.

In Eastern Europe and Russia, Specialty Products turnover climbedby 13% to C47 million, helping to push up the segment’s total sales by4% to C387 million. Specialty Products accounted for 48% of groupturnover that edged up by just over 1% to C804 million.

Another 5% came from third-party sales by the group’s Fermionbulk-drugs unit that rose by 23% to C40.5 million. That growth helpedto compensate for a 3% slip to C261 million in turnover from the group’sProprietary Products unit that is continuing to roll out its budesonide/formoterol Easyhaler device in Europe. G

RESULTS FORECAST/NINE-MONTH RESULTS

Finnish price reformexacts toll on Orion

Expanding its Russian product range with additions such as Vivaira(sildenafil) chewable tablets helped Podravka to increase its

Prescription drugs turnover by 8.4% to CrK436 million (US$67.4million) in the first nine months of this year.

Including Non-Prescription sales that advanced by just over a tenthto CRK72.3 million following OTC additions such as Naxil(acetylcysteine) effervescent tablets, the Croatian group’s totalPharmaceuticals turnover increased by 8.0% to CrK611 million. Thatequated to a 5.9% rise at constant exchange rates.

Russian growth lay behind a 29.8% Pharmaceuticals rise toCrK108 million in Podravka’s Eastern Europe region. Sales increasedby 3.1% to CrK452 million in the Croatian firm’s Adria region, whichincludes its domestic market, where the firm’s Belupo pharma unit inmid-May opened two plants for solid-dose and semi-solid drugsfollowing a CrK530 million investment. Pharmaceuticals sales in CentralEurope climbed by 9.1% to CrK39.5 million on turnover growth inPoland and the Czech Republic.

Higher fixed costs associated with new facilities contributed tothe Pharmaceuticals unit’s operating margin falling by 3.8 percentagepoints to 8.3%. Pharmaceuticals accounted for barely a fifth of thefood and drinks group’s sales, but nearly half of its operating profit.G

NINE-MONTH RESULTS

Russia swells Podravka’s sales

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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

Gen 3-11-17 Pgs.2-15.indd 9 01/11/2017 17:31


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].

Perindopril has concessionsAverage UK prices of perindopril tablets saw triple-digit rises

in October, according to the latest figures provided by WaveData.Three strengths of the long-acting ACE inhibitor – 2mg, 4mg and8mg – were among the top five biggest rises recorded by WaveData,based on averages calculated on the basis of at least 56 data points.

Comparing UK trade prices between the periods 1-30 September2017 and 1-31 October 2017, WaveData reported that 2mgperindopril tablets in 30-count packs saw an average rise of 498%to £3.75 (US$4.95) as the cheapest available offer almost doubledto £0.59. In response, the UK’s Department of Health (DoH) atthe end of October granted a concession price for the 2mg strengthdouble the average price at £7.50.

Perindopril 4mg tablets in the same pack size saw an averageprice rise of 320% to £4.55 and received a concession price fromthe DoH of £8.00, while the 8mg strength’s average rise of 227%to £5.46 was met with a concession of £8.50.

Separately, amlodipine 5mg and 10mg tablets in 28-countpacks saw average price rises of 238% to £2.08 and 161% to £1.78respectively. Concessions of £3.75 for the 5mg strength and £3.99for the 10mg strength were granted. The DoH’s list of concessionsincluded 40 molecules across more than 80 presentations.

Meanwhile, aspirin 300mg tablets saw the steepest averageprice decline of 57% to £0.86 for 32 tablets. G

PRICE WATCH ....... UK

Romania’s Prime Minister, Mihai Tudose, should dismiss thecountry’s health minister, Florian Bodog, local generics industry

association APMGR has urged, following controversy over the country’smandatory pharmaceutical clawback.

In response to interview comments made by Bodog that theclawback had “not increased and has been kept to a reasonable value”,APMGR said the statement was “completely false”. The clawback rateof 19.86% in the first quarter of 2017 had been more than fourpercentage points higher than the 15.62% rate in the first quarter of2016, the association pointed out, while the 18.59% rate in the secondquarter of 2017 was almost three points higher than the 15.64% rateseen in the prior-year period.

“To say that a 20% turnover tax is reasonable shows contemptfor the entire Romanian drug industry,” insisted APMGR executivedirector Laurentiu Mihai. “Unfortunately, the authorities have noteven taken a single measure to protect generic medicines,” hecomplained, despite such drugs being used by poor and elderly patients,often with chronic conditions.

APMGR recently complained that prices being kept “artificiallylow” in Romania could lead hundreds of generics to disappear fromthe market in the next year (Generics bulletin, 20 October 2017,page 8). More than 2,000 generics have already disappeared from themarket in recent years, the association claims. G

PRICING & REIMBURSEMENT

APMGR attacks overclawback in Romania

Legislative action must be taken by the European Commission tointroduce a waiver for generic manufacturing during the term of

a supplementary protection certificate (SPC), off-patent associationMedicines for Europe has urged in the wake of a consultation on SPCslaunched by the Commission that is running until 4 January 2018(Generics bulletin, 20 October 2017, page 1).

“Medicines for Europe calls for a swift introduction of the SPCmanufacturing waiver in European Union (EU) legislation and for awide definition of Bolar,” the association stated, referring to theearly-working exemption that already exists for research purposes.

Citing a report published by the European Commission and compiledby Charles River Associates (CRA) on ‘Assessing the economic impactsof changing exemption provisions during patent and SPC protectionin Europe’ (Generics bulletin, 20 October 2017, page 29), Medicinesfor Europe director general Adrian van den Hoven said “the CRA studyshows the huge benefits that the SPC manufacturing waiver and Bolarharmonisation offer Europe in terms of jobs, manufacturing and alower overall medicines bill”. “The Commission must now legislateto make this a reality,” he insisted.

“The European Commission’s public consultation on the SPCmanufacturing waiver is essential for pharmaceutical manufacturingin Europe,” Medicines for Europe emphasised. “The SPC manufacturingwaiver will create thousands of high-skill jobs and open new opportunitiesfor small- to medium-sized enterprises (SMEs) in Europe.”

Moreover, “the waiver will ensure that Europe maintains itstechnological leadership and capacity in the manufacturing and supplyof essential medicines and contribute to more competition on medicinecosts”, the association underlined.

According to the CRA report, Medicines for Europe pointed out,the SPC manufacturing waiver would create between 20,000 and 25,000additional manufacturing jobs in Europe by 2025. It would also increasethe net sales for the EU-based pharmaceutical industry by betweenC7.3 billion (US$8.5 billion) and C9.3 billion within the same period.

An SPC manufacturing waiver would also “ensure faster entry ofgeneric and biosimilar competition in the EU after SPC expiry, thusimproving access for patients”, Medicines for Europe maintained, aswell as enabling savings in pharmaceutical expenditure of betweenC1.6 billion and C3.1 billion “thanks to competition”.

Furthermore, the association added, an SPC manufacturing waivertogether with a broader Bolar exemption would generate additional EUactive pharmaceutical ingredient (API) sales of between C212 millionand C254 million by 2030, “creating an additional 2,000 jobs in that sector”.

“The SPC compensates originator drug manufacturers for regulatoryapproval delays by extending their monopoly for up to five years afterpatent expiry,” Medicines for Europe acknowledged. “Whilst ourindustry does not challenge the principle of compensation for delays,the application of the SPC forces generic and biosimilar manufacturersto manufacture outside of Europe for export to countries without SPCsor whose SPC expires earlier than in Europe.” “With the SPCmanufacturing waiver, European medicine manufacturers will be ableto re-invest in high-skill jobs in Europe,” the association noted.

“As proposed by the European Commission and confirmed inseveral studies,” Medicines for Europe concluded, “the SPC manufacturingwaiver will not affect originator drug manufacturers as they will continueto benefit from the longest period of monopoly protection globallyfor most drugs.” Gn [email protected]

INTELLECTUAL PROPERTY

Industry urges actionon SPC waiver in EU

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MARKET NEWS

Plans for a unique identifier code to be attached to biologicalinternational non-proprietary names (INNs) have been put on hold

by the World Health Organization (WHO), the global health body hasrevealed in its latest publication of details of an expert consultation.

In its report on the ‘expert consultation on improving access toand use of similar biotherapeutic products’ – which took place on 2-3 Mayin Geneva, Switzerland – the WHO notes that “no consensus wasreached on whether the WHO should continue with the biologicalqualifier (BQ)”. Therefore, “it should be noted that the WHO will notbe proceeding with this at present”.

Last year, the WHO unveiled its plans for a BQ comprising fourrandom consonants and a two-digit checksum (Generics bulletin, 11March 2016, page 6). However, the International Generics and BiosimilarMedicines Association (IGBA) warned that such a move would becomplicated and confusing, while Europe’s Biosimilar Medicines Group(BMG) urged the WHO to implement a moratorium on the BQ scheme(Generics bulletin, 21 October 2016, page 11).

Responding to the WHO’s decision to suspend plans for theinitiative, the IGBA said it “welcomes the WHO decision to finally putthe BQ on hold”. The international generics and biosimilars associationsaid it “continues to promote worldwide the thoughtful and successfulEuropean Union (EU) system for track-and-trace, which ensures properidentification through the product name – the trade name or the INNplus the manufacturer – and batch number”.

During the consultation, the WHO noted, there had been“considerable discussion on the pros and cons of the BQ scheme”.

Global brand industry association the International Federation ofPharmaceutical Manufacturers and Associations (IFPMA) said it“strongly supports INN expert group recommendations on the use of aBQ for naming biological and biotechnological products”. Meanwhile,international biotech group the Biotechnology Innovation Organization(BIO) “commended the WHO on its BQ proposal and expressed theirsupport for development and implementation of naming conventionsfor biologics and biosimilars which allow traceability”.

Patient body supports BQThe International Alliance of Patients Organisations (IAPO) said

it also “supports the current BQ proposal and suggested that BQ namingshould apply to originators and biosimilars, which will allow tracing ofeach product to its manufacturer”. Moreover, it claimed that the BQwould “help patients worldwide enjoy the benefits of distinguishablenaming, which will build patient and physician confidence”.

The WHO’s decision to not proceed with the BQ scheme camedespite “strong support for INN experts to promote BQ”, with claimsthat “currently-available tools are not being properly used” to enabletraceability, thus indicating “a need to implement BQ”.

As well as announcing a lack of consensus on the BQ scheme,the WHO said following the meeting that it would review and provideclarification on 2009 guidelines on similar biotherapeutic products“to reflect technological and analytical advances”. “It was suggestedthat the guidelines take into account the different needs for products,such as product-specific guidelines for insulin,” the WHO noted.

After the meeting, the WHO also noted that it would trial thepre-qualification of two biosimilar molecules, rituximab and trastuzumab(Generics bulletin, 12 May 2017, page 13), in a pilot programme thatbegan in October (Generics bulletin, 15 September 2017, page 5). Gn [email protected]

REGULATORY AFFAIRS

WHO halts plans fora biological qualifier

AUS generics antitrust lawsuit is set to expand to treble the numberof manufacturers cited to 18, raise the number of generic drugs

at issue from two to 15, and name as defendants two industryexecutives – Mylan president Rajiv Malik and Emcure’s chief executiveofficer and managing director, Satish Mehta.

An initial complaint filed in Connecticut that was recently transferredto multi-district litigation in the Eastern District of Pennsylvania citedsix companies: Aurobindo, Citron, Heritage, Mayne, Mylan and Teva.In the case, attorneys-general alleged that the six firms entered intoillegal conspiracies to unreasonably restrain trade, artificially inflateand manipulate prices and reduce prices in the US for two generics,the delayed-release antibiotic doxycycline hyclate and the oral diabetestreatment glyburide (Generics bulletin, 6 January 2017, page 1).

The 46 attorneys-general are now seeking court permission toexpand the complaint to add another 12 companies as defendants: twoActavis subsidiaries of Teva; Alkem’s Ascend; Apotex; Dr Reddy’s;Glenmark; Lannett; Endo’s Par; Sandoz; Sun and Zydus Cadila, aswell as Heritage’s Indian parent company, Emcure.

Emcure’s Mehta and Mylan’s Malik are the first industry executivesspecifically named as defendants in the suit as having engaged inillegal conduct. “Considering the personal conduct of the individualsin furthering the price-fixing scheme, and the brazen and broad natureof the scheme, we believe suing individuals is justified and will senda powerful message deterring this type of conduct,” remarked theattorneys-general, who noted that some states had policies not to sueindividuals in antitrust cases, leaving them to be prosecuted by theUS Department of Justice (DoJ) in criminal cases.

Mylan responded by insisting it had “deep faith in the integrityof its president, Rajiv Malik”. “We have been investigating theseallegations thoroughly and have found no evidence of price-fixing onthe part of Mylan or its employees,” the company stated.

“The litigation thus far has centred on conspiracies in whichHeritage Pharmaceuticals served as a central player,” the attorneys-general commented. Two former Heritage executives, Jeffrey Glazerand Jason Malek, earlier this year pleaded guilty to criminal chargesof conspiring to fix the prices of generic doxycycline hyclate andglyburide in the US (Generics bulletin, 20 January 2017, page 16).

To those two drugs, the complaint adds 13 generics, includingdoxycycline monohydrate and the glyburide/metformin combination.Glipizide/metformin and fosinopril/hydrochlorthiazide are listed, asare acetazolamide, leflunomide, meprobamate and nimodipine, plusnystatin, paromomycin, theophylline, verapamil and zoledronic acid.

“Generic drug manufacturers argued publicly that significantprice increases over the last several years were due to benign factorslike industry consolidation, mandated plant closures or eliminationof unprofitable generic product lines,” the attorneys-general observed.

Rather, they alleged, senior industry executives colluded both atindustry meetings and through e-mails, phone calls and text messagesto inflate prices. “To avoid competing with each other and avoid priceerosion,” they claimed, “the companies communicated with each otherto determine and agree on how much market share and which customerseach company was entitled to.”

Noting that the DoJ was in parallel conducting a criminalinvestigation, the attorneys-general said they would oppose moves bythe DoJ that would delay discovery in the multi-district antitrustlitigation “for at least another six months”. Gn [email protected]

LITIGATION

US attorneys aimingto widen suit’s scope

Gen 3-11-17 Pgs.2-15.indd 11 01/11/2017 17:31


MARKET NEWS

Asix-point policy proposal aimed at improving the regulatoryenvironment in Ukraine for biosimilars as well as original biological

drugs has been published by local brand industry body the Associationof Pharmaceutical Research and Development (APRaD). “Fundamentalchanges” to the Ukrainian regulatory system would “harmoniseUkrainian legislation with the requirements of the European Union(EU)”, the APRaD said, providing “effective and optimal” treatmentapproaches for doctors and patients.

Firstly, the proposals suggest that the local definition of the term‘biosimilar’ should be brought in line with EU legislation, “bindingbiosimilar registrability to the expiration date of data exclusivity” forthe brand. Secondly, the APRaD proposes, automatic substitutionof a biosimilar in place of a branded biologic “should be consideredunacceptable, as they are non-exchangeable unlike generic medicines”.

Decisions on substitution should, the third point of the proposaladvocates, be “based on scientific data”, should be “made and controlledby the attending physician after proper medical evaluation”, and shouldbe made with the awareness of the patient. “Appropriate directions”would need to be developed on this subject, the APRaD suggests.

Mandatory tracking of trade names and batch numbers forpharmacovigilance purposes is urged as the fourth point.

Biological drugs previously registered in Ukraine as genericsshould, the fifth point argues, be “re-evaluated and re-registered asbiosimilars”. The APRaD suggests using World Health Organization(WHO) recommendations as the basis for this process, “includingintroducing the 12-month period for submission of the updated dossiers”.

Finally, on public procurement policies, the APRaD advocatesincluding both original biologics and biosimilars in procurement lists andthe national essential medicines list “by the trade name of such medicines”.

Referring to the use of original biologics and biosimilars as “morethan a mere issue of economical availability of a medical treatment”,the APRaD said that “side-by-side market existence of several biosimilarsreferring to one and the same original biological medicinal productcan create a challenging environment for patients and physicians”. Theassociation said its proposals had been put forward “due to the importance,immediacy and insufficient regulation of the matter in Ukraine”. G

REGULATORY AFFAIRS

Originators lobby onUkrainian biosimilars

Acampaign highlighting the benefits of conducting biosimilar trialswithin the UK’s National Health Service (NHS) has been launched

by the country’s National Institute for Health Research (NIHR).Primarily using ‘talking head’ video clips in addition to written

content, the ‘Focus on biosimilars’ campaign provides information forcompanies, health professionals, and patients and carers. A range ofquestions are answered, including why firms should bring trials to theUK, why professionals should support trials, and why patients shouldconsider taking part in trials or switching programmes.

Observing that the “uptake and acceptance of biosimilars has rapidlyaccelerated across the NHS in recent years”, the NIHR said the “clinicalevidence base is growing, benefits are beginning to be realised, and costsavings are coming to the fore”. “With the promise of a smaller pricetag, biosimilars may well hold the key to ensuring the sustainabilityof our globally renowned public healthcare system,” the NIHR said. G

EDUCATIONAL CAMPAIGNS

UK promotes biosimilar trials

Amulti-phase business continuity plan (BCP) has been set out bythe European Medicines Agency (EMA) ahead of its relocation

in the wake of the UK’s ‘Brexit’ decision to leave the European Union(EU). However, implementing the BCP had “consequences as regardsto the current ‘business as usual’ operation of EMA”, the regulator warned.

Endorsed by the management board at the EMA’s June meeting,the BCP aims to “safeguard continuity of EMA’s operations to protectpublic health while the agency prepares for its relocation to a new hostcity”. The agency said the plan was “an essential tool to deal with theuncertainty and workload implications” following the move, addingthat it would be “continuously reviewed and adapted as necessary”.

“The first aim of the EMA Brexit preparedness BCP is to ensurethat the necessary human resources are available to work on EMApreparedness,” the regulator stated, “and subsequently, that activitieswith the highest priority will continue to operate ‘business as usual’,without interruption and to the same high standards.” Therefore, a‘phased approach’ would be used to implement the plan, which includestemporarily suspending or “scaling back” activities, starting with thosedescribed as being the “lowest priority”. The EMA also outlined plansto “reallocate resources to its core activities if needed”.

“The plan prioritises tasks and activities and classifies them intothree categories, according to their impact on public health and theagency’s ability to function,” the agency stated. These distinct categorieshad been identified by the EMA earlier this year, with ‘category 3’covering the lowest priority tasks, ‘category 2’ listing higher-priorityactivities, and ‘category 1’ concerning highest priority tasks (Genericsbulletin, 11 August 2017, page 13).

“Freeing up” necessary resources “until the end of 2017” was thefirst phase of the plan. Tasks would be temporarily “scaled back” orsuspended, firstly from ‘category 3’ and then from ‘category 2’,which divides activities into two sub-divisions, the EMA explained.Lower-medium priorities under ‘category 2B’ would be looked atfirst, followed by higher-medium priorities under ‘category 2A’.

Pointing out that the regulator had already since May started toscale back activities in ‘category 3’, the EMA said it would temporarilyreduce audits, self-assessment activities and ‘transparency’ requestsfor information. Meanwhile, activities concerning the regulator’sintegrated quality management system and meeting managementenlargement would be provisionally suspended.

Next, the focus will be on ‘category 2’ activities, including reducingthe development of new external policies and the revision of existingexternal policies and the EMA’s online programme. Temporarilysuspended tasks cover the EMA’s e-submission project and thepublication of clinical data.

A second phase would focus on freeing up additional resourcesfor EMA preparedness for 2018 and 2019, as well as “ensuring thatactivities with the highest priority can continue in a situation wherestaff loss can no longer be compensated through recruitment”.‘Category 3’ tasks would be further reduced, before moving to‘category 2’ activities, and “only in a worse case scenario, tocertain ‘category 1’ activities”.

“Although the de-prioritisation of activities under phase one ismainly affecting internal governance and support activities, with fewactivities impacting on EMA partners and stakeholders,” the EMAacknowledged, “the de-prioritisation of the large majority of activitiesunder phase two will impact deliverables in the work programme.”Gn [email protected]

REGULATORY AFFAIRS

EMA continuity plannot business as usual

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MARKET NEWS

Feedback on subjects including incentives for US generic entry,anti-competitive strategies to reduce competition to off-patent drugs,

the role of intermediaries in the pharmaceutical supply chain andprice-reduction proposals is being sought by the US Federal TradeCommission (FTC), to aid discussions at a workshop on 8 November.

Taking place in Washington DC, the Commission will host theworkshop on ‘Understanding competition in prescription drug markets:entry and supply chain dynamics’ (Generics bulletin, 13 October2017, page 7). Acting FTC chairman Maureen Ohlhausen and USFood and Drug Administration (FDA) Commissioner Scott Gottliebwill give keynote addresses during the workshop, which will be freeto attend, open to the public and webcast live.

An opening session will explore factors that could preclude genericmarket entry after relevant patents have expired, and discusses “priceand non-price factors that may influence entry in these markets”. Asecond session will “evaluate intermediaries in the pharmaceuticalsupply chain”, particularly pharmacy benefit managers (PBMs). Athird and final session covers group purchasing organisations (GPOs),including a discussion concerning the “potential next steps to encourageentry and expand access through lower prices”.

Among the panellists will be members from generics industrybody the Association for Accessible Medicines (AAM), as well as theHealth Transformation Alliance, US originator body PhRMA and theUS Pharmaceutical Care Management Association (PCMA).

The FTC is requesting comments on whether generic drugmanufacturers have sufficient incentives to enter off-patent marketsand whether policymakers “have a role in providing incentives toencourage entry decisions that better align with the public interest”.

In addition, the Commission is seeking input on anti-competitivestrategies and what more can be done to make generic entry more“robust”. Comments on the benefits and costs of intermediaries inprescription drug pricing has also been sought, as well as consideringhow stakeholders should evaluate proposals to reduce drug prices andincrease consumer access in prescription drug markets. G


FTC seeks feedbackon competition in US

Granting a 10-year period of market exclusivity in the EuropeanUnion (EU) through a paediatric-use marketing authorisation

(PUMA) aimed at stimulating the development of known moleculesfor children “has so far failed”, the European Commission has admitted.

Fulfilling its obligation to report to the European Parliament andCouncil on the 10th anniversary of the EU’s Paediatric Regulation1901/2006, the Commission observes that “to date, only three PUMAshave been granted”. “This is clearly below expectations,” it acknowledges.

“While the European Medicines Agency (EMA) agreed more than20 paediatric investigation plans (PIPs) with a view to submitting aPUMA,” the Commission continues, “it remains uncertain how manywill ever be completed and lead to commercialisation of a new product.”

Moves by the Commission and the EMA in 2014 to clarify thata PIP for a PUMA does not have to cover all age groups have, so far,had a limited impact, the report recognises. “While this may allowcompanies to focus research on the most prevalent paediatric subsets,it risks further reducing the target population and potential revenues.”

According to the Commission, the PUMA concept struggles withthe same issues facing any scheme aimed at encouraging firms torepurpose known compounds. “Medicine developers fear that a PUMAwill not necessarily prevent physicians from continuing to use competitorproducts with the same active ingredient but authorised for otherindications off-label, at lower costs, nor [prevent] substitution for cheaperforms at the level of pharmacies,” it says. And national payers “aregenerally hesitant to agree a premium price for such products”.

Acknowledging the limited evidence of just three PUMAs granted,the Commission said that while data “shows that the products authorisedthrough PUMAs have received positive reimbursement decisions inseveral member states and represent good business cases, it maysimply be the exception to the rule, partly supported by the specificitiesof the products rather than the PUMA concept alone”.

Such is the complexity of the factors influencing whether suchvalue added medicines are commercially successful that they “can behardly addressed at EU level”, the Commission concludes. “Theyconcern downstream decision-making at national level, which is outsidethe scope of EU law,” it admits, adding that “legislative incentivescannot compensate for economic success”.

By contrast, the Commission’s report suggests, the PaediatricRegulation – which offers a six-month extension to supplementaryprotection certificates (SPCs) for completing a PIP, as well as atwo-year extension to 10-year orphan exclusivity for rare diseases –has had “a clear positive effect” in widening the range of medicinesspecifically developed for children.

During the decade that the Regulation has been in effect, “over 260new medicines for use by children – new marketing authorisations andnew indications – were authorised”, the Commission points out. “Thenumber of agreed PIPs surpassed 1,000 in 2017, of which 131 werecompleted at the end of 2016.” However, it adds, “figures suggest that,up to now, only 55% of the completed PIPs benefited from a reward”.

Estimating an average research and development cost per PIP ofC18.9 million (US$22.0 million), the Commission measures the economicvalue of the six-month SPC extension for eight selected products tobe C926 million. By 2019, the Commission intends to evaluate thecombined effects of the EU’s Paediatric and Orphan Regulations,informed by the recently launched review of the SPC regime (Genericsbulletin, 20 October 2017, page 1). Gn [email protected]

VALUE ADDED MEDICINES

Commission admitsto PUMA plan failure

Knowledge and awareness of biosimilars among prescribing physicianshas improved in Canada between 2014 and 2017, according to the

latest survey by the originator-backed Alliance for Safe BiologicMedicines (ASBM). Of the 403 doctors spanning 13 therapeutic groupssurveyed by the ASBM, 28% said they were “very familiar” withbiosimilars, compared to 10% responding to a similar survey in 2014.

On biosimilar naming, ASBM said that more than two-thirds ofrespondents “overwhelmingly support Health Canada implementingdistinguishable names, yet there was no consensus as to best method”.Half favoured a completely different non-proprietary name, while 31%preferred a differentiating prefix, 11% a suffix and 7% a sharedinternational non-proprietary name (INN) with a manufacturer code.

Meanwhile, ASBM said, “54% believe a biosimilar which sharesan INN with its reference product implies the two are structurallyidentical, which is not the case”, while “63% believe a biosimilar whichshares an INN with its reference product implies the two were approvedfor the same indications, which may or may not be the case”. G

MARKET RESEARCH

Canada’s awareness improves

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MARKET NEWS

Establishing a patent-linkage system, implementing data protectionand awarding patent-term restorations are among the key priorities

for strengthening intellectual-property protection in China as part ofreforms to improve approval processes for, and encourage innovationof, medicines in the country.

Requiring generics filers to address applicable patents as part ofthe application process would, Minister Bi Jingquan believed, enablepatent disputes to be resolved during the drug-review process. “Thelegal risk for marketing generics will be lowered, and the patent holders’interests can be better protected,” he asserted.

A list of marketed drugs akin to the US Food and DrugAdministration’s Orange Book would inform physicians and pharmacistson both reference drugs and their generic equivalents, he outlined.

Bi noted that China had, when joining the World Trade Organization(WTO), committed to providing protection for clinical-trial data. Apre-condition of restoring the patent term lost during the regulatoryreview was, he said, changing the requirement for generic approvalfrom clinical to bioequivalence trials, thereby “achieving a balance”by cutting the cost of bringing generics to market. “We shall developa plan as soon as possible and carry out a pilot programme, after beingauthorised by the National People’s Congress,” he pledged.

Acknowledging the problem of China’s “under-development ofgenerics”, Bi bemoaned the lack of domestic generics that wereinterchangeable with originator brands. “For the treatment of seriousdiseases,” he said, “we still heavily rely on imported drugs.”

Domestic producers making ‘sub-standard drugs’Some domestic producers used “inferior materials” and turned

out “sub-standard drugs”, using manufacturing processes that couldhave “a serious impact” on safety and efficacy, Bi admitted. As potentialreasons for this problem he identified weak intellectual property, aswell as the lack of a system of marketing-authorisation holders.

While a process to evaluate more consistently oral generics hadbeen “thoroughly implemented”, re-evaluating generic injectables wasscheduled to take place over the next five to 10 years. “China’s Foodand Drug Administration (CFDA) will clarify the method and timetablefor injection re-evaluation as soon as possible,” Bi promised.

Another imminent task for the CFDA will be to implement amanufacturing verification system whereby all drug producers willhave to provide details of their active pharmaceutical ingredients (APIs),excipients, processes and other relevant information. Failure to providesuch information could result in products being withdrawn from themarket, Bi warned, adding that marketing-authorisation holders wouldalso be legally liable for the quality, safety and efficacy of their products.

To combat the threat of sub-standard and counterfeit medicines – aswell as problems with “low-price tender drugs” – Chinese authoritiesintend to step up regulatory oversight, including through plans to“strengthen on-site inspection and quality sampling and testing”. Bisaid creating a “professional inspector team” would be accelerated,while authorities would also focus on “capacity building” to establisha modern drug-review and inspection framework.

Co-ordination and co-operation between different ministerialdepartments is to be strengthened, as is “learning and training” at theCFDA. The regulatory responsibilities of both central and localgovernment would be clarified, Bi added, while clinical data generatedabroad would be more readily acceptable. Gn [email protected]

INTELLECTUAL PROPERTY

Patent linkage formskey priority in China

Biosimilars could bring the US cost savings of US$54 billion overthe next decade, according to a RAND Corporation report. “We

estimate that biosimilars will reduce direct spending on biologic drugsby US$54 billion from 2017 to 2026, or about 3% of total estimatedbiologic spending,” the RAND report states, acknowledging that thefinal figure could fall between US$24 to US$150 billion.

In a previous review, RAND predicted that US biosimilars wouldsave the country US$44 billion from 2014 to 2024 (Generics bulletin,14 November 2014, page 26). RAND said the latest figure was around20% larger than previously suggested due to “improved analysismethods and rapid growth in spending for biologics overall”. Theresearcher reviewed the sales history of more than 100 biologic drugsand analysed the performance of Sandoz’ Zarxio (filgrastim-sndz).

“Actual savings will hinge on industry and regulatory decisions,as well as potential policy changes to strengthen the biosimilar market,”RAND stated. “Payment arrangements, regulatory policies andguidance, patient and prescriber acceptance of biosimilars, and otherissues will also influence the magnitude of potential savings.” Referringto the Biosimilars Price Competition and Innovation Act (BPCIA) of2009 – which set out the US biosimilars framework – RAND describedthis as a “faster and less costly” biologics pathway that also promotedcompetition. The market researcher insisted that as additional biosimilarsare marketed in the US, future research would “help us to assess whetherthe BPCIA achieved competition and cost savings”.

Moreover, RAND said that the “pervasive uncertainty” as to“whether the market will be sustainable and lead to cost savings”,presented two options for policymakers. One was to pursue currentpolicies. “Increasing FDA and industry experience with approvalrequirements, precedent through early legal decisions, and evolvingpricing and market-share trends, will eventually provide clarity on thestability of the US biosimilar market and the significance of biosimilarsto the healthcare system.” Alternatively, the report suggests, policymakerscould “intervene to help steer the US biosimilar market more quicklyto a sustainable, competitive state”. G

US$54bn in savingsfrom US biosimilars

MARKET RESEARCH

Policymakers should consider the “differences inherent in thebranded and generic prescription drug markets” when considering

public policy changes on drug pricing, the US Association for AccessibleMedicines (AAM) has insisted. The statement came as AAM presidentand chief executive Chip Davis addressed a US Senate health, education,labour and pensions committee on the cost of prescription drugs.

Insisting that the sustainability of a competitive generics marketwas “in jeopardy”, Davis told the committee that “a failure of policy toaccount for the unique challenges facing generic and biosimilarmedicines” was one of three factors threatening the balance betweeninnovation and access to generics, along with changing reimbursementframeworks and “the abuse of laws and regulations by bad actors”.

“Generic drug markets are fundamentally different than brands,”Davis stated, citing differences in the supply chain, rebate models anddistribution channels. “It is critical that policymakers take steps toensure the continued supply of affordable FDA-approved genericmedicines,” Davis concluded. G


US must consider differences

Gen 3-11-17 Pgs.2-15.indd 14 01/11/2017 17:31


MARKET NEWS

An educational campaign about biosimilars has been launched bythe US Food and Drug Administration (FDA), to give providers

a “better understanding” of the drugs and their approval process.Noting that the agency had “planned and researched extensively”

prior to developing the materials, FDA Commissioner Scott Gottliebsaid that the FDA had “learned the specific areas that healthcareproviders had questions about”. This included gaining a betterunderstanding of biosimilars as well as their approval process.

Educational materials developed by the agency include factsheetsand graphics for healthcare professionals, and resources for organisationsto use in “disseminating this information to their interested members”.The materials, the FDA said, provided “basic definitions” of terms like‘biosimilar’, ‘reference product’, and ‘interchangeable’.

The resources also “describe the rigorous standards any biosimilarmust meet prior to approval, and explain how the FDA approval process

works”. Understanding the process the agency used to evaluate biosimilars,Gottlieb insisted, could “help providers and patients maximise thebenefits from these products”.

Furthermore, the resources provide “easily accessible informationabout the data and information the FDA reviews to determinebiosimilarity”, highlight information about the FDA’s Purple Bookrepository of biological approval and exclusivity information, and alsogive direction on how to find further materials.

“Next, the FDA plans to embark on additional research withhealthcare providers to learn more about the type of informationprescribers need to properly communicate with their patients aboutbiosimilars,” Gottlieb stated. “An increase in market competition, offeredby a growing complement of biosimilars, may lead to meaningfullyreduced costs for both patients and our healthcare system,” he continued.

“As with the significant savings that we’ve seen through theintroduction of generic drugs in the US,” Gottlieb said, “biosimilarscould also lead to substantial savings, thereby potentially improvingaccess and promoting better public health outcomes.”

Meanwhile, the FDA has released video presentations for industry,explaining features of the reauthorised Generic Drug User FeeAmendments (GDUFA II) programme. Content includes “the newavenues of communications that are possible between generic drugapplicants and the agency, especially for the review of complex genericproducts”, and the shorter review goals available for applications thatare public health priorities. Gn [email protected]

EDUCATIONAL CAMPAIGNS

FDA to educate withbiosimilars campaign

Anew fee for generic labelling in Canada has been proposed as partof a larger consultation on drugs and medical devices opened by

local agency Health Canada. Pointing out that the government had notupdated its fees for drugs and medical devices since 2011, HealthCanada said although the regulator had “remained internationallycompetitive in meeting performance standards, costs have increasedand taxpayers are assuming an increasing economic burden becauseof outdated fees charged to industry”.

Existing fees within the ‘human drug evaluation’ category would“remain unchanged”, Health Canada proposed, although new feeswould be created for ‘labelling only’ generic products and safetysupplemental new drug submissions.

Sponsors for generic products would have two filing options, theregulator noted, depending on the information submitted. ‘Labellingonly’ submissions would relate to products with labels differing fromthat of the Canadian reference product (CRP) and/or for which alabel review is required. Meanwhile, the newly-proposed fee category,‘labelling only to be in line with the CRP’, would be relevant if noadditional review was required.

“The new categories will have a performance standard of 120 days,to be consistent with the level of effort,” Health Canada commented.‘Labelling only’ fees are set to more than double from C$3,111(US$2,416) to C$6,298, while fees for labelling in line with the CRPis expected to drop from C$3,111 to C$2,626, the proposal outlines.

According to Health Canada, a company in 2017 paid C$89,080for a human generic drug submission to Australia’s Therapeutic GoodsAdministration (TGA), C$269,794 to the European Medicines Agency(EMA), and C$88,298 to the US Food and Drug Administration (FDA).“Health Canada is proposing C$70,383,” the national authority noted.

Turning to establishment licensing fees, Health Canada saidactivities included in the fees were “domestic and foreign buildinginspections and licensing/billing activities for active pharmaceuticalingredients (APIs), finished-dosage form drugs, veterinary drugs andmedical devices”. Health Canada is seeking feedback on its proposalsfrom stakeholders across the biotech, pharmaceutical, radiopharmaceutical,medical devices and veterinary drug/natural health product industries.The deadline for comments is 4 January 2018. G


Health Canada planslabelling fee overhaul

Indian exports of generics are “growing at around 22% per year”,according to the latest data published by the India Brand Equity

Foundation (IBEF) and the country’s Pharmaceuticals Export PromotionCouncil (Pharmexcil). India accounted “for around 20-22% of the world’sproduction, covering more than 60,000 brands and 60 therapeuticclasses”, the bodies stated, adding that total exports of pharmaceuticals –including active pharmaceutical ingredients (APIs), generics and“alternative systems of medicine” – reached US$16.8 billion during2016-17, of which 34% was supplied to the US and 15% to the EuropeanUnion (EU). The figure was expected to reach US$20 billion by 2020.

“According to the analysis, India has provided up to 50% of newdrug master files (DMFs) and between a quarter and a third of newabbreviated new drug applications (ANDAs) each year for the pastdecade,” the IBEF and Pharmexcil said. G

MARKET RESEARCH

Indian exports rise by a fifth

Gen 3-11-17 Pgs.2-15.indd 15 01/11/2017 17:31

MANUFACTURINGAND R&D CENTERS

200+GENERIC PROJECTSIN PIPELINE

5

75PIPELINEANDA‘S

59%CAGRSINCE 2009

00SIONATELOYEES

MERCIALWORK

The winner, Santiago Diaz Mejia, took home the 1st prize,a Motion PRO II Formula Wheel. Here he is with Robert WessmanCEO of Alvogen and Rasmus Rojkjaer CEO of Alvotech.

NEXT TIME!

280PASSEMPL

35COMMNETW

NEXT TIME!TILL

Alvogen and Alvotech would like to thank you all for visiting our booth atCPhl in Frankfurt this year.

Whether it was to meet our staff regarding a current project, inquireabout our businesses or just have a laugh by competing in our formulasimulator challenge, we‘re happy you came by.

Our special congratulations go to Santiago from Medinexo who won thecontest with his outstanding driving skills and focus.

This year‘s CPhl has drawn to an end, but Alvogen will continue to drivechange in our evolving industry and remain at the forefront of changewith our approach to generics, over-the-counter and biosimilar products.

See you in Madrid next year!

Connect with Alvogen on www.alvogen.com


PRODUCT NEWS

Fluticasone propionate metered aerosol for inhalation, as well as apowder for inhalation formulation, are among 33 new product-specific

guidances published by the US Food and Drug Administration (FDA)“describing the agency’s current thinking and expectations” on howto develop “therapeutically-equivalent” generic drug products.

In addition to the new guidelines, the agency has also released19 revised guidances, as part of the FDA’s efforts “to further facilitategeneric drug product availability and to assist the generic pharmaceuticalindustry with identifying the most appropriate methodology fordeveloping drugs and generating evidence needed to support abbreviatednew drug application (ANDA) approval”.

To establish bioequivalence for fluticasone propionate meteredaerosol for inhalation – the active ingredient in GlaxoSmithKline’s(GSK’s) Flovent HFA inhaler – the FDA recommends in vitro studiesincluding single actuation content, aerodynamic particle-size distribution,spray pattern, plume geometry and priming and repriming studies.

Meanwhile, the agency also recommends that applicants conducta fasted pharmacokinetic and comparative clinical endpoint bioequivalencestudy. And regarding the product device, the FDA advises sponsors torefer to draft guidance published about devices in January this year(Generics bulletin, 20 January 2017, page 6).

On fluticasone propionate powder for inhalation, which referencesGSK’s Flovair Diskus, the FDA recommends sponsors also conductin vitro and in vivo studies, but on the former only lists single actuationcontent and aerodynamic particle-size distribution studies. Again, theFDA recommends a fasted pharmacokinetic and comparative clinicalendpoint bioequivalence study.

In addition to fluticasone propionate, another of GSK’s respiratoryproducts is included on the FDA’s list of new guidances, salmeterolxinafoate, which is the active ingredient in the UK-based originator’sSerevent inhaler. The FDA said it would consider comments on theproducts’ draft guidance before responding to a GSK citizen petitionon establishing bioequivalence.

Additional respiratory products on the agency’s list of guidancesinclude mometasone furoate powder for inhalation and tiotropiumbromide powder for inhalation.

Meanwhile, other reference products cited as targets for genericdevelopment include Amedra Pharmaceuticals’ Adrenaclick (epinephrine)intramuscular injectable, Novartis’ Afinitor (everolimus) tablets forsuspension, AstraZeneca’s Lynparza (olaparib) capsules and Mylan’sAstepro (azelastine hydrochloride) nasal spray.

These come alongside guidelines for developing generic versionsof AstraZeneca’s Tagrisso (osimertinib mesylate) tablets, Valeant’sUceris (budesonide) rectal foam and Shire’s Vyvanse (lisdexamfetaminedimesylate) chewable tablets.

Lisdexamfetamine dimesylate in capsule formulation is moreoveramong 19 revised guidance documents, which also includes a numberof ophthalmic products such as brimonidine tartrate 0.1% and 0.2%solution/drops, ciprofloxacin hydrochloride drops, diclofenac sodiumdrops, ofloxacin drops and olopatadine hydrochloride drops.

Meanwhile, companies looking to develop generics of Eli Lilly’serectile dysfunction treatment Cialis (tadalafil) tablets – which are setto enter the US market in September 2018 under the terms of a patent-litigation settlement agreement agreed earlier this year (Genericsbulletin, 28 July 2017, page 15) – can also now find the FDA’srevised guidance on the molecule. Gn [email protected]

RESPIRATORY DRUGS

Fluticasone is amongnew FDA guidances

PERRIGO has received tentative approval from the US Food andDrug Administration (FDA) for a generic version of Leo Pharma’sPicato (ingenol mebutate) 0.015% gel, after filing a paragraph IVchallenge last year (Generics bulletin, 17 June 2016, page 12).

ACHIEVE LIFE SCIENCES has entered into an exclusive supplyagreement with Sopharma for the manufacture of cytisine activepharmaceutical ingredients (APIs) and finished tablets. Through thedeal, Sopharma will supply cytisine to Achieve “for up to 20 years”.

GLENMARK has been granted final approval in the US for a genericrival to Merck, Sharp & Dohme’s (MSD’s) Emend (aprepitant)40mg, 80mg and 125mg capsules. Citing QuintilesIMS data, theIndian firm observed that these strengths of Emend capsules achievedsales of US$64.9 million in the 12-month period ending August 2017.

AHF – the AIDS Healthcare Foundation – has called on GileadSciences to reduce the price of its tenofovir-based drug regimens,including Truvada (tenofovir disoproxil fumarate/emtricitabine),by “as much as 90%”. Pointing out that the firm had “made billions”off its tenofovir drugs since the US Food and Drug Administration(FDA) approved its Viread (tenofovir) in October 2001, AHFclaimed Gilead had “simultaneously sought to ‘evergreen’ andmanipulate the patent extension process”. Under the terms of apatent-litigation settlement, Teva can launch generic tenofovir inthe US from 15 December this year.

ACETO’S Rising Pharmaceuticals subsidiary has launched a genericversion of Pfizer’s Zoloft (sertraline) 20mg/ml oral solution in theUS. According to QuintilesIMS data, US sales of sertraline 20mg/mloral solution were US$9.94 million for the year to June 2017.

MIRACA LIFE SCIENCES has continued to “expand in clinicalpathology” after its InformTx therapeutic drug monitoring (TDM)began the validation process for Merck, Sharp & Dohme’s Renflexis(infliximab-abda), a biosimilar of Remicade (infliximab). Sincelaunching the InformTx service in June 2016, Miraca pointed outit had “expanded its TDM testing to now eight biologic drugs thattreat inflammatory bowel disease”.

AUROBINDO has obtained final approval from the US Food andDrug Administration (FDA) for its generic rival to Eli Lilly’s Effient(prasugrel) 5mg and 10mg tablets. The Indian company has alsoreceived final approval in the US to manufacture a generic versionof AstraZeneca’s Nexium 24HR (esomeprazole) delayed-release20mg capsules, to be launched immediately.

HIKMA’S US subsidiary West-Ward Pharmaceuticals has launchedpantoprazole sodium for injection, available in a 40mg dose. Thefirm said it was “successfully executing our injectables pipeline andleveraging the additional capacity we have been adding to ourPortuguese facility to support future growth”.

STATIN prescribing evidence suggests overtreatment of low-riskgroups and undertreatment of high-risk groups, according to a studypublished in the British Journal of General Practice. In a study of1.4 million patients, “most patients at high risk of cardiovasculardisease (CVD) were not initiated on statins”, while “one in six statininitiations were to low-risk patients”. Furthermore, the study foundthat after the UK’s National Institute for Health and Care Excellence(NICE) guidelines were updated in 2014 (Generics bulletin, 7March 2014, page 23), statin initiation rates declined in high-riskpatients, but increased in intermediate-risk patients. G

IN BRIEF

Gen 3-11-17 Pgs.18-32.indd 18 01/11/2017 17:33


PRODUCT NEWS

Sandoz’ Zioxtenzo (pegfilgrastim) biosimilar has been accepted forreview by the European Medicines Agency (EMA), less than a

year after concerns raised by the EMA’s committee for humanmedicinal products (CHMP) led the firm to withdraw its application.

According to Sandoz, the firm’s comprehensive data package,submitted as part of the marketing authorisation application (MAA),includes analytical, preclinical and clinical data, including Phase Ipharmacokinetic and pharmacodynamic studies in healthy volunteers,as well as Phase III safety and efficacy data in breast-cancer patients.

Sandoz insists that its clinical development programme for theproposed biosimilar version of Amgen’s Neulasta (pegfilgrastim)“strongly demonstrates that the biosimilar pegfilgrastim matches thereference medicine in terms of safety, efficacy and quality”.

At the beginning of this year, the CHMP adopted a provisionalopinion that Zioxtenzo “could not have been approved as a biosimilarof Neulasta”, leading Sandoz to notify the committee that it wished towithdraw the application (Generics bulletin, 3 February 2017, page 11).

The CHMP’s opinion was based on two “main” concerns: thatSandoz’ study results were not able to show that the concentrationsof pegfilgrastim in blood were the same after taking Zioxtenzo andNeulasta; and that the biosimilar’s manufacturing site lacked a certificateof good manufacturing practice (GMP).

The CHMP, at that time, described Sandoz’ study as “clearly under-powered”, noting that the pegfilgrastim exposure in healthy subjectswas “up to 36%” higher with Zioxtenzo than EU-approved Neulasta.

Stressing that it was the “European market leader” for biosimilarfilgrastim – which the firm markets under the Zarzio name – Sandozsaid it now had three biosimilars under EMA review. Pegfilgrastimjoins Sandoz’ applications for proposed versions of AbbVie’s Humira(adalimumab) and Janssen’s Remicade (infliximab).

Sandoz insisted that it was the “global leader in biosimilars”, withfive marketed worldwide, and a “leading global pipeline”.

Last month, Cinfa Biotech had its pegfilgrastim biosimilar MAAaccepted for review by the EMA (Generics bulletin, 13 October 2017,page 15), joining filings submitted by firms including Coherus. Abiosimilar alternative to the branded treatment for chemotherapy-induced neutropenia has, however, proved a hurdle for other players,with EMA applications submitted by Biocon and Mylan as well asGedeon Richter and Stada among those withdrawn in the last 12 months.

In late August this year, supplementary protection certificates(SPCs) shielding Neulasta in most European Union (EU) memberstates expired, based on Amgen’s European patent EP0,733,067, whichis entitled ‘N-terminally chemically modified protein compositionsand methods’ (Generics bulletin, 11 August 2017, page 18). G

NEUTROPENIA TREATMENTS

Sandoz resubmits EUpegfilgrastim dossier

Mylan and Synthon have seen invalidated a UK dosage-regimenpatent protecting Teva’s Copaxone (glatiramer acetate) 40mg/ml

formulation. The decision revokes the UK part of European patentEP2,949,335 that Teva licenses on an exclusive basis from Yeda. The‘335 patent covers treating relapsing forms of multiple sclerosis throughthree subcutaneous injections of glatiramer acetate 40mg/ml everyseven days, with at least one day between each injection.

Noting that Mylan and Synthon wished to “clear the way” for the40mg formulation for which they had obtained a marketing authorisationon 5 October, Patents Court Judge Richard Arnold said infringementwas not disputed if the ‘335 patent’s claims 1 and 3 were valid.

Among the key prior-art references relied upon by Mylan andSynthon to challenge the ‘335 patent’s novelty was the Pinchasiinternational patent application filed by Teva and published in July2007. This disclosed that “administration of glatiramer acetate at adose of 40mg/day significantly improves efficacy, but does not havea corresponding increase in adverse reactions suffered by the patient”.It also discloses administering such doses “every other day”.

Addressing obviousness, Arnold said “the sole difference betweenPinchasi and claim 1 of the patent is that Pinchasi discloses a regimenof 40mg every-other-day while claim 1 requires a regimen of 40mgthree-times-a-week”. He agreed with Mylan and Synthon that athrice-weekly regimen was “nothing more than a small and simplevariation on Pinchasi’s teaching”, so the claimed dosage would havebeen “obvious to try”. Similarly, the lower frequency of injection sitereactions (ISRs) covered by claim 3 was also obvious.

While he found claims 1 and 3 to be novel over Pinchasi, Arnoldnoted that the UK’s Supreme Court had recently introduced a doctrineof equivalents in a dispute between Actavis and Lilly over pemetrexed(Generics bulletin, 14 July 2017, page 1). “If it is legally possible fora claim to be deprived of novelty by virtue of the doctrine of equivalents,then claim 1 lacks novelty over Pinchasi,” he stated, adding thatclaim 3 would also lack novelty.

Having refused to issue an ‘Arrow’ declaration of invalidity fortwo pending divisional patent applications, Arnold noted that the basiclow-molecular-weight glatiramer acetate patent EP0,762,888 hadexpired on 23 May 2015. Furthermore, the European Patent Office’s(EPO’s) Technical Board of Appeal had recently revoked processpatent EP2,361,924 in its entirety. A UK dispute over another processpatent, EP3,050,556, is scheduled for trial in April next year.

Mylan said the UK victory would “further help pave the way” tolaunch glatiramer 40mg/ml “in certain European markets”. In Ireland,the generics firm said it had recently learned of an infringement actionbrought by Teva in the country’s High Court, alleging that Mylan’s40mg/ml injectable formulation infringes two European patents.

Counterpart dosage-regimen patents in the US had been held invalidby both a Delaware district court and the Patent Trial and Appeal Boardwithin the US Patent and Trademark Office (USPTO), pointed outMylan, which launched its three-times-a-week US rival to Copaxonein early October (Generics bulletin, 13 October 2017, page 14). G

MULTIPLE SCLEROSIS DRUGS

UK revokes a patentfor glatiramer dosage

Perrigo has settled US litigation brought by Valeant and DowPharmaceuticals relating to Onexton (clindamycin phosphate/

benzoyl peroxide) 1.2%/3.75% gel. As details of the settlement were“confidential”, no further information was disclosed. According to theUS Orange Book, four US patents expiring in 2029 protect the treatmentfor acne vulgaris. Perrigo observed that total brand sales for the yearended August 2017 were approximately US$120 million. G

DERMATOLOGY DRUGS

Perrigo settles over Onexton

TEVA has submitted a biologics license application (BLA) to theUS Food and Drug Administration (FDA) for TEV-48125, the Israelifirm’s fremanezumab investigational migraine treatment. G

IN BRIEF

Gen 3-11-17 Pgs.18-32.indd 19 01/11/2017 17:33


PRODUCT NEWS

Sawai will manufacture and market Zomig (zolmitriptan) 2.5mgtablets – as well as the Zomig Rapid Melt or RM orally-disintegrating

version of the migraine treatment – in Japan, after striking an exclusiveagreement with originator AstraZeneca.

“Under the terms of the agreement, Sawai is expected to take overthe manufacturing and marketing of the products in Japan by mid-2018from AstraZeneca,” the Japanese company noted.

“The Rapid Melt or RM preparation is designed to melt quickly inthe mouth,” the firm noted, “due to the actions of disintegrating andfoaming agents within the product, taken with or without water.” G

MIGRAINE DRUGS

Sawai strikes deal forzolmitriptan in Japan

Lannett will be able to manufacture and market in the US a rival toCelgene’s Thalomid (thalidomide) from 1 August 2019, or earlier

under certain circumstances, under the terms of a patent-litigationsettlement and licensing deal that the generics firm has struck with theoriginator. Other terms of the deal were not disclosed.

“We believe our thalidomide will be the first entrant in the USgeneric market,” said Lannett’s chief executive officer, Arthur Bedrosian.

Noting that Thalomid is subject to a Risk Evaluation and MitigationStrategies (REMS) programme, as mandated by the US Food and DrugAdministration (FDA), Lannett said it was seeking FDA approval forits pending abbreviated new drug application (ANDA) covering 50mg,100mg, 150mg and 200mg thalidomide capsules. G

ONCOLOGY DRUGS

Lannett settles over Thalomid

Teva’s Actavis has entered into a confidential settlement and licensingagreement with Neos Therapeutics to resolve all ongoing litigation

involving all four of Neos’ US patents protecting its Adzenys XR-ODT(amphetamine) extended-release orally-disintegrating tablets and Actavis’abbreviated new drug application (ANDA) for a generic version. Neos’Adzenys is a rival to Shire’s Adderall XR (amphetamine salts).

Under the agreement, Neos has granted Actavis the right tomanufacture and market its generic version of Adzenys beginning on1 September 2025, or “earlier under certain circumstances”. Reiteratingthat the settlement and licensing deal was “confidential”, Neos notedthat the agreement was also “subject to submission to the US FederalTrade Commission (FTC) and the US Department of Justice (DoJ)”.

In September last year, Neos filed a complaint against Actavis ina Delaware district court, alleging infringement of Neos’ four AdzenysUS patents: 8,709,491; 8,840,924; 9,017,731; and 9,265,737. Accordingto the Orange Book maintained by the US Food and Drug Administration(FDA), the ‘924 patent expires in April 2026, while the three remainingpatents protect Adzenys until June 2032.

Neos launched Adzenys, “the first and only extended-release orally-disintegrating tablet for the treatment of attention deficit hyperactivitydisorder (ADHD)” in the US in May 2016, after receiving approval via the505(b)(2) hybrid pathway (Generics bulletin, 5 February 2016, page 14).The firm recently got approval for an extended-release oral suspension.G

ATTENTION DEFICIT HYPERACTIVITY DISORDER DRUGS

Actavis eyes an Adzenys entry

Biosimilars have captured slightly less than 4% by volume of theoff-patent biologics market open to them in Germany during the

first eight months of this year, according to Insight Health data providedby local industry association Pro Biosimilars. Measured by value atretail prices, biosimilars’ share of the off-patent market was 11.9%, due inpart to the presence of several relatively low-value mature brands.

Taken as part of Germany’s total biologics market, includingpatented originals, biosimilars had just a 2.9% volume share with19.8 million defined daily doses (DDDs) sold in the January to Augustperiod, as the total market amounted to just almost 695 million DDDs. Ofthe total market, nearly 500 million DDDs were for off-patent biologics.

By value, biosimilars accounted for 5.2% of the total biologicsmarket with retail sales of around C280 million (US$326 million). Thesame share at ex-factory prices translated to sales of C214 million outof a total market worth C4.11 billion, of which C1.79 billion, or 43.6%,was off-patent.

“The enormous potential of biosimilars is not by any means beingexhausted,” Pro Biosimilars commented.

Etanercept biosimilars have steadily taken share since their marketintroduction just over a year ago to generate ex-factory sales of C76.7million in the first eight months of this year. The biosimilars’ marketshare reached 26.5% by value and 30.8% by volume.

By August, biosimilar sales of the rival to Pfizer’s Enbrel (etanercept)were running at around C12 million from more than 300,000 DDDsper month in a market that had expanded by around a tenth over thepast year to around 900,000 DDDs per month. But a national 31.1%DDD share for biosimilars in August covered regional penetration ratesthat ranged from just 14.8% in Thuringia to 63.8% in Westphalia-Lippe.

Etanercept accounted for a little over a third of all biosimilar salesin Germany (see Figure 1), while infliximab made up more than a quarterwith eight-month sales of C58.4 million. Biosimilar alternatives toJanssen’s Remicade (infliximab) captured 44.8% of ex-factory salesand 50.7% of DDDs in the eight-month period.

With ex-factory sales of C36.2 million and C16.5 million respectivelyin the January-August period, epoetin and filgrastim biosimilars heldvalue shares of just over a third and just under two-thirds of the totalmarkets for each molecule. Their volume shares of those marketswere 42.4% and 73.4% respectively. Gn [email protected]

BIOLOGICAL DRUGS

Germany is missingbiosimilars potential

EtanerceptC76.7m

FollitropinC3.8m

InfliximabC58.4m

Insulin glargineC9.2m

EpoetinC36.2m

FilgrastimC16.5m

SomatropinC13.7m

Figure 1: Sales by molecule of biosimilars in Germany that totalled C214 million inthe first eight months of 2017 (Source – Insight Health/Pro Biosimilars)

Gen 3-11-17 Pgs.18-32.indd 20 01/11/2017 17:33


PRODUCT NEWS

Six ‘core’ sofosbuvir patents belonging to Gilead Sciences “do notmeet the legal standards for novelty and non-obviousness”, according

to non-profit lobbying group Initiative for Medicines, Access &Knowledge (I-MAK), which has filed the “first-ever US patent challenges”against the hepatitis C treatment.

IMAK has filed an “unprecedented” set of inter partes reviewpatent challenges with the US Patent and Trademark Office (USPTO),including for sofosbuvir’s compound patent, 7,429,572, which expiresin April 2025. According to the group, all 19 claims of the ‘572 patentare unpatentable due to obviousness in light of two prior-art documents.

“The ‘572 patent claims pharmaceutical compounds that werealready published by the US government years before the patent ownerapplied for the ‘572 patent,” I-MAK insists. “Other scientists alsopublicly identified the pharmaceutical compounds claimed by the ‘572patent before the patent owner applied for the ‘572 patent. Thus, itsclaims are invalid based on that prior art.”

Meanwhile, I-MAK has filed challenges against sofosbuvir prodrugpatent 7,964,580 that expires in March 2029, additional prodrug patents8,735,372 and 8,334,270 that shield the molecule until March 2028,and crystalline structures patents 8,633,309 and 9,284,342, which expirein March 2029 and September 2030 respectively.

Sofosbuvir is the active ingredient in Gilead’s flagship Sovaldi(sofosbuvir) and Harvoni (sofosbuvir/ledipasvir) brands, as well as theoriginator’s Epclusa (sofosbuvir/velpatasvir). In 2016, Harvoni salesin the US were US$4.9 billion, Sovaldi sales were US$1.9 billion, andEpclusa turnover was US$1.6 billion.

“By reviewing evidence that the USPTO never considered, I-MAKhas found that sofosbuvir was developed through obvious tweaks toexisting compounds and formulations commonly used in older HIV andcancer drugs,” insisted I-MAK. “If Gilead’s six core patents forsofosbuvir are ruled unmerited, US taxpayers will save US$10 billion,and generics can get to market 14 years faster.”

“Every week, the US patent office grants 6,000 new patents,”I-MAK claims, “and some of those are not merited. Pharmaceuticalcorporations are over-patenting drugs even when there is no new sciencethat justifies their exclusivity and are stacking up as many unmeritedpatents as possible to prolong their monopolies and block cheapergenerics from entering the market.”

“As voters demand that Congress take action to lower prescriptiondrug prices,” I-MAK added, “Gilead Sciences has obtained unmeritedpatents for hepatitis C medicine sofosbuvir, blocking millions in theUS from affordable treatment.”

Earlier this year, a re-examination board within China’s patentoffice rejected Gilead’s appeal against a 2015 decision to deny a patenton the prodrug of sofosbuvir, after I-MAK filed third-party observationsagainst a Chinese patent application submitted by a Gilead affiliate(Generics bulletin, 12 May 2017, page 17).

“Since 2006, I-MAK has challenged unmerited patents worldwidewinning over 80 percent of its cases,” the group claimed. “Challengingand winning cases on four HIV drugs alone has helped save overUS$500 million – money that can be reinvested to treat more thanone million people.”

According to Gilead, generics manufacturers may submit Sovaldiabbreviated new drug applications (ANDAs) beginning in Decemberthis year, one year before the expiry of the brand’s new chemicalentity (NCE) exclusivity period. Gn [email protected]

HEPATITIS C DRUGS

Lobbying group filessofosbuvir challenges

Brazilian insulins and biosimilars specialist Biomm says it has hada marketing authorisation application for Glargilin (insulin glargine)

rejected by Brazil’s medicines regulatory agency, Anvisa. Biommoffered no comment on the grounds for rejection, but stressed thatAnvisa’s decision – which has now been published in Brazil’s officialjournal – is open to appeal.

Anvisa’s rejection of Biomm’s alternative to Sanofi’s Lantus(insulin glargine) blockbuster comes shortly after the Brazilian companybolstered its biosimilar pipeline by gaining exclusive sales and marketingrights in Brazil for the Herzuma (trastuzumab) biosimilar developedby South Korea’s Celltrion.

Citing Biomm’s expertise in both biopharmaceuticals and oncology,Celltrion Healthcare’s president and chief executive officer, Man HoonKim, said the Brazilian firm would be able to offer a new treatmentoption to thousands of breast-cancer patients in Brazil. “Followingour success with the first infliximab and rituximab biosimilars inEurope that broadened access to more economical life-saving treatments,”he commented, “we are confident that we will enjoy the same successthrough our partnership with Biomm in Brazil.”

“Through this exclusive partnership,” stated Biomm’s chiefexecutive officer, Heraldo Marchezini, “we are aligned with our corporatemission of offering an affordable portfolio of quality biopharmaceuticals,and to thereby offer treatment to an increasing number of people.” G

DIABETES DRUGS/ONCOLOGY DRUGS

Biomm hits a blockon Brazilian glargine

AUS process patent covering a stable formulation of Invanz(ertapenem) is invalid due to obviousness, the US Court of Appeals

has affirmed in a split decision. Merck & Co had appealed against aDelaware district court’s decision last year to invalidate 14 assertedclaims in US patent 6,486,150 as obvious in light of prior-art references(Generics bulletin, 21 October 2016, page 12).

On appeal, Merck argued that the district court had erred in findingobviousness in light of US patent 5,952,323 that expires next monthand an Almarsson patent application because none of the manufacturingsteps described in the ‘150 patent were disclosed in the prior art.Furthermore, the originator insisted, the prior art focused solely ondegradation by dimerization, not hydrolysis, thereby teaching awayfrom the claimed invention.

No more than conventional stepsWriting for the majority of the Court of Appeals panel, Judge

Alan Lourie said that “Merck’s problem is that the purported ‘solution’for minimising both degradation pathways constitutes nothing morethan conventional manufacturing steps that implement principlesdisclosed in the prior art”.

Armed with those prior-art references, a skilled person wouldhave arrived at the claimed invention “via routine experimentation”,Lourie objected, adding that Merck’s evidence of commercial successof the injectable antibiotic could not overcome the weight of primafacie evidence proving obviousness.

In a dissenting opinion, Judge Pauline Newman argued thatsecondary evidence such as copying and commercial success wasbeing under-valued. G

ANTIBIOTICS

Invanz process patent invalid

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22 GENERICS bulletin

PRODUCT NEWS

3 November 2017

Mylan’s proposed 505(b)(2) hybrid versions of Sanofi’s insulinglargine-based Lantus and Lantus SoloStar brands infringe 18

US patents assigned to the French originator, according to a lawsuitfiled by Sanofi in a New Jersey district court.

Sanofi’s complaint alleges infringement of 18 of the 19 patentslisted against Lantus and Lantus SoloStar in the US Food and DrugAdministration’s (FDA’s) Orange Book, the latest of which, entitled“pen-type injector”, expires in March 2028, including a six-monthpaediatric exclusivity period.

The French originator revealed that it received Mylan’s new drugapplication (NDA) with a notice letter – which disclosed that the genericsfirm’s application contained paragraph IV patent challenge certificationsfor the patents-in-suit – in mid-September. As Generics bulletin wentto press, Mylan’s NDA had not received any form of FDA approval.

“Since receiving Mylan’s notice letter and the accompanyingoffer of confidential access (OCA), Sanofi has negotiated in goodfaith with Mylan to procure a copy of [the] NDA and related productinformation under restrictions as would apply had a protective orderbeen issued,” Sanofi noted. “Sanofi timely responded to all correspondencewith Mylan and sought to reach reasonable compromise with Mylanregarding its OCA. These negotiations have been unsuccessful.”

Moreover, the complaint points out, Mylan in June this year alsofiled petitions with the US Patent and Trademark Office (USPTO)for inter partes review of two of the patents-in-suit, US patents7,476,652 and 7,713,930. For example, Mylan’s petition regardingthe ‘652 patent alleges “by a preponderance of evidence” that a skilledartisan would have had reason to combine the Lantus label with priorart to reach the claimed invention.

Although none of the four Mylan businesses named by theoriginator in the suit are based in New Jersey, Sanofi – which has a“principal place of business” in local Bridgewater through its Sanofi USaffiliate – insists in its complaint that “the venue is proper”. “MylanInc. and the other Mylan defendants have a regular and establishedplace of business in this district because they operate as ‘One Mylan’with Mylan Specialty and other Mylan subsidiaries in New Jersey.”

At the end of last year, Eli Lilly and Boehringer Ingelheim’sBasaglar (insulin glargine) 505(b)(2) hybrid became the first follow-oninsulin glargine available in the US, under the terms of a patent-litigation settlement deal struck with Sanofi in October 2015 (Genericsbulletin, 6 January 2017, page 18).

Furthermore, Merck & Co. and Samsung Bioepis earlier this yearreceived tentative FDA approval for their Lusduna Nexvue (insulinglargine) injectable follow-on hybrid 505(b)(2) version of Lantus.

However, Merck and Samsung may have to wait until early 2019to receive final approval for the diabetes treatment owing to ongoingpatent-infringement litigation with the French originator (Genericsbulletin, 28 July 2017, page 1). Sanofi has lawsuits against Merck inboth Delaware and New Jersey district courts.

Around a year ago, Mylan and its development partner Bioconhad their marketing authorisation application (MAA) for a biosimilarversion of Lantus accepted for review by the European MedicinesAgency (EMA). The firms’ filing included “analytical, functional andpre-clinical data, as well as results from the pharmacokinetics andconfirmatory efficacy/safety global clinical trial in type 2 diabetespatients” comparing the biosimilar against Lantus (Generics bulletin,11 November 2016, page 15). Gn [email protected]

DIABETES DRUGS

Mylan sued in the USover insulin glargine

ENDO has sued the US Food and Drug Administration (FDA) in aColumbia district court in a bid to block bulk compounding ofvasopressin. The firm, which markets the Vasostrict (vasopressin)injectable treatment for low blood pressure, believes that US DrugQuality and Security Act 2013 (DQSA) amendments require theFDA to implement a regulatory framework for bulk compoundingthat protects public health. Separately, Endo recently obtained threeUS patents that, like two existing listed patents, protect Vasostrictuntil 30 January 2035.

EGIS has acquired from AstraZeneca full rights in central andeastern Europe, as well as the Commonwealth of Independent States(CIS), to the Sorbifer (ferrous sulfate) drug for preventing andtreating anaemia. Since 1985, the Hungarian company has beenproducing, distributing and promoting in 18 countries the Sorbiferbrand that has since become its fifth-largest product with annualsales of around C20 million (US$23 million).

AMERIGEN has linked up with India’s Biophore to develop andmarket a generic version of Valeant’s Cuprimine (penicillamine),as well as other penicillinamine-based generics, for the US market.Amerigen, which will source active pharmaceutical ingredients(APIs) from Biophore, said it had already filed an abbreviated newdrug application (ANDA) for a generic rival to the Cupriminechelating agent for treating Wilson’s disease.

MAYNE PHARMA has been denied a review of a decision not toplace its oxycodone sustained-release tablets on the AustralianRegister of Therapeutic Goods (ARTG). Australia’s AdministrativeAppeals Tribunal determined that it lacked the jurisdiction to considernew material cited by Mayne in an attempt to force a listing of itsgeneric version of the discontinued OxyContin AU analgesic.Australia’s Therapeutic Goods Administration (TGA) had refusedto authorise Mayne’s version because it was not satisfied thatcomparative tests conducted against a discontinued Canadian referenceproduct adequately demonstrated the generic’s safety and therapeuticequivalence. Separately, Mayne has received TGA approval forMonurol (fosfomycin trometamol) 3g granules and has launchedUrorec (silodosin) 8mg capsules in Australia.

MYLAN has failed to persuade a Delaware district court to adoptits preferred construction of several terms contained in US patent8,946,292 that protects until March 2027 the Dyloject (diclofenacsodium) injectable marketed by Pfizer’s Hospira under licence fromJavelin. The court preferred Javelin’s proposed construction of theterms ‘about 82% of maximum observable total pain relief’, ‘visualanalog scale’ and ‘total pain relief’.

ACCORD HEALTHCARE has secured clearance in Germany tomarket adenosine in 6mg/2ml and 30ml/10ml ampoules.

AMNEAL has filed a citizen petition urging the US Food and DrugAdministration (FDA) not to approve any generics of Eli Lilly’sForteo (teriparatide) that contain a synthetically derived activeingredient. Only abbreviated new drug applications (ANDAs) basedon recombinant human parathyroid hormone will be truly equivalentto the original, Amneal argues. Synthetic peptides should be submittedas hybrid 505(b)(2) applications, the US firm insists.

CIPLA AND IMPAX have followed Aurobindo and Dr Reddy’s inobtaining US approval for, and launching, generics of Sanofi’s Renvela(sevelamer carbonate) 800mg tablets. Annual US brand sales ofRenvela are around US$1.85 billion, Cipla and Impax noted. G

IN BRIEF

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23GENERICS bulletin

PRODUCT NEWS

3 November 2017

AUS district court improperly relied on hindsight in deciding thatasserted claims in a key US patent shielding Merck & Co’s

NuvaRing (ethinylestradiol/etonogestrel) contraceptive vaginal ringwere obvious in light of prior art, a US Court of Appeals has decided,handing an unfavourable decision to abbreviated new drug application(ANDA) filer Warner Chilcott.

Reversing the district court’s decision, the panel of three appealscourt judges also remanded proceedings back to the lower court forfurther action. Warner Chilcott – now part of Teva – had previouslyconceded that its ANDA product would infringe US patent 5,989,581 –the sole US patent listed in the US Food and Drug Administration’s(FDA’s) Orange Book protecting NuvaRing – were the patent valid.

In August last year, Delaware District Judge Gregory Sleet hadruled that it would have been obvious to a person of ordinary skill tohave modified a prior art document – International Patent ApplicationWO 97/02015 (PCT ‘015) – to arrive at the ‘581 patent, whichshields NuvaRing until 8 April next year.

According to the appeals court, inventors had previously struggledto create a device that released both progestogenic and oestrogeniccompounds – in this case etonogestrel (ETO) and ethinylestradiol(EE) – at a stable rate, with earlier prior art designs combining ETOand EE in a single compartment that were however unable to properlycontrol releases for each compound simultaneously. “The ‘581 patentpurports to solve this problem by providing a vaginal ring made of apolymer that is supersaturated with ETO,” the appeals court noted.

“Like the ‘581 patent,” it added, “PCT ‘015 also discloses avaginal ring that prevents contraception by releasing ETO and EE.PCT ‘015, however, relies on a two-compartment design, in whicha first compartment includes ETO only, and a second compartmentincludes ETO and EE.”

In his ruling, Sleet found that it would have been obvious tomodify the two-compartment ring so that “pharmaceutically required”amounts of both ETO and EE were delivered from one compartment. “Thedistrict court also found that PCT ’015 discloses target release ratesfor ETO and EE, and that ‘it would have been obvious for a personof skill to derive the claimed ratios of progestin and oestrogen’ fromthe target release rates,” the appeals court noted.

Both conclusions were however rejected on appeal. In reachingthe first conclusion, the district court had, the appeals court found,improperly “relied on hindsight”, a viewpoint underscored by the priorart’s criticism of one-compartment vaginal rings. “PCT ‘015 expresslystates that one-compartment rings are undesirable because it is difficultto control the release rates for both compounds.”

“Because PCT ‘015 criticises the use of one compartment todeliver both compounds,” it ruled, “the person of ordinary skill wouldnot be motivated to modify ‘015 to make a one-compartment ring.”

Meanwhile, the appeals court also rejected Warner Chilcott’sargument that it would have been obvious to calculate the relativeconcentrations for each compound based on disclosures in the prior art,as the district court had ruled. “PCT ‘015 warns that release rates forsingle compartment rings are difficult to control,” the appeals courtcommented. “Indeed, PCT ‘015 explains that its design can achieveconsistent release rates because there are two compartments.”

Therefore, it concluded, an ordinary artisan would not discard thetwo-compartment design “but still expect the ring to deliver acontrolled dose of both compounds”. Gn [email protected]

CONTRACEPTIVES

US NuvaRing rulingis reversed on appeal

ANTIRETROVIRALS

Swiss court upholdsan SPC for TruvadaSwitzerland’s federal patent court has rejected an attempt by Teva’s

Mepha Pharma to invalidate a local supplementary protectioncertificate (SPC) protecting Gilead Sciences’ Truvada (tenofovirdisoproxil fumarate/emtricitabine) combination antiretroviral. But aDanish court has refused to grant Gilead an injunction to block Accord’stenofovir/emtricitabine combination on the basis of a similar SPC.

Mepha argued unsuccessfully that Swiss SPC C00915894/01 –based on European patent EP0,915,894 that expired on 25 July 2017 –was invalid because the Truvada combination was not “protected bya basic patent in force”, as required by Article 3(a) of the EuropeanUnion’s (EU’s) SPC Regulation 469/2009. Swiss courts, Mepha said,should follow EU law and jurisprudence in determining SPC validity.

In particular, Mepha insisted that the Swiss court should align withthe Court of Justice of the EU’s (CJEU’s) jurisprudence, especiallyits landmark Medeva ruling from 2011, which stated that Article 3(a)must be interpreted as precluding “granting a supplementary protectioncertificate relating to active ingredients which are not specified in thewording of the claims of the basic patent relied on in support of theapplication for such a certificate”.

Patent claims ‘other therapeutic ingredients’Claim 27 of the ‘894 patent covers tenofovir disoproxil, including

its fumarate salt, “together with a pharmaceutically acceptable carrierand optionally other therapeutic ingredients”.

Since a federal court ‘Fosinopril’ ruling from July 1998, Swisscourts have used an ‘infringement test’ to determine SPC validity. Thisrequires that the product protected by an SPC is covered by the basicpatent, but not that the product covered by the SPC be specifically namedin the basic patent, thus allowing SPCs for combinations such as Truvada.

“The jurisprudence of the federal court’s Fosinopril ruling on theinfringement test is clear and unmistakeable, and has stood unchallengedfor decades,” the patent court asserted. “Medeva seems to set anadditional – albeit negatively formulated – condition to the infringementtest,” the Swiss court observed. While the CJEU had been striving tocreate harmonisation on SPCs within the EU to avoid barriers to freemovement of medicines, “Switzerland is not part of the EU’s internalmarket,” the patent court stated. “The Medeva arguments about theinternal market therefore are not transferable to Switzerland.”

Pointing out that the SPC harmonisation in the EU was largelybased on a “parallel harmonisation of marketing authorisations”, thecourt said Switzerland had “an autonomous licensing procedure” thatresulted in different scope and duration of marketing authorisations.“Following the Medeva ruling would neither lead to SPCs in the EUand Switzerland being essentially the same, nor to a recognisably betterfree circulation of medicinal products,” it concluded.

Furthermore, the Swiss court commented, the disparate languageused in post-Medeva rulings in the EU, as well as recent CJEU referrals,showed that “the Medeva decision has not clarified the situation somuch as caused uncertainty”.

Meanwhile, Denmark’s Maritime and Commercial High Courtrefused to grant an injunction on the grounds that claim 27 of the ‘894patent did not comply with Article 3(a) of the EU’s SPC Regulation byspecifying emtricitabine either by name, chemical structure or functionaldefinition. Thus, local SPC CR 2005 00032 could not serve as a basisto bar from the Danish market Accord’s emtricitabine/tenofovir disoproxil200mg/245mg coated tablets, the court stated, awarding costs to Accord.Gn [email protected]

Gen 3-11-17 Pgs.18-32.indd 23 01/11/2017 17:33


PRODUCT NEWS

US President Donald Trump has officially declared the country’sopioid crisis a national public health emergency under federal law,

after a determination was signed by acting secretary of health andhuman services Eric Hargan.

Pointing out that nearly US$1 billion in grants for addictionprevention and treatment were already being distributed, Trump alsostated that the federal government would potentially “bring majorlawsuits against bad actors”. Moreover, the National Institute of Healthhad “taken the first steps of an ambitious public-private partnershipwith pharmaceutical companies to develop non-addictive painkillersand new treatments for addiction and overdose”, as well as working onan advertising campaign to prevent opioid uptake, especially in children.

Trump also outlined actions made by the US Food and DrugAdministration (FDA), such as requiring drug companies thatmanufacture prescription opioids to provide more training to prescribers.

Addressing Trump’s “important efforts to address the opioid crisis”,FDA Commissioner Scott Gottlieb said that the agency was “committedto taking additional steps” under the new declaration. “The FDA hasa vital role to play in curbing new addiction,” he commented.

A focus for the agency would be on “promoting the developmentof opioids that are harder to manipulate and abuse, and non-opioidpain treatments”, Gottlieb noted. Further actions included “supportingimportant efforts to increase the use of and access to the potentiallylife-saving antidote naloxone”, and “encouraging the safe adoption andmore widespread use of FDA-approved medically-assisted treatmentsto help combat addiction”.

The agency also plans to work with federal and internationalpartners to “stop the flow of heroin and extremely potent, and oftendeadly, synthetic drugs like illicitly-made fentanyl”.

“One area we’ve committed to exploring further is how opioiddrug products are packaged, stored, and ultimately – when no longerneeded – discarded,” Gottlieb continued. “It’s possible that a defined,short-term supply of medication could be packaged in a manner thatlimits the number of pills dispensed.” Other packaging innovationscould make it easier to track the number of doses that have been taken,he suggested, while other options could work to “improve storage andencourage prompt disposal to reduce the available supply and reducethe risk for third-party access”. Technologies could allow healthcareproviders, pharmacists or family members to monitor patient use ofprescription opioids, Gottlieb added.

The FDA has announced a two-day public workshop on opioidpackaging, storage and disposal options, to be held at its campus inSilver Spring, Maryland, on 11-12 December. Aiming to cover threeareas, the workshop will define the “specific problems that these typesof packaging and disposal solutions can help address”, as well asdefining the “guiding principles that the scientific community shouldconsider in designing product features that achieve these possiblesolutions”. A last point focuses on defining the “types of data neededto evaluate how these solutions are working”.

In July, Gottlieb outlined the agency’s latest actions on the opioidaddiction crisis, including benefit-risk assessment in the pre- and post-market setting, provider education, and steps to reduce overall exposureto these drugs (Generics bulletin, 28 July 2017, page 18). This followeda meeting on whether opioid medications with abuse-deterrent propertieswere “having their intended impact on limiting abuse” (Genericsbulletin, 23 June 2017, page 13). Gn [email protected]

OPIOID-DEPENDENCE DRUGS

US opioid crisis is anational emergency

Celltrion’s CT-P13 biosimilar rival matched the efficacy and safetyof Janssen’s Remicade (infliximab) in a switching study conducted

in Crohn’s disease patients, the South Korean company has told ameeting of European gastroenterologists.

Presenting data from a randomised Phase III trial that was jointlyfunded by its US marketing partner Pfizer, Celltrion told the 25thUnited European Gastroenterology (UEG) Week that 166 out of 220patients across 16 countries had completed the study to 54 weeks. Atweek 30, around half of the patients in each double-blind group wereswitched to the alternative treatment.

“Efficacy, pharmacokinetics (PK) and safety were comparableamong all treatment groups up to week 30,” Celltrion stated, addingthat several disease-activity and quality-of-life metrics showed similarresults in each group at week 54. “The safety profiles among alltreatment groups – including adverse reactions, serious adverse events,infections and immunogenicity – were similar throughout the one-yeartreatment period,” the South Korean developer added.

During UEG Week, Celltrion also presented PK data from aninitial open-label study of a subcutaneous form of CT-P13 in healthyvolunteers. Such an administration route was “found to be feasible interms of bioavailability and safety profile, and could provide patientswith a more convenient and accessible treatment option,” the firm said.

Pfizer – which markets CT-P13 in the US under the Inflectra(infliximab-dyyb) brand name – stressed the biosimilar’s comparableefficacy, safety and tolerability over a 24-week period after switching.The firm said the results added to a “considerable body of evidence,including real-world studies and the Nor-Switch trial”. G

GASTROINTESTINAL DRUGS

Celltrion and Pfizerstress switching data

Apotex has failed to convince the Supreme Court of Canada toorder a re-hearing of a ruling that AstraZeneca’s Canadian patent

2,139,653 is not invalid for want of utility. The ‘653 claims opticallypure salts of the proton-pump inhibitor esomeprazole.

In a landmark decision handed down earlier this year, the SupremeCourt had overturned previous findings that the ‘653 patent was invalidbecause it unjustifiably promised a specific utility – the so-called‘promise doctrine’ (Generics bulletin, 7 July 2017, page 1). Rather, theSupreme Court said, courts should consider whether identified subjectmatter in the patent is useful, adding that “a scintilla of utility will do”.G


Canada denies Apotex appeal

Mylan and Teva have obtained summary judgements of non-infringement for US patent 6,649,180 that protects until April

2020 Allergan’s Delzicol (mesalamine) capsules for ulcerative colitis.Eastern Texas District Judge Rodney Gilstrap noted that the judgements“may allow the Food and Drug Administration (FDA) to lift the regulatory30-month stay” on generic approval for Mylan and Teva. Gilstrapfound no error with a magistrate’s construction of ‘gelling agent’ to meana ‘substance that gels the film composition’ which is not water. G


Two toss out Delzicol case

Gen 3-11-17 Pgs.18-32.indd 24 01/11/2017 17:33

26 GENERICS bulletin

AWARD WINNERS

3 November 2017

SAVE THE DATE ...The Global Generics & Biosimilars Awards 2018 will take place on

Tuesday 9 October 2018 and be held in Madrid, Spain.

Award: Company of the YearSponsor: QuintilesIMSWinner: Hikma Pharmaceuticals

Award: Company of the Year, AmericasSponsor: Chartwell PharmaceuticalsWinner: Amneal Pharmaceuticals

Award: Company of the Year, Asia-PacificSponsor: EvapharmaWinner: Aurobindo

Award: Company of the Year, EMEASponsor: PanaceaWinner: Medis

Award: Acquisition of the YearSponsor: PharmawiseWinner: Accord Healthcare

Award: Leader of the YearSponsor: PharmacloudWinner: Amneal Pharmaceuticals

Gen 3-11-17 Pgs.18-32.indd 26 01/11/2017 17:33

27GENERICS bulletin

AWARD WINNERS

3 November 2017

Award: API Supplier of the YearSponsor: Clarivate AnalyticsWinner: Laurus Labs

Award: Biosimilar Initiative of the YearSponsor: Generics bulletinWinner: Sandoz

Award: Patent Litigation of the YearSponsor: QuintilesIMSWinner: Accord Healthcare

Award: Regulatory Achievement of the YearSponsor: EignapharmaWinner: Sandoz

Award: Industry Partner of the YearSponsor: mAbxienceWinner: Piramal Pharma Solutions

Award: Corporate Social Responsibility (CSR) Initiative of the YearSponsor: International Health Partners (IHP)Winner: Alvogen

Award: Innovation of the YearSponsor: Piramal Pharma SolutionsWinner: Chemo Group

Award: Business Development of the YearSponsor: James Dudley ManagementWinner: Accord Healthcare

Gen 3-11-17 Pgs.18-32.indd 27 01/11/2017 17:33


AWARDS

With thanks to our sponsors:

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JAMES DUDLEYMANAGEMENT

®

To find out more aboutsponsoring an Award at theGlobal Generics & BiosimilarsAwards 2018, please contact

[email protected] orvisit www.generics-bulletin.com

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Gen 3-11-17 Pgs.18-32.indd 28 01/11/2017 17:33

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MERGERS & ACQUISITIONS

Amneal and Impax eye newchannels for US distribution

Immediate-release tablets

37%Capsules/soft gels

14%

Oral liquids7%

Extended-releasetablets15%

Topicals7%

Nasal sprays1%

Transdermals2%

Injectables14%

Figure 1: Breakdown by product type of Amneal’s and Impax’combined pipeline of approximately 150 abbreviated new drugapplication (ANDA) filings (Source – Amneal/Impax)

Immediate-releasetablets21%

Capsules/soft gels16%

Oral liquids14%

Extended---releasetablets

5%

Topicals5%

Nasal sprays2%

Transdermals5%

Injectables23%

Figure 2: Breakdown by product type of Amneal’s and Impax’combined development pipeline of approximately 165 products(Source – Amneal/Impax)

Inhalation6%

Other2%

Alittle under two months ago, Paul Bisaro, ImpaxLaboratories’ president and chief executive officer,expressed his belief that manufacturers in the US

were likely to explore relationships with consumer-focused operators, against the backdrop of customerconsolidation in the market that has created just threekey buying groups for retail generics.

“I think we are at the cusp of a time when we willstart seeing new distribution channels coming to fruition,just because of the dynamics of the industry,” Bisarotold investors (Generics bulletin, 22 September 2017,page 4). “And we now live in an environment and timewhere companies like Amazon, Federal Express andUPS, who have direct access to consumers, will finda way to participate in the channel.”

By using “an Amazon or direct-to-patient model”,Bisaro opined, Impax could “ sell our product at probablythe same margin, or maybe at even a slightly highermargin, because we are now cutting our way aroundall the people who had to take a piece of the pie”.

Such strategies are now high on Bisaro’s agendamoving forward, following Impax’ agreement withAmneal Pharmaceuticals to merge into a new publicly-traded company. The all-share transaction, which isexpected to close in the first half of next year, is set tocreate the fifth-largest generics business by sales inthe US (Generics bulletin, 20 October 2017, page 1).

Alongside Impax’ chief financial officer BryanReasons, and Amneal’s founders and co-chief executiveofficers, Chirag Patel and Chintu Patel, Bisaro toldinvestors that the new company would have the “scaleand flexibility to be creative in all commercial strategiesin the evolving generics industry”.

Describing product distribution as a “challenge”the industry was currently facing, Bisaro raised thepossibility of the new Amneal Pharmaceuticals companyadopting a ‘cash-pay’ direct-to-patient distribution

model for certain generics, under which Amneal couldbypass payers and create a direct relationship with patients.

“In the past we’ve thought mostly about ourcustomers as being the wholesalers, retailers and themail-order companies,” Bisaro acknowledged. “And Ithink we as a generics industry need to start thinkingabout our customers as patients, and find ways to bemore connected to those patients. That is going to be oneof the ways that we address some of the challenges thatthis industry is facing.”

“The great news about new Amneal is we now havethe resources to be able to do that,” he insisted, “and notjust from a product perspective, but from a financialperspective. So that’s what makes me so excited aboutthis transaction, and why I think we can be successfulin what is clearly a challenging industry right now.”

With the combination forecasting a sales compoundannual growth rate (CAGR) of around 12% over thenext three years, the “challenging” nature of the industrywas high on investors’ list of queries as they faced bothmanagement teams. “I think it’s fair to say investorsare a little bit gun-shy about signing up for revenuegrowth in the generics business, let alone double-digitgrowth,” one analyst commented.

Under its sales forecast, the new firm expects proforma sales to rise from approximately US$1.75-US$1.85billion this year to around US$2.6 billion in 2020.

Acknowledging the intensity of pricing pressurefacing manufacturers in the US market, Reasons saidthat the combination had factored in base price erosionof around 8.5-10%, “if there were no other competitivereasons to model something differently”. “We have oneof the nicest houses in the neighbourhood, Bisaro said,“and what we need to do is improve the neighbourhood.”

To achieve the double-digit sales growth, Amnealand Impax aim to capitalise sales on the combination’s“significantly expanded generics portfolio”, covering “just

Becoming a leader in

alternative, direct-to-

patient distribution is

among the numerous

benefits that Amneal

and Impax expect to

drive future growth as

a combined company.

Dean Rudge reports.

Other3%

Gen 3-11-17 Pgs.18-32.indd 30 01/11/2017 17:33


MERGERS & ACQUISITIONSabout every dosage form available”, as well as executeon its “exceptional generics pipeline”.

According to Chirag Patel, the combination’sportfolio will number approximately 165 marketed genericproduct ‘families’ in the US, of which around halfhold either the number one or two position by sales.

Meanwhile, Patel stressed, all of Amneal’s productswere manufactured in-house, meaning that no profits

derived were shared with partners.“I don’t think we’ll be rationalising our portfolio

in the generics space,” Bisaro said in response to aninvestor query. “However, we’ll certainly continue tomonitor products where they fall below direct costs.”

Meanwhile, the combination’s pipeline will becomposed of approximately 150 abbreviated new drugapplications (ANDAs) pending US Food and DrugAdministration (FDA) approval, as well as 165 projectscurrently under development.

Of these approximate 315 pipeline assets, roughly50% are defined as ‘high-value’ opportunities by themerger partners, representing projects that are exclusivefirst-to-file, first-to-file, first-to-market or “other high-value opportunities with zero to three competitors”.

As Figure 1 shows, just less than two-fifths of the150 pending ANDAs reference immediate-release tabletformulations. Extended-release tablet formulations makeup another 15% of ANDA filings, capsules or soft-gelproducts and injectables each comprise 14%, and oralliquids and topicals another 7% each.

Among the combination’s leading ANDAs currentlypending FDA approval are rivals to Teva’s Copaxone(glatiramer acetate), Shire’s Lialda (mesalamine) andJazz Pharmaceuticals’ Xyrem (sodium oxybate).Moreover, Impax has just launched generic rivals toSanofi’s Renvela (sevelamer carbonate) immediatelyupon obtaining FDA approval (see page 22).

Concerning the development pipeline, Chintu Patelpointed out that “the future of our generics franchiseis more heavily weighted towards complex products, suchas injectables, topicals and transdermal and respiratoryproducts”. As Figure 2 shows, injectables comprise justunder a quarter of development assets, while transdermalproducts and inhaled products also represent a greaterproportion compared with filed ANDAs.

And, Patel added, becoming a publicly-tradedcompany meant investors could hope “to see many moreproducts from our pipeline” moving forward.

“Amneal overinvested in research and developmentin the first 10 years of its life, and new Amneal is goingto enjoy the fruits of that,” Bisaro insisted. “I can’tguarantee that all of these products will not haveadditional competition, but I am confident that we willhave a limited number of competitors in some of theseprojects. We have a lot of shots on goal.”

In addition to capturing value from its own pipeline,the combination also aims to derive value through itsnascent biosimilars pipeline, in conjunction with Amneal’spartner Adello Biologics. The combination will holdcommercial rights in the US to both Adello’s Neupogen(filgrastim) and Neulasta (pegfilgrastim) biosimilars.

Amneal noted that the Neupogen biosimilar hadbeen filed with the FDA, while the Neulasta biosimilar –for which approval has so far proved elusive for severalbiosimilars developers – would be filed in “early 2018”.

“With respect to biosimilars going forward, we seeourselves as more of a commercial partner, as opposed

to a developer,” Bisaro underlined. “We have plenty onour plate right now, with very complex molecules,peptides and difficult projects.” Impax’ chief noted thatthe new company would “figure out a path later if wewant to get into manufacturing biosimilars”.

Supporting the firms’ portfolio and pipeline ambitionsis the combination’s “fully diversified, cost-efficient”global manufacturing and research and developmentnetwork. “We have a consistent track record [of quality],with 59 successful FDA inspections across themanufacturing network,” Chintu Patel pointed out.

Across the US and Europe, the combination willboast oral-solid manufacturing facilities in Hayward,California, and Brookhaven and Hauppauge, New York;liquid and topicals facilities in Branchburg and Piscataway,New Jersey, as well as transdermal capabilities at thePiscataway facility; and the capability to manufacturerespiratory products at a facility in Cashel, Ireland.

Outside of the US and Europe, the firms will havesterile, aseptic and oral-solid dosage facilities inAhmedabad and Hyderabad, India, as well as activepharmaceutical ingredient (API) manufacturing in Vizagand Dehej, India. Of the firms’ global manufacturingfootprint, seven facilities had research and developmentcentres co-located within, Chintu Patel pointed out.

Moving forward, the combination is mulling theidea of bringing in-house Impax’ current roster ofproducts currently manufactured by contractmanufacturers, in an effort to drive further efficiencies,and improve the combined company’s gross margins.

Quizzed on whether the firms had any plans toconsolidate the combined manufacturing network, Bisarosaid a decision had not been made. “As it evolves, wewill keep you guys informed,” he said. But, Bisaroopined, the combination currently had “plenty of capacityto manufacture products that are filed, as well as theproducts that are in the pipeline.”

In addition to these strategic benefits, the firms alsofeel the combination will be “financially compelling”,with the new company projected to generate annualcost savings of US$200 million within three years.

The combined synergies would be in addition tothose achieved from Impax’ existing ‘cost improvementplan’, through which the US-based firm has announcedUS$135 million worth of savings over the last 18 months,according to Reasons (Generics bulletin, 1 September2017, page 7). Impax’ cost savings were now startingto “kick in”, Reasons said, and would be more tangiblein the remainder of this year and into 2018.

Together, these cost savings will help the firmsachieve their goal of reporting adjusted pro formaearnings before interest, tax, depreciation and amortisation(EBITDA) of approximately US$1.1 billion in 2020,up from approximately US$600-US$650 million in2017, representing a CAGR of around 22%.

Commenting further on the double-digit sales andearnings guidance over the next three years, Bisaroobserved that the “law of large numbers is in our favourright now”. “We are a small company that is growing,which is why we feel very comfortable about double-digit growth,” he insisted.

“As we get out five-to-seven years, we have torecognise that the growth profile of our generics businessis going to slow down, and so we need to deploy ourcapital in a way that gives us adjacencies that allow usto grow beyond those years at this fast rate.” G

“Amneal overinvested

in research and

development, and new

Amneal is going to enjoy

the fruits of that”

Gen 3-11-17 Pgs.18-32.indd 31 01/11/2017 17:33


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NEWFOR

2017

Australia’s Generic and Biosimilar Medicines Association (GBMA)is looking to recruit a new chief executive officer (CEO), after

the incumbent, Belinda Wood, announced plans to stand down fromthe post in February 2018.

Having served as CEO of the GBMA since 2014, Wood had been“pivotal in the signing of, and subsequent extension to, the strategicagreement with government”, the association said, referring to thefive-year deal struck in 2015 (Generics bulletin, 5 June 2015, page 14)that was extended by two years earlier in 2017 (Generics bulletin,26 May 2017, page 1). The GBMA’s “enhanced reputation withgovernment” had enabled the association to “have a ‘seat at the table’for ongoing policy discussions”, the group stated.

“It has been an honour to lead GBMA as its CEO for the past threeyears,” Wood said. “When I took the role, my focus was to delivercertainty for the generic and biosimilar medicines industry, to increasethe use of affordable medicines and to secure a predictable marketaccess pathway for biosimilars. Having achieved these goals, andsecuring and extending the strategic agreement with government, thetime is right for me to look for the next opportunity, knowing I leavethe GBMA well-placed for the future.”

Wood’s successor as CEO of the GBMA will be asked to “leadthe association through its next phase in implementing the key elementsof the extended strategic agreement”. G

RESIGNATIONS

GBMA seeks a chiefas Wood steps down

Teva has announced that its new president and chief executiveofficer (CEO), Kåre Schultz, has begun his tenure as leader of the

Israeli firm and as a member of its board from 1 November. FormerLundbeck chief Schultz was announced as the successor to interimchief Yitzhak Peterburg in September (Generics bulletin, 15September 2017, page 1), ending a search that began when ErezVigodman resigned “by mutual agreement” at the start of February(Generics bulletin, 10 February 2017, page 1).

“I am looking forward to getting to work as Teva’s CEO alongsidethe Teva team,” Schultz stated. “I look forward to travelling throughoutTeva’s global operations and reviewing the opportunities we have tobetter serve patients and healthcare systems in each of our markets.”Schultz said his focus would be on “strengthening Teva’s businessand enhancing our leadership in specialty and generic medicines todeliver sustained shareholder value creation”.

Schultz joining the company was “the start of a new chapter atTeva”, said board chairman Sol Barer. With “extensive globalpharmaceutical experience and a strong track record in corporateturnarounds, as well as in driving growth and leading internationalexpansion”, Schultz would help “position Teva for long-term success”,Barer said. Teva suffered a US$5.74 billion operating loss in the secondquarter of 2017, due to weakness in US generics that led to a US$6.1billion goodwill impairment (Generics bulletin, 11 August 2017, page 1).G

APPOINTMENTS

Teva’s Schultz plansto start global review

Stada has announced that Luc Slegers is stepping down as managerof Stada Europe and retiring after 26 years with the company.

“With the new majority owners Cinven and Bain Capital as well asthe new chief executive officer Claudio Albrecht, Stada is very well-positioned,” Slegers stated. “I see tremendous opportunities for growthin segments where we were previously limited due to financial resources.”

Executive board chairman and chief executive Albrecht wasnominated to replace Engelbert Coster Tjeenk Willink earlier thisyear following Stada’s takeover by Bain Capital and Cinven (Genericsbulletin, 8 September 2017, page 1). He said Slegers “leaves behinda foundation that we can use to build Stada into an even more importantand bigger player in the generics and OTC businesses”.

Meanwhile, Stada has named Frank Staud as its executive vice-president of corporate communications, branding and sponsoring. Aswell as being responsible for “the image of the Stada brand”, he willalso manage the group’s communication activities, including corporateand product communication, change communication, external andinternal communications, branding, and sponsorship. Staud will reportdirectly to Albrecht.

“Stada currently finds itself in the midst of the biggest transformationphase in its history. Outstanding internal and external communicationis therefore of utmost importance,” Albrecht pointed out. “I am thereforeextremely pleased that we have been able to attract Frank Staud, aproven expert, for this important task – someone who is a specialistin change communication.” Staud – who “has more than 20 years ofexperience” in communications – previously served as executive vice-president of corporate communications at Actavis, where Albrechtwas formerly chief executive. G

RESIGNATIONS

Slegers steps down at Stada

Gen 3-11-17 Pgs.18-32.indd 32 01/11/2017 17:33

eight eu authorities are deemed equivalent to us · “following the creation of aristo pharma...

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