gen 14-9-18 pgs.1-16 · 2018. 10. 29. · 14september2018 genericsbulletin 5 companynews...

14 September 2018

Aurobindo snaps up USbusinesses from SandozAurobindo is set to become the second largest generics player in the US by number ofprescriptions, and the second largest dermatology player in the US, after agreeing toacquire Sandoz’ dermatology and oral solids businesses in a deal worth US$1.0 billion.

Expected to close “in the course of 2019” following the completion of customary closingconditions, including clearance from the US Federal Trade Commission (FTC), the all-cashdeal includes an upfront payment of around US$900 million, and another US$100 million inperformance-based earn-outs, financed through a fully-committed debt facility. The acquiredbusinesses achieved sales of US$1.2 billion in 2017.

Noting that deal would add approximately 300 products to Aurobindo’s operations in theUS, including authorised generics, in-licensed and branded dermatology products, “as well asadditional development projects”, the Indian firm said its “market-leading, vertically-integrated,highly-efficient manufacturing base” would “enhance the position of the acquired portfolioover the medium term”. Aurobindo will pick up certain operations from the former FougeraPharmaceuticals dermatology business, as well as taking full control of Sandoz’ Eon Labs unit.

“The portfolio being divested generated sales of [around] US$600 million in the first halfof 2018 for Sandoz,” Aurobindo revealed. “After expiration of certain in-licensed productcontracts, and rationalisations of acquired products that will not negatively impact profitability –but before the impact of any potential FTC-led divestments – the portfolio is expected togenerate over US$900 million in sales for the first 12 months after completion of the transactionfor Aurobindo.” No details on the acquired businesses’ profitability were revealed by Aurobindo,which saw its annual US Formulations sales increase by 9% to Rs74.4 billion.

Commercial and manufacturing capabilities in the US set to be added through the dealinclude a “fully-dedicated dermatology sales force”, along with three manufacturing facilities inthe US, bringing “specialised capabilities in creams, ointments, lotions, topical solutions andtopical suspensions that are highly complementary to Aurobindo’s current manufacturingfootprint”. Aurobindo says it and Sandoz will enter into a transitional services agreement to“support the ongoing growth plans of the businesses”. G

For Sandoz’ rationale and further details of the transaction, turn to page 3.

Amgen launches first biosimilarAmgen says it has entered “fully into the field of biosimilars” after announcing the launchof the company’s first biosimilar; its Kanjinti (trastuzumab) version of Roche’s Herceptinin Spain. “The comprehensive clinical data that supported the authorisation of Kanjinti in Europeand now the funding from [Spain’s] National Health System confirms the drug is equivalent tothe reference product,” commented José Motellón, medical director of Amgen Iberia.

“Amgen and [development partner] Allergan are working with local markets to ensurethe timely launch of Kanjinti in Europe and intend to make Kanjinti available to patients in theEuropean Union (EU),” a spokesperson for Amgen told Generics bulletin. “We expect tolaunch on a country-by-country basis with exact timing dependent on each individual country.”The European Commission granted Amgen an EU marketing authorisation for the oncologybiosimilar at the end of May (Generics bulletin, 1 June 2018, page 5).

Commenting on the launch, Amgen said that not using its vast knowledge in originalbiologics to develop and produce more cost-effective biosimilars “would have been irresponsibleon our part”. Amgen has a second oncology biosimilar approved in the EU, Mvasi (bevacizumab),but the product has not yet been launched. G

COMPANY NEWS 3

Teva tasks Nason to 3head TAPI business

Aurobindo deal gives Sandoz 3room to focus

Lupin in the clear on firm’s 4‘sartan’ drugs

Julphar hails progress 5despite sales decline

Licences and launches let 5JGL bounce back

Regional differences show 7Mylan’s potential

MARKET NEWS 8

Global bio reference comes 8under attack

US industry identifies a trinity 8of obstacles

EU switching is safe but 9needs more data

Canada should resist 9US trade proposition

REMS abuses in US cost 10US$13bn a year

FDA lists risk factors 11for facility inspections

France trials range of 11biosimilar incentives

PRODUCT NEWS 12

Celltrion wants lower 12RA criteria in the UK

Glenmark’s Seretide approved 13in Germany

Xbrane ‘shifts focus’ to 13biosimilar portfolio

Oracea ruling leaves 15Amneal waiting years

Alvogen’s gefitinib is 15approved in the EU

REGULARS

Events – Conferences and meetings 8Price Watch UK – Our regular listing 13People – Albrecht hands over 16Stada to Goldschmidt

Issue No.368

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3GENERICS bulletin14 September 2018

COMPANY NEWS

MANUFACTURING

Sun’s Halol gets observationsSun Pharma’s Halol formulations manufacturing facility in Gujarat,India, is back under US Food and Drug Administration (FDA)scrutiny, after receiving six ‘Form 483’observations.

Clarifying media reports, Sun revealed in a filing with the BombayStock Exchange (BSE) that the observations pertained to a pre-approval inspection at Halol that took place at the end of August. “Thecompany will be submitting its response to the observations to theFDA within 15 business days,” the Indian firm noted.

After almost four years of compliance issues at Halol, Sunreceived an establishment inspection report (EIR) from the FDA forthe facility in June this year clearing the way for new product approvals(Generics bulletin, 22 June 2018, page 3). G

BUSINESS STRATEGY

Teva tasks Nason tohead TAPI businessTeva’s senior vice-president for European Technical Operations,John Nason, has been appointed president of the Israeli firm’sstand-alone Teva Active Pharmaceutical Ingredients (TAPI) businesswith additional responsibility for the company’s Biologics operations.

In his new role, Nason, who joined Teva three years ago, leadsthe company’s vertically-integrated business unit responsible for thedevelopment, production, marketing and sales of bulk API for boththird-party formulators and for Teva.

Referring to his European Technical Operations role, Teva saidNason had “worked closely with the company’s commercial andresearch and development (R&D) organisations to meet customer andpatient needs while closely managing the competitiveness of theproduct portfolio”. “In that position, Nason was an active member ofthe operations leadership team responsible for setting strategy andmanaging Teva’s global operations,” Teva noted, “a role he will retainas president of TAPI and Teva’s Biologics operations.”

Based at Teva’s global headquarters in Petach Tikva, Israel, Nasonreports directly to Carlo de Notaristefani, executive vice-president forTeva’s Global Operations. His previous employers include Bristol-Myers Squibb and Novartis. G

BUSINESS STRATEGY

Civica is new non-profit in USAgroup of seven US healthcare organisations representing around500 hospitals has realised plans to form a non-profit genericscompany, as a means to tackle shortages and address rising drug costs,officially establishing itself as Civica Rx and naming former Amgenexecutive Martin VanTrieste as its chief executive officer.

The number of representatives has risen since it was announced inJanuary this year (Generics bulletin, 26 January 2018, page 3), with“more than 120 health organisations representing about a third of thenation’s hospitals” in the meantime having contacted Civica Rx andexpressing a “commitment or interest in participating with the new firm”.

“Civica Rx has identified 14 hospital-administered generic drugsas the initial focus,” the company said. Headquartered in Utah, Civica Rxexpects to have products on the market “as early as 2019”. G

MERGERS & ACQUISITIONS

Aurobindo deal givesSandoz room to focusSandoz plans to focus more intently on “higher growth areas” inthe US to “achieve sustainable and profitable growth”, includingcomplex generics, value-added medicines and biosimilars, after agreeingto sell its dermatology and oral solids businesses to Aurobindo in a dealworth US$1.0 billion. “Through this transaction, we are refocusingour business but also striving to ensure continuity of supply ofimportant long-used generic medicines for patients and customersin the US,” stated Sandoz’ chief executive Richard Francis.

Complex generics on which Sandoz intends to focus, in terms ofclinical development, business development and investment efforts,include injectables, respiratory products and ophthalmics. “Sharpening ourportfolio focus in the US allows us to devote more time and resourcestoward our strategy,” said Francis, “creating higher value and opening upaccess to important medicines where alternatives are truly needed.”

Rumours have dogged Sandoz for months about the potential saleof certain assets, amid steep price erosion in the US market. Earlierthis year, parent company Novartis said it would “not consider a firesale” for Sandoz’ US oral solids unit, “given it is still profitable andhighly cash-generative” (Generics bulletin, 23 February 2018, page 3).

Through the agreed sale to Aurobindo, Sandoz will hand over threemanufacturing facilities in the US: Fougera Pharmaceuticalsdermatological facilities in Hicksville and Melville, New York, alongsideSandoz’ dermatology development centre; and the Eon Labs oral-solid dosage facility in Wilson, North Carolina.

Around 750 employees in Hicksville, Melville and Wilson, aswell as the field representatives for Fougera’s PharmaDerm brandeddermatology business and Sandoz employees based in Princeton,North Carolina, are expected to transfer to Aurobindo upon closing.

“We recognise that the transfer of ownership for a business ofthis size is a complex process, and we are aware that it may createsome uncertainties for our associates in the US,” acknowledged CarolLynch, Sandoz’ US president. “It is thus a priority for us to make thetransition as clear and quick as possible.”

From a portfolio of around 300 products, Aurobindo will gain accessin the generic dermatology portfolio to a “wide range of therapeuticareas”, including topical antibiotics, gynaecological and dermatologicalantifungal agents, anti-acne agents, local anaesthetic analgesics, anti-itch, and a dermatological chemotherapeutic agent. For the oral non-dermatological basket of products, therapeutic categories includeautoimmune disease treatments, oncology drugs and hormones.

“The acquisition enhances Aurobindo’s market leading pipeline ofabbreviated new drug application (ANDA) filings with additionalpipeline projects, including ANDAs that have already been filed,products under development, and first-to-file opportunities whichhave the potential to be exclusive,” Aurobindo noted.

“We expect a seamless integration of the acquired businesses withthe rest of the Aurobindo group given the success we have achievedin our acquisitions to date,” commented N Govindarajan, Aurobindo’smanaging director. “We will be focused on leveraging our group’smarket-leading vertically-integrated and highly efficient manufacturingbase to enhance the market position and medium-term profitabilityof the businesses we are acquiring.”

Jefferies, which acted as financial advisor to Aurobindo, said thatthe deal “represents the largest out-bound merger and acquisition(M&A) transaction by an Indian pharma company and would provideAurobindo a meaningful entry into the US dermatology space”. Gn [email protected]

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4 GENERICS bulletin 14 September 2018

COMPANY NEWS

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Issue 368 l 14 September 2018

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MANUFACTURING

Lupin in the clear onfirm’s ‘sartan’ drugsValsartan active pharmaceutical ingredient (API) manufactured byLupin is “safe” with “no chance” of containing the toxic impurityfound in some other valsartan active ingredients, an inspection ofone of the Indian firm’s facilities by US regulators has confirmed.

Lupin’s announcement followed the US Food and DrugAdministration (FDA) completing a current good manufacturing(cGMP) inspection at the firm’s Tarapur manufacturing site inMaharashtra, India, conducted from 27-31 August by three agencyinvestigators. “The inspection closed with one observation, a proceduraldeficiency,” the Indian firm noted, releasing no further details.

As well as valsartan, the inspection had focused on the safety oftwo other ‘sartan’ APIs, losartan and irbesartan. All three drugs arein the angiotensin II receptor blocker (ARB) therapeutic class, usedto treat high blood pressure.

In July, the FDA announced that low levels of the impurityN-nitrosodimethylamine (NDMA), which can cause cancer, had beenfound in valsartan API manufactured by a Chinese supplier, leadingthe FDA to issue recalls (Generics bulletin, 27 July 2018, page 17).

Follows global valsartan recallsValsartan finished-dose drugs, including combination products,

using API made by Zhejiang Tianyu were affected by the recall.Regulators across the globe, including in Canada and Europe, havealso acted, with NDMA classified a probable human carcinogen.

Referring to the inspection at Tarapur, Lupin underlined that,“during the inspection, the FDA concluded that manufacturing processesof Lupin sartans are safe with no chance of presence of the NDMAimpurity in the APIs”.

Earlier this month, the FDA announced that a “major operation”was underway to investigate and address the “troubling finding”,leading the agency to also test all ARBs for traces of the toxic material(Generics bulletin, 7 September 2018, page 15). The US agencymaintained that it was still not “100 percent sure” what the root causeof the impurity was, noting that full understanding would require“correlation of multiple test results from valsartan APIs made bydifferent processes with the various process steps used by differentmanufacturers or at different times”.

The European Directorate for the Quality of Medicines (EDQM)recently took further action on valsartan API suppliers (see page 12). G

CONCORDIA INTERNATIONAL has completed its recapitalisationtransaction that reduces the Canadian firm’s total debt by aroundUS$2.4 billion and its annual cash interest expense by about US$170million. In return for a US$586.5 million private placement, investorshave received 87.69% of the firm’s voting shares, with existingshareholders getting just one share for each 300 they previouslyheld. The deal gives Concordia approximately US$200 million ofunrestricted cash on hand. “We have an enviable global specialtygenerics platform, and will be seeking both organic and inorganicgrowth opportunities to leverage this platform to its full potential,”chief executive officer Graeme Duncan maintained.

JB CHEMICALS & PHARMACEUTICALS has secured boardapproval for a share buy-back of up to 9.46% of the Indian firm’sequity for an amount not exceeding Rs1.30 billion (US$18.1 million).

AVARA PHARMACEUTICAL SERVICES has completed its purchaseof Sandoz’ injectables facility in Boucherville, Canada. The contractdevelopment and manufacturing organisation (CDMO) had struckthe deal earlier this year (Generics bulletin, 1 June 2018, page 3).

AMPAC FINE CHEMICALS is now part of South Koreanconglomerate SK Holdings after the active pharmaceutical ingredient(API) producer completed its transition from its previous owner,private-equity firm HIG Capital, announced earlier this year(Generics bulletin, 27 July 2018, page 3).

CSPC PHARMACEUTICAL said its “common generic-drug businessincreased market penetration” and its “bulk-drug business keptmarket-leader position” as the Hong Kong-based company increasedits turnover by 49.8% to HK$10.8 billion (US$1.37 billion) in thefirst half of this year. That total included common generics salesahead by 42.3% to HK$3.31 billion as the firm’s azithromycin,captopril and tramadol tablets passed consistency evaluations.

INTAS PHARMACEUTICALS increased its turnover by 30.6% toRs109 billion (US$1.52 billion) in its financial year ended 31 March2018. The privately-owned Indian group – which operates under theAccord name in Europe and North America – improved its profitbefore interest, tax and depreciation by 39.3% to Rs24.6 billion.

GRINDEKS has formed a “strategic long-term co-operation” ondrug research and development with the Latvian Institute of OrganicSynthesis. The agreement replaces a current partnership that focuseson individual research projects, such as into cardiovascular drugs.G

IN BRIEF

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COMPANY NEWSFIRST-HALF RESULTS

Julphar hails progressdespite sales declineJulphar says it has made “significant progress in the GulfCo-Operation Council (GCC) and North Africa” even as the UnitedArab Emirates (UAE)-based group posted a 4% sales fall to AED558million (US$152 million) in the first half of this year. However,second-quarter sales advanced by 19% to AED294 million.

Highlighting the “solid financial results”, general manager JeromeCarle described the first six months of 2018 as “a busy but veryproductive period”. “We saw an acceleration of our revenue in theLevant region in the second quarter and continue to improve on lastyear’s performance,” he commented. “Our subsidiaries, led by GCCand Egypt, are also delivering strong performances locally.”

“We have made significant progress in North Africa by deliveringstrong results in Libya and Morocco,” Carle continued, noting that

the firm had also “divested several non-strategic assets” during thesecond quarter that would improve its cash-flows and enable it to focusmore clearly on core operations.

“We have just launched several new products in key therapeuticareas, such as cardiovascular, and our expansion plans are on track,particularly in Saudi Arabia and Africa, where we are making inroadsin a number of key markets,” he explained.

As Figure 1 shows, Julphar’s first-half sales shortfall was duepredominantly to turnover in Saudi Arabia – where the firm holds a51% stake in the Julphar Saudi Arabia venture – tumbling by nearlya third to AED124 million, and to a lesser extent to a 2% slip to AED134million in the UAE-based group’s domestic market.

With 25 product launches planned in the UAE this year, and200 product registrations scheduled in the region, Carle maintainedthat continued investment in its pipeline and expansion in key marketswould “keep Julphar on track to return to sustainable growth in linewith its targets”.

“Our balance sheet looks stronger as we continue to reduce ourlong-term debts and manage our working capital position,” he stated.Having seen its first-half gross margin weaken by just over 10percentage points to 39.1%, Julphar – which is also known as GulfPharmaceutical Industries – posted a 22% slide in operating profit toAED57.6 million. But second-quarter operating profit climbed by43% to AED35.6 million. G

Region First-half sales(AED millions)

Change(%)

Proportionof total (%)

Synthesis 541 +65 10

Ingredients 190 +29 4

Finished doses 51 +919 1

Julphar 557.6 -4 100Figure 1: Breakdown of Julphar’s sales in the first half of 2018 (Source – Julphar)

FIRST-QUARTER RESULTS

API gains boost Ipca’s salesA27% rise in turnover from active pharmaceutical ingredients(APIs) contributed to Ipca Laboratories increasing its groupturnover by just over a fifth to Rs8.68 billion (US$121 million) inits financial first quarter ended 30 June 2018. Exports of APIs climbedby 17% to Rs1.58 billion, while the Indian company’s domestic salesof bulk drugs shot up by two-thirds to Rs600 million (see Figure 1).

India was the driving force behind Ipca’s total Formulations salesadvancing by 18% to Rs6.25 billion. Domestic sales ahead by 36%to Rs4.01 billion more than compensated for Formulations exportssliding by 5% to Rs2.24 billion despite stronger institutional sales.

Holding cost of materials consumed steady, despite the salesgrowth, enabled Ipca to bounce back from a prior-year pre-tax lossof Rs212 million to post a pre-tax profit of Rs782 million. G

Business segment First-quarter sales(Rs millions)

Change(%)

Proportionof total (%)

India 4,009 +36 46

Exports 2,240 -5 26

Formulations 6,249 +18 72

India 600 +66 7

Exports 1,577 +17 18

APIs 2,178 +27 25

Others 249 +48 3

Ipca 8,676 +21 100

Figure 1: Breakdown by business segment and region of Ipca Laboratories’ salesin its financial first quarter ended 30 June 2018 (Source – Ipca)

BUSINESS STRATEGY/FIRST-HALF RESULTS

Licences and launcheslet JGL bounce backStarting to sell in 17 new markets through partners and business-to-business deals while launching 28 products itself helped Croatia’sJGL to significantly reduce its pre-tax loss in the first half of 2018.The firm also almost halved its net debt to earnings before interest,tax, depreciation and amortisation (EBITDA) ratio from 7.98 to 4.27.

Growth in Croatia and Ukraine, as well as in Russia – where theOTC specialist increased its market shares for key brands like theAqua Maris and Meralys nasal sprays, and also “successfully completed”an inventory reduction process – pushed up sales by JGL’s core Pharmabusiness by around a quarter to CrK269 million (US$42.1 million).

In Croatia, JGL “grew faster than the market” for OTC products,helping to compensate for the “constant pressures on prescription drugprices”. Turnover in Ukraine nearly doubled amid a market recovery.

Russia accounted for two-fifths of JGL Pharma’s first-half sales,Croatia 22% and Ukraine 5%, with another 11% derived from business-to-business licensing. Viewed by product, Aqua Maris made up 32%or CrK86.9 million, of sales, followed by Dramina (dimenhydrinate)with CrK22.3 million, Meralys with CrK18.9 million and Vizol S(ectoin) eye drops with CrK6.7 million.

Including Pablo pharmacies, group turnover grew by a fifth toCrK349 million. Hailing the “excellent sales results”, chief executiveofficer Mislav Vučić insisted that the group would persist with its“chosen path of transformation”. Having bounced back to profitabilityat EBITDA level, JGL cut its pre-tax loss by 70% to CrK20.7 million.G

TJOAPACK is partnering with UK-based technology firm Veratrak to“establish the use of blockchain across the pharmaceutical industry”.The two firms believe the technology can improve the pharma supplychain. Netherlands-based contract packager Tjoapack has also launcheda postponement packaging service whereby patient informationleaflets and national legislative requirements are implemented aslate as possible to meet local demand. G

IN BRIEF

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COMPANY NEWS

Figures 1-4: Breakdown of Mylan’s second-quarter product sales totalling US$2.76 billion by therapeutic franchise, shown in each of its three operating regions andglobally (Source – Mylan)

Central Nervous System &AnaesthesiaUS$220.7m

InfectiousDisease

US$58.2m

Respiratory &Allergy

US$129.4m

CardiovascularUS$149.1m

GastroenterologyUS$145.1m

Diabetes &MetabolismUS$80.2m

DermatologyUS$74.3m

Women’sHealthcareUS$66.8m

OncologyUS$18.4m

ImmunologyUS$2.5m

OtherUS$45.9m

Europe


InfectiousDisease

US$251.6m

Respiratory & AllergyUS$53.7m




DermatologyUS$27.2m


OncologyUS$32.8m

ImmunologyUS$10.7m

OtherUS$117.7m

Rest of World


InfectiousDisease

US$372.4m


US$364.7mCardiovascularUS$271.4m



DermatologyUS$186.0m


OncologyUS$153.4m

ImmunologyUS$27.3m

OtherUS$210.2m

Mylan

Considerable regional variations in the balance of Mylan’s saleswhen measured by therapeutic franchise suggest that the globalplayer still has local portfolio gaps that could be filled.

For example, oncology drugs accounted for US$153 million, or5.6%, of the company’s total product sales in the second quarter ofthis year that decreased by 6% to US$2.76 billion, excluding US$52.8million of ‘other’ revenues (Generics bulletin, 31 August 2018,page 3). But the bulk of that oncology total came from the US, wheresales of US$102 million made up just over a tenth of the regionaltotal (see Figure 1).

By contrast, cancer therapies made up less than 2% of all Mylanproduct sales in Europe, with oncology sales of just US$18.4 millionin the three-month period (see Figure 2).

Brands including EpiPen (epinephrine) and its authorised generic,as well as Perforomist (formoterol fumarate), ensured that respiratoryand allergy medicines made up well over a sixth of North Americanproduct sales. That proportion could increase substantially if Mylansucceeds in bringing a generic of Advair Diskus (fluticasone/salmeterol) to the US market. Having responded to issues raised by

the US Food and Drug Administration (FDA), Mylan has an FDAaction date for its substitutable generic in mid-October this year(Generics bulletin, 31 August 2018, page 19).

CNS and anaesthesia leadCentral nervous system (CNS) and anaesthesia drugs were

responsible for at least a fifth of product sales in both Mylan’s NorthAmerica and Europe regions during the second quarter, but only a tenthof turnover in its Rest of World region. With the latter encompassingmost emerging markets and developing countries, nearly a third of Rest ofWorld sales came from treatments for infectious diseases (see Figure 3).

On a global basis, treatments for infectious diseases and forrespiratory and allergy complaints each contributed more than 13%of total product sales (see Figure 4).

Mylan is currently “evaluating a wide range of alternatives” forits business amid “negative trends and dynamics” that it sees as“unsustainable for the US healthcare system” (Generics bulletin,10 August 2018, page 1). Gn [email protected]

BUSINESS STRATEGY/SECOND-QUARTER RESULTS

Regional differences show Mylan’s potential


InfectiousDisease

US$62.6m


US$181.6m




DermatologyUS$84.5m


OncologyUS$102.2m

ImmunologyUS$14.1m

OtherUS$46.6m

North America

Gen 14-9-18 Pgs.1-16.indd 7 11/09/2018 15:55


FDA BIOLOGICS HEARINGREGULATORY AFFAIRS

Global bio referencecomes under attackMoves to facilitate biosimilar development by encouraging theUS Food and Drug Administration (FDA) to accept non-UScomparator drugs came under attack from originators’ body PhRMAduring an FDA public hearing on biologics competition and innovation.

“PhRMA is concerned with proposals to waive bridging-studyrequirements based on non-public information where a non-UScomparator is produced at the same facility as the reference product,”stated the association’s vice-president of intellectual property and law,David Korn. Only if biosimilar applicants could use “publicly availableinformation” to demonstrate that the non-US reference drug had “thesame drug substance, dose, dosage form, and route of administrationas the US reference product”, as was made using the same cell line,should bridging-study requirements be waived, he argued.

“In cases where this information is a trade secret, FDA relianceon these trade secrets, or disclosure of them to the biosimilar developereither explicitly or implicitly through waiver of a bridging-studyrequirement, would raise serious issues under federal law and thetakings clause,” Korn warned.

Shortly beforehand, Christine Simmon – executive director atthe Biosimilars Council within the Association for Accessible Medicines(AAM) – had expressed strong support for “eliminating the requirementfor sponsors to conduct expensive and unnecessary bridging studieswhen using a non-US-licensed reference product”.

“We are concerned that some aspects of the FDA’s draft guidanceon interchangeability impose unnecessarily burdensome scientificstandards on interchangeability determinations or may be inconsistentwith statutory requirements,” Simmon said, adding that such standardscould deter biosimilar development programs, thereby significantlyaffecting patient access. G

REGULATORY AFFAIRS

Originators query switchingOne interchangeable biosimilar should not be substituted for anotherin the US, and US Food and Drug Administration (FDA) guidanceshould reflect that, several biologics originators argued during an FDApublic hearing on biologic competition and innovation. The same pointwas echoed by the originator-backed Alliance for Safe BiologicMedicines (ASBM).

AbbVie’s Nathan Doty described switching between interchangeablebiosimilars of the same reference brand as “not scientifically justifiable”due to structural differences that could “induce immunogenicity whenpatients are switched between them”. “You cannot predict in advancewhat differences might prompt an immune response,” he argued.

Similarly, Janssen’s Andrew Greenspan urged the FDA to “addressbiosimilar-to-biosimilar switching”, as Veterans Affairs hospital ashad done with different brands of infliximab. “The FDA should considermethods of obtaining post-marketing data about biosimilar-to-biosimilarswitching,” he advised. Absent such data, he demanded that biosimilarlabelling convey the lack of switching data and that, if interchangeable,that interchangeability was only with the reference product.

Urging the agency to finalise its draft interchangeability guidance,trade body BIO’s executive vice-president for emerging companies,Cartier Esham, insisted clinical switching studies were essential forpharmacy-level substitution. G

PRICING & REIMBURSEMENT/INTELLECTUAL PROPERTY

US industry identifiesa trinity of obstaclesReimbursement issues, patent tactics to extend monopolies and“unwarranted restricted access to reference products” are the threebiggest obstacles to biosimilars reaching the hands of healthcareproviders and patients in the US, Christine Simmon, executive director ofthe Biosimilars Council within the Association for Accessible Medicines(AAM), told a US Food and Drug Administration (FDA) public hearing.

Addressing the hearing on facilitating biologic competition andinnovation, Simmon pointed out that FDA approval was no guaranteeof biosimilar availability. “You might believe that I have just namedthree things the agency can’t do anything about – we would disagree,”she told the FDA. “The FDA is more than a regulator of biosimilars.”

On reimbursement, Simmon encouraged the FDA to work withthe US Department of Health and Human Services (HHS) and itsCenters for Medicare and Medicaid Services (CMS) to promote low-cost biologics by addressing barriers to access created by rebate trapsand exclusionary contracting.

Originators manipulating intellectual-property provisions to procure‘patent thickets’ remained “a primary reason” approved biosimilarswere not being launched, she highlighted. The “exorbitant cost oflitigating meritless patents” was chilling competition, she said inurging the FDA to work with the US patent and Trademark Office(USPTO) not only to “stem the issuance of non-innovative patents”but also to support the use of inter partes reviews that gave biosimilardevelopers “an earlier and more accurate picture of the patent landscapein a timely and less expensive manner”.

While Simmon said the Biosimilars Council and AAM appreciatedthe FDA’s move to name originators that were blocking access tosamples needed for biosimilarity testing, they were “not aware of anycompanies that have changed their practices as a result of the FDA’snaming and shaming”. Pointing to a report that the AAM had justcommissioned that showed the cost of restricted access to samples tobe over US$13 billion per year (see page 10), she insisted passing theproposed Creating and Restoring Equal Access to Equivalent Samples(CREATES) Act would force originators to change their behaviour.

Supporting Pfizer’s recent citizen petition that seeks to combatmisinformation on biosimilars (Generics bulletin, 7 September 2018,page 9), Simmon said several statements around ‘non-medical switching’ignored both routine physician-led switching between biologics inthe US and extensive data from Europe. G

REGULATORY AFFAIRS

Gottlieb promises FTC actionThe US Food and Drug Administration (FDA) is working closelywith the US Federal Trade Commission (FTC) to address anti-competitive behaviour on biological drugs, FDA Commissioner ScottGottlieb told a public hearing. “We will be taking some steps inconjunction with them in the coming months,” he heralded.

The biosimilars action plan that the agency recently unveiled wasintended not only to make the biosimilar development and reviewprocess “more efficient and predictable”, it was also aimed at improvingcommunication with patients, physicians and payers, Gottlieb explained(Generics bulletin, 27 July 2018, page 9). “Our action plan is dynamic,and we continue to evaluate additional FDA actions that are needed toshape the appropriate balance between innovation and competition”. G

Gen 14-9-18 Pgs.1-16.indd 8 11/09/2018 15:55


MARKET NEWS

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INTELLECTUAL PROPERTY

Canada should resistUS trade propositionCanada’s government must resist proposals from the US that wouldsee restrictive and onerous intellectual-property provisionsintroduced as part of a trade deal between the two countries, theCanadian Generic Pharmaceutical Association (CGPA) has warned.

Commenting on the resumption of trade negotiations betweenthe US and Canada – shortly after the US and Mexico struck anagreement-in-principle that would include 10 years of data exclusivityfor biologics (Generics bulletin, 7 September 2018, page 1) – CGPApresident Jim Keon said the association understood that “there aremany US proposals on the table that would require changes to Canadianlaw and delay competition from generic and biosimilar medicines,including longer periods of data protection for biologic drugs”.

“If such proposals were adopted, they would create billions ofdollars in new costs for employers who sponsor employee drug benefitprograms, governments, and patients who pay for medicines out ofpocket,” Keon warned. “It is our understanding that the measurespursued by the US in the negotiations go far beyond the measuresincluded in the Comprehensive Economic and Trade Agreement(CETA) with the European Union,” he added, “and would be far moreharmful for Canadians if adopted.”

“Canada must not agree to North American Free Trade Agreement(NAFTA) concessions that reduce access to essential medicines andincrease costs for those who pay for drugs,” Keon concluded. G

REGULATORY AFFAIRS

EU switching is safebut needs more dataCollaborative switching studies are needed across Europe to help“clarify all aspects of switching to biosimilars”, according to astudy that has just been published in the European Medical Journal.Acknowledging that data on switching from a brand biologic to itsbiosimilar suggest that “switching is not detrimental for patients bothin terms of safety and efficacy”, Syneos Health’s ‘overview of theEuropean experience’ nevertheless suggests that “large-scale andlong-term data are warranted to provide a more robust assessment”.

Numerous switching studies – including high-profile and large-scale examples such as Norway’s NOR-SWITCH study – had led toan “overall conclusion…that switching to the biosimilar product didnot raise special concerns in terms of either efficacy or safety”, theoverview points out. However, a “nocebo” effect – whereby negativepatient perceptions cause an unexpected and unexplained worseningin treatment outcomes – was cited as a potential reason for a tendencytowards higher discontinuation rates following switches.

“It is of fundamental importance to collect real-world data derivedfrom large-scale observational or registry studies,” the report insists,recommending that “specific collaborative switching programmesshould be implemented that involve all stakeholders, with physiciansmaintaining a leading role”. Moreover, “a communication strategyinvolving the patient and all other stakeholders that focuses on thepatient’s specific circumstances... will play a crucial role”. G

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MARKET NEWS

9-11 Octobern CPhI Worldwide

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

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

22-23 Octobern Next Steps: Manufacturing &

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

Contact: AAM. Tel: +1 202 249 7127.E-mail: [email protected]. Website www.accessiblemeds.org.

24-26 Octobern 21st APIC/CEFIC European Conference

Budapest, HungaryThis conference will discuss the latest development in the field ofGMP and regulatory compliance.

Contact: Concept Heidelberg. Tel: +49 6221 84 44-0.E-mail: [email protected]. Website www.api-conference.org.

29-30 Octobern World Biosimilar Congress

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

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

21 Novembern 2nd Value Added Medicines Conference

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

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

26-27 Novembern EuroPLX 68

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

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

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REGULATORY AFFAIRS

REMS abuses in UScost US$13bn a yearMore than US$13 billion in annual lost savings stems from brandindustry abuses of Risk Evaluation and Mitigation Strategies(REMS) and safety programs in the US, according to a Matrix GlobalAdvisors study commissioned by the country’s Association for AccessibleMedicines (AAM). Matrix Global Advisors chief executive Alex Brillsaid the findings were “conservative”, adding that “absent congressionalaction, these costs can be expected to increase”.

Noting that this figure represented “an increase of 250% in thelast four years”, the AAM said that such abuses – revolving largelyaround brand companies using risk programs as a pretext to denysamples to generics firms that are needed to conduct studies requiredfor US Food and Drug Administration (FDA) approval – “can beexpected to affect more biosimilars as their development increases”.

“Unfortunately, withholding samples is an accepted businesspractice for some as a means to artificially protect and extend theirmonopolies beyond what Congress intended,” commented AAMpresident and chief executive officer Chip Davis. “That is why Congressmust pass the bipartisan Creating and Restoring Equal Access toEquivalent Samples (CREATES) Act.”

According to the study, the total US$13.4 billion figure in unrealisedsavings includes US$5.8 billion for private insurers, US$5.2 billionfor the federal government and US$1.8 billion for consumers.

“Of the total US$13.4 billion in lost savings, US$3.1 billion isattributable to products restricted by REMS, and US$10.3 billion toproducts with non-REMS restrictions created by brand manufacturers,”the study states.

The AAM pointed out that FDA Commissioner Scott Gottliebhad already highlighted the importance of the issue, when he last yearcalled on originators to “end the shenanigans” (Generics bulletin,17 November 2017, page 11), while the FDA publicly released a‘name and shame’ list earlier this year of “access inquiries” relatingto difficulties experienced by generics firms in obtaining samplesfor development (Generics bulletin, 25 May 2018, page 9).

And at a recent FDA hearing on ‘facilitating competition andinnovation in the biological products marketplace’ (see page 8), AAMsenior vice-president of policy and strategic alliances ChristineSimmon – who is also executive director of the AAM’s BiosimilarsCouncil – pointed to the harmful effects of REMS abuses.

“As biologic spending continues to grow,” Simmon said, “restrictedaccess schemes will have an increasingly harmful effect on potentialcost-saving biosimilar competition.” Noting that there were currently“more than 60 biosimilar development programs underway, promisingnew savings and access for patients”, Simmon warned that “withoutaccess to samples of the brand reference products, it is simply impossiblefor biosimilar manufacturers to develop more affordable alternativesto what is currently available to America’s patients”.

Separately, a report by I-MAK highlighted by the AAM haspointed out the scale of “excessive pharmaceutical patenting” byoriginators. According to the ‘Overpatented; Overpriced’ report, thetop 12 branded drugs on the US market last year are protected by atotal of 848 patents, or an average of 71 per drug.

“We are increasingly seeing evidence of how the patent systemis being used to tip the balance and delay patient access to a point wellbeyond what Congress intended,” the AAM commented, pointing inparticular to Humira (adalimumab) with 132 patents that blockedcompetition for up to 39 years. Gn [email protected]

Gen 14-9-18 Pgs.1-16.indd 10 11/09/2018 15:55


MARKET NEWS

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REGULATORY AFFAIRS

France trials range ofbiosimilar incentivesFrench legislation setting out an ‘experiment’ to trial several differentmethods of incentivising biosimilar prescription in hospitals has beenwarmly welcomed by local generics and biosimilars association Gemme.

Published in France’s Journal Officiel, the detailed decree setsout a plan that has been developed with local health insurer CNAMand will run for three years from 1 October 2018. Its stated objectiveis to “test a new incentive mechanism to encourage and promoteprescribing of biosimilar medications” for hospital prescriptionsthat are dispensed by community pharmacies, to “find the best wayto promote the development of biosimilars”. Etanercept and insulinglargine will be the focus of these efforts.

“The principal objective of this experiment is to achieve a morerapid rise of at least 15 points in biosimilar prescribing,” the legislationstates, with a maximum of 40 healthcare establishments participatingin the experiment. In the interests of balance, around 16 universityhospitals and three private establishments will be included amongthe total number of establishments.

Various incentive mechanisms are outlined in the text, including“innovative financial models” that adopt a gainsharing approach, aswell as “innovative organisational models” that cover the structureof healthcare professionals as well as the use of digital tools to boostbiosimilar prescribing. Meanwhile, ways of “improving the efficiencyand quality of procurement” are also set out by the document.

Ultimately, the legislation states, the goal of promoting biosimilaruptake is to stimulate competition and give healthcare establishmentsenhanced negotiating power when buying from suppliers.

Taking into account the expected costs of the experiment, netsavings of around C6 million (US$7 million) for health insurers areexpected in 2018, the decree states, with a further C12 million tofollow in 2019 and 2020. In 2018, the legislation notes, the figurewill contribute to an overall C40 million savings goal set out in France’slatest healthcare budget that is linked to developing biosimilars(Generics bulletin, 6 October 2017, page 4).

A “periodic review” of progress will take place, with a finalevaluation published in early 2022 at the latest. Evaluation methods willinclude comparing the evolution of biosimilar penetration rates over thecourse of the experiment, in both participating and non-participatinghealthcare establishments. Meanwhile, “qualitative” evaluation methodswill include questionnaires and focus groups for participating doctorsthat will address practical aspects of the experiment as well as evaluatingtheir knowledge and experience of biosimilars.

Local industry association Gemme, which has long campaignedfor government policy proposals to bolster the biosimilars market inFrance, responded positively to the experiment. “Gemme welcomesthe publication of this decree,” the association told Generics bulletin,noting that it “translates, through an initial experiment, the will of thegovernment to develop biosimilars in France”. Furthermore, Gemmeadded, “we would like to see other similar experiments in the future”.

France recently set a goal of achieving 80% biosimilar penetrationfor individual molecules within their markets by 2022 as part of abroader five-year healthcare strategy (Generics bulletin, 12 January2018, page 1). After last year setting out a list of 11 similarity groupsshowing which biosimilars correspond to certain brand biologics(Generics bulletin, 10 November 2017, page 11), local medicinesagency ANSM recently added a further three reference brands tothe list (Generics bulletin, 7 September 2018, page 13). Gn [email protected]

REGULATORY AFFAIRS

FDA lists risk factorsfor facility inspectionsFacilities’ compliance history, their recalls history and the “inherentrisk” of the drugs made at the plant are all factors that that the USFood and Drug Administration (FDA) should take into account whendeciding which sites to visit for routine current good manufacturingpractice (cGMP) surveillance inspections. Other factors listed in anew manual of policies and procedures (MAPP), effective from 26September, are whether the site has been inspected within the pastfour years and any inspections conducted by overseas authorities.

This internal policy forms part of the US commitment to “providegreater transparency regarding prioritisation and scheduling ofinspections”, as well as to communicate information following audits,under the revised Generic Drug User Fee Amendments (GDUFA II).

Efforts include updating the agency’s publicly available inspectionclassifications database, communicating with foreign regulatoryauthorities regarding the compliance status of establishments, providinginformation on the agency’s risk-based site selection model, andcommunicating information from inspections that may impactapprovability to applicants and facility owners.

FDA Commissioner Scott Gottlieb noted that the agency had alsopursued opportunities to collaborate with other countries. The FDAalso recently updated its inspections classifications database, whichnow supports inclusion of facility status based on classification ofinspection reports from recognised foreign regulatory authorities. G

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PRODUCT NEWSBIOLOGICAL DRUGS

Celltrion wants lowerRA criteria in the UKLeading biosimilars player Celltrion Healthcare has claimed thatthe UK “lags behind most of Europe” in access to biologics forpatients with rheumatoid arthritis (RA), as it called for easing ofinitiation boundaries for biologics that Celltrion says will help thecountry’s National Health Service (NHS) address access inequality.

“There are set thresholds in disease activity before biologics canbe used in RA patients, but these thresholds vary across Europe,”Celltrion explained. According to the Korean firm, the percentage ofpatients who are treated with tumour necrosis factor alpha (TNF-α)inhibitors, such as infliximab, is 24% or higher in countries includingItaly and France, “however, in the UK this drops to just 15%”.

“This is because in the UK a patient must have a higher DAS-28[a measure of how severe the disease is] threshold of 5.1 comparedto only 3.2 in other European countries. Despite the [UK’s] NationalInstitute for Health and Care Excellence (NICE) widely acknowledgingthat appropriate biological treatments are clinically effective for allsub-groups of RA patients, access to these therapies remains restrictedin the UK on grounds of cost-effectiveness.”

Celltrion’s Remsima (infliximab) biosimilar of Janssen’s Remicadebegan rolling out across European markets in early 2015. Switchingpatients to biosimilar infliximab delivered the NHS savings of £99.4million (US$127 million) in its most recent financial year (Genericsbulletin, 10 August 2018, page 13).

As well as the National Rheumatoid Arthritis Society (NRAS)and the British Society for Rheumatology (BSR), Celltrion receivedbacking in its plight for NICE to lower the DAS-28 score from 5.1from Ben Parker, a consultant rheumatologist at ManchesterUniversity Hospitals.

“We have identified clear disparities in access to biologics acrossEurope,” noted HoUng Kim, Celltrion Healthcare’s head of strategyand operations. “With the proven savings gained through the use ofbiosimilars, this could be a real opportunity for the NHS to addressthese concerning inequalities.” G

EPILEPSY DRUGS

Oxtellar XR ruling is upheldTWi Pharmaceuticals’ proposed generic versions of SupernusPharmaceuticals’ Oxtellar XR (oxcarbazepine) 150mg, 300mgand 600mg extended-release tablets infringe three patents shieldingthe branded epilepsy treatment, a US Court of Appeals has ruled,upholding an earlier district court decision.

New Jersey District Judge Renee Marie Bumb had, in herAugust 2017 decision, also rejected TWI’s assertions that US patents7,722,898, 7,910,131 and 8,821,930 were invalid, a decision alsoupheld on appeal (Generics bulletin, 1 September 2017, page 24).

The three patents, of eight listed in the US Food and DrugAdministration’s (FDA’s) Orange Book, all expire on 13 April 2027.

The decision comes after an appeals court at the end of 2016affirmed a prior district court decision, also handed down by Bumb,that Actavis infringed certain Oxtellar XR patents (Genericsbulletin, 6 January 2017, page 19).

Commenting on the TWi appeals court ruling, Supernus saidit marked “the end of any outstanding litigation issues and genericchallenges to Oxtellar XR”. G

EDQM – the European Directorate for the Quality of Medicines –has stopped the distribution of medicines containing valsartan froma further two Chinese manufacturers, following the detection of thetoxic impurity N-nitrosodimethylamine (NDMA) in the activepharmaceutical ingredient (API) that could cause cancer. HeteroLabs’ and Zhejiang Changming’s certificates of suitability (CEP)have been suspended by the EDQM, shortly after Zhejiang Huahaiand Zhejiang Tianyu had theirs suspended (Generics bulletin, 13July 2018, page 1; Generics bulletin, 31 August 2018, page 21).The EDQM has requested that CEP holders with substances that maypresent a contamination risk investigate and address the possiblepresence of NDMA, including evaluating manufacturing processes.Noting it had “been assessing the data received”, the EDQM said that“it seems that a limited number of sources of valsartan and otherstructurally-related active substances may present a risk ofcontamination”. Meanwhile, Health Canada has updated its list ofvalsartan products that are not recalled, including to add a Mylanproduct. The agency also noted that “no additional products havebeen recalled”.

SAMSUNG BIOEPIS has been sued by Genentech in a Delawaredistrict court for allegedly infringing 21 US patents protecting theoriginator’s Herceptin (trastuzumab) breast-cancer treatment.Despite alleging that the firms engaged in the ‘patent dance’ exchangeof information to assert the patents in suit, Genentech’s complaintalso contends that Bioepis failed to comply with its obligationsunder Section 262(l)(2) of the Biologics Price Competition andInnovation Act (BPCIA) to produce to the firm a complete copy ofthe abbreviated biologic license application (aBLA) and additionalmanufacturing process information for its SB3 candidate.

CHILE’S Health Minister Emilio Santelices Cuevas has reaffirmedthe country’s path to compulsory licences for hepatitis C drugs,after rejecting an attack by Gilead and an undisclosed pharmaceuticalassociation on Resolution 399/2018, which sets out public healthjustifications for the issuing of such licences for sofosbuvir totreat Chile’s hepatitis C epidemic.

JULPHAR has signed an agreement with Becton, Dickinson andCompany (BD) to supply disposable insulin pens in the UnitedArab Emirates (UAE). Through the deal, Julphar’s human insulinformulations including Jusline R, Jusline N and Jusline 30/70 willbe available for administration through BD’s portfolio of BD Vystradisposable pens. The same device will be used for insulin analogues –including insulin glargine and insulin lispro – which are still underdevelopment. “The disposable insulin pens are now in the final stagesof the approval process,” Julphar noted, “and are due to be launched assoon as they have been officially registered by the Ministry of Health.”

UPSHER-SMITH has launched in the US an AA-rated genericversion of Lomotil (diphenoxylate/atropine) 2.5mg/0.025mgtablets. Citing data from Iqvia, Upsher-Smith observed that thediphenoxylate/atropine tablet market had US sales of approximatelyUS$64 million for the 12 months ended May 2018.

GERMAN generics players including Sandoz’ 1A Pharma andHexal, Stada’s Aliud, Teva’s AbZ and Zentiva have securedclearance to offer olmesartan/amlodipine tablets. Zentiva has alsoobtained clearance for emtricitabine/tenofovir tablets. Furtherapprovals have been given to Luye Pharma for fentanyl transdermalplasters, Glenmark for nortriptyline tablets and salmeterol powderfor inhalation, Acino for pregabalin capsules and Cipla fortenofovir tablets. G

IN BRIEF

Gen 14-9-18 Pgs.1-16.indd 12 11/09/2018 15:55


PRODUCT NEWS

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

Price WatchIndex

PharmacyProfit Index55.6 63.5

Monthly change -3.3 Monthly change +19.2

August 2018 August 2018

Profits enjoyed by UK independent pharmacists rocketedupwards in August, according to the latest figures from WaveData,which reflected a rise of more than a third in pharmacy profits,based on our representative basket of generics.

As the reimbursement price for the basket jumped by just overan eighth to £2,252.48 (US$2,902.72) – compared to £1,999.88 inJuly (Generics bulletin, 3 August 2018, page 12) – the basket priceslid slightly to £1,183.34 from the previous figure of £1,254.09.This generated a pharmacy profit value of £1,069.14, comparedto just £745.79 in July.

Based on Index values of 100 that were set in March 2016,the Pharmacy Profit Index leapt by 19.2 index points comparedto the 44.3 Index value seen in July, while the Price WatchIndex slid by 3.3 index points to 55.6. G

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

August 2018

PRICE WATCH ....... UK

Basket Price Reimbursement Price Pharmacy Profit£1,183.34 £2,252.48 £1,069.14

RESPIRATORY DRUGS

Glenmark’s Seretideapproved in GermanyGlenmark has edged closer to launching its first inhalation productin Germany after securing a local marketing authorisation forits substitutable generic of GlaxoSmithKline’s Seretide Accuhaler(fluticasone/salmeterol) dry-powder inhaler.

“There is huge potential for the product in Germany,” commentedAchin Gupta, executive vice-president and Glenmark’s business headfor Europe and Latin America. “We are optimistic that it will helpenhance growth of the European business.”

The Indian firm will sell the generic treatment for asthma andchronic obstructive pulmonary disease (COPD) in Germany underthe name Salflutin.

Glenmark’s fluticasone/salmeterol is the result of a developmentand licensing agreement signed with Polish firm Celon Pharma in2015, which gave Glenmark semi-exclusive marketing distributionrights in 15 European markets. As well as Germany, these includethe UK, Belgium, Italy, the Netherlands and Romania, along with anumber of Nordic markets.

After successfully closing the decentralised registration procedurefor the respiratory product in the Nordic region late last year, Glenmarkhas to date launched the generic inhaler, known as Salmex in somemarkets, in Denmark, Norway and Sweden, while also securingmarketing approvals in Finland and Iceland (Generics bulletin, 25May 2018, page 13). G

BIOLOGICAL DRUGS

Xbrane ‘shifts focus’to biosimilar portfolioXbrane Biopharma has announced that it is shifting its full strategicfocus to its biosimilars pipeline in the wake of striking a globalco-development deal with Stada for its Xlucane (ranibizumab) rival toLucentis. The strategic shift means that the Swedish firm will abandon,at least for the time being, development efforts on generic long-actinginjectables beyond its existing Spherotide (triptorelin) product.

“As Xbrane’s leading biosimilar Xlucane moves into the pivotalclinical trial,” the firm observed, “Xbrane is accelerating developmentof Xcimzane (certoizumab) and Xoncane (pegaspargase) and willinitiate development of two additional biosimilars on biologics withpatent expiration in 2026-2028.” As a consequence, it acknowledged,further development of long-acting injectables beyond Spherotide“will only be pursued if additional resources become available”,either “internally or via strategic partnerships”.

“The co-development agreement for Xlucane entered with Stada inJuly validated the quality and commercial viability of Xbrane’stechnological platform and capability in biosimilar development,”the firm insisted (Generics bulletin, 27 July 2018, page 19). This,combined with the “inherent attractiveness” of biosimilars, had led thefirm to concentrate on biosimilars and move away from generic long-acting injectables projects including risperidone, leuprolide, exenatideand octreotide. “Initially the development of the biosimilars in thepipeline is done with freed-up resources from Xlucane development,”the firm said, “However, long-term successful development requiresthat sufficient capital can be raised in the market.”

Xcimzane will rival the Cimzia brand, a rheumatoid arthritis,psoriasis and Crohn’s disease treatment for which the main patentsare set to expire in 2024 in Europe and the US, Xbrane noted. Meanwhile,Xoncane’s branded equivalent is the Oncaspar leukaemia drug.For both biosimilars, Xbrane says it is “leveraging the company’spatented e.coli-based protein expression technology”, which offers“significant yield and cost advantage compared to standard systems”.

“As Xlucane moves into the clinical trial,” said Xbrane chiefexecutive Martin Åmark, “we are now able to dedicate more developmentresources to Xcimzane and Xoncane programs. We see very limitedcompetition and an opportunity to bring the first biosimilars to market.”

For the two further undisclosed biosimilars, Xbrane said it would be“expanding its technological platform and capabilities to the developmentof mammalian cell-based biosimilars”, including through “strategicpartnerships and a few key recruitments”. Xbrane once again said it saw anopportunity to be “ahead of the game and amongst the first to launch”.G

ONCOLOGY DRUGS

Australia approves FulphilaAustralia’s Therapeutic Goods Administration (TGA) has endorsedMylan’s Fulphila (pegfilgrastim) biosimilar, according to a listof new approvals published by the medicines agency. Registeredthrough Mylan’s local Alphapharm subsidiary, the Fulphila pre-filledsyringes are indicated “for the treatment of cancer patients followingchemotherapy, to decrease the duration of severe neutropenia and soreduce the incidence of infections, as manifested by febrile neutropenia”.

Other TGA approvals included Alphapharm’s atazanavir capsules,Neo Health’s anagrelide capsules and latanoprost eye drops, Apotex’eplerenone tablets, and AFT’s pantoprazole powder for injection. G

Gen 14-9-18 Pgs.1-16.indd 13 11/09/2018 15:55

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

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

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

PenaltiesWhat is the penalty for not paying the program fee?1) If the fee is not paid within 20 calendar days after the due date, the parent company will be placed on a

publicly available arrears list.2) Any ANDA submitted by the applicant or its affiliateswill not be received.3) All drugs marketed pursuant to any abbreviated new drug application held by such applicant or an affiliate

of such applicant shall be deemed misbranded.

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

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

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Gen 14-9-18 Pgs.1-16.indd 14 11/09/2018 15:55

15GENERICS bulletin

PRODUCT NEWS

AUTOIMMUNE DISEASES TREATMENTS

Remsima broadens accessHikma says it has considerably broadened access to infliximab inMorocco by introducing its Remsima biosimilar early last year.The Jordanian firm claims to have helped increase the size of thelocal market by about 50% to 11,000 vials per year whilst raisingRemsima’s market share to more than 75%. “This example demonstrateshow we grow our business and we are not limited to taking marketshare from the originator,” commented Hikma’s chief executiveofficer Siggi Olafsson.

Olafsson said Morocco represented about US$3 million of a totalUS$45 million infliximab market in the Middle East and North Africa(MENA) region where Hikma has to date launched Remsima in fiveother countries – Iraq, Jordan, Libya, Saudi Arabia and Tunisia. By theend of this year, infliximab launches in a further two MENA marketsare planned under a licensing deal with South Korea’s Celltrion. G

DERMATOLOGY DRUGS

Oracea ruling leavesAmneal waiting yearsAmneal Pharmaceuticals has received a mixed verdict in patent-infringement proceedings with Galderma Laboratories over eightUS patents shielding Oracea (doxycycline) 40mg capsules. The rulingmeans Amneal is forbidden from obtaining final abbreviated newdrug application (ANDA) approval until at least one asserted patentexpires in December 2025.

Delaware District Judge Leonard Stark handed down the rulingto Amneal, finding that the company’s generic infringed claims offive patents and did not infringe claims of the remaining three. At thesame time, Stark batted away an array of invalidity attacks launchedby the US generics player against certain Oracea patent claims.

In an 88-page ruling involving eight of the 10 patents listed inthe FDA’s Orange Book against Oracea, Stark found that Amneal’sproposed generic product infringed certain claims of US patents:8,206,740; 8,394,405; 8,470,364; 8,603,506 and 9,241,946. The ‘946and ‘506 patents expire in April 2022, the ‘405 and ‘364 in April 2024and the ‘740 patent in December 2025, excluding extension periods.

On the other hand, Amneal’s product did not infringe US patents7,749,532, 7,211,267 and 7,232,572. The latter two patents expire alsoin April 2022, while the ‘532 patent covers the brand until December 2027.

The patents at-issue were split into two camps: the Chang patents –‘740, ’405, ’364 and ’532 – and the Ashley patents –’267, ’572, ’506and ‘946. “The Chang and Ashley patents are generally directed tolow-dose doxycycline formulations for the treatment of the papulesand pustules of acne rosacea,” the court noted.

According to Stark, Amneal failed to prove “by clear andconvincing evidence” that the Ashley patents were invalid for lackof enablement, lack of written description or obviousness.

Individual claims of the ’267, ’506 and ’946 patent were not invalidas anticipated, Stark also found. Finally asserted claims of the ‘267and ‘572 patents were not found to be indefinite by Stark.

Stark’s ruling comes more than three years after the US PatentTrial and Appeal Board (PTAB) rejected Amneal’s assertions that the‘740 and ‘405 patents, as well as US patent 8,394,406 that expires inApril 2024, were not invalid as obvious (Generics bulletin, 16 January2015, page 18). Amneal currently holds a tentative approval for itsANDA, alongside Lupin and Mylan. G

ONCOLOGY DRUGS

Alvogen’s gefitinib isapproved in the EUAlvogen says it has “successfully concluded multiple registrationapplications” in the European Union (EU) for generic alternativesto AstraZeneca’s Iressa (gefitinib) 250mg tablets. Having fully developedthe lung-cancer therapy in-house through its Taiwanese affiliate, LotusPharmaceuticals, Alvogen and its partners have filed for marketingauthorisations in 24 European countries.

Citing Iqvia data showing that European sales of Iressa totalledUS$136 million last year, Alvogen claims it is “among the firstcompanies in Europe to obtain approval” for a bioequivalent versionof the treatment for non-small cell lung cancer.

Mylan recently secured a positive opinion from the committeefor human medicinal products (CHMP) within the European MedicinesAgency (EMA) for its gefitinib 250mg tablets (Generics bulletin,3 August 2018, page 17). The register of decentralised and mutual-recognition approvals maintained by EU Heads of Medicines Agencies(HMA) shows gefitinib authorisations for companies including DrReddy’s Betapharm, Doc Generici, Krka, Sandoz, Stada and Synthon.

AstraZeneca enjoys supplementary protection certificate (SPC)protection for Iressa until early March next year. Those SPCs arebased on European patent EP0,823,900, which expired in April 2016,and a first marketing authorisation in Liechtenstein that was grantedin March 2004, 15 years before the SPCs expire, on the basis of legalarrangements with Switzerland’s Swissmedic agency.

In the UK, AstraZeneca challenged the local SPC expiry date of1 March 2019 and argued instead that the SPC should run until 22April 2021, based on the first marketing authorisation having beenan EU approval for Iressa granted in 2009. The UK referred the issueto the Court of Justice for the EU (CJEU), which in November 2013determined that “an administrative authorisation issued for a medicinalproduct by Swissmedic, which is automatically recognised in Liechtenstein,must be regarded as the first authorisation to place that medicinalproduct on the market” (Generics bulletin, 6 December 2013, page 17).G

ANTIDEPRESSANTS

Ranbaxy dodges bupropion barSun Pharma’s Ranbaxy has avoided a legal bar on obtaining Canadianapproval for its generic Wellbutrin XL (bupropion) 150mg and300mg extended-release tablets. Federal Court Judge Glennys McVeighfound that Ranbaxy’s formulation of the antidepressant did not infringeValeant’s Canadian patent 2,524,300, which expires on 8 August 2023.Immediately after the ruling was delivered, Health Canada approvedRanbaxy’s generics.

Noting that Ranbaxy had not challenged the validity of the ‘300formulation patent, McVeigh said the dispute centred on whether thegenerics firm’s tablets fell within the scope of the ‘300 patent’s soleindependent claim by containing a permeation enhancer in an amountof “about 20% to about 40% of the moisture barrier dry weight”.

On claim construction, McVeigh construed both ‘permeationenhancer’ and ‘about 20% to about 40% of the moisture barrier dryweight’ to be essential elements in the ‘300 patent, and said that‘about’ indicated a variance of up to 10%, giving an effective rangeof 18% to 44%. As silicon dioxide, the only permeation enhancerin Ranbaxy’s formulation, fell outside of that range, the generic didnot infringe, McVeigh ruled. G

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APPOINTMENTS

Dierks follows Walzas NuPharm’s chiefNuPharm has appointed former Meda chief executive officer (CEO)Jörg-Thomas Dierks to become CEO of the European centralnervous system (CNS) specialist, replacing with immediate effectStephan Walz, who has “decided to step down in order to pursueother activities”.

Boasting “30 years of healthcare experience”, Dierks has heldpositions including chief operating officer and chief scientific officerof Meda, as well as CEO – leading up to the company being boughtby Mylan in 2016 (Generics bulletin, 26 August 2016, page 3) – aswell as chief operating officer of Germany’s Viatris.

NuPharm was created in 2016 by combining five companies –Spain’s Qualigen, Laboratorios Lesvi and Inke; Germany’s Neuraxpharm,which also operates in Poland; and Italy’s FB Health – with investmentgroup Apax Partners. It recently completed a deal to add France’sBiodim for an undisclosed sum (Generics bulletin, 13 July 2018,page 3). “I am delighted to be joining NuPharm at an excitingtime,” Dierks commented.

Noting that the company “has successfully created a Europeanplatform of scale and become a key player in the treatment of CNSdiseases”, Dierks said he would work with the management team to“build on the positive developments that have been made and lead thecompany through its next phase of growth, with the objective to makeit a prominent European player in the CNS field”. G

APPOINTMENTS

Albrecht hands overStada to GoldschmidtFormer Sandoz US president Peter Goldschmidt has taken overas chief executive officer of Stada, taking the reins from ClaudioAlbrecht. The “professional and amicable” handover is in line withsuccession plans announced by the German company early this year(Generics bulletin, 9 February 2018, page 1). According to Stada,Goldschmidt will use the first 100 days of his tenure to “intensivelyget to know the group, its partners, and its customers, and will thendiscuss his strategic priorities with his team”.

“I look forward to working with the highly experienced team atStada to continue the group’s long-term growth,” Goldschmidt said.“I have known Stada as a key player in the industry for many years, andI see enormous potential for the group. Together with all employeeswe will strive to fully capitalise on the opportunities for growth.”

Goldschmidt said he was “in complete alignment with our majorityowners, Cinven and Bain Capital” – which took control of Stada lastyear and appointed Albrecht as chief executive (Generics bulletin,8 September 2017, page 1) – “on their strategy for building a companywith long-term growth potential”. “Our focus remains on continuingto market a competitive portfolio and working closely with our globalnetwork of strategic partners.”

Under German ‘cooling-off’ regulations, Albrecht will not take aseat on Stada’s supervisory board, but will return to his AlbrechtProck & Partners consultancy business. G

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