Generics ulletin nforma · 2019-04-16 · tection certificate (SPC) expiring in mid-October last...

19 April 2019No.395

Pharma IntelligenceInformaBulletin

Genericsg e n e r i c s . p h a r m a i n t e l l i g e n c e . i n f o r m a . c o m

SANDOZ

Sandoz Strikes Shionogi Partnership As Part Of Pain Play, p. 17

AMBRISENTAN

US Ambrisentan Approvals Hint At Different Commercial Approaches, p. 7

INDIAN PHARMACEUTICAL ALLIANCE

Top India Drugmakers’ Body Names Industry Veteran Sudarshan Jain New Secretary General, p. 11

Battle-Lines Built Up On Biologic Substitution In GermanyAIDAN FRY [email protected]

In an unusual show of unity, all Germany’s major bodies representing the prescrip-tion pharmaceutical industry have voiced

opposition to plans for pharmacy-level substitution of biological drugs ahead of a parliamentary hearing on 10 April.

But while industry’s position is sup-ported by several doctors’ groups, they will face opposition at that Bundestag health committee hearing from associa-tions appearing for payers, pharmacists and consumers, as well as from the G-BA federal joint committee that is slated to draw up a list of which biological medi-cines can be substituted.

Draft healthcare reforms put forward last year under the medicines safety, or GSAV,

bill sought to increase biosimilar uptake in Germany by entrusting the G-BA with drawing up a guideline to state which ref-erence biologics could be substituted with biosimilars at pharmacy level.

By the time the GSAV bill reached consid-eration by the country’s federal cabinet, the substitution measure had been watered down, principally by pushing back phar-macy-level switching for at least the next three years while scientific evidence is com-piled. “In this period,” an explanatory note on the cabinet draft explains, “substitution on the basis of the G-BA’s determinations can only occur at the physician’s level under the supervision of the treating doctor”.

In a position paper submitted ahead

of the parliamentary health committee hearing on 10 April, Germany’s Pro Ge-nerika off-patent industry association ar-gues that the section in the draft law pro-posing biologic substitution at pharmacy level be “deleted without replacement”.

FOUR REASONS WHY SUBSTITUTION IS UNNECESSARY

The trade body lays out four key reasons why the proposed switching measure, which is similar to Germany’s aut idem pharmacy substitution model for small molecules, is unnecessary.

Firstly, Pro Generika argues, existing agreements on regional prescribing tar-gets and quotas are already ensuring that biosimilars are rapidly being used. Rivals to AbbVie’s Humira (adalimumab) launched last year needed just nine weeks to capture a third of the German market, it points out, citing IQVIA data showing that the rate of uptake has in-creased with each biosimilar entry. As a result, the share for trastuzumab biosimi-lars exceeded 50% within six months.

Secondly, the submission contends, the level of biosimilar competition in Germany has intensified considerably, not least because multiple ‘day one’ en-trants upon Humira’s supplementary pro-tection certificate (SPC) expiring in mid-October last year led to 40% discounts of the reference brand’s list price.

Thirdly, once further rebates offered through multi-supplier ‘open house’ ten-ders are factored in, Pro Generika estimates that annual savings on adalimumab alone could run to EUR500-600 million ($565-$675 million). Such savings, it stresses, can be achieved without affecting quality of care.

CONTINUED ON PAGE 4

2 | Generics Bulletin | 19 April 2019 © Informa UK Ltd 2019

I N T H I S I S S U E

from the [email protected]

German plans for pharmacy-level substitution of biologics were in the spotlight this week, with a parliamentary hearing attracting the attention of stakeholders from across the industry (see front cover). While European Union biosimilar approvals are central-ized, individual member states have a certain amount of freedom in how such drugs are managed on a national basis, and it has been interesting to see differing approaches adopted across the EU.

Also this week, India’s IPA industry body has named its new head, with Sudarshan Jain taking on the secretary general role (p.11). And Neuraxpharm has named Wojciech Góra to lead its Polish business with the establishment of a new dedicated subsidiary in Poland (p.5).

Canadian industry has reacted warmly to Health Canada propos-als to streamline the regulatory pathway for generics (p.6), while in the UK, our regular Price Watch feature shows the list of gov-ernment price concessions lengthening amid ongoing uncertainty over Brexit (p.10).

It has also been a busy week for deals. Mérieux and ICG have ac-quired Italy’s Doc Generici (p.5) as Sandoz has bolstered its anti-pain franchise with an agreement that gives it rights to Shionogi’s Rizmoic in Germany, the Netherlands and the UK (p.17). Mean-while, Apotex has refused to be drawn on rumors that it is weigh-ing a $3bn sale of the business (p.16).

And Medicines for Europe has set out its stall ahead of upcom-ing European Parliament elections with its ‘Together for Health’ manifesto for pharmaceutical policy (p.18).

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“Individual EU member

states have a certain

amount of freedom in

how biosimilars

are managed on a

national basis, and

it has been interesting

to see differing

approaches adopted”

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COVER / Battle-Lines Built Up On Biologic Substitution In Germany

5 Góra Leads Neuraxpharm’s Push Into Poland

5 Mérieux And ICG Buy Italy’s Doc Generici

6 Health Canada Seeks To Streamline Generics Pathway

7 US Ambrisentan Approvals Hint At Different Commercial Approaches

8 English Adalimumab Tender Marks Progress, But Is Not Perfect

10 Price Watch UK UK Price Concessions List Lengthens Amid Brexit Uncertainty

11 Top India Drugmakers’ Body Names Industry Veteran Sudarshan Jain New Secretary General

13 Aurobindo In Trouble Again With FDA, Gets Form 483 With 11 Observations

14 Lack Of Lilly Litigation Clears Path For Pfenex’ Forteo Rival

14 Tailored Approach To Orphan Biosimilars Is On EMA’s Agenda

16 Apotex Rumored To Be Weighing $3bn Sale

17 Sandoz Strikes Shionogi Partnership As Part Of Pain Play

18 EU Industry To Politicians: Deliver On Equitable Access

19 Coherus Reveals Sales Have Started Piling In On Pegfilgrastim

Value-Added Schizophrenia Round-Up: Luye Expects Chinese First With US RisperidoneSeveral firms are making progress on added-value risperidone formulations: Luye Pharma anticipates FDA approval for its extended-release microspheres; Rovi is moving towards a US 505(b)(2) filing for its Doria once-monthly formulation; and Indivior has introduced its Perseris subcutaneous suspension in the US.

https://bit.ly/2DifLgm

US House Committee Clears Bills To Prevent Pay-For-Delay Deals, Assure Generic Access To Samples Legislation on patent settlement agreements will not be retroactive; CREATES Act amended to give brand companies affirmative defense to litigation.

https://bit.ly/2U5MXx5

Wockhardt Refuses To Comment On Formulations DemergerWockhardt has stayed quiet on reports that it is planning to spin off its formulations business into a separate operation and then sell a sizeable chunk of it to cut a massive debt load.

https://bit.ly/2DgqrMn

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B I O S I M I L A R S

And fourthly, the association argues, health insurance funds are already able to shape the market and maximize sav-ings through tender contracts that cover each biosimilar from the moment it en-ters the German market.

Introducing pharmacy-level substitu-tion would, the industry body warns, weaken competition in Germany. It cites research conducted by Duisburg univer-sity which found that 70% of biosimilar firms said the pricing and reimbursement framework in Germany would influence their launch plans for Europe.

“Substitution defined by the G-BA would not create trust in this new product category among doctors or patients,” Pro Generika insists. It points out that the current wording in the draft legislation excludes reference biologics, thereby precluding the original-to-bio-similar switching most likely to generate significant savings.

If legislators insist on pushing ahead with the substitution measure, the associa-tion pleads for greater clarity, both for the G-BA in terms of creating a switch list and for industry in terms of being able to give input. It proposes that new biosimilars, such as in ophthalmology, be spared from the G-BA process for three years from mar-ket entry so that competition can develop and experience with the drugs built up.

Two industry bodies that represent largely local players, the BAH and the BPI, echo similar arguments and also raise is-sues around patient compliance, particu-larly when switching between different delivery devices, as well as around pharma-covigilance and liability for adverse events.

ORIGINATORS CITE PHARMACOVIGILANCE WORRIES

Research-led multinational pharma com-panies, through their VFA body, have also come out against pharmacy-level biologic

substitution, arguing that it is unneces-sary to spur competition and would also weaken pharmacovigilance and risk-man-agement strategies.

Support for industry comes, perhaps not surprisingly, from doctors who would see their role diluted by pharmacists as-suming greater responsibility for which biological brand is dispensed.

The KBV alliance of health-insurance physicians argues that evidence of ther-apeutic equivalence “does not imply that biosimilars can automatically be substituted by pharmacists”, as gener-ics are, without close oversight from a doctor. It claims that “there are no data to date” that can rule out “negative con-sequences for patients” from switching, such as different immunogenicity to the reference biologic.

Similarly, Germany’s federal doctor’s chamber, the BÄK, believes that doctors are best placed to decide on whether to use a biosimilar, based on considerations around factors such as manufacturing processes,

authorized indications and delivery devices.But pharmacists’ union ABDA insists

that substitution by its members, draw-ing on the G-BA’s guidelines, is “imple-mentable”, even if changes to the form of application could create “massive uncer-tainty among patients” that could lead to non-compliance. Stressing that its mem-bers must be “adequately compensated” for advising patients, ABDA welcomes a proposal put forward by Germany’s up-per house of parliament, the Bundesrat, that the effects of the legislative change be assessed after two years.

German consumers’ association Verbr-aucherzentrale Bundesverband supports the substitution proposal, having identi-fied “considerable potential for savings” from raising biosimilars’ share of pre-scription volumes. It cites a report from the country’s Paul Ehrlich Institute (PEI) regulatory body showing that there is no evidence to date that switching from the reference biologic to a biosimilar has cre-ated any problems.

While the body representing German statutory health insurance funds, GKV-Spitzenverband, welcomes the switch-ing proposal, it bemoans the proposed delay for three years after the GSAV legis-lation is enacted. “Through this delayed implementation,” it maintains, “the cur-rent savings potential upon patent ex-piry for a series of biological medicines will not be exploited”.

Also citing the PEI switching report, the G-BA insists that “a general exclusion from substitution of biological medicines with the same active ingredient is not supported by facts”. It proposes adding a paragraph to the draft legislation to clari-fy that it can, in drawing up its list of sub-stitutable biologics, request information from the PEI or from Germany’s drugs and medical devices agency, BfArM.

Published online 10 April 2019

CONTINUED FROM PAGE 1

“Through this delayed implementation,

the current savings potential upon patent

expiry for a series of biological medicines will not be exploited”

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H E A D L I N E N E W SA P P O I N T M E N T S

Góra Leads Neuraxpharm’s Push Into PolandDAVID WALLACE [email protected]

N euraxpharm has launched a dedicated subsidiary in Poland, Neuraxpharm Polska, to be led

by Wojciech Góra as general manager.Warsaw-based Neuraxpharm Polska is

the latest local operation to be set up by central nervous system (CNS) specialist Neuraxpharm, which has a direct pres-ence in nine European countries.

Citing Góra’s “over 20 years of experi-ence in building and managing European pharmaceuticals operations” – including launching and building Meda’s subsidiary in Poland as country manager – Neuraxpharm said establishing a Polish business would help to “drive growth in [this] significant market”. To date, Neuraxpharm has market-ed its drugs in Poland through its German subsidiary under the NeuroPharma brand.

Neuraxpharm CEO Jörg-Thomas Di-erks, who previously led Meda, said the launch of Neuraxpharm Polska “reinforc-es our ambition to be a leading CNS play-er in the central and eastern Europe re-gion” and would enable the firm to “bring differentiated products to local patients and healthcare professionals”.

Góra pointed out that Poland was “the sixth-biggest CNS European market, with double-digit growth. He said he would look forward to building and establishing Neuraxpharm as a recognized and trust-ed partner as we look towards launching

new CNS products in the region.”“A key pillar of Neuraxpharm’s growth

strategy is to establish its own operations in high growth markets in Europe,” the firm explained. “Neuraxpharm aims to build its position as a CNS specialist in Poland offer-ing nutraceuticals, standard generics and added value medicines and plans to launch five new CNS products in 2019.”

Neuraxpharm said it was “investing in its pipeline by developing differentiated and

high-tech barrier products in CNS that will be launched in Poland as well as in other Neuraxpharm countries”.

Góra’s appointment follows Neurax-pharm’s recent recruitment of Dan Furrer – who also previously worked at Meda, as country manager for Germany and Swit-zerland – as Neuraxpharm’s head of cor-porate marketing.

LATEST MOVE AS PART OF EUROPEAN EXPANSION

The Neuraxpharm group was formerly known as NuPharm and was originally cre-ated in 2016 by combining five companies – Spain’s Qualigen, Laboratorios Lesvi and Inke; Germany’s Neuraxpharm; and Italy’s FB Health – with the backing of invest-ment group Apax Partners. It rebranded it-self under its current identity in late 2018.

Earlier this year, Pierre-Hervé Brun was named as general manager of Neurax-pharm’s French affiliate. Neuraxpharm had entered France in mid-2018 after buying Laboratoire Biodim from Weinberg Capital Partners’ Pharma Omnium International.

In early 2019 Neuraxpharm also ac-quired CNS specialty pharmaceutical com-pany Farmax from SVUS Pharma, allowing it to entering the Czech Republic, Slovakia and Hungary.


H E A D L I N E N E W SD E A L S

Mérieux And ICG Buy Italy’s Doc GenericiDAVID WALLACE [email protected]

I taly’s Doc Generici has been bought by private-equity firms Mérieux Eq-uity Partners and Intermediate Capital

Group (ICG) from CVC Capital Partners in a deal that is subject to antitrust approval.

Referring to Doc Generici as “Italy’s larg-est independent generic pharmaceutical company” – the Milan-based firm holds over 15% of the local retail generics market – Mérieux noted that the company “oper-ates an asset-light model and benefits from

a consolidated network of suppliers primar-ily based in Europe”, with a “broad product portfolio and a strong presence in areas including cardiovascular, gastrointestinal, metabolism and neurological treatments”.

“Doc Generici exhibits the classic charac-teristics we look for in an investment,” ob-served ICG’s head of Italian debt & equity investments, Luigi Bartone. “The company is well-established, highly cash-generative, and led by a best-in-class, committed

management team. It benefits from a resil-ient and growing market driven by the on-going penetration of generics in the Italian pharmaceutical market. We believe there are significant opportunities to continue to grow the business, and ICG resources and global networks will support manage-ment’s and Mérieux Equity Partners’ vision.”

Meanwhile, Mérieux senior partner Benoit Chastaing said Doc Generici’s fa-cilitation of patient access to high-value

“A key pillar of Neuraxpharm’s growth strategy is to establish its own operations in high growth markets

in Europe”

PHOTO: Neuraxpharm


D E A L S / P O L I C Y & R E G U L AT I O N

medicines was in line with Mérieux’ in-vestment strategy of supporting “fast-growing companies within the health-care and nutrition markets”, adding that the transaction “also constitutes the first landmark investment of Mérieux Equity Partners in Italy”. “We will share our ex-pertise and industrial network with Doc Generici and ICG over the coming years.”

ICG chief executive Benoit Durteste said the “milestone deal for ICG in Italy” demon-strated “how our local teams continue to find attractive investment opportunities across Europe which have the potential to produce strong growth and enable us to deliver on behalf of our fund investors”.

And CVC senior managing director Giorgio De Palma pointed to Doc Gener-ici’s record of “consistent organic growth and high cash generation led by an out-standing management team”.

Thanking CVC for their support, Doc Generici CEO Gualtiero Pasquarelli con-curred that the firm had “delivered very solid results in terms of sales and earn-ings before interest, tax, depreciation and amortization (EBITDA), outperform-ing the reference market, and has sig-nificant potential for further growth. We now look forward to working with ICG in the next stage of our development.”

DOUBLE-DIGIT GROWTH TO OVER €200M

Doc Generici – which was acquired by CVC in 2016 – recently revealed that for the 12 months ended 30 September 2018, its sales rose by 13% to €202.3 mil-lion (US$228 million). Over the same pe-riod of time, its EBITDA climbed by more than a fifth – 22% – to €77.5 million.

Discussing market conditions for play-ers in the Italian retail market, Pasquarelli noted that with generics having achieved around a 22.3% share by volume of the market, penetration was “far below” oth-er major European markets; nevertheless, he underlined, margins on such products were typically much higher in Italy.

Pasquarelli was optimistic about Doc Generici’s prospects in the coming years. He pointed to a patent cliff that would take place between 2022-2024, when a “whole class” of type 2 diabetes drugs and oral an-ticoagulants will lose protection in Italy.


Health Canada Seeks To Streamline Generics PathwayDAVID WALLACE [email protected]

D raft regulations seeking to alter the generics approval framework in Canada to improve access to generics, “improve clarity and predictability for manufactur-ers” and create more consistent and transparent labelling have been published by

Health Canada. They have been welcomed by local generics industry association the Cana-dian Generic Pharmaceutical Association (CGPA) as a way of cutting regulatory “red tape”.

Noting that it was “proposing regulatory amendments to the Food and Drug Regula-tions that would give generic drug manufacturers greater flexibility in how they de-velop drugs, while maintaining the safety, quality and efficacy of these drugs,” the regu-lator explained that the revisions would “allow for the authorization of generic drugs that have the same active ingredients as brand name drugs but in different forms – eg. different salts – provided they achieve the same dose and effect and maintain safety.”

“This change would result in the greater availability of lower-cost generic drugs for Canadians,” Health Canada declared. Firms would still have to prove equivalence to the brand and safety, quality and efficacy, the regulator emphasized.

ADDRESSING DIFFERENT FORMS OF INGREDIENTSIn particular, Health Canada explained, the revisions were intended to address differences such as different salts, polymorphic forms, hydrates or solvates being used by generics, leading to difficulties in determining whether drugs are pharmaceutically equivalent such that they can be approved via the abbreviated new drug submission (ANDS) pathway.

By amending the definition of “pharmaceutical equivalent” in the Food and Drug Regulations, Health Canada said it would be able to address cases where active pharma-ceutical ingredients undergo changes in form during the manufacturing process of the dosage form, to help determine whether the ANDS pathway is the “appropriate route for assessment” and if so whether additional data is required.

Different complexes, clathrates, esters and isomers or mixtures would not be eligible to be assessed through the ANDS pathway, Health Canada indicated.

The proposed amendments will also “streamline labelling practices” by clarifying label-ling requirements for ingredients in certain drugs, thus providing healthcare professionals with “clearer and more accurate information about their medications,” Health Canada said.

No increased costs for government, industry or consumers are anticipated by Health Canada as a result of the changes. Moreover, the regulator suggested the proposals “could reduce regulatory difference with other jurisdictions such as the US Food and Drug Admin-istration (FDA) and the European Medicines Agency (EMA),” both of which address generics with different forms of the medicinal ingredient within their regulatory frameworks.

“Health Canada published the draft regulation to bring Canada more in line with other leading international regulatory authorities,” a CGPA spokesperson told Generics Bulletin.

“If approved, it will reduce the Canadian-specific requirements and red tape that companies must navigate to bring new generic medicines to Canada and improve Ca-nadians’ access to safe, effective, cost-saving generic prescription medicines.”

Interested parties have until 7 June to comment on the proposals, which have been published in the Canada Gazette. “Health Canada will consider the comments received and will revise the proposal as needed,” the regulator indicated.

On 29 April, Health Canada and the FDA will hold a joint public consultation at the US agency’s center in Silver Spring, MD, on the activities of the International Council for Harmonisation. “The purpose of the public meeting is to solicit public input prior to the next ICH Assembly meeting and the expert working group meetings in Amsterdam, the Netherlands, scheduled for 1-6 June 2019,” the agencies explained.



S T R AT E G Y

US Ambrisentan Approvals Hint At Different Commercial ApproachesAIDAN FRY [email protected]

F our leading generics players in the US – Mylan, Sun Pharma, Teva’s Watson and Zydus Pharma – have

simultaneously obtained final approval from the Food and Drug Administration for generic versions of Gilead’s Letairis (ambrisentan) 5mg and 10mg tablets.

“With the approval of these first ge-nerics, and their associated risk evalua-tion and mitigation strategy (REMS) pro-grams, patients will now have access to additional products and additional types of pharmacies to fill their prescriptions,” the FDA commented.

Given that Gilead reported US Letairis sales ahead by more than 6% to $943 mil-lion last year, the financial reward for ge-nerics firms that adopt a successful com-mercial approach could be considerable.

The approvals for the pulmonary arterial hypertension (PAH) treatment include two separate REMS programs: the first, named ‘Ambrisentan REMS’ covers Letairis and three of the abbreviated new drug appli-cations (ANDAs) in just the specialty phar-macy channel, while the second program known as ‘PS-Ambrisentan REMS’ denotes a parallel system for one ANDA sponsor, Zydus. An endothelin receptor antagonist, ambrisentan is associated with embryo-fetal toxicity that can cause birth defects.

SINGLE REMS REQUIREMENT WAIVED FOR ZYDUS

In its approval letter for the ambrisentan ANDA submitted by Zydus, which is mak-ing the tablets at its formulations facil-ity in a special economic zone (SEZ) near Ahmedabad, India, the FDA says it has ap-proved the firm’s PS-Ambrisentan REMS program under a waiver of the single, shared-system requirement normally re-quired under section 505-1(i) of the Fed-eral Food, Drug and Cosmetic (FD&C) Act. The agency had in June last year released draft guidance for industry on waiving sin-gle REMS with elements to assure safe use (ETASU) covering both the reference listed drug (RLD) and ANDAs that reference it.

Stressing that Zydus’ bespoke REMS,

comprising EATSU and an implementa-tion plan, “must be fully operational” be-fore the firm introduced its ambrisentan tablets into interstate commerce, the FDA said it would post the program to its website. “Your waiver-granted REMS system shall be open to all future spon-sors of ANDAs or NDAs for ambrisentan products,” the agency clarified.

In a press release, the FDA explained that it had granted Zydus a waiver “because it found in this case the burden of form-ing a single, shared system, which would have prevented the use of retail pharma-cies, outweighed the benefits.” The parallel PS-Ambrisentan REMS achieved “the same level of safety” as the program covering Le-tairis and the three other ANDAs, it added.

To date, the FDA has posted ambrisen-tan approval letters for the ANDAs submit-ted by Zydus and Sun, but not for Mylan and Watson. In both the Zydus and Sun letters, the agency notes that the firms have carved out three Orange Book meth-od-of-use patents, two of which expire in December 2027 and one in October 2031.

AMBRISENTAN COMPOUND PATENT EXPIRED LAST YEAR

Reissued US patent RE42,462 that covered the ambrisentan compound expired on 29 July 2018. The ‘462 patent, which Gil-ead licensed from Royalty Pharma, had been the subject of litigation brought by Gilead and its partner in a New Jersey dis-trict court against ANDA filers Watson and Sigmapharm. However, that litigation was settled in early 2017 on confidential terms.

According to Gilead’s trial lawyers, Quinn Emanuel Urquart & Sullivan, both Watson and Sigmapharm had stipulated to infringe-ment, but argued that the ‘462 patent was invalid for obviousness-type double pat-enting over an earlier patent that claimed a broader genus of compounds. Alleging that the generics firm’s argument was “based entirely on hindsight”, Quinn Emanuel said both Watson and Sigmapharm had “accept-ed Gilead’s long-standing settlement offer” as a trial was about to be scheduled.

Letairis had already been the subject of litigation in Minnesota and New Jersey district court after Natco and Zydus each sued Gilead. They alleged that the origina-tor had breached antitrust laws by using its Letairis Education and Access Program (LEAP) safety scheme as an excuse to deny the generics firms multiple requests for the samples needed to perform bioequiv-alence testing. But after Natco saw its ar-gument dismissed in Minnesota, Zydus dropped its case in New Jersey.

FIRST ANDA FILING YEARS AFTER NCE EXCLUSIVITY ENDED

The alleged difficulty in obtaining sam-ples appears to be borne out by other facts. The FDA said it received the first ANDA filing for ambrisentan on 9 Febru-ary 2015, three-and-a-half years after the prospective first possible filing date on 15 June 2011, one year before Letairis’ new chemical exclusivity (NCE) expired.

And a list posted by the FDA last year identifying all drug products for which agency had received an RLD access in-quiry related to limited distribution high-lighted similar problems.

With 10 such requests received for Le-tairis, the PAH brand was behind only Ac-telion’s Tracleer (bosentan) and Celgene’s Revlimid (lenalidomide) blockbusters.

As one of his final acts as FDA commis-sioner, Scott Gottlieb on 4 April this year affirmed the agency’s commitment to ensuring that REMS “do not impede ge-neric drug development”. Final guidance issued on the same day clarified “how


S T R AT E G Y

the FDA applies six factors that impact the agency’s decision-making process regarding whether a REMS is required for a particular drug and what type of REMS might be necessary.”

The guidance, which finalizes a draft document issued in September 2016, lists the six factors influencing whether a REMS is required as:

• The seriousness of any known or potential adverse events that may be related to the drug and the back-ground incidence of such events in the population likely to use the drug

• The expected benefit of the drug with respect to the disease or condition

• The seriousness of the disease or condi-tion that is to be treated with the drug

• Whether the drug is a new molecular entity

• The expected or actual duration of

treatment with the drug• The estimated size of the population

likely to use the drug“In some cases,” Gottlieb observed,

“branded sponsors have refused to sell samples of brand products with REMS with ETASU impacting distribution of the drug to potential generic competitors. The FDA cannot stand idly by and allow companies to abuse the system, frustrat-ing generic-drug manufacturers and ulti-mately keeping patients from accessing lower-cost generic drugs.”

US legislators are also doing their part to tackle REMS abuse that can de-rail generic development by denying access to samples. Earlier this month, the House Energy and Commerce Com-mittee unanimously passed the Cre-ating and Restoring Equal Access to Equivalent Samples (CREATES) Act, H.R.

965, albeit with an amendment to pre-vent frivolous litigation against origina-tors who provide requested samples of their products.

Hailing the bipartisan supporters of the bill, especially Democrat Peter Welch and Republican David McKinley, the Association for Accessible Medi-cines described the 51-0 vote in favour as “an important step along the path to providing patients with relief from high drug prices.”

“We look forward to the House Judicia-ry Committee’s prompt consideration of the CREATES Act – where it enjoys strong bipartisan support – and its subsequent passage by the House of Representa-tives,” generics and biosimilars industry body AAM stated.


P R I C I N G & R E I M B U R S E M E N T

English Adalimumab Tender Marks Progress, But Is Not PerfectAIDAN FRY [email protected]

A multisource adalimumab tender run by England’s National Health Service (NHS) on a regional basis

late last year was a marked improvement over previous procurement practices for biosimilars, according to Warwick Smith, director general of the British Biosimilars Association (BBA). But it could have been better, he told delegates to Medicines for Europe’s biosimilar medicines conference held in Amsterdam, the Netherlands.

Admitting a degree of surprise at how the industry’s arguments around sustain-ability had been reflected in the adalim-umab tender, Smith stated: “I would not say it is perfect, but I think it does show a way forward for the future.”

“If your commercial judgment as a man-ufacturer is that you do not want to go to the bottom [on price], but rather you want to make a first reduction in price and ac-cept a smaller market share, you can do that,” he commented.

A briefing issued by NHS England’s Regional Medicines Optimisation Com-mittee (RMOC) as the tender framework

agreement came into effect on 1 Decem-ber 2018 explained that “to support plu-rality of supply in future years, the tender makes available different medicines in different parts of the NHS”.

“Previous frameworks for biosimilars have included all brands on an unranked framework. Consequently, trusts have tended to switch to the lowest-cost bio-

logic for financial reasons, but other com-panies have struggled to gain market share,” it recognized.

While the most competitive adalimum-ab suppliers have been rewarded with a greater share of the English market, each of the four biosimilars in the market – Am-gen’s Amgevita, Biogen’s Imraldi, Mylan’s Hulio and Sandoz’ Hyrimoz – were se-

“Trusts have tended to switch to the lowest-cost biologic for financial

reasons, but other companies have struggled to gain market share”


P R I C I N G & R E I M B U R S E M E N T

lected as the first line 40mg biosimilar in at least one of 11 regions. Amgevita was the sole selected 20mg/0.4ml biosimilar nationwide, while AbbVie’s Humira refer-ence brand can be used “where clinically appropriate or where it is the best value”.

Upon Humira losing exclusivity in mid-October last year, NHS England said hospitals could save up to £150 million (US$196 million) per year by switching to less expensive adalimumabs, resources that they could “reinvest in frontline care”.

But once it had received the tender bids, it doubled the savings forecast to around £300 million, or about 75% of the more than £400 million that it previously spent on Humira.

Smith said NHS England’s contracting process showed that it had heeded warn-ings about the dangers of single-supplier tenders. “There was a recognition that we need a competitive system, not a race to the bottom where the lowest-price man-ufacturer takes everything,” he stated.

In creating a system whereby steep-er discounts to the brand price were rewarded by higher market share through the tender, NHS England had, he believed, created a reasonable ap-proach to a multisource market. “All four biosimilars have a piece of the market,” he observed.

However, Smith outlined two areas in which he felt the adalimumab ten-der had been sub-optimal. Firstly, he described as “a mistake” NHS England’s emphasis on ensuring a choice between products that used a citrate excipient and those that did not, even though its own chief pharmaceutical officer had described evidence for this being a rel-evant factor as “very thin”. Both Biogen’s Imraldi and Sandoz’ Hyrimoz contain ci-trate as a non-active ingredient.

Smith also highlighted failures in communication between NHS England and industry after the tender had been awarded, a problem that he attributed in part to “a change of personnel”.

Furthermore, Smith also criticized the tender model for carving up the entire English adalimumab market, thereby locking out until at least 1 December 2019 any subsequent entrants in “a breach of good procurement practice”. This point was echoed by former NHS procurement pharmacist Maggie Dolan, who last year

joined industry as Biogen’s associate di-rector of market access.

Nevertheless, he praised NHS Eng-land’s “real solid steps to find a way for a huge product to make sure that was not a race to the bottom and to ensure com-petition is there”.

CREATED A UNIQUE MULTI-DISCIPLINARY GROUP

While effecting change in the “huge monolithic structure” of the NHS was not easy, he said the its chief pharmaceutical officer had a few years ago recognized that it was lagging behind other parts of Europe in terms of biosimilar uptake. On his initiative, the NHS had brought to-gether a multidisciplinary group that was “probably unique in the world” in includ-ing not only the biosimilar and originator industries, but also patients’ and health-care professionals’ bodies.

Relatively quickly, this diverse group created the basis for an NHS commis-sioning framework that calls on trusts and clinical commissioning groups (CCGs) to start nine out of 10 naïve patients on the best-value biologic medicine within three months of a biosimilar launch. At least 80% of exist-ing patients should be switched to the best-vale biological medicine within 12 months, it recommends.

“One of the reasons for that was, along with education and making sure every-body understood the facts and not ru-mors, that we did not talk about reduc-

tion in price,” Smith explained. “We talked about increase in access.”

“Getting everybody together in that huge group, representing all interests, was key. What the framework then did was to encapsulate that into clear policy guidance,” he added.

Once the benefit to both the patient and the payer became clear, under-pinned by an understanding of the sci-ence, stakeholders were comfortable with using biosimilars, Smith comment-ed. “With infliximab after two or three years, a third more patients are being treated at half of the cost originally – what is not to like?” he asked.

In taking a 90% volume share through an 80% discount to the brand, biosimilar infliximab in the UK had followed “the classic British generics model where you trade low price for high volume, low barriers to entry and low levels of bureaucracy”, he acknowledged. “That is not sustainable because you need the revenue from the last product to invest in the next one.”

Asked by the moderator, Sandoz’ Flo-rian Turk, about what to expect next in the UK following the adalimumab ten-der, Smith answered: “I think the NHS will be very reluctant to go to that level of tender model complexity for a small-er-value product.”

The NHS, he suggested, still had “to take a step forward” on recognizing in tender processes competitive fea-tures on non-financial factors such as homecare delivery. Shifting factors throughout the adalimumab process had also, he said, undermined biosimi-lar developers’ confidence in making commercial decisions based on antici-pated outcomes.

“I don’t think we have cracked it, but I think the plurality of supply point has been made and accepted,” Smith con-cluded. “I think there has been a learning that if you just drive competition on price, it eventually drives out competition.”


“I think there has been a learning that

if you just drive competition on price,

it eventually drives out competition”

ANALYZE

Further information related to this story is available here: https://bit.ly/2UXo9Me


P R I C E WAT C H U K

RECENT LAUNCHES

PRODUCT/STRENGTH/PACK SIZE

FEB 2019

MINIMUM

MINIMUM

CHANGE

(%)

FEB 2019

AVERAGE

AVERAGE

CHANGE

(%)

Aripiprazole Tabs 10mg 28 £0.73 0% £1.42 6%

Carbimazole Tabs 5mg 100 £10.50 -9% £18.00 -8%

Celecoxib Caps 200mg 30 £0.86 0% £7.32 158%

Cilostazol Tabs 100mg 56 £3.25 0% £3.90 3%

Duloxetine E/C Caps 30mg 28 £0.77 3% £1.75 21%

Eplerenone Tabs 25mg 28 £2.53 0% £4.99 4%

Escitalopram Tabs 10mg 28 £0.50 4% £0.91 0%

Etoricoxib Tabs 90mg 28 £1.96 -4% £2.53 1%

Ezetimibe Tabs 10mg 28 £0.99 -13% £1.48 -5%

Frovatriptan Tabs 2.5mg 6 £2.25 -10% £3.71 -2%

Ivabradine Tabs 5mg 56 £3.62 13% £4.83 3%

Memantine Tabs 10mg 28 £0.62 2% £0.93 1%

Nefopam Tabs 30mg 90 £3.74 -6% £5.29 -9%

Comparison between the periods 1-28 February 2019 and 1-31 March 2019 of UK trade prices of the most recently-launched generics listed in category M of the Drug Tariff of pharmacy-reimbursement prices. Averages calculated from at least 24 data points (Source - WaveData)

Up to the minute live retail market pricing is available at wavedata.net and historical prices at https://www.bppi.co.ukAlternatively, contact WaveData at [email protected] or +44 (0)1702 425125

ANALYZE

Further information related to this story is available here: https://bit.ly/2ZiVIrB

RECENT LAUNCHES

PRODUCT/STRENGTH/PACK SIZE

FEB 2019

MINIMUM

MINIMUM

CHANGE

(%)

FEB 2019

AVERAGE

AVERAGE

CHANGE

(%)

Nortriptyline Tabs 10mg 100 £4.95 228% £8.26 -7%

Olmesartan Medoxomil Tabs 10mg 28

£0.59 -6% £1.15 -12%

Pregabalin Caps 150mg 56 £2.15 0% £3.50 -4%

Rasagiline Tabs 1mg 28 £1.25 0% £1.87 -13%

Rizatriptan Tabs 10mg 3 £1.38 0% £4.75 -6%

Rosuvastatin Tabs 5mg 28 £0.62 0% £1.12 7%

Sevelamer Tabs 800mg 180 £23.10 0% £145.62 23%

Sildenafil Tabs 100mg 4 £0.25 0% £0.44 -2%

Tadalafil Tabs 10mg 4 £0.74 -1% £1.33 2%

Telmisartan Tabs 80mg 28 £6.97 -13% £10.49 -13%

Travoprost Eye Drops 40mcg/ml 2.5ml

£1.92 0% £3.10 5%

Zonisamide Caps 100mg 56 £2.40 -12% £4.56 -6%

UK Price Concessions List Lengthens Amid Brexit UncertaintyDAVID WALLACE [email protected]

A lmost 100 separate presentations of generic medicines were featured on the UK’s list of monthly price conces-sions granted by the Department of Health and Social

Care for March, as the latest figures from market researcher WaveData showed average prices to UK independent pharma-cists that grew by as much as five times that month.

The lengthy concessions list of 96 individual presentations comes as the UK’s Pharmaceutical Services Negotiating Com-mittee (PSNC) has made a series of public comments about the increasing difficulties in sourcing generics that are being experi-enced by community pharmacies, against a backdrop of uncer-tainty and contingency planning around Brexit as well as other factors that are affecting supply.

Last month, the PSNC reported supply issues around metopro-lol – including discontinuation of the product by some manufac-turers and supply difficulties for others – that were driving up prices. And this month, the UK Epilepsy Society has complained that patients are being “forced to trawl around pharmacies in search of their drugs”, citing a “steep rise in the number of people who are struggling to get hold of medication”.

However, musculoskeletal drugs led the biggest risers in March, with risedronate and two presentations of ibandronic acid registering treble-digit increases according to WaveData.

Among the DHSC’s concessions were a concession price of £7.55 (US$9.88) for four risedronate sodium 35mg tablets that

comfortably exceeded the average up by 425% to £2.73 record-ed by WaveData. Similarly, a £17.53 concession for a single iban-dronic acid 150mg tablet was much higher than the average price that rose by 174% to £6.28.

However, the concessions were not all sufficient. Carvedilol 12.5mg tablets in 28-count packs received a concession price of £2.75 that almost matched their average that more than dou-bled to £2.84, while 56-tablet packs of riluzole 50mg tablets that saw their average leap by 96% to £60.65 were rewarded with a concession of just £17.94. And celecoxib 100mg capsules in packs of 60 that experienced an 85% average rise to £3.92 re-ceived a concession price of £3.29.

Chief among the biggest fallers were 28-count packs of levo-thyroxine 12.5μg tablets that saw their average price more than halved to £2.08. Dosulpein 25mg capsules in the same pack size followed with a 38% average drop to £2.98.

Among recent launches, a handful of molecules saw double-digit average price drops but the biggest change seen was in the low-est price of 100-count packs of nortriptyline 10mg tablets, which jumped by 228% to £4.95. “The triple-digit minimum price rise is due to Trident increasing their February price of £1.51 to £5.80 in March,” WaveData commented. “The lowest price recorded in March of £4.95 was for stock being advertised by Elite Pharma & Lexon.”



A P P O I N T M E N T S

Top India Drugmakers’ Body Names Industry Veteran Sudarshan Jain New Secretary GeneralPENELOPE MACRAE

I ndian pharmaceutical industry veteran Sudarshan Jain takes up his new role this week as Secretary General of the

Indian Pharmaceutical Alliance, the or-ganization which has been a key voice in promoting the interests of the country’s flagship generic drug industry.

Jain, who has more than four decades of experience in the pharmaceutical in-dustry, starts his new role on 8 April, re-placing IPA founder Dilip Shah who died in late February at the age of 77. Shah was instrumental in spearheading the Indian generics industry’s transformation into becoming known as the “pharmacy to the world.”

Like Shah, Jain also comes from a mul-tinational pharmaceutical background and was an alumnus of the Indian In-stitute of Management, India’s premier business school.

Jain, who served as former managing director of Abbott Healthcare, a subsid-iary of US drugmaker Abbott Laborato-ries, as well as in leadership positions with Johnson & Johnson and Piramal among other companies, paid tribute to his predecessor who enjoyed powerful clout in the industry. “I am going to build on the foundation (Shah laid),” he told Ge-nerics Bulletin.

On his watch, Jain said the IPA will “con-tinue to be a catalyst in shaping policy en-vironment to unleash the potential of Indi-an industry in line with national priorities.”

Under Shah, the IPA, which he spear-headed out of a clutch of generic com-panies in 1999, was a strong defender of India’s patent law which seeks to balance recognizing innovation and ensuring healthcare access in a coun-try where millions of people live in poverty. A particular gripe of multina-tionals has been India’s refusal to allow “evergreening” or tweaks to medicines to extend exclusivity and its insistence a drug must display “novelty” to get in-tellectual property protection. At the same time, Shah was vocal in criticis-ing Indian government policies he be-lieved might damage the industry such as regulatory pricing controls he said could slow investment.

OPPORTUNITY FOR INDIAN COMPANIES TO ‘MAKE A DIFFERENCE’

Going forward, “there is opportunity for Indian companies to make a difference both in access and innovation,” Jain said.

IPA’s membership has grown from half a dozen founding Indian firms that included Cipla Ltd, Sun Pharmaceutical Industries Ltd and Dr Reddy’s Labora-tories Ltd to 22 companies which com-bined count for over 85% of private sector investment in pharmaceutical research and development, more than 80% of India’s pharmaceutical exports and over 50% of the domestic pharma-ceutical market.

“Over the years, IPA has played a pivot-al role in placing Indian pharmaceutical companies on the global map and we are happy that now Mr Sudarshan Jain will be deeply involved in the activities of the group,” Glenn Saldanha, president of the IPA and chairman of Glenmark Pharma-ceuticals Ltd, said in a statement.

Jain’s appointment comes as the IPA is waiting to see whether the US Trade Representative in its annual report on intellectual property rights removes In-dia from the Priority Watch List on which the country has languished for years. The USTR identifies in the report which na-

tions it believes do not provide effective protection of IP rights or fair market ac-cess to US products.

WAITING FOR USTR PRIORITY WATCH LIST DECISION

In its submission to the USTR early in Feb-ruary, the IPA noted India had made rapid progress on various fronts cited by the US body when it kept India on the Priority Watch List in 2018 in the company of 11 other nations including Canada.

The IPA has long maintained Indian IPR laws are compliant with the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) and that India is entitled to make full use of the flexibili-ties for protecting public health.

The USTR in 2018 cited India’s overall levels of IP enforcement which it said “remains deficient,” though it praised the country’s work in reducing processing of patent applications. Shah said in the IPA’s submission India had made further prog-ress in addressing the USTR’s complaints.

“India now has one of the lowest exam-ination times for trademark registration in the world and the indications are the patent examination backlog will be elim-inated in about two years. Processing de-lays are no longer a concern and we hope the USTR will take note of this” and recog-nize the “strides India has made.”

The USTR will issue its IP report card around 26 April.


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M A N U FA C T U R I N G

Aurobindo In Trouble Again With FDA, Gets Form 483 With 11 ObservationsPENELOPE MACRAE

Quality control issues keep dogging India’s Aurobindo. The US Food and Drug Administration has issued another Form 483, this one containing 11 observations, to Aurobindo

over its newly commissioned Unit XVI sterile manufacturing unit at its plant in Bachupally in the southern Indian state of Telangana.

The FDA led off its observations with a statement saying the factory’s quality control unit had failed in its job to ensure “objectionable conditions do not negatively affect the aseptic manufacturing process.”

The FDA team, which inspected the plant from 22 February to 1 March, said control procedures had not been established to moni-tor output and validate the performance of manufacturing process-es. Among the litany of problems listed were red particles found in product batches that turned out to be shredded particles from a gasket, stoppers coming loose, failure to carry out proper visual inspections and risk of contamination from the equipment setup.

Other issues cited included failure of laboratory controls to ensure “drug products conform to appropriate standards of identity, strength, quality and purity.” Also, the FDA noted a lack of proper employee training and “appropriate” computer con-trols to assure changes to records were done only by authorized personnel. In addition, it reported “the accuracy, sensitivity and specificity of test methods have not been documented.”

Some of the issues may be start-up problems at the newly com-missioned XVI unit, one drug industry observer said. Aurobindo’s shares, which have been trending broadly higher in the past year, closed down 1% at INR782.80 ($11.32) on 11 April. Mumbai bro-kerage Prabhudas Lilladher, which has an INR952 target on Au-robindo’s shares, said in a 20 March note it was “confident on man-agement initiatives to address quality control issues.”

Receipt of a Form 483 means a company must respond within 15 days to the FDA outlining what it plans to do to remedy the watch-dog’s complaints. Failure to act on the letter can lead to a warning letter which has far more serious implications, such as withholding US regulatory product approval.

SECOND FORM 483 IN TWO MONTHSIn February, the FDA posted a Form 483 for the Unit IV sterile inject-ables facility at Aurobindo’s nearby manufacturing plant in Pashamy-laram that it had inspected two months earlier. That Form 483 con-tained two observations – rapping the company over equipment cleaning and airflow. Back in March 2018, that same unit received a

Form 483 which said the building used for manufacturing was “not free from infestation by rodents, birds, insects and other vermin.”

The company said last year it aimed to remedy its quality issues but they have kept cropping up. However, a senior company exec-utive, who did not wish to be named, told Generics Bulletin on 11 April the company has been able to prevent issues raised in Form 483s from escalating to far more serious import alerts since 2011.

The Aurobindo executive said the company would respond to the FDA within the specified 15-day time-frame. “Inspections are part of our life. We will send them our responses and – at the end of the day, with the FDA – if you’re clear and transparent, you won’t face a prob-lem,” the executive said. He noted neither of the Form 483s served on the company related to data integrity. Wrong data, either as a result of employee mistakes or sometimes fraud involving Indian plants, has been an area of concern in the past with the FDA.

Despite its FDA troubles, Aurobindo’s financial third-quarter profit to 31 December 2018 jumped 19.7% to INR7.12bn year-on-year on sales that grew by a robust 21.5% to INR52.69bn. Aurobindo’s prod-uct portfolio spans antibiotics to antiretrovirals and diabetes drugs. The US and Europe are Aurobindo’s two most important markets, accounting for over 70% of the company’s $2.6bn annual sales.

AUROBINDO BETS BIG ON USThe latest FDA problems for Aurobindo comes as the company gears up to digest its $1bn purchase last September – $900m plus performance payments for pipeline products – of the US dermatol-ogy and generic oral solids business belonging to Sandoz. That ac-quisition, which included three manufacturing plants and was the largest overseas purchase by an Indian drug company, made Au-robindo the second-biggest generic prescription player in the US.

Aurobindo is betting its cost-competitiveness and vertical inte-gration will turn what was a low-margin asset for Novartis into a winner for the Indian company. The transaction, on which Novartis booked a $70mn charge, is expected to close sometime in 2019.

While Indian firms continue to receive FDA 483 Forms, a new study by global consultancy McKinsey and the Indian Pharmaceuti-cal Alliance, which represents big Indian drug-makers, has reported a “visible decline” in the volume of action being taken by USFDA. Ac-cording to FDA data, out of 174 inspections of Indian firms in 2018, only 4% of inspections were classified as Official Action Indicated or OAI that involves withholding new approvals, sending warning let-ters and issuing import alerts. That was down from 15% in 2017. The rest of the communications in 2018 from the FDA to Indian firms in-volved Voluntary Action Indicated (VAI) or No Action Indicated (NAI).

McKinsey noted a significant reduction in data-reliability errors that plagued industry. Most concerns about non-compliance are now related to gaps in manufacturing systems and laboratory controls as seen in the FDA 483s sent to Aurobindo.


The factory’s quality control unit had failed to ensure “objectionable conditions do not negatively affect the aseptic manufacturing process”


I N T E L L E C T UA L P R O P E R T Y

Lack Of Lilly Litigation Clears Path For Pfenex’ Forteo RivalDAVID WALLACE [email protected]

P fenex has removed a barrier to po-tentially launching its rival to Eli Lilly’s Forteo (teriparatide) 0.6mg/2.4ml in

the US later this year, after the originator failed to respond to a Paragraph IV certi-fication over a device patent by suing the company within 45 days.

Having sent its notice letter to Lilly on 19 February claiming that its PF708 ver-sion of teriparatide – a 505(b)(2) new drug application filing for which is cur-rently being reviewed by the US Food and Drug Administration – does not infringe any valid claim of US patent 7,517,334, Pfenex said no litigation was initiated within the statutory 45-day period.

“Because Lilly did not file a lawsuit within this time period, there will be no 30-month litigation stay delaying ap-proval of PF708, and if approved by the FDA, Pfenex will be able to engage in the commercial manufacture, use, or sale of PF708,” the company declared.

The ‘334 patent is listed against Forteo in the FDA’s ‘Orange Book’ with an expiry date of 25 March 2025.

Earlier this year, the FDA accepted the 505(b)(2) NDA filed by Pfenex, setting a target goal date of 7 October 2019. This is almost two months after three method-of-treatment patents – the only other US patents listed against Forteo in the Or-ange Book – expire on 19 August.

Pfenex had previously indicated a “po-tential US launch as early as the fourth quarter of 2019” for PF708, with “limited competition expected”.

NO FDA ADVISORY COMMITTEE MEETING PLANNED

Pfenex – which has enlisted Alvogen as its commercial partner for PF708 in the

US, as well as in other global territories, along with NT Pharma in China and cer-tain other Asian markets – said feedback it had received from the FDA did not show that the agency is planning to hold an advisory committee meeting to dis-cuss the 505(b)(2) NDA.

“The acceptance of the NDA indicates the application is sufficiently complete to permit a substantive review by the FDA,” Pfenex stated. A Phase III study, PF708-301, comparing Pfenex’ product and For-teo in osteoporosis patients previously demonstrated “comparable overall pro-files across multiple endpoints.”

“Pfenex is pleased with the outcome of the 45-day waiting period process for PF708,” stated CEO Eef Schimmel-pennink. “Pfenex, along with its partner Alvogen, continue to focus on launch preparation and look forward to the op-portunity of providing access to patients in need of this critical therapy if ap-proved by the FDA.”



Tailored Approach To Orphan Biosimilars Is On EMA’s Agenda AIDAN FRY [email protected]

F lexibility on clinical requirements for orphan biosimilar development programs will be essential, given

the relatively small patient populations for each disease, the European Medicines Agency recognizes.

“Obviously it is difficult to demand the full equivalence trials in situations where you rarely have patients, so we are think-ing of alternative models there,” the chair of the EMA’s biosimilars working party (BMWP), Elena Wolff-Holz, told delegates to Medicines for Europe’s biosimilars

medicines conference held in Amster-dam, the Netherlands.

Noting that orphan biosimilars were increasingly requiring the BMWP’s at-tention, Germany’s Wolff-Holz drew a parallel with developing next-generation biosimilars of biological drugs with mar-ginal, often single-digit additive effects that could display low systemic serum concentrations. Following traditional clinical models for such combination therapies would, she acknowledged, “re-quire very large equivalence trials”.

“We need to recognize that science is

moving rapidly towards every drug

being an orphan drug”



ASSAY GROUP MAY REDUCE CLINICAL WORK

A BMWP functional assay group was, she noted, reviewing mechanisms of actions for all monoclonal antibodies, including suitable assays, validation procedures and “pharmacodynamic (PD) markers that may be available in different indications”. “This may possibly in the future reduce the necessity for clinical work,” Wolff-Holz remarked, adding that the primarily goal of the group was not so much producing a public guidance document as creating training material for assessors.

Other topics being discussed among BMWP members, she revealed, included ethical approaches to developing pediat-ric biosimilars and whether animal mod-els and pharmacokinetic (PK) data would be sufficient to demonstrate equivalence of biosimilars developed to prevent, rath-er than treat, diseases.

“These are all things that could be taken up in future guidelines,” Wolff-Holz sug-gested, adding that it was likely that the EMA’s overarching scientific guideline on biosimilars would need to be revised.

Participating during the conference in a session on a tailored approach to compar-ative clinical trials, the BMWP’s vice-chair Niklas Ekman concurred that the working group recognized the importance of con-sidering options on orphan biosimilars. “We are certainly thinking about it,” he as-sured conference delegates.

“We need to come up with some-thing to make it possible to developt biosimilars also for orphan indications,” Ekman acknowledged.

BMWP observer member René Anour commented: “In general, there is no al-leviation of development for biosimilar orphan products. However, if we want to see them – and we are discussing with companies that are in development – you cannot, of course ask for the same amount of data.”

TAILORED APPROACH ‘HAS TO HAPPEN’“It is an area where tailoring has to hap-pen,” Austria’s Anour insisted. “We are at the moment working on the basis of case-to-case decisions, because we do not have any guidance out yet.” The key, he believed, would be to find a way forward with tailored approaches on clinical requirements while maintaining a rigorous evidence base.

Orphan biosimilars represented a good area in which to start thinking about tailored approaches to compara-tive clinical trials, he felt, “not because the molecules are simpler, but because we have to think in a different way be-cause there are just not enough pa-tients.” He encouraged developers to seek scientific advice from the EMA.

In a separate session on future policy and framework needs, Anour forecasted that “we are probably going to see the first candidates in the authorization pro-cess in the next couple of years.”

“We do not offer special incentives or alleviations for orphan biosimilar medi-cines,” he acknowledged, contrasting this with the framework of regulatory exclu-sivities and incentives such as reduced fees and parallel scientific advice on of-fer for novel treatments for rare diseases. However, he said, the EMA would on a case-by-case basis “take into account fea-sibility” of regulatory demands around comparability. “We cannot expect a fully powered study in an indication that is so rare that you could never come up with the patient numbers,” he conceded.

Murray Aitken, executive director of the IQVIA Institute, suggested that poli-cymakers and payers might be well ad-vised to consider mirroring the measures used to stimulate research and devel-opment of original orphan drugs to en-courage orphan biosimilars. “We need to recognize that science is moving rap-idly towards every drug being an orphan drug,” he insisted, pointing to indications covering ever smaller and more targeted patient populations.

“The sales and usage of many drugs ap-proved with an orphan indication is much less than it should be, based on the epi-demiology of the diseases,” he observed, highlighting research that showed on av-erage only 20% of eligible US patients got access to orphan treatments, in part due to other bottlenecks such as diagnostic testing and financial considerations.

PAYERS LOSING PATIENCE WITH ORPHAN PRICING

Speaking from a payer’s perspective, Ad Schuurman – chairman of the Euro-pean social health insurance organiza-tion’s medicine evaluation committee, Medev – objected that it was impossible

for healthcare systems to keep paying for high-priced original orphan drugs. Where a cheaper biosimilar was available, it was essential that payers demand that they were used, he argued.

Representing industry, Mylan’s com-mercial head of biologics in Europe, Erin Federman, observed that origina-tors were investing not only in orphan-drug development, but also in disease awareness. Increasingly, she said, bio-similar developers were looking ahead and weighing up potential investments in orphan candidates that could take 10 years to reach the market. These con-siderations, she outlined, were factor-ing in “whether the environment would be welcoming enough for us to take that step”.

“I don’t think there is a lack of sci-entific interest, or a lack of interest in treating these patient populations, be-cause we would welcome anything that would reduce costs and expand access,” stated Federman, who also chairs Medi-cines for Europe’s biosimilar market ac-cess committee. “It is more that we are watching very carefully to look into the crystal ball and ensure there is a place for us.”


“We need to come up with something to make

it possible to develop biosimilars also for orphan indications”


S T R AT E G Y

Canada’s Apotex Is Rumored To Be Weighing $3bn SalePENELOPE MACRAE

C anada’s largest generics drug-maker Apotex Inc. is considering a partial or full sale of the closely

held business, according to media reports.Quoting people familiar with the matter,

Bloomberg said Apotex was working with a financial adviser as it reviews options that might lead to partial or full sale of the busi-ness. It reported the disposal of the entire company could fetch up to $3bn.

The children of Apotex founder Barry Sherman and his wife Honey now con-trol the company after their parents were found murdered at their home in late 2017. The family owns around 90% of Apotex through a trust controlled by son Jonathon Sherman and sisters Lauren, Alexandra and Kaelen, while employees hold the balance, according to Toronto daily The Globe and Mail. Jonathon joined Apotex’s four-person board early in 2018 and has emerged as a key decision maker in a restructuring of one the world’s largest generic drug mak-ers, the newspaper said.

The company decided to look at sale options as some large pharmaceutical companies and investors have voiced interest in acquiring the Toronto-based drug-maker, the sources quoted by Bloomberg said, adding talks were at a confidential preliminary stage and there was no decision on details of any deal, in-cluding how it might structured.

Apotex, which produces more than 300 generic molecules in 4,000 different dos-ages, could not be immediately reached for comment. Bloomberg said it hadn’t re-ceived any response from the drugmaker to its queries about a possible sale. Apo-tex, which makes generics, biosimilars, APIs and innovative drugs, was set up in 1974 by Barry Sherman who began the company with two employees and turned it into a global commercial force operat-ing in over 45 nations with more than 6,500 employees worldwide.

APOTEX COMPLETES SALE OF COMMERCIAL OPERATIONS IN FIVE EUROPEAN COUNTRIES

Two months ago, Apotex, which clocks around $2bn in annual global revenue,

completed the sale of commercial op-erations and supporting infrastructure in Poland, the Czech Republic, the Neth-erlands, Spain and Belgium to Indian ge-nerics manufacturer Aurobindo Pharma Ltd. for €74m (US$83m). Aurobindo said the deal, which had to clear European regulatory hurdles, would add over 200 generics and more than 80 OTC prod-ucts with annual sales of €133mn to its European portfolio, while Apotex said the divestment would allow it to “fur-ther accelerate” efforts “to drive addi-tional growth in the Americas.”

In December 2017, Apotex was rocked when Barry Sherman, 75, and his wife Hon-ey, 70, were discovered strangled in their Toronto mansion. Last November, their four children held a news conference at which their lawyer accused police of bungling the investigation. Police suspected the deaths might be a murder-suicide but a report by an independent pathologist hired by the family concluded the bodies were too neat-ly positioned for that theory to be correct. The family offered a C$10m (US$7.5m) re-ward for solving the mystery of the deaths which police later described as “targeted” homicides. No breakthroughs in the case have yet been reported. Canadian media re-ported much speculation that the slayings were linked to business disputes involving

Sherman who was famously litigious.Adding to the turmoil, less than a

month after the Shermans’ deaths, Apo-tex chief executive Jeremy Desai resigned following a lawsuit alleging he had ob-tained trade secrets from a girlfriend who worked at Israel’s Teva Pharmaceutical. Desai denied the accusations.

SPECULATION ABOUT SALE OF APOTEX HAS BEEN BREWING

The Globe reported in late December that “outside and inside Apotex” there had been “widespread expectation that the family and executive team are polishing up the business as a prelude to sale.” The newspaper, quoting unnamed company insiders and advisers who it described as privy to the private company’s financial results, said changes overseen by Jona-thon Sherman such as trimming Apotex’s drug portfolio, resolving lawsuits and sell-ing underperforming foreign assets, had boosted profit margins.

The newspaper suggested an important consideration in any sale might be honour-ing Barry Sherman’s Canadian loyalties in finding an owner who would preserve the 2,000 Apotex manufacturing jobs located mainly in the province of Ontario.


Bloomberg said Apotex was working with a financial adviser as it reviews options that might

lead to partial or full sale of the business.


S T R AT E G Y

Sandoz Strikes Shionogi Partnership As Part Of Pain PlayAIDAN FRY [email protected]

S andoz has obtained commercial rights in Germany, the Nether-lands and the UK to Shionogi &

Co’s Rizmoic (naldemedine) novel treat-ment for constipation induced by opioid analgesics. The Novartis division also has right of first refusal to Rizmoic 200µg tablets “for certain other European mar-kets” under an agreement that the two parties have signed.

Novartis said the agreement “reinforc-es Sandoz’ anti-pain franchise and com-mitment to pioneer access to healthcare in areas of unmet medical need”.

“Our purpose at Sandoz is to pioneer access by focusing increasingly on dif-ferentiated, value-added therapeutics that can make a real difference when it comes to meeting unmet medical needs,” expounded Francesco Bales-trieri, who became the division’s acting CEO on 1 April following the departure of Richard Francis.

COMMITTED TO BUILDING AN ANTI-PAIN FRANCHISE

“This agreement,” he added, “represents a significant step forward for that strategy and for patients in Europe, reinforcing our long-term commitment to building a leading anti-pain franchise and comple-menting our portfolio dedicated to mini-mizing the side effects of opioid use.”

Sandoz and its affiliates already mar-ket a wide array of off-patent analge-sics in Europe, supported by “a comple-mentary strategic focus on innovative therapeutic alternatives to combat opi-oid dependency”.

Building on Novartis CEO Vas Narasim-han’s vision of making the Swiss group a leading force in advanced therapy plat-forms and data science via an “enterprise-wide digital transformation”, Sandoz be-gan a wide-ranging process under former head Francis of shifting its focus not only towards biosimilars and higher-barrier, more complex generics that promised po-tentially stronger profit margins, but also towards digital health technologies.

At the start of this year, Sandoz intro-duced in the US reSET-O, “the first US Food and Drug Administration-cleared prescription digital therapeutic (PDT) for patients with opioid use disorder”. Developed through an alliance with Pear Therapeutics, the reSET-O PDT is “a 12-week cognitive behavioral therapy intended to be used in addition to out-patient treatment”. It includes transmu-cosal buprenorphine to treat opioid ad-diction “and contingency management designed to provide incentives to rein-force positive behaviors”.

Sandoz has also been encouraging ideas for improving healthcare access through

digital means, recently announcing three winners of its Healthcare Access Chal-lenge (HACk) 2019: US-based Regulora, a prescription-only digital therapeutic for irritable bowel syndrome; Netherlands-based SocialGenomics, a social network for patients with rare and undiagnosed diseases; and Uganda-based Mobile Clin-ic, an app and mobile van clinic providing maternal healthcare services.

A peripherally-acting mu-opioid re-ceptor antagonist (PAMORA), naldeme-dine was developed by Shionogi as a once-daily treatment for opioid-induced constipation (OIC).

RIZMOIC WAS APPROVED BY COMMISSION IN FEBRUARY

Following a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) within the European Medicines Agency in December last year that the drug be indicated for treating OIC in adult patients who have previously been treated with a laxative, the Europe-an Commission granted a pan-European centralized marketing authorization for Rizmoic 200µg film-coated tablets on 18 February 2019.

Under the terms of the agreement, San-doz will handle commercialization in Ger-many, the Netherlands and the UK, while

Shionogi will remain responsible for de-velopment and manufacturing. No further details of the deal were disclosed.

At around the same time as unveiling the Sandoz deal in Europe, Shionogi li-censed full US commercial rights to nalde-medine 200 µg tablets to BioDelivery Sci-ences International. The FDA had in March 2017 approved the drug for treating OIC in adults under the brand name Symproic. Shionogi initially enlisted Purdue Pharma as its US marketing partner, but took back rights midway through last year.


“Our purpose at Sandoz is to pioneer access by focusing increasingly

on differentiated, value-added therapeutics that can make a real

difference when it comes to meeting unmet

medical needs”


P O L I C Y & R E G U L AT I O N

EU Industry To Politicians: Deliver On Equitable AccessAIDAN FRY [email protected]

Ensuring equitable access to medi-cines across Europe, upholding robust and responsive regulatory

frameworks, creating leadership in man-ufacturing and empowering the health-care community must be priorities for Eu-ropean politicians and policymakers over the coming months and years, European off-patent industry group Medicines for Europe is insisting.

Unveiling its ‘Together for Health’ manifesto for pharmaceutical policy ahead of European Parliament elec-tions set to take place at the end of May, Medicines for Europe called for a partnership with the EU to “deliver on the promise of generic, biosimilar and value-added medicines”.

The ‘Together for Health’ policy vision and accompanying campaign is built around four pillars:

1. Equitable access to medicines for all patients in Europe

2. A responsible industry in a respon-sive regulatory framework

3. Leadership in medicines manu-facturing

4. Empowering the healthcare com-munity by improving existing ther-apeutic options

On equitable access, the manifesto observes that patients’ recourse to treatments currently depends on the wealth of the country or region in which they live, thereby undermining public health “at a time of growing chronic dis-ease rates”.

In a bid to improve this situation, Medi-cines for Europe is asking the EU to rec-ognize that generic, biosimilar and value-added medicines are “the biggest drivers in enhancing equitable access across the EU” and to promote the removal of all barriers to competition in the off-patent sector. In particular, the industry asso-ciation wants to see EU policymakers “encourage the development of com-petitive, yet sustainable, market policies, rather than applying cost-containment measures” that threaten the long-term sustainability of the industry.

REGULATORY FRAMEWORK IN EU IS FRAGMENTED

For the second pillar, Medicines for Europe is pledging to “address concerns over the environment and anti-microbial resistance (AMR)”, as well as to “engage in construc-tive dialogue with regulators” to make a fragmented regulatory environment more

efficient. In return, it is calling on the EU to “assess the coherence and fitness for pur-pose of the current regulatory framework to ensure patient access to generic, bio-similar and value-added medicines”.

In particular, the association is seeking measures to optimize R&D and to tailor regulatory processes to the needs of the off-patent sector. As part of this, it wants EU policymakers to support moves to-wards global regulatory harmonization, especially in backing “a single develop-ment program and single data package” to be submitted to regulators worldwide, thereby reducing “unnecessary and un-ethical duplication of tests and trials”.

The manifesto’s third pillar focuses on delivering jobs and economic growth in the EU by promoting a leading position for local manufacturers.

“Our industry supplies close to 70% of Europe’s dispensed medicines through over 400 factories located across the con-tinent,” Medicines for Europe points out.

To a considerable extent, EU politicians and the Commission have already gone a considerable way towards Medicines for Europe’s demand that they “boost Europe-an industry and create a level playing field between EU and non-EU companies” by tackling current EU laws and regulations that “force manufacturers to delocalize”.

A waiver that permits EU-based pro-ducers to manufacture for export, as well as to stockpile for an EU launch up to six months ahead, during the term of an originator’s supplementary protection certificate (SPC) looks likely to come into effect from 1 July, although it may take until 2022 for the commercial impact of the provision to show.

While Medicines for Europe has misgiv-ings about some elements of the waiver, particularly around requirements to reveal commercially sensitive and confidential in-formation to SPCs holders, the association has hailed a compromise deal struck by EU authorities in mid-February as contributing “to better patient access, to creating manu-facturing opportunity and to increasing Eu-rope’s capacity to manufacture and supply its own medicines”.

“Our industry supplies close to 70% of Europe’s dispensed medicines through over 400 factories located across the continent”


P O L I C Y & R E G U L AT I O N / B I O S I M I L A R S

INDUSTRIAL STRATEGY SHOULD SUPPORT MANUFACTURING JOBS

In its manifesto, the industry body ap-peals for “an ambitious industrial strate-gy” to help secure drug supplies and calls on the authorities to “create incentives for the manufacturing of essential medi-cines, ensuring security of supply and re-ducing the risk of shortages”.

If they take steps to build on EU in-dustry’s technological and development heritage, Medicines for Europe says its members – which directly employ around 190,000 people – will reciprocate by “scal-ing up our manufacturing investment by investing in R&D and creating more high-skilled jobs for Europeans”. Member com-panies will also “develop more complex medicines in Europe to meet the health-care needs of our communities”.

Adding value by improving existing therapies that can empower the health-care community is central to the mani-festo’s fourth pillar.

To support industry’s plans to invest in new indications for existing therapies, as well as in technologies that can address unmet patient needs, while partnering with other healthcare stakeholders on digitalization, the manifesto makes sev-eral suggestions.

Broadly, it wants policymakers to en-courage European member states to “in-tegrate and recognize” off-patent drugs, such as value-added medicines, in their healthcare policies, thereby support-ing timely access and sustainability of health systems.

More specifically, Medicines for Eu-rope calls on the EU to “promote modern and efficient digitalization and develop-ment of health telematic systems” that will improve connectivity in healthcare communities and empower patients in a meaningful way.

Commenting on the manifesto launch, Medicines for Europe’s director general, Adrian van den Hoven, stated: “The EU elections are an opportunity to improve healthcare across Europe. The EU can do more to ensure equitable access to medi-cines for patients for all Europeans. Our industry is ready to engage with the EU, national governments and stakeholders to make this happen.”


Coherus Reveals Sales Have Started Piling In On PegfilgrastimAIDAN FRY [email protected]

C oherus BioSciences Inc. ex-pects to report net sales of its Udenyca (pegfilgrastim-cbqv)

biosimilar of $36.0-38.0 million in its first three months on the US market. The US-based biosimilars developer launched the rival to Amgen’s Neulas-ta neutropenia treatment on 3 Janu-ary this year into clinics as well as hospitals that do and do not participate in the federal 340B drug-pricing program.

Noting that it intended to release its full financial results for the first quarter of 2019 on 9 May, Coherus said it would reveal details of top-line gross sales, as well as discounts granted to arrive at the net figure, in its quarterly 10-Q filing with the US Securities and Exchange Commission.

Investors appeared to be pleasantly surprised by Coherus’ announcement on 5 April. The company’s share price on the Nasdaq stock exchange rose by about 3.5% to $14.49.

By setting an initial list price of $4,175 per Udenyca 6mg/0.6ml pre-filled syringe, Coherus matched the first biosimilar entrant, Mylan’s Fulphila (pegfilgrastim-jmdb), in offering a 33% discount to the wholesale acquisition cost (WAC) of the reference brand, Amgen’s Neulasta.

But Coherus insisted it was taking “a very different approach” to Mylan by formulating a commercial approach that mirrored that for a branded injectable drug. This included reaching a deal with insurance giant Anthem.

Having struck a 340B contract with hospital outpatient specialist Apexus, Coherus in mid-March announced that it had received transitional pass-through status from the Centers for Medicare and Medicaid Services, effective for 36 months from 1 April.

PASS-THROUGH STATUS CONFERS REIMBURSEMENT BOOSTUnder this program, reimbursement for Udenyca in the 340B hospital outpatient setting will be calculated at the biosimilar’s WAC list price, plus 6%. Once the CMS establishes an average sales price (ASP) for Udenyca, reimbursement will be based on Udenyca’s ASP plus 6% of the ASP for Neulasta. Amgen’s reference brand is currently reimbursed at its ASP less 22.5%.

Udenyca entered the US market around six months after Mylan had led the way with the Fulphila biosimilar it co-developed with India’s Biocon. By early November last year, Mylan said Fulphila had captured an 8% share of the pre-filled syringe market. And by the time the company reported its 2018 annual results at the end of February this year, that share had almost doubled to 15%.

Highlighting the “comprehensive patient resources” including a call center and co-pay assistance program that Mylan had put in place to support the “successful launch”, chief commercial officer Tony Mauro told investors the company had been “very selec-tive on the customers who we went after”.

The ability of both Coherus and Mylan to capture share may also give cause for hope among the biosimilar developers looking to follow in their footsteps. Sandoz recently resubmitted its pegfilgrastim dossier to the Food and Drug Administration, including new data from a pivotal pharmacokinetics (PK) and pharmacodynamics (PD) study.

Apotex announced at the end of 2014 that the FDA had accepted for filing its biosimi-lar application for pegfilgrastim. However, the agency has not to date approved that candidate that Apotex jointly developed with India’s Intas.



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