biosimilares state of art

8/10/2019 Biosimilares State of Art

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CLINICAL PHARMACOLOGY & THERAPEUTICS| VOLUME 91 NUMBER 3| MARCH 2012 405

nature publishing group STATE ART

Te term biosimilar has been used loosely to describe anyollow-on biologic drug whose target is the same as that oan originator biologic drug. It includes ollow-on biologicsthat are not comparable to the originator drugs, having beendeveloped or markets that are not highly regulated. Te cor-

rect use o biosimilar is with reerence to biologics that havebeen approved in highly regulated markets such as Europe andthat meet strict criteria o quality and comparability to theirrespective originator biologics. One o the concerns expressedwith respect to biosimilars is that the savings in costs not bereflected as losses in the quality, saety, or efficacy o these criticaland ofen liesaving medicines. However, the experience withrigorously evaluated and approved biosimilars in Europe hasdemonstrated that savings as well as improvement in access canbe achieved without compromising patient outcomes. Tis isachieved by applying consistent and appropriate science-basedregulatory standards to biosimilars in the same manner as theyare applied to originator biologics. Te United States can nowbenefit rom the European experience, given the concordantregulatory approaches o the two key authoritiesthe EuropeanMedicines Agency (EMA) in Europe and the Food and DrugAdministration (FDA) in the United Statesalready in placeor the regulation o originator biologics.

Te FDA has had limited authority to review and approvebiosimilars, and this has led to delays in the availability o theseagents in the United States. Tis situation changed with the

passage o health-care-reorm legislation in March 2010,1whenthe FDA was given explicit authority to review and approvebiosimilars. Tis authority included consideration o publicinormation on a previously approved biologic as a critical ele-ment in the approval o a biosimilar, provided the biosimilar

is considered highly similar to the original reerence drug.Tere are differences in the approval processes or biosimilarsand generic drugs because separate statutes govern the reerenceproducts; most biologics are licensed under the Public HealthServices Act2whereas all drugs are approved under the Food,Drug, and Cosmetic Act.3

In this article, we discuss the progress made in Europe withbiosimilars, rom a regulatory perspective as well rom the view-point o patients needs. We also examine to what extent thisexperience may accelerate the FDAs efforts to address the issueso access and affordability or the US population. Biosimilarsdraw on scientific principles that have been used by industryand regulators or decades. Because o alterations to the ear-lier manuacturing process or biologics, ew, i any, originatorbiologic therapeutics are identical to the products originallylaunched years or decades ago.4,5Tereore, the experience andexpertise o all stakeholders in dealing with such manuacturingchanges can be used to create, evaluate, and commercialize high-quality biosimilars in a cost-effective manner or US patients.Tis should happen as soon as possible because patient accessto these therapeutics is an unmet need.6

1Global Biopharmaceutical Development, Sandoz International, Holzkirchen, Germany; 2Avalere Health, Washington, DC, USA. Correspondence: Gillian Woollett

([email protected])

Received 12 October 2011; accepted 30 November 2011; advance online publication 8 February 2012. doi:10.1038/clpt.2011.343

The State of the Art in the Development ofBiosimilarsMark McCamish1and Gillian Woollett2

The development of biologic therapeutics using advanced technology to copy and improve on natures design of

complex peptides, proteins, and glycoproteins has enabled the treatment of diseases in entirely new ways and brought

unique and lifesaving treatments to many people. However, at least in part because of cost pressures, access to these

truly amazing products has not been uniformly available; many patients do not qualify for these treatments, or the

treatment is postponed until disabilities accumulate. The development of biosimilarsessentially copies of the originalbiologic drugs after patent expirationallows for wider and, as important, earlier access to these agents because of

their lower cost and consequently greater affordability. The development and commercialization of biosimilars can help

address unmet medical needs by improving access to well-established therapeutic interventions while improving health-

care affordability.

Open
mailto:[email protected]://www.nature.com/doifinder/10.1038/clpt.2011.343http://www.nature.com/doifinder/10.1038/clpt.2011.343http://www.nature.com/doifinder/10.1038/clpt.2011.343mailto:[email protected]


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STATE ARTSTATE ART

ALL BIOSIMILARS ARE BIOLOGICS AND WILL FOLLOW THE

ORIGINATOR PIPELINE

First and oremost, a biosimilar is a biologic, which is a medicinederived rom a living system. Biologics may be either sourcedrom nature or produced using recombinant techniques. Teyare increasingly well characterized, including their proposed

mechanism o action. Approximately 30% o the industrysresearch and development outlay is dedicated to the develop-ment o biologics. Consequently, an increasing proportion onewly developed medicines are biologics, and, o these, a steadilyrising proportion consists o recombinant products (also ofencalled biotech or genetically engineered).7

Te recombinant products are most likely to become the initialcandidates or biosimilars in the United States, as has occurred inEurope. Tey vary rom simple replacement hormones to largecomplex molecules with extensive posttranslational modifica-tions, such as monoclonal antibodies (mAbs). Te first approvedbiotech products contained the smaller peptides and were madein bacterial systems (ergo nonglycosylated); these led to some

o the first biosimilars. As or generic drugs, the pipeline orbiosimilars will match, broadly speaking, that or the respectiveoriginator products, except that there will be a delay o at least12 years to allow or the exclusivity period dictated by law (theBiologics Price Competition and Innovation Act (BPCIA)) andprovisions o the Patient Protection and Affordable Care Actenacted in March 2010).1

Sponsors o biosimilars are also likely to pay particular atten-tion to biologics that have been most successul commercially.8Tese may include products that have added major indications,even i initially approved as orphan products (epoetins), thosethat are essential or prolonging lie even though they are used

by very ew patients (the replacement proteins or rare diseases),or products that have disparate indications but affect large num-bers o patients (such as antitumor necrosis actor biologics ortreatment o autoimmune disease).

Access to biologics can be dramatically improved throughthe development o biosimilars, provided such development isappropriately incentivized and the products can be manuac-tured and licensed cost-effectively. Many candidate reerenceproducts or biosimilars; patents are expiring and the pool ooriginator candidates is expanding.9Consequently, there is acompelling unmet medical need as well as an economic driveror competitionhence the inclusion o provisions with respectto biosimilars in the US health-care-reorm legislation o 2010.1Whether biosimilars will become a reality in the United Statesjust as they have in the rest o the world depends to a significantdegree on how the FDA approaches review and approval o theseproducts as well as whether appropriate incentives or payersand health-care personnel will be put in place.

THE FDA HAS EXPERTISE IN EVALUATING MANUFACTURING

CHANGES IN BIOLOGICS AND EXPERIENCE COMPARING

BIOLOGICS FROM DIFFERENT SOURCES

Te ollowing examples demonstrate that the FDA already hasextensive experience with two groups o products, and that thisexperience is directly applicable to the approval o biosimilars.

Some biologics are regulated as drugs under the FD&C Act

Te FDA has approved a ew biologics through new drug appli-cations (NDAs) under the FD&C Act, and copies o these drugscan ollow a generic pathway. Te so-called originator biologicdugs provide interesting examples o the agencys scientific rea-soning when approving copies o the originator drugs, and this

logic is applicable to their review o biosimilars.In 1984, with the enactment o the HatchWaxman Act, theregulatory pathways 505(j) (also called abbreviated new drugapplications (ANDAs) or generics) and 505(b)(2) were created.Te ANDAs are approved with the same label and as ully sub-stitutable products (A-rated and so listed by the FDA in theOrange Book).10Products approved under 505(b)(2) may ormay not be labeled as substitutable and may have only a subset othe indications o their reerence product (however, more indi-cations can be added at any time, using a supplemental NDA).

Te FDA has approved three ollow-on biologic drugs asANDAs11and eight ollow-on biologic drugs in the 505(b)(2) category12,13under the FD&C Act. Te approval o these

products (see Table 1) became possible because the FDA hadapproved several originator products that are biologics o the505(b)(1) category o NDAs under the FD&C Act. For theANDAs as well as or the 505(b)(2) approvals, the sponsor othe copy product relied on prior findings o saety and efficacyo the reerence product that were in the public domain. Teseare illustrations o the scientific approach that the FDA uses toconclude that sameness exists between two products. In nocase does the FDA reveal the actual data o the originator appli-cation to the subsequent sponsor; indeed, this is not requiredbecause the sponsors o the generic products must use their owntools or analytical characterization o both originator and copy

products so as to provide convincing proo o sameness.Although the demonstration o sameness is a requirement or

such applications, they are not required toand generally do notattempt todemonstrate a priorithe saety and efficacy o theactive moiety in the product because this has previously beendemonstrated with respect to the original product application.Indeed, or an ANDA, clinical data cannot be included in theapplication (beyond bioequivalence data, which is justified aslimited confirmatory testing).14

he approval o Sandozs Enoxaparin in June 2010 andAmphastars Enoxaparin in September 2011, both as ANDAs,illustrates the scientific approach that the FDA employed in itsevaluation. Enoxaparin is a complex biologic product with thesource material harvested rom porcine intestines; it comprisesa complex mixture o polysaccharides. Te drug was originallyapproved or treating and preventing various complex throm-boembolic events. he ANDA applications were approvedby demonstrating the sameness o the generic vis--vistheoriginator (fingerprinting, as the FDA recently described it)15without any clinical trials. Tis approval provides evidence othe FDAs confidence in the value o chemical and biological ana-lytical inormation; indeed, the FDA provided detailed scientific

justification or its rejection o the reerence product sponsorscitizen petition.16Briefly, the FDA developed five criteria to carryout scientific evaluation o the sameness o generic enoxaparin


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and Lovenox, the reerence product: (i) the physical and chemi-cal characteristics, (ii) the nature o the source material and the

method used to split the polysaccharide chains, (iii) the natureand arrangement o components that constitute enoxaparin, (iv)laboratory measurements o anticoagulant activity, and (v) cer-tain ex vivoaspects o the drugs effects on humans. Te approvalprocess or enoxaparin is important because the hierarchy oreasoning that the FDA used in that case, being undamentallygrounded in science, can be applied to any biologic product.

A second example is the approval o Omnitrope (somatro-pin), the only product approved as a biosimilar in Europe thathas also been approved in the United States. Te approvals inboth jurisdictions, and also in Australia, occurred in the springo 2006. Tis was prior to the enactment o the Biologics PriceCompetition and Innovation Act (BPCIA), but even now the lawdoes not allow biosimilar applications with respect to biologicsthat have been approved as NDAs (this is set to change afer23 March 2020). In the United States, the reerence product,Genotropin, was approved under the FD&C Act as a 505(b)(1)NDA in 1995, and Sandoz chose to file as a 505(b)(2) applica-tion to provide the FDA with all the supporting clinical datathat the company had collected as part o the development oOmnitrope as the first biosimilar in Europe. In evaluating theproduct or approval, the FDA used the highly similar stand-ard o comparability17indeed, the term highly similar is used28 times in the FDAs rejection o the three citizen petitions romBIO, Pfizer (the reerence product sponsor), and Genentech

that were submitted immediately prior to the US approval oOmnitrope.

Fundamentally, the approval o these products relied on thesame concept that was established or comparability in the FDAs1996 guidance.18Later this evolved to become a tripartite guide-line, International Conerence on Harmonisation (ICH) Q5E,or use in Europe, Japan, and the United States; this became thebasis or the EU biosimilars pathway.

Biologics subjected to manufacturing changes using a

comparability protocol

Sponsors routinely change the manuacturing process or bio-logics or a variety o reasons, including scaling up the processto deal with commercial demand, improving the efficiency o theprocess, and modernizing the process when major equipmentneeds to be replaced or updated. Te concept o comparabil-ity allows manuacturing changes to occur without having toundertake a completely new product-development program.

Comparability protocols were developed in the United States,through guidance, as a mechanism to provide input to theFDA as well as assurance to the sponsor that, should there be amanuacturing change, the FDA could determine whether thepre- and postchange products were sufficiently similar (highlysimilar, as described in the BPCIA) or the purposes o ongo-ing marketing under the same label. It was clear that the moreextensive the manuacturing changes were, the greater the likeli-hood o changes in product attributes, and, thereore, the more

Table 1 Biologic drugs already approved by the FDA for which a previously approved reference product is cited as an integral part of

their dossier

Brand name Generic name

Regulatory

pathway

Date of FDA

approval Sponsor

Reference product (sponsor, date of original

approval)

Naturallysourcedproducts

Repronex Menotropins ANDA 10 January 1997 Lederle/Ferring Pergonal (Serono, 22 August 1975)

EnoxaparinSodium

Enoxaparin ANDA 23 June 2010 Sandoz (Momenta) Lovenox (Sanofi-Aventis, 29 March 1993)

EnoxaparinSodium

Enoxaparin ANDA 19 September2011

Amphastar Pharma Lovenox (Sanofi-Aventis, 29 March 1993)

Naturallysourcedproducts

Repronex Menotropins 505(b)(2) 27 August 1999 Ferring Pergonal (Serono, 22 August 1975)

Vitrase Hyaluronidase 505(b)(2) 5 May 2004 Ista Pharms Wydase (Baxter, 22 March 1950)

Amphadase Hyaluronidase 505(b)(2) 26 October 2004 Amphastar Wydase (Baxter, 22 March 1950)

Hydase Hyaluronidase 505(b)(2) 25 October 2005 Primapharm Wydase (Baxter, 22 March 1950)

Recombinantproducts

Glucagen Glucagonhydrochloride

recombinant

505(b)(2) 22 June 1998 Novo Nordisk Glucagon (Lilly, 14 November 1960)

Fortical Calcitonin salmonrecombinant

505(b)(2) 12 August 2005 Upsher Smith Miacalcin (Novartis, 17 August 1995)

Hylenex Hyaluronidaserecombinanthuman

505(b)(2) 2 December 2005 Haloz yme Wydase (Baxter, 22 March 1950)

Omnitrope Somatropin 505(b)(2) 30 May 2006 Sandoz/Novartis Genotropin (Pharmacia and Upjohn, 24 August 1995)

Three ANDAs and eight 505(b)(2) category products have been approved by the FDA.

ANDA, abbreviated new drug application; FDA, US Food and Drug Administration.


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data the agency was likely to require to ensure that the resultingproducts had highly similar quality attributes (see the 1996 FDAComparability Guidance, background section).18Tis regula-tory initiative evolved to become the basis or ICH Q5E, adoptedin the highly regulated markets in the mid-2000s,19and it hasshown ew, i any, instances o ailure.5,20

Fundamentally, comparability relies on the data relating tothe original (prechange) biologic product that established,a priori, its saety, purity, and potency. he FDA, JapansPharmaceuticals and Medical Devices Agency, and the EMArely on these data plus the results o the evaluation o changesin quality attributes o the new product (afer the change inmanuacturing method) to make a scientific judgment onwhether the new product is highly similar to the original oneand can be used by physicians and patients under the samelabel. Tis bridge between the old product and the new oneis built, in the vast majority o cases, using analytical dataalone,21that is, by establishing highly similar quality attributesand bioanalytical sameness. In some cases, analytical data

alone may be insufficient as the basis or judging whether theattributes o the two products are sufficiently similar. In suchcases, preclinical or clinical data may be required.22Althoughbiosimilarity evaluation may represent an extreme orm o acomparability exercise, the scientific concept involved is iden-ticalnamely, that o building a bridge o evidence betweentwo biological products without undertaking a complete newproduct-development program. Indeed, some o the instanceso establishing comparability have included those or whichno clinical studies at all were conducted, even with the prod-uct that was first marketed.23Te FDAs ability and discretionin making these judgments is based on a scientifically rigorous

process. Te FDAs authority to use the comparability processhas been upheld by the courts.24

Comparability goes urther than merely illustrating the prin-ciple o bridging between different biologics as a scientific exer-cise. Because biologics ofen have a shel lie o just 12 years,the original product could be on the market simultaneously withthe newer one. Te pharmacist, clinician, payer, and patientdo not know which o the two products is being dispensed atany given time point (the products have identical labels andpackaging, and the only difference is the batch number, whichdoes not in itsel indicate that a manuacturing change hasoccurred). Tereore, these products are interchangeable, andextrapolation between all indications always occurs irrespectiveo whether the mechanism o action is known. Te FDA, unlikethe EMA, does not publicly note the use o comparability in theregulatory record (in the United States there is no public regu-latory determination o comparability equivalent to the EUsEuropean Public Assessment Report).25In the United States,thereore, patients and their providers may never know that amanuacturing change has occurred, let alone the extent o thechange. Nonetheless, the prechange and postchange productscan be assumed to be equally sae, pure, and potent, based onthe FDA review o the analytical data (or any requested pre-clinical or clinical studies)26that supported the comparabilitydetermination.

It is air to conclude not only that the use o biosimilars iseasible but also that most, i not all, o the issues concern-ing their regulation lie within the FDAs current expertiseand experience; no new regulatory or scientific conceptsare needed, given that the regulatory principles establishedor comparability are also the ones used or biosimilarity. In

effect, thereore, the FDAs experience with comparability opast and current biologic products and biologic drugs regu-lated as NDAs and ANDAs can be applied to the evaluationo biosimilarsespecially given the act that these previouslyapproved products are also the reerence products or thebiosimilars. Furthermore, the European experience, includingpublicly developed and in-use guidelines, can expedite theormalization o a US approach to the review and approvalo biosimilars. Finally, harmonization across the highly regu-lated markets o the regulation o the originator biologicsshould help to ensure that the FDAs regulatory decisionsregarding biosimilars are consistent with those o the EMAand relevant agencies in Japan, Australia, Canada, and other

countries.

THE US REGULATORY PATHWAYS CREATED BY THE BPCIA

In March 2010,27as part o health-care reorm, the USCongress enacted the BPCIA. Te legislation gives the FDAthe authority to approve any biologic or which the reerenceproduct is a previously licensed biologic (i.e., one alreadyapproved through the stand-alone biologics license appli-cation (BLA) or 351(a) pathway). Te BPCIA offered 12 yearso exclusivity to biologics28; thereore, by law, the FDA can-not approve a biosimilar until 12 years afer approval o thereerence product.

Te 351(k) pathway enables the approval o biosimilarsand also allows the FDA to designate the biosimilar as inter-changeable with its reerence product (legally defined as beingthe same as substitutable). Tis latter eature is unique to theUnited States. Te European law is silent on interchangeabilitybecause o jurisdictional issuesit is the health authority ineach EU country that makes decisions concerning the practiceo medicine, not the central regulatory approval authority. TeEU standard or biosimilarity, however, is explicitly defined ascomparability.

Te FDA held a public meeting in November 2010 to discussits new statutory authority and to obtain input rom a broadgroup o stakeholders. Presentations made at this meeting andsubmissions to the relevant docket are available.29A secondpublic process initiated by the FDA ocused on the user eesthat the BPCIA authorized the FDA to collect in order to helpderay the costs o the agencys review and approval o biosimilarapplications.30Te FDA continues to conduct ormal, sponsor-initiated, product-specific meetings because the pathway createdby the BPCIA became available or use on the day o enactment.No regulations are required, and no guidances need be pub-lished by the FDA beore it accepts, reviews and/or approvesbiosimilar submissions. Te FDA has stated that it planned toissue guidances beore the end o 2011, but the scope o theseguidances is not yet public.


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THE SCIENTIFIC DEMONSTRATION OF BIOSIMILARITY

STARTS WITH DEMONSTRATION OF COMPARABILITY

Although much rhetoric has surrounded the definition o abiosimilar, and terminology varies by jurisdiction, the termalways reers to a biologic product that is comparable (EU) orhighly similar (United States) to a previously approved bio-

logic.

31

Te sponsor o the biosimilar is thereore correlatingthe attributes o the product to the quality, saety, and efficacy(Europe) or saety, purity, and potency (United States) o thepreviously approved product. Te sponsor must thereore firstdemonstrate that its product is comparable/biosimilar to theearlier one; equally important, once biocomparability is estab-lished, the sponsor must demonstrate that there is no need to re-establish the saety and efficacy o the active ingredient(s). In theUnited States, a biosimilar will be reviewed under section 351(k)o the Public Health Services Act, and thereore applications orbiosimilars are also called (k) applications. A ull stand-alonebiologics license application is submitted under a 351(a) BLA.

Posttranslational modifications, such as glycosylation, are not

controlled by the recombinant DNA inserted into the host cellthat is making the biologic. Te host cell used and the environ-ment in which the host cell is grown impact these modifica-tions. Tereore, changes in the manuacturing process, whetherinvolving scaling up o a process or the original product orcreating a biosimilar, will create slight changes in the structureo the resulting biomolecules through altered posttranslationalmodifications. It is these modifications that lead to the termbiosimilar, rather than biogeneric or bioidentical. Also,with Europe having established the term similar biologicalmedicinal products and its reduction in common usage tobiosimilar, it was logical to codiy the biosimilar terminology

in the US statute itsel.Products that are not subjected to this rigorous comparison

are not biosimilars. Some regulators, especially in emergingmarkets, have approved subsequent versions o popular biotechproducts, but in many cases these are independently approved.Although they ulfill local regulatory requirements and areappropriate or use in these markets to meet patients needs,they are ofen not based on a rigorous demonstration o compa-rability to a highly regulated reerence product. Such productsare termed noncomparable or alternative biologics, and theirproduct attributes should not be used to impugn biosimilarsapproved or use in the highly regulated markets.

Demonstrating biosimilarity: the nuts and bolts of sound

development methods for biosimilars

Biosimilarity is defined by the law in each country. However,the scientific concepts supporting a determination o biosimi-larity or high similarity are universal in highly regulated mar-kets and have been used or decades to enable changes to bemade in the manuacturing processes or originator biologics.In Europe this link is explicit, and biosimilar products are calledcomparable to the relevant reerence product. In the UnitedStates, the BPCIA1statutory term used instead o comparableis highly similar. However, comparability is defined in ICHQ5E19(the guidance dealing with manuacturing changes) as

highly similar quality attributes, and this guidance alreadyapplies in the United States to all biologics, whether they areregulated under the Public Health Services Act or under theFD&C Act. Whether one uses the term comparable or highlysimilar, evaluation o the product rom scientific and regulatoryviewpoints is identical.

o establish biosimilarity, the sponsor must show that the candi-date product is highly similar to the originator (reerence) productat the analytical level, including structural characteristics as well asbiological unctions. For the purpose o establishing a baseline, thesponsor must perorm a detailed analysis o the originator reer-ence product, using a variety o orthogonal analytical techniquesthat measure multiple attributes in multiple ways. Tese data arethen used to create the boundaries, or goalposts, o acceptableeatures or the biosimilar. Te originator product will have var-ied over its lietime, and thereore multiple batches o originatorproduct must be acquired, and analysis should occur across theshel lie o each batch. Batch-to-batch variability in the reer-ence product is ofen minimal, but, larger variations can be ound

afer manuacturing changes (which in Europe can be linked tocomparability through a public disclosure in the European PublicAssessment Report). Importantly, because both pre- and post-change products have already been in use in patients, the range ovariation between them with respect to product attributes is pre-sumed to be acceptable to regulators4and judged as not impactingsaety, purity, or potency. All pre- and postchange products areused interchangeably, and both can be on the market at the sametime; thereore, several switches can and do occur between theseproducts during the course o a treatment regimen.5

Indeed, as revealed in Figure 1, a specific product attributewas very consistent across two ormulations o the product

(lyophilized and liquid) in both European and US marketsuntil a sudden shif (via a change in the manuacturing proc-ess) resulted in a decrease in enrichment rom ~50 to 30%.Te EU- and US-labeled products displayed the exact samechange, and the two orms (lyophilized and liquid orms) ineach o these regions exactly mirrored these changes, therebyindicating the comparability o the final dosage orms in thetwo markets.

Analytical methods are sensitive to differentiate between

Analytical methods can

determine whether batches

sourced in different countries

are identical or not

Batch to batch

Batches before and after a change of the manufacturing process

Batches from different sites

Microheterogeneity of protein structure

Purity profilesGlycan distribution

Enbrel(entanercept) batches -G2F amounts% G2F

60

50

40

30

20

10

0

01.200

7

02.200

8

03.200

9

05.201

0

06.201

1

Expiration date

US LyoUs Liq

EU Lyo

EU Liq

Manufacturing

process

change

Figure 1 Variability seen in Enbrel as documented in ref. 4 across various

regions (United States and European Union) and across product forms

(lyophilized and liquid).


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Several points can be made rom this inormation: Over the multiyear time period of product characterization,

there was no perceptible drif in the product attributethe percentage enrichment o this glycosylation species wasvery stable until the manuacturing change took place

Because both products were concurrently on the market

with the same label, they would be considered clinicallycomparable, delivering the same efficacy and having thesame saety profiles

A biosimilar product with this specic product attributewithin this enrichment pattern would be considered highlysimilar

It was possible to determine that the EU and US productswere comparable

Afer determining the goalposts or allowable product-attribute variation or the originator reerence product,32thesponsor will then utilize a complex iterative process to createa biologic product that would be considered highly similar to

the originator product. Te additional challenge o making theposttranslational modifications overlapping with the origina-tor product requires greater time and resources than creating

an original biologic that does not require matching productattributes. Figure 2(lower lef panel) depicts a clone-selectionprocess that is dependent on analytical and unctional charac-terizationin this case, evaluating ucosylation o the result-ant antibody to antibody-dependent cellular cytotoxicity. Tepanel on the right depicts adjustments in bioreactor conditions

to achieve specific posttranslational modification patterns.Ultimately, the analytical parameters that will orm the basisor the development o the biosimilar are chosen and the biosim-ilar can be developed iteratively to fit those specifications. Temeasure o the match can include unctional as well as analyticalattributes, as shown in Figure 1. Note that, depending on theassay system chosen, reverse engineering can use a unctionalassay as part o the early screening.

Once the biosimilar candidates product attributes are withinthe goal posts, the sponsor can conclude that their candidate ishighly similar to its reerence originator product. Any param-eter or the biosimilar that is outside the goalpost o the reer-ence product must be demonstrated to have no impact on the

clinical attributes o the final product.Once the analytic data demonstrate comparability with the

originator reerence product, the sponsors will then determine,

0

700

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A

DCC(%o

freference)

2 4 6 8

bG0-F (rel. %)Range of originator on

market too narrow to

deduce structure/function

relationship

Variability observed duringcell line development

enables elucidation of

quantitative structure/

function-relationship

Charge variants are typical product-related variants for

monoclonal antibodies (mAbs):

Acidic variants (e.g., deamidation of asparagine)

Basic variants (e.g., amidation of proline)

Pyroglutamate/glutamine at N-terminus

Lysine variants at C-terminus

Monoclonal antibody fragments

Charge variants can be adjusted in the bioreactor by

optimization of

Process parameters

Media components

10

8

6

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0

Qualityattribute(%)

Parentalcell linepools

Clonescell linepool A

Clonescell linepool A

Clonescell linepool B

Final clonecell linepool B

Screening of bioreactorconditions

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0Ch

angevariant(%)

7.2 7.0 6.8

Targeting a charge variant via pHin bioreactor

Targeting a charge variant via media

components in bioreactor

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Targetrange

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Chargevariant(%)

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Figure 2 The iterative process development for reverse-engineering the biosimilar candidate product. ADCC, antibody-dependent cellular cytotoxicity.


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along with the regulatory authorities, the preclinical and clinicalstudies necessary to confirm biosimilarity. In highly regulatedmarkets, it is assumed that clinical data will be a prerequisiteor obtaining approval or biosimilars. Such clinical trials willgenerally include PK/pharmacodynamic studies to demonstratebioequivalence, and phase III trials confirming biosimilarity,

ofen using equivalence trial designs. Te extent o comparabilityo the proposed biosimilar to the originator dictates the extento the clinical trials required; highly similar product attributeswould justiy a tailored or abbreviated clinical trial program.

Once the ull package o data proving biosimilarity is submit-ted and confirmed (overlapping product attributes, comparableCMC inormation on drug substance and drug product, bio-assays confirming binding and biological unction, preclinicaltoxicology, and comparable phase I and phase III trials), jus-tification o extrapolation to other indications is considered.Usually, the phase III trial is conducted in the most relevantand ofen the most sensitiveindication so that differences, iany, between the originator and the biosimilar can be deter-

mined. I no differences are documented and biosimilarity isconfirmed, extrapolation to other indications that appear inthe originator product label can be justified. Ofen this requiresdemonstration o shared mechanisms o action in these otherindications. As with variations in product attributes afer majormanuacturing changes, scientific justification is the benchmarkor acceptance o comparability.

Although an initial application in the United States or abiosimilar can be or an interchangeable product, it is expectedthat most sponsors will seek to establish biosimilarity first andthen supplement their dossier with additional data to supportinterchangeability.

How does analytic similarity translate into successful

biosimilar product development?

Although conceptually comparability and biosimilarity are basedon the same scientific principles, these need to be translated intoa product-development approach that is undamentally differentrom those o either originator biopharmaceuticals or genericdrugs, but containing essential elements rom each.

Analytic development generates the hypothesis that the re-erence product and the biosimilar are indeed comparable andbioanalytically similar. Overall, biosimilarity is then confirmedby specifically tailored or abbreviated preclinical and clinicalstudies. Te extent o this abbreviation is at the center o thedebate in the United States with respect to biosimilar productdevelopment, given that all the stakeholders generally accept thatthese studies are rarely necessary or originator biologics that aremaking a manuacturing change (and in act in the past havebeen required by the FDA in ewer than 12% o such cases).33I a scientifically acceptable approach is taken to show that thebiosimilar is as close to the originator product as the originatorproduct is to itsel (allowing or manuacturing changerelatedvariability), an abbreviated clinical trial program is easily justi-fied. Incurring the costs o a ull development program, includ-ing ull clinical trials and the extensive technical developmentactivities required to produce the biosimilar product, is not a

viable approach to commercialization o less expensive biologictherapies. Tis is where the tradeoff becomes essential or spon-sors o biosimilars; i sponsors cannot expect a very real andsignificant regulatory relie with regard to the requirements oranimal and clinical studies, the pathway reaches an impasse. Iunknown (unmeasured) attributes o pre- and postchange prod-

ucts can be assumed to be the same, an equitable applicationo scientific regulatory standards should suggest that unknown(unmeasured) attributes o a biosimilar under development can-not automatically be assumed to be different. In other words, ithe same regulatory standard is applied in two situations, thesame set o assumptions as to what is known/unknown shouldbe made in both cases, purely on the basis o the data.

THE SANDOZ MODEL FOR BIOSIMILAR PRODUCT

DEVELOPMENT

It is conceivable to have more than one model or biosimilardevelopment, and indeed biosimilar sponsors should be encour-aged to develop whichever science-based and data-supported

models they wish, given that the responsibility o demonstrat-ing biosimilarity will be on them, just as the responsibility todemonstrate saety, purity, and potency lies with the origina-tor sponsor. In Europe, sponsors have taken entirely differentapproaches, resulting in very different regulatory dossiers.34Inthis article, we describe a model, developed by Sandoz, that hasresulted in a series o biosimilar products obtaining marketingapproval around the world, including in all the highly regulatedmarkets (even in the United States, albeit through the serendip-ity that resulted in some biologic products being regulated viaentirely different pathways, namely Omnitrope (somatropin)and Enoxaparin). It is a robust model, and the demonstration o

comparability/biosimilarity is ar rom trivial because it includesthe need to iterate analytical and biologic characterization withmodifications in process development to achieve highly simi-lar product attributes.35A key question, thereore, is whetherthe FDA will implement the BPCIA-enabled 351(k) biosimilarpathways in a manner that allows or a meticulously developedbiosimilar such as this to receive permission or appropriatelyabbreviated clinical trials and be commercially viable in the USmarket.

Te Sandoz model o biosimilar product development out-lined here is undamentally based on creating biosimilars thatmatch the product attributes o the originator product througha complex and resource-intensive process. Te key is that over-lapping and highly similar product attributes oster the bestpatient care, and this justifies an abbreviated clinical develop-ment program. Tis approach has resulted in the approval andsuccessul use by patients o a number o products, each withunique aspects, including glycosylated and naturally sourcedproducts. An overview o our development approach is shownin Figure 3, emphasizing a two-step approach: demonstratinganalytic and unctional similarity (the lef side o the figure) ol-lowed by confirmation o clinical biosimilarity (the right side othe figure). Te extent o clinical trials required to confirm ordemonstrate biosimilarity depends on negotiations with regu-latory authorities and will be based on their evaluation o the


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chemical and biological comparability o the biosimilar to therelevant originator product.

Figure 4shows an example o the biosimilarity process orcommercial granulocyte colony-stimulating actor, or filgras-tim. It is a nonglycosylated peptide, which makes it one o theeasiest biologics to re-create. Te first step in the process wasto demonstrate chemical and biological comparability to the

originator. Figure 4documents overlapping peptide map-ping, higher-order structures, and binding comparing multiplebatches o the biosimilar with the originator product. Althoughit is impossible to produce a bioidentical glycosylated protein,it is possible to document a bioidentical drug substance whendealing with a peptide. In this case, even a bioidentical drugsubstance must be placed in a drug product ormulation, andthis must be documented as being equivalent through a ormalPK study.

Figure 5shows an example o head-to-head PK/pharmacody-namic studies conducted with Zarzio (filgrastim) rom Sandoz.Te curves representing the originator and the biosimilar are di-ficult to portray because the concordance between the data is soclose, thereby ormally demonstrating bioequivalence o the twodrug products. Tis was accepted by the EMA as demonstrationo comparable products, thereby allowing or an abbreviatedormal clinical trial program. Te products were considered sosimilar that a saety exposure study designed as a single-arm,open-label study was sufficient to confirm biosimilarity.

What is not depicted in this figure was the challenge aced indocumenting bioequivalence with this product with regard toanalytic characterization. For example, given the act that Sandozreezes its filgrastim drug, there are ewer oxidized and deami-dated variants as compared with Neupogen. I total filgrastimis measured using high-perormance liquid chromatography

(HPLC) to separate these variants rom the nonmodified prod-uct, one is likely to underestimate total filgrastim and variantfilgrastim during a PK study. In this case, concentration o fil-grastim in the blood is determined using enzyme-linked immu-nosorbent assay, which does not differentiate between filgrastimand its variants. Tereore, i treatment regimens are determinedbased on the HPLC content o filgrastim, bioequivalence will not

be achieved. Consequently, i the phase I study is conducted withequal concentrations o the product as determined by HPLC,bioequivalence will not be confirmed because o the higher pro-portion o filgrastim and filgrastim variants in the originatorproduct. Tis illustrates how important it is or the sponsor oa biosimilar to have a complete understanding regarding thecharacterization o the originator product so that the appropri-ate tests are used and the clinical trials are designed correctly.

POTENTIAL US REGULATORY INTERACTIONS

Once initial development has been achieved, and assuming thatpreclinical and clinical studies are anticipated, it is likely that thesponsor o a biosimilar will open an investigational new drugapplication (IND) with the FDA (this is not inevitable, but highlylikely initially as the 351(k) pathway becomes established). Anopen IND provides a protected space (trade secret and businessconfidentiality) in which sponsors and the FDA reviewers canshare and discuss data and work together to agree on the natureand extent o subsequent preclinical and clinical studies thatmay be required in support o a biosimilar (and interchangeablebiosimilar) application, just as or any other biologic.

Te specific nature o the meetings that will be available to US351(k) applicants orm part o the biosimilar user negotiations.Most important will be the opportunity to gain the regulatoryagencys concurrence o biosimilarity or the candidate substance

Develop highly similar product

Initial similarity

Confirm biosimilarity

Analysis referenceAnalysis reference

Cell lineDrug substance

pilot scaleDrug substance

final scale

Formulation/drug product

In vitro/in vivomodels

DS/DP

validation

GLP tox.

Phase I Phase II

Analytical

toolbox

Pilot scale DS

Goal posts

Confirm similarity

Final scale DS

Final formulation

In vitro/in vivo data

Final biosimilarity

Validated DS

Validated DP

Figure 3 An overview of the Sandoz biosimilar development approach.


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manuactured on a pilot scale (to be confirmed with ull-scaledata afer filing). It is this confidence in biosimilarity, as shownanalytically, that orms the basis or the case or regulatory relieregarding preclinical and clinical studies, mirroring the demon-stration o comparability beore and afer changes in the manu-acturing process o a biologic substance. Te absence o relevantanalytical differences and the expectation o applicability o the

351(k) biosimilars pathway to regulatory approval are essentialor going orward with the development o a biosimilar. Tegoal is to have regulatory reviewers affirm that the candidatedrug substance is highly similar to the originator product. Wepreer to show regulators that our biosimilar drug substance isas similar to the reerence product as that reerence product isto itsel over its lietime.

06

02+03 0704

(2.2)012 09+010 011

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Bioactivitysurface plasmon resonance spectroscopy

Higher order structureUV CD spectroscopy

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icity(mdcg/((g/l)cm))

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800 1,000 1,200 1,400

Comparability performed for EUbiosimilar applications showedhighly similar results with state ofthe art methods for the twofilgrastims Neupogen and Zarzio

Figure 4 Biosimilar filgrastim compared to reference product (Neupogen) using three state-of-the-art analytical techniques.

40

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99.68 (96.95102.47)

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Dose: 10 g/kg SC for 7 days

CD34+count = surrogate marker for efficacy in stem cell mobilization

Curves for both ANC and CD34+cells superimposable for Zarzioand Neupogen

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neutrophil count (ANC)

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/l)

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Figure 5 Pharmacokinetics (left) and pharmacodynamics (right) for both Zarzio and Neupogen.


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I such agreement can be achieved, then all subsequent pre-clinical and clinical studies are designed only to confirm thebiosimilarity that has already been achieved in producing ahighly similar drug substance. In Europe, the reciprocal exchangeo inormation between sponsor and regulator was invaluable orthe regulatory authorities to learn how and under what circum-

stances sponsors make critical go/no-go investment decisionsand or sponsors to understand the major concerns o regulatorsin approving biosimilars. Indeed, the give and take o the scien-tific advice process in Europe became the basis or the drafingo the individual, product-specific guidelines. Guidelines werenot always developed beore the first biosimilar was approved,but in all cases their development was concurrent.36

It is presumed by most stakeholders that biosimilars willalways be subjected to head-to-head preclinical and clinicalstudies prior to approval, although the European Union ismoving away rom this assumption or preclinical animalstudies, as illustrated by its Draf Biosimilar mAbs Guideline,37and the FDA acknowledged the thoughtulness o this guide-

line in a paper in the New England Journal of Medicine.38Indeed, as more experience is gained by both industry andregulators, we can expect a greater confidence in the abilityo different sponsors to make highly similar products usingboth the same standard o comparability and the same datarequirements as those currently applied to manuacturingchanges. In Europe, we have seen this progression in regulatorconfidence, and it has allowed reaffirmation o science-basedconsistency in standards being applied to all biologics. Tistrend, in and o itsel, has great value to patients and theirhealth-care providers.

Also, given the differences in the statutes governing the EMA

and the FDA, the latter has unique additional opportunities todesignate products as interchangeable (substitutable), therebyorming an interesting link to comparability approaches. In theUnited States, afer a manuacturing process change, a productcannot be other than interchangeable, comarketing o pre- andpostchange products is possible, and treatment regimens areswitched between the two products without either the patient orthe health-care provider being aware o the switch. For biosimi-lars, however, a sponsor must demonstrate biosimilarity, affirmthe expectation o identical clinical results or the two productsin any given patient, and show that efficacy or saety are notdiminished by the switch.

Immunogenicity is important or all biologics and is there-ore not a unique issue or biosimilars (and is already a con-sideration in ICH Q5E). o date, there has been no report oa biosimilar on the market being associated with any unusualor unexpected adverse events as compared with the relevantreerence product. Nonetheless, the BPCIA contains an explicitmention o immunogenicity and the need or sponsors to assessit in a clinical study unless this requirement is waived by theFDA. Te imposition o a similar requirement or demonstratingcomparability would be air but unortunate. In act, it would begenerally regarded by most stakeholders as being scientificallyunnecessary. Europe has meanwhile revised its immunogenicityguidelines, and they apply to all biologics.39,40

In Europe, as in the United States, biosimilars must undergopharmacovigilance and postmarketing studies like any otherapproved medicinal product.

THE EUROPEAN EXPERIENCE HAS BEEN SUCCESSFUL AND

HAS BENEFITED PATIENTS

Europe has a vibrant and commercially successul, yet still-emerging, biosimilars market under the progressive but cau-tious oversight o the EMA. Although each o the 27 countriesin the EU has its own health authority, there is generally anincreasing amiliarity with biosimilars, starting rom the firstapproved biosimilar product, Omnitrope (somatropin) in 2006.Tis has led to greater acceptance and quicker uptake or epoet-ins andeven more soor filgrastims.41In Europe, there seemto be ewer and ewer apprehensions among consumers aboutany premise o ineriority o biosimilars. In act, the EuropeanCommission (EC) has actively countered the misinormationpropagated by some sponsors o originator products who sug-gested that biosimilars were less sae than the originator prod-

uctsa suggestion that implicates the regulator along with thesponsor o the biosimilar.

Given the common approaches to the development o origi-nator products in highly regulated markets (as exemplified bythe ICH), there arises a undamental question: how much o thebiosimilar wheel needs be reinvented in the United States?Tis is the challenge, because the FDA led with the basic con-cept o comparability promulgated by guidance alone in 1996.Te FDA continues to be ahead in its regulation o Enoxaparinas a generic biologic (in the European Union, low-molecular-weight heparins are considered biosimilars); this example showsthat, when making a science-based decision, the FDA can and

does act confidently. No unusual or unexpected adverse eventshave been seen with products approved as biologic drugs inthe United States on the basis o abbreviated data packages (seeTable 1).

In Europe, general and class-specific guidelines were writtenconcurrently with the development o the first biosimilar can-didates, and that experience should be relevant in the UnitedStates too.35In the European Union, biosimilars o somatro-pin, epoetin, and filgrastim have been approved, and there havebeen no unusual or unexpected clinical events with any o thebiosimilars in any o the highly regulated markets. In each case,the sponsor o the biosimilar selected a development approachand negotiated with the EMA separately or review and approval,as is done or any originator biologic. Te studies conducted orthese biosimilar products varied greatly, even when the reer-ence product was identical. Given that the investment in clinicalstudies is a significant component o the development costs oany medicinal product, sponsors need to propose a careullytargeted clinical approach.

An additional hurdle to a global development approach isthe act that regulatory authorities preer that the compara-tor product be one that is labeled or that regulatory region;that is, US-labeled comparator products are to be used or USapplications and EU-labeled ones are to be used or EU appli-cations. Tis requirement would essentially double the cost


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burden in the development o a global biosimilar. In this mat-ter, too, the scientific basis o comparability should be kept inmind. As demonstrated in Figure 6, it is possible to confirmthe comparability o EU and US reerence products; given sucha confirmation, a global clinical development program can beperormed with a single comparator reerence product. In the

absence o this approach, to what extent will the EU-approvedbiosimilars, with their compelling pre- and postmarketing datasets demonstrating comparability, need to be redeveloped orthe United States? Will the FDA demand that entirely new clini-cal studies be conducted with US-labeled reerence products?Such a requirement would not be scientifically justifiable, butsome would interpret it as being legally necessary. Nonetheless,

in the absence o scientific justification, the repetition o animaland clinical studies could be considered unethical (apart rombeing prohibitively expensive). It would be unortunate i a situ-ation arises in which the EU biosimilars could be imported orpersonal use in the United States,42whereas the BPCIA is inter-preted in such a manner as to prevent them rom being reviewed

and approved by the FDA or general use.As an illustration o how critical this could be or patients, wediscuss the example o filgrastim below. When filgrastim wasapproved as a biosimilar in Europe, the United Kingdom, usingtender pricing, allowed physicians to prescribe it as recommendedin clinical guidelines as primary prophylaxis against ebrile neu-tropenia. Previously, because o pricing issues, patients were ofengiven this product only afer ebrile neutropenia had developed.Figure 7reveals how overall usage o the product increased dra-matically consequent to improved access and more appropriateuse or primary prophylaxis. Tis example emphasizes the impor-tance o access. Te economic efficiencies associated with biosimi-lars are desperately needed in the United States as well.

Te BPCIA was enacted as part o health-care reorm on 23March 2010, in part because o the expectations o savings to theUS Medicare and Medicaid programs. It contains no require-ment that the FDA issue any regulations or guidance beoreapproving biosimilars. However, the FDA has yet to receive anyapplications under 351(k).43

Te FDA recognizes that its authority to approve biosimilarscame late in the day, and that it would thereore be receivingapplications or products already approved in other highlyregulated markets such as the European Union, Australia,Japan, and Canada. Tis also means that the FDA must addressthe issue o biosimilars that have been developed using a or-

eign reerence product. However, given that all regions wantto address unmet patient access needs through biosimilars,regulators are evaluating various ways to consider inorma-tion generated with comparator products that have not beenapproved in their region.44Te FDA has explicitly stated thatit is interested in access to the inormation involving oreigncomparator products but, surprisingly, only in the context ostand-alone BLAs under 351(a).

Clinicaltrials

PK/PD

Preclinical

Biological

characterization

Physicochemical

characterization

Analytics

Process

development

Desig

nspecifi

catio

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Figure 6 Development of a biosimilar is founded on state-of-the-art

analytics. Quality cannot be tested into a product subsequently and must be

established initially. The fundamental premise of development of a biosimilar

is therefore the establishment of comparability (European Union)/high

similarity (United States) based on analytics. This can take multiple iterations

in early-stage development and takes more time that would normally be

required of an originator product this early in development. This process

is followed by preclinical and clinical trials appropriate to document full

biosimilarity on all levels.

UK filgrastim volume growthpercent change vs. previous year

November 2008

biosimilarapproved

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5

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17

Many physicians moved

filgrastim back to 1st-line cancer treatmentdue to lower biosimilars cost

G-CSF prevents hospital readmission

due to infection Biosimilars are less expensive than

originator biologics

Zarzio patient support kits

expand patient access:

Patients self administer at home

Efficiency savings repatriated

2007 2008 2009 2010

Note: Zarzio (filgrastim) is not marketed in the United States.

Figure 7 Example of a change in the practice of medicine enabled through the affordability created by entry of biosimilar granulocyte colony-stimulating factor

into an originator-only marketplace. Data from IMS, National Health Service, UK.


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CONCLUSIONS

We expect that biosimilars will be approved in the United Statesas they have been in Europe. However, these products may beapproved as stand-alone 351(a) BLAs or through the new 351(k)pathway depending on the sponsors choice. Indeed, Sandozalready has direct experience o the differing approaches o the

EMA and the FDA. Te first biosimilar approved in Europe,Omnitrope (somatropin), was approved in the United States as a505(b)(2) new drug application. Also, the low-molecular-weightheparin Enoxaparin has been approved in the United States asa ully substitutable ANDA, whereas in Europe low-molecular-weight heparins are considered biosimilars.

Biosimilar products have already brought benefit to patientsin Europe and elsewhere through lower acquisition costs, andthe contrast has been sufficient to produce improvement in thepractice o medicine. Making these sae and effective medicinesavailable will also improve access to them in the United States.Various commercial models will be used to accomplish this, butregulatory approval is the essential first step. Tis is achievable

scientifically and technically. Nonetheless, the FDA must catchup with other regulators or patients, insurers, payers, managed-care organizations, and the Centers or Medicare and MedicaidServices to ully benefit rom the development, approval, andcommercialization o these wonderul medicines.

CONFLICT OF INTEREST

M.M. is head of Global Biopharmaceutical Development at Sandoz

International. Sandoz is the leading sponsor of approved similar biological

medicinal products in Europe, with three products: somatropin, epoetin

alfa, and filgrastim. G.W. is vice president at Avalere Health and works with

multiple stakeholders in health care, including but not limited to biopharma

companies (originator and generic).

2012 American Society for Clinical Pharmacology and Therapeutics

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Commissioner, Chief Medical Officer Food and Drug Administration beforethe House Committee on Oversight and Government Reform, 26 March2007, and Question and Answer Session .22. Aranesp EPAR .

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30. FDA Biosimilars User Fee Federal Register Notice . Docket number FDA-2011-N-0326; Public Submissions: .

31. Novartis Submission to docket FDA-2010-N-0477 the November 2010 FDAPublic Meeting .
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32. McCamish, M. & Woolett, G. Worldwide experience with biosimilardevelopment. MAbs 3, 209217 (2011) .33. Follow-on Protein Products. Statement of Janet Woodcock, M.D., Deputy

Commissioner, Chief Medical Officer Food and Drug Administration beforethe House Committee on Oversight and Government Reform, 26 March 2007.

34. European Public Assessment Reports (EPARs) for Biosimilar Filgrastims..35. EMA Guidelines on Comparability/Biosimilarity .

36. EMA Guidelines for Similar Biological Medicinal Products .

37. EMA Guideline on Similar Biological Medicinal Products containingMonoclonal Antibodies .

38. Kozlowski, S., Woodcock, J., Midthun, K. & Sherman, R.B. Developing thenations biosimilars program.New Engl. J. Med. 365, 385388 (2011).

39. CHMP Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins, April 2008 .

40. EMA Guideline on Immunogenicity Assessment of Monoclonal AntibodiesIntended for In Vivo Clinical UseDraft .

41. EMA Product Specific Approval Documentation .42. FDA Information on Importation of Drugs Prepared by the Division of Import

Operations and Policy .

43. BioCentury Extra for Thursday, 2 June 2011. No FDA Biosimilars ApplicationsFiled .

44. Kozlowski, S. Presentation at DIA FDLI Biosimilars Meeting, Bethesda, MD, 45May 2011.

45. Patient Protection and Affordable Care Act (PPACA) .
http://www.landesbioscience.com/journals/mabs/article/15005/http://www.landesbioscience.com/journals/mabs/article/15005/http://www.fda.gov/NewsEvents/Testimony/ucm154070.htmhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdfhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124http://www.fda.gov/ForIndustry/ImportProgram/ImportPolicyandInformationbyProduct/default.htmhttp://www.fda.gov/ForIndustry/ImportProgram/ImportPolicyandInformationbyProduct/default.htmhttp://www.biocentury.com/dailynews/topstory/2011-06-02/no-fda-biosimilars-applications%20-filedhttp://www.biocentury.com/dailynews/topstory/2011-06-02/no-fda-biosimilars-applications%20-filedhttp://www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.%20pdfhttp://www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.%20pdfhttp://www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.%20pdfhttp://www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.%20pdfhttp://www.biocentury.com/dailynews/topstory/2011-06-02/no-fda-biosimilars-applications%20-filedhttp://www.biocentury.com/dailynews/topstory/2011-06-02/no-fda-biosimilars-applications%20-filedhttp://www.fda.gov/ForIndustry/ImportProgram/ImportPolicyandInformationbyProduct/default.htmhttp://www.fda.gov/ForIndustry/ImportProgram/ImportPolicyandInformationbyProduct/default.htmhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdfhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002958c&jsenabled=truehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.jsp&murl=menus/regulations/regulations.jsp&mid=%20WC0b01ac058002956b#%20Comparability%20Biosimilarityhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125http://www.fda.gov/NewsEvents/Testimony/ucm154070.htmhttp://www.landesbioscience.com/journals/mabs/article/15005/http://www.landesbioscience.com/journals/mabs/article/15005/

biosimilares state of art

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