biosimilares 2.0

8/10/2019 biosimilares 2.0

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mAbs 3:3, 318-325; May/June 2011; 2011 Landes Bioscience

POINTOFVIEW

318 mAbs Volume 3 Issue 3

Key words:biotechnology, biosimilars,generic drugs, monoclonal antibodies,pharmacodynamics, pharmacokinetics

Abbreviations:ADRs, adverse drug

reactions; EMA, European MedicinesAgency; hGH, human growth hormone;IgG, immunoglobulin G;PD, pharmacodynamics;PK, pharmacokinetics

Submitted: 03/24/11

Accepted: 03/24/11

DOI: 10.4161/mabs.3.3.15599

*Correspondence to: Geoffrey Eich;

Email: [email protected]

In the European Union, biosimilarproducts have been approved since2006 under an abbreviated pathway thatleverages their similarity to an exist-ing reference biological product. The

products approved to date are based onrecombinant versions of endogenous pro-teins with well-understood structuresand pharmacology, but complicatedsafety and immunogenicity profiles. Theperiod during the 2000s that includedthe first reviews, approvals, sale and useof biosimilars is referred to herein asBiosimilars 1.0. Over the next several

years, a new and advanced tranche ofbiosimilars will be developed for com-plex reference products, including medi-

cines used in the treatment of cancer andautoimmune diseases. A global marketfor biosimilars is developing and thismay well foreshadow the beginning ofthe second era of product development.This Biosimilars 2.0 period will likelybe characterized by the development ofcomplex products, global harmonizationof standards and the increasing demandfor long-term monitoring of pharmaceu-ticals. The products developed in thisperiod should exhibit high levels of fidel-ity to the reference products and should

be rigorously evaluated in analytical,non-clinical and clinical comparisons.

Additional ly, Biosimilars 2.0 manufac-turers should strive for transparency intheir labels and take proactive strides tobe accountable to providers and patientsfor the quality of their products. Animportant opportunity now exists forthe healthcare community, industryand regulators to work in partnership,to outline the appropriate standards for

Biosimilars 2.0Guiding principles for a global patients first standard

Joseph Miletich,1Geoffrey Eich,1,* Gustavo Grampp2and Barbara Mounho1

Amgen Inc. ; 1Thousand Oaks, CA USA; 2Longmont, CO USA

these products and to facilitate increasedaccess while meeting patients needs.

Introduction

Over the course of the past decade, theEuropean Commission and EuropeanMedicines Agency (EMA) establishedan abbreviated pathway for biologicmedicines, and this pathway was used tolaunch the first generation of similar bio-logical medicinal products, now widelyreferred to as biosimilars.1According toEMA guidelines, the pre-approval evalu-ation of these products required robust,side-by-side studies of the analytical,non-clinical and clinical similarity of the

biosimilar product to the reference prod-uct. The resulting biosimilarity exerciseadopted components of a comparabilityexercise while acknowledging data defi-ciencies that result from the reverse-engi-neering of a finished reference productand production in a discrete manufactur-ing process.2-6This early period, includingthe first reviews, approvals, sale and useis herein referred to as Biosimilars 1.0.Biosimilar 1.0 products were approved inthe European Union (EU) beginning in2006, and the products approved to date

are based on recombinant versions of nat-urally occurring hormones and cytokinesthat have well-understood structures andpharmacology, but complicated safety andimmunogenicity profiles.7 Many aspectsof the European biosimilar pathway havealso been adapted by policymakers aroundthe world.

In the next several years, a large num-ber of innovative biologic medicines willreach patent expiry.8Within this group are


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This, combined with the ability to studythe pharmacodynamics (PD) of theseproducts in rodents, has facilitated theassessment of their pharmacology in non-clinical studies.12-14 Robust and sensitiveendpoints of efficacy exist for Biosimilar1.0 products, which allows applicants to

effectively compare the biosimilar prod-ucts efficacy in abbreviated clinical trials.Furthermore, based on the known mecha-nisms of action and risk-benefit profilesin different patient populations, selec-tive extrapolation to additional approvedindications for the reference product wasapproved by EMA for Biosimilar 1.0products.6

Experience with Biosimilar 1.0 prod-ucts to date has been generally positiveand has served to both elevate the stat-ure of the European regulatory approach,

as well as to substantiate the potential ofbiosimilars in the market. However, someconcerns related to biosimilar product reg-ulation have arisen and been evaluated inthe European scientific community. Theseconcerns include the limits that currentlyexist on the ability to identify all criticalquality attributes or define the extent ofacceptable differences in comparison tothe reference product. This has resulted infailures on the part of some manufactur-ers to achieve comparable drug products

that show equivalence in dose, concen-tration or response in all of the referenceproducts routes of administration.15,16For example, unexpected differences wereobserved in exposure for one biosimilarfilgrastim product and in titrated dose forone biosimilar epoetin.16Although regu-lators determined that these differenceshad no affect on the overall conclusionson the safety or efficacy of these biosimi-lar products, the unexpected differencesdemonstrate that clinical studies are a crit-ical component of biosimilar evaluations

and can be sufficiently sensitive to detectdifferences in dose-concentration-effectbetween structurally related biologics.

Experience with several of the approvedbiosimilars has also reinforced that validconcerns remain about divergent immu-nogenicity profiles for similar biologics.One biosimilar product exhibited elevatedincidence of anti-product antibodies dur-ing clinical development. After identifi-cation this issue was resolved through a

the development and approval of medici-nal products claiming to be similar to anexisting or reference biological medi-cines product authorized in the EuropeanCommunity. The EU biosimilar pathwayis distinct from the rules governing theapproval of generic medicines. The bio-

similar pathway was framed to addressthe advances as well as the limitations ofmethods and techniques available todayfor the full characterization of such medic-inal products that include a recombinantprotein as the active substance.2,4

To date, 14 biosimilar marketingauthorizations have been granted: twohuman growth hormones, five erythropoi-etins (comprising two distinct products)and seven granulocyte-colony stimulatingfactors (comprising three distinct prod-ucts; Table 1). These 14 biosimilar prod-

ucts have seen varying degrees of uptake,depending on country and product class.9These factors have resulted in differinglevels of long-term safety and efficacy datain patients treated with biosimilars.

Biosimilar 1.0 products were, in manycases, developed by European biotech-nology companies (e.g., Hexal, Stada,Arzneimittel, Sicor, Pliva and Ratiopharm)before the European approval pathwaywas established.10 Once innovator pat-ents for products such as human growth

hormone, epoetin alfa and filgrastimapproached expiry, large generic firmsbegan to in-license biosimilar versions ofthese products or to acquire the compa-nies developing the biosimilars. Genericcompanies such as Sandoz, Teva andHospira entered the recombinant biotech-nology market during 20062008.11

The key features of Biosimilar 1.0products relate to the circumstances inwhich they came to market. They areprimarily European in origin, were devel-oped and evaluated under the EMA bio-

similar review process and were approvedfollowing innovator patent expiries. Theseproducts are exclusively marketed bygeneric drug companies (or generic divi-sions of pharmaceutical companies suchas Novartis) and are approaching three tofive years of clinical use in some countries.9

Biosimilar 1.0 products are struc-turally related to naturally occurringgrowth factor proteins and, overall, havewell-understood mechanisms of action.7

complex and advanced medicines used in awide range of therapeutic areas, includingthe treatment of cancer and autoimmunediseases, where they are often part of theexisting standard of care. These complexand multifunctional molecules, includingfusion proteins and monoclonal antibod-

ies (mAbs) with targeted and cytotoxicmechanisms of action, will form a sub-stantial portion of the new and advancedtranche of biosimilars.

Commensurate with the increasedcomplexity of the reference products,questions about the standards requiredfor demonstration of similarity andfidelity will emerge. Answers to thesequestions will likely be provided by anexpanding group of regulators, actingnationally or internationally and facili-tated by ever-increasing analytical, pro-

cess development and manufacturingcapabilities. In addition, a global marketspanning the International Conferenceon Harmonisation regions, as well as theemerging markets, is now developing. Thecombination of these factors may wellforetell the beginning of the secondera of biosimilars, referred to herein asBiosimilars 2.0. While the Biosimilar 1.0period was characterized by the definitionof the initial framework, the Biosimilar2.0 period will likely be marked by chal-

lenges in the manufacturing and clinicaldevelopment of complex products, globalharmonization of standards and theincreasing demand for long-term safetyand efficacy data for all pharmaceuticals.

In the past few years, global companieswith differing levels of skill, experienceand resource have begun to develop bio-similars of complex products. An impor-tant opportunity now exists for thehealthcare community, industry and reg-ulators to work in partnership to outlinethe scientifically appropriate standards

for these complex products to facilitateincreased access while meeting the increas-ingly discerning standards of regulators,physicians, payers and most importantly,patients.

Biosimilars 1.0

In the EU, biosimilar products have beenapproved since 2006 under a speciallyadapted pathway designed to abbreviate


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development, manufacturing and com-mercial capabilities to bear and it is likelythat both the strategies and products willreflect the diversity of the competitors.

As scientific teams consider oppor-tunities and strategies, some consistentthemes are emerging that allow contraststo be drawn between Biosimilars 1.0 and

the aspirations and anticipated challengesfor Biosimilars 2.0. These patient-focusedprinciples and scientific capabilities, ifreinforced by regulatory agencies, holdgreat promise for biotechnology andhealthcare.

Highly Similar

As manufacturers target more complexmolecules in the future, they will havethe means to achieve a higher standardof analytical similarity to their reference

products than was feasible in the past.Advances in protein engineering, under-standing of critical quality attributes andthe development of high-throughput,high-resolution technologies for screeningprocess conditions will enable Biosimilar2.0 manufacturers to achieve high similar-ity to complex reference products.

Increasingly, flexibility is discussedas a regulatory approach for biosimilars;however, alterations to host cell expression

opportunity and required remediationto meet the standards that all patientsdeserve. However, it is likely that the nextfew years will mark the beginning of newand different challenges for the healthcarecommunity and patients alike.

Biosimilars 2.0

In 2011, for the first time, the majorregions (e.g., EU, US, Japan, Canada)have pathways for biosimilar productapproval in place and many of the larg-est emerging markets (e.g., South Africa,Brazil, India) have either finalized or arein the process of crafting biosimilar guide-lines. Importantly, since 2010 the WorldHealth Organization has offered a final-ized guidance document on biosimilarapproval standards that is intended to beused as a basis for regulatory agencies to

set local requirements.19

For the first time,Biosimilars 2.0 manufacturers can nowdesign global development plans that takeinto account key regional guidance.

The challenge and opportunity of glob-ally marketed biosimilars have attractedthe attention of a range of innovativepharmaceutical and biotechnology com-panies in addition to the worlds genericdrug industry.8This broad range of manu-facturers will bring differing research and

manufacturing change.17 Another bio-similar product being studied in a post-marketing clinical trial was associatedwith cases of anti-product neutralizingantibodies in nephrology patients treatedusing the subcutaneous route of admin-istration.18 Although concerns aboutBiosimilar 1.0 products and more complex

products without an endogenous coun-terpart may well differ, regulators andbiologics manufacturers should considerthese examples when determining theappropriate balance between pre-approvaldata requirements and post-approvalmonitoring of the safety and efficacy ofBiosimilar 2.0 products. Immunogenicityremains a relatively difficult phenomenonto assess in non-clinical studies or abbre-viated clinical studies, so the importanceof assuring unique identification of a par-ticular marketed product in order to facili-

tate accurate attribution of adverse eventscannot be overstated.

Biosimilars 1.0 has served as an insight-ful pilot program in that it has con-firmed, in concept, that the developmentof biosimilar products is possible. Theexperience of implementing the Europeanbiosimilar pathway has informed physi-cians, regulators, legislators and industryabout the unique aspects of biotechnol-ogy medicines and highlighted areas of

Table 1.Biosimilar product marketing applications submitted to the European Medicines Agency

Trade name Generic/common name Owner of trade name Reference product Decision Decision date

Omnitrope somatropin Sandoz Genotropin Approved April 12, 2006

Valtropin somatropin BioPartners Humatrope Approved April 24, 2006

Alpheon interferon alfa-2a BioPartners Roferon-A Rejected June 28, 2006

Binocrit

Epoetin alpha Hexal

Abseamedepoetin alfa

Sandoz

Hexal

Medice

Eprex Approved Aug. 28, 2007

Retacrit

Silapoepoetin zeta

Hospira

StadaEprex Approved Dec. 18, 2007

Insulin Rapid Marvel soluble insulin Marvel Humulin Withdrawn Jan. 16, 2008

Insulin Long Marvel isophane insulin Marvel Humulin Withdrawn Jan. 16, 2008

Insulin 30/70 Marvel biphasic insulin Marvel Humulin Withdrawn Jan. 16, 2008

Tevagrastim

Ratiograstim

Filgrastim Ratiopharm

Biograstim

filgrastim

Teva

Ratiopharm

Ratiopharm

CT Arzneimittel

Neupogen Approved Sep. 18, 2008

Zarzio

Filgrastim Hexalfilgrastim

Sandoz

HexalNeupogen Approved Feb. 6, 2009

Nivestim filgrastim Hospira Neupogen Approved June 10, 2010

Note: Some products are marketed in different jurisdictions under different brand names. Data source: European Public Assessment Reports pub-

lished on European Medicines Agency website; www.ema.europa.eu/pdfs/human/press/pr/4031706en.pdf


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A sophisticated and comprehensiveanalytical comparison will increasinglybe reinforced with highly sensitive phar-macology and an informative PK equiva-lence evaluation en route to clinical trialsevaluating for the equivalent efficacy andnon-inferior safety of the biosimilar prod-

uct. Experience shows that some effectsof relevant differences in structure or for-mulation can be detected at early stageslike PK and hence, these results should beconsidered the first gate in a demonstra-tion of similarity or cause for remediationbefore evaluations of clinical performanceare initiated.29

A unique characteristic of Biosimilar2.0 products in comparison to theirBiosimilar 1.0 predecessors is that manyof these products will be mAbs, whichare structurally more complex and may

have more than one mechanism ofaction involved in their pharmacologi-cal effect through target-antigen bind-ing, Fc-effector function(s) or Fc-receptorbinding. Due to this structural and func-tional complexity, it is critical that anydifferences that exist between the variousstructural attributes of a biosimilar fusionmolecule or mAb and its reference productare evaluated in nonclinical in vitro or invivo pharmacology studies. Such studiesshould compare binding affinities to the

target and to Fc receptors, as well as tocomplement. They should also comparebiological activities mediated by targetbinding and any relevant immunochemi-cal functions such as antibody-dependentcell-mediated cytotoxicity and comple-ment dependent cytotoxicity.

A further challenge with some mAbtherapeutics is that there is no estab-lished in vivo pharmacology model otherthan non-human primates. Biosimilar2.0 manufacturers should evaluate the invivo toxicology of their products in pri-

mates, if necessary, prior to proceedingwith human clinical studies. Toxicologystudies are warranted because alterationsto various regions on some mAbs, includ-ing post-translational modifications, canaffect the safety profiles of these prod-ucts, resulting in off-target adverse effectsincluding thrombocytopenia and ane-mia associated with monocyte activationand phagocytosis (unpublished results)and thrombocytopenia associated with

Biosimilar 2.0 era address the complexoptimization problem.

A comparison between human growthhormone (hGH) and immunoglobulin(Ig) G highlights the difference in scaleand complexity of protein-based medi-cines. HGH has a single-chain primary

structure consisting of 191 amino acidswith two intramolecular disulfide bondsand no glycosylation.25 In comparison,IgG is a glycoprotein with a primary struc-ture consisting of two light chains andtwo heavy chains (approximately 220 and500 amino acids respectively dependingon subclass) that are bound by a complexand variable series of disulfide linkagesand electrostatic interactions both withinand between the four chains.26

The field of analytical technology isadvancing quickly, which will serve as both

an asset and liability to Biosimilar 2.0 man-ufacturers. The technology will reveal moreinformation about the reference product,but will commensurately show more differ-ences that exist in a biosimilar product dur-ing comparative analysis. More knowledge,however, is being generated and publishedabout the relevance of certain structuralvariants to the bioavailability, safety andefficacy of biologics, including mAbs.27,28This knowledge can be leveraged for aparticular biosimilar product to prioritize

development efforts towards those attri-butes that are likely to be critical to safetyand efficacy. Prior to conducting expensiveclinical studies, sponsors of Biosimilar 2.0products will likely demonstrate a robustknowledge of known critical quality attri-butes in order to prevent failed studies.

Holistically Evaluated

As with Biosimilars 1.0, manufacturersin the Biosimilar 2.0 era should convinc-ingly establish the existence of a highly

similar dose-concentration-effect of thebiosimilar to that of the reference prod-uct through a combination of non-clinicalstudies followed by PK, PD where applica-ble and clinical efficacy and safety studiesin patients. These principles for a holisticnon-clinical and clinical evaluation ofsimilarity of safety and efficacy are ar ticu-lated in the various guidelines for biosimi-lars that have been adopted by multipleregulatory authorities.19

systems, formulations and containers willintroduce new variables with the potentialto affect efficacy, safety and product stabil-ity. While Biosimilar 2.0 companies maypursue such strategies, development costsand risks will increase with each addi-tional variable introduced. Many com-

panies may seek approval of potentiallydifferentiated products through originalmarketing applications rather than as bio-similar products. Regulators will need todetermine which alterations are acceptablefor a product to qualify as a biosimilar.

At a minimum, biosimilar productsmust have identical primary structuresto their reference products and very closefidelity in post-translational modificationsthat could affect the safety or efficacy ofthe medicine. In contrast to generic drugsthat are required to have identical molecu-

lar structures to their reference products, asimilar biologic medicine may be permit-ted to have some differences in structuralvariants. For example, small differencesin the nature or distribution of glycosyl-ation structures or glycoforms may beacceptable, but in some cases differencesin such structures could affect a productsfunction or pharmacokinetics (PK).20,21Furthermore, structural variations notpresent in the reference product (e.g., dis-tinct post-translational modifications or

alterations that occur during purification,formulation, storage or shipping) mayhave a profound impact on the efficacy,safety or immunogenicity of biologics.22,23The relevance of these variations com-pared to the innovator product can onlybe confirmed in clinical studies.

A particular challenge for theBiosimilar 2.0 era will be the successfuldevelopment of biosimilar mAbs that canhave multiple structural variants influenc-ing their binding affinity, PK, stability andimmunochemical parameters.24This may

result in a greater number of critical struc-tural attributes compared with simplerprotein products and makes it more likelythat a manufacturer will have to accepttradeoffs in the degree of similarity ofsome attributes in order to assure similar-ity in others. Technology now allows highthroughput screening of cell lines and pro-cess variables. Coupled with high through-put analytics, these scientific advancescan help biosimilar manufacturers in the


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evaluated in a comparative study using sen-sitive patient populations. Biosimilar 2.0manufacturers should confirm the safetyprofile of the product with post-approvalmonitoring as a component of a robust riskmanagement plan.

Globally Developed

Given the new expansion of the biosimi-lar marketplace to include Canada, Japan,Australia, the United States and others,manufacturers in the Biosimilar 2.0 erawill likely seek harmonization of globalapproval requirements and will proposeglobal development programs, where sci-entifically justified by a consistent refer-ence product, to achieve developmentefficiencies and avoid duplicative clinicalstudies. Foreign clinical data often helps

assure that medicines are evaluated indiverse but representative patient popu-lations before approval. A unique chal-lenge, however, will be in how to definea global reference product and demon-strate that comparator products sourcedfrom various regions are suitable to repre-sent the reference product that a patient ina given region might receive.36

Because biologic products are sensi-tive to differences in cell lines, cultiva-tion, harvest, purification and packaging,

products manufactured and distributedin disparate regions can differ signifi-cantly or drift apart through manufactur-ing changes after once being comparableto each other.37Products that are sold byindependent manufacturers or that havedrifted from comparability can exhibitdifferences in key quality attributes,including the structural properties ofthe product. Additionally, differences inraw materials and manufacturing equip-ment will frequently exist. In some cases,there are differences in specifications and

methods for intermediate or final productevaluation, as well as formulation and fill-ing for varied product presentations. Ifmanufactured by different companies, theproduct and quality control standards willlikely differ.

Regulatory agencies will likely be cau-tious when accepting data from com-parative studies using foreign comparatorproducts as they may differ substantiallyfrom the locally approved reference

markers and the clinical response can behighly variable. Indeed, in these situationsthe challenge of demonstrating an equiva-lent clinical response of two similar prod-ucts may be more significant than that ofdemonstrating efficacy per se against aplacebo control.

To address these situations, the EMAdraft guideline for development of bio-similar mAbs issued in November 2010suggests selecting relatively homogenous,sensitive subpopulations for the compara-tive evaluations of clinical efficacy bio-similarity. Using this strategy, Biosimilar2.0 manufacturers should carefully selectsuch populations such that conclusions ofsimilarity in efficacy might be appropri-ately extrapolated to broader populationsor additional conditions of use. Sponsorswill need to consider, however, that while

a particular patient population may be themost sensitive for a comparative assess-ment of efficacy, a different populationmay be the most sensitive for an assess-ment of safety or immunogenicity.

Surrogate endpoints for clinical effi-cacy should only be considered whenthey provide a scientifically robust alter-native versus the standard efficacy mea-surement and where biosimilarity can bedemonstrated accurately. Biosimilar 2.0manufacturers should pursue appropri-

ate endpoints and proper assessments asopposed to using surrogate endpoints sim-ply as a trade off for lower developmenteffort. Biosimilars fulfill a valid need inthe healthcare system, but do not meetrequirements for accelerated approval.35

The final challenge in Biosimilar 2.0development will be to define the appro-priate safety and immunogenicity data setrequired prior to registration. Reliance onPD or surrogate endpoints in selected sub-populations for the efficacy component ofthe exercise would commensurately reduce

the nature and amount of clinical experi-ence. The extent to which a biosimilarproduct can rely on a prior finding of safetyand effectiveness should be dependenton the structural, functional and clinicalsimilarity to the reference product. TheBiosimilar 2.0 manufacturer will need todevelop additional clinical data supportingconditions of use where this reliance is notfully justified and where immunogenicityand other adverse drug reactions should be

platelet activation.30However, it may notbe ethical to perform a statistically pow-ered, comparative evaluation of PD innon-human primates if data derived fromthe study will not be material to the bio-similarity exercise. Therefore, the evalu-ation of functional similarity for such

products will rely to a greater extent on invitro studies and clinical studies. This isin contrast to the Biosimilar 1.0 productsfor which it was possible to compare PD instatistically powered rodent models priorto proceeding with clinical studies.

A demonstration of equivalent PK inhumans is normally a required componentof a biosimilar development program.Development programs for innovatorproducts, including mAbs, have revealedunexpected changes in PK following man-ufacturing process changes.31-33 Just as

these originator drug development find-ings have undermined early confidencein the ability to bridge to earlier findingsof safety, efficacy or appropriate dose, afinding of non-equivalent PK of a pur-ported biosimilar could give pause to fur-ther development of the biologic using anabbreviated pathway.

However, a combination of equivalentnon-clinical pharmacology and equivalenthuman PK is insufficient to infer similarefficacy and safety of biologics in humans.

To supplement this gap, PD markers,when validated and robust, will provideevidence of biosimilarity through pre-determined equivalence margins. Wherevalidated PD markers do not exist, clinicalefficacy studies are needed to confirm per-formance. In all cases, non-inferior safetyand immunogenicity should be demon-strated in patients before submission of anapplication to rule out major differencesand, like all biologic products, biosimilarsshould be evaluated in post-approval set-tings to confirm equivalent benefit-risk

profiles and to evaluate rates of serious butinfrequent adverse events.

The need to perform statistically sensi-tive comparisons of PK, PD or clinical out-comes poses challenges in circumstanceswhere there is a high level of variabilityin bio-absorption, elimination or PDresponse within and between subjects.29,34This will be the case for many Biosimilar2.0 products for inflammation or oncol-ogy wherein there may not be relevant PD


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prevalence or severity of ADRs. The mostcommon manifestation of this phenom-enon has been observed with unwantedimmunogenicity profiles that have differedsubstantially among closely related biolog-ics. For example, incidence of pure red cellaplasia in nephrology patients treated with

subcutaneous erythropoiesis stimulatingagents has varied over time and betweenmembers of the product class, presumablydue to process-specific factors.39Similarly,the incidences of neutralizing antibodiesin interferons diminished over time as aresult of changes in the manufacturingprocess and formulation.40It is the poten-tial for process-specific ADRs, in addi-tion to class effect ADRs that necessitatesenhanced accountability of innovatorcompanies and Biosimilar 2.0 manufac-turers once multiple versions of a biologic

are on the market.Given that differences between prod-

ucts can occur because the biosimilarand reference products are preparedunder different conditions such as dif-ferent manufacturing and formulationprocesses, Biosimilar 2.0 manufacturersshould seek unique brand and non-pro-prietary names for their products becausethese are the most common means for apatient or physician to accurately commu-nicate his or her experience to an account-

able manufacturer.

41,42

It is essential thatadverse events be linked to the associatedproduct and manufacturer; without such alink, unique ADRs or a disproportionateprevalence of ADRs for a given product,could be missed in the overall surveil-lance dataset or attributed to the wrongmanufacturer.

For product classes known to exhibitclinically-relevant unwanted immunoge-nicity, manufacturers of approved biolog-ics, including biosimilars, should makeavailable anti-drug antibody testing, in

accordance with regulatory requirementsof the country, so that doctors and patientscan make the right decisions about ongo-ing therapy. For example, loss of efficacyto anti-tumor necrosis factor biologics canbe attributed to either the underlying dis-ease or to the immunogenicity of a specificproduct.43Doctors and patients need theright information to determine whetherto switch to a structurally distinct mem-ber of the class or to a different therapy.43

be assured of providing a similar clinicaleffect at a given dose. Dose conversions oradjusted concentration or formulation tomatch the strength or potency of the refer-ence product should never be permitted.Each of these instances would be cause toterminate development or to remediate the

situation. Differences in strength pose aclear risk for medication errors and shouldnot occur in the Biosimilar 2.0 era.

Additionally, biosimilar sponsorsshould advocate transparency of data gen-erated with their product to both providersand patients. They will want both partiesto know the extent to which their prod-ucts have been evaluated clinically beforeapproval and in which indications. Unlikegeneric drugs that do not undergo clinicaltesting, medicines in the Biosimilar 2.0era will be evaluated clinically for both

efficacy and safety and manufacturers willopenly and accurately present this infor-mation in the product insert and label.

Ultimately, when payers, doctors andpatients decide among therapeuticallysimilar biologics, either a lack of clini-cal data or the existence of differences inproduct strength or potency should notconfound their decision.

Accountable

Biosimilar 2.0 manufacturers must alwaysbe accountable for the quality of theirproduct and should exhibit a patient-focused commitment to upholding thehighest standards. All biologics manu-facturers should stand behind their prod-ucts and should not adopt identificationmechanisms that risk confounding phar-macovigilance data with those of othermanufacturers. The accountable biosimi-lar sponsor should do whatever is neces-sary to allow reliable and rapid tracingof adverse drug reactions (ADRs) to the

actual biologic product, especially oncesingle-source manufacturing is no longeran aid to event attribution.

Biologics have a unique risk profilecompared with traditional pharmaceu-ticals in that ADRs can occur as a resultof the interaction of specific structuraldifferences with the physiology of indi-vidual patients. Because these structuralattributes can be process-specific, highlysimilar biologics could diverge in terms of

products in manufacturing, processingor evaluation.37 Subject to this need forcaution, in certain circumstances it maybe acceptable for regulatory agencies toaccept and review the comparative non-clinical and clinical data generated using areference product sourced in a region dif-

ferent from the one in which approval issought. First, biosimilar manufacturers inthe Biosimilar 2.0 era should not rely onany data relating to a foreign product thatis not manufactured by the same com-pany that holds the license in the regionfor which approval is sought. Additionally,Biosimilar 2.0 manufacturers should con-vincingly establish a scientific basis forrelying on tests with a foreign productand a lack of any relevant differencesbetween the comparator products. Whena global reference product is not avail-

able, Biosimilar 2.0 manufacturers shoulddevelop an original marketing applicationor perform additional clinical studies toensure that every patient, regardless ofregion, receives biosimilars that exhibit nodifferences in safety or efficacy from thatwhich they would experience with theirregional reference product.

Accurate and Transparent

Biosimilar 2.0 manufacturers must

develop products that are of the same dos-age form, for the same route of administra-tion and, most importantly, designed andformulated to achieve the same strength asthat of the reference product. With skillin the art, a Biosimilar 2.0 manufacturerwill know that the strength of a biologicmust be evaluated in both its concentra-tion (just as with a generic), but also inits potency. The challenge of achievingthis standard is illustrated by the fact thatnot only some follow-on biologics sold inemerging markets, but also some EU bio-

similars approved during the Biosimilar1.0 era have demonstrated differences instrength or potency relative to their ref-erence products even though they arelabeled with the same nominal strengthand dose.15,38

Biosimilar 2.0 manufacturers shouldensure that a quality biosimilar productexhibits the same concentration as andequivalent potency to, the reference prod-uct so that the biosimilar product can


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8. Lanthier M, Behrman R, Nardinelli C. Economicissues with follow-on protein products. Nat RevDrug Discov 2008; 7:733-7; PMID: 18654570;DOI:10.1038/nrd2636.

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K. Biosimilars: a marathon, not a sprint. Bain &Company Industry Brief 2009; December 16; www.bain.com/bainweb/publications/publications_detail.asp?id = 27518&menu_url=publications_results.asp

12. Committee for Medicinal Products for Human Use(CHMP), CHMP/94528/05, Annex to Guidelineon Similar Biological Medicinal Products containingBiotechnology-Derived Proteins as Active Substance:Non-Clinical and Clinical IssuesGuidance onSimilar Medicinal Products containing Somatropin,2006; www.ema.europa.eu/docs/en_GB/docu-ment_l ibrary/Sc ient i f ic_guidel ine/2009/09/

WC500003956.pdf

13. Committee for Medicinal Products for Human Use(CHMP), EMEA/CHMP/BMWP/301636/08,Guideline on non-clinical and clinical developmentof similar biological medicinal products containingrecombinant erythropoietins (Revision), 2010; www.

ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/04/WC500089474.pdf

14. Committee for Medicinal Products for Human Use(CHMP), CHMP/31329/05, Annex to Guidelineon Similar Biological Medicinal Products con-taining Biotechnology-Derived Proteins as ActiveSubstance: Non-Clinical and Clinical IssuesGuidance on Biosimilar Medicinal Products contain-ing Recombinant Granulocyte-Colony StimulatingFactor, 2006; www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/

WC500003955.pdf

15. Schellekens H. Assessing the bioequivalence of bio-similars: the Retacrit case. Drug Discov Today2009; 14:495-9; PMID: 19429509; DOI: 10.1016/j.drudis.2009.02.003.

16. Schellekens H, Moors E. Clinical comparability andEuropean biosimilar regulations. Nat Biotechnol2010; 28:28-31; PMID: 20062035; DOI: 10.1038/nbt0110-28.

17. US Food and Drug Administration. OmnitropeSummary Basis for Approval Medical Review 47:58-9 available at www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021426s000TOC.cfm

18. Schellekens H. Biosimilars: the long and windingroad to clinical equivalence. Hosp Pharm Europe2009; 47:40-2.

19. Mounho B, Phillips A, Holcombe K, Grampp G,Lubiniecki T, Mollerup I, et al. Global regulatorystandards for the approval of biosimilars. Food DrugLaw J 2010; 65:819-837.

20. Walsh G, Jefferis R. Post-translational modifica-tions in the context of therapeutic proteins. NatBiotechnol 2006; 24:1241-52; PMID: 17033665;DOI: 10.1038/nbt1252.

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22. Sauerborn M, Brinks V, Jiskoot W, Schellekens H.Immunological mechanism underlying the immuneresponse to recombinant human protein therapeu-tics. Trends Pharmacol Sci 2010; 31:53-9; PMID:19963283; DOI: 10.1016/j.tips.2009.11.001.

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Adv 2007; 25:325 -31; PMID : 17337334; DOI:10.1016/j.biotechadv.2007.01.007.

efficacy should only be considered whenthey provide a scientifically robust alter-native versus the standard efficacy mea-surement and where biosimilarity can bedemonstrated accurately; (4) It will be achallenge to demonstrate that comparatorproducts sourced from various regions are

suitable to represent the reference producta patient receives in a given region, butmay be justifiable if certain conditions aresatisfied; (5) A quality biosimilar productmust exhibit the same concentration asand equivalent potency to, the referenceproduct so that the biosimilar product canbe assured of providing a similar clinicaleffect at a given dose; (6) Biosimilar 2.0manufacturers should provide the neededclinical diagnostic support so that the doc-tor and patient can make the right deci-sions about ongoing therapy.

Biosimilar manufacturers in the 2.0 erashould embrace pharmacovigilance sys-tems and programs that will enable regu-lators and the public to have confidencein the risk-based extrapolation of productsafety. These attributes will bring choicesto patients, prescribers and payers in manymarkets without asking them to maketrade-offs between cost and the benefit-risk of a biologic.

References

1. Schellekens H. The first biosimilar Epoetin: but how

similar is it? Clin J Am Soc Nephrol 2008; 3:174-8;PMID: 18057303; DOI: 10.2215/CJN.04251007.

2. Commission Directive 2003/63/E C of June 25,2003, amending Directive 2001/83/EC of theEuropean Parliament and of the Council on thecommunity code relating to medicinal products forhuman use, OJ 46.

3. Council Directive 2004/27/EC of March 31, 2004,amending Directive 2001/83/EC on the Communitycode relating to medicinal products for human use,OJ 34.

4. Committee for Medicinal Products for Human Use(CHMP), CHMP/437/04, Guideline on SimilarBiological Medicinal Products, 2005; www.ema.e u r o p a . e u / d o c s / e n _ G B / d o c u m e n t _ l i b r a r y /Scientific_guideline/2009/09/WC500003517.pdf

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Use (CHMP), EMEA/CHMP/BWP/49348/2005,Guideline on Similar Biological Medicinal ProductsContaining Biotechnology-derived Proteins as ActiveSubstance: Quality Issues, 2006; www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf

6. Committee for Medicinal Products for HumanUse (CHMP), CHMP/42832/05, Guideline onSimilar Biological Medicinal Products containingBiotechnology-Derived Proteins as Active Substance:Non-Clinical and Clinical Issues, 2006; www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf

7. Schellekens H. Biosimilar therapeuticswhat do weneed to consider? NDT Plus 2009; 2:27-36; PMID:19461855; DOI:10.1093/ndtplus/sfn177.

If a disproportionate risk of immunoge-nicity is detected for a given marketed bio-logic via pharmacovigilance or antibodytesting data, this should be of concern to amanufacturer and to regulators since somepatients could be unnecessarily denied thebenefits of the therapeutic class.

Traceability of an adverse event tothe correct product is especially impor-tant because the effects of differences inquality attributes of biological productson their safety profiles are not completelyunderstood.41,44 Without traceability,adverse safety outcomes related to differ-ences in quality could go unrecognized orundetected, thus increasing the likelihoodthat emerging adverse events would notbe recognized as being uniquely relatedto a particular product. If the relationshipbetween a significant event and a particu-

lar product is unrecognized, appropriateclinical, manufacturing and, potentially,regulatory actions cannot be taken.

Conclusion

The Biosimilar 2.0 era can be charac-terized by high-quality products anddata-rich global development programs.Patients have a right to demand highlysimilar and holistically evaluated productsand the organizations, infrastructure and

expertise to meet these requirements effi-ciently and effectively now exist.Regulators and manufacturers will

learn from experiences of the Biosimilar1.0 product approvals and marketing todrive efficient and science-based compara-tive evaluations in the non-clinical andclinical settings. As the healthcare com-munity, industry and regulators considerappropriate standards for Biosimilar 2.0products, a few considerations stand out:(1) The evaluation of functional similarityfor some Biosimilar 2.0 products will rely

to a greater extent on in vitro studies andclinical efficacy studies given limitationsin animal testing of these complex mol-ecules; (2) Where there are no appropriateand validated PD markers and the clini-cal response can be highly variable, thechallenge of demonstrating an equivalentclinical response of two similar productsmay be higher than that of demonstrat-ing efficacy per se against a placebo con-trol; (3) Surrogate endpoints for clinical


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