Biosimilar Safety Considerations in Clinical Practice

Edwin Choya and Ira Allen Jacobsb

Biologics are important treatments for a number of cancers. Patents for several biologics will

expire over the next d

biosimilars. As biolog

multifaceted manufaccannot be considered

markets, biosimilars ca

original drug from anshown to have no clin

European Medicines A

the biosimilar infliximprovide context regard

delivery, as well as in

biosimilars. Pertinentcurrently in use also w

Semin Oncol 41:S3-S1

0093-7754/& 2014 Elshttp://dx.doi

This suppleConflicts oPfizer Inc fJacobs, MDwriting andby JennifeHealthcarehas the follfor Amgen

aDirector oMassach

bPfizer EmeGroup, N

Address coGeneralechoy@p

Seminars

ecade, removing a barrier to the development and commercialization of

ics differ from small-molecule drugs due to their size and complexity,

turing process, and their potential for immunogenicity, biosimilars“generic versions” of currently approved biologics. In highly regulated

n be authorized only if they are demonstrated to be highly similar to the

analytical and clinical perspective. Any differences must be justified andically meaningful effect on the safety and efficacy of the biosimilar. The

gency has approved a number of biosimilars and the recent approval of

ab monoclonal antibody is another regulatory milestone. This article willing key safety issues addressed in biosimilar development, approval, and

form oncologists on matters of safety to consider when prescribing

issues about safety from countries or regions where biosimilars areill be reviewed.

4 & 2014 Elsevier Inc. All rights reserved.

Biologic drugs, as opposed to small-molecule

drugs, are highly complex, large proteins thatrequire living reagents for production. Exam-

ples of biologics include blood products, vaccines,

recombinant proteins, gene therapies, and antibodies.They have advanced the treatment of many diseases

ranging from cancer and inflammatory diseases to

chronic lung disease such as cystic fibrosis. Severalnational and international oncology guidelines recom-

mend biologics as part of a first-line regimen.1 Based

on current trends in drug development, the use ofbiologics is expected to increase.1 Patents for several

- see front matterevier Inc. All rights reserved..org/10.1053/j.seminoncol.2013.12.001

ment was funded by Pfizer Inc.f interest: Edwin Choy, MD, PhD, was a paid consultant toor the research and/or authorship of this supplement. Ira A., MBA, FACS, is an employee of Pfizer Inc. Medicaleditorial support to prepare this supplement was providedr Ghith, MS, and Stephen Strudwick, PhD, of QDGroup and funded by Pfizer Inc. Edwin Choy, MD, PhD,owing additional conflict of interest to disclose: consultantInc.

f Sarcoma Research, Division of Hematology Oncology,usetts General Hospital, Boston, MA.rging Markets/Established Products Medicines Developmentew York, NY.

rrespondence to Edwin Choy, MD, PhD, MassachusettsHospital, 55 Fruit St, Boston, MA 02114. E-mail:artners.org.

in Oncology, Vol 41, No S1, February 2014, pp S3-S14

biologic drugs used in cancer treatment2 will expire

during the next decade (Table 1).The impending patent expirations will remove

a barrier to the commercialization of biosimilars.1,2 A

biosimilar is a biologic drug that is highly similar toan approved reference biologic (ie, the two drugs

usually have the same drug target, mechanism of

action, and primary structure among other molecularsimilarities).3 Biosimilars may help clinicians opti-

mize health outcomes by allowing patients increased

affordability and access to biologics.1

Several biosimilars including somatotropins, fil-

grastims, and epoetins have already been licensed

in the European Union (EU), where a biosimilarapproval pathway has been implemented since

2005.4 In the United States, the Biologics Price

Competition and Innovation (BPCI) Act of 2009was signed into law in 2010 as a component of the

Affordable Care Act, with the goal of allowing price

competition among biologics, thus potentially reduc-ing costs of therapy and increasing access to these

therapeutic agents.1 In February 2012, the US Food

and Drug Administration (FDA) issued three draftguidance documents for industry on biosimilars:

quality considerations, scientific considerations,

and questions and answers regarding implementa-tion of the BPCI Act of 2009.3,5,6

The objective of a biosimilar development program

is to manufacture a product that is highly similarto the reference product via a reverse engineering

S3

Table 1. Estimated Patent Expiration Datesfor Selected Biologic Drugs

Expiration DateBiologic US EU

Adalimumab 2016 2018Bevacizumab 2019 2022Cetuximab 2016 2014Darbepoetin alfa 2024 2016Etanercept 2028 2015Filgrastim 2013 ExpiredInfliximab 2018 2015Interferon beta-1a 2015 2015Palivizumab 2015 2015Pegfilgrastim 2015 2017Rituximab 2016 2013Trastuzumab 2019 2014*

⁎ In the United Kingdom. Expiration in other major Europeanmarkets will follow in 2015.

EU provides 10 years of data exclusivity, United Statesprovides 12 years of exclusivity.Abbreviation: EU, European Union.Data from Generics and Biosimilars Initiative Online.2

E. Choy and I.A. JacobsS4

approach, such that the resulting product not only

has a similar primary amino acid sequence but also

retains post-translational modifications that are assimilar as feasible.7,8 This is notwithstanding any

minor differences and/or clinically inactive compo-

nents, and with no demonstrated clinically mean-ingful differences between the biosimilar and its

reference biologic product in terms of safety, purity,

and potency.3 The foundation of biosimilar develop-ment is extensive structural and functional character-

ization and comparison of a biosimilar to its reference

product.4 Ultimately, the FDA and European Medi-cines Agency (EMA) base the approval of

a biosimilar on its similarity to an approved biologic,

not on its efficacy and safety de novo.9 The clinicaldevelopment program is tailored using the most up-

to-date analytical tools and testing models that allow

investigators to detect small differences between thebiosimilar and the reference product. Where deemed

appropriate based on scientific reasoning, study end-

points may be different from those used for thereference product trials such that the most clinically

meaningful data are obtained.4

The purpose of this article is twofold. It willprovide context regarding key safety issues

addressed in biosimilar development, approval, and

delivery as well as inform oncologists on safetymatters to consider when prescribing biosimilars.

Thorough knowledge about biosimilars may help

clinicians make informed decisions when treatingpatients.4

REGULATORY PATHWAYS WITH BIOSIMILARS

Safety monitoring that is systematic and ongoing is

necessary for all approved drugs.9 Physicians, pharma-cists, payors, and patients must have confidence in

quality, safety, and efficacy data provided by manufac-

turers to regulatory agencies for approval to integratebiosimilars into treatment.1 The principles guiding

biosimilar development are science-based and shared

by the EU, the United States, and other regulated worldregions.4 Biosimilarity has been codified by the World

Health Organization (WHO), the FDA, the EMA, the

Korean Food and Drug Administration, the JapaneseMinistry of Health Labor and Welfare, and Health

Canada (Table 2).10 Each definition differs slightly,

but they share three common elements9:

○

Biosimilar should be a biologic

○

Reference product should be a biologic already

licensed on the basis of a full nonabbreviatedsubmission including all necessary clinical, pre-

clinical, and quality data (ie, a biosimilar may not

serve as a reference product)

○

Necessity for a high similarity in safety, quality,and efficacy

In 2005, the EMA became the first region tointroduce guidance on biosimilars11 (CHMP/437/04

30 October 2005) with “overarching” guidance that

established the principle of a comparative develop-ment approach to the reference product to establish

similarity. The approval of the first biosimilar prod-

uct, Omnitrope, followed in 2006.12 The EMA sub-sequently has produced extensive guidance on

quality, safety, and efficacy of biosimilars in general

as well as product- and class-specific guidance.Following suit, FDA draft guidance on biosimilarity

was issued in the United States in 2012.13 The FDA

stated it would use a “risk-based totality of evidence”approach in evaluating demonstration of biosimilar-

ity. The body of evidence needed includes structural

and functional characterization, nonclinical evalua-tion, data from human pharmacokinetic/pharmaco-

dynamic (PK/PD) studies, clinical immunogenicity

data, and data from clinical safety and effectivenessstudies.3 In the United States, the assessment of

biosimilarity will be determined on a case-by-case

basis, not a one size fits all standard.14

Until recently, relatively simple biologic com-

pounds such as growth hormone, erythropoietin,

and granulocyte colony-stimulating factor have beenbrought to the European market.15 The EMA is

continuing to revise its guidance documents to

reflect its experiences. For example, the overarchingguidance is being revised, and the 2013 draft states

that the key principle in the development of a

biosimilar should be to establish biosimilarity bythe “best possible means.” It should be ensured that

Table 2. Definitions of Biosimilar Products

Term Definition Issued by Definition

Biosimilar11 EMA11 A biosimilar is a biologic medicine that is developed to besimilar to an existing biologic medicine (the “referencemedicine”)

The relevant regulatory authority applies stringent criteriain their evaluation of the studies comparing quality,safety, and effectiveness. The studies on quality includecomprehensive comparisons of the structure andbiologic activity of active substances, while the studieson safety and effectiveness should show that there areno significant differences in their benefits and risks,including the risk of immune reactions

Similarbiotherapeuticproduct10

WHO10 A biotherapeutic product similar to an already licensedreference biotherapeutic product in terms of quality,safety, and efficacy11

Proposedbiosimilarproduct3

US FDA3 A product highly similar to the reference product withoutclinically meaningful differences in safety, purity, andpotency10

Subsequent-entrybiologics10

Health Canada10 A biologic drug that enters the market subsequent to aversion previously authorized in Canada withdemonstrated similarity to a reference drug11

Biosimilar10 Korean Food and DrugAdministration10

Biologic product that demonstrated its equivalence to analready approved reference product with regard toquality, safety, and efficacy11

Biosimilar10 Japanese Ministry ofHealth, Labor andWelfare10

A biosimilar is a biologic medicine that is developed to besimilar to an existing biologic medicine (the “referencemedicine”)

Unlike in the EU, polyglycans (eg, low-molecular weightheparin) and synthetic peptides are excluded

Abbreviations: EMA, European Medicines Agency; EU, European Union; US FDA, US Food and Drug Administration; WHO, WorldHealth Organization.

Data from FDA3; Wang et al10; EMA.11

Biosimilar safety considerations in clinical practice S5

previously confirmed safety and efficacy data for thereference biologic also apply to the biosimilar.16 Any

observed differences should be justified with respect

to their impact on efficacy and safety.16

Monoclonal antibodies (mAbs) are more complex

than other biosimilars approved to date. They are

large proteins that include multiple domains thatcontribute to their mechanism of action along with

their diverse clinical properties.17 Despite this, some

financial analysts have estimated that by 2018, bio-similars will occupy up to a 40% share of the Euro-

pean market for therapeutic mAbs.18–20 Reflecting the

ongoing evolution of the EMA’s stance on biosimilars,separate guidance was issued regarding steps for their

approval in 2012.21 The separate EMA guidance

includes recommendations for pharmacotoxicologic,PK/PD, efficacy, and safety assessments.21

On June 27, 2013, the EMA’s Committee for Medic-inal Products for Human Use adopted a positive

opinion for the biosimilars Remsima (Celltrion Health-

care, Incheon, South Korea) and Inflectra (Hospira UKLimited, Warwickshire, UK), which contain the active

substance that was found to be highly similar to

Remicade (infliximab; Janssen Biotech, Inc., Horsham,PA).22,23 Marketing authorization was subsequently

granted.24 The biosimilar infliximab will be marketed

separately by Celltrion (Remsima) and Hospira (Inflec-tra) under a co-exclusivity agreement.24 They will be

used to treat inflammatory conditions including rheu-

matoid arthritis (RA), ankylosing spondylitis, Crohn’sdisease, ulcerative colitis, psoriatic arthritis, and psor-

iasis.25,26 In a phase III randomized, double-blind study

in RA (n ¼ 606), the primary endpoint of therapeuticequivalence to infliximab (as measured by percentage

404550

ents

(%)

3639

44

E. Choy and I.A. JacobsS6

of patients who achieved an American College of

Rheumatology (ACR) 20 response at week 30) wasmet. Safety results were similar to results from the

infliximab pivotal trials.27

These will be the first biosimilar antibodies avail-able to patients in the highly regulated EU, and their

respective approval by the FDA and Japanese regu-

latory authorities may follow after patent expirationof the originator infliximab. FDA approval will be

based on the integration of various types of analyses

(the totality of the evidence approach) used tofurther evaluate any residual uncertainties regarding

potential clinically meaningful differences in safety

and efficacy between the biosimilars and the inno-vator.28 Although a reduction in data requirements is

possible for biosimilars, the prelicensing data pack-

age is nevertheless substantial.8

Because biosimilars are licensed based on a

reduced data package, some clinicians may have

concerns regarding the robustness of the data. Infact, with biosimilars, licensing is scientifically tail-

ored and includes an extensive comparability exer-

cise that helps provide information that thebiosimilar and reference product are indeed highly

similar.4 The nonidentical nature of a biosimilar and

its reference product is inherent to all biologics: it iscommon for biopharmaceuticals to undergo process

improvements and changes during their life cycle

that trigger comparability studies that must bereviewed and accepted by regulators.29 For a bio-

similar, as with any new drug, a comprehensive risk

management plan (including a plan for postmarket-ing surveillance) is submitted to the authorities with

the marketing authorization application.4

05

101520253035

Not at allfamiliar

Slightlyfamiliar

Somewhatfamiliar

Moderatelyfamiliar

Extremelyfamiliar

Pharmacists(n = 38)

Nurses(n = 71)

Physicians(n = 129)

Overall(n = 277)

Perc

enta

ge o

f Res

pond

7

15

231919

812

22

1313

2420 1818

29

21

Figure 1. NCCN Survey: Biosimilars–response to: Pleaserate your overall familiarity with developments for biosi-milars, including recent legislation that provides anapproval pathway for noninnovator (eg, “generic”) man-ufacturers to introduce copies of biologic drugs throughan abbreviated review process. Zelenetz AD, Ahmed I,Braud EL, Cross JD, Davenport-Ennis N, Dickinson BD,et al. Safety perspectives NCCN Biosimilars White Paper:regulatory, scientific, and patient safety perspectives. JNatl Compr Canc Netw. 2011;9:S-1-S-22,1 reprintedwith permission from JNCCN—Journal of the NationalComprehensive Cancer Network.

BIOSIMILARS FROM DEVELOPMENT TODELIVERY: IMPLICATIONS FOR SAFETY

All of the steps in production, purification, and

formulation influence the biologic and clinical proper-ties of a final biologic product, including biosimilars.

Generic small-molecule compounds can be made such

that they are identical to the original compoundsimply by following the previously patented produc-

tion process, while creation of biologics requires more

than just “recipe knowledge.” It requires the physicalbiologic reagent that creates the drug together with

biologics manufacturing and characterization exper-

tise, which are generally proprietary.1,7,30

Currently it is not possible to recreate the exact

original biologic drug without introducing at least

subtle differences.30 For that reason, extensive com-parability exercises with the originator are required.

Similar physiochemical characteristics, biologic

activity, pharmacokinetics, and efficacy will providereassurance that adverse drug reactions can be

expected at similar frequencies to the reference

product. The risk for new adverse events (in somecases, reported qualitatively) after licensing is con-

sidered to be lower for a biosimilar compared with a

new/modified active substance.4

Manufacturing: The Product Is the Process

The complex manufacturing processes for bio-

logics, and by extension biosimilars, are controlledcarefully through each stage.31,32 Consistent with

the concept of biosimilarity pioneered in the EU in

2005,11 the WHO has suggested the manufacturingprocess for biosimilars be designed to minimize

differences between the reference biologic and the

biosimilar. The aim is to reduce the clinical testingrequirements for the biosimilar based on the history

of the reference product33 and to ameliorate any

predictable impact on clinical safety and efficacy33

(Figure 1).

An alteration or deviation in the manufacturing

process can produce functional changes in theprotein that can result from subtle structural alter-

ations or changes in post-translational modifications(eg, level of glycosylation [Figure 2]). Because all the

steps involved in production, purification, and for-

mulation can affect the clinical and biologic proper-ties of the final product, each step in the process is

monitored carefully for quality control.7,17,32,34

O-glycosylationN-glycosylation

Lipid attachment

Cleavage

Phosphorylation

Signalling

Increased activityor serum half-life

Membranelocalization

Activation

Activation orinhibition

Figure 2. Schematic of a protein with common post-translational modifications and their functional effects.Kuhlmann M, Covic A. The protein science of biosimilars.Nephrol Dial Transplant. 2006;21 Suppl 5:v4-v8,32 bypermission of Oxford University Press.

Biosimilar safety considerations in clinical practice S7

European guidelines have evolved to take this into

account, and the amount of clinical data required

depends on the nature of the protein under consid-eration.32 For example, with epoetin products the

EMA has established product-specific approval

requirements and recognizes it as one of the mostdifficult products to develop as a biosmilar.7 In a

study of the bioactivity of 11 epoetin products from

four countries (Korea, Argentina, China, India), sixof the 11 products met their manufacturers’ specifi-cations. That said, variability in isoform distribution

and bioactivity were observed in some cases. Manyof these products might not meet the standard for

biosimilar licensure in the EU or the United States

where a stepwise development process has beenproposed by the FDA that compares the biosimilar

product with the reference biologic product at each

stage of development.3,8 They are thus referred to as“intended copies” and not biosimilars.

The biosimilar approval process is being devel-

oped and refined. In some cases, products that havenot been initially developed in a comparative fashion

subsequently are shown not to be similar to the

reference products and are sometimes of poorquality.8 Characterizing these products as “biosimi-

lars” in the press has led to a misconception that all

biosimilars are of equally poor quality and may beunsafe.8

Formulation and Packaging Also MayAffect Safety

The FDA and EMA allow sponsors to demonstratebiosimilarity, even if there are formulation differ-

ences relative to the reference product, but the

manufacturer must provide data demonstrating thatthe differences are not clinically meaningful.3,16 One

example of a difference that has been accepted by

the EMA is the increased level of phosphorylatedhigh mannose-type structures in a biosimilar epoetin-

alfa compared with the reference product. This

difference was deemed not clinically meaningfulbecause these are common glycoforms of recombi-

nant erythropoietins, cytokines, and a large variety

of nonlysosomal proteins from human plasma.4

Small differences that may influence efficacy or

safety would also normally be picked up early on

in product development as a result of the extensivephysicochemical and functional characterization that

is required.4

In contrast, an example of how differences informulation and packaging can affect safety is the

case of the subcutaneous administration of a

recombinant human erythropoietin to patients withchronic kidney failure.35 Despite established similar-

ity between biosimilar Eprex (Janssen-Cilag, New

Brunswick, NJ) and its reference product Epogen(Amgen, Thousand Oaks, CA), an increased inci-

dence of pure red-cell aplasia (PRCA) was identified.

This safety concern was attributed to anti-erythropoietin antibodies that targeted endogenous

erythropoietin. Retrospective analyses concluded

that more than 90% of these adverse events (AEs)were associated with Eprex.36 Following a technical

investigation, the increased incidence of PRCA

among Eprex users was attributed to a combinationof a formulation change, as well as the development

and use of a prefilled packaging system for subcuta-

neous administration. Polysorbate 80 in the newformulation reacted with the uncoated rubber stop-

pers of the syringe, resulting in the leaching of

substances from the stoppers, which may have actedas adjuvants to increase the immunogenicity of

Eprex in humans.36 Fluororesin coating has been

added to the vial stoppers, leading to a decrease inreported PRCA.36 This example shows that for any

biologic (originator or biosimilar), the potential for

immunogenicity issues to arise from changes to theformulation, route of administration, or packaging is

possible because of the complexity of these mole-

cules. It also highlights the importance and need forpostmarketing safety surveillance activities for bio-

similars.

Interchangeability or How Similar Is Similar?

Interchangeability (or a therapeutic alternativeinitiated by and under surveillance of a treating

physician)4 and biosimilarity are related but not

identical concepts. For example, while the EMAcan designate a compound as a biosimilar, it does

not have the authority to designate the biosimilar as

interchangeable with its reference biologic as thisissue is nationally determined by each member state.4

E. Choy and I.A. JacobsS8

Under the BPCI Act, the FDA may designate a bio-

similar as interchangeable with the reference biologic.However, it should be noted that in addition to the

FDA’s authority to designate biosimilars as interchange-

able, each state has its own legislative framework thatmay or may not permit this to occur in practice.37

Interchangeability determinations have profound

implications for patients, clinicians, and healthcaresystems. A key consideration in the use of biosimilars

is how biosimilarity and interchangeability will be

clinically defined or proven. How similar should“highly similar” be? Are or should biosimilars and

their reference compounds be interchangeable?10 A

product needs to be established first as a biosimilarin an indication approved for a reference product

(ie, it needs to be highly similar).1 Then, additional

standards are applied, including: whether a biosimi-lar can be expected to produce the same clinical

result in any individual patient or subgroup of

patients; and if administered more than once,whether an individual has a greater risk of immuno-

logic complications or diminished effectiveness if

it is alternated with the reference product than thereference product would on its own.1,10

To date, no methods have been defined or

developed for adequately investigating the effectsof switching or alternating to and from biosimilars

and their respective reference biologics.1 Addition-

ally, the FDA has yet to issue guidance on inter-changeability.38 As it stands, attaining inter-

changeability in accordance with these set standards

may not be possible, and in the future may only bepossible for certain limited biologics.10

Automatic Substitution

Interchangeability is a switch driven by a physi-

cian4 based on knowledge of the specific productand the patient. In contrast, automatic substitution is

the practice where substitution occurs at the phar-

macy level without the involvement or even theknowledge of the prescribing physician.1 These two

types of switching raise very different medical and

policy issues.In the United States the policies and regulations

regarding the substitution of a reference biologic

with a biosimilar may become complex. For exam-ple, although the BPCI Act allows the FDA to make

an interchangeability determination for biosimilars,

substitution practices are governed by state laws.1

Because biosimilars are not identical to their

reference biologics and some statutes have clauses

stating that substituted drugs must have the “sameactive chemical ingredients,” some uncertainty as

to how states will determine whether biosimilar

manufacturers will attain interchangeability statusis likely.37 Current state laws regarding automatic

drug substitution (ie, the substitution of a generic for

the original product unless the prescriber specifiesotherwise) were enacted before the advent of bio-

similars.1 Individual states may or may not take into

account FDA-directed interchangeability determina-tions when developing new laws and regulations

governing the use of biosimilars; this could lead to

further confusion for clinicians.1,37

The complexity of biologics means that they

currently cannot be exact copies and therefore

automatic substitution is not appropriate.7 More-over, automatic substitution makes the process of

tracking adverse events very difficult. A given safety

issue might be attributed to the wrong product. Inaddition, patients may receive multiple biosimilars

over a given treatment course that may confound

pharmacovigilance assessments. From a practicalstandpoint, automatic substitution may result in

patients having to accommodate differences in

injection devices, preparation, and medication han-dling.4 Physicians should make the decision to

substitute a biosimilar; automatic substitutions by

pharmacists or others should not be permittedbecause physicians should have the freedom to

prescribe the medicines they deem most appropriate

for a particular patient.7

It should be noted that physician-prescribed

switching from the reference product to a product

approved by the EMA or FDA as a biosimilar raisesnone of the profound issues raised by interchange-

ability at the pharmacy level because this kind of

switching will be driven by the prescribing physi-cian, rather than the pharmacy.

Immunogenicity

Because they are complex molecules synthesized in

living systems, mAbs (as well as other biologics) andtheir biosimilar counterparts are potentially immuno-

genic.17 Currently, it is not possible to develop an exact

copy of a biologic or to duplicate the manufacturingprocess of the reference biologic, so it is essential that a

biosimilar be assessed for its immunogenic potential in

comparison with its reference biologic.4

Immunogenicity represents a significant safety

concern for all biopharmaceuticals and is driven by

several risk factors, including properties of the bio-logic, patient characteristics, concurrent treatments,

and previous exposure to similar biologic agents

(Figure 3).39,40 Most of the observed clinically mean-ingful effects attributed to immunogenicity are due to

neutralizing antibodies, which are produced by the

host against the biologic or its endogenous biologiccounterpart. Neutralizing antibodies not only lower

the bioavailability of a biologic drug by its elimina-

tion, they also neutralize the effects of a givenbiologic drug by binding to its active region. They

Structural propertiesGlycosylationSequence variation

BacterialHuman

Contaminants and impurities(from initial production

or downstream processing) DoseFormulation

Patient characteristicsAssay technologiesLength of treatment

TT

CN

A

AL

K

KKF

FI

SN

A

AL

K

KKF

1 2 3 4 5 67 8 9 10 11 12

13 14 15 16 17 1819 20 21 22 23 24

25 26 27 28

FEBRUARY

Other factors

Route of application

Unknown factors

Immunogenicity

Figure 3. Factors that influence immunogenicity of biopharmaceuticals. Reprinted by permission from MacmillanPublishers Ltd: Seminars in Oncology. Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. NatRev Drug Discov. 2002;1:457-62,40 copyright 2002.

Biosimilar safety considerations in clinical practice S9

can further worsen the clinical state of the patient by

binding to and neutralizing the endogenous counter-

part of a biologic drug.38 Effects from the formationof antidrug antibodies (ADAs) or antibodies produced

by the host against a given biologic therapy can range

from asymptomatic responses to clinically meaning-ful serious adverse events (SAEs).38

In its 2007 guidelines on immunogenicity in

biopharmaceuticals, the EMA recommended that thisimportant safety issue be addressed through a risk

management strategy, including the use of bioassays

and comparability studies to confirm that a biosimi-lar is no more immunogenic than its reference

product. The FDA also will require comparability

studies.38,39 Immunogenicity studies should includean evaluation of ADAs to determine whether these

act as neutralizing antibodies for the biosimilar as

compared with the reference biologic.38

There are four classes of ADA response where

ADA binding: (1) increases or decreases drug clear-

ance; (2) neutralizes pharmacologic action of thedrug; (3) neutralizes pharmacologic action and its

endogenous cross-reactive counterpart (leads to a

potential deficiency syndrome); or (4) leads to animmune response or hypersensitivity reaction.38 The

development of immunogenicity assays is challeng-

ing because there is more than one drug product

being assessed (ie, the biosimilar and one or morereference biologic products).38 Immunogenicity

assays in preclinical and clinical studies also are

difficult to interpret as they are presented in termsof a rate. However, immunogenicity can be difficult

to measure at low incidence and this presents a

practical challenge for comparative clinical studies.This may mean that regulators will need to ensure

that post-approval follow-up of immunogenicity is

carefully monitored. PK/PD data as well as clinicaladverse event data also should be considered when

interpreting immunogenicity.38

POSTMARKETING SURVEILLANCE ANDPHARMACOVIGILANCE: CRITICAL ELEMENTSIN MONITORING BIOSIMILAR SAFETY

Pharmacovigilance refers to data collection relatedto the detection, assessment, understanding, and

prevention of potential safety signals with drug

products (eg, immunogenicity).9,41 The goal of phar-macovigilance is to promptly identify and evaluate

E. Choy and I.A. JacobsS10

safety signals so that risks can be appropriately

managed.9 In the EU, the EMA has issued guidelinesfor manufacturers of biopharmaceuticals (including

biosimilars) to address the issue of immunogenicity

through the use of bioassays as well as the provisionof monitoring strategies, risk minimization strategies

Table 3. Examples of Additional Pharmacovigilance

BiosimilarComparator

Generic (brand)

EpoetinsHX57 (Abseamed, Binocrit,

Epoetin-α Hexal)Epoetin-α

(Eprex)Co

Su

SB-309 (Retacrit, Silapo) Epoetin-α(Eprex)

Clo

Stu

Po

Pro

Dr

G-CSFsXM02 (Biograstim, Filgrastim,

Ratiopharm, Ratiograstim,Tevagrastim)

Filgrastim(Neupogen)

Sig

Co

EP2006 (Zarzio,Filgrastim Hexal)

Filgrastim(Neupogen)

Ph

A 1

5-y

PLD108 (Nivestim) Filgrastim(Neupogen)

TaFoCo

SpAbbreviations: EU, European Union; G-CSFs, granulocyte colony stiChronic Neutropenia International Registry.

Reprinted by permission from Macmillan Publishers Ltd: Seminars iInterchangeability, immunogenicity and biosimilars. Nat Biotechno

(patient registries and postmarketing clinical trials),

and plans for risk communications measures.42 Anoverview of pharmacovigilance activities for biosimi-

lars currently approved in the EU shows a range of

activities from patient questionnaires and registries topostmarketing surveillance studies (Table 3).42

Activities for EU-Approved Biosimilars

Additional Pharmacovigilance Activities

hort study to monitor incidence ofthromboembolic eventsrvey to establish (off-label) subcutaneous use

se monitoring using specific questionnaires toestablish PRCA and thromboembolic eventsdy to evaluate safety and tolerability of epoetin-zeta administered intravenously for themaintenance treatment of renal anemia (CT-830-04-004)stauthorization cohort study of epoetin-zeta forthe treatment of renal anemia (PMS-830-07-043)spective, open, noncontrolled, multicenter studyto evaluate safety and tolerability of epoetin-zetaadministered subcutaneously for the treatment ofanemia in cancer patients (CT-830-05-0009)ug utilization study on use of epoetin-zeta

nal detection procedure for all incoming adversedrug response reports from whatever sources(including the SCNIR) and indications, andscheduled antibody assessment in case ofsuspected immunogenicityoperation with SCNIR and analysis ofcorresponding Biograstim-SCNIR data

armacovigilance program for patients with severechronic neutropenia2-month phase 4 study in patients with severeneutropenia, followed by a 5-year safety follow-upof study patients in cooperation with the SCNIRear safety follow-up study of healthy stem celldonors in cooperation with apheresis centers

rgeted questionnairellow-up of patients through SCNIR registryoperative program with hematologic transplantcentersecialized follow-up for long-term datamulating factor; PRCA, pure red-cell aplasia; SCNIR, Severe

n Oncology. Ebbers HC, Crow SA, Vulto AG, Schellekens H.l. 2012;30:1186-90,42 copyright 2012.

Figure 4. Risk management and pharmacovigilance with biosimilars. Casadevall et al,9 Calvo et al.43

Biosimilar safety considerations in clinical practice S11

Pharmacovigilance guidance will call for the

reporting of AEs associated with the use of biosimi-

lars. This includes voluntary, spontaneous reportingof AEs (ie, reporting of AEs to the FDA and/or the

manufacturer) and medication errors by healthcare

professionals (HCPs) to the FDA or manufacturerand the mandatory reporting by manufacturers to

the FDA of the reports they receive. The FDA enters

these notifications into a monitoring system andpotential safety signals are subsequently identified.9

A pharmacovigilance system includes strategies for

timely AE collection, tracking, and tracing. This willfacilitate the identification of newly emergent, wor-

sening, or increased frequency of known safety

concerns such as product recalls and/or safetyalerts.43 This traceability requires the adoption of a

rational international nomenclature system for bio-

similars (Figure 4).9 For example, in the UnitedStates it is recommended that for each product,

biosimilar nomenclature should include a unique

nonproprietary name, Healthcare Common Proce-dure Coding System/National Drug Code, and a

manufacturing lot number. This is necessary to

ensure that any potential AE associated with aparticular product (ie, molecule-specific) is not

erroneously attributed to a class of biologic drugs.9

If the FDA determines that a given drug (whichcould apply to a number of drug classes, including

biologics and biosimilars) is associated with a new

or worsening significant safety risk, the product’sprescribing information may be updated to include

the new safety information. In some instances it may

result in the establishment of or a change to a Risk

Evaluation and Mitigation Strategy (REMS), includinga medication guide, communication plan or other

elements to ensure safe use (eg, restricted access),

postapproval pharmacoepidemiologic studies, oradditional randomized clinical trials (Figure 4).9

However, it should be noted that at the time of

publication of this article, only one biologic therapyused to treat cancer (ipilimumab) is included on the

list of currently approved REMS.44

Pharmacovigilance plans are adopted by manufac-turers to address known safety issues. Under current

FDA pharmacovigilance guidelines and where a safety

risk has already been identified, it is recommendedthat the manufacturer consider the following in

deciding whether to establish a pharmacovigilance

plan (Figure 4)41:

○

“The likelihood that the AE represents a potentialsafety risk”

○

“The frequency with which the event occurs (eg,

incidence rate, reporting rate, or other measures

available)”

○

“The severity of the event”

○

“The nature of the population(s) at risk”

○

“The range of patients for which the product is

indicated (broad range or selected populations

only)”

○

“The method by which the product is dispensed”

E. Choy and I.A. JacobsS12

The FDA has the expressed authority under anamendment to the Federal Food, Drug, and Cosmetic

Act to require safety labeling changes in certain

circumstances that are described in Guidance forIndustry that was released in July 2013.45 Specifi-

cally, the FDA can order labeling changes if it

becomes aware of new safety information such as aserious risk or unexpected safety risk.45 The new

labeling requirement can be based on new analysis

of existing information or information obtained sincethe last risk assessment of the drug under a risk

evaluation and mitigation strategy.45

Currently pharmacovigilance guidelines are not spe-cifically available for biosimilars in the United States.9

As a starting point, it will be important to show that

biosimilars exhibit a comparable safety profile to thereference product.1 Guidance from the FDA on good

pharmacovigilance practices for any new drug states a

plan may include one or all of the following41:

○

Expedited submission of specific SAE reports

○

More frequent submission of AE report summaries

at prespecified intervals (ie, quarterly rather than

annually)

○

Active surveillance to identify AEs that may ormay not be reported through passive surveillance.

This process can be (1) drug-based: identifying

AEs in patients taking certain products; (2) set-ting-based: identifying AEs in certain healthcare

settings where they are likely to present for

treatment (eg, emergency departments, etc);(3) event-based: identifying AEs that are likely to

be associated with medical products (eg, acute

liver failure)

○

Additional postmarketing (phase IV), pharmacoepi-

demiologic studies (eg, automated claims databases

or other databases) using cohort, case-control, orother appropriate study designs

○

Creation of registries or implementation of patient

or HCP surveys

○

Additional postmarketing and controlled clinical

trials

It is especially important that physicians under-

stand the complexity of producing biologic drugs

and the potential clinical implications of using bio-similar preparations that can be considered similar,

but not identical, to the reference biologic.1,30 Addi-

tionally, as the FDA has not issued guidance regard-ing pharmacovigilance of biosimilars, the guidelines

for biosimilars may differ from those required for

their reference biologics.

NOMENCLATURE: MITIGATING CONFUSION

The naming of biosimilars is unlike the process forsmall-molecule drugs because small-molecule generic

drugs will by definition have the same nonproprietary

name as the original compound.1 A nomenclaturesystem for biosimilars remains a challenge for regu-

lators because it will be used not only during the

distribution of biosimilars but also during pharmaco-vigilance.9 Guidance on naming conventions for bio-

similars in the United States is yet to be determined.

The FDA will consider several factors when imple-menting a system of nomenclature for biosimilars,

including whether to: (1) assign unique, similar, or

generic names (ie, the same name as the respectivereference biologic products) to biosimilar com-

pounds; (2) consider structural relationships or classes

when naming biosimilars; or (3) make the nomencla-ture of biosimilars systematic or predictable.46

In the EU there is an inconsistent pattern with

respect to international nonproprietary names(INNs) for biosimilars. For example, among the five

recombinant human erythropoietin products that

have received marketing authorization in the EU asbiosimilars of Eprex/Erypo (epoetin-alfa, Janssen-

Cilag GmbH, Neuss, Germany), three were found

to have differences in glycosylation relative to thereference product. Nonetheless, they were assigned

the same INN: epoetin-alfa. The two other biosimi-

lars displayed differences in relative amounts of O-glycan chain variants compared with the reference

product and were designated the INN epoetin-zeta.9

Currently, the INN system is optional, meaningmanufacturers are not obligated to consult with

WHO on the INN for their biosimilar. Those that

did so and whose products had differences inglycosylation were granted an INN with a suffix

and those that did not consult simply used the

reference product INN.47

Ultimately, educating prescribers on the impor-

tance of providing a full product name will be crucial,

regardless of which naming convention is used.9 On aseparate note, because the need for thorough phar-

macovigilance has been recognized by the European

Commission, a directive was issued that requiresmembers to take measures to ensure that biologics,

which can be the subjects of AE reports, are clearly

identifiable with regard to nomenclature.48 As aresult, several member countries require that physi-

cians prescribe biologics by brand name, whether it

is the reference biologic or a biosimilar.9,46

SUMMARY AND CONCLUSIONS

Biopharmaceuticals are an important component

of the treatment armamentarium for a range of

cancers.1 Biosimilars are biologics that are highlysimilar but not identical to their reference products.3

Biosimilars may have the potential to increase

patient access to potentially valuable therapies at alower cost.1 The goal of a biosimilar development

Biosimilar safety considerations in clinical practice S13

program is not to replicate the efficacy and safety

profile of a given reference biologic, but to demon-strate that the biosimilar and the reference biologic

product are “highly similar” in terms of analytical,

nonclinical, and clinical data based on the totality ofavailable evidence.3

Specific requirements to demonstrate sufficient

similarity between biosimilars and reference biologicswill likely be considered on a case-by-case basis.14 To

answer the key question of how much clinical testing

is required to satisfy requirements for safety andequivalent efficacy regulators will likely adopt a

stepwise approach. Continued guidance from regu-

latory agencies with regard to safety issues forbiosimilars, as well as those for pharmacovigilance

and risk mitigation activities, is anticipated and will be

critical to the further development of biosimilars.12,13

There remains an unmet need for the education of

HCPs, payors, and patients on the integration

of biosimilars into oncology therapy.1,4 A numberof considerations exist, including the related issues

of interchangeability, automatic substitution,4 immu-

nogenicity,39 monitoring for adverse events (eg,through effective pharmacovigilance activities) so

that any emerging safety signals can be identified

in a timely manner and addressed through appropri-ate risk mitigation strategies, as well as safety issues

that may arise from nomenclature considerations.1 In

summary, information such as that discussed in thisarticle may be helpful in identifying and mitigating

concerns about the use of biosimilars in clinical

practice. Regulatory pathways for biosimilars, inparticular biosimilar mAbs, may represent a potential

way to increase access and decrease cost.

REFERENCES1. Zelenetz AD, Ahmed I, Braud EL, Cross JD, Davenport-

Ennis N, Dickinson BD, et al. Safety perspectives

NCCN Biosimilars White Paper: regulatory, scientific,

and patient safety perspectives. J Natl Compr Canc

Netw. 2011;9:S-1–22.

2. Generics and Biosimilars Initiative Online. US$67

billion worth of biosimilar patents expiring before

2020. http://www.gabionline.net/Biosimilars/General/

US-67-billion-worth-of-biosimilar-patents-expiring-be

fore-2020. Accessed September 20, 2013.

3. US Food and Drug Administration. Guidance for

industry: scientific considerations in demonstrating

biosimilarity to a reference product. http://www.fda.

gov/downloads/Drugs/GuidanceComplianceRegulator

yInformation/Guidances/UCM291128.pdf. Accessed

September 5, 2013.

4. Weise M, Bielsky M-C, de Smet K, et al. Biosimilars:

what clinicians should know. Blood. 2012;120:5111–7.

5. US Food and Drug Administration. Guidance for

industry: biosimilars: questions and answers regarding

implementation of the biologics price competition and

innovation act of 2009. http://www.fda.gov/down

loads/Drugs/GuidanceComplianceRegulatoryInforma

tion/Guidances/UCM273001.pdf Accessed Septem-

ber 20, 2013.

6. US Food and Drug Administration. Guidance for indus-

try: quality considerations in demonstrating biosimilarity

to a reference protein product. http://www.fda.gov/

downloads/Drugs/GuidanceComplianceRegulatoryIn

formation/Guidances/UCM291134.pdf Accessed Sep-

tember 20, 2013.

7. Mellstedt H, Niederwieser D, Ludwig H. The challenge

of biosimilars. Ann Oncol. 2008;19:411–9.

8. Weise M, Bielsky M-C, De Smet K, et al. Biosimilars-

why terminology matters. Nat Biotechnol. 2011;29:

690–3.

9. Casadevall N, Edwards IR, Felix T, et al. Pharmacovi-

gilance and biosimilars: considerations, needs and

challenges. Expert Opin Biol Ther. 2013;13:1039–47.

10. Wang J, Chow S-C. On the regulatory approval path-

way of biosimilar products. Pharmaceuticals. 2012;5:

353–68.

11. European Medicines Agency. Committee for Medicinal

Products for Human Use(CHMP). Guideline on similar

biological medicinal products. http://www.ema.europa.

eu/docs/en_GB/document_library/Scientific_guide

line/2009/09/WC500003517.pdf. Accessed September

16, 2013.

12. European Medicines Agency. Omnitrope. http://www.

ema.europa.eu/ema/index.jsp?curl=pages/medicines/

human/medicines/000607/human_med_000946.jsp&

mid=WC0b01ac058001d124. Accessed September 5,

2013.

13. US Food and Drug Administration. Biosimilarity. http://

www.fda.gov/Drugs/GuidanceComplianceRegulator

yInformation/Guidances/ucm290967.htm. Accessed

September 5, 2013.

14. Jeske W, Walenga JM, Hoppensteadt D, Fareed J.

Update on the safety and bioequivalence of

biosimilars-focus on enoxaparin. Drug Healthc Patient

Saf. 2013;5:133–41.

15. Generics and Biosimilars Initiative Online. Biosimilar

monoclonal antibodies – challenges and opportunities

in Europe. http://gabi-journal.net/biosimilar-monoclo

nal-antibodies-challenges-and-opportunities-in-europe.

html. Accessed September 12, 2013.

16. European Medicines Agency. Guideline on immunoge-

nicity of biotechnology-derived therapeutic proteins.

http://www.ema.europa.eu/docs/en_GB/document_li

brary/Scientific_guideline/2009/09/WC500003947.pdf.

Accessed September 5, 2013.

17. Declerck PJ. Biosimilar monoclonal antibodies: a

science-based regulatory challenge. Expert Opin Biol

Ther. 2013;13:153–6.

18. Kay J, Smolen JS. Biosimilars to treat inflammatory

arthritis: the challenge of proving identity. Ann Rheum

Dis. 2013;72:1589–93.

19. Jack A. Regulators pave the way for ‘biosimilar’ drugs.Financial Times. June 28, 2013.

20. Decision Resources. Biosimilar ESAs to account for 40

percent of the G7 ESA market in 2020. October 27,

2011.

21. European Medicines Agency. Guideline on immuno-

genicity assessment of monoclonal antibodies

E. Choy and I.A. JacobsS14

intended for in vivo clinical use. http://www.ema.

europa.eu/docs/en_GB/document_library/Scientific_

guideline/2012/06/WC500128688.pdf. Accessed Sep-

tember 5, 2013.

22. European Medicines Agency. Committee for Medicinal

Products for Human Use (CHMP). Summary of opinion

(initial authorization) Inflectra. http://www.ema.

europa.eu/docs/en_GB/document_library/Summary_

of_opinion_-_Initial_authorisation/human/002778/

WC500144831.pdf. Accessed September 23, 2013.

23. European Medicines Agency. Committee for Medicinal

Products for Human Use (CHMP). Summary of opinion

(initial authorization) Remsima. http://www.ema.

europa.eu/docs/en_GB/document_library/Summary_

of_opinion_-_Initial_authorisation/human/002576/W

C500144832.pdf. Accessed September 23, 2013.

24. Hospira’s Inflectra (infliximab) the first biosimilar

monoclonal antibody to be approved in Europe. [press

release]. Leamington Spa, England/PRNewswire/ –

Hospira; September 10, 2013.

25. European Medicines Agency. Committee for Medicinal

Products for Human Use (CHMP). Inflectra Summary

of Product Characteristics. http://www.ema.europa.

eu. Accessed September 23, 2013.

26. European Medicines Agency. Committee for Medicinal

Products for Human Use (CHMP). Remsima Summary

of Product Characteristics. http://www.ema.europa.

edu. Accessed September 23, 2013.

27. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski

M, Shevchuk S, et al. A randomised, double-blind,

parallel-group study to demonstrate equivalence in

efficacy and safety of CT-P13 compared with innovator

infliximab when coadministered with methotrexate in

patients with active rheumatoid arthritis: the PLAN-

ETRA study. Ann Rheum Dis. 2013;72:1613–20.

28. Kozlowski S, Woodcock J, Midthun K, Sherman RB.

Developing the nation’s biosimilars program. N Engl J

Med. 2011;365:385–8.

29. Beck A, Reichert JM. Approval of the first biosimilar

antibodies in Europe: a major landmark for the bio-

pharmaceutical industry. MAbs. 2013;5(5) [Epub

ahead of print].

30. Lee JF, Litten JB, Grampp G. Comparability and

biosimilarity: considerations for the healthcare pro-

vider. Curr Med Res Opin. 2012;28:1053–8.

31. Nowicki M. Basic facts about biosimilars. Kidney

Blood Press Res. 2007;30:267–72.

32. Kuhlmann M, Covic A. The protein science of bio-

similars. Nephrol Dial Transplant. 2006;21(Suppl 5):

v4–v8.

33. World Health Organization. Guidelines on evaluation of

similar biotherapeutic products (SBPs). http://www.

who.int/biologicals/areas/biological_therapeutics/BIO

THERAPEUTICS_FOR_WEB_22APRIL2010.pdf. Accessed

September 5, 2013.

34. Schellekens H, Ryff J-C. ‘Biogenerics’: the off-patent

biotech products. 2002. Trends Pharm Sci. 2002;23:

119–21.

35. Woodcock J, Griffin J, Behrman R, et al. The FDA’s

assessment of follow-on protein products: a historical

perspective. Nat Rev Drug Discov. 2007;6:437–42.

36. Boven K, Stryker S, Knight J, et al. The increased

incidence of pure red cell aplasia with an Eprex

formulation in uncoated rubber stopper syringes.

Kidney Int. 2005;67:2346–53.

37. Kanter J, Feldman R. Understanding and incentivizing

biosimilars. The Hastings Law Journal. 2012;64:57–83.

38. Cai XY, Thomas J, Cullen C, Gouty D. Challenges of

developing and validating immunogenicity assays to

support comparability studies for biosimilar drug

development. Bioanalysis. 2012;4:2169–77.

39. European Medicines Agency. Committee for Medicinal

Products for Human Use (CHMP). Guideline on

immunogenicity assessment of biotechnology-derived

therapeutic proteins. http://www.ema.europa.eu/docs/

en_GB/document_library/Scientific_guideline/2009/09/

WC500003947.pdf. Accessed September 16, 2013.

40. Schellekens H. Bioequivalence and the immunogenic-

ity of biopharmaceuticals. Nat Rev Drug Discov.

2002;1:457–62.

41. US Food and Drug Administration. Guidance for indus-

try: good pharmacovigilance practices and pharmacoe-

pidemiologic assessment. US Department of Health

and Human Services, US Food and Drug Administra-

tion, Center for Drug Evaluation and Research, Center

for Biologics Evaluation and Research, Rockville, MD;

2005.

42. Ebbers HC, Crow SA, Vulto AG, Schellekens H.

Interchangeability, immunogenicity and biosimilars.

Nat Biotechnol. 2012;30:1186–90.

43. Calvo B, Zuniga L. Risk management plan and pharma-

covigilance system – biopharmaceuticals: biosimilars

risk management trends. In: Nota G, ed. Risk manage-

ment trends. InTech; 2011:chapter 13. http://www.

intechopen.com/books/risk-management-trends/risk-ma

nagement-plan-and-pharmacovigilance-system-biophar

maceuticals-biosimilars. Accessed September 23, 2013.

44. US Food and Drug Administration. Approved risk

evaluation and mitigation strategies. http://www.fda.

gov/Drugs/DrugSafety/PostmarketDrugSafetyInforma

tionforPatientsandProviders/ucm111350.htm.

Accessed September 23, 2013.

45. US Food and Drug Administration. Guidance for Indus-

try Safety Labeling Changes – Implementation of

Section 505 (o) (4) of the FD&C Act http://www.fda.

gov/downloads/Drugs/GuidanceComplianceRegulator

yInformation/Guidances/UCM250783.pdf Accessed

September 23, 2013.

46. Rader RA. Nomenclature of new biosimilars will be

highly controversial. http://www.bioprocessintl.com/

multimedia/archive/00173/BPI_A_110906AR04_O_17

3322a.pdf. Accessed September 5, 2013.

47. World Health Organization. WHO informal consultation

on International Nonproprietary Names (INN) Policy for

biosimilar products. http://www.who.int/medicines/

services/inn/BiosimilarsINN_Report.pdf. Accessed Sep-

tember 5, 2013.

48. Directive 2010/84/EU of the European Parliament and

of the Council of 15 December 2010 amending, as

regards to pharmacovigilance, directive 2001/83/EC

on the Community code relating to medicinal

products for human use. Off J Eur Union. 2010;348:

74-99.