Introduction and Comme

ntary: Paving the Way forBiosimilars in Oncology

Few areas of medicine have been as impactedby the development of biologic drugs as

oncology. Over the last decade, the introduc-

tion and integration of biologic therapies into clinicalpractice have led to entirely new treatment para-

digms where specific tumor types can be targeted in

a more effective and less toxic manner than previousstandards of care. Thus, many oncology treatment

guidelines, including those of the National Compre-

hensive Cancer Network (NCCN), now incorporatebiologic agents into the continuum of care (eg,

monoclonal antibodies [mAbs]) and supportive treat-

ment (eg, colony-stimulating factors).1

As patent protection on some of the most widely

used biologic drugs begins to expire, interest is

increasing among biopharmaceutical manufacturersseeking to develop and market biosimilars, as shown

in Table 1.1–3 Biologic drugs are unique molecules

that typically are difficult and expensive to manufac-ture, because they are produced in living biologic

systems that are inherently subject to variation.4,5

Thus, unlike most conventional small-molecule drugs(eg, statins) and chemotherapeutic agents, biologic

drugs are impossible to exactly replicate using exist-

ing technology, and “generic” versions of such drugscannot be produced.3,6 The term “biosimilar” refers toa biologic product that is developed to be highly

similar, as opposed to identical, to an existinglicensed biologic product (the reference or innovator

product), such that there are “no clinically meaningfuldifferences between the biological product and the referenceproduct in terms of safety, purity, and potency of theproduct.”3,7

0093-7754/ - see front matter& 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1053/j.seminoncol.2013.09.014

This supplement was funded by Pfizer Inc.Statement of conflict of interest: Jame Abraham received no financialsupport from Pfizer Inc for the research and/or authorship of this sup-plement. Medical writing and editorial support to prepare this supple-ment was provided by Joseph Abrajano, PhD, and Stephen Strudwick,PhD, of QD Healthcare Group and funded by Pfizer Inc.

Seminars in Oncology, Vol 40, No 6, Suppl 1, December 2013,

The development and integration of biosimilars hasalready begun in Europe and elsewhere throughout the

world. The Biologics Price Competition and Innovation

(BPCI) Act of 2009 has initiated the process for devel-oping a biosimilar program in the United States, and the

US Food and Drug Administration (FDA) has begun to

provide guidance outlining the general principles ofdemonstrating biosimilarity. Still, unanswered questions

remain, and developing the necessary regulatory infra-

structure to accommodate biosimilars will continue toevolve. Cooperation, communication, and consensus

among the key stakeholders in biosimilars, including

the manufacturers (of the biosimilar and the referencebiologic), legal and regulatory authorities, payors,

insurers, providers, clinicians, and patients, will be

needed to effectively integrate biosimilars into the healthcare system (Figure 1).1 Ultimately, healthcare providers

(HCPs) must evaluate the scientific and clinical data

associated with using biosimilars. To do this, they musthave a sufficient understanding of the complexities

associated with the development and manufacturing of

biologic drugs and how these processes differ fromthose of small-molecule drugs and traditional chemother-

apeutic agents.1,8 In this supplement series, we highlight

the key topics surrounding the development of biosimi-lar drugs and the major challenges ahead as these drugs

are integrated into US clinical practice.

THE BASICS OF BIOSIMILARS

This first supplement in this series, “DevelopingOncology Biosimilars: An Essential Approach for the

Future,” serves as a primer on biosimilars, outlining theimpact of biologic drugs in oncology and their asso-

ciated costs, the key differences between biologics

compared with small-molecule drugs and biosimilarscompared with small-molecule generic drugs, and the

current legislative environment driving the develop-

ment of biosimilars. The development and manufactur-ing process of biologics is considerably more complex

than that of small-molecule drugs and conventional

chemotherapeutic agents, produced through chemical

pp S1-S4 S1

Table 1. Anticipated Patent Expirations ofthe Most Widely Used Biologic Drugs in theUnited States

Biologic Drug(s) Anticipated PatentExpiration

Trastuzumab 2019 (US)2014 (EU)

Adalimumab 2016 (US)2018 (EU)

Rituximab 2018 (US)2013 (EU)

Bevacizumab 2019 (US)2022 (EU)

Generics and Biosimilar Initiative (GABI) Online 2011.2

J. AbrahamS2

synthesis.1 Biologic drugs are produced throughrecombinant DNA methodology, which typically

involves cloning and expression of the protein mole-

cule into a carefully chosen host cell line (ie, yeast,mammalian, bacterial).5,9 This is followed by a specifi-

cally designed expansion, production, recovery, pur-

ification, and packaging process; all of these conditionsmust be controlled if the efficacy and safety of the final

product are to be retained.9 The resulting product,

typically a glycoprotein, has multiple levels of structureincluding its primary amino acid sequence, secondary

structure resulting from hydrogen bonding, tertiary

interactions between strands, and quaternary associa-tions between protein subunits.10 Also integral to the

function and safety of biologic drugs are different types

of post-translational modifications (eg, glycosylation).11

Due to the inherent complexity of biologics, while

“generic” versions cannot be produced, a similar

product (biosimilar) is produced. As such, the regula-tory environment associated with biosimilars continues

to evolve and includes such issues as nomenclature,

substitution practices, postmarketing safety and sur-veillance, and pharmacovigilance activities. Some

• Understanding, accepPhysicians andpatients

• Reimbursement issuePayors, insurers,and providers

• Approval pathway• Guidance for demons• Safety and pharmaco• Nomenclature

Legislative and regulatory authorities

• Manufacturing and ch• Demonstrating biosimManufacturers

Figure 1. Key stakeholder resp

preliminary experience with biosimilars has been

gained outside the United States; regulatory guidanceoutlined by the European Medicine Agency (EMA) can

serve as a practical model for the US regulatory

process.12 Current recommendations of the WorldHealth Organization (WHO), the FDA, and a special

NCCN Biosimilars Work Group that was convened in

2011 also will be discussed, as will the findings of asurvey examining overall familiarity with biosimilars

and the accompanying regulatory issues among HCPs.1

CLINICAL TRIALS AND SAFETY OFBIOSIMILARS

The second supplement in this series on biosimilars

will examine clinical trial design and safety. Central to

the success of biosimilars is the clear definition andsubsequent demonstration of biosimilarity with

respect to the reference biologic. Specifically, how

do the manufacturers of biosimilars demonstrate thattheir product is sufficiently similar to the reference

biologic in terms of efficacy and safety? The WHO,

EMA, and preliminary guidance from the FDA haveoutlined a “comparability exercise,” a stepwise process

beginning with analytical testing to demonstrate

structural similarity followed by preclinical in vitroand in vivo assays to demonstrate functional similar-

ity.13 Assuming the biosimilar is sufficiently similar to

the reference biologic by these criteria, the processthen moves to clinical studies, where appropriate end

points are used to show pharmacokinetic and phar-

macodynamic similarity with the reference biologic.13

In addition, a key question is how trials should be

designed (ie, equivalence or noninferiority testing)

and, with respect to the findings of such trials, thedegree of similarity necessary to be able to substitute a

biosimilar for a reference biologic.5,14 Another issue is

to determine whether the approval of a biosimilar forone indication should be extrapolated to other indica-

tions for which the reference biologic is approved.7,15

Safety is critical to the acceptance of biosimilarsinto clinical practice, and there are safety consid-

tance, and uptake of biosimilars into clinical practice

s (eg, biosimilar vs reference biologic product)

trating biosimilarity and interchangeabilityvigilance procedures

aracterization of biosimilar productilarity with reference biologic product

onsibilities of biosimilars.

Table 2. The Biosimilar Approval Process: Competing Advantages and Disadvantages

Amount of Data Required forRegulatory Approval and

Process Advantages Disadvantages

Larger amount of datarequired (stricter process/policies for approval)

� Greater HCP and patientconfidence in efficacy and safety

� Greater availability of data forextrapolation/use in otherindications of the reference product

� More extensive costs ofdevelopment could reducepharmacoeconomic benefit

� Higher costs could limit accessand affordability

Smaller amount of datarequired (more lenientprocess/policies for approval)

� Lower production costs could allowgreater cost reductions versus thereference product

� Lower costs could allow broaderaccess to medications

� Lower HCP and patientconfidence in efficacyand safety

� Less data available forextrapolation to otherindications

Zelenetz et al.1

Paving the way for biosimilars in oncology S3

erations throughout the biosimilar developmentcontinuum. One of the most important safety con-

siderations is immunogenicity, which refers to the

process by which large molecules can initiate anantibody immune response and result in events

such as hypersensitivity reactions or loss of efficacy

(ie, neutralizing antibodies).3 Another possible con-sequence of immunogenicity is the development of

an autoimmune response to an essential endogen-

ously produced protein such as erythropoietin,which was the case with the development of pure

red cell aplasia following the use of a specific

erythropoietin preparation (subsequent to a changein formulation and packaging).8 The technology

does not exist to fully characterize a biosimilar

relative to its reference biologic at every level.6 Assuch, at the manufacturing level, the WHO recom-

mends that the biologic manufacturing process be

as close to that of the reference biologic as possibleto minimize the clinical testing requirements

needed and to limit any potential impact on efficacy

and safety.15 Because biologic drugs may be parti-cularly sensitive to changes in physical conditions

(eg, temperature and pH), it is also important that

the formulation, packaging, and storage require-ments be tightly controlled and monitored.16,17

The potential threat of immunogenicity remains

even after biosimilarity has been established, andit is not currently possible to fully assess this risk

with a biosimilar versus its reference biologic.5,8

Therefore, there will be a need for robust post-marketing surveillance and pharmacovigilance

activities with biosimilars to detect any potential

safety issues associated with a biosimilar product.8

These processes will, in turn, depend on a globally

standardized system for naming biosimilars that willenable the rapid identification of a specific biosimi-

lar relative to its reference biologic (or another

biosimilar), so that any unique adverse events canbe correctly identified and associated with the

correct product.1 These requirements, as well as

other requirements to ensure the safety of biosimi-lars across the development-to-delivery continuum,

are discussed.

CLINICAL AND PHARMACOECONOMICIMPACT OF BIOSIMILARS

The third supplement in this series on biosimilars

will examine the clinical practice issues that oncologistswill be addressing as biosimilars become available and

the potential pharmacoeconomic impact of biosimilars.

As biosimilars become available for use, it is essentialthat clinicians understand the potential ramifications of

these products in clinical practice.1 Whereas some

initial guidance for demonstrating biosimilarity hasbeen provided by the FDA and other regulatory

authorities, there are a number of outstanding ques-

tions, including whether a given biosimilar is “inter-changeable” with its reference product. Initial guidance

from the FDA, under the BPCI Act, has authorized an

“abbreviated pathway” for approval of biologics that are“biosimilar” to their reference product.14 Moreover, an

assignment of interchangeability relates to the existing

substitution practices in the United States. Would abiosimilar be automatically substituted for the reference

biologic drug unless the physician specifically requests

otherwise?14 Substitution laws, however, were devel-oped and implemented for use with generic small-

J. AbrahamS4

molecule drugs, and as such do not apply to biosimi-

lars.1 As substitution practices are governed by statelaw, it is also unclear the extent to which individual

states will abide by FDA guidance as to the interchan-

geability of biologic medications.1 Finally, it is uncertainhow treatment guideline committees such as those of

the NCCN will integrate and prioritize the use of

biosimilars in their treatment plans. Much will dependon the concept of “how similar is similar enough?” Thisarticle will discuss these issues in relation to how

biosimilars will be integrated into clinical practice.The aim of biosimilars is to provide safe, effective,

and less expensive biologic drugs and increase

patient access to these medications; however, theextent to which this goal can be accomplished

remains to be seen. Although the approval process

for biosimilars is expected to be less than that for anew biologic, it is still considerably more extensive

than that of a generic drug, and therefore the extent

of savings over the reference product is yet to bedetermined.6 For example, with generic drugs, sav-

ings of up to 90% over the branded product can be

achieved; by comparison, the estimated savings withbiosimilars ranges from at least 15% to 30%.4 A range

of other factors are also expected to affect the

economic success of biosimilars, including clinicianand patient attitudes about switching to an

unbranded product and safety issues that may emerge

with biosimilars as they enter the market.1,4 Otherissues to consider include formulary and insurance

coverage for biosimilars and possible price reductions

by the reference product manufacturer, which maybe implemented to dissuade switching to biosimilar

versions.1,4 The impact of these and other factors on

pharmacoeconomics of biosimilars will be discussed.

SUMMARY AND OUTLOOK

There is likely to be debate over the key issues on

biosimilar approval, most importantly, the amount of

data required for approval. There are clearly benefitsand drawbacks for the key stakeholders in either case

(Table 2).1 Regardless of the outcome, oncologists will

need to have a solid understanding of biosimilars froma scientific, regulatory, and economic perspective, as

well as the ultimate clinical impact for the patients

they treat. It is the aim of this series to educate andinform HCPs on important developments as biosimilars

become available and accepted into clinical practice.

Jame AbrahamDirector of Breast Oncology Program

Taussig Cancer InstituteCleveland ClinicCleveland, OH

E-mail: abrahaj@ccf.org

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