developing oncology biosimilars: an essential approach for the future
TRANSCRIPT
Developing Oncology Biosimilars: An Essential Approachfor the Future
Jame Abraham
The treatment of many diseases, particularly cancer, has been profoundly impacted by the
introduction of bioloalgorithms of most on
structurally complex pthe patents of key biol
future, a number of ph
the goal of developmereference biologic pro
drugs are small chem
molecule drugs. It is“biosimilar” was chose
access to cancer thera
the US Government;instrumental in accom
Semin Oncol 40 (Supp
0093-7754/& 2013 Elshttp://dx.doi
This suppleStatement osupport frosupplementplement wStrudwick,
Director oClevelan
Address cocer InstitOH 4419
Seminars
gic therapies (biologics), which are incorporated into the treatment
cology clinical practice guidelines. Biologics are large molecular weight,
roteins that are produced via complex manufacturing processes. Withogics, including many widely used in oncology, set to expire in the near
armaceutical companies have focused on developing biosimilars. While
nt is to demonstrate that the biosimilar product is highly similar to theduct, biosimilars should not be viewed as “generic” biologics. Genericical moieties that are identical to the patent-expired “reference” small-
not possible to produce an identical copy of a biologic, so the termn to define an appropriately similar biologic product. Improving patient
pies such as biologics and reducing healthcare costs are key initiatives of
the integration of approved biosimilars into clinical practice will beplishing these goals.
l 1):S5-S24 & 2013 Elsevier Inc. All rights reserved.
Biologic drugs (biologics) are produced in
living biological systems, whereas small-
molecule drugs (eg, aspirin, statins, and ben-zodiazepines) are manufactured using standard
chemical synthesis procedures.1 The methods used
to develop most small-molecule drugs are relativelyeasy to replicate, which facilitates the eventual
availability of generics upon patent expiration.2 In
contrast, the multifaceted manufacturing processesrequired to produce biologics are rendered even
more complex by the high level of structure asso-
ciated with functional proteins.3 Due to these com-plexities, not to mention the proprietary nature of
manufacturing processes, competing pharmaceutical
companies are unable to exactly duplicate approved
- see front matterevier Inc. All rights reserved..org/10.1053/j.seminoncol.2013.09.015
ment was funded by Pfizer Inc.f conflict of interest: Jame Abraham received no financialm Pfizer Inc for the research and/or authorship of this. Medical writing and editorial support to prepare this sup-as provided by Joseph Abrajano, PhD, and StephenPhD, of QD Healthcare Group and funded by Pfizer Inc.
f Breast Oncology Program, Taussig Cancer Institute,d Clinic, Cleveland, OH.
rrespondence to Jame Abraham, MD, FACP, Taussig Can-ute, Cleveland Clinic, 9500 Euclid Ave R-35, Cleveland,5. E-mail: [email protected]
in Oncology, Vol 40, No 6, Suppl 1, December 2013,
biologics. These issues have resulted in the develop-
ment of “biosimilars.”2
Biosimilars are considered as “highly similar” butnot identical to their reference biologic products
(ie, they should not be viewed as “biogenerics”).4 Asdefined by federal law (section 351(i) of the PublicHealth Service [PHS] Act), the term “biosimilar”refers to a “biologic product that is highly similar
to the reference biologic product, notwithstandingminor differences in clinically inactive compo-
nents.”5 There should be no clinically meaningful
differences between biosimilars and reference bio-logics in terms of safety, purity, and potency
(Table 1).6,7 Unlike small-molecule generic drugs,
biosimilars are structurally complex, large molecularweight proteins that are subject to a variety of post-
translational modifications.2,8–10
To increase patient access to cancer therapies,
more cost-effective biosimilars may become available
in the United States upon patent expiration of theirreference biologic products.2,6,11,12 However, the
anticipated entry of oncology biosimilars into the
US market in the next few years creates a unique set
of challenges for stakeholders (eg, the pharmaceut-
ical companies involved in the development of
biosimilars), as well as legal and regulatory author-
ities, healthcare providers (HCPs), and patients. The
US regulatory and approval processes for small-
molecule generic drugs are not applicable to
pp S5-S24 S5
Table 1. FDA Definitions of Biologics, Biosimilars, and Generic Drugs
Biologicalproducts
� The term ‘‘biological product’’ means a virus, therapeutic serum, toxin, antitoxin,vaccine, blood, blood component or derivative, allergenic product, protein (exceptany chemically synthesized polypeptide), or analogous product, or arsphenamine orderivative of arsphenamine (or any other trivalent organic arsenic compound)applicable to the prevention, treatment, or cure of a disease or condition of humanbeings
Biosimilars � The term ‘‘biosimilar’’ or ‘‘biosimilarity,’’ in reference to a biological product that isthe subject of an application under subsection (k), means:(A) The biological product is highly similar to the reference biologic product
notwithstanding minor differences in clinically inactive components(B) There are no clinically meaningful differences between the biological product
and the reference biologic product in terms of the safety, purity, and potency ofthe product
Generic drugproducts
� A generic drug is the same as a brand name drug in dosage, safety, strength, how itis taken, quality, performance, and intended use. Before approving a generic drugproduct, the FDA requires many rigorous tests and procedures to assure that thegeneric drug can be substituted for the brand name drug. The FDA bases evaluationsof substitutability, or therapeutic equivalence, of generic drugs on scientificevaluations. By law, a generic drug product must contain the identical amounts ofthe same active ingredient(s) as the brand name product. Drug products evaluatedas therapeutically equivalent can be expected to have equal effect and no differencewhen substituted for the brand name product
US House of Representatives,5 Generics and Biosimilar Initiative.6
J. AbrahamS6
biosimilars. Some key questions to be discussed in
this article include the necessity of safety surveil-
lance (pharmacovigilance) procedures, the appropri-ateness of interchangeability and substitution
practices, and the need for appropriate nomencla-
ture for biosimilars.Because all biologic drugs (ie, biosimilars and
their reference biologic products) are proteins, they
have the potential to induce antibody responses inpatients, which may result in hypersensitivity reac-
tions and/or other adverse events (AEs). The immu-
nogenic potentials and AE profiles of biologics arealways assessed in clinical trials and monitored post-
approval. Biosimilars are not identical to the licensed
reference biologic products, thus the safety ofbiosimilars up to and postapproval needs to be
monitored closely (eg, through postmarketing phar-
macovigilance procedures).Despite these considerations, the hope is that the
US Food and Drug Administration (FDA) approval
process for biosimilars will be abbreviated (com-pared with the approval process for a new biologic
drug application), with biosimilars effectively pro-
duced at lower costs than their reference biologicproducts.2,13 Although specific requirements for the
demonstration of appropriate similarity between
biosimilars and their reference biologic productshave not been fully defined by the FDA, these
requirements likely will be tailored for each of the
different types of biologics. For example, the
requirements for similarity for very structurally com-plex protein molecules such as monoclonal anti-
bodies (mAbs) will likely be more extensive than
those for biologics with simpler structures (eg,somatotropin). Not surprisingly, the FDA most likely
will consider applications on a case-by-case basis
using a review process that considers the “totality ofthe evidence.”2,14
Biosimilars are expected to increase global patient
access to therapies for a range of diseases includingcancer. The integration of biosimilars into clinical
practice has already begun in countries including
those in the European Union (EU). In 2005, theEuropean Medicines Agency (EMA) issued general
guidelines on biosimilars, and the European Commis-
sion subsequently implemented revised pharmaceut-ical legislation, which established the first formal
regulatory framework for the evaluation, authoriza-
tion, and monitoring of biosimilars.13–17 The refer-ence biologic product for the applicant biosimilar
must be registered in the EU, and the applicant
biosimilar must be similar in pharmaceutical form,mode of administration, and strength to the reference
biologic product.13,17 A biosimilar for somatotropin
was approved in the EU in 2006, followed bybiosimilars for erythropoietin and filgrastim.
Developing oncology biosimilars S7
Key understandings from the integration of biosimi-
lars into healthcare practices in the EU and other largeand emerging markets (eg, Brazil, China, and India) are
discussed in this review.18 The federal government, and
biotechnology and pharmaceutical industries shouldlearn from global experiences with biosimilars and
develop effective manufacturing and approval proc-
esses to facilitate the safe integration of biosimilars intoUS clinical practice. In 2012, the FDA took a significant
step toward this goal by releasing draft guidance on the
development and approval of biosimilars.19
INTRODUCING BIOSIMILARS TO EXPANDPATIENT ACCESS TO CARE
Biologic drugs have had a significant impact on all
areas of medicine, most notably in the fields ofoncology and rheumatology. Biologics are included
in treatment guidelines such as those of the National
Comprehensive Cancer Network (NCCN).1 Examplesof biologics that have had a significant impact on the
practice of oncology include rituximab (FDA
approved for the treatment of diffuse large B-cellnon-Hodgkin’s lymphoma) and trastuzumab (FDA
approved for the treatment of HER2-overexpressing
breast cancer, and metastatic gastric or gastroesopha-geal junction adenocarcinoma). Biologics also play an
active role in other types of cancers including colon,
head and neck, kidney, non–small-cell lung cancers,and chronic lymphocytic leukemia.1 The driving
forces behind the development of oncology biosimi-
lars include expanding patient access to these effec-tive biologic therapies, which has been shown to be
an important predictor of survival by the American
Cancer Society, and reducing healthcare costs.12,20
The US Hatch-Waxman Act of 1984 enhanced
patient accessibility to small-molecule drugs and
increased affordability by allowing abbreviatedapproval of thousands of small-molecule generic
(ie, nonbiologic) drugs following patent expiration
of the small-molecule reference products.21,22 Inmuch the same way, the Biologics Price Competition
and Innovation (BPCI) Act of 2009, a component of
Epoetin alfaFilgrastim PegUnited
States
Europe RituximabCetuximabInfliximab
Trastuzumab
2013 2014
Figure 1. Patents for many biologics are set to expire in
the Patient Protection and Affordable Care Act
(PPACA) signed into US law in 2010, was enactedwith the goal of expanding patient accessibility by
allowing price competition among biologics and
reducing costs. Such legislation has encouragedpharmaceutical and biotechnology companies to
develop biosimilars for use in the United States,
especially as the patents of several key biologics,including several widely used in oncology, are set to
expire in the near future (Figure 1).17,23–25
The use of biosimilars in the EU is beginning toshow evidence of healthcare improvements predicted
to arise from expanding patient access to effective
biologic therapy.3,11 The EU introduction of a biosimilarfor the biologic reference product filgrastim has been
accompanied by a trend towards increased overall use
of filgrastim as prophylaxis against primary neutrope-nia, which has been effective in preventing chemo-
therapy dose reductions and discontinuations.3,11 In the
United Kingdom, the launch of a biosimilar of filgrastimhas reduced per patient spending and increased access
for patients. Specifically, while spending rose only 38%,
filgrastim volume more than doubled from Q1 2008 toQ2 2012. The improved healthcare afforded by the
introduction of this biosimilar may relate in part to the
decision by physicians to preferentially use it earlier inthe course of disease, given its lower cost versus the
reference biologic product. The cost-savings afforded
by using biosimilars in supportive care settings (eg,biosimilars for the biologic reference products of
filgrastim and erythropoietin) may allow more patients
to use life-saving biologic therapies such as rituxi-mab.3,11 The incorporation of biosimilars into US
oncology clinical practice is likely to significantly
impact the cost of cancer therapy.
EXPANDING PATIENT ACCESS TO CARE BYREDUCING HEALTHCARE COSTS
Of the nearly $287 billion spent by Americans
on prescription drugs in 2007, approximately $40billion was attributable to biologics.20,21 Recent data
indicate that 60% of expenditures for the top 10
filgrastimAdalimumabCetuximab
BevacizumabDarbepoetin
InfliximabTrastuzumabRituximab
DarbepoetinAdalimumabBevacizumabPegfilgrastim
2015 2016 2017+
the near future. Generics and Biosimilar Initiative.25
37.7%
62.7%
Nonbiologics$2785
Biologics$4610
Figure 2. Distribution of drug expenditures for the top10 antineoplastic drugs in outpatient clinics (in millionsof dollars). Zelenetz et al,1 Doloresco et al.26
J. AbrahamS8
antineoplastic drugs in 2010 were attributed to theuse of biologics (Figure 2).1,26
The biologic drugs bevacizumab, rituximab, and
trastuzumab were the top three antineoplastic drugsused in 2010, and they collectively accounted for
approximately 58% of the top 10 total antineoplastic
drug expenditures (Table 2).1,26 By comparison, thetop three nonbiologic antineoplastic drugs (doce-
taxel, pemetrexed, and oxaliplatin) accounted for
approximately 24% of the total expenditures.1,26
The eventual integration of biosimilars into oncol-
ogy treatment regimens may significantly impact
patient care in the United States, especially as thecost of biologics is a limiting factor for many
patients. The introduction of biosimilars in the EU
may be resulting in expanded access to life-savingtherapies and use of effective therapies much earlier
in the course of disease.3,11 Given the complex,
multifaceted manufacturing processes required toproduce biologics, it is estimated that biosimilars
will cost between at least 15% and 30% less than the
Table 2. Top 10 Antineoplastic Drug Expenditures i
Rank Drug Type of Drug2010 Exp
($ Mi
1 Bevacizumab Biologic 182 Rituximab Biologic 143 Trastuzumab Biologic 94 Docetaxel Nonbiologic 65 Pemetrexed Nonbiologic 56 Oxaliplatin Nonbiologic 57 Gemcitabine Nonbiologic 48 Cetuximab Biologic 39 Bortezomib Nonbiologic 3
10 Leuprolide Nonbiologic 2Total (Top 10) — 73
Zelenetz et al1 and Doloresco et al.26
reference biologic products. In the EU, biosimilar
versions of recombinant human erythropoietin(rhEPO) have been reported to be 25% to 30% lower
in cost than the reference biologic products. In
comparison, small-molecule generic drugs lowercost up to 90% compared with the small-molecule
reference products.27
In terms of the EU economy, it is too soon toevaluate the impact of biosimilars on the biologics
market. It is important to note, however, that some
EU manufacturers of reference biologic productshave lowered their prices in response to the intro-
duction of biosimilars, which will complicate the
assessment of the economic impact of biosimilarsin the EU and may cause a decrease in interest in
switching to biosimilars.13,27
BACK TO BASICS: COMPARING BIOLOGICSWITH SMALL-MOLECULE DRUGS
For the purposes of this discussion, a “small-molecule drug” refers to any chemically synthesized
drug for which a generic version can be produced
easily (eg, statins and benzodiazepines). Biologics arelarger molecules with many more levels of complex-
ity than small-molecule drugs (Table 3).2,7–10,23,28–31
For example, aspirin is a small-molecule drug with
a well-defined and homogeneous chemical structure;
by comparison, biologics such as trastuzumab maybe between 100 to 1,000 times larger in molecular
weight and are more structurally complex
(Figure 3).8,9,32,33
All biologic drugs are proteins and as such consist
of a defined sequence of amino acids, which con-
stitute the primary structure.1,9 While the primarystructure is essential for biologic activity, additional
n Outpatient Clinics
endituresllions)
Percent of TotalExpenditures
84 26% Top 366 20% Biologics31 13% 59%88 9% Top 379 8% Nonbiologics08 7% 24%63 6%29 4%27 4%20 3%95 100%
Table 3. Key Differences Between Biologics and Conventional Small-Molecule Drugs
Difference Small-Molecule Drugs Biologic Drugs
Size Generally small molecules � Large, complex, protein/glycoproteinmolecules
Structure Simple, noncomplex structure; impurities/contaminants can be easily assessed inrelation to the reference biologic product
� Multiple levels of structure (primary,secondary, tertiary, quaternary) as well aspost-translational modifications; exactstructure cannot be easily assessed inrelation to the reference biologic product
Forms Typically only 1 form and homogeneous � Heterogeneous; multiple distinct isoformsmay be present in a given preparation
Immunogenicity Generally immunologically inert � Potentially immunogenic;immunogenicity versus the referencebiologic product cannot be fullyevaluated
Manufacturingprocess
Produced via chemical synthesis;manufacturing process of the referenceproduct can easily be replicated
� Produced in living systems; manufacturingprocess of the reference biologic productis typically proprietary and cannot beexactly replicated
Stability Typically stable and predictable � May be exquisitely sensitive to physicalconditions (eg, storage conditions, pH,temperature, agitation)
Declerck,2 Cai et al,7 Lee et al,8 Kuhlmann et al,9 Kanter et al,10 Mellstedt et al,23 Nowicki,28 Rathore et al,29 Vulto et al,30 EMA.31
Developing oncology biosimilars S9
levels of structure, including secondary (ie, protein
folding due to hydrogen bonding), tertiary (ie, associ-ations between secondary structures) and quaternary
(ie, associations between two or more protein chains)
structures, also may be essential to confer the ther-apeutic and even the toxic effects of a biologic
(Figure 4).1,10 In addition, the functionality of a
biologic drug may be altered by a wide range ofpost-translational modifications, such as glycosylation,
methylation, acetylation, phosphorylation, and/or
hydroxylation.2
Figure 3. Compared with small-molecule drugs, biologic drugs aversion of this article at seminoncol.org for color figure. (Note: figur
The term “generic” should not be associated with
biosimilars, and should be used to refer to identicalcopies of small-molecule drugs that possess
precisely-defined atomic structures.9,23 In general,
small-molecule generic drugs are identical to thereference small-molecule drugs and can be synthe-
sized reliably and consistently (Table 3). As a result,
the manufacturing, marketing, and integration ofsmall-molecule generic drugs into clinical practice
has been relatively straightforward. A manufacturer
of a small-molecule generic drug needs to demon-
re larger and more complex in structure. Refer to the webe is for illustrative purposes and not intended to be to scale.)
N
Tertiary
C
N N
Quaternary
NN
CC
C C
SecondaryPrimary
F
L
KD
F L
LV T
T S
S
VT P A
F A H
A
S V
K Y
Figure 4. Levels of protein structure (ie, for biosimilars and the reference biologic products). Refer to the web version ofthis article at seminoncol.org for color figure.
J. AbrahamS10
strate physiochemical identity with the reference
biologic product and pharmacokinetic equivalence;the approval process typically requires proof of
quality and pharmacokinetic bioequivalence to the
reference biologic product, and no substantive clin-ical data.9
While biosimilars can be considered to be “sim-
ilar” to the reference biologic products, they cannotbe deemed “identical” due to the inherent complex-
ity of proteins (Table 3).1,17 Differences in any
structural characteristics (eg, more or less glycosyla-tion of a biosimilar versus its reference biologic
product) may potentially impact the efficacy of the
biosimilar, and may increase the potential for AEs.7
Even in the event that all levels of structure for a
given reference biologic product can be reproduced
sufficiently and the biosimilar shows similar activity,the potential still exists for some minute differences
to go undetected, which may result in unforeseen
AEs.10 In addition, even slight differences in abiosimilar (compared with the reference biologic
product) could be sufficient to stimulate an immune
response (eg, a hypersensitivity reaction) not typi-cally observed with the reference biologic prod-
uct.2,10 Finally, even if a biosimilar uses the same
cell lines, reagents, and methodologies as those usedby the reference biologic product, it may not be
possible to completely replicate the exact cell
culture fermentation conditions needed to producethe reference biologic product.7 Because the activity
of biologics is highly dependent on the manufactur-
ing conditions and process, this can lead to productheterogeneity and differences in activity between a
biosimilar and a reference biologic product that can
potentially extend to different manufactured batchesor lots of the biosimilar.1,9
Because biosimilars are different from small-
molecule generic drugs, the manufacturing proc-esses are different, and the regulatory and safety
surveillance (ie, pharmacovigilance) processes that
ultimately are implemented in the United States willbe specific to biosimilars. The United States will
likely follow the lead of the EMA, which authorizes
the use of biologics, whereas use of chemically-derived medicines can be authorized by the member
country’s regulatory agency.13 The regulatory appro-
val pathway for biosimilars has not been fullydefined by the FDA,1 but based on initial draft
guidance, this approval pathway will require a
stepwise “totality of evidence” approach, wherebythe extent of the data provided may be variable
based on type of biosimilar under consideration (to
be further discussed later in this review).19,34
THE BIOSIMILAR MANUFACTURING PROCESS
The World Health Organization (WHO) has sug-
gested that the manufacturing process for bio-
similars be designed to minimize the differencesbetween the biosimilar and the reference biologic
product. The goal of minimizing differences is to
reduce the clinical testing requirements for thebiosimilar by referring to as much of the clinical
history of the reference biologic product as possi-
ble, while decreasing any predictable impact onclinical safety and efficacy.35 Initial guidance from
the FDA has recommended that manufacturers
follow the principles outlined within the Interna-tional Conference on Harmonization (ICH) Q5E
guidelines relating to any change in the manufactur-
ing process for a marketed protein product to “assessthe effects of the [manufacturing] change and demonstratethrough appropriate analytical testing, functional assays,and/or in some cases animal and/or clinical studies, that thechange does not have an adverse effect on the identity,strength, quality, purity, or potency of the product as theyrelate to the safety or effectiveness of the product.”19 None-theless, because the manufacturer of the biosimilar
will be different from the manufacturer of the
reference biologic product, additional data beyondthat required in ICH Q5E guidelines will be needed
to effectively demonstrate biosimilarity.19 Accord-
ingly, a major technical challenge in manufacturingbiosimilars is the knowledge gap caused by the fact
Figure 5. Manufacturing process for biosimilars. Refer to the web version of this article at seminoncol.org for colorfigures. Black and white images: Kuhlmann M, Covic A. The protein science of biosimilars. Nephrol Dial Transplant.2006;21(Suppl 5):v4–8,9 by permission of Oxford University Press. Color images: Iculig/Shutterstock.com; Webspark/Shutterstock.com; Dr Gopal Murti/Science Photo Library; Jennifer Waters/Photo Researchers.
Developing oncology biosimilars S11
that the process for developing and manufacturingthe reference biologic is proprietary.8,23
The key steps involved in producing a biologic are
outlined in Figure 5.9,23,28 These steps includeexpressing the protein in the most appropriate cell
line, producing protein at a commercial level, down-
stream processing, and purification.9,23,28 The cellculture process required for producing a biologic
is considered especially critical in determining identity,
purity, and potency of the finished product.8 Specif-ically, the manufacturing process generally begins
with the gene sequence of the protein of interest
being cloned into an expression vector that is thentransfected and expressed in a unique cell line
derived from a single clonal cell.28 The cell line
expressing the protein must then be rigorouslyevaluated for a number of performance parameters,
including integrity and quality, as well as growth and
viability under the required manufacturing condi-tions.28 Several additional factors can impact the
quality of a manufactured biologic drug, including
source/batch of any of the required raw materials,conditions (eg, temperature, pH, light exposure, and
agitation), chemical substances that can leach from
storage containers, and the equipment used to massproduce the product.8,29
Some of the stages in the biosimilar manufactur-
ing process where potentially significant differen-ces from the manufacturing process of the refer-
ence biologic product may emerge are outlined in
Figure 6.9,28,36 The increased sensitivity of biologicsto changes in physical conditions necessitates strict
control not only over the manufacturing process,but also over the storage and administration con-
ditions for the finished product.8,28 Unlike chemi-
cally synthesized small-molecule drugs that aremore stable and have predictable characteristics,
biologics can be more sensitive to changes in
physical storage conditions of the final product(eg, temperature and pH). Finally, the conditions
in which biosimilars are administered can affect
the final product. For example, whereas most small-molecule drugs can be taken orally, many biologics
must be either injected or inhaled as they are
more sensitive to enzymatic degradation in the dig-estive tract.28
Special Considerations: Biosimilar MonoclonalAntibodies
The top three oncology biologics (bevacizumab,rituximab, trastuzumab) in terms of the expenditures
of outpatient clinics are mAbs (Table 2).26 The
manufacturing process for mAbs can be compli-cated, as mAbs may exist in different structural
isoforms or structural variants, and their activity may
be sensitive to factors such as glycosylation or otherpost-translational modifications.8 The predominance
of a given isoform or variant and/or the presence of
other isoforms or variants in a specific biosimilarpreparation versus its reference biologic product
should be characterized, as this could significantly
impact the efficacy and safety, as well as immuno-genicity of the mAb.8,37
Cell expansion
Cell production in bioreactors
Recovery throughfiltration or
centrifugation
Purification throughchromatography
Characterizationand stability
Different cell line,growth media,
method of expansion
Different cell line,growth media,
bioreactor conditions
Different operatingconditions
Different binding and elution conditions
Different methods,reagents, reference
standards
PurifiedBulk Drug
Figure 6. Manufacturing biosimilars: differences from the reference biologic product may occur at multiple steps in theprocess. Mellstedt et al.23
J. AbrahamS12
In addition to “magic bullet” type specificity of
antigen binding, mAbs have fragment-crystallizable(Fc) regions that can mediate a variety of important
effector functions, such as antibody-dependent cell
cytotoxicity (ADCC) and complement dependentcytotoxicity (CDC), which may be related to their
therapeutic effects.2 Therefore, even if antigen bind-
ing is believed to be the primary mechanism ofaction, it cannot be assumed that Fc effector func-
tions are clinically irrelevant.38 The type and level
glycosylation of the Fc portion of a mAb has thepotential to impact some of the effector functions of
mAbs, such as ADCC and CDC, as well as their
clearance from the body.2 Accordingly, when devel-oping and testing biosimilar mAbs, it will be impor-
tant to evaluate not only the major antibody binding
characteristics, but also the effector functions.Extensive in vitro studies should be conducted to
assess activities such as target antigen binding,
Table 4. Potential Challenges When Bringing Biosim
Challenge
Complex production and analysis procedures,relative to other non-mAb biosimilar products
� Hsa
Competing development of next-generationmAbs with improved stability and/or efficacy
� Sgg
Competing emergence of other antibody-therapeutic technologies (eg, bi-specific mAbs,Fc-linked fusion molecules)
� Sg
Competing emergence of cheaper antibody-producing methodologies (eg, nanoantibodiesproduced in bacteria)
� Prb
Declerck.2
binding to relevant Fc gamma receptors, the func-
tion of the “Fab” portion (including receptor func-tion and ligand neutralization), as well as the Fc-
mediated actions such as complement activation,
ADCC, and CDC functions.2
Because murine-derived mAbs may be potentially
immunogenic in humans and may lack necessary
Fc-mediated actions, many mAbs are fully human(eg, panitumumab) or have been engineered
through recombinant DNA technology to be chi-
meric (ie, having mouse and human portions; eg,rituximab) or humanized (eg, trastuzumab).2 Differ-
ences in immunogenicity between biosimilar mAbs
and the reference mAbs is important to consider, asthese differences could lead to loss of efficacy,
serious AEs, or death associated with the biosimilar
mAb.7 The higher level of complexity associatedwith developing and evaluating biosimilar mAbs
poses several challenges that need to be overcome
ilar mAbs to Market
Anticipated Impact
igher costs of development resulting in muchmaller difference in price between the biosimilarnd reference biologic productmaller perceived benefit of substituting a first-eneration biosimilar product versus a second-eneration productmaller perceived benefit of substituting a first-eneration biosimilar product
otential for further lowering production costs foreference biologic product versus producing theiosimilar product
Developing oncology biosimilars S13
if biosimilar mAbs are to gain widespread use in
clinical practice (Table 4).2
CHALLENGES ASSOCIATED WITHINTEGRATING BIOSIMILARS INTO CLINICALPRACTICE
Key challenges associated with integrating biosi-
milars into clinical practice may include multipleFDA-approved indications for the reference biologic
products, off-label uses of the reference biologic
products, economic and uptake issues, substitutionpractices, and the need for HCP education (Table 5).
Many of these challenges relate to the way biosimi-
larity will be defined and demonstrated. For exam-ple, a key question is how similar is “highly similar,”which means how much evidence must be provided
to gain regulatory approval for biosimilars; thisquestion can also be applied to another important
issue, the interchangeability of the biosimilar and the
reference biologic product from a prescribing stand-point.17 According to the 351(k)(4) of the PHS Act,
biosimilars may be considered “interchangeable” if
an applicant provides sufficient information to dem-onstrate biosimilarity and that the biosimilar can be
expected to produce the same clinical result as the
reference biologic product in any given patient, and,if the biosimilar is administered more than once to
an individual, the risk in terms of safety or dimin-
ished efficacy of alternating or switching betweenthe use of the biosimilar and the reference biologic
product is not greater than the risk of using the
reference biologic product without such alternationor switch. Because such similarity would be difficult
to clinically demonstrate, alternative definitions have
been suggested, such as producing the same ther-apeutic effect within a reasonable degree of statis-
tical assurance. From a practical standpoint, data
from bioanalytical, animal, and clinical studies maybe used to demonstrate biosimilarity with a refer-
ence biologic product.1 Appropriate guidance from
the EMA or the FDA regarding the design andrequirements for biosimilar bioanalytical studies
has yet to be provided.7
Safety and Pharmacovigilance Issues
Pharmacovigilance refers to scientific and data
collection activities related to the detection,
assessment, understanding, prevention, and com-munication of potential safety concerns with drug
products.24,39,40 The goal of pharmacovigilance is
to promptly identify and evaluate safety signals sothat risks can be appropriately managed.39 Phar-
macovigilance programs for biosimilars should
include strategies for AE tracking and tracing topromote responses such as recalls and/or alerts.
This traceability requires the adoption of a rational
international nomenclature system for biosimilars,which has yet to be fully elucidated.39 Such bio-
similar nomenclature may include a unique non-
proprietary name, the Healthcare Common Pro-cedure Coding System/NDC number and the lot
number for each biosimilar; this is needed to
ensure that any potential AE associated with aparticular biosimilar (ie, molecule-specific) is not
erroneously attributed to an entire class of bio-
logics.39 For example, in the EU, use of the Inter-national Nonproprietary Name (INN), which iden-
tifies active pharmaceutical substances and is
crucial for drug substitutions and postmarketingsurveillance reports, as the reference biologic
product may result in safety issues for patients
(eg, AE reporting).13 In addition, pharmacovigi-lance systems must have the flexibility and real-
time data collection capabilities to identify unique
and/or unexpected AEs associated with the bio-similar versus the reference biologic product (eg,
AEs potentially resulting from immunogenicity).39
Ultimately, education of HCPs on pharmacovigi-lance procedures will be required, as they will
bear much of the responsibility for accurately
identifying, recording, and reporting an AE asso-ciated with a biosimilar.1,39
Although it is not possible to predict how
differences in manufacturing or purification of agiven biosimilar will ultimately impact its efficacy
and safety, some insight can be gleaned from the
safety experience with biosimilars in Europe.9,39
For example, most EU countries, in cooperation
with WHO resources, have developed post-
marketing pharmacovigilance programs enablingHCPs, and in some cases patients, to report
any unanticipated AEs and/or lack of efficacy
for a particular biosimilar.30 This type of riskassessment may be particularly useful for detect-
ing rare AEs only observed in large numbers of
patients.30
In Europe, exposure to biosimilars has been
steadily accumulating: for example, as of 2013,
exposure (Binocrit, Sandoz International GmbH,BU Biopharmaceuticals, Holzkirchen, Germany)
was 216,000 patient-years with more than 5,000
patients studied, and exposure to one biosimilarfilgrastim (Zarzio, Sandoz International GmbH,
Kundl, Austria) was 3.5 million patient-days.3 To
date, there have been no relevant efficacy or safetyconcerns with the use of biosimilar versions of
filgrastim in Europe.16 The use of biosimilar fil-
grastims for the prophylaxis of febrile neutropeniais now addressed in the European Organization for
Research and Treatment of Cancer (EORTC) guide-
lines; however, their use is regarded as a change intherapy owing to the possibility of differences
Table 5. Challenges Associated With Incorporating Biosimilars Into Oncology Practices in theUnited States
Topic Challenges
Clinical trials for biosimilars � Although the amount of data needed to approve biosimilardrugs will be less than that needed for a new biologic drug, itwill be greater than that needed for a small-molecule genericdrug; it is expected that clinical trials will be required.However, overall clinician and patient interest in enrolling insuch trials may be low
Economic considerations ofbiosimilars
� Cost-savings with biosimilars will be less than that seen forgeneric small-molecule drugs, because manufacturing anddevelopment costs will be higher; it is unclear how payors willdeal with coverage and reimbursement issues related tobiosimilars; competing cost reductions by the referencebiologic product manufacturer also could impact the overallsavings realized by substituting biosimilars
Safety and pharmacovigilance � Because biosimilars cannot be considered completely identicalto their reference biologic product, they cannot be fullycharacterized from a safety perspective and rigorouspharmacovigilance procedures are needed
Tracking of biosimilars in clinicalpractice
� Tracking the source of biologic drugs (ie, biosimilar vs thereference biologic product) may be challenging, particularlyin community settings, which lack the tracing infrastructureused at larger institutions (ie, which drug was used in whichpatient); effective tracking also requires the reference biologicproduct and the biosimilar to be named differently withdifferent drug codes
Substitution of biosimilars � The FDA may determine that a biosimilar is interchangeablewith a given reference biologic product, however, substitutionpractices vary based on state laws, and these practices will bedifferent from those used for small-molecule generic drugs
Extrapolation of data for other approvedindications or off-label use
� Based on data submitted for 1 indication, the FDA willdetermine whether the use of biosimilars can be extrapolatedto all approved indications of a reference biologic product; itis unclear whether clinicians, payors, and other stakeholderswill consider such data sufficient for extrapolation to otherindications or off-label use
Patient and provider education � The manufacturing and development of biologic drugs andbiosimilars is complex, and physicians need to be aware of thedifferences between biosimilars and generic drugs; educationon the use of biosimilars is needed
Zelenetz et al,1 Schellekens,4 Niederweiser et al,15 Blackstone et al.27
J. AbrahamS14
between the biosimilar and the reference biologic
product. As such, a biosimilar filgrastim cannot be
exchanged without physician and patientknowledge.16
Immunogenicity
The overall immunogenicity of biosimilars can be
impacted by the manufacturing and purificationprocess.3,16 Given that slight differences in biologics
may occur as a result of different manufacturing
processes, it is important to evaluate the immunoge-
nicity of a biosimilar versus the reference biologicproduct.2,10 As shown in Figure 7, subtle variations in
manufacturing and/or storage conditions could have
an impact on the immunogenicity of biologics.41
Immunogenicity studies should include an assess-
ment of the presence of antidrug antibodies (ADAs)
and a determination of whether these ADAs act asneutralizing antibodies that effectively reduce or even
Figure 7. Immunogenicity in patients treated with dif-ferent interferon alpha preparations. Abbreviations: HSA,human serum albumin; IFN, interferon. Refer to the webversion of this article at seminoncol.org for color figure.Reprinted by permission from Macmillan Publishers Ltd:[Seminars in Oncology], Schellekens H. Bioequivalenceand the immunogenicity of biopharmaceuticals. Nat RevDrug Discov. 2002;1:457–62,41 copyright 2002.
Developing oncology biosimilars S15
eliminate activity.7 Specifically, the presence of ADAs
can impact the clinical response to a biologic by
increasing or decreasing drug clearance, neutralizingthe pharmacologic action of the drug and potentially
an endogenous cross-reactive counterpart (which
may lead to a potential deficiency syndrome), orcausing an immune response or hypersensitivity
reaction.7 Development of immunogenicity assays is
challenging because there is more than one drugproduct being assessed (ie, the biosimilar and one or
more reference biologic products).7 Assessment of
immunogenicity is also hampered by a lack of stand-ardization among different laboratories (eg, types of
assays used and methods used to report the data).24
Pharmacokinetic and pharmacodynamic data, aswell as clinical AE profile data, also must be consid-
ered when interpreting immunogenicity.7 Both the
FDA and the EMA require that results of comparativestudies demonstrate that the biosimilar is no more
immunogenic than the reference biologic product.7
Despite these requirements and regardless of theresults of immunogenicity testing, the postmarketing
pharmacovigilance plan, such as the plan developed
in the EU, will be key to the safe use of biosimilars,especially biosimilar mAbs. This is especially impor-
tant because there currently are no means of reliably
predicting immunogenicity in humans, and thereforesuch assessments must be based on risk.2,38
Of note, in 2002 and 2003, European patients with
chronic renal failure who received rhEPO developedan erythropoietin-resistant, transfusion-dependent
severe anemia caused by antibody-mediated pure red
cell aplasia.39,42,43 Most of these cases ultimately wereattributed to a specific preparation of erythropoietin
made by a single manufacturer, and among the
possible causes identified were differences in manu-facturing, formulation, and the primary container
used.38,44,45 Although these experiences were based
on a slight change in the manufacturing process andnot the use of a biosimilar, they highlight the need for
immunogenicity testing when assessing biosimilarity,
as well as the importance of having rigorous pharma-covigilance procedures in place to detect and track
unanticipated AEs.24
Provider and Payor Issues
Ensuring that providers have confidence in the
safety and efficacy of biosimilars is paramount.Physicians, pharmacists, and payors are likely to
have the most impact on the use and assimilation
of biosimilars into clinical practice, and they must beconfident in the data provided to regulatory agencies
for approval (including demonstrations of biosimi-
larity and interchangeability with the reference bio-logic product regarding safety and efficacy), as well
as the resulting regulatory agency guidance.1 It is
especially important that HCPs understand the com-plexities involved in producing biologic drugs and
the potential clinical implications of using biosimi-lars that are considered similar, but not exactly
identical, to the reference biologic product.1,8 As
such, an in-depth understanding of biosimilars as adrug class will be required for physicians, pharma-
cists, and those responsible for reimbursement of
treatment costs.16 Evidence from the NCCN suggestthat significant knowledge gaps currently exist.1
Nomenclature Issues
Generic drugs, by definition, have the same non-
proprietary name as the original reference drug.1
Because biosimilars are not identical to referencebiologics, one possible naming convention is that
biosimilars should be assigned a related, but unique
and distinguishable nonproprietary name. Thisapproach may facilitate postmarketing safety mon-
itoring and AE data collection by ensuring that
specific events can be correctly attributed to thebiosimilar or the reference biologic.1 For example,
J. AbrahamS16
for naming biosimilars in Japan, both the brand name
and the nonproprietary name of the reference bio-logic product are used, with the nonproprietary
name followed by “kozoku-1,” which means follow-
on biologic-1 or biosimilar-1 (eg, Avastin bevacizu-mab kozoku-1).45
Since biosimilars cannot be considered identical
to reference biologics, the United States AdoptedName Council (USANC) has stated that biosimilar
manufacturers should not assume biosimilars will
have the same nonproprietary names as the refer-ence biologics.1 Guidance from the regulatory agen-
cies is needed to determine whether a biosimilar and
its reference biologic will have the same nonpropri-etary name.1 One disadvantage to the unique naming
of biosimilars is the potential for confusion among
HCPs and patients regarding comparability with thereference biologic products; even if biosimilarity has
been adequately proven, different names may bias
HCPs and/or patients into thinking that safety andefficacy is not equivalent.1
Regulations Regarding Biosimilar Substitution
The process (ie, policies and regulations) for
substituting the reference biologic for a biosimilarmay be difficult for HCPs to navigate. Although the
BPCI Act allows the FDA to make an interchange-
ability determination for biosimilars, substitutionpractices are governed by state laws.1 Current state
laws regarding automatic drug substitution (ie, the
substitution of a generic for the original referencebiologic product unless the prescriber specifies
otherwise) were developed and enacted before the
emergence of biosimilars.1 As such, individual statesmay or may not take into account FDA-directed
interchangeability determinations when developing
new laws and regulations governing the use ofbiosimilars, which could lead to further confusion
among HCPs.1
THE BIOSIMILAR EXPERIENCE IN COUNTRIESOTHER THAN THE UNITED STATES
The integration of biosimilars has already begun incountries other than the United States, putting the
US government, biotechnology, and pharmaceutical
industries in a position to learn from these experi-ences and develop effective manufacturing and
approval processes that facilitate the safe integration
of biosimilars into clinical practice. Although indi-vidual requirements, definitions, and scope of guid-
ance may differ, most regulatory authorities around
the world appear to adhere to several key principlesregarding the characterization of biosimilars17:
●
The regulatory approach to biosimilars should bedifferent from that used for generic drugs, andsimilarity in terms of quality, efficacy, and safety
must be proven for the biosimilar and the refer-ence biologic product
●
As a prerequisite for reducing the amount ofnonclinical and clinical data submitted for appro-
val, a stepwise approach is needed to ensureadequate similarity in quality between the biosi-
milar product and the reference biologic product
●
Different classes of biologics may necessitatedistinct biosimilarity assessment requirements
●
Close attention to pharmacovigilance is neededfor biosimilarsThe EU was an early adopter of biosimilars and
provides examples of what the regulatory process
will likely entail for the United States. In addition, anumber of emerging markets have some experience
with biosimilars. In Brazil, a two-pathway system
was developed in 2010 to help foster the use ofbiosimilars.46 The first of these pathways, termed the
“individual pathway,” was developed in response to
high expenditures for pegylated interferons for thetreatment of hepatitis C. In this pathway, the devel-
opment process, dossier, quality issues, and require-
ments for clinical studies are reduced, butindications cannot be extrapolated.46 The second
pathway, termed the “comparability pathway,”allows extrapolation to other indications; however,the pathway is more rigorous and requires compa-
rative phase I, II, and III clinical trials with the
reference biologic product.46 While the adoption ofthese pathways may help drive the integration and
utilization of biosimilars, it is not yet known how
these regulatory pathways might be impacted withdevelopment of more complex biosimilars such as
biosimilar mAbs.46
China and India represent two very large andemerging markets for biosimilars; however, there
may be some unique challenges as Western bio-
similar manufacturers enter these markets and viceversa.18 In China, domestically produced biosimi-
lars have been available for use for more than 20
years, and there is no specific regulatory processfor approval, with the State Food and Drug Admin-
istration overseeing a similar regulatory process for
all pharmaceuticals.18 In India, there has been arobust acceptance of biosimilars, with some 50
biopharmaceuticals on the market, of which
greater than half are biosimilars; nonetheless, someconcern has been raised over the standards of the
Indian regulatory authorities in terms of the purity
of its biosimilars and control over postmanufactur-ing storage and distribution conditions.18,47 Indian
biosimilar manufacturers will need to adhere to
EMA guidelines as they begin to enter the globalbiosimilars market.47
Developing oncology biosimilars S17
EXAMINING THE CURRENT STATE OF AFFAIRS
The NCCN Biosimilars Work Group
In 2011, the NCCN formed a Biosimilars Work
Group consisting of a multidisciplinary group ofproviders (physicians, pharmacists, and nurses), man-
ufacturers, patients, payors, and government offi-
cials.1 The purpose of the work group was toadvise oncology practitioners and other key stake-
holders on the major challenges ahead and provide
recommendations for developing and using biosimi-lars in oncology.1 The key consensus statements and
recommendations of the NCCN Biosimilars Work
Group are summarized in Tables 6 and 7.1 Briefly,with regard to recommendations of the work group,
it is expected that clinical trials incorporating rele-
vant and sensitive end points will be needed to
Table 6. Biosimilars in Oncology: Consensus Statem
Importance, access, andaffordability
● The overall goal ofto biologic medicatherapies for cance
● The NCCN Work Goncology care andpathway (character
Approval pathway shoulddemonstrate similarity
● At the time of bioshigh similarity to thpharmacodynamic
● Efficacy and safety ono clinically meaninreference biologic p
Standardization with referencebiologic product
● The NCCN Work Gelements of a biosibiologic product (fomedication errors).should be the sameAdditionally, Risk Ethe associated provbetween biosimilar
Tracking product use ● The ability to trackroutine clinical usebatch was seen assafety of these med
Need for educating patients andHCPs
● Patients and HCPs rof biosimilars. Patiereceive
● In the context of mhelp avoid medicatthey receive
Zelenetz et al.1
demonstrate similarity between the biosimilars and
the reference biologic product.1 It was also agreedthat guidance is needed from the FDA on key issues
such as specifically defining what is meant by a “highdegree of similarity” and “no clinically meaningfuldifferences in efficacy and safety.”1 It is also expected
that NCCN guideline panels will need to evaluate
recommendations about the use of biosimilars rela-tive to specific diseases to provide guidance for
pharmacy and therapeutics committees and other
practitioners in community practice. It also wasrecognized that educational activities are required
to inform HCPs, including physicians, nurses, phar-
macists, physician assistants, and nurse practitionersof the development, evaluation, and pharmacovigi-
lance efforts that will be necessary to make biosimi-
lars viable options for the treatment of malignances.1
ents From the NCCN Biosimilars Work Group
biosimilars is to increase affordability and accesstions for patients, which are often importantr careroup believes biosimilars are important tois supportive of defining a biosimilars approvalized in the BPCI Act of 2009)
imilar approval, a biosimilar must have showne reference product in quality attributes andand pharmacokinetic parametersf the biosimilar product must be comparable (ie,gful difference in safety and efficacy) to theroduct
roup agrees with current regulations thatmilar drug product should follow the referencer the purpose of consistency of practice avoidingFor example, the dosing for a biosimilar agentas for the reference biologic product.
valuation and Mitigation Strategies (REMS) andider workflow process should be standardizedand reference biologic products
a patient’s receipt of a biosimilar product duringdown to the level of a specific manufacturer anda critical element of assessing and ensuring theications
equire education to increase their understandingnts also should know all the medicines they
ultisourced biologics being available, this mayion errors if patients know the exact drug product
Table 7. Considerations and Recommendations Regarding Biosimilars in Oncology: The NCCNBiosimilars Work Group
Considerations Recommendations
Use of appropriate endpoints
� End points studied must be sensitive enough to show differences, if any,between biosimilar and the reference biologic product; end points suchas overall response, overall survival, and/or progression-free survival willbe most helpful for HCPs
Consistency andtransparency
� A consistent and transparent approach is recommended for the FDAprocess of determining biosimilarity, including definitions of highly similarquality attributes and “no meaningful differences in efficacy or safety”;required scientific data should be based on known safety and efficacyprofile of the reference biologic product
Use in NCCN Guidelines � NCCN Guideline Panels should evaluate biosimilars and their potentialrole in treatment and provide recommendations for their use;recommendations against biosimilars are not anticipated, but informationwill be helpful to provide clarity for key stakeholders (ie, clinicians,patients, payors)
Pharmacy and Therapeutics(P&T) Committees
� Institutional P&T committees should evaluate biosimilars for use in theirspecific populations and this approach should be different from that ofgeneric small-molecule drugs; as with other drugs, for those practitionersnot under P&T guidance, consideration and review of individualbiosimilars is recommended before routine use is implemented
HCP and policymakereducation
� Education about basic scientific principles of biologic drugs and biosimilars,as well as their manufacturing processes and associated pharmacovigilanceprocedures, should be disseminated to HCPs (ie, physicians, pharmacists,nurses), in addition to legislators and policy makers
Safety, tracking, andnomenclature
� Guidance is needed from the FDA about naming of biosimilars (eg, willthey have unique nonproprietary names)
Zelenetz et al.1
J. AbrahamS18
WHO and FDA Guidance
In 2010, the WHO provided guidance for evaluat-
ing “similar biotherapeutic products” or SBPs.35 Thisguidance recognizes the differences betweengeneric drugs and biosimilars and the processes
required to conclude their therapeutic equiva-
lence.35 Some of the key principles of the WHOguidance regarding the licensing of biosimilars are
listed in Table 8.35 The BPCI Act, by comparison,
only serves to outline broad concepts related to USbiosimilar approval policy, and it was recognized
that additional information from the FDA was
needed.48
A significant step toward integrating biosimilars
into clinical practice was made by the FDA with the
release in 2012 of draft guidance for the develop-ment and approval of biosimilars.19 Further draft
guidance on biosimilars was provided by the FDA in
2012, but some important questions remain.48 In2013, Li and Hoffman reviewed the draft FDA
guidance from the point of view of practicing
oncologists.48 The main purpose of the first FDAdocument, Quality Considerations in Demonstrating
Biosimilarity to a Reference Protein Product is to provide
information on determining biosimilarity to thereference biologic product.48 The document specif-
ically summarizes the FDA’s position on demonstrat-
ing biosimilarity to a reference biologic product thatis listed under Section 351(a) of the PHS Act, for the
purposes of submitting a marketing application
under Section 351(k) of the PHS Act. The documentalso provides the definition of biosimilarity included
in Table 1.34 The document concludes that the
demonstration of biosimilarity with a reference bio-logic product involves “the robust characterization of theproposed biosimilar product, including comparative physico-chemical and functional studies.”34
The second document, Scientific Considerations inDemonstrating Biosimilarity to a Reference Product, pro-vides information on the types of evidence requiredto demonstrate biosimilarity.19,48 The proposed evi-
dence to be provided includes structural and func-
tional analyses comparing the biosimilar with thereference biologic product, as well as in vivo animal
studies comparing toxicity, pharmacokinetic, phar-
macodynamic, and potentially immunogenicityparameters between the products.19,48 Also of
Table 8. WHO Guidance on Biosimilars: Key Principles Regarding the Licensing of Similar BiologicProducts
● The development of a SBP involves stepwise comparability exercise(s) starting with comparison of thequality characteristics of the SBP and RBP. Demonstration of similarity of a SBP to a RBP in terms ofquality is a prerequisite for the reduction of the nonclinical and clinical data set required for licensure.After each step of the comparability exercise, the decision to proceed further with the development ofthe SBP should be evaluated
● The basis for licensing a product as a SBP depends on its demonstrated similarity to a suitable RBP inquality, nonclinical, and clinical parameters. The decision to license a product as a SBP should bebased on evaluation of the whole data package for each of these parameters
● If relevant differences are found in the quality, nonclinical or clinical studies, the product will not likelyqualify as a SBP and a more extensive nonclinical and clinical data set will likely be required to supportits application for licensure. Such a product should not qualify as a SBP as defined in this guideline
● If comparability exercises and/or studies with the RBP are not performed throughout the developmentprocess as outlined in this guidance document, the final product should not be referred to as a SBP
● SBPs are not “generic medicines” and many characteristics associated with the authorization processgenerally do not apply
● SBPs, like other biotherapeutic products, require effective regulatory oversight for the management ofpotential risks and to maximize benefits
Abbreviations: RBP, reference biologic product; SBP, similar biologic product.WHO.35
Developing oncology biosimilars S19
importance in this draft guidance is the requirementfor human clinical studies aimed at showing “noclinically meaningful differences between the [biosimilar]product and the reference biologic product in terms of safety,purity, and potency.”19,48 The document suggests a
need for clinical pharmacokinetic/pharmacodynamic
data, clinical efficacy and safety data, and clinicalimmunogenicity data, as well as postmarketing sur-
veillance measures for biosimilars.19,48 The docu-
ment also notes that specific clinical/preclinicaldata required will differ depending on the type of
product, and that a “totality of the evidence”approach will be used to consider biosimilars.19,48
With such an approach, all data submitted by the
sponsor, with regard to structural and functional
characterization, nonclinical evaluation, humanpharmacokinetic and pharmacodynamic data, clini-
cal immunogenicity data, and clinical safety and
efficacy data will be evaluated.19,34
Some of the key limitations of this draft FDA
guidance include a lack of advice on what types of
clinical trials will be required for which products,although each biologic will likely be assessed on a
case by case basis, with more complex biologic
products (eg, mAbs) requiring additional evalua-tion compared with simpler products.2,19,48
Current automatic substitution policies are notapplicable to biosimilars; further guidance is
needed in this area. There also may be a need
for additional explicit guidance to individualstates on the substitution of biosimilars without
notification of the prescriber or patient.48 In
addition, questions may arise if a product isdemonstrated to be a biosimilar for only one of
several indications held by the reference biologic
product. Whether or not clinical trials for otherindications will be mandated by the FDA is unclear
(Table 5).48 Some of the key points in the FDA
guidance from 2012 are summarized in Table 9.7
In March 2013, the FDA issued further guidance
titled Formal Meetings Between the FDA and Biosimi-lar Biological Product Sponsors or Applicants. Thepurpose of this document is to provide nonbind-
ing recommendations to industry regarding formal
meetings between the FDA and biosimilar spon-sors or applicants.49
The NCCN Survey
In 2011, the NCCN published the results of a
survey on HCP knowledge of biosimilars. This surveywas conducted at the NCCN 16th Annual
Table 9. FDA Draft Guidance on Biosimilars: Key Points
● FDA will use a risk-based, totality of evidence approach when evaluating data to determinebiosimilarity
● Sponsors should develop a stepwise approach to demonstrating biosimilarity, including structural andfunctional characterization of the biosimilar and the reference biologic product (eg, post-translationalmodifications)
● A full nonclinical program may not be needed if extensive structural and functional similarity isdemonstrated in comparative studies and animal toxicology studies
● Comparative clinical studies must demonstrate purity, potency and safety though an evaluation ofimmunogenicity, pharmacokinetics, and pharmacodynamics in a condition for which the referencebiologic product is approved
Cai et al.7
Figure 8. NCCN Survey: Biosimilars – Response to:“Please rate your overall familiarity with developmentsfor biosimilars, including recent legislation that providesan approval pathway for nonreference (eg, ‘generic’)manufacturers to introduce copies of biologics throughan abbreviated review process.” Refer to the web versionof this article at seminoncol.org for color figure. ZelenetzAD, Ahmed I, Braud EL, et al. NCCN Biosimilars WhitePaper: regulatory, scientific, and patient safety perspec-tives. J Natl Compr Canc Netw. 2011;9(Suppl 4):S1–22,1
reprinted with permission from JNCCN—Journal of theNational Comprehensive Cancer Network.
J. AbrahamS20
Conference (March 2011), and 277 participants
responded including physicians (47%), nurses
(26%), and pharmacists (14%); a smaller percentageof other clinicians and nonclinicians also responded.1
Respondents were asked about their overall familiarity
with developments around biosimilars, includingawareness of legislation providing for abbreviated
approval.1 The results indicated that 55% of respond-
ents were either not at all familiar or only slightlyfamiliar with the developments around biosimilars
(Figure 8).1
The respondents’ overall interest in prescribing,dispensing, and administering biosimilars, once FDA
approved for use, also was assessed. The results
indicated a high level of interest (62% rating theirinterest as high or moderately high) (Figure 9).1
Notably, just over a quarter of the respondents said
they need more information about biosimilars beforemaking their decision.1 Respondents were asked
to evaluate the importance of specific types of
information when making decisions about biosimi-lars.1 Results for this question showed that, whereas
studies comparing clinical end points in safety and
efficacy appeared most important (with 74% ratingthis type of information as very important), 86%
of respondents indicated that all the types of infor-
mation identified in the survey were at least some-what or very important (Figure 10).1
Additional data from the survey also highlighted
those respondents who were familiar with biosimilardevelopments had defined opinions on whether they
would immediately use or not use biosimilars once
they become available. Most respondents who hadonly somewhat or slight familiarity with biosimilars
stated they would require further review and discus-
sion before making a decision to use biosimilars.1 TheNCCN noted that because a “convenience sample” (ie,
surveying a nonspecific group) was used, the respond-
ents may not be representative of US oncology
practitioners. This may be a reason why their overallknowledge of biosimilars was fairly low.1 Despite the
limitations, the overall conclusions from this survey
indicate that while there was a high level of interest inusing biosimilars, awareness of biosimilars is subopti-
mal, and a need exists for greater patient and provider
education about these emerging products.1
Figure 9. NCCN Survey: Biosimilars – Response to: “Onceapproved by the FDA, what is your interest in prescribing,dispensing, or administering biosimilars in your practice set-ting?” Refer to the web version of this article at seminoncol.org for color figure. Zelenetz AD, Ahmed I, Braud EL, et al.NCCN Biosimilars White Paper: regulatory, scientific, andpatient safety perspectives. J Natl Compr Canc Netw. 2011;9(Suppl 4):S1–22,1 reprinted with permission from JNCCN—Journal of the National Comprehensive Cancer Network.
Developing oncology biosimilars S21
BIOSIMILARS: COMPETING INTERESTS, RISKS,AND BENEFITS
The development and implementation of biosimi-lars is of interest to a wide range of stakeholders,
including the patients who will ultimately use them,
HCPs who prescribe them, manufacturers of thereference biologic products and biosimilars, as well
as payors and government regulatory agencies.1 The
successful integration of biosimilars into the
Figure 10. NCCN Survey: Biosimilars – Response to: “As more infothe following types of information in helping you decide to use bioseminoncol.org for color figure. Zelenetz AD, Ahmed I, Braud EL, etpatient safety perspectives. J Natl Compr Canc Netw. 2011;9(Supplthe National Comprehensive Cancer Network.
pharmaceutical marketplace will require a consensus
among all the stakeholders involved.1 The benefits ofinnovation, expanded drug access, and affordability of
medications must be balanced with the need for
sufficient safety and efficacy data, as illustrated inFigure 11.1 For example, from an economic stand-
point, an extensive verification process may impact
production costs, resulting in less pharmacoeconomicbenefit versus the reference biologic product. From
the patient and HCP perspective, a more extensive
verification process will provide more comprehensivesafety and efficacy data versus the reference biologic
product, which may allow greater patient/provider
acceptance and integration into practice. The sameset of examples also can be applied from the insurers’and payors’ perspective, and thus it remains to be
seen how these factors will come together to impactthe ultimate success of biosimilars.
SUMMARY AND CONCLUSIONS
While biologics have helped revolutionize the
treatment of cancer, they are expensive, accountingfor more than half of the healthcare expenditures
in oncology. The Patient Protection and Affordable
Care Act, signed into law by President Obama onMarch 23, 2010, has amended the PHS Act and
provided for an abbreviated approval pathway for
biologics that are demonstrated to be “biosimilar” or“interchangeable” with an FDA-licensed reference
biologic product. This has helped pave the way for
the eventual emergence of biosimilars in the UnitedStates.19 The development and implementation of
biosimilars has the potential to create a truly com-
petitive and innovative environment in which the
rmation on biosimilars becomes available, how important aresimilar products?” Refer to the web version of this article atal. NCCN Biosimilars White Paper: regulatory, scientific, and4):S1–22,1 reprinted with permission from JNCCN—Journal of
Figure 11. Biosimilars: risks and benefits in the development and approval process. Zelenetz et al.1
J. AbrahamS22
cost of biologics may be reduced, increasing their
overall affordability and accessibility for patients. It isclear that access to therapy is an important predictor
of outcome and that the availability of lower cost
biosimilar treatments could make treatments an optionfor more patients earlier in the course of disease.
The process involved in developing biosimilars is,
however, markedly different from that for producinggeneric versions of small-molecule drugs, which has
important implications for manufacturing, approval,
regulatory, and substitution processes. In addition,several key oncology drugs are mAbs, which have
many levels of molecular complexity that make them
especially challenging to produce as biosimilars.There also are several regulatory issues associated
with the development and implementation of bio-
similar drugs that remain unresolved. Overall,because they involve a more complex development
process, the level to which they will reduce costs
over the reference biologic products is likely to beless than that of generics. How biosimilar products
will be received by patients and providers remains to
be seen. Because they can be considered “highlysimilar” but not exactly identical to the reference
biologic product, new policies regarding the nomen-
clature of biosimilars, as well as extensive pharma-covigilance procedures to quickly identify any
important differences in efficacy and/or safety from
the reference biologic product, are needed.Results from a recently published NCCN survey
suggest that, despite a high interest in the potential
benefits of using biosimilar drugs, there is a need forgreater education on biosimilars for oncologists,
nurses, pharmacists, and other HCPs. It will be
essential that all key stakeholders, including physi-cians, pharmacists, and payors, possess an in-depth
understanding of biosimilars so that the potential for
improving access and outcomes in oncology can berealized. Important additional guidance from the
FDA regarding biosimilars is also needed and
expected and this will be critical to the furtherdevelopment of biosimilars in the United States.
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