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690743

research-article2017
AOPXXX10.1177/1060028017690743Annals of PharmacotherapyStevenson et al

Review Article
Annals of Pharmacotherapy

Biosimilars: Practical Considerations


1­–13
© The Author(s) 2017
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DOI: 10.1177/1060028017690743
https://doi.org/10.1177/1060028017690743
journals.sagepub.com/home/aop

James G. Stevenson, PharmD1,2, Robert Popovian, PharmD3,


Ira Jacobs, MD4, Susan Hurst, RPh, PhD5, and Lesley G. Shane, PharmD6

Abstract
Objective: To review the scientific and regulatory aspects of biosimilar development and practical considerations for the
use of biosimilars that are relevant to pharmacists. Data Sources: Literature searches of PubMed and congress abstracts
for publications pertaining to biosimilars were conducted from January 2016 to January 2017. Individual drug company web
pages and governmental, regulatory, and other agency websites were also reviewed. Study Selection/Data Extraction:
Published articles, regulatory guidelines, and other sources covering biologic/biosimilar development and approval,
reporting results of biosimilar studies or survey research, and/or identifying biosimilars in development or approved for use
in Europe or the United States were reviewed and included. Data Synthesis: Biologic therapies have revolutionized the
treatment of serious diseases, including hematological or autoimmune disorders and cancers. A biosimilar is highly similar
to a licensed biologic (ie, reference or originator) and has no clinically meaningful differences in safety, purity, and potency.
Unlike small-molecule drugs, biologics are large, complex proteins that cannot be exactly replicated, so the concept
of a generic equivalent cannot be applied to biologics. Regulatory agencies have provided a framework for biosimilar
approval, but there are many practical considerations for pharmacists, including interchangeability, substitution, naming,
indication extrapolation, product labeling, therapeutic drug monitoring, manufacturer attributes, logistics of product use,
and reimbursement. Conclusions: Pharmacists will play a key role in managing the introduction of biosimilars into health
care systems. Understanding the principles of biosimilar development and evolving regulatory guidelines relevant to their
use will allow pharmacists to make informed decisions regarding formulary inclusion and educate patients and other health
care providers about biosimilars.

Keywords
biotechnology, legal/regulatory issues, formulary, clinical practice, postmarketing surveillance

Introduction evidence generated during biosimilar development and


robustness in the biosimilar manufacturing process.2-5
Biologic therapies have revolutionized treatment of patients The biosimilar market is expanding, and pharmacists will
with serious diseases, such as hematological (eg, anemia, help manage the introduction of biosimilars into health care
hemophilia) or autoimmune (eg, rheumatoid arthritis [RA], systems. Understanding the scientific principles of biosimi-
Crohn’s disease) disorders and cancers. As patents or data lar development and requirements for biosimilar approval
protection for many biologics expire,1 biosimilar agents will allow pharmacists to make informed decisions about
will become available that offer additional options and may
address the unmet need for broader access to biologic thera- 1
College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
pies. A biosimilar is a biologic product that is highly similar 2
Hospital & Health Systems Services, Visante Inc, St. Paul, MN, USA
to and shows no clinically meaningful differences from a 3
US Government Relations, Pfizer Inc, Washington, DC, USA
licensed biologic (ie, reference or originator) in terms of 4
Oncology Biosimilars, Pfizer Inc, New York, NY, USA
5
safety, purity, and potency.2-5 Unlike traditional pharmaceu- Development Strategies Group in the Pharmacokinetics, Dynamics, and
tical or small-molecule agents, biologics have large, com- Metabolism Department, Pfizer Inc, Groton, CT, USA
6
Outcomes and Evidence, Global Health and Value, Pfizer Inc, New
plex, and heterogeneous structures that are difficult to fully York, NY, USA
characterize and impossible to replicate exactly.6-10
Therefore, the concept of a generic equivalent cannot be Corresponding Author:
James G. Stevenson, Department of Clinical Pharmacy, College of
applied to biologics,2 and biosimilar approval pathways Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI 48109-
must consider the degree of similarity between a proposed 1065, USA.
biosimilar and reference product based on the totality of the Email: jimsteve@med.umich.edu
2 Annals of Pharmacotherapy 

Monoclonal Antibody
~150,000 Da

Aspirin
180 Da

Small-molecule drugs Biologics

1000 Da

Figure 1.  Biologics are larger and more complex than small-molecule drugs.
Abbreviation: Da, Dalton.

product safety and efficacy during formulary review. It will and have simple, well-defined structures (Figure 1).6-10 In
also help them educate patients and other health care provid- contrast, biologics are large, complex proteins that are pro-
ers about biosimilars. This review provides an overview of duced in living systems.6-10 Their primary structure is an
biosimilars and discusses practical considerations for their amino acid chain, which is folded into patterns that estab-
use that are relevant to pharmacists. lish secondary structure and create a unique 3-dimensional
shape difficult to fully characterize.
Compared with chemical synthesis, biological reactions are
Data Sources and Selection inherently variable and yield heterogeneous products that are
Searches of PubMed and congress abstracts for literature also highly sensitive to their manufacturing and handling con-
pertaining to biosimilars were performed from January 2016 ditions.6-10 Changes in the production process (eg, cell culture,
through January 2017 using terms that included biosimilar(s), protein recovery and purification, formulation, storage, or
interchangeability, naming, substitution, labeling, extrapo- packaging) may lead to variations in primary amino acid
lation, and reimbursement. Relevant English-language pub- sequence or posttranslational modifications (eg, glycosylation)
lications were selected and included. Additional information that could disrupt higher-order structure and, therefore, the bio-
about biologic/biosimilar development and approval was logical properties of the protein.6-14 For instance, glycosylation
obtained from drug regulatory, governmental, and other (eg, can potentially influence biologic activity directly by altering
World Health Organization [WHO]) agency websites. effector functions or indirectly by prolonging or shortening
Biosimilars in development and those authorized in Europe half-life.7,11,15-19 Other chemical modifications (eg, oxidation
or licensed in the United States were identified from drug or deamidation) may occur that promote degradation or dena-
regulatory, drug company, and/or other authoritative (eg, turation and the formation of protein aggregates that have little
Generics and Biosimilars Initiative) websites. or no drug activity and can contribute to the higher potential
for immunogenicity with biologics versus small-molecule
drugs.6,7,12,14,20 Although rare, the presence of antidrug antibod-
Biologics Versus Traditional ies (ADAs) may cause allergy, anaphylaxis, and serum sick-
Pharmaceutical Agents ness or loss of efficacy6,20; therefore, immunogenicity and
Traditional pharmaceutical agents are small-molecule drugs product safety must be assessed in clinical studies and moni-
that are manufactured through standard chemical synthesis tored through postmarketing pharmacovigilance.
Stevenson et al 3

The manufacturing process for a licensed biologic is In the United States, small-molecule drugs are approved
legally patented and protected by law; thus, biosimilar under the Food, Drug, and Cosmetic Act (FDCA) either as
manufacturers must independently develop their own pro- new drugs following section 505(b) or as generic drugs fol-
duction processes to create biologic products that are lowing section 505(j), which was added by the Hatch-
highly similar to reference products. Methodological dif- Waxman Act of 1984.24 In contrast, biologics are approved
ferences between the development of reference and bio- under the Public Health Service Act (PHSA) either as new
similar products may result in structural and functional biologics following section 351(a) or as biosimilar biolog-
differences. The potential impact of this heterogeneity on ics following section 351(k), which was established by the
drug safety and efficacy must be evaluated when seeking Biologics Price Competition and Innovation (BPCI) Act of
biosimilar approval. 2009.4,25
Each pathway has different requirements for regulatory
Overview of Regulatory Approval for approval. Compared with a new biologic license applica-
tion, the biosimilar drug application places greater empha-
Biosimilars sis on findings from analytical assessments.3,4 This approach
Biosimilar approval is based on a demonstration of biosimi- reduces unnecessary testing and provides the rationale for
larity, which confirms that the biosimilar product is highly abbreviated, comparative, nonclinical and clinical pharma-
similar to and has no clinically meaningful differences in cokinetics studies and confirmatory efficacy trials.2,3,5 In
safety, purity, and potency from the reference product.2,3,5 A contrast, regulatory approval for small-molecule generic
determination of biosimilarity is based on the totality of the drugs is based on a demonstration of therapeutic equiva-
evidence generated during biosimilar development, which lence (ie, pharmaceutical equivalence and bioequivalence).
follows a stepwise approach and begins with extensive Once established, the safety and efficacy of a small-mole-
structural and functional characterization.2,3,5 To be consid- cule generic drug can be inferred from its brand-name coun-
ered for clinical development, a proposed biosimilar must terpart, thus eliminating a need for clinical testing.26
have the same primary amino acid sequence as and be Some biologics approved as biosimilars by the EMA
highly similar to the reference product in terms of higher- have been approved by the FDA through alternate regula-
order structures, posttranslational modifications, isoform tory pathways, meaning they are not classified as biosimi-
profile, and product purity.2,3,5 The proposed biosimilar lars in the United States.27 For instance, the FDA approved
should also demonstrate biologic activity that is highly sim- nonoriginator low-molecular-weight heparin and insulin
ilar to and dependent on the same mechanism(s) of action as products as well as human growth hormones either as
the reference product.2,3,5 generic drugs under section 505(j) or as new drugs via sec-
After demonstrating analytical and functional similarity tion 505(b) of the FDCA.28-30 A provision of the BPCI Act
to the reference product, nonclinical pharmacokinetic and requires all biologic products previously approved under
pharmacodynamics studies are conducted to address the FDCA to be regulated as biologics under the PHSA as of
remaining uncertainties.2,3,5,21 Animal toxicity studies, March 2020.4,31 The FDA issued draft guidance on its
where applicable, should demonstrate high similarity approach to implementing this provision and may reclassify
between the proposed biosimilar and reference product in such biologics as biosimilars.31 Another example is the
terms of drug exposure and response and may include granulocyte colony-stimulating factor (G-CSF) tbo-filgras-
immunogenicity assessments to support the interpretation tim, which was approved in the United States using a full
of nonclinical results.2,3,21 Finally, comparative clinical biologics license application, prior to the BPCI Act.32
studies are conducted to demonstrate pharmacological However, this agent was approved by the EMA as a filgras-
(pharmacokinetic/pharmacodynamics) and clinical (safety, tim biosimilar of Neupogen (Amgen) and marketed under
efficacy, and immunogenicity) similarity to the reference the trade name Tevagrastim in Europe.
product.2,3,5,21,23 Biosimilars must not be confused with noncomparable
Considerations for the evaluation of biosimilars (eg, biotherapeutic products (ie, intended copies). Intended cop-
quality and manufacturing, nonclinical and clinical assess- ies have been introduced in some countries as biosimilars
ments) are similar across European Medicines Agency but are not truly biosimilars because they have not met
(EMA) and Food and Drug Administration (FDA) guide- EMA, FDA, or WHO requirements of biosimilarity.33-35
lines; however, there are some differences.2,3,5,13,21-23 For Because the quality and clinical profiles of intended copies
instance, EMA outlines additional, product-specific require- have not been characterized, there is an increased potential
ments, based on biologic classification. In contrast, FDA risk to patient safety and drug efficacy. Finally, biologic
uses a risk-based approach to evaluate the totality of the products that have been altered (structurally and/or function-
evidence from all stages of development and determines ally) to achieve improved efficacy and/or safety over the
product requirements for biosimilar approval on a case-by- originator biologic cannot be classified as biosimilars.36,37
case basis.3 An example may be the recombinant chimeric monoclonal
4 Annals of Pharmacotherapy 

antibody CMAB009 because there is evidence for an interchangeable designation.4 In contrast, in Europe, indi-
improved safety profile for CMAB009 versus its reference vidual member states, not the EMA, determine interchange-
product, cetuximab.38 ability status.5,62
In January 2017, the FDA issued draft guidance for dem-
Practical Considerations for the Use onstrating interchangeability.63 Similar to the overall pro-
cess for biosimilar approval, the agency will consider the
of Biosimilars That Are Relevant to totality of the evidence when evaluating proposed inter-
Pharmacists changeable products and recommends a stepwise approach
Since publishing its first biosimilar guideline in 2005, the for generating data to support a demonstration of inter-
EMA has granted marketing authorization approval for 26 changeability.63 The data and information that is required
biosimilar agents within the product classes of low-molecu- may depend on and be influenced by product complexity,
lar-weight heparin, insulin, human growth hormone, G-CSF, the extent of comparative and functional characterization,
erythropoiesis-stimulating agents, follicle-stimulating hor- and product-specific immunogencity risk. For products that
mone, and tumor necrosis factor inhibitors (Table 1).39-42 Of demonstrate meaningful fingerprint-like analytical similar-
these, marketing authorization approval was voluntarily ity to the reference product, and have low structural and
withdrawn for 2 because of commercial reasons43,44; there- functional complexity, and low immunogencity risk, data
fore, to date, 24 biosimilars are marketed in Europe. from a switching study(ies) may be sufficient to support a
Additional biosimilar applications are under evaluation by demonstration of interchangeability.63 In contrast, for prod-
the EMA, including applications for insulin glargine and ucts that are highly similar but do not demonstrate meaning-
insulin lispro, pegfilgrastim, etanercept, adalimumab, ritux- ful fingerprint-like analytical similarity to the reference
imab, and trastuzumab.45 product, and that have high structural and functional com-
Four biosimilars are currently approved in the United plexity, and high immunogenicity risk postmarketing data
States: Zarxio (filgrastim-sndz), a biosimilar of Neupogen for the product as a licensed biosimilar may also be needed.63
(filgrastim); Inflectra (infliximab-dyyb), a biosimilar of In other cases, data from a switching study may not be
Remicade (infliximab); Erelzi (etanercept-szzs), a biosimi- needed, i.e., for products that are intended to be adminis-
lar of Enbrel (etanercept); and Amjevita (adalimumab-atto), tered only once, but this decision should be justified.63
a biosimilar of Humira (adalimumab).46-49 Additional bio- A switching study(ies) should include at least 2 alternat-
similars are under review by the FDA (Table 2),50-58 and ing exposures (switch intervals) to the proposed inter-
many more are in research and development (Table 3). As changeable product and to the reference product.63 The
more agents gain regulatory approval, the biosimilars mar- design and analysis of switching studies should also con-
ket will expand and pharmacists will play an important role sider how the proposed interchangeable product will be
in their formulary evaluation, dispensing, and postmarket- used in clinical practice to guide selection of an appropriate
ing surveillance and monitoring. Regulatory agencies have study population, calculate sample size, and determine the
provided a framework for biosimilar approval. However, number and duration of switches.63 Primary study endpoints
the review process is evolving, and there are several practi- should include those which are most sensitive to detecting
cal considerations for pharmacists, including interchange- changes in immunogenicity and/or exposure that may result
ability, substitution, naming, indication extrapolation, from alternating or switching, i.e., clinical pharmacokinet-
product labeling, therapeutic drug monitoring (TDM), man- ics and pharmacodynamics (if available).63 Draft guidance
ufacturer attributes, and logistics of product use as well as also recommends choosing an indication that would support
reimbursement.8,59-61 interchangeable approval for use in an indication(s) that
was not directly compared to the licensed biologic in a com-
Interchangeability and Biosimilar Substitution parative clinical trial but for which the reference product is
approved (i.e., extrapolation).63
A provision of the BPCI Act created a second level of None of the biosimilars approved in the United States
approval that goes beyond biosimilarity, called interchange- has received interchangeable designation. However, clini-
ability.4 Interchangeability is intended to mean that the bio- cal trials have been conducted or are in progress to evaluate
similar product “can be expected to produce the same the efficacy and safety of switching between a biosimilar
clinical result as the reference product in any given patient”; and reference product.64-67 A comparative clinical trial
furthermore, the risk to efficacy or safety with alternating or (PIONEER; NCT01519700) in patients with breast cancer
switching between the 2 products is not greater versus con- treated with myelosuppressive chemotherapy showed no
sistent use of the reference product.4 Under the BPCI Act, increased risk to safety or loss of efficacy with switching
interchangeability status may be granted by the FDA; fur- between filgrastim (Neupogen) and filgrastim-sndz (Zarxio)
thermore, a 1-year exclusivity period will be granted to versus consistent use of either product.64 Other comparative
the first biosimilar of a reference product that receives clinical trials have adopted this crossover design to evaluate
Stevenson et al 5

Table 1.  Biosimilar Development in Europe.

Year of Market
Reference, Brand Name Authorization,
Product Class Biosimilar (Manufacturer) (INN) Status Withdrawal, or Refusal
low-molecular- Inhixa (Shenzhen Techdow Clexane (enoxaparin Authorized 2016
weight heparin Pharmaceutical Co, Ltd) sodium)
  Thorinane (Shenzhen Techdow Clexane (enoxaparin Authorized 2016
Pharmaceutical Co, Ltd) sodium)
Insulin Abasaglar (Lilly del Caribe, Inc; Eli Lantus (insulin glargine) Authorized 2014
Lily and Company)
Lusduna (Merck Sharp & Dohme Lantus (insulin glargine) Authorized 2017
Corp)
Solumarv (Marvel Lifesciences Humulin S (human insulin) Refuseda 2015
Ltd; BIOTON Sp)
Human growth Omnitrope (Sandoz GmbH) Genotropin (somatropin) Authorized 2006
hormone Valtropin (LG Life Sciences Ltd) Humatrope (somatropin) Withdrawnb 2012
G-CSF Accofil (Intas Pharmaceuticals Neupogen (filgrastim) Authorized 2014
Ltd)
Biograstim (SICOR Biotech UAB) Neupogen (filgrastim) Authorized 2008
Filgrastim Hexal (Sandoz GmbH) Neupogen (filgrastim) Authorized 2009
Filgrastim ratiopharm (SICOR Neupogen (filgrastim) Withdrawnb 2011
Biotech UAB)
Grastofil (Intas Pharmaceuticals Neupogen (filgrastim) Authorized 2013
Ltd)
Nivestim (Hospira Zagreb) Neupogen (filgrastim) Authorized 2010
Ratiograstim (SICOR Biotech Neupogen (filgrastim) Authorized 2008
UAB)
Tevagrastim (SICOR Biotech Neupogen (filgrastim) Authorized 2008
UAB)
Zarzio (Sandoz GmbH) Neupogen (filgrastim) Authorized 2009
Erythropoiesis- Abseamed (Rentschler Eprex/Erypo (epoetin alfa) Authorized 2007
stimulating Biotechnologie GmbH; Lek
agents Pharmaceuticals d.d.)
Binocrit (Rentschler Eprex/Erypo (epoetin alfa) Authorized 2007
Biotechnologie GmbH; Lek
Pharmaceuticals d.d.)
Epoetin Alfa Hexal (Rentschler Eprex/Erypo (epoetin alfa) Authorized 2007
Biotechnologie GmbH; Lek
Pharmaceuticals d.d.)
Retacrit (Norbitec GmbH) Eprex/Erypo (epoetin alfa) Authorized 2007
Silapo (Norbitec GmbH) Eprex/Erypo (epoetin alfa) Authorized 2007
Follicle- Bemfola (Polymun Scientific GONAL-f (follitropin alfa) Authorized 2014
stimulating Immunbiologische Forschung
hormone GmbH)
Ovaleap (Merckle Biotec GmbH) GONAL-f (follitropin alfa) Authorized 2013
TNF inhibitors Benepali (Biogen [Denmark] Enbrel (etanercept) Authorized 2016
Manufacturing ApS)
Flixabi (Biogen [Denmark] Remicade (infliximab) Authorized 2016
Manufacturing ApS)
Inflectra (Celltrion Inc) Remicade (infliximab) Authorized 2013
Remsima (Celltrion Inc) Remicade (infliximab) Authorized 2013
Interferon-α Alpheon (LG Life Sciences, Ltd) Roferon-A (interferon Refuseda 2006
alfa-2a)

Abbreviations: G-CSF, granulocyte colony-stimulating factor; INN, international nonproprietary name; TNF, tumor necrosis factor.
a
Market authorization was refused because of concerns related to product quality and manufacturing.41,42
b
Market authorization was voluntarily withdrawn for commercial reasons.43,44
6 Annals of Pharmacotherapy 

Table 2.  Biosimilar Biologics License Applications Submitted to the FDA.

Proposed Biosimilar
Product Class (Manufacturer) Reference, Brand Name (INN) Filing Status With the FDA
G-CSF Grastofil (Apotex/Intas Neupogen (filgrastim) Accepted for review, February
Pharmaceuticals Ltd)50 2015
Biosimilar pegfilgrastim (Apotex/ Neulasta (pegfilgrastim) Accepted for review, December
Intas Pharmaceuticals Ltd)51 2014
CHS-1701 (Coherus Neulasta (pegfilgrastim) Accepted for review, October
BioSciences)52 2016
LA-EP2006 (Sandoz)53 Neulasta (pegfilgrastim) Accepted for review, last quarter
2015a
Erythropoiesis- Retacrit (Hospira)55 Epogen/Procrit (epoetin alfa) Submitted January 2015
stimulating agents
TNF inhibitors BI695501 (Boehringer Humira (adalimumab) Accepted for review, January
Ingelheim)56 2017
  SB2 (Merck/Samsung Bioepis Co, Remicade (infliximab) Accepted for review, May 2016
Ltd)57
HER2 inhibitors Myl-1401O (Mylan/Biocon)58 Herceptin (trastuzumab) November 2016

Abbreviations: FDA, Food and Drug Administration; G-CSF, granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2;
INN, international nonproprietary name; TNF, tumor necrosis factor.
a
Application rejected by the FDA, July 2016.54

switching from infliximab (Remicade) to CT-P13 substitutions. Entry of the specific product administered to
(Remsima, Inflectra) in patients with autoimmune or the patient into an electronic records system (eg, electronic
chronic inflammatory disorders.65-67 The PLANETRA medical record, pharmacy benefit management system)
extension study (NCT01571219) in patients with RA and would be sufficient for meeting the prescriber notification
PLANETAS extension study (NCT01571206) in patients and records standards. In some cases, state law requires
with ankylosing spondylitis demonstrated similar efficacy patient consent prior to interchangeable biosimilar substi-
and tolerability for switching from infliximab to CT-P13 tution. Pharmacists may also be required to explain treat-
versus continued treatment with CT-P13.66,67 Furthermore, ment costs and, in some states (eg, Georgia, Illinois, North
initial results from the ongoing NOR-SWITCH study Carolina, and Texas), must dispense the lowest retail priced
(NCT02148640) in patients with RA, spondyloarthritis, interchangeable biologic product that is in stock. Immunity
psoriatic arthritis, ulcerative colitis, Crohn’s disease, and may be provided for pharmacists who perform substitu-
chronic plaque psoriasis demonstrated noninferior efficacy tions in compliance with state law on biologics. However,
and similar safety and immunogenicity profiles for switch- prescribers may block substitution by indicating “dispense
ing from infliximab to CT-P13 versus continued treatment as written” or “brand medically necessary.” Finally, indi-
with infliximab.65 vidual states may be required to maintain a public or web-
Interchangeable designation may permit substitution of based list of permissible interchangeable products. The
biosimilars for the originator without intervention of the Purple Book provides a listing of all originator, biosimilar,
prescriber; however, both US and EU substitution policies and interchangeable biosimilar products approved by the
are determined by (member) state laws, not by the FDA or FDA.69 It also includes information regarding a biologic’s
EMA.5,62 To ensure efficacy and safety, each US state or licensure pathway and exclusivity status. This resource
European country should evaluate the applicability of tradi- will enable pharmacists to quickly identify interchangeable
tional pharmacy laws to interchangeable biosimilar substi- biosimilars.
tution, especially those pertaining to the recording of
substitutions. This is important because failure to record
Naming
interchangeable biosimilar substitutions could result in
misattribution of AEs to reference biologics. A consensus on whether a biosimilar should have an inter-
At the time of this publication, 25 US states and Puerto national nonproprietary name (INN) distinct from or shared
Rico have enacted laws regarding interchangeable biosimi- with its reference product is lacking. Distinct INNs for bio-
lar substitution.68 State legislation varies, but typically similar and reference products would facilitate pharmaco-
requires FDA approval of a product as interchangeable. In vigilance and product tracking and reduce the possibility of
most states, pharmacists must notify prescribers and inappropriate or inadvertent product switching that may
patients and retain records of interchangeable biosimilar occur if products share a single INN. However, it may also
Stevenson et al 7

Table 3.  Proposed Biosimilar Products in Development With previously licensed.72 The first biosimilar approved in the
Registered Phase III Clinical Trials.a United States, Zarxio, was assigned an INN that included a
Active Substance Biosimilar Manufacturer suffix tied to the manufacturer name: filgrastim-sndz. While
this may have set a precedent for using a meaningful suffix,
Filgrastim MK-4214 Merck it should be noted that filgrastim-sndz was designated a
Epoetin alfa Apo-EPO Apotex “placeholder nonproprietary name” for Zarxio, and its
HX575 Sandoz approval preceded FDA guidance for nonproprietary nam-
Adalimumab BCD-057 Biocad ing of biological products.46 Nonproprietary naming of bio-
CHS-1420 Coherus similars subsequently approved in the United States
FKB327 Fujifilm/Kyowa Hakko
followed current FDA guidance in that all products contain
Kirin
a suffix devoid of meaning: Inflectra (infliximab-dyyb),
GP2017 Sandoz
M923 Momenta Pharmaceuticals/
Erelzi (etanercept-szzs), and Amjevita (adalimumab-atto).
Baxalta The naming convention for interchangeable biosimilar
MSB11022 Merck KGaA products (ie, suffix that is distinct from or shared with its
ONS-3010 Oncobiologics/Viropro reference product) is still under consideration.72
SB5 Samsung Bioepsis A naming convention that includes an INN and distin-
Infliximab BCD-055 Biocad guishing suffix, rather than prefix, would allow products to
NI-071 Nichi-Iko Pharmaceutical be grouped together by their INN in electronic databases to
Co, Ltd help identify them for ordering, prescribing, dispensing,
PF-06438179 Pfizer and pharmacovigilance.71,72 However, prescribers and/or
Rituximab ABP 798 Amgen pharmacists may have difficulty differentiating products by
BCD-020 Biocad a suffix devoid of meaning, and this may lead to inadvertent
BI 695500 Boehringer Ingelheim selection errors.73 One approach to reduce the likelihood of
CT-P10 Celltrion selection errors would be to include brand names as biolog-
GP2013 Sandoz ics are integrated into electronic systems.73 Consistent with
MabionCD20 Mabion this, a recent survey of US pharmacists indicated that
PF-05280586 Pfizer respondents who preferred the INN-plus-suffix naming
RTXM83 mAbxience
convention also favored the use of a suffix tied to the manu-
SAIT101 Archigen Biotech Ltd
facturer name over one devoid of meaning.70 Despite these
Trastuzumab ABP-980 Amgen
reported preferences, pharmacists were most confident with
BCD-022 Biocad
interchangeable biosimilar substitution when the biosimilar
CT-P6 Celltrion
PF-05280014 Pfizer
and reference products shared the same INN.70 Thus, phar-
SB3-G31-BC Samsung Bioepis macists’ perspectives on biosimilar naming conventions
Bevacizumab ABP 215 Amgen may also influence the likelihood to substitute interchange-
BCD-021 Biocad able biosimilars for licensed biologics, thereby affecting
BI 695502 Boehringer Ingelheim their uptake to market.
PF-06439535 Pfizer
a
Registered on ClinicalsTrials.gov, the International Clinical Trials Extrapolation
Registry Platform, or the European Union Clinical Trials Register.
Regulatory guidelines also permit extrapolation of clinical
data from one indication to support biosimilar approval for
cause confusion among prescribers or consumers and slow use in an indication that was not directly compared to the
the uptake of biosimilars to market.8,59,70 licensed biologic in a comparative clinical trial but for
The WHO guidelines propose a system in which a 4-let- which the reference product is approved.2,3,5 However,
ter biological qualifier (randomly generated consonants extrapolation must be scientifically justified and based on
devoid of meaning) is retrospectively or prospectively the totality of the evidence from all stages of biosimilar
assigned as a suffix to all biologic products, including bio- development.2,3,5 For example, the FDA approved Inflectra,
similars, that have or are eligible to have an INN.71 In the an infliximab biosimilar, across all indications of originator
European Union, biosimilar and originator biologics share infliximab based on data from comparative nonclinical
the same INN. For example, the originator G-CSF Neupogen assessments and comparative clinical efficacy and safety
and its biosimilar Zarzio both share the same INN of fil- studies in patients with RA or ankylosing spondylitis.47,66,67
grastim. Consistent with WHO recommendations, FDA Extrapolation reduces the need for duplicative clinical stud-
guidance also recommends the addition of a distinguishing ies in indications already approved for the reference prod-
suffix devoid of meaning to all biologics newly or uct.74 However, in certain circumstances, additional data
8 Annals of Pharmacotherapy 

may be required to justify extrapolation, such as when the Omitting results from comparative clinical trials in the bio-
mechanism(s) of action or target receptors or safety and similar product label may affect the ability of pharmacists
immunogenicity profiles differ between indications.2,3,22 to communicate with patients about the safety and efficacy
A formulary committee may authorize a biologic for of biosimilars. For example, excluding clinical immunoge-
indications for which it has not received regulatory approval nicity data from biosimilar switch studies could make it dif-
based on evidence from clinical studies. Thus, pharmacists ficult for pharmacists to address questions asked by patients
could also consider whether available data support using a who switched from an originator to a biosimilar.
biosimilar for nonlabeled indications of the originator.59
Authorization for nonlabeled uses of a biosimilar within a Therapeutic Drug Monitoring
formulary system is distinct from regulatory extrapolation;
however, it may be supported by the same scientific princi- Clinicians and pharmacists may use TDM to optimize dos-
ples (eg, similar mechanisms and sites of action between ing when treating patients with biologic therapies. For
indications). instance, infliximab demonstrates large, interpatient phar-
macokinetic variability, and infliximab serum trough con-
centrations are positively associated with clinical outcomes
Product Labeling in patients with inflammatory bowel disease.80,84 In this
Prescription drug labels (prescribing information or sum- case, TDM may help clinicians individualize dosage to
mary of product characteristics [SmPC]) are an important minimize or avoid secondary loss of response to infliximab
source of information for health care practitioners at the that may develop as a result of subtherapeutic drug concen-
point of care because they are regularly updated to reflect trations or the formation of ADAs.85,86
licensed indications and provide a summary of evidence As biosimilars become available and are added to a for-
generated with a particular medicine. mulary, it will be important to ensure that each biosimilar
In a recent survey of physicians in the European Union, whose reference product is part of a TDM program is appro-
90.5% reported “frequently” or “occasionally” using the priately incorporated into the bioanalytical assays for TDM
SmPC when prescribing biologics, including biosimilars.75 along with its ADA levels. In a recent study of originator
Furthermore, nearly 70% of respondents reported using the infliximab (Remicade) and 2 Remicade biosimilars
SmPC when prescribing a biologic for the first time, mak- (Remsima and Inflectra), concentrations of all 3 infliximab
ing it the most frequently consulted information source in products were equally well quantified using a commercially
this situation.75 SmPCs for biosimilars report data generated available ELISA developed for originator infliximab
with the reference product and include a statement that the (apDia, Belgium).87
product is a biosimilar; however, they omit results from A separate study showed good correlation of Remsima
comparability studies that supported biosimilar approval.76,77 serum trough concentrations quantification among 3 differ-
Draft guidance issued by the FDA also recommends that ent infliximab ELISAs: SHIKARI Q-Inflixi (Matriks Biotek,
biosimilar product labeling incorporate relevant data from Turkey), LISA-Tracker Duo Infliximab (Theradiag, France),
the reference product labeling (along with a biosimilarity and RIDASCREEN IFX (R-Biopharm, Germany).88 Finally,
statement) and advises against including comparative MA-IFX10F9, a neutralizing antibody against infliximab,
data.78 Confirmatory comparative clinical studies are con- demonstrated equal reactivity toward Remicade, Remsima,
ducted to demonstrate that there are no clinically meaning- and Inflectra in anti-infliximab-bridging ELISAs, support-
ful differences between a biosimilar and reference product, ing its use as a universal calibrator.87 This would allow stan-
using the most sensitive patient population and efficacy end dardization and comparison of anti-infliximab titers against
points.3,5,21,23 In some cases, study conditions may differ different biosimilar products or of the same product evalu-
from those used in pivotal trials that supported approval of ated using multiple assays.87
the reference product,3,5,21,23 which may cause confusion for
the prescriber.78 However, a product label that includes Manufacturer Attributes and Logistics of Product
results from comparative clinical trials and other data that
supported biosimilar approval (eg, analytical studies) would
Use
increase transparency and build trust with health care prac- It will also be important for pharmacists to consider manu-
titioners and patients. Indeed, in one recently conducted facturer attributes and logistics of product use when evalu-
survey of US physicians, approximately 83% of respon- ating biosimilars for formulary inclusion. As a biologic, the
dents considered it important to include analytical and clini- physicochemical and functional attributes of a biosimilar
cal data in the biosimilar label.79 are dependent on and sensitive to changes in its manufactur-
The prescription drug label is readily accessible to phar- ing process.6-10 Thus, a manufacturer’s handling practices
macists, and many rely on its contents to answer questions and history of recalls associated with product quality should
about and help patients understand treatment options. be evaluated to ensure drug efficacy and patient safety.59
Stevenson et al 9

Patient care will depend on a reliable and consistent supply same discount programs as its originator.59,94 However, it
of biosimilar medications, so drug availability should also could be addressed by requiring a biosimilar manufacturer
be assessed to determine whether a manufacturer can main- to provide patient assistance programs that are similar to or
tain adequate production and stock to meet product better than those for the originator product.
demand.59 This includes a review of the manufacturer’s his-
tory of drug shortages and its processes and procedures for
Summary and Conclusions
mitigating such shortages (eg, multisite manufacturing
capabilities).59 Supply chain security should also be consid- Biosimilars have the potential to increase accessibility to
ered; antitheft and anticounterfeiting measures decrease the and expand the use of biologic therapies worldwide.
risk of drug shortages and ensure product quality.59,89 Biosimilar approval is granted through regulatory pathways
Biologics are often administered to patients in hospital that are distinct from small-molecule generics and novel
and physician office settings; therefore, biosimilar formu- therapeutics. Pharmacists will play an important role in
lary review should also consider the logistics of product use managing the introduction of biosimilars into health care
in these settings. Any differences in product packaging (eg, systems. As pharmacists consider biosimilar products for
vial size) and/or stability between biosimilar and reference formulary inclusion, they should evaluate the totality of the
products should be evaluated to determine the potential evidence for biosimilarity, including analytical, nonclinical,
impact on product integrity and drug waste.59 Factors that and clinical data that demonstrate product quality, safety,
affect the ability to differentiate between products (eg, and efficacy; economic factors, such as reimbursement and
product labeling, storage) and capabilities of information treatment costs; postmarketing pharmacovigilance data, if
technology systems for product tracking should be consid- available; manufacturer attributes; and logistics of product
ered to minimize the potential for dispensing errors and use.59 Pharmacists will also rely on data from both analytical
facilitate traceability of adverse events.59 assessments and comparative clinical trials of the biosimilar
and reference products to make informed decisions regard-
ing product use. Finally, evolving regulatory guidelines for
Reimbursement interchangeability, naming, and product labeling may influ-
The US prescription drug coverage and reimbursement pol- ence substitution practices, product tracking, and postmar-
icies vary with distribution channel.61 Whereas pharmacy- keting pharmacovigilance as well as the type and extent of
dispensed drugs are covered under pharmacy benefits (eg, information pharmacists can communicate to patients and
private insurance, Medicare part D, or Medicaid), those other health care providers about biosimilar products.
administered by health care providers (eg, physician office
and hospital settings) are usually covered under medical Acknowledgments
benefits (eg, private insurance, Medicare part A, Medicare Medical writing support was provided by Elyse Smith, PhD, of
part B, or Medicaid).61 For Medicare part B, biosimilar Engage Scientific Solutions and funded by Pfizer Inc.
products and other physician-administered drugs are coded
using the US Healthcare Common Procedure Coding Declaration of Conflicting Interests
System and reimbursed at rates determined by the Centers The authors declared the following potential conflicts of interest
for Medicare and Medicaid Services.90,91 with respect to the research, authorship, and/or publication of this
Although typically administered to patients in physician article: James G. Stevenson is an employee of Visante and reports
office and hospital outpatient settings, biologics may also providing compensated consulting for Amgen, receiving fees from
be considered specialty drugs, which are managed under Pfizer Inc for serving on an advisory board, and fees from AbbVie
pharmacy benefits.61 Most private and public (eg, Medicare for his participation in an educational program. Robert Popovian,
part D) health plans use a formulary design, with tiered cost Ira Jacobs, Susan Hurst, and Lesley G. Shane are full-time employ-
sharing and access controls to manage drug costs.61 A recent ees of and declare stock holdings and/or stock options from Pfizer
survey of health plans revealed that many are considering Inc.
placing biosimilars on a lower cost-sharing tier than origi-
nator biologics and may implement step-edits for the use of Funding
biosimilars prior to originators.92 These reimbursement The authors disclosed receipt of the following financial support
policies could increase accessibility to and use of biosimi- for the research, authorship, and/or publication of this article: This
lars. The availability of manufacturer assistance programs review was supported by Pfizer Inc.
that subsidize treatment costs should also be considered.59
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