Drug Discovery Today  Volume 20, Number S2  May 2015 REVIEWS

The development of biosimilar products is an area of growing interest in the

global medical community. This article will review current regulatory
recommendations, as well as discuss key considerations for the
early clinical phases of biosimilar development.

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Considerations in the early
development of biosimilar products
Edward C. Li1,*, Richat Abbas2, Ira A. Jacobs3 and Edward C. Li, PharmD, BCOP, is
Associate Professor in the Department
of Pharmacy Practice at the University
Donghua Yin4 of New England (UNE) College of
Pharmacy in Portland, Maine, USA.
Dr Li maintains a clinical practice in
ambulatory oncology at the New
1
Pharmacy Practice, University of New England College of Pharmacy, Portland, ME 04103, USA England Cancer Specialists in
2 Scarborough, USA. Dr Li earned his
Clinical Pharmacology, Pfizer, Collegeville, PA 19426, USA Doctor of Pharmacy degree from the
3 Philadelphia College of Pharmacy. He
Pfizer Emerging Markets/Established Products Medicines Development Group, Pfizer, New York, NY 10017, USA completed a pharmacy practice
4 residency at the University of Wisconsin Hospital and Clinics in
Biotechnology Clinical Development, Pfizer, San Diego, CA 92121, USA Madison and an oncology pharmacy practice residency at the
University of Maryland School of Pharmacy in Baltimore. Dr Li is a
board-certified oncology pharmacist and his research interests
include the analysis of practice trends and outcomes research using
The widespread use and patent expiration of many biologics have led to large claims databases, such as SEER-Medicare data and the Maine
All-Payer Claims Database.
global interest in development of biosimilar products. Because the Richat Abbas, PhD, is Clinical
Pharmacology Lead/Director at Pfizer,
manufacture of biologics, including biosimilars, is a complex process Inc. Dr. Abbas earned his PhD in
Pharmaceutics, with focus on
involving living systems, the development of a biosimilar is more rigorous Pharmacokinetics (PK) and
Pharmacodynamics (PD), from the Ohio
State University. He has more than
than the development of a generic small molecule drug. Several regulatory 20 years of pharmaceutical discovery,
research and development experience,
agencies have established or are proposing guidelines that recommend a obtained at research laboratory, biotech,
and medium to large international
pharmaceutical companies. Dr. Abbas
stepwise process to ensure the efficacy and safety of a biosimilar are highly has contributed to the research and
development, and approval of a number of new oncology, CNS,
similar to the reference product. This article also explores the early clinical cardiovascular and metabolism, and biosimilar drugs. He has authored/
co-authored over 100 peer-reviewed publications, abstracts and
presentations, patents and book chapters. Dr. Abbas’s expertises include
phase of biosimilar development, which is particularly important to clinical pharmacology study design, implementation, data analysis, PK/PD
modeling & simulation, quantitative pharmacology, QTc evaluation,
resolving any uncertainties that might remain following in vitro and in biomarker, drug metabolism/interaction evaluation, biosimilar,
bioanalysis, and clinical studies in support of new drug development,
formulation development/product enhancement/maintenance, and
vivo evaluations and to enable a selective and targeted approach to Phase management.
Ira A. Jacobs is a fellowship trained
III clinical efficacy and safety investigation. surgical oncologist who started
Pfizer in November 2012 as the
oncology biosimilars global medical
lead. Prior to Pfizer, Doctor Jacobs
worked as a medical director in
Introduction oncology global development at
Amgen for four years. He led clinical
The introduction of targeted biologics has been a major advance for the treatment of diseases and development programs in breast,
lung, prostate, and bone
cancers. Prior to transitioning into
conditions such as cancer (active treatment and supportive care), rheumatoid arthritis, diabetes industry, Dr. Jacobs was a staff
surgical oncologist. He received his
mellitus and other autoimmune disorders. The rapid emergence of biologics has led to widespread BA, MD, and MBA degrees from the George Washington
University. He completed a general surgery residency at Morristown
and global use. In 2012, five of the top ten global prescription products were biologics [1]. Sales of Memorial Hospital in Morristown, New Jersey and a surgical oncology
fellowship at the University of Illinois in Chicago. He is the author of
biosimilars, accounting for 0.4% of the global biologics market, are increasing [2]. In Europe, by more than 25 publications and has received numerous awards and
honors. He is currently an active member of the American Society of
volume, biosimilars make up 12% of the epoetin alfa market, 7% of the growth hormone market Clinical Oncology, European Society of Medical Oncology, American
Society of Hematology, International Association for the Study of
and 18% of the filgrastim market [3]. Lung Cancer, American Association for Cancer Research, Society of
Surgical Oncology, American Society of Breast Surgeons, and
The patents of some key biologics recently expired, and many more are going off-patent in the American College of Physician Executives.

Donghua Yin, PhD, is currently a

coming years. Coupled with current global socioeconomics, ongoing concern regarding patient Senior Director of Clinical
Pharmacology at Worldwide
access to biologics and further technologic innovations, a shift in pharmaceutical product Research and Development, Pfizer
Inc. His research in the
development is occurring, giving rise to the development of biosimilars [1,4]. Whereas the active pharmaceutical industry focuses on
pharmacokinetics and pharmaco-
ingredient of a generic drug product is chemically identical to a brand name drug, a biosimilar as a dynamics, and their applications in
the discovery and development of
biological product cannot be identical to its reference product. The biosimilar product must be therapeutic agents for oncology and
inflammatory diseases. At Pfizer he
highly similar to an existing biologic branded product with no clinically meaningful differences. has been Clinical Pharmacology Lead
of multiple clinical development
programs for small molecules, therapeutic proteins, and
therapeutic vaccines. He obtained his Ph.D. in Pharmaceutics from
the University of Tennessee Health Science Center in 2000, and
conducted postdoctoral research at the Ohio State University.
*Corresponding author: Li, E.C. ([email protected])

1359-6446/ß 2015 Published by Elsevier Ltd.

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 REVIEWS Drug Discovery Today  Volume 20, Number S2  May 2015

GLOSSARY The stepwise development of a biosimilar involves an extensive

side-by-side comparison of quality data between the biosimilar
Biosimilar from the European Medicines Agency (EMA) –
and its reference biological product followed by a transition from
biological medicinal product that contains a version of the
active substance of an already authorized original biological nonclinical laboratory and animal testing to early clinical devel-
medicine product (reference medicinal product). A biosimilar opment (Phase I) and finally Phase III development in humans to
demonstrates similarity to the reference medicinal product in resolve any remaining uncertainty that the biosimilar might not
terms of quality characteristics, biological activity, safety and be similar to the reference product. (While there are variations in
efficacy based on a comprehensive comparability exercise [6].
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how they are defined, for the purposes of this article, preclinical
From the US Food and Drug Administration (US FDA) – the studies refer to studies conducted in animals, whereas nonclinical
biological product is highly similar to the reference product
studies include all studies not conducted in humans. Therefore,
notwithstanding minor differences in clinically inactive
components and that there are no clinically meaningful nonclinical studies include preclinical studies, as well as physico-
differences between the biological product and the reference chemical and biological studies.) This article explores the regula-
product in terms of safety, purity and potency of the product [7]. tory guidelines for early clinical development of a biosimilar
Pharmacodynamics the effects of a drug on the body [7]. product, because these guidelines shape the clinical development
Pharmacokinetics how the body acts on the drug [7]. program, and defines key considerations in the early clinical
Residual uncertainty properties, information or some other development program. Additional considerations in the early
characteristic that remains unclear from previous
clinical development of a biosimilar also are explored, with sug-
investigations.
Stepwise approach an iterative process for comparing a gestions to resolve decisions commonly encountered in the early
biosimilar with a reference biological product. clinical development of a biosimilar.
Totality of evidence an assessment that considers the
quantity and quality of evidence to support biosimilarity Overarching goal of the early clinical development
[7,33]. program of a biosimilar product
An overarching goal of the biosimilar development program for its
sponsor is to receive the same approved labeling as the reference
Because the molecules are unlikely to be chemically identical, a product without having to repeat clinical studies in every licensed
biosimilar cannot be considered a generic form of an existing indication. This requires evidence gained through the compre-
biological product. Definitions of a biosimilar by regulatory agen- hensive development process of a biosimilar. Although there is no
cies, as well as other related terms discussed in this article, are one path to develop a given biosimilar product, regulatory agen-
provided in the Glossary [5–7]. cies have put guidelines in place that recommend an extensive
In 2005, the European Medicines Agency (EMA) became the first comparability exercise consisting of a rigorous, scientific-focused,
drug regulatory body to develop, approve and publish guidelines for stepwise development process, with each step building on previ-
the development of biosimilars [8]. The EMA approved the first ous ones (Fig. 1) [6,7]. Clinical development consists of an early
biosimilar product (somatropin) in April 2006. In 2009, WHO phase (typically considered Phase I) and a late phase (Phase III).
released its own guidelines for biosimilar development, which were Early clinical development includes evaluations of pharmacoki-
based on the EMA principles [9]. The FDA released a series of draft netics (PK), pharmacodynamics (PD) and safety/immunogenicity
guidances from 2012 to 2013 following authorization under the in humans.
Biologics Price Competition and Innovation Act subsection of the
Patient Protection and Affordable Care Act of 2009 [10]. Several Regulatory guidelines regarding biosimilars: European
countries (e.g. Australia, Canada, China, India, Japan, Korea, Union and USA
Mexico, among others) have developed or are developing their The legal pathway for the regulatory approval of biosimilars was
own pathways for biosimilar approval based in part on the regula- first adopted in European Union (EU) legislation in 2004 and came
tory paradigm for biosimilar products outlined by the EMA. As of into effect in 2005. Based on this, the EMA established the regula-
December 2014, the EMA has approved more than 20 biosimilar tory pathway in 2005 with the release of guideline CHMP/437/04
products, including the first biosimilar monoclonal antibody [11]. [8]. This guideline provided the regulatory framework as a resource
Although in draft form, the FDA guidances provide comprehen- for sponsors that ‘may choose to develop a new biological medici-
sive recommendations to sponsors. Until the FDA validates this nal product claimed to be ‘similar’ to a reference medicinal prod-
guidance by approving the first biosimilar via the 351(k) pathway, uct, which has been granted a marketing authorization in the
uncertainties regarding the standards required for biosimilarity [European] Community’ [8]. In addition to the 2005 guideline,
could remain. Unlike the EMA, the FDA has the statutory authority which is undergoing revision, the EMA has released several prod-
to approve biosimilar products as interchangeable. The higher uct-class-specific guidelines (e.g. for low-molecular-weight hepar-
standards required to qualify as interchangeable have not yet been ins and monoclonal antibodies).
issued by the FDA. In general, the EMA and FDA biosimilar guide-
lines are aligned, considering the differing level of maturity of the EMA and FDA biosimilar guidelines
biosimilar pathways put into place by different legislative bodies Despite sharing many fundamental points, there are differences
worldwide. In general, regulatory guidelines make it evident that between the EMA and FDA biosimilar guidelines that could
development of a biosimilar requires extensive investigation to be important considerations when undertaking the biosimilar
demonstrate that the proposed biosimilar is highly similar to the development process (Table 1). The FDA can approve both a
reference biological product. biosimilar and an interchangeable biosimilar [7]. Individual

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Drug Discovery Today  Volume 20, Number S2  May 2015 REVIEWS

Phase II/III

Immuno-
Effectiveness Safety
genicity
Pharmaco-
vigilance

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Clinical studies

Preclinical studies Phase I

Biological characterization
Immuno-
PK, PD Safety
genicity
Physicochemical characterization

Drug Discovery Today

FIGURE 1
Stepwise development of a biosimilar. The stepwise development of a biosimilar involves the five major steps shown: physicochemical characterization, biological
characterization, nonclinical studies in animals, clinical studies in humans and postmarketing pharmacovigilance. Early clinical development in humans involves
pharmacokinetic (PK) and pharmacodynamic (PD) investigation, as well as safety investigations focusing on immunogenicity. Phase III clinical development
involves one or more studies to assess effectiveness and safety in humans relative to the reference biological product.

states, however, can pass legislation to regulate interchangeability. more simple biological medicinal products, a clinical efficacy
Although biosimilars are approved by the EMA, which issues a Pan study might not be necessary if similarity of physicochemical
EU Marketing Authorisation, the EMA is silent on interchange- characteristics and biological activity or potency of the proposed
ability status for this reason and each individual national member biosimilar and the reference product can be convincingly shown
state must determine their policy with respect to interchangeabil- and similar efficacy and safety can clearly be deduced from these
ity. For the FDA to approve a biosimilar as interchangeable with data and comparative PK data. In vitro and/or clinical PD data
the reference product, the sponsor must demonstrate that ‘the risk might be needed for support [6]. Although not described by the
in terms of safety or diminished efficacy of alternating or switching EMA or FDA, examples of structurally less complex biosimilars
between use of the biological product [biosimilar] and the refer- might be insulin and heparin.
ence product is not greater than the risk of using the reference To establish similarity between the proposed biosimilar and
product without such alternation or switch’ [12,13]. reference biological product, the EMA and FDA require that the
Another, more-data-driven difference is that EMA guidelines stepwise comparability assessment be scientifically rigorous. The
emphasize in vitro nonclinical assessment rather than in vivo type and amount of analyses and testing that will be sufficient to
toxicology studies, which is in keeping with EU Directive 2010/ demonstrate biosimilarity will be determined on a product-specific
63/EU regarding the protection of animals used for scientific basis [7]. Each step of the comparability assessment is intended to
purposes [14]. The FDA has the ability to waive requirements build on the preceding steps, with each step serving to resolve as
for in vivo toxicology assessment, but typically does not do so in much remaining uncertainty as possible regarding similarity be-
the absence of sufficient clinical data. tween the proposed biosimilar and reference biological product.
Among the commonalities of the EMA and FDA guidelines for Consequently, physicochemical and biological characterizations
biosimilar development is to approve biological products for serve as the beginning and foundation of the stepwise approach.
marketing that have established similarity between the proposed Together with the subsequent preclinical studies (in vitro and, if
biosimilar and reference biological product through extensive needed, in vivo), these preceding steps collectively serve to inform
comparative assessments. This goal differs from that of generic the nature and extent of the clinical development program [6,7].
small molecules, where establishing bioequivalence to the refer- Thus, more comprehensive and robust physicochemical, biologi-
ence product through an exercise comparing bioavailability is cal and preclinical investigations provide scientific justification for
sufficient [6]. In establishing similarity between the proposed a selective and targeted approach to clinical testing [7]. A targeted
biosimilar and the reference biological product, it is important approach is further supported by resolving the clinical importance
to show that the previously demonstrated safety and efficacy of the of any differences found between the proposed biosimilar and
reference biological product also applies to the proposed biosimi- reference biological product early in the stepwise development
lar [6,7]. In general, at least one Phase III clinical efficacy and safety process.
trial is required to demonstrate similarity relative to the reference In the EU and the USA, the reference product is legally defined as
product. However, establishing efficacy and safety of the proposed having been approved or licensed in the respective region using a
biosimilar are not objectives of the biosimilar development pro- full complement of safety, quality and efficacy data; thus, a
cess [6,7]. In limited circumstances, such as for structurally biosimilar product cannot serve as a reference product for another

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 REVIEWS Drug Discovery Today  Volume 20, Number S2  May 2015

TABLE 1
General guidelines for biosimilar developmenta
Guideline Effective date Purpose or focus
European Medicines Agency
Guidelines on Similar Biological Medicinal Products October 2005 To introduce the concept of similar biological medicinal products; to outline
(under revision) the basic principles to be applied; and to provide applicants with a ‘user
guide’, showing where to find relevant scientific information in the various
Committee for Medicinal Products for Human Use (CHMP) guidelines, to
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substantiate the claim of similarity [8]

Guideline on Similar Biological Medicinal Products June 2006 To outline the nonclinical and clinical requirements for a biological medicinal
Containing Biotechnology-Derived Proteins as (under revision) product claiming to be similar to another one already marketed. The
Active Substance: Non-Clinical and Clinical Issues nonclinical section addresses the pharmaco-toxicological assessment. The
clinical section addresses the requirements for pharmacokinetics (PK),
pharmacodynamics (PD), efficacy studies. The section on clinical safety and
pharmacovigilance addresses clinical safety studies as well as the risk
management plan with special emphasis on studying the immunogenicity of
the similar biological medicinal product [34]
Guideline on Similar Biological Medicinal Products June 2006 To outline the quality requirements for a biological medicinal product
Containing Biotechnology-Derived Proteins as Active (under revision) claiming to be similar to another one already marketed. The guideline
Substances: Quality Issues addresses the requirements regarding manufacturing processes, the
comparability exercise for quality, considering the choice of reference
product, analytical methods, physicochemical characterization, biological
activity, purity and specifications of the similar biological medicinal product
[35]
Questions and Answers on Biosimilar Medicines September 2012 Not stated
(Similar Biological Medicinal Products)
FDA
Guidance for Industry: Scientific Considerations in Draft To assist sponsors in demonstrating that a proposed therapeutic protein
Demonstrating Biosimilarity to a Reference Product product is biosimilar to a reference product for purposes of the submission of
a marketing application under section 351(k) of the Public Health Service
(PHS) Act [7]
Guidance for Industry: Quality Considerations in Draft To provide recommendations to applicants on the scientific and technical
Demonstrating Biosimilarity to a Reference Product information of the chemistry, manufacturing and controls (CMC) section of a
marketing application for a proposed biosimilar product submitted under
section 351(k) of the PHS Act [10]
Guidance for Industry: Formal Meetings Between the Draft To provide recommendations to industry on formal meetings between the
FDA and Biosimilar Biological Products Sponsors Draft FDA and biosimilar biological product sponsors or applicants [36]
for Applicants
Guidance for Industry: Biosimilars: Questions and Draft To provide answers to common questions from sponsors interested in
Answers Regarding Implementation of the Biologics developing proposed biosimilar products, biologics license application
Price Competition and Innovation Act of 2009 holders and other interested parties regarding the FDA interpretation of the
Biological Price Competition and Innovation Act of 2009 [37]
Guidance for Industry: Clinical Pharmacology Data to Draft To assist sponsors with the design and use of clinical pharmacology studies
Support a Demonstration of Biosimilarity to a to support a decision that a proposed therapeutic biological product is
Reference Product biosimilar to its reference product [38]
WHO
Guidelines for Evaluation of Similar Biotherapeutic October 2009 To provide globally acceptable principles for licensing biotherapeutic
Products (SBPs) products that are claimed to be similar to biotherapeutic products of assured
quality, safety and efficacy that have been licensed based on a full licensing
dossier [9]
a
Product-specific and other relevant biosimilar guidelines developed by the European Medicines Agency, available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/
general/general_content_000408.jsp&mid=WC0b01ac058002958c.

proposed biosimilar. To facilitate global development, however, another regulatory agency must be made and supported by data
the EU and the USA allow bridging to the respective EU or USA from analytical and/or comparative PK studies [6]. Prior to using a
reference product (or a reference product approved or licensed in product approved by another regulatory agency as a comparator, it
another region with standards compatible with the International might be advisable for the sponsor to consult with the regulatory
Conference on Harmonization) via comparative analytical and PK agency and provide the scientific justification for using the select-
data to allow selection of a single comparator to be used in the ed product.
single global Phase III study and any preceding in vivo toxicology
studies [6,7]. Comparison to a reference biological product ap- General considerations for clinical development of a
proved or licensed by another regulatory agency with similar biosimilar
scientific and regulatory standards (i.e. one that adheres to stan- Comparative assessments of PK and PD occur in early clinical
dards adopted by the International Conference on Harmoniza- development, whereas evaluations related to unresolved efficacy,
tion) is required. Justification for the use of a product approved by safety and immunogenicity issues mainly occur in Phase III

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Drug Discovery Today  Volume 20, Number S2  May 2015 REVIEWS

clinical development of a biosimilar (Fig. 1) [7,15]. Following biosimilar agent. For example, significant differences in the
regulatory approval of a biosimilar (and biologics in general), immune response profile in inbred strains of mice can indicate
postmarketing surveillance, particularly to identify rare adverse the proposed biosimilar and reference product differ in one or
events, is an important step [7,15]. Clinical development must more product attributes not previously identified. If identified,
include studies (including PK, PD and assessment of immuno- this information could inform the design of the immunogenicity
genicity) sufficient to demonstrate safety, purity and potency of assessment in humans [7].
the proposed biosimilar in appropriate conditions for which the The question of ‘how similar is similar enough’ must be

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reference product is licensed and for which licensure is sought considered in the context of the time and resources needed
for the biosimilar [7]. In conducting clinical studies, endpoints to resolve uncertainties. As a general principle, uncertainties
and study populations are selected that will be clinically remaining after completing early clinical development should
relevant and sensitive in detecting clinically meaningful be those that can be resolved only with a Phase III clinical trial
differences [7]. of efficacy, safety and immunogenicity. Statistical approaches
should be considered when determining the similarity of the
Strategic design of early clinical development of a proposed biosimilar to the reference product. For example, the
proposed biosimilar biosimilarity index assesses the probability that the observed
A strategically designed early clinical development program could significant result from a clinical trial is reproducible [17]. It uses
allow a selective and targeted approach to the Phase III clinical a stepwise process that is robust to the study endpoints,
trial(s) of efficacy, safety and immunogenicity. Establishing the PK criteria and study designs [18]. Scientific- and risk-based
similarity to a licensed or approved reference product in a sensitive approaches to resolving uncertainties to an acceptable level
and homogeneous population is the first step of the clinical in any given clinical setting are a key principle of the FDA
program of a proposed biosimilar. When clinically relevant PD guidances [16].
markers are available, comparative assessment of the PD effects
between the proposed biosimilar and a reference product can add Targeting the profile of the proposed biosimilar product
information for the biosimilarity determination and lead to a more The profile of the reference product and others within the same
targeted approach to the Phase III clinical program. Evaluation of class, if any, is another consideration in designing early clinical
immune response in the early clinical stage can provide initial studies. For example, if the PK of the reference product is known to
immunogenicity data for the proposed biosimilar. It also can be different among different subpopulations, conducting the PK
facilitate the use of appropriate assays and an optimal study design similarity study of the proposed biosimilar in a representative but
for the comparative immunogenicity assessment in the Phase III sensitive and homogenous subpopulation will provide a clearer
trial. comparison of the intrinsic PK properties for the proposed biosi-
milar and the reference product. Comparisons of the interactions
Approach to resolving remaining uncertainties with various factors affecting the PK between the proposed biosi-
Another strategic decision relates to the extent of the uncertain- milar and the reference product can be further assessed in a larger
ties regarding similarity that remain following the nonclinical Phase III trial in the target patient population using a population
phase of development. In considering which of these remaining PK approach.
uncertainties to address, the key question for the sponsor of the
biosimilar, as well as the regulatory agency, is: how similar is Stakeholder perspectives and needs
similar enough [16]? If no or minimal differences between the Increased patient access is a factor stimulating biosimilar devel-
proposed biosimilar and reference product are observed during opment. A survey conducted by the National Comprehensive
the physicochemical and in vivo nonclinical investigations, the Cancer Network (NCCN) found that stakeholders, including
clinical investigations can follow a targeted approach to address physicians, nurses and pharmacists, had a high interest in pre-
residual uncertainties related to PK, efficacy, safety and immuno- scribing, dispensing and administering biosimilars [19]. This and
genicity. Owing to the species difference, investigation in animals other surveys have found that stakeholders want to understand
will not adequately address the residual uncertainties related to the concepts related to biosimilar development and the regulato-
PK and PD, but it might identify any substantial differences ry process involved. Currently, this knowledge often is limited
between the proposed biosimilar and the reference product. [19,20].
Regardless of whether differences are observed, the value of ani- Unlike generic small molecules, where adoption by hospitals
mal PK and PD investigations is limited and does not negate the is often without formal review by the Pharmacy & Therapeutics
need for the quantitative data derived from PK and PD studies in Committee, the NCCN survey, which included 277 participants
humans [7]. in the 16th annual NCCN congress (physicians, nurses, phar-
Similarly, immunogenic assessment in animals is not necessari- macists and other clinicians and nonclinicians from the USA
ly predictive of immunogenic responses to protein products in and around the world), found the majority of respondents
humans, because animals can be overly reactive to human protein would require a review and discussion before using a biosimilar
[7]. In addition, animal studies typically involve a small number of [19]. Moreover, two-thirds of respondents indicated informa-
animals, thus making it difficult to draw conclusions on the tion about PK was very important and three-quarters indicated
comparison of immunogenicity between the proposed biosimilar Phase III clinical studies directly comparing the safety and
and a reference product. Despite these limitations, immunogenic- efficacy of the biosimilar with the reference product were very
ity assessment in animals adds value during the development of a important [19].

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 REVIEWS Drug Discovery Today  Volume 20, Number S2  May 2015

Stakeholders are looking for clinical results showing a biosimilar known inter-subject variability in PK with the reference product
product is highly similar to the reference product without unex- [7]. In a crossover design, subjects are randomized to receive the
pected side-effects or other complications [19–23]. Specifically, the biosimilar or reference product sequentially during the first treat-
need for safety data was shown in the results of a recent European ment period followed by the alternative treatment during the
Crohn’s and Colitis Organisation survey of nearly 275 members second treatment period, with a washout between the two treat-
[24]. The majority of respondents were aware that biosimilar ment periods [27].
monoclonal antibodies are not the same molecules as the refer- The dose and route of administration used in the PK investiga-
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ence product, with nearly seven of ten citing immunogenicity as tion should be those determined to be the most sensitive to detect
their main concern. These considerations must be balanced by the differences in PK between the proposed biosimilar and the refer-
fact that unwanted immunogenicity is a risk with any new biolog- ence product [7]. When multiple therapeutic dose levels are used
ical product and is not specific to biosimilars. In addition, for the reference product, a low dose might be more sensitive than
advances in science could mean the methods used to assess a high dose for detecting differences in the target-mediated dispo-
immunogenicity by biosimilar sponsors could be more sensitive sition involved in the distribution and elimination mechanisms
than those used for the reference product at the time of approval. for some biologics [28]. If the biosimilar can be administered
Early clinical studies provide a means to evaluate not only com- intravenously and subcutaneously, PK studies using the subcuta-
parative PK and PD but also initial assessment of immunogenicity. neous route generally are sufficient because absorption and elimi-
Interchangeability and automatic substitution also are important nation characteristics can be evaluated [15].
considerations to healthcare providers [22], and there is a diversity For a single-dose study, key parameters for the PK similarity
of opinion regarding how these issues should be addressed. assessment will include the maximum drug concentration (Cmax),
area under the concentration–time curve (AUC) from zero to the
PK and PD last time point with measurable concentration (AUC0–t) and AUC
A study to demonstrate the PK similarity between the proposed from time zero extrapolated to infinite time (AUC0–1). For a
biosimilar and the relevant reference product is a key component multiple-dose study, the key PK parameters will include Cmax,
of the early clinical development of a biosimilar program. The AUC within one dose interval (AUCtau) and the trough concentra-
primary objective of this study is to compare the intrinsic PK tion (Ctrough) under steady-state conditions [7,15]. PK similarity of
properties of a proposed biosimilar with the reference product. the proposed biosimilar to the reference product will be estab-
In the cases when PD markers are available, comparative PD lished through bioequivalence testing of the key PK parameters,
assessment can be added as a study objective. using predefined acceptance criteria [29]. When the acceptance
A key question in designing the PK similarity study is whether to criteria of PK similarity are not met, investigations will be needed
conduct the study in healthy volunteers or patients with the to determine whether the observed difference is due to study
disease that is relevant to the target indication. The choice of design limitations or to differences in intrinsic PK properties.
the PK study population should take into account factors includ- Additional assessment will be needed to address the residual
ing prior clinical experience of the reference product, sensitivity to uncertainty in PK and determine the clinical meaningfulness of
detect intrinsic differences in PK and variability of PK among the the observed difference.
candidate populations. If safety differences compared to the refer- Whenever a clinically relevant PD marker is available in the
ence biologic are not a concern, healthy subjects generally are population selected for the PK comparability study, comparative
preferred for the PK comparability study because this population assessment of the PD effect also can be considered as part of the
can be associated with fewer complicating factors that affect PK objectives for the PK similarity study. Investigation of the PD
(e.g. disease status, concomitant medications) than patient popu- profile of a biosimilar can add value to the totality of evidence
lations, thereby representing a relatively homogeneous popula- for demonstrating biosimilarity and reduce the residual uncertain-
tion to compare intrinsic PK properties sensitively. The healthy ties after the early clinical development. When the PD marker is
subject population could have a different immune response to the involved in the mechanisms-of-action shared by multiple indica-
treatment than disease populations, because patients can have tions, the PD data could also be used as strong evidence to support
altered immune status owing to their disease or the need to receive the extrapolation across approved indications of the innovator
concomitant immune-modulating medications. In cases where product beyond those selected for the Phase III testing for the
the development of antidrug antibodies can substantially alter proposed biosimilar. Furthermore, the comparative PD data are
the PK and thus affect the PK assessment, conducting the PK especially valuable when the PD endpoints are more sensitive than
comparability study in a less immunogenic population might the efficacy or safety endpoints of the Phase III trial in detecting
be desirable. In cases where the safety profile of the product does small differences between the proposed biosimilar and the refer-
not allow a study in healthy subjects, the PK similarity will need to ence product. In specific cases (e.g. for structurally less complex
be assessed in an appropriate patient population in which the biosimilars) the EMA and FDA note that addition of comprehen-
disease state is consistent with the indication for which the sive PD data to PK and other investigations that convincingly
proposed biosimilar is being developed [25,26]. demonstrate high similarity between the biosimilar and reference
For the PK comparability study, a parallel design generally is product could obviate the need for a comparative Phase III clinical
needed when the elimination half-life of the proposed biosimilar efficacy and safety study [6,7].
is long. A crossover design can be used when the elimination half- Key criteria for selection of PD measures include the following:
life of the biosimilar is short (e.g. fewer than five days), the (i) relevance to clinical outcomes; (ii) ability to be assessed after a
incidence of immunogenicity is expected to be low or there is sufficient period following dosing with appropriate precision; and

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Drug Discovery Today  Volume 20, Number S2  May 2015 REVIEWS

(iii) availability of assays with appropriate sensitivity to detect assays for testing samples from the comparative immunogenicity
clinically meaningful differences between the proposed biosi- assessment in Phase III trials.
milar and reference product [7,15]. Examples might be the The assessment of immunogenicity in early clinical studies can
hemoglobin level with epoetin alfa or the American College be conducted using the same assay format and sampling schedule
of Rheumatology 20% response rate with infliximab. Although for the proposed biosimilar and reference product. Assays capable
uncommon, the inclusion of PD data where there is an estab- of sensitively detecting immune responses, even in the presence of
lished association between the PD endpoint and clinical efficacy circulating drug product, might need to be developed [7]. The

Reviews  KEYNOTE REVIEW

can add support to the determination of similarity and provide assay strategy follows a tiered approach of screening, confirmation
added support for a selective and targeted approach to later and titer determination. The samples confirmed as positive for
clinical Phase III safety and efficacy studies [7,15]. In some cases, antidrug antibodies are further tested for the neutralizing capacity
sensitive and clinically important PD endpoints or assays are of the antibodies [31,32]. The immunogenicity assessment end-
not available. If this occurs, discussion with regulatory agencies points in the early clinical trials include antibody titer, time course
might be appropriate. In addition, a combination of markers of development, persistence, disappearance and association with
that assess different domains of activities and are based on clinical sequelae [7].
sound pharmacologic principles, including dose–concentration
sensitivity, can provide sufficient evidence to assess clinical Assessment of the early clinical development program
comparability [7,15]. A final task in the early clinical development of a biosimilar
product is to determine whether the objectives of the early
Clinical safety and immunogenicity clinical development program have been achieved and the
PK and PD studies conducted at the early clinical development extent to which uncertainties remain regarding similarity with
stage are not designed to compare the safety and immunogenicity the reference product [7]. Remaining uncertainties that do
of the proposed biosimilar with the reference product, especially not require a Phase III clinical trial for resolution could be
when these studies are not conducted in the therapeutic setting. addressed using a targeted approach in further early clinical
Nevertheless, the safety and immunogenicity data gathered from development.
these studies are valuable in the context of biosimilarity determi-
nation. Observation of a substantial difference in the safety or Summary and concluding remarks
immunogenicity profiles could help identify potential product Clinical development of a biosimilar is a stepwise process that
differences, providing information to guide the design and con- includes early clinical investigations in humans. Clinical investi-
duct of the Phase III trials. gation standards needed to demonstrate that a proposed biosimi-
The scope of investigations related to clinical safety is depen- lar is highly similar to the reference biological product are based on
dent on residual uncertainty regarding the proposed biosimilar, as guidelines from the EMA and FDA. Although these guidelines
well as safety concerns, if any, related to the reference product and share some similarities, there are important differences between
its class [7,15]. To assess safety, the type, severity and frequency of them, for example, the statutory ability of the regulatory agency to
adverse reactions observed with the proposed biosimilar are com- define an interchangeable biosimilar, as well as differences in the
pared with those observed during the clinical use of the reference approach to in vivo clinical data requirements. Furthermore, these
product. Safety related to infusion-related reactions and immuno- guidelines continue to evolve as more biosimilar products are
genicity is an important consideration because of the immuno- submitted for regulatory approval and considerations associated
genic potential of all biologics and the potential impact of with clinical development (such as appropriate compound no-
immune responses on safety and efficacy [7,15]. menclature and labeling of biosimilars) are identified.
For the PK and PD studies conducted in early development, the Strategically designed early clinical studies can address the resid-
goals of immunogenicity testing are severalfold. The first is to ual uncertainty following nonclinical investigations and guide a
monitor the incidence and severity of human immune response to selective and targeted approach to Phase III clinical trials. For
the treatment, especially if these are the first studies of the pro- biosimilars, the uncertainties addressed by early clinical studies
posed biosimilar being given to humans. Although the sample size are related to PK, PD and, to a lesser degree, safety and immunoge-
of these studies might be limited, they could identify the substan- nicity in humans. The PK comparability assessment should be
tial differences, if any, in immunogenicity properties between the conducted in a relatively homogeneous population and under
products so as to inform the nature and extent of immunogenicity sensitive conditions. Comparative PD assessment can add value
investigation during Phase III clinical development [7,30,31]. to the biosimilarity determination, leading to a targeted approach
Second, information about the presence and magnitude of anti- in Phase III investigations. Evaluation of safety and immunogenici-
drug antibodies and neutralizing antibodies will help evaluate if ty as secondary objectives in PK and PD studies can identify sub-
the PK or PD assessment is affected by the development of immune stantial differences in the proposed biosimilar and the reference
response. It is known that the formation of antidrug antibodies product. The immunogenicity assessment in early-stage studies can
can alter the PK behavior of the drug molecule. Third, the immu- help evaluate adequacy of the immunogenicity assays to be used for
nogenicity assessment in early trials can help evaluate perfor- sample analysis in Phase III trials. These extensive clinical evalua-
mance of the immunogenicity assays for analyzing clinical tions in early-phase studies can allow a more targeted Phase III
samples, providing valuable data to support the use of adequate clinical program and approval process for a given biosimilar.

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 REVIEWS Drug Discovery Today  Volume 20, Number S2  May 2015

Most recent FDA draft guidance for industry: clinical pharmacology data to support a demonstration of biosimilarity to a reference
product

The Guidance for Industry: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, issued by the FDA
in May 2014, is the fifth and latest in a series of draft guidances to industry that the FDA is developing to implement the Biologics Price
Competition and Innovation Act of 2009 [38]. This draft guidance provides additional detail on the use of clinical pharmacology studies to
support biosimilarity and focuses on three key concepts [38]:

 Exposure and response assessment

Reviews  KEYNOTE REVIEW

 Evaluation of residual uncertainty

 Four tiers relating to analytical quality and similarity (not similar, similar, highly similar and similar with fingerprint-like similarity)

The draft guidance describes the value of exposure–response data for pharmacokinetic (PK) assessments or pharmacodynamic (PD) markers
in demonstrating no clinically meaningful differences between a proposed biosimilar and a reference biologic [38]. As described in previous
guidances, biosimilar development uses a stepwise, risk-based comparability exercise to resolve residual uncertainty regarding the similarity
between the proposed biosimilar and the reference biologic. In its review of the biosimilar data package, the FDA uses a ‘totality of the
evidence analysis’ [38].
Although not part of clinical development, the key role of comparative structural and functional studies to inform clinical development is
detailed [38]. The FDA introduced the concept of four assessments that could result from the comparative analytical characterization: ‘not
similar’, ‘similar’, ‘highly similar’ and ‘highly similar with fingerprint-like similarity’ [38]. These tiers relate to analytical similarity. The ultimate
goal is to achieve the statutory standard for analytical similarity (highly similar) that allows approval of the product as a biosimilar as per the
351(k) pathway when supported by other appropriate data [38]. The greater the level of analytical similarity achieved the more targeted the
clinical data package can be [38]. The tiers are intended to form a point in time assessment that can change when more data are generated
to compensate for residual uncertainty [38]. The importance of comparative PK/PD assessments to resolve any residual uncertainty in the
analytical similarity is highlighted [38].
Regarding the use of clinical pharmacology studies to support biosimilarity, the importance of using appropriate bioanalytical methods to
evaluate the PK and PD properties is emphasized, with considerations given to general assay selection [38]. The benefits and limitations of
specific assays (i.e. ligand binding, concentration and activity) and considerations for PD assay selection are described [38].
The clinical pharmacology studies should also collect safety and immunogenicity data [38]. The assessment of safety and immunogenicity
should consider published data regarding the reference biologic including those related to the time-course of the safety signals or immune
responses [38]. Several other considerations are noted, including the selection between crossover and parallel study designs used to evaluate
clinical PK and PD similarity, the requirement to use the US-licensed reference product or establish bridging to the US-licensed reference
product and the relevance of specific characteristics of the proposed biosimilar in selecting the study design (study population, dose
selection, route of administration) [38]. The PK endpoints for the different study design (single- vs multiple-dosing) and different routes of
administration (intravenous and subcutaneous routes) also are discussed [38]. Extensive information is provided regarding how human PD
data can be used to assess the clinically meaningful differences and address the residual uncertainty and the design considerations for the
PD assessment (e.g. sampling time points and duration, PD endpoint for comparison) [38]. Statistical evaluation of PK and PD results is based
on: (i) a criterion to allow the comparison; (ii) a confidence interval for the criterion; and (iii) an acceptable limit [38].
The current draft FDA guidance addresses the use of modeling and simulation tools when designing a PK and/or PD study [38]. These tools
can be used to analyze publicly available data for the dose–response or exposure–response relationship of the reference biologic, or
information generated by the sponsor using a small PK/PD study, to justify the biosimilar dose used in the study [38]. A similarity study with
multiple dose levels to compare PK/PD between the proposed biosimilar and the reference product could also be considered when clinical
pharmacology evaluation is likely to be the major source of information to assess clinically meaningful differences [38]. In addition, modeling
and simulation can also be used to define the acceptable limits for PD similarity using publicly available information on biomarker–clinical-
endpoint relationships [38].

Conflicts of interest Medical writing and editorial support to prepare this supplement
This supplement was funded by Pfizer Inc. Edward C. Li, PharmD, was provided by Clint Earnheart, PhD, and Jacqueline Egan of QD
BCOP, was a paid consultant to Pfizer for the research and author- Healthcare Group. This support was also funded by Pfizer. Edward
ship of this supplement. Richat Abbas, PhD, Ira A. Jacobs, MD, C. Li has the following additional conflicts of interest to disclose:
MBA, FACS, and Donghua Yin, PhD, are employees of Pfizer. Advisor for Amgen and Hospira.

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