state

nature publishing group

art

Open

The State of the Art in the Development of

Biosimilars
Mark McCamish1 and Gillian Woollett2
The development of biologic therapeutics using advanced technology to copy and improve on natures design of
complex peptides, proteins, and glycoproteins has enabled the treatment of diseases in entirely new ways and brought
unique and lifesaving treatments to many people. However, at least in part because of cost pressures, access to these
truly amazing products has not been uniformly available; many patients do not qualify for these treatments, or the
treatment is postponed until disabilities accumulate. The development of biosimilarsessentially copies of the original
biologic drugs after patent expirationallows for wider and, as important, earlier access to these agents because of
their lower cost and consequently greater affordability. The development and commercialization of biosimilars can help
address unmet medical needs by improving access to well-established therapeutic interventions while improving healthcare affordability.
The term biosimilar has been used loosely to describe any
follow-on biologic drug whose target is the same as that of
an originator biologic drug. It includes follow-on biologics
that are not comparable to the originator drugs, having been
developed for markets that are not highly regulated. The correct use of biosimilar is with reference to biologics that have
been approved in highly regulated markets such as Europe and
that meet strict criteria of quality and comparability to their
respective originator biologics. One of the concerns expressed
with respect to biosimilars is that the savings in costs not be
reflected as losses in the quality, safety, or efficacy of these critical
and often lifesaving medicines. However, the experience with
rigorously evaluated and approved biosimilars in Europe has
demonstrated that savings as well as improvement in access can
be achieved without compromising patient outcomes. This is
achieved by applying consistent and appropriate science-based
regulatory standards to biosimilars in the same manner as they
are applied to originator biologics. The United States can now
benefit from the European experience, given the concordant
regulatory approaches of the two key authoritiesthe European
Medicines Agency (EMA) in Europe and the Food and Drug
Administration (FDA) in the United Statesalready in place
for the regulation of originator biologics.
The FDA has had limited authority to review and approve
biosimilars, and this has led to delays in the availability of these
agents in the United States. This situation changed with the

passage of health-care-reform legislation in March 2010,1 when

the FDA was given explicit authority to review and approve
biosimilars. This authority included consideration of public
information on a previously approved biologic as a critical element in the approval of a biosimilar, provided the biosimilar
is considered highly similar to the original reference drug.
There are differences in the approval processes for biosimilars
and generic drugs because separate statutes govern the reference
products; most biologics are licensed under the Public Health
Services Act2 whereas all drugs are approved under the Food,
Drug, and Cosmetic Act.3
In this article, we discuss the progress made in Europe with
biosimilars, from a regulatory perspective as well from the viewpoint of patients needs. We also examine to what extent this
experience may accelerate the FDAs efforts to address the issues
of access and affordability for the US population. Biosimilars
draw on scientific principles that have been used by industry
and regulators for decades. Because of alterations to the earlier manufacturing process for biologics, few, if any, originator
biologic therapeutics are identical to the products originally
launched years or decades ago.4,5 Therefore, the experience and
expertise of all stakeholders in dealing with such manufacturing
changes can be used to create, evaluate, and commercialize highquality biosimilars in a cost-effective manner for US patients.
This should happen as soon as possible because patient access
to these therapeutics is an unmet need.6

1Global Biopharmaceutical Development, Sandoz International, Holzkirchen, Germany; 2Avalere Health, Washington, DC, USA. Correspondence:Gillian Woollett

(gwoollett@avalerehealth.net)

Received 12 October 2011; accepted 30 November 2011; advance online publication 8 February 2012. doi:10.1038/clpt.2011.343
Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

405

state

art

All Biosimilars Are Biologics and Will Follow the

Originator Pipeline

First and foremost, a biosimilar is a biologic, which is a medicine

derived from a living system. Biologics may be either sourced
from nature or produced using recombinant techniques. They
are increasingly well characterized, including their proposed
mechanism of action. Approximately 30% of the industrys
research and development outlay is dedicated to the development of biologics. Consequently, an increasing proportion of
newly developed medicines are biologics, and, of these, a steadily
rising proportion consists of recombinant products (also often
called biotech or genetically engineered).7
The recombinant products are most likely to become the initial
candidates for biosimilars in the United States, as has occurred in
Europe. They vary from simple replacement hormones to large
complex molecules with extensive posttranslational modifications, such as monoclonal antibodies (mAbs). The first approved
biotech products contained the smaller peptides and were made
in bacterial systems (ergo nonglycosylated); these led to some
of the first biosimilars. As for generic drugs, the pipeline for
biosimilars will match, broadly speaking, that for the respective
originator products, except that there will be a delay of at least
12 years to allow for the exclusivity period dictated by law (the
Biologics Price Competition and Innovation Act (BPCIA)) and
provisions of the Patient Protection and Affordable Care Act
enacted in March 2010).1
Sponsors of biosimilars are also likely to pay particular attention to biologics that have been most successful commercially.8
These may include products that have added major indications,
even if initially approved as orphan products (epoetins), those
that are essential for prolonging life even though they are used
by very few patients (the replacement proteins for rare diseases),
or products that have disparate indications but affect large numbers of patients (such as antitumor necrosis factor biologics for
treatment of autoimmune disease).
Access to biologics can be dramatically improved through
the development of biosimilars, provided such development is
appropriately incentivized and the products can be manufactured and licensed cost-effectively. Many candidate reference
products for biosimilars; patents are expiring and the pool of
originator candidates is expanding.9 Consequently, there is a
compelling unmet medical need as well as an economic driver
for competitionhence the inclusion of provisions with respect
to biosimilars in the US health-care-reform legislation of 2010.1
Whether biosimilars will become a reality in the United States
just as they have in the rest of the world depends to a significant
degree on how the FDA approaches review and approval of these
products as well as whether appropriate incentives for payers
and health-care personnel will be put in place.
The Fda has Expertise in Evaluating Manufacturing
Changes in Biologics and Experience Comparing
Biologics From Different Sources

The following examples demonstrate that the FDA already has

extensive experience with two groups of products, and that this
experience is directly applicable to the approval of biosimilars.
406

Some biologics are regulated as drugs under the FD&C Act

The FDA has approved a few biologics through new drug applications (NDAs) under the FD&C Act, and copies of these drugs
can follow a generic pathway. The so-called originator biologic
dugs provide interesting examples of the agencys scientific reasoning when approving copies of the originator drugs, and this
logic is applicable to their review of biosimilars.
In 1984, with the enactment of the HatchWaxman Act, the
regulatory pathways 505(j) (also called abbreviated new drug
applications (ANDAs) or generics) and 505(b)(2) were created.
The ANDAs are approved with the same label and as fully substitutable products (A-rated and so listed by the FDA in the
Orange Book).10 Products approved under 505(b)(2) may or
may not be labeled as substitutable and may have only a subset of
the indications of their reference product (however, more indications can be added at any time, using a supplemental NDA).
The FDA has approved three follow-on biologic drugs as
ANDAs11 and eight follow-on biologic drugs in the 505(b)
(2) category12,13 under the FD&C Act. The approval of these
products (see Table1) became possible because the FDA had
approved several originator products that are biologics of the
505(b)(1) category of NDAs under the FD&C Act. For the
ANDAs as well as for the 505(b)(2) approvals, the sponsor of
the copy product relied on prior findings of safety and efficacy
of the reference product that were in the public domain. These
are illustrations of the scientific approach that the FDA uses to
conclude that sameness exists between two products. In no
case does the FDA reveal the actual data of the originator application to the subsequent sponsor; indeed, this is not required
because the sponsors of the generic products must use their own
tools for analytical characterization of both originator and copy
products so as to provide convincing proof of sameness.
Although the demonstration of sameness is a requirement for
such applications, they are not required toand generally do not
attempt todemonstrate a priori the safety and efficacy of the
active moiety in the product because this has previously been
demonstrated with respect to the original product application.
Indeed, for an ANDA, clinical data cannot be included in the
application (beyond bioequivalence data, which is justified as
limited confirmatory testing).14
The approval of Sandozs Enoxaparin in June 2010 and
Amphastars Enoxaparin in September 2011, both as ANDAs,
illustrates the scientific approach that the FDA employed in its
evaluation. Enoxaparin is a complex biologic product with the
source material harvested from porcine intestines; it comprises
a complex mixture of polysaccharides. The drug was originally
approved for treating and preventing various complex thromboembolic events. The ANDA applications were approved
by demonstrating the sameness of the generic vis--vis the
originator (fingerprinting, as the FDA recently described it)15
without any clinical trials. This approval provides evidence of
the FDAs confidence in the value of chemical and biological analytical information; indeed, the FDA provided detailed scientific
justification for its rejection of the reference product sponsors
citizen petition.16 Briefly, the FDA developed five criteria to carry
out scientific evaluation of the sameness of generic enoxaparin
VOLUME 91 NUMBER 3 | march 2012 | www.nature.com/cpt

state

art

Table 1 Biologic drugs already approved by the FDA for which a previously approved reference product is cited as an integral part of
their dossier

Naturally
sourced
products

Naturally
sourced
products

Brand name Generic name

Regulatory Date of FDA

pathway
approval

Repronex

Menotropins

ANDA

10 January 1997 Lederle/Ferring

Pergonal (Serono, 22 August 1975)

Enoxaparin
Sodium

Enoxaparin

ANDA

23 June 2010

Sandoz (Momenta)

Lovenox (Sanofi-Aventis, 29 March 1993)

Enoxaparin
Sodium

Enoxaparin

ANDA

19 September
2011

Amphastar Pharma

Lovenox (Sanofi-Aventis, 29 March 1993)

Repronex

Menotropins

505(b)(2)

27 August 1999

Ferring

Pergonal (Serono, 22 August 1975)

Vitrase

Hyaluronidase

505(b)(2)

5 May 2004

Ista Pharms

Wydase (Baxter, 22 March 1950)

Amphadase Hyaluronidase

505(b)(2)

26 October 2004 Amphastar

Wydase (Baxter, 22 March 1950)

Hydase

Hyaluronidase

505(b)(2)

25 October 2005 Primapharm

Wydase (Baxter, 22 March 1950)

Glucagon
hydrochloride
recombinant

505(b)(2)

22 June 1998

Novo Nordisk

Glucagon (Lilly, 14 November 1960)

12 August 2005

Upsher Smith

Miacalcin (Novartis, 17 August 1995)

Recombinant Glucagen
products

Sponsor

Reference product (sponsor, date of original

approval)

Fortical

Calcitonin salmon 505(b)(2)

recombinant

Hylenex

Hyaluronidase
recombinant
human

505(b)(2)

2 December 2005 Halozyme

Wydase (Baxter, 22 March 1950)

Omnitrope

Somatropin

505(b)(2)

30 May 2006

Genotropin (Pharmacia and Upjohn, 24 August 1995)

Sandoz/Novartis

Three ANDAs and eight 505(b)(2) category products have been approved by the FDA.
ANDA, abbreviated new drug application; FDA, US Food and Drug Administration.

and Lovenox, the reference product: (i) the physical and chemical characteristics, (ii) the nature of the source material and the
method used to split the polysaccharide chains, (iii) the nature
and arrangement of components that constitute enoxaparin, (iv)
laboratory measurements of anticoagulant activity, and (v) certain ex vivo aspects of the drugs effects on humans. The approval
process for enoxaparin is important because the hierarchy of
reasoning that the FDA used in that case, being fundamentally
grounded in science, can be applied to any biologic product.
A second example is the approval of Omnitrope (somatropin), the only product approved as a biosimilar in Europe that
has also been approved in the United States. The approvals in
both jurisdictions, and also in Australia, occurred in the spring
of 2006. This was prior to the enactment of the Biologics Price
Competition and Innovation Act (BPCIA), but even now the law
does not allow biosimilar applications with respect to biologics
that have been approved as NDAs (this is set to change after
23 March 2020). In the United States, the reference product,
Genotropin, was approved under the FD&C Act as a 505(b)(1)
NDA in 1995, and Sandoz chose to file as a 505(b)(2) application to provide the FDA with all the supporting clinical data
that the company had collected as part of the development of
Omnitrope as the first biosimilar in Europe. In evaluating the
product for approval, the FDA used the highly similar standard of comparability17indeed, the term highly similar is used
28 times in the FDAs rejection of the three citizen petitions from
BIO, Pfizer (the reference product sponsor), and Genentech

that were submitted immediately prior to the US approval of

Omnitrope.
Fundamentally, the approval of these products relied on the
same concept that was established for comparability in the FDAs
1996 guidance.18 Later this evolved to become a tripartite guideline, International Conference on Harmonisation (ICH) Q5E,
for use in Europe, Japan, and the United States; this became the
basis for the EU biosimilars pathway.
Biologics subjected to manufacturing changes using a
comparability protocol

Sponsors routinely change the manufacturing process for biologics for a variety of reasons, including scaling up the process
to deal with commercial demand, improving the efficiency of the
process, and modernizing the process when major equipment
needs to be replaced or updated. The concept of comparability allows manufacturing changes to occur without having to
undertake a completely new product-development program.
Comparability protocols were developed in the United States,
through guidance, as a mechanism to provide input to the
FDA as well as assurance to the sponsor that, should there be a
manufacturing change, the FDA could determine whether the
pre- and postchange products were sufficiently similar (highly
similar, as described in the BPCIA) for the purposes of ongoing marketing under the same label. It was clear that the more
extensive the manufacturing changes were, the greater the likelihood of changes in product attributes, and, therefore, the more

Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

407

state

art

data the agency was likely to require to ensure that the resulting
products had highly similar quality attributes (see the 1996 FDA
Comparability Guidance, background section).18 This regulatory initiative evolved to become the basis for ICH Q5E, adopted
in the highly regulated markets in the mid-2000s,19 and it has
shown few, if any, instances of failure.5,20
Fundamentally, comparability relies on the data relating to
the original (prechange) biologic product that established,
a priori, its safety, purity, and potency. The FDA, Japans
Pharmaceuticals and Medical Devices Agency, and the EMA
rely on these data plus the results of the evaluation of changes
in quality attributes of the new product (after the change in
manufacturing method) to make a scientific judgment on
whether the new product is highly similar to the original one
and can be used by physicians and patients under the same
label. This bridge between the old product and the new one
is built, in the vast majority of cases, using analytical data
alone,21 that is, by establishing highly similar quality attributes
and bioanalytical sameness. In some cases, analytical data
alone may be insufficient as the basis for judging whether the
attributes of the two products are sufficiently similar. In such
cases, preclinical or clinical data may be required.22 Although
biosimilarity evaluation may represent an extreme form of a
comparability exercise, the scientific concept involved is identicalnamely, that of building a bridge of evidence between
two biological products without undertaking a complete new
product-development program. Indeed, some of the instances
of establishing comparability have included those for which
no clinical studies at all were conducted, even with the product that was first marketed.23 The FDAs ability and discretion
in making these judgments is based on a scientifically rigorous
process. The FDAs authority to use the comparability process
has been upheld by the courts.24
Comparability goes further than merely illustrating the principle of bridging between different biologics as a scientific exercise. Because biologics often have a shelf life of just 12 years,
the original product could be on the market simultaneously with
the newer one. The pharmacist, clinician, payer, and patient
do not know which of the two products is being dispensed at
any given time point (the products have identical labels and
packaging, and the only difference is the batch number, which
does not in itself indicate that a manufacturing change has
occurred). Therefore, these products are interchangeable, and
extrapolation between all indications always occurs irrespective
of whether the mechanism of action is known. The FDA, unlike
the EMA, does not publicly note the use of comparability in the
regulatory record (in the United States there is no public regulatory determination of comparability equivalent to the EUs
European Public Assessment Report).25 In the United States,
therefore, patients and their providers may never know that a
manufacturing change has occurred, let alone the extent of the
change. Nonetheless, the prechange and postchange products
can be assumed to be equally safe, pure, and potent, based on
the FDA review of the analytical data (or any requested preclinical or clinical studies)26 that supported the comparability
determination.
408

It is fair to conclude not only that the use of biosimilars is

feasible but also that most, if not all, of the issues concerning their regulation lie within the FDAs current expertise
and experience; no new regulatory or scientific concepts
are needed, given that the regulatory principles established
for comparability are also the ones used for biosimilarity. In
effect, therefore, the FDAs experience with comparability of
past and current biologic products and biologic drugs regulated as NDAs and ANDAs can be applied to the evaluation
of biosimilarsespecially given the fact that these previously
approved products are also the reference products for the
biosimilars. Furthermore, the European experience, including
publicly developed and in-use guidelines, can expedite the
formalization of a US approach to the review and approval
of biosimilars. Finally, harmonization across the highly regulated markets of the regulation of the originator biologics
should help to ensure that the FDAs regulatory decisions
regarding biosimilars are consistent with those of the EMA
and relevant agencies in Japan, Australia, Canada, and other
countries.
The Us Regulatory Pathways Created By the Bpcia

In March 2010, 27 as part of health-care reform, the US

Congress enacted the BPCIA. The legislation gives the FDA
the authority to approve any biologic for which the reference
product is a previously licensed biologic (i.e., one already
approved through the stand-alone biologics license application (BLA) or 351(a) pathway). The BPCIA offered 12 years
of exclusivity to biologics28; therefore, by law, the FDA cannot approve a biosimilar until 12 years after approval of the
reference product.
The 351(k) pathway enables the approval of biosimilars
and also allows the FDA to designate the biosimilar as interchangeable with its reference product (legally defined as being
the same as substitutable). This latter feature is unique to the
United States. The European law is silent on interchangeability
because of jurisdictional issuesit is the health authority in
each EU country that makes decisions concerning the practice
of medicine, not the central regulatory approval authority. The
EU standard for biosimilarity, however, is explicitly defined as
comparability.
The FDA held a public meeting in November 2010 to discuss
its new statutory authority and to obtain input from a broad
group of stakeholders. Presentations made at this meeting and
submissions to the relevant docket are available.29 A second
public process initiated by the FDA focused on the user fees
that the BPCIA authorized the FDA to collect in order to help
defray the costs of the agencys review and approval of biosimilar
applications.30 The FDA continues to conduct formal, sponsorinitiated, product-specific meetings because the pathway created
by the BPCIA became available for use on the day of enactment.
No regulations are required, and no guidances need be published by the FDA before it accepts, reviews and/or approves
biosimilar submissions. The FDA has stated that it planned to
issue guidances before the end of 2011, but the scope of these
guidances is not yet public.
VOLUME 91 NUMBER 3 | march 2012 | www.nature.com/cpt

state

Manufacturing
process
change

40
30
20
10

US Lyo
Us Liq
EU Lyo
EU Liq

1
01

0
.2
06

01

9
00

.2
05

00

.2
03

structure
Purity profiles
Glycan distribution

50

.2

Analytical methods can

determine whether batches
sourced in different countries
are identical or not
Microheterogeneity of protein

Enbrel (entanercept) batches G2F amounts

% G2F
60

00

Biosimilarity is defined by the law in each country. However,

the scientific concepts supporting a determination of biosimilarity or high similarity are universal in highly regulated markets and have been used for decades to enable changes to be
made in the manufacturing processes for originator biologics.
In Europe this link is explicit, and biosimilar products are called
comparable to the relevant reference product. In the United
States, the BPCIA1 statutory term used instead of comparable
is highly similar. However, comparability is defined in ICH
Q5E19 (the guidance dealing with manufacturing changes) as

Batch to batch
Batches before and after a change of the manufacturing process
Batches from different sites

02

Demonstrating biosimilarity: the nuts and bolts of sound

development methods for biosimilars

Analytical methods are sensitive to differentiate between

.2

Although much rhetoric has surrounded the definition of a

biosimilar, and terminology varies by jurisdiction, the term
always refers to a biologic product that is comparable (EU) or
highly similar (United States) to a previously approved biologic.31 The sponsor of the biosimilar is therefore correlating
the attributes of the product to the quality, safety, and efficacy
(Europe) or safety, purity, and potency (United States) of the
previously approved product. The sponsor must therefore first
demonstrate that its product is comparable/biosimilar to the
earlier one; equally important, once biocomparability is established, the sponsor must demonstrate that there is no need to reestablish the safety and efficacy of the active ingredient(s). In the
United States, a biosimilar will be reviewed under section 351(k)
of the Public Health Services Act, and therefore applications for
biosimilars are also called (k) applications. A full stand-alone
biologics license application is submitted under a 351(a) BLA.
Posttranslational modifications, such as glycosylation, are not
controlled by the recombinant DNA inserted into the host cell
that is making the biologic. The host cell used and the environment in which the host cell is grown impact these modifications. Therefore, changes in the manufacturing process, whether
involving scaling up of a process for the original product or
creating a biosimilar, will create slight changes in the structure
of the resulting biomolecules through altered posttranslational
modifications. It is these modifications that lead to the term
biosimilar, rather than biogeneric or bioidentical. Also,
with Europe having established the term similar biological
medicinal products and its reduction in common usage to
biosimilar, it was logical to codify the biosimilar terminology
in the US statute itself.
Products that are not subjected to this rigorous comparison
are not biosimilars. Some regulators, especially in emerging
markets, have approved subsequent versions of popular biotech
products, but in many cases these are independently approved.
Although they fulfill local regulatory requirements and are
appropriate for use in these markets to meet patients needs,
they are often not based on a rigorous demonstration of comparability to a highly regulated reference product. Such products
are termed noncomparable or alternative biologics, and their
product attributes should not be used to impugn biosimilars
approved for use in the highly regulated markets.

highly similar quality attributes, and this guidance already

applies in the United States to all biologics, whether they are
regulated under the Public Health Services Act or under the
FD&C Act. Whether one uses the term comparable or highly
similar, evaluation of the product from scientific and regulatory
viewpoints is identical.
To establish biosimilarity, the sponsor must show that the candidate product is highly similar to the originator (reference) product
at the analytical level, including structural characteristics as well as
biological functions. For the purpose of establishing a baseline, the
sponsor must perform a detailed analysis of the originator reference product, using a variety of orthogonal analytical techniques
that measure multiple attributes in multiple ways. These data are
then used to create the boundaries, or goalposts, of acceptable
features for the biosimilar. The originator product will have varied over its lifetime, and therefore multiple batches of originator
product must be acquired, and analysis should occur across the
shelf life of each batch. Batch-to-batch variability in the reference product is often minimal, but, larger variations can be found
after manufacturing changes (which in Europe can be linked to
comparability through a public disclosure in the European Public
Assessment Report). Importantly, because both pre- and post
change products have already been in use in patients, the range of
variation between them with respect to product attributes is presumed to be acceptable to regulators4 and judged as not impacting
safety, purity, or potency. All pre- and postchange products are
used interchangeably, and both can be on the market at the same
time; therefore, several switches can and do occur between these
products during the course of a treatment regimen.5
Indeed, as revealed in Figure1, a specific product attribute
was very consistent across two formulations of the product
(lyophilized and liquid) in both European and US markets
until a sudden shift (via a change in the manufacturing process) resulted in a decrease in enrichment from ~50 to 30%.
The EU- and US-labeled products displayed the exact same
change, and the two forms (lyophilized and liquid forms) in
each of these regions exactly mirrored these changes, thereby
indicating the comparability of the final dosage forms in the
two markets.

01

The Scientific Demonstration of Biosimilarity

Starts with Demonstration of Comparability

art

Expiration date

Figure 1 Variability seen in Enbrel as documented in ref. 4 across various

regions (United States and European Union) and across product forms
(lyophilized and liquid).

Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

409

state

art

Several points can be made from this information:

Over the multiyear time period of product characterization,
there was no perceptible drift in the product attribute
the percentage enrichment of this glycosylation species was
very stable until the manufacturing change took place
Because both products were concurrently on the market
with the same label, they would be considered clinically
comparable, delivering the same efficacy and having the
same safety profiles
A biosimilar product with this specific product attribute
within this enrichment pattern would be considered highly
similar
It was possible to determine that the EU and US products
were comparable
After determining the goalposts for allowable productattribute variation for the originator reference product,32 the
sponsor will then utilize a complex iterative process to create
a biologic product that would be considered highly similar to
the originator product. The additional challenge of making the
posttranslational modifications overlapping with the originator product requires greater time and resources than creating

an original biologic that does not require matching product

attributes. Figure2 (lower left panel) depicts a clone-selection
process that is dependent on analytical and functional characterizationin this case, evaluating fucosylation of the resultant antibody to antibody-dependent cellular cytotoxicity. The
panel on the right depicts adjustments in bioreactor conditions
to achieve specific posttranslational modification patterns.
Ultimately, the analytical parameters that will form the basis
for the development of the biosimilar are chosen and the biosimilar can be developed iteratively to fit those specifications. The
measure of the match can include functional as well as analytical
attributes, as shown in Figure1. Note that, depending on the
assay system chosen, reverse engineering can use a functional
assay as part of the early screening.
Once the biosimilar candidates product attributes are within
the goal posts, the sponsor can conclude that their candidate is
highly similar to its reference originator product. Any parameter for the biosimilar that is outside the goalpost of the reference product must be demonstrated to have no impact on the
clinical attributes of the final product.
Once the analytic data demonstrate comparability with the
originator reference product, the sponsors will then determine,

a
Screening of bioreactor
conditions

10

600
500

8
Quality attribute (%)

ADCC (% of reference)

700

400
300
200
100
0
0

Range of originator on
market too narrow to
deduce structure/function
relationship

bG0-F (rel. %)

6
4
2

6
8
Variability observed during
cell line development
enables elucidation of
quantitative structure/
function-relationship

0
Parental
cell line
pools

Charge variants are typical product-related variants for

monoclonal antibodies (mAbs):
Acidic variants (e.g., deamidation of asparagine)
Basic variants (e.g., amidation of proline)
Pyroglutamate/glutamine at N-terminus
Lysine variants at C-terminus
Monoclonal antibody fragments

Change variant (%)

80
60

Clones Clones
cell line cell line
pool A pool A

Clones Final clone

cell line cell line
pool B
pool B

Targeting a charge variant via pH

in bioreactor

40
20
0

Target range
7.2 7.0 6.8

Charge variants can be adjusted in the bioreactor by

optimization of

14
12
10
8
6
4
2
0

Target
range

0/
0
/ /0/0
//
/
/ //

/
/ /
/ //

/
/ /
/ /
/
/
/ /
/ /
/
//
/
/ //

/
/ /
//
/
//
/
/ /
/
/
/ /
/
/

Process parameters
Media components

Charge variant (%)

Targeting a charge variant via media

components in bioreactor

Media components

Figure 2 The iterative process development for reverse-engineering the biosimilar candidate product. ADCC, antibody-dependent cellular cytotoxicity.
410

VOLUME 91 NUMBER 3 | march 2012 | www.nature.com/cpt

state
along with the regulatory authorities, the preclinical and clinical
studies necessary to confirm biosimilarity. In highly regulated
markets, it is assumed that clinical data will be a prerequisite
for obtaining approval for biosimilars. Such clinical trials will
generally include PK/pharmacodynamic studies to demonstrate
bioequivalence, and phase III trials confirming biosimilarity,
often using equivalence trial designs. The extent of comparability
of the proposed biosimilar to the originator dictates the extent
of the clinical trials required; highly similar product attributes
would justify a tailored or abbreviated clinical trial program.
Once the full package of data proving biosimilarity is submitted and confirmed (overlapping product attributes, comparable
CMC information on drug substance and drug product, bioassays confirming binding and biological function, preclinical
toxicology, and comparable phase I and phase III trials), justification of extrapolation to other indications is considered.
Usually, the phase III trial is conducted in the most relevant
and often the most sensitiveindication so that differences, if
any, between the originator and the biosimilar can be determined. If no differences are documented and biosimilarity is
confirmed, extrapolation to other indications that appear in
the originator product label can be justified. Often this requires
demonstration of shared mechanisms of action in these other
indications. As with variations in product attributes after major
manufacturing changes, scientific justification is the benchmark
for acceptance of comparability.
Although an initial application in the United States for a
biosimilar can be for an interchangeable product, it is expected
that most sponsors will seek to establish biosimilarity first and
then supplement their dossier with additional data to support
interchangeability.
How does analytic similarity translate into successful
biosimilar product development?

Although conceptually comparability and biosimilarity are based

on the same scientific principles, these need to be translated into
a product-development approach that is fundamentally different
from those of either originator biopharmaceuticals or generic
drugs, but containing essential elements from each.
Analytic development generates the hypothesis that the reference product and the biosimilar are indeed comparable and
bioanalytically similar. Overall, biosimilarity is then confirmed
by specifically tailored or abbreviated preclinical and clinical
studies. The extent of this abbreviation is at the center of the
debate in the United States with respect to biosimilar product
development, given that all the stakeholders generally accept that
these studies are rarely necessary for originator biologics that are
making a manufacturing change (and in fact in the past have
been required by the FDA in fewer than 12% of such cases).33
If a scientifically acceptable approach is taken to show that the
biosimilar is as close to the originator product as the originator
product is to itself (allowing for manufacturing changerelated
variability), an abbreviated clinical trial program is easily justified. Incurring the costs of a full development program, including full clinical trials and the extensive technical development
activities required to produce the biosimilar product, is not a

art

viable approach to commercialization of less expensive biologic

therapies. This is where the tradeoff becomes essential for sponsors of biosimilars; if sponsors cannot expect a very real and
significant regulatory relief with regard to the requirements for
animal and clinical studies, the pathway reaches an impasse. If
unknown (unmeasured) attributes of pre- and postchange products can be assumed to be the same, an equitable application
of scientific regulatory standards should suggest that unknown
(unmeasured) attributes of a biosimilar under development cannot automatically be assumed to be different. In other words, if
the same regulatory standard is applied in two situations, the
same set of assumptions as to what is known/unknown should
be made in both cases, purely on the basis of the data.
The Sandoz Model For Biosimilar Product
Development

It is conceivable to have more than one model for biosimilar

development, and indeed biosimilar sponsors should be encouraged to develop whichever science-based and data-supported
models they wish, given that the responsibility of demonstrating biosimilarity will be on them, just as the responsibility to
demonstrate safety, purity, and potency lies with the originator sponsor. In Europe, sponsors have taken entirely different
approaches, resulting in very different regulatory dossiers.34 In
this article, we describe a model, developed by Sandoz, that has
resulted in a series of biosimilar products obtaining marketing
approval around the world, including in all the highly regulated
markets (even in the United States, albeit through the serendipity that resulted in some biologic products being regulated via
entirely different pathways, namely Omnitrope (somatropin)
and Enoxaparin). It is a robust model, and the demonstration of
comparability/biosimilarity is far from trivial because it includes
the need to iterate analytical and biologic characterization with
modifications in process development to achieve highly similar product attributes.35 A key question, therefore, is whether
the FDA will implement the BPCIA-enabled 351(k) biosimilar
pathways in a manner that allows for a meticulously developed
biosimilar such as this to receive permission for appropriately
abbreviated clinical trials and be commercially viable in the US
market.
The Sandoz model of biosimilar product development outlined here is fundamentally based on creating biosimilars that
match the product attributes of the originator product through
a complex and resource-intensive process. The key is that overlapping and highly similar product attributes foster the best
patient care, and this justifies an abbreviated clinical development program. This approach has resulted in the approval and
successful use by patients of a number of products, each with
unique aspects, including glycosylated and naturally sourced
products. An overview of our development approach is shown
in Figure3, emphasizing a two-step approach: demonstrating
analytic and functional similarity (the left side of the figure) followed by confirmation of clinical biosimilarity (the right side of
the figure). The extent of clinical trials required to confirm or
demonstrate biosimilarity depends on negotiations with regulatory authorities and will be based on their evaluation of the

Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

411

state

art

Develop highly similar product

Confirm biosimilarity

Confirm similarity

Initial similarity
Pilot scale DS
Goal posts

Analytical
toolbox

Final biosimilarity

Final scale DS
Final formulation
In vitro/in vivo data

Analysis reference

Cell line

Drug substance
pilot scale

Validated DS
Validated DP

Analysis reference
Drug substance
final scale
DS/DP
validation

Formulation/drug product

In vitro/in vivo
models

GLP tox.

Phase I

Phase II

Figure 3 An overview of the Sandoz biosimilar development approach.

chemical and biological comparability of the biosimilar to the

relevant originator product.
Figure4 shows an example of the biosimilarity process for
commercial granulocyte colony-stimulating factor, or filgrastim. It is a nonglycosylated peptide, which makes it one of the
easiest biologics to re-create. The first step in the process was
to demonstrate chemical and biological comparability to the
originator. Figure4 documents overlapping peptide mapping, higher-order structures, and binding comparing multiple
batches of the biosimilar with the originator product. Although
it is impossible to produce a bioidentical glycosylated protein,
it is possible to document a bioidentical drug substance when
dealing with a peptide. In this case, even a bioidentical drug
substance must be placed in a drug product formulation, and
this must be documented as being equivalent through a formal
PK study.
Figure5 shows an example of head-to-head PK/pharmacodynamic studies conducted with Zarzio (filgrastim) from Sandoz.
The curves representing the originator and the biosimilar are difficult to portray because the concordance between the data is so
close, thereby formally demonstrating bioequivalence of the two
drug products. This was accepted by the EMA as demonstration
of comparable products, thereby allowing for an abbreviated
formal clinical trial program. The products were considered so
similar that a safety exposure study designed as a single-arm,
open-label study was sufficient to confirm biosimilarity.
What is not depicted in this figure was the challenge faced in
documenting bioequivalence with this product with regard to
analytic characterization. For example, given the fact that Sandoz
freezes its filgrastim drug, there are fewer oxidized and deamidated variants as compared with Neupogen. If total filgrastim
is measured using high-performance liquid chromatography
412

(HPLC) to separate these variants from the nonmodified product, one is likely to underestimate total filgrastim and variant
filgrastim during a PK study. In this case, concentration of filgrastim in the blood is determined using enzyme-linked immunosorbent assay, which does not differentiate between filgrastim
and its variants. Therefore, if treatment regimens are determined
based on the HPLC content of filgrastim, bioequivalence will not
be achieved. Consequently, if the phase I study is conducted with
equal concentrations of the product as determined by HPLC,
bioequivalence will not be confirmed because of the higher proportion of filgrastim and filgrastim variants in the originator
product. This illustrates how important it is for the sponsor of
a biosimilar to have a complete understanding regarding the
characterization of the originator product so that the appropriate tests are used and the clinical trials are designed correctly.
Potential Us Regulatory Interactions

Once initial development has been achieved, and assuming that

preclinical and clinical studies are anticipated, it is likely that the
sponsor of a biosimilar will open an investigational new drug
application (IND) with the FDA (this is not inevitable, but highly
likely initially as the 351(k) pathway becomes established). An
open IND provides a protected space (trade secret and business
confidentiality) in which sponsors and the FDA reviewers can
share and discuss data and work together to agree on the nature
and extent of subsequent preclinical and clinical studies that
may be required in support of a biosimilar (and interchangeable
biosimilar) application, just as for any other biologic.
The specific nature of the meetings that will be available to US
351(k) applicants form part of the biosimilar user negotiations.
Most important will be the opportunity to gain the regulatory
agencys concurrence of biosimilarity for the candidate substance
VOLUME 91 NUMBER 3 | march 2012 | www.nature.com/cpt

state

140
120
100
80
60
40
20
0

02+03 07

01

04
02 (2.2) 012

06

10

15

20

09+010 011

25

30

Zarzio
Neupogen
05
(1.4)

35

Minutes
Relative response (RU)

Bioactivitysurface plasmon resonance spectroscopy

Higher order structureUV CD spectroscopy

Specific ellipticity (mdcg/((g/l)cm))

mAU

Primary structurepeptide mapping

art

6,000

Zarzio
Neupogen

5,000
4,000
3,000
2,000
Wave length (nm)

1,000
0

195 200 205 210 215 220 225 230 235 240 245 250

1,000
2,000
3,000

80
60

Comparability performed for EU

biosimilar applications showed
highly similar results with state of
the art methods for the two
filgrastims Neupogen and Zarzio

40
1 nmol/l Zarzio
1 nmol/l Zarzio
1 nmol/l Zarzio
1 nmol/l Neupogen
1 nmol/l Neupogen
1 nmol/l Neupogen

20
0
20

200

400

600

800 1,000 1,200 1,400

Time (s)
Association rate

Dissociation rate

Figure 4 Biosimilar filgrastim compared to reference product (Neupogen) using three state-of-the-art analytical techniques.

40
35
30
25
20
15
10
5
0

Ratio (%) and 90% CI

AUC

99.68 (96.95 102.47)

Cmax

99.83 (95.76101.98)

Time after administration (h)

Dose: 5 g/kg IV single-dose
Curves superimposable for Zarzio
and Neupogen-both filgrastims

Zarzio
Neupogen
0

12

16

20

Zarzio and Neupogen show

bioequivalence after a single IV dose

24

28

32

36
Development of CD34+ cells

Development of absolute
neutrophil count (ANC)

b
100
80

Zarzio
Neupogen

ANC (1 x 10 /l)

PK parameter

60
40
20
0

CD34+ (/l)

Concentration (/l)

80
70
60
50
40
30
20
10
0

0 20 40 60 80 100 120 140 160 180 200 220

Plateau after
5th injection: spc
for stem cell mob
is five injections

Zarzio
Neupogen

20 40 60 80 100 120 140 160 180 200 220

Time after administration (h)

Time after administration (h)

Dose: 10 g/kg SC for 7 days

CD34+ count = surrogate marker for efficacy in stem cell mobilization

Curves for both ANC and CD34+ cells superimposable for Zarzio and Neupogen

Figure 5 Pharmacokinetics (left) and pharmacodynamics (right) for both Zarzio and Neupogen.

manufactured on a pilot scale (to be confirmed with full-scale

data after filing). It is this confidence in biosimilarity, as shown
analytically, that forms the basis for the case for regulatory relief
regarding preclinical and clinical studies, mirroring the demonstration of comparability before and after changes in the manufacturing process of a biologic substance. The absence of relevant
analytical differences and the expectation of applicability of the

351(k) biosimilars pathway to regulatory approval are essential

for going forward with the development of a biosimilar. The
goal is to have regulatory reviewers affirm that the candidate
drug substance is highly similar to the originator product. We
prefer to show regulators that our biosimilar drug substance is
as similar to the reference product as that reference product is
to itself over its lifetime.

Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

413

state

art

If such agreement can be achieved, then all subsequent preclinical and clinical studies are designed only to confirm the
biosimilarity that has already been achieved in producing a
highly similar drug substance. In Europe, the reciprocal exchange
of information between sponsor and regulator was invaluable for
the regulatory authorities to learn how and under what circumstances sponsors make critical go/no-go investment decisions
and for sponsors to understand the major concerns of regulators
in approving biosimilars. Indeed, the give and take of the scientific advice process in Europe became the basis for the drafting
of the individual, product-specific guidelines. Guidelines were
not always developed before the first biosimilar was approved,
but in all cases their development was concurrent.36
It is presumed by most stakeholders that biosimilars will
always be subjected to head-to-head preclinical and clinical
studies prior to approval, although the European Union is
moving away from this assumption for preclinical animal
studies, as illustrated by its Draft Biosimilar mAbs Guideline,37
and the FDA acknowledged the thoughtfulness of this guideline in a paper in the New England Journal of Medicine. 38
Indeed, as more experience is gained by both industry and
regulators, we can expect a greater confidence in the ability
of different sponsors to make highly similar products using
both the same standard of comparability and the same data
requirements as those currently applied to manufacturing
changes. In Europe, we have seen this progression in regulator
confidence, and it has allowed reaffirmation of science-based
consistency in standards being applied to all biologics. This
trend, in and of itself, has great value to patients and their
health-care providers.
Also, given the differences in the statutes governing the EMA
and the FDA, the latter has unique additional opportunities to
designate products as interchangeable (substitutable), thereby
forming an interesting link to comparability approaches. In the
United States, after a manufacturing process change, a product
cannot be other than interchangeable, comarketing of pre- and
postchange products is possible, and treatment regimens are
switched between the two products without either the patient or
the health-care provider being aware of the switch. For biosimilars, however, a sponsor must demonstrate biosimilarity, affirm
the expectation of identical clinical results for the two products
in any given patient, and show that efficacy or safety are not
diminished by the switch.
Immunogenicity is important for all biologics and is therefore not a unique issue for biosimilars (and is already a consideration in ICH Q5E). To date, there has been no report of
a biosimilar on the market being associated with any unusual
or unexpected adverse events as compared with the relevant
reference product. Nonetheless, the BPCIA contains an explicit
mention of immunogenicity and the need for sponsors to assess
it in a clinical study unless this requirement is waived by the
FDA. The imposition of a similar requirement for demonstrating
comparability would be fair but unfortunate. In fact, it would be
generally regarded by most stakeholders as being scientifically
unnecessary. Europe has meanwhile revised its immunogenicity
guidelines, and they apply to all biologics.39,40
414

In Europe, as in the United States, biosimilars must undergo

pharmacovigilance and postmarketing studies like any other
approved medicinal product.
The European Experience has Been Successful and
has Benefited Patients

Europe has a vibrant and commercially successful, yet stillemerging, biosimilars market under the progressive but cautious oversight of the EMA. Although each of the 27 countries
in the EU has its own health authority, there is generally an
increasing familiarity with biosimilars, starting from the first
approved biosimilar product, Omnitrope (somatropin) in 2006.
This has led to greater acceptance and quicker uptake for epoetins andeven more sofor filgrastims.41 In Europe, there seem
to be fewer and fewer apprehensions among consumers about
any premise of inferiority of biosimilars. In fact, the European
Commission (EC) has actively countered the misinformation
propagated by some sponsors of originator products who suggested that biosimilars were less safe than the originator productsa suggestion that implicates the regulator along with the
sponsor of the biosimilar.
Given the common approaches to the development of originator products in highly regulated markets (as exemplified by
the ICH), there arises a fundamental question: how much of the
biosimilar wheel needs be reinvented in the United States?
This is the challenge, because the FDA led with the basic concept of comparability promulgated by guidance alone in 1996.
The FDA continues to be ahead in its regulation of Enoxaparin
as a generic biologic (in the European Union, low-molecularweight heparins are considered biosimilars); this example shows
that, when making a science-based decision, the FDA can and
does act confidently. No unusual or unexpected adverse events
have been seen with products approved as biologic drugs in
the United States on the basis of abbreviated data packages (see
Table1).
In Europe, general and class-specific guidelines were written
concurrently with the development of the first biosimilar candidates, and that experience should be relevant in the United
States too.35 In the European Union, biosimilars of somatropin, epoetin, and filgrastim have been approved, and there have
been no unusual or unexpected clinical events with any of the
biosimilars in any of the highly regulated markets. In each case,
the sponsor of the biosimilar selected a development approach
and negotiated with the EMA separately for review and approval,
as is done for any originator biologic. The studies conducted for
these biosimilar products varied greatly, even when the reference product was identical. Given that the investment in clinical
studies is a significant component of the development costs of
any medicinal product, sponsors need to propose a carefully
targeted clinical approach.
An additional hurdle to a global development approach is
the fact that regulatory authorities prefer that the comparator product be one that is labeled for that regulatory region;
that is, US-labeled comparator products are to be used for US
applications and EU-labeled ones are to be used for EU applications. This requirement would essentially double the cost
VOLUME 91 NUMBER 3 | march 2012 | www.nature.com/cpt

state
burden in the development of a global biosimilar. In this matter, too, the scientific basis of comparability should be kept in
mind. As demonstrated in Figure6, it is possible to confirm
the comparability of EU and US reference products; given such
a confirmation, a global clinical development program can be
performed with a single comparator reference product. In the
absence of this approach, to what extent will the EU-approved
biosimilars, with their compelling pre- and postmarketing data
sets demonstrating comparability, need to be redeveloped for
the United States? Will the FDA demand that entirely new clinical studies be conducted with US-labeled reference products?
Such a requirement would not be scientifically justifiable, but
some would interpret it as being legally necessary. Nonetheless,

PK/PD

Va
li

da

tio

Clinical
trials

Biological
characterization

Analytics

De

sig

ns

pe

cif

ica

tio

Preclinical

Physicochemical
characterization
Process
development

Figure 6 Development of a biosimilar is founded on state-of-the-art

analytics. Quality cannot be tested into a product subsequently and must be
established initially. The fundamental premise of development of a biosimilar
is therefore the establishment of comparability (European Union)/high
similarity (United States) based on analytics. This can take multiple iterations
in early-stage development and takes more time that would normally be
required of an originator product this early in development. This process
is followed by preclinical and clinical trials appropriate to document full
biosimilarity on all levels.

art

in the absence of scientific justification, the repetition of animal

and clinical studies could be considered unethical (apart from
being prohibitively expensive). It would be unfortunate if a situation arises in which the EU biosimilars could be imported for
personal use in the United States,42 whereas the BPCIA is interpreted in such a manner as to prevent them from being reviewed
and approved by the FDA for general use.
As an illustration of how critical this could be for patients, we
discuss the example of filgrastim below. When filgrastim was
approved as a biosimilar in Europe, the United Kingdom, using
tender pricing, allowed physicians to prescribe it as recommended
in clinical guidelines as primary prophylaxis against febrile neutropenia. Previously, because of pricing issues, patients were often
given this product only after febrile neutropenia had developed.
Figure7 reveals how overall usage of the product increased dramatically consequent to improved access and more appropriate
use for primary prophylaxis. This example emphasizes the importance of access. The economic efficiencies associated with biosimilars are desperately needed in the United States as well.
The BPCIA was enacted as part of health-care reform on 23
March 2010, in part because of the expectations of savings to the
US Medicare and Medicaid programs. It contains no requirement that the FDA issue any regulations or guidance before
approving biosimilars. However, the FDA has yet to receive any
applications under 351(k).43
The FDA recognizes that its authority to approve biosimilars
came late in the day, and that it would therefore be receiving
applications for products already approved in other highly
regulated markets such as the European Union, Australia,
Japan, and Canada. This also means that the FDA must address
the issue of biosimilars that have been developed using a foreign reference product. However, given that all regions want
to address unmet patient access needs through biosimilars,
regulators are evaluating various ways to consider information generated with comparator products that have not been
approved in their region.44 The FDA has explicitly stated that
it is interested in access to the information involving foreign
comparator products but, surprisingly, only in the context of
stand-alone BLAs under 351(a).

UK filgrastim volume growth

percent change vs. previous year

Many physicians moved

filgrastim back to 1st-line cancer
treatment due to lower biosimilars cost
G-CSF prevents hospital readmission
due to infection

November 2008
biosimilar
approved

17
13

Biosimilars are less expensive than

originator biologics
Zarzio patient support kits
expand patient access:
Patients self administer at home
Efficiency savings repatriated

2
5
2007

2008

2009

2010

Note: Zarzio (filgrastim) is not marketed in the United States.

Figure 7 Example of a change in the practice of medicine enabled through the affordability created by entry of biosimilar granulocyte colony-stimulating factor
into an originator-only marketplace. Data from IMS, National Health Service, UK.
Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

415

state

art

Conclusions

We expect that biosimilars will be approved in the United States

as they have been in Europe. However, these products may be
approved as stand-alone 351(a) BLAs or through the new 351(k)
pathway depending on the sponsors choice. Indeed, Sandoz
already has direct experience of the differing approaches of the
EMA and the FDA. The first biosimilar approved in Europe,
Omnitrope (somatropin), was approved in the United States as a
505(b)(2) new drug application. Also, the low-molecular-weight
heparin Enoxaparin has been approved in the United States as
a fully substitutable ANDA, whereas in Europe low-molecularweight heparins are considered biosimilars.
Biosimilar products have already brought benefit to patients
in Europe and elsewhere through lower acquisition costs, and
the contrast has been sufficient to produce improvement in the
practice of medicine. Making these safe and effective medicines
available will also improve access to them in the United States.
Various commercial models will be used to accomplish this, but
regulatory approval is the essential first step. This is achievable
scientifically and technically. Nonetheless, the FDA must catch
up with other regulators for patients, insurers, payers, managedcare organizations, and the Centers for Medicare and Medicaid
Services to fully benefit from the development, approval, and
commercialization of these wonderful medicines.
Conflict of Interest
M.M. is head of Global Biopharmaceutical Development at Sandoz
International. Sandoz is the leading sponsor of approved similar biological
medicinal products in Europe, with three products: somatropin, epoetin
alfa, and filgrastim. G.W. is vice president at Avalere Health and works with
multiple stakeholders in health care, including but not limited to biopharma
companies (originator and generic).
2012 American Society for Clinical Pharmacology and Therapeutics

1. Title VII: Improving Access to Innovative Medical Therapies. Subtitle A: Biologic

Price Competition and Innovation (BPCIA) Provisions of the Patient Protection
and Affordable Care Act (PPACA) <http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/UCM216146.pdf>.
2. Public Health Service Act, Title 42 United States Code 262 Regulation
of Biological Products <http://www.fda.gov/RegulatoryInformation/
Legislation/ucm149278.htm>.
3. Federal Food, Drug, & Cosmetic Act [21 USC 355] SEC. 505.
New Drugs <http://www.fda.gov/RegulatoryInformation/
Legislation/FederalFoodDrugand CosmeticActFDCAct/
FDCActChapterVDrugsandDevices/ ucm108125.htm>.
4. Schiestl, M.,, Stangler, T., Torella, C., Cepeljnik, T., Toll, H. & Grau, R. Acceptable
changes in quality attributes of gylcosylated biopharmaceuticals. Nat.
Biotechnol. 29, 310312 (2011).
5. Casadevall, N. Immune-response and adverse reactions: PRCA case
example <http://www.ema.europa.eu/docs/en_GB/document_library/
Presentation/2009/11/WC500011064.pdf>.
6. Sullivan, R., et al. Delivering affordable cancer care in high income countries.
The Lancet 12, 933980 (2011).
7. PhRMA Biotech Medicines in Development, September 2011 <http://www.
phrma.org/sites/default/files/1776/biotech2011.pdf>.
8. McCamish, M. , MD, PhD presentation. 2011 AAPS Biotechnology Conference,
San Francisco, CA, 16 May 2011.
9. PhRMA Biotech Medicines in Development, September 2011 <http://www.
phrma.org/sites/default/files/1776/biotech2011.pdf>.
10. US Food and Drug Administration. Orange Book: Approved Drug Products
with Therapeutic Equivalence Evaluations <http://www.accessdata.fda.gov/
scripts/cder/ob/default.cfm> (2011).
11. Federal Food, Drug, & Cosmetic Act [21 USC 355] SEC. 505(j). Abbreviated
New Drug Applications (ANDA) <http://www.fda.gov/RegulatoryInformation/
Legislation/FederalFoodDrugandCosmeticActFDCAct/
FDCActChapterVDrugsandDevices/ucm108125.htm>.
416

12. Federal Food, Drug, & Cosmetic Act [21 USC 355] SEC.
505(b)(2) <http://www.fda.gov/RegulatoryInformation/
Legislation/FederalFoodDrugandCosmeticActFDCAct/
FDCActChapterVDrugsandDevices/ucm108125.htm>.
13. FDA Guidance on 505(b)(2) <http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/ucm079345.pdf>.
14. Bioavailability and Bioequivalence Requirements; Abbreviated Applications;
Final Rule <http://www.fda.gov/OHRMS/DOCKETS/98fr/02-31996.pdf>.
15. Kozlowski, S., Woodcock, J., Midthun, K. & Sherman, R.B. Developing the
nations biosimilars program. New Engl. J. Med. 365, 385388 (2011).
16. FDA Response to Sanofi Aventis Citizen Petition on Lovenox, 23 July 2010.
Docket Number FDA-2003-P-0273 <http://www.fda.gov/downloads/Drugs/
DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
UCM220083.pdf>.
17. FDA Response to BIO, Genentech and Pfizer Citizen Petitions, 30 May 2006.
<http://www.fda.gov/ohrms/dockets/dockets/04P0231/04P-0231-pdn0001.
pdf>.
18. US Food and Drug Administration. Guidance: Demonstration of
Comparability of Human Biological Products, Including Therapeutic
Biotechnology-derived Products, Center for Biologics Evaluation and
Research (CBER), Center for Drug Evaluation and Research (CDER) April 1996
<http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm122879.htm>.
19. International Conference on Harmonisation. ICH Q5E: Comparability
of Biotechnological/Biological Products Subject to Changes in Their
Manufacturing Process. EU: Adopted by CMPM, December 1, 2004, CPMP/
ICH/5721/03, date for coming into operation: June 2005; MHLW: Adopted 26
April 2005, PFSB/ELD Notification No. 0426001; FDA: Published in the Federal
Register, Vol. 70, No. 125, 30 June 2005 , pp. 3786137862 <http://www.ich.
org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5E/
Step4/Q5E_Guideline.pdf>.
20. Usdin, S. Myozymes zig zags. BioCentury 16, A1A6 (2008).
21. Follow-on Protein Products. Statement of Janet Woodcock, M.D., Deputy
Commissioner, Chief Medical Officer Food and Drug Administration before
the House Committee on Oversight and Government Reform, 26 March
2007, and Question and Answer Session <http://www.fda.gov/NewsEvents/
Testimony/ucm154070.htm>.
22. Aranesp EPAR <http://www.ema.europa.eu/ema/index.jsp?curl=pages/
medicines/human/medicines/000332/human_med_000651.
jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d125&js
enabled=true>.
23. Avonex (INTERFERON BETA-1A), BLA 103628 Approval History <http://www.
accessdata.fda.gov/drugsatfda_docs/label/1996/ifnbbio051796lb.pdf>.
24. Berlex Laboratories, Inc., Plaintiff, v. Food and Drug Administration, et al.,
Defendants. James Robertson, United States District Judge 7 October 1996
<http://www.fda.gov/ohrms/dockets/dockets/04p0171/04p-0171-cp0000105-exhibit-4.pdf>.
25. European Public Assessment Report (EPAR) for Aranesp <http://
www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/000332/human_med_000651.jsp&murl=menus/medicines/
medicines.jsp&mid=WC0b01ac058001d125&jsenabled=true>
26. Assessing the Impact of a Safe and Equitable Biosimilar Policy in the United
States. Statement of Janet Woodcock, M.D., Deputy Commissioner, Chief
Medical Officer, Food and Drug Administration before the Subcommittee on
Health, House Committee on Energy and Commerce 2 May 2007. <http://
www.fda.gov/NewsEvents/Testimony/ucm154017.htm>.
27. Patient Protection and Affordable Care Act (PPACA) <http://www.gpo.gov/
fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.pdf>.
28. Patient Protection and Affordable Care Act (PPACA). Title VII: Improving Access
to Innovative Medical Therapies. Subtitle A: Biologic Price Competition and
Innovation (BPCIA) provisions of the Patient Protection and Affordable Care
Act (PPACA)exclusivity provisions <http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/UCM216146.pdf>.
29. FDA Public Meeting November 2010 Docket Link Federal Register Notice
5October 10. <http://edocket.access.gpo.gov/2010/pdf/201024853.
pdf>; Docket number FDA-2010-N-0477; Public submissions: <http://
www.regulations.gov/#!searchResults;rpp=10;po=0;s=FDA -2010-N0477>.
30. FDA Biosimilars User Fee Federal Register Notice <http://www.gpo.gov/
fdsys/pkg/FR-2011-05-10/pdf/201111348.pdf>. Docket number FDA2011-N-0326; Public Submissions: <http://www.regulations.gov/#!search
Results;rpp=10;po=0;s=FDA-2011-N-0326>.
31. Novartis Submission to docket FDA-2010-N-0477 the November 2010 FDA
Public Meeting <http://www.regulations.gov/#!documentDetail;D=FDA2010-N-0477-0064>.
VOLUME 91 NUMBER 3 | march 2012 | www.nature.com/cpt

state
32. McCamish, M. & Woolett, G. Worldwide experience with biosimilar
development. MAbs 3, 209217 (2011) <http://www.landesbioscience.com/
journals/mabs/article/15005/>.
33. Follow-on Protein Products. Statement of Janet Woodcock, M.D., Deputy
Commissioner, Chief Medical Officer Food and Drug Administration before
the House Committee on Oversight and Government Reform, 26 March 2007
<http://www.fda.gov/NewsEvents/Testimony/ucm154070.htm>.
34. European Public Assessment Reports (EPARs) for Biosimilar Filgrastims.
<http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/
epar_search.jsp&mid=WC0b01ac058001d125>.
35. EMA Guidelines on Comparability/Biosimilarity <http://www.ema.europa.
eu/ema/index.jsp?curl=pages/regulation/general/general_content_000330.
jsp&murl=menus/regulations/regulations.jsp&mid= WC0b01ac058002956b#
Comparability Biosimilarity>.
36. EMA Guidelines for Similar Biological Medicinal Products <http://www.
ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_
content_000408.jsp&murl=menus/regulations/regulations.jsp&mid= WC0b0
1ac058002958c&jsenabled=true>.
37. EMA Guideline on Similar Biological Medicinal Products containing
Monoclonal Antibodies <http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2010/11/WC500099361.pdf>.
38. Kozlowski, S., Woodcock, J., Midthun, K. & Sherman, R.B. Developing the
nations biosimilars program. New Engl. J. Med. 365, 385388 (2011).
39. CHMP Guideline on Immunogenicity Assessment of Biotechnologyderived Therapeutic Proteins, April 2008 <http://www.ema.europa.

40.
41.
42.
43.
44.
45.

art

eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003946.pdf>.
EMA Guideline on Immunogenicity Assessment of Monoclonal Antibodies
Intended for In Vivo Clinical UseDraft <http://www.ema.europa.eu/docs/
en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdf>.
EMA Product Specific Approval Documentation <http://www.ema.
europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.
jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d124>.
FDA Information on Importation of Drugs Prepared by the Division of Import
Operations and Policy <http://www.fda.gov/ForIndustry/ImportProgram/
ImportPolicyandInformationbyProduct/default.htm>.
BioCentury Extra for Thursday, 2 June 2011. No FDA Biosimilars Applications
Filed <http://www.biocentury.com/dailynews/topstory/2011-06-02/no-fdabiosimilars-applications -filed>.
Kozlowski, S. Presentation at DIA FDLI Biosimilars Meeting, Bethesda, MD, 45
May 2011.
Patient Protection and Affordable Care Act (PPACA) <http://www.gpo.gov/
fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148. pdf>.

Clinical pharmacology & Therapeutics | VOLUME 91 NUMBER 3 | march 2012

417