Innovations in-biosimilar-product-development

1. www.healthnetworkcommunications.com/biosimsus
Thoughts from top industry opinion leaders
eBook Contributors
Dr Alex Kudrin, Medical Assessor in Licensing of Biological Products, MHRA
Rajiv Dua, Analytical and Stability Coordinator, Lupin Biotech
Roman Ivanov, Ph.D, Vice President, Research & Development, CJSC BIOCAD
Jim Roach, M.D., FACP, FCCP, Senior Vice President, Development and Chief Medical Officer, Momenta Pharmaceuticals, Inc.
Anjan Selz, CEO, Finox

2. The potential benefits that biosimilars offer are well celebrated through providing improved patient access to
affordable, effective and complex treatments. The demand for affordable treatments in the face of escalating
healthcare costs is high but a number of hurdles present themselves when bringing a biosimilar from bench to
market. In this rapidly changing marketplace with its recently implemented and still evolving regulatory
framework, it is critical to adopt the right strategy, overcome barriers to entry and stay ahead of the game.
The starting point is to have a solid understanding of biosimilar development and the clinical trials environment.
We asked some industry and regulatory experts to provide their opinion on best practice in biosimilar
development, manufacturing and clinical stages. Take a look at what they had to say.
Alice Fairchild
General Manager
Biosimilar Drug Development World Americas
+44 (0)207 608 7054
afairchild@healthnetworkcommunications.com
www.healthnetworkcommunications.com/biosimsus
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3. Dr Alex Kudrin
Medical
Assessor in
Licensing of
Biological
Products
MHRA
What are the current
hurdles that you face in
biosimilar development?
There are numerous
regulatory, development and
legal resistors to development
of complex biosimilars. Some
of the challenges could be
divided into two groups:
internal factors related to lack
of expertise in developing
biosimilars and external
challenges related to
stakeholders and competitive
forces that are driven by
reference product
developers.
The problem is that many
biosimilar companies as well
as some regulatory agencies
are still learning from the "first
time experiences and trial and
error approach" with complex
biosimilars. Second group of
factors represent external
factors attributed to regulatory
barriers in some regions
(even in the US despite that
new guidelines were recently
enacted by FDA), clinical
environment hurdles
associated with the lack of
education amongst
prescribers and support
from some key opinion
leaders. These hurdles are
often triggered by the fact
that prescribers are relatively
familiar with the use of
reference products
and unfamiliar with the
concept of biosimilarity. Lets
not forget the fact that some
key opinion leaders also were
providing input in
development and clinical trials
with reference products and
therefore might be biased
towards competitive biosimilar
development. Increasingly a
new wave of biosimilar-driven
key opinion leaders is
emerging in developing
markets. Inherently, some
prescribers are concerned
about theoretical risks
associated with switching
between reference and
biosimilar products. Despite
of the contrast between EU
and US regulatory positions
on the interchangeability
requirements, most of
biosimilar developers will
have to address the
interchangeability issue at
some stage in the life cycle of
the product as this might be a
critical factor in determining a
market size. Biosimilar
developers will need to drive
a global educational
campaign on the use of both
biologics and biosimilars
especially in emerging
markets where the use of
biologics was, until recently,
relatively uncommon.
What are the hurdles in
qualifying biosimilarity
between a reference
product and comparator?
Not many companies are
capable to successfully
complete a first step of quality
and in vitro functional
comparability. Unfortunately a
stepwise approach is not
always followed and some
developers launch clinical
studies well before initial
steps of biosimilarity
exercises are fully concluded.
In vitro functional assays
represent a pivotal step in
demonstrating biosimilarity
and not many developers
either develop a full
armamentarium of functional
assays and cellular assays
or do not fine-tune results of
these assays with non-clinical
and clinical steps of
development. Therefore some
differences in the
performance of antibodydependent functions may
preclude these products from
being qualified as biosimilars
or indeed preclude the
extrapolation of all available
clinical indications. There is
also a great deal of confusion
in industry around so called
"biobetters" which are nothing
to do with appropriately
defined biosimilar products.
Hence some developers
consider using different
primary sequence structures
or heterogeneous expression
systems in developing
biosimilars. Because
"biobetters" potentially may
exhibit dramatically different
features to those known with
reference products, such as
enhanced efficacy, different
pharmacokinetic properties,
different posology or route of
administration, these products
would not fall under biosimilar
category and would have to
follow “stand-alone” pathway
for regulatory approval.
Cont...
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4. Hence inappropriate use of
“biosimilar” term around
products that would be
normally classified as “new
biological substances” can be
damaging to nascent
biosimilar industry striving to
develop high-quality and
highly similar products.
Do you feel the clinical trial
environment for biosimilars
is robust?
There are numerous
challenges in clinical trial
environment for biosimilars.
Firstly, there are ethical
issues around appropriate
consenting of patients who
participate in biosimilar
studies, especially if those
enrol healthy volunteer
subjects. The assay
sensitivity in pharmacokinetic
and therapeutic equivalence
studies should be robust
enough to identify any
potential differences between
the reference and biosimilar.
This possible to achieve in
most sensitive settings and
less heterogeneous patient
population.
As a consequence, biosimilar
studies are invariably carried
out in patients who are naive
to reference products and in
order to identify sufficient
number of patients
companies are forced to open
numerous clinical sites across
the globe, primarily in
developing countries. There
are particular hurdles in
conducting oncology
biosimilar studies.
The rate of patient recruitment
can be very slow due to low
number of available patients
and growing competition
between numerous biosimilar
developers for conducting
studies at the same sites.
Therefore the future
regulatory requirements
around the size and scope of
required oncology studies
should be revised in
accordance with evolving
clinical trial environment and
accumulating experience with
approved biosimilar products.
An overarching biosimilar
guideline by the EMA is
currently under revision and,
as the concept paper details,
the position on different study
design might be further finetuned in the new draft. There
might be scenarios where due
to the heterogeneity of the
clinical condition and the
highly variable performance
of clinical outcomes, the
conduct of equivalence
studies will not be feasible.
These scenarios include
evaluation of overall response
rates and disease free or
overall survival in oncology
indications or assessment of
multiple sclerosis activity
( e.g. for biosimilar
natalizumab or interferons). In
some of these complex
cases, the PK-based
equivalence may not be
straightforward as PK/PD
relationships with disease
activity are not very clearly
defined. Therefore, in some
cases, supportive noninferiority studies might be
allowed in the future along
with PK equivalence
approach, or PK equivalence
study alone might be
sufficient to complete a
clinical biosimilarity exercise.
In addition, sensitive but not
necessarily approved
indications might be allowed
for comparability exercise.
However there is no
harmonised regulatory
position on this matter yet.
Therefore in order to comply
with EU, US and other
regulatory requirements,
developers may need to
address the requirements
imposed by different agencies
in one single (but relatively
complex) or
in several biosimilar studies.
The situation will be much
more harmonised and
clearer as soon as first
complex
biosimilar monoclonal
antibodies will be approved
both in the EU and USA.
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5. Roman
Ivanov, Ph.D.
Vice
President,
Research &
Development
CJSC BIOCAD
What are the current
hurdles that you face in
biosimilar development?
Uncertainties in regulations
regarding biosimilars on
many emerging markets
represent a major obstacle
for biosimilar developers.
These uncertainties in
combination with lack of
proper expertise of
regulators create an
environment where
commercial success is not
always guaranteed for
those companies that use
science-based approaches
for biosimilar development.
In addition, originators put
a lot of effort into creating a
negative attitude towards
biosimilars among
prescribers and regulators,
decreasing market
penetration of biosimilars.
What are the hurdles in
qualifying biosimilarity
between a reference
product and
comparator?
Procurement of multiple
batches of innovator’s
product from different
target markets sometimes
requires significant time
and resources. However, it
is necessary for
justification of an
acceptable margin in
comparability studies.
Do you feel the clinical
trial environment for
biosimilars is robust?
Conducting a clinical trial
for biosimilar product in a
situation when multiple
companies (both biosimilar
developers and innovators)
are performing clinical
trials in identical patient
population is a real
challenge.
What is your
organizations approach
to biosimilar
development?
BIOCAD approach is to
perform analytical
characterization and nonclinical studies in
accordance with EMA
guidelines, while clinical
development strategy is
adapted to expectations of
regulators from our target
markets.
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6. Rajiv Dua
Analytical and
Stability
Coordinator
Lupin Biotech
What are the current
hurdles that you face in
biosimilar development?
I think for Biosimilar
development today, the
major hurdle is less clarity
and complexity in terms of
intellectual property and
lack of marketing strategies
besides huge cost involved
in complicated
manufacturing, establishing
physicochemical and
Clinical comparability to get
the biosimilar products
comparable to Reference
Medicinal Product (RMP) in
terms of quality, Safety and
Efficacy.
Analytical characterization
incapability is other
technical hurdle.
What are the hurdles in
qualifying biosimilarity
between a reference
product and comparator?
Unlike traditional generic
pharmaceuticals, biosimilars
aim to copy a complex
recombinant, three
dimensional protein
structures with high
molecular weight. Small
changes in the
manufacturing process can
alter the product’s effect and
safety. The first challenge in
assessing the comparability
of biologics is understanding
exactly what is meant by the
terms ‘comparable’, ‘similar’
and ‘highly similar’. Despite
such significant
improvements in analytical
techniques, however,
current analytical
methodology are not be
able to detect all relevant
structural and functional
differences between two
proteins, that’s the reason
extensive animal and
clinical studies are need to
determine comparability
(These factors increase the
time and money
investment).
is required after post
approval.
What is your
organizations approach to
biosimilar development?
While conventional generics
are expected to face
competition and pricing
pressures in most
developed markets, Lupin
pharmaceutical have
already started gearing up
for biosimilars.
Lupin LTD (Biotech Div.)
have outlined plans,
identified products and set
aside investment budgets to
develop a robust product
pipeline. Lupin is now on its
way and plans to soon
launch its first of two
biosimilar drugs for
oncology in India by the end
of this year. The company
currently has a total of 10
proteins in different stages
of development.
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Do you feel the clinical
trial environment for
biosimilars is robust?
Due to the limited clinical
database at the time of
approval of a biosimilar,
vigorous pharmacovigilance
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7. Jim Roach, M.D.,
FACP, FCCP,
Senior Vice
President,
Development and
Chief Medical
Officer, Momenta
Pharmaceuticals,
Inc
What is Momenta’s approach
to biosimilar development?
Momenta’s approach to
biosimilar development is very
much in line with the approach
outlined in the three FDA draft
guidance documents on
biosimilar development (see
further below). We begin by
structurally and functionally
characterizing a reference
protein product (RPP) as deeply
as is technically feasible. Our
goal is to determine
“fingerprints”, or very specific
molecular product attributes and
patterns that fully define the
RPP. Our analytics and scientific
approach have facilitated the
development of generic versions
of complex drugs such as
enoxaparin (approved in the US
in July 2010) and glatiramer
acetate (currently under FDA
review), and it is this prior
experience that has given us an
appreciation on how product
quality attributes (PQAs) for
biologic products may be
controlled and modified from
clonal selection through
downstream process
development. We believe that
determining relevant RPP
“fingerprints”, combined with our
understanding of PQA controls,
will allow us to reverse engineer
the process in order to develop
not only biosimilar, but also
potentially interchangeable
biologic products. Following
extensive characterization of the
RPP, we then compare it to our
product and evaluate the extent
of similarity/equivalence. In the
event “residual uncertainties”
remain, these will be evaluated
for potential clinical significance
and addressed by additional
studies as needed. Our hope
and expectation is that to the
extent we have been able to
thoroughly understand the RPP
through this extensive
“fingerprint-like” characterization,
the scope of any clinical studies
required, if any, may be
substantially reduced relative to
competitors in this space. We
have as a goal the development
of technology that will enable,
over time, the ability to reduce
“residual uncertainties” to not
only minimize, but potentially
eliminate clinical trials for some
products. We also believe that
thorough structural and functional
characterization may offer viable
means for demonstrating, in
whole or in part,
“interchangeability” and reducing
any “residual uncertainty”
associated with that decision.
What are the key takeaways
from the FDA draft guidance?
Key takeaways from our
perspective across the three
guidance documents include, but
are not limited to:
The Agency “encourages the
Sponsor to initiate early
discussions” and frequent
consultation.
The Agency will use a “stepwise,”
“risk-based,” “totality of the
evidence” approach to evaluate
biosimilar candidates, allowing
for the science to dictate
additional requirements (if any)
following review of structural and
functional characterization data.
There is a certain degree of
flexibility to facilitate
development, with FDA retaining
scientific discretion to review
each application on a “case-bycase” basis without a priori
mandating requirements; noting
that the “assessment of one
element at one step can
influence decisions about the
type and amount of subsequent
data for the next step.”
The FDA supports
“fingerprint‐like” characterization
using multiple complementary
analytical methods with high
sensitivity.
Data derived from analytical
studies, animal studies, and a
clinical study/studies will be
required for biosimilarity unless
FDA determines an element
unnecessary.
What are the scientific studies
needed to establish and
qualify the similarities and
differences between a protein
reference product and
comparator?
Without providing an exhaustive
list of specific analytics/tools
(e.g., mass spectrometry, certain
in vitro or in vivo assays, etc.) or
endpoints, in general, the
scientific studies needed for
comparator development should
include whatever technology and
assays that will provide a
comprehensive picture of the
structure and function of, and
process-related fingerprints
associated with, both the RPP
and comparator product. At
Momenta, we use multiple,
redundant, and orthogonal
assays to permit a thorough
understanding of both
products. We believe that this
approach is the most appropriate
and efficient way to demonstrate
to extent possible “structural and
functional equivalence” and
assure that the patient
experience with the comparator
product will be the same as with
the RPP.
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8. www.healthnetworkcommunications.com/biosimilaramericas
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Anjan
Selz, CEO,
Finox
What are the current
hurdles in biosimilar
development?
The major issue we are
confronted with at FINOX
Biotech is the nonhomogenuous regulatory
landscape across the
globe. And this makes
biosimilar development a
very tough venture.
Even-though the
development pathway may
be somewhat abbreviated
compared to a new
biologics development, still
and in general, you have to
present a very
comprehensive data set in
order to obtain approval.
Such comprehensive data
set results only by
conducting extensive
process, product and
patient studies, head-tohead to your reference
product and that take years
to conclude and absorb
millions of dollars. And for
the sake of patient safety,
this is definitely ok.
But, given that biosimilars
do not cover an unmet
need and are competing
from day one on in a
mostly saturated market,
such heavy development
costs do not results in
attractive business cases
for all biosimilar
candidates. If such
development costs are
then further multiplied due
to non-homogenuous
expectations by regulatory
agencies across the globe,
then even less bioismilar
candidates will make up a
good business case.
And given that situation,
how should the industry
then cope with the
healthcare payor's
expectation to have more
affordable drugs brought to
the patient?
What are and how do you
assess the IP
challenges?
The most challenging
issue in IP is how to
assess freedom-to-operate
(FTO) for one's product
and processes.
The loss of patent
protection for the molecule
and its expression system
is a good beginning for
FTO, but probably not the
area where patent issues
will be fought over. Given
the numerous production
and analytics processes
involved for manufacturing
a biologic and also given
that such processes may
be applicable to products
totally different to the one
you are assessing, it is
extremely difficult to obtain
a clear YES from the
patent attorneys in regards
to FTO. Further areas of
uncertainty are
composition of
formulations, use of
excipients and other
elements involved in
producing and presenting
a final product. And finally,
there are even some
legislations that know
patents of use that would
theoretically block the use
of a given competitor
product.
On top of this comes the
complexity of the IP
landscape not being a
static but a dynamic issue.
And be it competing
biosimilar developers, or
be it originator companies
defending their market
share, there will be
certainly someone who
tries to block your market
entry by issuing new patent
applications and claims
along your product and
process development - and
it may be difficult to avoid
these the further your
development has already
advanced.
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10. We’re hosting Biosimilar Drug Development World 2013 in Boston this November 19-21 and would love to
see you there.
Biosimilar manufactures will be discussing:
•Overcoming the challenges in development and commercialisation
•Regulatory issues surrounding biosimilar development
•Manufacture, process development and scale up
•Immunogenicity testing required
•Best practices in clinical trial design and execution
•Sourcing innovators for all levels of research
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& much more!
It’s a business event
Biosimilar Drug Development World America will discuss the scientific and technical considerations needed to navigate
the challenges in manufacture and development of biosimilar medicines. The sessions will include case studies,
discussion and insight about the application on biosimilar manufacture and development. This year’s event features
Hospira, Pfizer, Baxter, Polpharma, Momaneta Pharmaceuticals, Rothschild, Novartis, Sandoz, & many more. Learn from
them to manage the complexities in biosimilar development.
www.healthnetworkcommunications.com/biosimsus
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