A Comparison of US and EU Biosimilars

Regimes

summary statement (but this period may be expanded depending on the

outcome of patent litigation, as set forth in 42 USC
Economic barriers, along with regulatory complexity 262(k)(6)).
and uncertainty, are shaping the biosimilars industry
into something entirely different from the generic The BPCI defines a biosimilar product as “
small molecule pharmaceutical industry. The sharp (A). . . highly similar to the reference product
demarcation between branded and generic small notwithstanding minor differences in clinically inactive
molecule pharmaceutical companies may not exist components; and (B). . . no clinically meaningful
in the biologics context. The emerging biosimilars differences between the biological product and the
industry may present opportunities for both reference product in terms of the safety, purity, and
pioneering and follow-on companies. The regulations, potency of the product.”1 The interchangeable product
both in the United States and Europe, are still in a very must meet all the same requirements as a biosimilar
early, formative stage. This presents an opportunity and in addition have the same route of administration,
for commentary and an exploration of comparative dosage form and strength as the reference product.
advantage. This article presents an overview of the US 2
An interchangeable “may be substituted for the
and EU biosimilars regulations, in order to help legal reference product without the intervention of the
and executive decision makers at biopharmaceutical health care provider who prescribed the reference
companies begin to think about the range of product.”3
expenditures that may be necessary for approval of a
biosimilar. The BPCI defines a biological product as “a virus,
therapeutic serum, toxin, antitoxin, vaccine,
a comparison of us and eu biosimilar blood, blood component or derivative, allergenic
regulations product, protein (except any chemically synthesized
polypeptide) or analogous product. . . applicable to
At the end of March 2010 the United States enacted the prevention, treatment, or cure of a disease or
the Biologics Price Competition and Innovation Act condition of human beings.”4
(BPCI), the long awaited US pathway to biosimilars.
Europe has had an established pathway for biosimilars The regulatory definition of a protein is yet to be
since 2005. FDA has indicated it will seek to learn determined by FDA. Will the regulatory definition,
from the European experience with biosimilars as it once established, mesh with Congress’ presumed
promulgates regulations pursuant to BPCI. This article intent to distinguish proteins created recombinantly,
will explore the basics of the BPCI, compare and via biological processes, from proteins - presumably
contrast it with the European approach, and suggest shorter chain proteins, such as short peptides -
some possible near and medium turn scenarios for that are created via chemical reaction? The FDA
biosimilars in the United States. has indicated that some peptides are not proteins
even if created in living cells. Would this mean
The Biologics Price Competition and Innovation Act that short-chain therapeutic polypeptides such as
might be made, for example, via plasmid vector in a
The BPCI provides an application pathway for follow-
bacterium or yeast, not be covered by BPCI? These and
on biological products, codified in 42 USC 262(k). The
other questions will hopefully be answered as FDA
Act further categorizes such follow-on products as
rulemaking proceeds.
“biosimilar” or fully “interchangeable.” While there
is no incentive for a company to be the first-to-file a
1 42 USC 262(i)(2)
biosimilar application (in contrast with Hatch-Waxman) 2 42 USC 262(i)(3); 42 USC 262(k)(IV)
there is a one-year market exclusivity associated with 3 42 USC 262(i)(3)
being the first to file an “interchangeable” product 4 42 USC 262(i)(1)

fenwick & west

It should be noted that there is no such thing as a Setting aside the question of interchangeability for the
“biogeneric” because unlike in the small molecule moment, what degree of testing should be required
context the follow-on can never be an exact, to the for mere biosimilarity? Does the crux of biosimilarity
atom, duplicate. “Interchangeable” is the closest any lay in the achievement of the same clinical results to
biologic regulatory regime can come to ‘generic’. Of the pioneer product? That is to say, should FDA require
course this raises the question: what is similar enough? the same multi-year span of data that the pioneer
originally used to convince the FDA to approve the
Regulations Governing Biosimilarity product in the first place?

In the small molecule (Hatch-Waxman) context, As discussed below, this is not the requirement in
the substitutable small molecule must have the Europe. The European Medicines Agency (“EMA”)
“same active moiety” as well as identical ingredient regulations do not require the applicant to obtain
(chemical structure of active property), strength, and comprehensive data on patient benefit. The EMA
route of administration as the pioneer product. In requires the follow-on applicant demonstrate “similar
contrast, in the biological context, molecules may not efficacy and safety compared to the reference
be identical even from batch to batch within a single product.”
manufacturing facility. Given that follow-on biologics
will be made in different facilities and via a different Clearly the follow-on applicant will have to conduct
process (because of patent or trade secret protection) testing and a clinical trial of some sort, but for the
than the pioneer product, the difference between biosimilar pathway to have any practical meaning
putatively similar biologics could be structurally quite such trials must, as they are in Europe, be significantly
significant. Therefore the biosimilars regulations shorter and less comprehensive than the original
must, by biochemical necessity, provide more flexible applicant’s.
definitions. The BPCI provides that a biosimilar can
have significant differences from the pioneer product In a recent article in the New England Journal of
but still be “highly similar” so long as any differences Medicine, doctors from FDA’s Center for Drug
in purity, potency and safety are not “clinically Evaluation and Research (CDER) voiced some optimism
meaningful”.5 The question then becomes, how will on the FDA’s ability to use assay data to assess
FDA determine if a difference between a pioneer sufficient similarity.
and follow-on biologic is sufficiently “clinically
“[P]rogress in the characterization and
meaningful” so as to require FDA rejection of the
understanding of biologics now permits
follow-on? FDA began holding hearings on these
demonstration that some products are highly
issues in November, 2010.
similar to a reference product. [P]hysicochemical
Since then the FDA has obtained commentary from and functional assays have been used to
industry and interested parties on the range of characterize changes in manufacturing processes
structural differences that would be acceptable within for some biologics, and then animal or clinical
the “highly similar” standard (or, put another way, studies are used to resolve any remaining
would be an unacceptable “clinically meaningful” uncertainties about the comparability of the
difference) in the BPCI, but has not yet promulgated a products created before and after such changes
specific rule as of the date of this writing. and to provide sufficient confidence that safety
and efficacy are not diminished. . . There may
Some parties have set forth standards that make be strategies that allow a “fingerprint”-like
interchangeability practically impossible. For example, identification of very similar patterns in two
the American Medical Association and others argued different products. Such strategies were used
for the need for clinical testing before approval, as in supporting the approval of a generic low-
well as clear labeling and no automatic substitution molecular-weight heparin product, enoxaparin —
right for pharmacists, essentially asking the FDA to which, though it differs from proteins in important
set a regulatory bar so high that “interchangeability” ways, is structurally complex. Although additional
becomes an impossible threshold to meet. animal and clinical studies will generally be
5) 42 U.S.C. 262(i)(1)
needed for protein biosimilars for the foreseeable

2 a comparison of us and eu biosimilars regimes fenwick & west

 future, the scope and extent of such studies may a new exclusivity period does not begin to run if the
be reduced further if more extensive fingerprint- pioneer files a subsequent application that changes
like characterization is used.”6 dosage or route of administration or modifies the
structure of the molecule in a way that “does not result
The scientists also indicated that they would look in a change in safety, purity, or potency.”
closely to the European approach and experience,
integrating various types of information and taking a There is no equivalent to the Orange Book in the BPCI
“totality of the evidence” approach. They then referred scheme. Instead, there is a private exchange of patent
to the recent EMA draft guidance on biosimilar information and the biosimilar application itself is
monoclonal antibodies (discussed below) as a fully disclosed. Unlike in the Hatch-Waxman regime
source of guidance for the structure and conduct of there is no automatic stay of an FDA approval.
biosimilarity clinical studies.
The procedure is roughly as follows: after the follow-
As high a standard as FDA sets for biosimilarity it will on application is accepted by FDA, but 180 days
nevertheless be lower than for interchangeability. This prior to marketing, the applicant must disclose the
may, as a practical matter, indeed make applications application to the original BLA holder. The original
for a declaration of interchangeability highly unlikely. BLA holder then has 60 days to provide the follow-on
The CDER scientists note in passing that “a biologic applicant with a list of patents. The applicant then
will be considered interchangeable with a reference has 60 days to respond with detailed statements and
product if the developer demonstrates that it can a counter list of patents, which is then followed by a
be expected to produce the same clinical result in further response and negotiation period before the
any given patient and that the risk associated with BLA holder can file a lawsuit.
alternating or switching between the two products is
not greater than that involved in continuing to use the The detailed mechanics of the process of information
reference product.”7 disclosure (including confidential information
disclosure) and possible litigation between original
The EMA’s case-by-case approach to biosimilarity is BLA holders and follow-on applicants envisioned in
articulated directly in its regulations. The FDA, even as the BPCI is far beyond the scope of this article. But
it promulgates more specific rules in the near future, there can be little doubt that the complexities and
will likely also make its determinations on a case-by- potential gamesmanship that may emerge could rival
case basis as a practical matter. Applicants, if they those of the Hatch-Waxman regime.
are to be successful, will need to marshal their best
clinical, legal and regulatory professionals into the Europe
process. Each new application will be a significant
Europe is ahead of the United States when it comes
learning experience for the entire industry.
to biosimilar adoption. The EMA approved its first
Exclusivity biosimilar in 2006. In June 2010, a biosimilar version
of Amgen’s Neupogen was approved.
The BPCI grants a 12 year exclusivity to the pioneer
product. Specifically, the FDA may not grant a The exclusivity period in Europe is the same for both
biosimilar application until 12 years after the grant of biologics and chemical drugs: 10 years. Europe also
the original biologic license to the pioneer. It would requires follow-on biologics to adhere to the same
thus appear that a follow-on applicant can submit his post-marketing adverse-event vigilance and reporting
application before the expiration of the pioneer’s 12 requirements as the pioneer.
year exclusivity but the FDA will not be able to act on it
The Committee for Medicinal Products for Human Use
until the appropriate date.
(CHMP) is the EMA’s equivalent of FDA’s CDER and set
There are also provisions in the BPCI to keep pioneers forth the concept of a “comprehensive comparability
from “evergreening” their exclusivity. For example, exercise” in the original Guideline On Similar
Biological Medicinal Products in 2005.8
6) http://www.nejm.org/doi/full/10.1056/NEJMp1107285
8) CHMP/437/04 London, 30 October 2005
7) http://www.nejm.org/doi/full/10.1056/NEJMp1107285

3 a comparison of us and eu biosimilars regimes fenwick & west

The CHMP has published over half-a-dozen Genentech (Roche) has taken the position that “the
“guidelines” related to biosimilar products, including properties of the biologic often depend directly on the
guidelines on specific classes of biological products nature of the manufacturing process. Furthermore,
such as insulin and somatropin, as well as draft proteins have unique structural organization patterns
guidelines on monoclonal antibodies and a “concept (referred to as “folding”) that affect the way that they
paper” on low-molecular weight heparins. A complete work in the body; even biologics that are chemically
assessment of these guidelines documents are the same may have differing biological effects due
beyond the scope of this article but will be the subject to differences in the structural folding. An example
of a future article on European regulations. But for now of this folding effect is the difference between a raw
we can say that, at a minimum, pharmacokinetic and egg and a cooked one: chemically the two are the
pharamacodynamic (PK/PD) studies would be required same, but they are physically and biologically very
to establish sufficient similarity. different.”11 The company supports clinical trials for
each biosimilar indication.
Although further along than the United States, the
Europeans nevertheless continue to grapple with Amgen, in testimony before the FDA, asserted that
fundamental issues, such as proper nomenclature. half of the biosimilars developed in Europe had
In a recent article in Nature Biotechnology, members unexpected clinical outcomes, and therefore relying
of the EMA’s Biosimilar Medicinal Products Working on pharmacokinetic and pharmacodynamic studies
Party (BMWP) argued for more specific definitions alone should never be enough.
of the term biosimilar and criticized recent incorrect
labeling of some protein products as biosimilars. On the other side, the large generic pharmaceutical
companies such as Teva and Sandoz have indicated
Of the dozen or so true biosimilars licensed in that they may, in the near term, forego the uncertain
Europe thus far, almost all fall into three categories: BPCI process and instead use the existing BLA process
somatropin, epoetin alfa, and filgrastim. These are for their versions of popular biologic drugs, such as
all relatively small biologs. None of are as large or monoclonal antibodies.
complex as the monoclonal antibodies - such as
Rituxan or Herceptin - envisioned to be the subject One interesting idea aimed at avoiding clinical
of future biosimilar applications. On the other hand, duplication is to allow follow-on applicants to
these approvals have at least demonstrated proof purchase clinical trial data from pioneers. Another
of concept that biosimilars can be manufactured in idea is to allow data from non-US licensed products.
different expression systems yet still be “similar.” For
The approval of a biosimilar that does not meet
example, the biosimilar Valtropin is expressed in yeast
the definition of interchangeable will not result in
culture, whereas the original Humatrope is expressed
the near-instantaneous market penetration that
in E coli systems. 9
we observe in the Hatch-Waxman (small molecule)
Near term predictions: 2012-2013 context. From an economic standpoint, the critical
issue in biologics, as opposed to small molecules,
As noted, at the time of this writing the FDA has may be in convincing doctors, patients and other
not yet approved a follow-on biologic under healthcare stakeholders that the follow-on has
BPCI. 10 Nevertheless, several large “branded” demonstrated sufficient similarity to risk adopting it
biopharmaceutical companies have indicated that over the pioneer product. We can begin to get a sense
they will seek to market biosimilars in the future. of what will be acceptable to the FDA, but we have no
For example Merck, through its Merck BioVentures way of knowing what will be acceptable to the market.
subsidiary, is committed to biosimilar development This, along with the practical difficulties and expense
and intends to market a biosimilar version of Enbrel. of mass biological manufacturing, suggests that the
major biosimilar competitors will likely be other large,
9) EMEA biosimilars pathway presentation. June 2011
10 The July 2010 approval by FDA of Momenta Pharmaceuticals and Sandoz
pioneering biopharmaceutical companies.
generic version of Sanofi-Aventis’s blood-thinner Lovenox (enoxaparin so-
dium) came under the existing Hatch-Waxman regime for small molecules. In 11) http://www.gene.com/gene/about/views/followon-biologics.html
any event, enoxaparin sodium would likely not fit the definition of a biological
product as set forth by BPCI and understood by FDA.

4 a comparison of us and eu biosimilars regimes fenwick & west

Longer term predictions: 2016 and beyond For more information, contact:

Recent forecasts for biosimilar monoclonal antibody Michael J. Shuster, Ph.D.

sales reach upwards of $20B by 2020 , with the first Partner, Intellectual Property Group
monoclonal antibody (MAb) approvals to come (in Co-Chair, Life Sciences Group
Europe) by 2013.12 415.875.2413; mshusterfenwick.com

If biosimilar MAb products prove successful in Europe, Pauline Farmer-Koppenol, M.S.

with no more adverse effects than the pioneer MAb, Associate, Intellectual Property Group
this would likely prove influential to FDA. 415.875.2406; [email protected]
In 2010 the top ten MAb were, in order: Remicade,
Avastin, Rituxan, Humira, Herceptin, Erbitux, Lucentis, the views expressed in this publication are solely those of the author,
and do not necessarily reflect the views of fenwick & west llp or its
Tysabri, Xolair, and Synagis. Together they produced clients. the content of the publication (“content”) is not offered as
legal should not be regarded as advertising, solicitation, legal advice
$45B in sales.13 At least some of these monoclonal or any other advice on any particular matter. the publication of any
content is not intended to create and does not constitute an attorney-
antibody products could see biosimilar versions by client relationship between you and fenwick & west llp. you should
2016. This will almost certainly be the case in Europe. not act or refrain from acting on the basis of any content included in
the publication without seeking the appropriate legal or professional
Will such products, if they exist, be interchangeable advice on the particular facts and circumstances at issue.
by pharmacists with the original? At this stage
that would seem unlikely. Nevertheless, the $20B
by 2020 prediction in this context does not seem
unreasonable.

In the final analysis it would appear that any

biosimilar product, approved under either the EMA
biosimilar regulations, the US BPCI, or simply as a
new BLA, will require a level of clinical, marketing
and education support that entry into the market
by smaller generic small-molecule drug companies
would be highly unlikely. In the biosimilar context the
sharp line between “branded” and “generic” drug
companies that we see in the Hatch-Waxman context
may be blurred to the point of meaninglessness. It
will likely be the large, pioneering biopharmaceutical
companies that will create both pioneering and
biosimilar biological products, and they will pursue
the regulatory regime and jurisdiction best suited to
market conditions as they emerge.

12) http://www.marketwatch.com/story/forecasted-sales-of-biosimilar-
monoclonal-antibodies-for-oncology-indications-will-reach-more-than-4-
billion-in-2020-2011-11-15
13) http://knol.google.com/k/krishan-maggon/top-ten-monoclonal-antibod-
ies-2010/3fy5eowy8suq3/143#

5 a comparison of us and eu biosimilars regimes fenwick & west