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Disentangling Biobetters under

the Biologics Price Competition
and Innovation Act of 2009
by Brian J. Malkin and Andrew S. Wasson

F
ollowing the passage of the
Biologics Price Competition
and Innovation Act (the BPCI
or the Act) in April 2010, the industry
and media have devoted an increasing
amount of attention to a class of bio-
logical products referred to as “biobet-
ters,” which are cast as an alternative
to both de novo biological products
and biosimilars. As the name “biobet-
ter” suggests, in the broadest strokes, a
biobetter is a new and improved version
of an already-marketed (but related)
biological product. Even pharmaceuti-
cal companies who were traditional
stalwarts of brand-name “big pharma”
have set their sights on biobetter targets.
In fact, it was reported recently that one
industry pioneer in biological products,
MedImmune, has decided to concen-
trate solely on biobetters.1
While some have concluded that
the BCPI will not govern biobetters,2
this article tests that hypothesis and
provides a rigorous analysis of the
definition of biosimilarity. Whether a
biobetter product can avail itself of the
BPCI will depend on whether it meets
the definition of “biosimilar” set forth
by the Act. In turn, the definition of bio-
similar depends on terms like “highly
similar” and “clinically meaningful,”
which present their own difficulties of
interpretation. In the end, even a close
reading of the BPCI and all available
materials does not provide a definitive
conclusion about how the Agency will
deal with biobetter products. The uncer-
tainty is compounded by the likelihood
that the Food and Drug Administration
(FDA) will approach each situation on a
case-by-case basis. Having said that, the
BPCI does not appear to lend itself eas-
ily to products that have been character-
ized as “biobetter,” and neither does its
definition of “biosimilar.”
What are Biobetters?
As described above, the term “bio-
better” refers to a biological product
that is similar to an already-approved
biological product, but is also superior
in one or more product characteristics.
Product characteristics often targeted by
biobetter applicants may include longer
product half-life in the body, lower like-
lihood of aggregation, greater efficacy,
greater purity or fewer adverse events.
These are a few characteristics poten-
tially available for improvement, but the
possibilities are truly endless.
Researchers looking to improve the
characteristics of a biological product
may employ the process of PEGylation.
PEGylation involves the covalent attach-
ment of a polyethylene glycol moiety (a
neutral and hydrophilic polyether) to a
peptide.3 Researchers first observed the
beneficial effects of PEGylation in the
late 1970s.4 Covalently attaching PEG to
a peptide confers a number of advan-
tages, chief among them an increase
in the in-vivo circulation half-life. Scien-
tists speculate that the hydrophilic PEG
polymers increase the molecular size
of a protein as well as mask its surface,
thereby increasing its half-life by reduc-
ing renal filtration and protecting it
from proteolytic degradation. Several
products currently on the market em-
ploy PEGylation technology including
Adagen (PEGgylated bovine adenos-

Mr. Malkin Mr. Wasson

is a Partner in the law firm of is a Associate in the law firm of
Frommer, Lawrence & Haug LLP Frommer, Lawrence & Haug LLP
in New York, NY. in New York, NY.

Posted with permission of the Food and Drug Law Institute (FDLI) ©2011. Originally published in FDLI’s Update.
60 Update January/February 2011 www.fdli.org

ine deaminase), Oncaspar (PEGylated
asparaginase), PEGIntron (PEGgylated
interferon), PEGASYS (PEGylated inter-
feron), Neulasta (PEGylated granulocyte
colony-stimulating factor) and Somavert
(PEGylated human growth hormone).
Given its long track record of improving
the properties of protein products, PE-
Gylation is a natural strategy for creating
additional biobetter products.
Another potential strategy to improve
peptide-based biological products relies
on the process of glycosylation. Glycosyl-
ation is a naturally-occurring post-trans-
lational phenomenon whereby oligosac-
charides are enzymatically linked to the
surface of proteins. Researchers discov-
ered that the addition of these glycan
appendages often imparts stability, and
thereby can also lead to increased half-
life for therapeutic proteins.5 Thus, re-
searchers have been able to guard against
aggregation, degradation or denaturation
by adding sites prone to glycosylation.
Many biologic products have already
employed this technique. For example,
Amgen designed Aranesp (darbepoetin
alfa) to have a longer in-vivo half-life by
engineering two new glycosylation sites.6
Biobetters under the BPCI
The BPCI, signed into law on March
23, 2010, sought to deliver on the long-
awaited promise of a framework for
biological products that matched the
framework for small-molecule drugs
existing in the Drug Price Competition
and Patent Term Restoration Act of 1984
(widely known as the Hatch-Waxman
Act). Despite the logical appeal of a
matching framework for biological prod-
ucts, the relative complexity of biological
products created significant practical
problems. Consequently, the BPCI as
enacted only bears a rough resemblance
to the Hatch-Waxman Act.
Posted with permission of the Food and Drug Law Institute (FDLI) ©2011. Originally published in FDLI’s Update.
FDLI
Under the BPCI, an applicant who
wishes to rely on an earlier determina-
tion of safety, purity and potency, as well
as effectiveness of an earlier biological
may do so by filing an application under
subsection (k) of the Public Health
Service Act (PHSA) added by the BPCI.
The BPCI authorizes FDA to approve
subsection (k) applications that demon-
strate that the biological product is either
“biosimilar” to or “interchangeable” with
a reference product. The BPCI envi-
sions a two-tiered system of products.
To qualify under the BPCI, an applicant
must at very least show biosimilarity to
a reference product, but also must meet
the more rigorous standard of inter-
changeability before being awarded first
applicant exclusivity under the Act.7 The
BCPI sets forth the following two-part
definition of “biosimilarity”:
(A) that the biological product is
highly similar to the reference product
notwithstanding minor differences in
clinically inactive components; and
(B) there are no clinically meaningful
differences between the biological
product and the reference product in
terms of the safety, purity, and potency
of the product.8
The BPCI makes clear that the informa-
tion necessary to support an application
under subsection (k) will far outstrip what
is necessary to support a generic approval
under Hatch-Waxman. Indeed, many in
the industry speculate that it will even
outstrip BLA approval requirements.
While the term “biobetter” is a conve-
nient shorthand for biological products
sharing certain enhanced characteristics,
the BPCI does not recognize “biobet-
ters” as a concept. The critical analysis,
therefore, compares the actual charac-
teristics of the biological product to the
provisions of the Act. Even though the
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BPCI is at best opaque on its face with
regard to biobetters, it is not a blank slate.
The BPCI is the product of a decade-long
dialogue between industry stakehold-
ers, FDA, the legislature and academia.
Accordingly, one can find precedent in a
number of sources including FDA’s prac-
tice of approving protein products under
Section 505(b)(2) of the Food, Drug, and
Cosmetic Act (the FDCA).
Can a Biobetter Product
be “Highly Similar” to a
Reference Product?
Is it possible for a biobetter sponsor
to satisfy the first prong of the defini-
tion of biosimilarity? In other words,
can a biobetter product be “better” in
some way and still be “highly similar”
under the Act? The concept of similar-
ity is a difficult one to employ because
of its ultimately subjective foundations.
Indeed, the language of the BPCI wades
even farther into the swamp by requiring
FDA to determine degrees of similarity.
Thus, in the abstract, a determination
that one product is “highly similar” to
another starts fraught with a number of
philosophical problems that will subtly
confound its application.
Practically speaking, past FDA deci-
sions relating to the approval of so-called
“follow-on” protein products under Sec-
tion 505(b)(2) of the FDCA inform the
meaning of “highly similar.” While the
BPCI amended the PHSA to provide a
framework for follow-on biological prod-
ucts, some protein products were already
marketed under the FDCA.9 Thus, even
before the BCPI, follow-on manufactur-
ers sought to avail themselves of Section
505(b)(2) of the FDCA to market protein
products governed by the FDCA. In this
limited context, follow-on manufactur-
ers forced FDA to determine whether a
follow-on product filed under Section
January/February 2011 Update 61
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505(b)(2) could appropriately rely on
FDA’s finding of safety and efficacy for
another protein product filed under
the FDCA.
In one such situation, FDA determined
that Sandoz’ application for somatropin
recombinant growth hormone, which
it proposed to market as Omnitrope,
could appropriately reference Pfizer’s
application for Genotropin and repeat-
edly characterized Omnitrope as “highly
similar” to Genotropin (the Ominitrope
Decision).10 Omnitrope and Genotropin
both contain the same active ingredi-
ent, somatropin recombinant growth
hormone, which is a “single chain, 191
amino acid, non-glycosylated protein
with two intramolecular disulfide bonds”
and a “long history of clinical use.”11 FDA
determined Omnitrope and Genotropin
were “highly similar with regard to their
physicochemical, biological, pharmaco-
kinetic, pharmacodynamic and clinical
characteristics.”12 Specifically speaking to
the term “highly similar,” FDA addition-
ally stated, “[w]e use the term highly
similar in this response to describe
the degree to which certain properties
of Omnitrope resemble properties of
Genotropin, as shown by the above-
referenced methods.”13 It should be noted
that FDA declined to address “scientific
issues associated with glycosylation” and
neither Omnitrope nor Genotropin were
glycosylated proteins.14
As described above, some biobet-
ter manufacturers hope to enhance
currently-known protein products by
increasing product half-life, including
through glycosylation or PEGylation.
The Omnitrope Decision obliquely
addressed what FDA will consider as
“highly similar” half-lives.15 In com-
ments in the docket opened by FDA to
address scientific issues, Amgen noted
that the terminal half-lives for human
Posted with permission of the Food and Drug Law Institute (FDLI) ©2011. Originally published in FDLI’s Update.
62 Update January/February 2011
growth hormone products vary “tremen-
dously,” ranging from 1.75 to 10 hours.16
Amgen stated that, “the clearance of a
protein product can impact the effective-
ness of the product, as well as the body’s
potential immune response to it.”17 FDA
declined to substantively weigh in on this
issue in the Omnitrope Decision, because
it could characterize the Omnitrope and
Genotropin half-lives as “highly simi-
lar.”18 Specifically, subcutaneously-ad-
ministered Omitrope exhibits a half-life
of 2.5-2.8 hours,19 while subcutaneously-
administered Genotropin exhibits a 3
hour half-life.20
Thus, we conclude that whether a
biobetter product can be “highly similar”
to a reference product, will likely be
situation-specific. No evidence sug-
gests that the term “highly similar”
categorically excludes products display-
ing enhanced characteristics. Yet, the
discussion on half-lives in the Omni-
trope Decision casts doubt on whether
a product boasting markedly better
characteristics would be “highly similar”
to a reference product. For example, FDA
determined that although the half-life
of Omnitrope and Genotropin were not
identical (2.5-2.8 hours versus 3 hours),
they were still “highly similar.” Compare
these half-lives to the half-life of Aranesp,
an epoetin product touted for its longer
half-life. Aranesp displays a termination
half-life of 21 hours, three times that of
any other epoetin alfa product.21 It ap-
pears that a biobetter product seeking to
characterize such a change in half-life as
“highly similar” to a reference product
would face an uphill battle.
Can a Biobetter Product
Display No Clinically
Meaningful Differences to
a Reference Product?
In addition to demonstrating that a
proposed product is “highly similar” to
a reference product, a subsection (k) ap-
plicant must also meet the second prong
of the definition: “there are no clinically
meaningful differences between the bio-
logical product and the reference product
in terms of the safety, purity, and potency
of the product.” “Clinically meaning-
ful” is not a well-defined standard and it
is distinct from its more easily-defined
cousin, “statistically significant.”22 One
clue to the meaning of the “clinical
meaningfulness” in this context may
lie in the definition of “comparability”
from Senator Henry Waxman’s proposed
Access to Life-Saving Medicine Act of
2006. Under that bill, a proposed product
would be “comparable” to a reference
listed product “in the absence of clini-
cally meaningful differences . . . in terms
of the safety, purity and potency.”23
Documents previously posted on Sena-
tor Waxman’s website summarized the
highlights of the bill, stating that it called
for prospective applicants to also submit
all information “necessary to show that
there are no clinically meaningful differ-
ences between the two products (i.e., that
the two products will produce the same
effects in patients).”24 Thus, the focus for
applying “clinically meaningful” should
be on comparing effects in patients.
The concepts of safety, purity and po-
tency are each described in regulations to
the PHSA. For example, the regulations
define safety as “the relative freedom
from harmful effect to persons affected,
directly or indirectly, by a product when
prudently administered, taking into con-
sideration the character of the product in
relation to the condition of the recipient
at the time.”25 Indeed, in the context of
considering follow-on products for the
peptide calcitonin under the FDCA, FDA
found that it would likely require a Sec-
tion 505(b)(2) applicant to include clini-
cal data demonstrating safety, including
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the potential for immunogenicity.26 The
statute does not distinguish between
positive and negative clinically meaning-
ful differences. Therefore, it appears that
a biobetter applicant would be hard-
pressed to show that a demonstrably
safer product would be biosimilar under
the BPCI, although small improvements
in safety might be tolerated as long as
they are not “clinically meaningful.”
FDA has extensive experience review-
ing the purity of biological products.
FDA regulations define purity as the “rel-
ative freedom from extraneous matter
in the finished product, whether or not
harmful to the recipient or deleterious
to the product. Purity includes but is not
limited to relative freedom from residual
moisture or other volatile substances and
pyrogenic substances.”27 FDA addressed
arguments relating to impurities in the
Omnitrope Decision. Indeed, FDA deter-
mined that Omnitrope and Genotropin
need not match impurity profiles. FDA
found that “[d]ifferences in the impuri-
ties and molecular variants for these
products do not preclude the approval of
Omnitrope under section 505(b)(2) of the
Act”28 as long as the safety and effec-
tiveness of the follow-on product is not
compromised.29 Therefore, it certainly
appears possible that a biobetter appli-
cation could have a different impurity
profile as long as that difference is not
clinically meaningful.
Similarly, FDA is quite familiar with
the concept of potency. Regulations
define potency as “the specific ability
or capacity of the product, as indicated
by appropriate laboratory tests or by
adequately controlled clinical data ob-
tained through the administration of the
product in the manner intended, to effect
a given result.”30 In the Section 505(b)(2)
context, FDA stated that while a follow-
on product may be “substantially differ-
ent” in terms of formulation or manufac-
turing process, a bioassay would “enable
the applicant to show that the manufac-
turing process can consistently produce
the new product in accordance with USP
standards and that the proposed shelf-life
is adequate.”31
Here, again, a biobetter product may
not have to match the potency of the ref-
erence product, but any differences must
not be “clinically meaningful.” Thus,
taken separately, none of the require-
ments of the second prong of the defini-
tion of biosimilarity appear to in and of

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FDLI January/February 2011 Update 63
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themselves bar a biobetter, yet, viewed
together it is unlikely that a biological
product that is marginally safer, purer or
more potent, would truly be marketed
as “biobetter.”
The standard for “interchangeability”
is even more difficult to meet under the
BPCI. The Act defines “interchangeable”
products as those that “may be substitut-
ed for the reference product without the
intervention of the health care provider
who prescribed the reference product.”32
The BPCI provides that an applicant
attempting to show interchangeability
must demonstrate that its product is not
only biosimilar, but that it also “can be
expected to produce the same clinical re-
sult as the reference product in any given
patient.”33 The Act also provides that for
products intended for repeated use, an
applicant must also demonstrate that “the
risk in terms of safety or diminished ef-
ficacy of alternating or switching between
use of the biological product and the ref-
erence product is not greater than the risk
of using the reference product without
such alternation or switch.”34 Most agree
that biobetters will probably not be able
to meet such heightened standards.
Conclusion
There are many complex incentives
that would encourage the manufacturer
of a biological product to brand their
product as “biobetter,” not the least of
which is marketing. It is important to re-
alize that the Act does not recognize such
an appellation. Consequently, the analy-
sis involves a concrete understanding of
product characteristics and the meaning
of the operative terms in the statute:
“biosimilar”, and in turn, “highly simi-
lar” and “clinically meaningful.” Draw-
Posted with permission of the Food and Drug Law Institute (FDLI) ©2011. Originally published in FDLI’s Update.
64 Update January/February 2011
ing from a number of sources, including
past FDA decisions and proposed bills, a
rigorous analysis of biobetters is possible
under the BCPI. Given this analysis, it
appears that the Act does not categorical-
ly exclude biological products that offer
some benefit compared to the reference,
however, it is unlikely that biobetters that
provide marked improvement could avail
themselves of the BCPI. FDLI
1 Walter Armstrong, MedImmune Bets Its Fate on
“Biobetters”, PharmExecBlog (Sept. 9, 2010), http://
blog.pharmexec.com.
2 See e.g. Cathy Kelly, Biosimilar Payments Under
Medicare: On Closer Look, Is It Worth It?, The Pink
Sheet (June 11, 2010).
3 See e.g. Fee et al., PEG-proteins: Reaction Engineer-
ing and Separation Issues, 61 Chem. Engineering Sci.
924 (2006).
4 Abuchowski et al., Effect of Covalent Attachment
of Poly(ethylene glycol) on Immunogenicity and
Circulating Life of Bovine Liver Catalase, 252 (11) J.
Biol. Chem. 3582 (1977).
5 Sola et al., Effects of Glycosylation on the Stability
of Protein Pharmaceuticals, 98(4) J. Pharm. Sci. 1223
(2009).
6 Aranesp® prescribing information.
7 The BPCI awards one year of exclusivity to the first
interchangeable product, subject to a number of
qualifications. 42 U.S.C. § 262(k)(6).
8 42 U.S.C. § 262(k)(i)(2).
9 The reason why some protein products are marketed
under the PHSA and some are marketed under the
FDCA is the result of pure historical and administra-
tive accident.
10 FDA response to Citizens Petition Docket Nos.
2004-P-0231, 2003-P-0176, 2004-P-0171 (May 30,
2006).
11 Id. at 8.
12 Id. at 14.
13. Id. at 9, n.23. See also 21 C.F.R. 316.3, which states
that in the orphan drug context, “[t]wo protein
drugs would be considered the same if the only
differences in structure between them were due to
post-translational events or infidelity of translation
or transcription or were minor differences in amino
acid sequence; other potentially important differ-
ences, such as different glycosylation patterns or dif-
ferent tertiary structures, would not cause the drugs
to be considered different unless the differences were
shown to be clinically superior.” It is unclear how far
one can take this regulation outside of the orphan
drug context.
14 Id. at 4.
15 Id. at 34.
16 Amgen comments submitted to Docket No. 2004-N-
0355/C3 at 5-6 (November 12, 2004).
17 Id. at 6.
18 Omnitrope® Decision at 36.
19 Omnitrope® prescribing information.
20 Genotropin® prescribing information.
21 Aranesp® prescribing information.
22 See Greenstein, Clinical Versus Statistical Signifi-
cance as they relate to the Efficacy of PeriodontalT-
therapy, 134(5) J. Am. Dent. Assoc. 583 (2003)
(cataloging definitions of clinical significance); see
also Jaeschke et al., Ascertaining the Minimal Clini-
cally Important Difference, 10 Cont Clin Trials 407
(1989); see also Cook, Clinimetric Corner: The Mini-
mal Clinically Important Change Score (MCID): A
Necessary Pretense, 16(4) J. Manual & Manipulative
Ther. E82-E83 (2008).
23 Access to Life-Saving Medicine Act (H.R. 6257; S.
4016)
24 Short Summary to Access to Life-Saving Drugs Act
(once available on Senator Waxman’s website, now
available at http://www.fdalawyersblog.com/resourc-
es/biosimilars.html) (emphasis added).
25 21 C.F.R. § 600.3(p).
26 2005-P-0367 (“the Fortical® Decision”) at 22.
27 21 C.F.R. § 600.3(r)
28 Omnitrope® Decision at 17.
29 It is important to note that this does not stand for
the proposition that FDA may approve a molecular
variant under the BPCI. On the contrary, FDA’s
statements in its Omnitrope® Decision merely note
that when the proposed product and the reference
are highly similar, the presence or absence of a
molecular variant in addition to the active form will
not prevent approval. See also International Confer-
ence on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use
(ICH) guidance for industry entitled Q6B Specifica-
tions: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products (August 1999).
30 21 C.F.R. § 600.3(s).
31 Fortical® Decision at 21-22.
32 42 U.S.C. § 262(i)(3).
33 42 U.S.C. § 262(k)(4)(A)(ii).
34 42 U.S.C. § 262(k)(4)(B).
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