Disentangling Biobetters under the Biologics Price Competition and Innovation Act of 2009

60 w w w . f d l i . o r gUpdate January/February 2011

Digital-Only Content

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

Following 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

de!nition of biosimilarity. Whether a

biobetter product can avail itself of the

BPCI will depend on whether it meets

the de!nition of “biosimilar” set forth

by the Act. In turn, the de!nition of bio-

similar depends on terms like “highly

similar” and “clinically meaningful,”

which present their own di"culties of

interpretation. In the end, even a close

reading of the BPCI and all available

materials does not provide a de!nitive

conclusion about how the Agency will

deal with biobetter products. #e 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

de!nition 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 o$en targeted by

biobetter applicants may include longer

product half-life in the body, lower like-

lihood of aggregation, greater e"cacy,

greater purity or fewer adverse events.

#ese 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 !rst observed the

bene!cial e%ects 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 !ltration and protecting it

from proteolytic degradation. Several

products currently on the market em-

ploy PEGylation technology including

Adagen (PEGgylated bovine adenos-

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

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

Posted with permission of the Food and Drug Law Institute (FDLI) ©2011. Originally published in FDLI’s Update.

January/February 2011 Update 61FDLI


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 o$en imparts stability, and

thereby can also lead to increased half-

life for therapeutic proteins.5 #us, 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#e 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 signi!cant practical

problems. Consequently, the BPCI as

enacted only bears a rough resemblance

to the Hatch-Waxman Act.

Under the BPCI, an applicant who

wishes to rely on an earlier determina-

tion of safety, purity and potency, as well

as e%ectiveness of an earlier biological

may do so by !ling an application under

subsection (k) of the Public Health

Service Act (PHSA) added by the BPCI.

#e 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. #e 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 !rst

applicant exclusivity under the Act.7 #e

BCPI sets forth the following two-part

de!nition of “biosimilarity”:

(A) that the biological product is

highly similar to the reference product

notwithstanding minor di!erences in

clinically inactive components; and

(B) there are no clinically meaningful

di!erences between the biological

product and the reference product in

terms of the safety, purity, and potency

of the product.8

#e 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. #e critical analysis,

therefore, compares the actual charac-

teristics of the biological product to the

provisions of the Act. Even though the

BPCI is at best opaque on its face with

regard to biobetters, it is not a blank slate.

#e BPCI is the product of a decade-long

dialogue between industry stakehold-

ers, FDA, the legislature and academia.

Accordingly, one can !nd 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 !rst prong of the de!ni-

tion of biosimilarity? In other words,

can a biobetter product be “better” in

some way and still be “highly similar”

under the Act? #e concept of similar-

ity is a di"cult 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.

#us, 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 #us, 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 !led under Section




505(b)(2) could appropriately rely on

FDA’s !nding of safety and e"cacy for

another protein product !led 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 P!zer’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 disul!de 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 Speci!cally 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 “scienti!c

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.

#e 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 scienti!c issues, Amgen noted

that the terminal half-lives for human

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 e%ective-

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 Speci!cally, 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

#us, we conclude that whether a

biobetter product can be “highly similar”

to a reference product, will likely be

situation-speci!c. 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 de!nition: “there are no clinically

meaningful di%erences 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-de!ned standard and it

is distinct from its more easily-de!ned

cousin, “statistically signi!cant.”22 One

clue to the meaning of the “clinical

meaningfulness” in this context may

lie in the de!nition 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 di%erences . . . 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 di%er-

ences between the two products (i.e., that

the two products will produce the same

e%ects in patients).”24 #us, the focus for

applying “clinically meaningful” should

be on comparing e%ects in patients.

#e concepts of safety, purity and po-

tency are each described in regulations to

the PHSA. For example, the regulations

de!ne safety as “the relative freedom

from harmful e%ect to persons a%ected,

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


January/February 2011 Update 63FDLI


the potential for immunogenicity.26 #e

statute does not distinguish between

positive and negative clinically meaning-

ful di%erences. #erefore, 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 de!ne purity as the “rel-

ative freedom from extraneous matter

in the !nished 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 pro!les. FDA

found that “[d]i%erences 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 e%ec-

tiveness of the follow-on product is not

compromised.29 #erefore, it certainly

appears possible that a biobetter appli-

cation could have a di%erent impurity

pro!le as long as that di%erence is not

clinically meaningful.

Similarly, FDA is quite familiar with

the concept of potency. Regulations

de!ne potency as “the speci!c 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 e%ect

a given result.”30 In the Section 505(b)(2)

context, FDA stated that while a follow-

on product may be “substantially di%er-

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 di%erences must

not be “clinically meaningful.” #us,

taken separately, none of the require-

ments of the second prong of the de!ni-

tion of biosimilarity appear to in and of

THE FOOD AND DRUG LAW INSTITUTE

THANKS THE SILVER SPONSORS FOR THEIR GENEROUS CONTRIBUTION

TO THE 2010 ANNUAL HOLIDAY AND LEADERSHIP AWARDS RECEPTION.

Each year FDLI recognizes up to four individuals from various areas of the food and drug law community for their notable service and leadership. FDLI

announces the recipients at its Annual Holiday and Leadership Awards Reception held in December of each year.




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.”

#e standard for “interchangeability”

is even more di"cult to meet under the

BPCI. #e Act de!nes “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

#e 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 #e 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-

!cacy 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#ere 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-

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 o%er

some bene!t 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?, #e 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., E%ect 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., E%ects of Glycosylation on the Stability

of Protein Pharmaceuticals, 98(4) J. Pharm. Sci. 1223

(2009).

6 Aranesp® prescribing information.

7 #e BPCI awards one year of exclusivity to the !rst

interchangeable product, subject to a number of

quali!cations. 42 U.S.C. § 262(k)(6).

8 42 U.S.C. §&262(k)(i)(2).

9 #e 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

di%erences in structure between them were due to

post-translational events or in!delity of translation

or transcription or were minor di%erences in amino

acid sequence; other potentially important di%er-

ences, such as di%erent glycosylation patterns or dif-

ferent tertiary structures, would not cause the drugs

to be considered di%erent unless the di%erences 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 Signi!-

cance as they relate to the E"cacy of PeriodontalT-

therapy, 134(5) J. Am. Dent. Assoc. 583 (2003)

(cataloging de!nitions of clinical signi!cance); see

also Jaeschke et al., Ascertaining the Minimal Clini-

cally Important Di%erence, 10 Cont Clin Trials 407

(1989); see also Cook, Clinimetric Corner: #e Mini-

mal Clinically Important Change Score (MCID): A

Necessary Pretense, 16(4) J. Manual & Manipulative

#er. 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 Speci!ca-

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).


Disentangling Biobetters under the Biologics Price Competition and Innovation Act of 2009

Documents

Transcript of Disentangling Biobetters under the Biologics Price Competition and Innovation Act of 2009