AIPLA Webinar_US Biosimilars Pathway_John Engel Presentation ...

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& ENGEL NOVITT
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US Regulatory Pathway For Biosimilars
US Regulatory Pathway For Biosimilars
Practical Legal/Regulatory Considerations
Practical Legal/Regulatory Considerations
Arising In The Course Of The Pathway’s
Arising In The Course Of The Pathway’s
Implementation
Implementation
. , .John M Engel Esq
Managing Partner
& , ENGEL NOVITT
L
LP
THE LAW FIRM THAT KNOWS ITS SCIENCE
- AIPLA American Intellectual Property Law Association
Biotechnology Committee Webinar
25 September 2012
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DISCLAIMER

The Material And Viewpoints Set Forth In This Slide Deck And Conveyed During The Presentation
Are Presented By The Author In His Capacity As Founding & Managing Partner Of Engel & Novitt,
LLP. They Do Not Represent And Do Not Purport To Represent The Views Of The Law Firm Or
Of Any Former, Current Or Prospective Client Of The Firm,
And Should Not Be Construed As Such
.

This Presentation Does Not Provide Legal Advice, And Nothing In This Presentation Constitutes
Legal Advice, Which Should Be Sought From Independently Engaged Legal Counsel Based Upon
Individual Circumstances .
Ø
US Statutory Framework For Biosimilars
Ø
US Regulatory Framework For Biosimilars
Ø
Practical Considerations In Implementation
Ø
( ) . ( )351 k vs 351 a
Ø
’ What s In A Name?
Ø
( ) Do Constitutional Takings Issues
Remain?
Ø
( )( ) How Safe Is The 271 e 1 Safe Harbor?
Ø
- Surviving A Rube Goldberg Like Patent
Scheme
Ø
Further Reading That Might Be Of Interest
PRESENTATION OUTLINE – US BIOSIMILARS
PRESENTATION OUTLINE – US BIOSIMILARS
PATHWAY
PATHWAY
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US Statutory Framework For Biosimilars (1)
US Statutory Framework For Biosimilars (1)

Biosimilars pathway enacted as part of health-care
Biosimilars pathway enacted as part of health-care
reform,
reform,
Patient Protection & Affordable Care Act,
Public Law No. 111-148, 124 STAT. 119-1024
(23 March 2010)

Available at
http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname =111_cong_public_laws&docid=f:publ148.111.pdf

The “Biologics Price Competition and Innovation
Act” (Title VII, Subtitle A) establishes “biosimilars
pathway”

Derived from unamended, Senate-passed BPCIA (S. 1695)
adopted in 110
th
Congress by Senate HELP Committee (27
June 2007; reported 19 Nov 2008)

Grants FDA express new authority to review
applications for, license, and regulate biosimilar
biological products

New PHS Act provisions for biosimilars are much more explicit
and detailed than 50-plus yr-old provisions for originator BLAs
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US Statutory Framework For Biosimilars (2)
US Statutory Framework For Biosimilars (2)

A “biosimilar” is a biological product that is

Highly similar in quality attributes
to the reference, with
minor
differences in clinically inactive components
OK

Has
no clinically meaningful differences
from the reference in
terms of safety, purity, and potency

An “interchangeable biosimilar” is a biologic that is

Biosimilar to the reference biological product

Expected to produce same clinical result in any given patient

During repeat administration, presents
no greater risk
in terms
of safety or diminished efficacy from alternating or switching
products
than use of reference without switching


Interchangeable”/”Interchangeability” mean the biosimilar
may be substituted
for reference
without the
intervention of the health care provider
who prescribed
the reference
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Biosimilar is limited to
single reference
biologic (RB)

Biosimilar
must rely on FDA’s prior S&E finding
for
RB

Biosimilar sponsors effectively follow
two-step
process
:
1)
Biosimilarity based on
specific statutory
requirements

Analytics, preclinical, & clinical studies incl.
immunogenicity
Ø
Any of these
can be waived
by FDA
2)
Interchangeability presumably based on
switching
studies

Biosimilar sponsors can pursue a
subset of
indications

Clinical
studies in all uses not mandated
if MoA is
shared

Facilitates extrapolation
consistent with sound science

Biosimilar
applications can proceed
w/out FDA
guidance

Biosimilars must
follow standard biologics’
requirements

User fees, risk-mitigation strategies, etc.
US Statutory Framework For Biosimilars (3)
US Statutory Framework For Biosimilars (3)
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FDA issued three draft biosimilar guidances (Feb.
2012)
1)
Scientific Considerations in Demonstrating Biosimilarity to a
Reference Product
2)
Biosimilars: Q&A Regarding Implementation of the Biologics
Price Competition and Innovation Act of 2009
3)
Quality Considerations in Demonstrating Biosimilarity to a
Reference Protein Product

NOTE
: AIPLA submitted comments on all three guidances
addressing issues impacting IP rights (focusing on 12-year
exclusivity for biologics)

Three draft biosimilar guidances focus on technical
regulatory aspects of biosimilar development and
review

Characterizing a proposed biosimilar product and the reference
product [Scientific Considerations; Quality Considerations]

Delineating necessary data, such as pharmacokinetic/
pharmacodynamic, preclinical, and clinical data [Scientific
Considerations; Q&A]

Answering common questions regarding FDA’s interpretation of
certain statutory terms and requirements [Q&A]
US Regulatory Framework For Biosimilars (1)
US Regulatory Framework For Biosimilars (1)
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FDA’s stated goal in issuing guidances is an
efficient, predictable, and transparent regulatory
pathway

FDA convened public hearing on guidances (May
2012)

At public hearing, FDA heard testimony on these
issues and also sought stakeholder input on
future guidances

351(k) applications seeking a determination of
interchangeability

Requests for reference product exclusivity

Naming issues

Clinical pharmacology evaluation of biosimilar products

Q&As regarding implementation of BPCI Act (next set of Q&As)

Guidances not yet finalized heading into FY‘13

As new Fiscal Year approaches (Oct 1
st
), FDA has said it is
working “diligently” to finalize the guidances, but timeline not
provided
US Regulatory Framework For Biosimilars (2)
US Regulatory Framework For Biosimilars (2)
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Debate persists over the viability of the biosimilars
pathway and the value of pursuing approval of a
biological product under 351(k) rather than 351(a)

Significant questions remain as to whether the regulatory
burden and timelines for development and approval of a
351(k) biosimilar are that much less than those for
development and approval of a traditional 351(a)

Any approved biosimilar is not expected to be interchangeable
with its reference, thus requiring a sales force like a
traditional 351(a) biologic

FDA itself recently has warned that the biosimilars program will
be “under-resourced” for the next several years because
user fees will accrue slowly over time given the absence of
established facilities/products, and Congress did include
biosimilar user fees in the recently-passed CR

FDA already has demonstrated the capacity to a biosimilar-like
351(a) BLA

Teva’s BLA (125294) for Neutroval® (tbo-filgrastim)
approved 8/29/12

Pre-BPCIA BLA based upon Teva’s biosimilar approved
in the EU with clinicals using a foreign (non-U.S.-
approved) filgrastim comparator
Practical Considerations In Implementation:
Practical Considerations In Implementation:
351(k)
351(k)
vs.
vs.
351(a)
351(a)
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High-pitched debate about biosimilars sharing the
same names as their reference products
continues to escalate

The BPCIA includes no provision on USANs/INNs/established
names for biosimilars, and FDA’s draft guidances are silent
on naming

Originators generally contend that, because biosimilars are
merely similar and not the same, biosimilars must have
distinctive names to be distinguished from their counterparts
to prevent marketplace confusion, enable track and trace,
and facilitate pharmacovigilance

Biosimilar companies generally contend that, as with other
highly similar biological products, a biosimilar should carry
the identical USAN/INN/ established name as its reference
product in order to minimize confusion and mitigate counter-
detailing, with pharmacovigilance managed as it always has
been using NDCs and lot #s

In approving Neutroval®, FDA went to great lengths to
underscore that the “requirement for a unique nonproprietary
name,” tbo-filgrastim, “is separate from any future decision
FDA will make regarding the naming scheme for biosimilar
and interchangeable products”
Practical Considerations In Implementation:
Practical Considerations In Implementation:
What’s In A Name?
What’s In A Name?
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Although Chief Justice Roberts’ Opinion in
NFIB et
al. v Sebelius
has taken the PPACA constitutional
limelight, a separate constitutional claim is
percolating at FDA

On April 2, 2012, Abbott Laboratories filed a Citizen’s Petition
presenting various Fifth Amendment Takings claims
challenging the BPCIA on its face and as applied to Abbott’s
Humira® (adalimumab) or any other biological product
approved pursuant to a BLA prior to the BPCIA’s enactment
date

In at least three pre-BPCIA administrative decisions, and,
importantly, one post-BPCIA decision issued just two months
prior to Abbott’s Petition, FDA previously has rejected all
such Takings claims

Applying the Supreme Court’s regulatory-taking decisions in
Ruckelshaus v. Monsanto Co.
(1984) and its progeny, it is
unclear whether a colorable Takings claim can be
established under the BPCIA, which does not require
disclosure of trade secret data to third parties like biosimilar
applicants

Abbott’s Petition does not address its post-enactment
concession (in an 2010 docket submission) as to the
absence of any Takings claims as a result of the “just
compensation” Congress bestowed in the BPCIA
Practical Considerations In Implementation:
Practical Considerations In Implementation:
Do Constitutional (Takings) Issues Remain?
Do Constitutional (Takings) Issues Remain?
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Conflicting 2-1 decisions by two CAFC panels have
opened debate on the 271(e)(1) safe harbor’s
application

In
Classen Immunotherapies , Inc. v. Biogen Idec
(2006-1634,
8/31/11), the panel ruled that 271(e)(1) safe harbor did not
apply to patented methods used in studies to evaluate the
correlation between child vaccination schedules and the
incidence of immune-mediated disorders, because activities
involved information routinely reported to FDA post-approval

Petition for a writ of
certiorari
is pending before the
Supreme Court

In
Momenta Pharmaceuticals v. Amphastar Pharmaceuticals

(2012-1062, 8/3/12), another panel distinguished
Classen

and held, over Chief Judge Rader’s dissent, that batch
testing methods for enoxaparin (a biological drug regulated
under the FD&C Act) were pivotal to the alleged infringer’s
“very ability to continue its FDA approval” and
manufacturing/marketing

Opinion by Judge Moore (dissenter in
Classen
); Chief
Judge Rader (who had been in majority in
Classen
)
suggested an
en banc
hearing

These rulings, and any decision forthcoming from the Supreme
Court, could have potentially-significant implications for
biosimilars given analytical-method patents claiming FDA-
mandated testing methods
Practical Considerations In Implementation:
Practical Considerations In Implementation:
How Safe Is The 271(e)(1) Safe Harbor?
How Safe Is The 271(e)(1) Safe Harbor?
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Practical Considerations In Implementation:
Practical Considerations In Implementation:
Surviving A Rube Goldberg-Like Patent Scheme
Surviving A Rube Goldberg-Like Patent Scheme


(Making “Apple v. Samsung” Litigation Look Simple By Comparison
(Making “Apple v. Samsung” Litigation Look Simple By Comparison
)
)
FDA files the
( ) Subsection k
biosimilar BLA
( accepts it for
)review
20 Days
( ) Subsection k
biosimilar BLA
applicant notifies
reference biologic
& BLA holder
provides copy of BLA
& ’ entire mf g
process
60 Days
Reference biologic BLA
holder provides list of
“ patents it reasonably
” believes would be
infringed to
( ) Subsection k
biosimilar BLA
, applicant identifying
those prepared to
license
60 Days
( ) Subsection k biosimilar BLA
applicant provides detailed
statement to reference
: “ biologic BLA holder it does
” -not intend to market pre
; -expiry or asserting non
, , infringement invalidity
unenforceability
60 Days
Reference
biologic BLA
holder
responds to
Subsection
( ) k biosimilar
BLA
’ applicant s
statements
Negotiations
If negotiations
fail
( )presumed
15
Days
5 Days
( ) Subsection k
biosimilar BLA
applicant
notifies
reference
biologic BLA
# holder of of
patents to be
litigated
Parties
exchange lists
of patents
to be litigated
30 Days
Reference
biologic BLA
holder must
initiate
“ ” immediate
infringemen
t action
Nebulous
Nebulous
Negotiation
Negotiation
Trigger
Trigger
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Further Reading That Might Be Of Interest
Ø
Most recently-published manuscripts presenting
Most recently-published manuscripts presenting
additional background and analysis from this
additional background and analysis from this
author’s perspective:
author’s perspective:
Ø
John M. Engel,
John M. Engel,
Biosimilars Approvals In The US:
Biosimilars Approvals In The US:
The Path Forward
The Path Forward
,
,
Biopharm
Biopharm


International
International


(Sep. 2010): 46-52 (addressing the law’s
(Sep. 2010): 46-52 (addressing the law’s
unprecedented patent provisions)
unprecedented patent provisions)

(
(
Available
Available


at
at


http://digital.findpharma.com/nxtbooks/advanstar/biopharm0910/#/48
http://digital.findpharma.com/nxtbooks/advanstar/biopharm0910/#/48
)
)
Ø
John M. Engel,
John M. Engel,
Biosimilars In The US: Applying
Biosimilars In The US: Applying
Europe’s Leadership on Biosimilars & FDA’s
Europe’s Leadership on Biosimilars & FDA’s
Century Of Experience Implementing The
Century Of Experience Implementing The
Broad Provisions Of The PHS Act
Broad Provisions Of The PHS Act
, DIA
, DIA
Global
Global


Forum
Forum
EGA Special Issue (Vol. 3, Feb.
EGA Special Issue (Vol. 3, Feb.
2011):30-34 (addressing the global
2011):30-34 (addressing the global
comparability (highly similar) standard applied
comparability (highly similar) standard applied
to all biological products)
to all biological products)

(
(
Available at
Available at


http://www.globalforum-digital.org/globalforum/20110203?pg=35#pg33
http://www.globalforum-digital.org/globalforum/20110203?pg=35#pg33
)
)
(Restricted Access – DIA Members)
(Restricted Access – DIA Members)
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Thank You!
Thank You!
Any Questions?
Any Questions?
. , .John M Engel Esq
Managing Partner
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