Biosimilars -- Wave of the Future or Child of the Privileged Few?

Law Offices of Michael A. Swit

Biosimilars -- Wave of the Future or
Child of The Privileged Few?

Licensing Executives Society (LES)
San Diego Chapter

February 21, 2012

Michael A. Swit, Esq.
Vice President, Life Sciences
FDA Legal Services -- for the life of a Life Sciences Company www.fdacounsel.com


Standard Disclaimers

• Views expressed here are solely mine and do
not reflect those of my firm or any of its
clients.

• This presentation supports an oral briefing and
should not be relied upon solely on its own to
support any conclusion of law or fact.

FDA Legal Services -- for the life of a Life Sciences Company 2 www.fdacounsel.com


What We Will Cover
• Contrasting the Past – How Small Molecule Generics
are Regulated and Early Attempts to Approve “Generic”
Biologics
• Biosimilars – Basic FDA Provisions of the Biologics
Price Competition & Innovation Act of 2009 (BPCIA)
– Patent provisions are not covered by today’s talk
• The Draft Guidances – What Hath FDA Wrought?
• Biosimilar User Fees – Paying the Way Forward?
• Lessons for Licensing Executives



Contrasting The Past

How Small Molecule Generics Are
Regulated And Early Attempts To
Approve “Generic” Biologics



The Past
• Biologics approved under Public Health Services
Act – until 2010, no abbreviated pathway
– Precursor? -- Comparability Guidance, April 1996
• NDAs -- for few biologics (e.g., HGH, insulin) –
were approved
– No set criteria on appropriate data set to support approval
– Evaluated on a case-by-case basis
• Therapeutic Biologics – transferred from CBER to
CDER – June 2003



Bioequivalence
• Lynchpin to traditional Waxman-Hatch generic
approval process – depends on:
– Pharmaceutical “equivalents” – active ingredient, dosage form,
strength, etc., must be SAME
– Highly unlikely with Biosimilars –
• Characterization – still a challenge even for the innovators –

clinical trials may be needed to show comparability after process
changes
• Chances of “equivalence” conclusions faint as even a single amino acid
can throw off conclusion (e.g., HGH)
• Lovenox – only 70% characterized (but, is under an NDA and
approved under an ANDA in summer 2010)



Bioequivalence …
• Janet Woodcock, Director, Center for Drugs (before Congress,
March 2007):
– “there is general recognition that the idea of sameness, as the term

is used in the generic drug approval process under the Federal
Food, Drug, and Cosmetic (FD&C) Act and applied to small
molecules, will not usually be appropriate for more structurally
complex molecules of the type generally licensed as biological
products under the Public Health Service Act.”



Substitutability …
• Substitution -- core of classic Generic Industry Business
Model
– Depends on therapeutic equivalence
– Allows for minimal sales forces
– Drives pricing down -- multiple generics common – the generic
becomes a commodity
• Biosimilar world –
– Substitution – aka “interchangeability” -- may evolve, but on a very,
very limited basis
• Woodcock – must be able to handle repeated brand/follow-in
switching without adverse events
• Thus, business model will not be multiple generics & not a commodity
– Without interchangeability, the Biosimilar IS a branded drug



2006 – FDA Approves Omnitrope®
• A Biosimilar?
– approved as a 505(b)(2) NDA
– no interchangeability
– extensive data requirements – rumored to cost well into eight
figures, if not nine
• No floodgates because the NDA pathway was
limited to a handful of products



Biosimilars

Basic FDA Provisions Of The
Biologics Price Competition &
Innovation Act Of 2009 (BPCIA)



What Hath Health Care Reform Spawned?

• Biologics Price Competition & Innovation Act of 2009
(BPCIA)
– Creates an abbreviated pathway for “biosimilar” versions of
biologics, but gives FDA great flexibility/discretion in how it
implements statute
• Key features
– Abbreviated pathway created under the Public Health Service Act
(PHSA) by adding Subsection (k) to Section 351 of the PHSA
– Exclusivity – 12 years for new biologics
– Complex handling of patents
– FDA – flexibility granted in how it regulates biosimilars



What’s Required for a Biosimilar
Application?
• Must be biosimilar to Reference Product, by including:
– Analytical studies to show your product is Highly similar to the
Reference Product (RP) – i.e., the Biosimilar has no clinically
meaningful differences from the RP in terms of safety, purity and
potency, notwithstanding minor differences in clinically inactive
components; and
– Animal Studies – including toxicity studies; and
– “A clinical study or studies” -- including assessment of
immunogenicity and pharmacokinetics or pharmacodynamics
• to show safe, pure and potent
• in 1 (one) or more appropriate conditions of use for which the RP is
licensed and intended to be used
• FDA – can decide any of the above are unnecessary


Required for a Biosimilar Application …
• Must use same mechanism(s) of action – if the MOA is
known for the RP
• Conditions of use in labeling -- have to be previously
approved for the RP
• Must match RP as to:
– Route of administration
– Dosage form
– Strength
• Facility in which manufactured, processed, packed or
held – must meet standards designed to assure the biosimilar
continues to be: Safe. Pure. Potent.



Interchangeability
• Not required – 351(k)(2)(B)
• To prove interchangeability – 351(k)(4)
– Drug must be biosimilar to RP
– BP “can be expected to produce the same clinical result” as the
RP “in any given patient”
– If BP is administered more than once to patient, the risk in
terms of safety or diminished efficacy of switching between
the BP and the RP is “not greater than the risk of using the
RP” without switching
• How to study – multiple switch study



Miscellaneous Rules
• Only One RP per BP application – 351(k)(5)(A)
• Reviewing division – same as handled the RP – 351(k)(5)(B)
• REMS authority under FDAAA -- applies to Biosimilars –
351(k)(5)(C)
• Biologics approved under Section 505 of Federal Food,
Drug, and Cosmetic Act as New Drug Applications
(NDAs)
– Can still be filed as NDAs (indeed, must be until an “innovator” BLA
is approved)
– However, if there is a BLA-licensed biologic that you want to use as
the RP, the biosimilar application must be filed as a BLA
– Ten years after enactment – all NDAs for biologics are deemed
approved under Section 351 of PHSA



Miscellaneous …
• Guidances
– Not required prior to approval of a biosimilar application
• No biosimilar application yet approved; draft guidances published on
Thursday, February 9, 2012
– Regulations – also not mandated
– Product Class Specific Guidances
• Can be issued
• FDA – can issue one saying that the science is not sufficient to allow a
biosimilar application
– Later can be reversed
– Absence of such a guidance does not mandate that a biosimilar application can
be approved
• Pediatrics – all the rules and benefits under 2007 FDAAA for
both doing studies and pediatric exclusivity apply to biologics



Uncertainty … Was Rampant
• How will FDA implement BPCIA?
– Teva – announced it was pursuing full BLAs as of now –
– Leah Christl, Ph.D. – Acting Director in CDER for Biosimilars
• FDA – Public Meeting on Biosimilars
– Oct. 5, 2010 Federal Register – 75 Fed. Reg. 61497
– Nov. 2 & 3, 2010 in Maryland (were webcast)



Input FDA Sought at Hearing
• Scientific and technical information on how to
implement the statute
• “Extra-statutory Issues”
– Pharmacovigilance
– Common or usual names
– Safeguards on unsafe substitution
– Bridging data needed when comparing a BP to an RP after
prior studies done on BP vs. a non-U.S. biologic (e.g., in EU)

The result ?? … the February 9, 2012 Draft Guidances …??



The Draft Guidances – What Hath
FDA Wrought?



Three Draft Guidances
• Biosimilars: Questions and Answers Regarding
Implementation of the Biologics Price Competition and
Innovation Act of 2009 -- “Q&A Guidance” or “Q&AG”
– http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM273001.pdf
• Scientific Considerations in Demonstrating Biosimilarity to a
Reference (Protein) Product – “Scientific Guidance” or “SG”
• Quality Considerations in Demonstrating Biosimilarity to a
Reference Protein Product – “Quality Guidance” or “QG”



What Did FDA Clarify?
• Protein products – direct subject of new guidances, but guidance
does provide general advice for other biologics subject to BPCIA
• Three Key Messages:
– Development process towards demonstrating biosimilarity -- should be
“stepwise”
– FDA’s evaluation will be on the “totality of the evidence”
– The more you can analytically compare the BP to the RP and the closer the
two products are in all key respects, the less you may need to do to (a) show
biosimilarity, and (b) secure approval.

“The more comprehensive and robust the comparative structural and
functional characteristics are, the stronger the scientific justification for
a selective and targeted approach to animal or clinical testing.” See SG
at 9.



What Did FDA Clarify … ?
• Early interaction with FDA –
– expected – but don’t do so until you :
• can provide a plan for development;
• have manufacturing process information – including planned
methodology and assay validation; and
• have preliminary comparative analytical data with the RP
– may need to be frequent due to the stepwise approach to
development contemplated
• but no guidance on how often FDA will meet with you
• Biosimilarity – type and amount of data, analyses, testing,
etc., required will be determined on a product-specific basis.



The “Stepwise” Approach
1 – Extensive Structural and functional
characterization of RP and BP, including:
– Mechanism of Action (MOA)
– clinical relevance of any observed structural differences
– clinical knowledge of RP and its class shows overall safety risk
is low
– availability of clinically relevant PD measure
More you understand these, less you may need to do later
2 – Role of animal data in assessing toxicity, including
immunogenicity assessment.



Stepwise Approach …
3 – Comparative human PK and PD studies (if a
clinically relevant PD measure exists)
4 – Comparative clinical immunogenicity studies
5 – Comparative clinical safety and effectiveness
studies
FDA – can waive certain requirements if “unnecessary in an
application” under 351(k)



Clinical Studies
• Legal standard – “no clinically meaningful differences” between the
BP and RP “in terms of safety, purity and potency …” – 351(i)(2)(B)
of PHSA; 21 USC 262(i)(2)(B)
• SG, at 12:
– In general, the clinical program for a 351(k) application must include a
clinical study or studies (including an assessment of immunogenicity and PK
or PD) sufficient to demonstrate safety, purity, and potency in one or more
appropriate conditions of use for which the reference product is licensed
and intended to be used and for which licensure is sought for the biological
product, as set forth in the PHS Act.
– The scope and magnitude of clinical studies will depend on the extent of
residual uncertainty about the biosimilarity of the two products after
conducting structural and functional characterization and possible animal
studies.
– The frequency and severity of safety risks and other safety and effectiveness
concerns for the reference product may also affect the design of the clinical
program.



Clinical Studies …
• SG, at 16:
– As a scientific matter, comparative safety and effectiveness
data will be necessary to support a demonstration of
biosimilarity if there are residual uncertainties about the
biosimilarity of the two products based on structural and
functional characterization, animal testing, human PK and PD
data, and clinical immunogenicity assessment.
– A sponsor may provide a scientific justification if it believes
that some or all of these comparisons on clinical safety and
effectiveness are not necessary.
• Endpoints – can be different from sponsor’s own
clinicals if “scientifically justified” – SG at 18.



CMC Considerations
• Quality Guidance – aimed at CMC considerations
• Key attributes to analyze to show similarity:
– Molecular weight
– Complexity of protein, including higher order structure and
post-translational modifications
– Degree of heterogeneity
– Functional properties
– Impurity profiles
– Degradation profiles denoting stability
• Different excipients – possible, but need tox data
(existing or new) to support use in formulation


What Else Did FDA Clarify … ?
• Do not have to secure approval of all
“presentations” of the innovator’s product
• Foreign comparative data on non-U.S. licensed
innovator product – can be used:
– “bridging” data will be needed – likely a clinical PK and/or PD
study
– could allow you to use data from an EU approval where the
RP was “different from” the U.S. RP (e.g., different facility not
covered by U.S. BLA approval)



What Else Did FDA Clarify … ?
• Interchangeability – not addressed in guidances in any
detail, except that FDA states that “it would be difficult”
to establish interchangeability in the initial 351(k)
application “given the statutory standard for
interchangeability and the sequential nature of that
assessment.” See Q&AG, at 11.
– Why? – not stated, but likely because the interchangeability
standard under 351(k)(4)(A)(ii) is that the BP “can be
expected to produce the same clinical result” as the RP “in any
given patient…”
• but, FDA may not allow extrapolation of data to all indications
in first 351(k) application



User Fees

Paying Forward??



User Fees for Biosimilars
• FY 2012 – Subject to PDUFA rules
• FY 2013 – 2017 – Proposal Sent to Congress –
“BSUFA”
• Four types of fees proposed
– Developmental – Initial and Annual = 10% of the application
fee under PDUFA until year filed or discontinued
– Application – PDUFA fee less (-) cumulative payments under
Developmental fee program
– Establishment – same as PDUFA
– Product – same as PDUFA



Proposed User Fee Performance Goals
• Application review – 70%/10 mos.; 90% by 2017
– Resubmittals -- 70%/6 mos.; 90% by 2017
• Supplements with Clinicals – 90%/10 mos.
– Resubmittals – 90%/6 mos.
• Manufacturing Supplements – 90%/6 mos.
• Proprietary name review –
– During development -- 90%/180 days
– With BLA – 90%/90 days



Performance Goals …
• Major dispute resolution
– Written appeals – 90%/30 days
• Clinical holds
– Complete response -- 90%/30 days
• Special Protocol Assessments – 70%/45 days; 90% by
2017



Meetings Created Under User Fees …
• Biosimilar Initial Advisory Meeting” -- (90 days after request
package) -- initial assessment and general discussion of
whether 351(k) is feasible for a product. No substantive
review of data.
• BPD Meetings – “Biological Product Development”
– Type 1 -- (30 days) --
• necessary for an “otherwise stalled drug development program to
proceed”
• Special Protocol Assessment (SPA)
• Important Safety Issue
– Type 2 -- (75 days) – specific issue or questions; summary data only
– Type 3 -- (120 days) – in-depth data review and advice meeting
– Type 4 -- (60 days) – to discuss format and content of an application
or supplement



Lessons For The Licensing Executive



Traps for the Unwary
• Development Plans – highly variable and will require
considerable “stepwise” FDA input –
– licensing payments – may be difficult to structure or should be
tied to more interim milestones
– time lines – still unpredictable as path has not been used
• Omnitrope® – took at least 7 years (after initial FDA filing)
• DMFs not allowed (QG) – sponsor must be able to
control manufacturing either directly or consistent with a
an arrangement contemplated by FDA’s 2008 guidance -
- Cooperative Manufacturing Arrangements for Licensed Biologics



Traps for the Unwary …
• Biosimilar products – trigger pediatric study
requirements under PREA – Pediatric Research Equity
Act – regarded as a new active ingredient unless found
to be interchangeable
• Multiple indications under a single 351(k)
application – allowed, but will need to be justified
scientifically.
– SG did not clarify under what circumstances this might be
allowed, but did list key factors to address (see SG at 19-20)
– Key here – may be to select an indication that is most able to
be extrapolated across multiple indications



Traps for the Unwary …
• Exclusivity – is retroactive, but there’s no “Orange
Book” to look up when it expires
– Can be extended via Pediatric Exclusivity
• Patent Process –
– very detailed; not same as Waxman-Hatch
– “opening the kimono”



Small vs. Large Molecule Realities
• Small Molecule • Biosimilar
– Therapeutically equivalent – Not therapeutically equivalent
• Same molecule • Not same molecule
– Substitutable – Substitutable only if interchangeable
– Multiple generics of same – Multiple biosimilars for same
innovator are common innovator less likely
– Multiple generics drive price down – Price difference to brand likely smaller
– Insurance coverage follows ANDA – Separate coverage likely needed for the
approval Biosimilar
– Marketing – cost sells; little need – Requires sales and marketing staffs to
for sales & marketing staff drive utilization vs. “Brand”
– Legal Pathway – clear under – Legal Pathway – clear(er)
Waxman-Hatch Act – 505(j) • BPCIA – new Biosimilar App.
• But can go full BLA
• 505(b)(2) – case-by-case -- for 10
yrs. under BPCIA


Questions?
Call, e-mail, fax or write:

1422 Caminito Septimo
Cardiff by the Sea, CA 92007
Phone 760.452.6568
Fax 760.454.2979
Cell 760.815.4762
mswit@fdacounsel.com
fdacounsel.com



About your Speaker …
Michael A. Swit, Esq. develops and ensures the execution of a broad array of regulatory and other services to clients.
His expertise includes regulated product development strategies, compliance and enforcement initiatives, recalls and
crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and
clinical research efforts for drug, biologic, device, IVD, and other life sciences companies, as well as those in the
food and dietary supplement industries.

Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His vast and multi-faceted
experience includes serving for three and a half years as corporate vice president, general counsel and secretary of
Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and
commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as
CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products
for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel
in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food &
Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first
practiced FDA regulatory law with the D.C. office of Burditt & Radzius.

Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial
activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and
editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the
Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences
sponsored by such organizations as RAPS, FDLI, and DIA. He received his A.B., magna cum laude, with high
honors in History, from Bowdoin College and his law degree from Emory University School of Law. Mr. Swit is a
member of the California Bar.


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