Presentation to webinar sponsored by FierceBiotech with a focus on: * background behind creation of new law * difference from chemical generic drug regulation * details of new law * challenges faced by new law * interchangeability

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FDA Regulatory Challenges for
Biosimilars and CMOs
A FierceBiotech Webinar
June 26, 2012
Michael A. Swit, Esq.
Special Counsel, FDA Law Practice

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Standard Disclaimers
• The views expressed here are solely my own and
do not necessarily reflect the views of my firm or
any of our clients.
• These slides support a verbal briefing and should
not be relied upon solely to support any
conclusion of law or fact.
• These slides and this webinar are intended for
general educational purposes and are not intended
to be, nor should be construed as constituting,
legal advice.
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Contrasting The Past
How Small Molecule Generics Are
Regulated And Early Attempts To
Approve “Generic” Biologics

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• Biologics “licensed” 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
The Past
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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 – allegedly was only 70% characterized
 under an NDA
 ANDA approved in summer 2010)
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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
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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
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Biosimilars
Basic FDA Provisions Of The
Biologics Price Competition &
Innovation Act Of 2009 (BPCIA)

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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
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• 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
What’s Required for a Biosimilar
Application?
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• 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.
Required for a Biosimilar Application …
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• 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
Interchangeability
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• 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 Rules
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• 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
Miscellaneous …
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• 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)
Uncertainty … Was Rampant
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• 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
…??
Input FDA Sought at Hearing
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The Draft Guidances – What Hath
FDA Wrought?

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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/
Guidances/UCM273001.pdf
• Scientific Considerations in Demonstrating Biosimilarity to a
Reference (Protein) Product – “Scientific Guidance” or “SG”
– http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM291128.pdf
• Quality Considerations in Demonstrating Biosimilarity to a
Reference Protein Product – “Quality Guidance” or “QG”
– http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM291134.pdf
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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.
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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.
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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.
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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)
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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.
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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.
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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
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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)
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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
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Uncertainty … Continues Still
• Supreme Court decision on Health Care Reform –
if overturned, arguably will take BPCIA with it
• Abbott Citizen Petition – filed in April 2012 –
argues that retroactive application of BPCIA to
already-approved biologics is unconstitutional
SO, STAY TUNED …
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Questions?
• Call, e-mail or fax:
Michael A. Swit, Esq.
Special Counsel, FDA Practice
Duane Morris LLP
San Diego, California
direct: 619-744-2215
fax: 619-923-6248
maswit@duanemorris.com
• Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel
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About Your Speaker
Michael A. Swit, Esq., is a Special Counsel in the San Diego office of the international law firm,
Duane Morris, LLP, where he focuses his practice on solving FDA legal challenges faced by
highly-regulated pharmaceutical and medical device companies. Before joining Duane Morris in
March 2012, Swit served for seven years as a vice president at The Weinberg Group Inc., a
preeminent scientific and regulatory consulting firm in the Life Sciences. His expertise includes
product development, compliance and enforcement, recalls and crisis management, submissions
and related traditional FDA regulatory activities, labeling and advertising, and clinical research
efforts for all types of life sciences companies, with a particular emphasis on drugs, biologics and
therapeutic biotech products. Mr. Swit has been addressing vital FDA legal and regulatory issues
since 1984, both in private practice with McKenna & Cuneo and Heller Ehrman, and as vice
president, general counsel and secretary of Par Pharmaceutical, a top public generic and specialty
drug firm. He also was, from 1994 to 1998, CEO of FDANews.com, a premier publisher of
regulatory newsletters and other specialty information products for FDA-regulated firms. He has
taught and written on many topics relating to FDA regulation and associated commercial
activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his
A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at
Emory University.
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