September 30, 2009 presentation to the the Foley & Lardner Life Sciences Transactions Conference, in San Diego.

1. Key Issues Impacting
The Future of Biosimilars
Foley & Lardner
Life Sciences Transactions Conference
San Diego
September 30, 2009
Michael A. Swit, Esq.
Vice President

2. 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.

3.  Biosimilars
 Overview of Current Situation in Europe
 Regulatory and Scientific Issues
 Product Development Issues
 U.S. Legislative Options
 Waxman/Schumer
 Eshoo
2
Agenda

4. Biosimilars in Europe:
The story so far ... Guidances
 1998 – Concept paper: Development of a CPMP
Guideline on Comparability of Biotechnology – Derived
Products
 2005 – General / Introductory guidance
 2006 – Similar Biological Medicinal Products ..... Quality
Issues
 2006 – Similar Biological Medicinal Products ..... Non-
clinical & Clinical issues
 2006 – First specific guidances issued
3

5. 4
Biosimilars in Europe:
The story so far ... Guidances
 Somatropin - Non-clinical & Clinical
 G-CSF - Non-clinical & Clinical
 Human insulin - Non-clinical & Clinical
 Erythropoietins - Non-clinical & Clinical (under
revision)
 Interferon alpha - Non-clinical & Clinical (draft)
 Low Molecular - Non-clinical & Clinical
Weight Heparins

6. 5
Biosimilars in Europe:
Current Approval Status
 Somatropin - 2 “Biosimilar Products”
 Erythropoietin Alpha - 3 “Biosimilar Products”
 Erythropoietin Zeta - 2 “Biosimilar Products”
 Filgrastim - 6 “Biosimilar Products”

7.  Europe is the only major territory with formal guidance for the
development and approval of Biosimilars
 Commitment to post-marketing safety studies
 Market is developing slowly
 Interchangability -- not awarded at EU level
 National rules on substitution e.g. France, Spain
 National rules on pricing and reimbursement
 EMEA: “… the decision to treat a patient with a reference or
Biosimilar medicine should be taken following the opinion of a
qualified healthcare professional”
Biosimilars in Europe:
Current Regulatory Status
6

8.  Biologics approved under Public Health Services Act –
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
FDA Hasn't Defined the Processes
7

9. Equivalence
 Lynchpin to traditional generic 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)
 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.”
8

10. Equivalence …
 Lynchpin to generic process – depends on:
 Bioequivalence study (occasionally clinical studies with efficacy
endpoints – e.g., topicals) –
 Accurate predictability also allegedly an issue with Biosimilars
 Biosimilars – even under an abbreviated pathway, will most
likely more resemble an NDA than an ANDA – clinical studies
to show efficacy and monitor immunogenicity concerns likely
 Omnitrope® -- Sandoz’s HGH product – rumored to have
cost tens of millions of dollars to develop
9

11. Substitutability
 Substitution -- core of classic Generic Industry Business
Model
 Depends on therapeutic equivalence
 Allows for minimal sales forces
 Price drivers
 Multiple generics common – drives price to commodity status
 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
 HHS – June 2007 letter to Senate HELP Committee – no
interchangeability
 Thus, business model will not be multiple generics & not a commodity
 Without interchangeability, the Generic’s Biosimilar IS really a
branded drug
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12. Marketing Challenges
 Classic Generic – substitutability pushes sales
 Biosimilar
 “Generic” – will have to go out and detail
 Costs higher
 Not their sweet spot traditionally
 Will they run into greater resistance on “substitution” from
doctors and patients?
 Innovator – may need to distinguish vs. its “generic”
 Internal and external pressure for outcomes studies
11

13. Active Ingredient Issues
 Classic Generic – many sources of API
 Biosimilar
 Technological barriers to API development greater; fewer sources
 Foreign sources – particularly from China – will be under great
scrutiny from FDA, even more so after Heparin scandal
 Immunogenicity concerns are very high –
 FDA -- on record that immune response is “impossible to
predict”
 see Dr. Janet Woodcock, FDA Deputy Commissioner,
Congressional Testimony, March 26, 2007
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14. Small vs. Large Molecule Realities
 Small Molecule
 Therapeutically equivalent
 Same molecule
 Substitutable
 Price drives– and multiple
generics drive price down
 Insurance coverage follows
ANDA approval
 Marketing – cost sells; little need
for formal sales & marketing
staff
 Legal Pathway – clear under
Waxman-Hatch Act
 Biosimilar
 Not therapeutically equivalent
 Not same molecule
 Not substitutable
 Price difference to brand likely
smaller
 Separate coverage likely needed for
the Biosimilar
 Will require professional sales and
marketing staffs to drive utilization
vs. “Brand”
 Legal Pathway –
 505(b)(2) – case-by-case
 PHSA -- nonexistent
13

15. Generics:
 Physicochemical identical to innovator drug
 Healthy subject pharmacokinetic equivalence to innovator
Biosimilars:
 Physicochemical characterization: similar to innovator
 Variable extent of preclinical data
 Extensive clinical database
 More like new drug application (NDA) than abbreviated new
drug application (ANDA)
Extensive Data Packages Needed
14

16. Biosimilar: Extensive Data Package
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Data
Omnitrope®
(vs.
Genotropin®)
Valtropin®
(vs.
Humatrope®)
Physicochemical characterization,
purity
√ √
Nonclinical pharmacodynamics √ √
Nonclinical toxicology √ √
Standard BE pharmacokinetic study √ √
Additional human
pharmacodynamics
√ √
Clinical studies -- in growth
hormone deficient children
√ √
Additional immunologic data √ √

17.  Torti Letter – September 2008 – concise statement of FDA’s
then (Bush Admin.) views on Biosimilars
 “Highly similar” active ingredients are sufficient standard for
determination of “sameness” to allow some reliance on innovator’s
approval (but so far only for NDA’d products)
 Similarity can be established without reference to proprietary chemistry
and manufacturing data of innovator
 Identical manufacturing process is not required
 Formulation differences may be allowable if they don’t impact critical
features (e.g., product stability, immunogenicity)
 Current medical knowledge of potential drug risks may deem certain
animal toxicology studies necessary, others unnecessary
 Interchangeability –possible, but very unlikely
 FDA – switching should not occur and, when it does, must be approved by
patient’s doctor
FDA Perspective – Somewhat Clarified through
Public Discussion
16

18.  Terminology -- “generic biologic” or “biogeneric” replaced by
“biosimilar” – other aliases:
 Follow-on protein products (FOPPs) – one U.S. version
 Follow-on biologics (FOBs) – one U.S. version
 Subsequent entry biologics (SEBs) -- Canada
 Subsequent entry protein products (SEPPs) -- Japan
 “Abbreviated” biosimilar development programs have been
extensive in CDER
 Data sets much closer to that of innovator drug than generic
Lessons Learned
17

19. Lessons Learned …
 Substitution based on therapeutic equivalence – the driver of
small molecule generic utilization – highly unlikely
 FDA pathway likely to be highly iterative … and slow
 Consumer cost savings -- modest:
 Evidence suggests discount may only be 20-25%
 Utilization slow – only about 1% of somatropin Rxs were filled
with Omnitrope in 2007 (source: Torti letter)
 Senate Finance Committee – 9/24/09 – backed an amendment to
Baucus Health Care Reform to reimburse doctors for prescribing
biogeneric or biosimilar drugs at an additional six percent over the
competitive rate.

20. Legislation
The Future?

21. Will It Happen This Year?
Top Democrat pushes for action on biotech drugs
By MATTHEW PERRONE – 18 hours ago (June 8, 2009)
WASHINGTON (AP) — As the Obama administration renews its
health care reform effort on Capitol Hill, a top Democrat is calling
for speedy action on a years long effort to create generic
competition for costly biotech drugs.
President Barack Obama used his weekly radio address on Saturday
to call on Congress to act on his proposal to overhaul the nation's
health care system.
In a letter Monday, Rep. Henry Waxman, D-Calif., reminded the
president of his stated commitment to lower the price of biotech
drugs, high-tech injectable medications that cost more than $40
billion per year.

22. The Current Bills
 Waxman Bill – HR 1427 & Schumer Bill – S 726 -- “Promoting
Innovation and Access to Life-Saving Medicine Act”
 Original Eshoo Bill – HR 1548 -- “Pathways for Biosimilars Act”
 Eshoo Health Care Reform “mark” – HR 3200

23. Key Issues in Debate
 “Biosimilar” – How Defined?
 How similar must Biosimilar be to Reference Product (RP)?
 How to handle heterogenicity, impurities
 What kind of studies must be done to show extent of similarity?
 Analytical
 Animal?
 Clinical
 Must mechanisms of action be same?
 Can any requirements be waived?
 Interchangeability – allowed?
 How proven
 Guidances needed?
 Naming of Biosimilar Actives

24. Key Issues in Debate …
 Exclusivity
 Types:
 “Data” – can not even submit BP application
 “Market” – can not get approval, but FDA can review BP
application
 Length: Major area of dispute – 5 to 14??
 Exclusivity for First Interchangeable Biosimilar
 Possible?
 Likely?
 Figment of imagination?

25. Key Issues in Debate …
 Authorized Generics
 Waxman – bars them
 Eshoo – silent
 Patents and Litigation – two very different and
complicated systems for learning about patents and
notifications
 Guidances –
 Waxman – not needed before FDA may approve
 Eshoo #1 – arguably essential (like EU) before approval
 Eshoo #2 – not needed before FDA approval

26. Call, e-mail, fax or write:
Michael A. Swit, Esq.
Vice President
The Weinberg Group Inc.
336 North Coast Hwy. 101
Suite C
Encinitas, CA 92024
Phone 760.633.3343
Fax 760.454.2979
Cell 760.815.4762
michael.swit@weinberggroup.com
www.weinberggroup.com
Questions?

27. About your speaker…
Michael A. Swit, Esq., is a Vice President at THE WEINBERG GROUP, where he develops and ensures the
execution of a broad array of regulatory and other services to drug, biologics and medical device/diagnostic clients
seeking to market products in the United States. His expertise includes 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.
Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His 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. A magna cum laude graduate of Bowdoin College, he received his
law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.

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