Key Issues Impacting The Future of Biosimilars

Foley & LardnerLife Sciences Transactions Conference

San DiegoSeptember 30, 2009

Michael A. Swit, Esq.Vice President

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.

Biosimilars Overview of Current Situation in Europe

Regulatory and Scientific Issues Product Development Issues U.S. Legislative Options

Waxman/Schumer Eshoo

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Agenda

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

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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

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Biosimilars in Europe: Current Approval Status

Somatropin - 2 “Biosimilar Products” Erythropoietin Alpha - 3 “Biosimilar

Products” Erythropoietin Zeta - 2 “Biosimilar

Products” Filgrastim - 6 “Biosimilar

Products”

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

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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

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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.”

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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

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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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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

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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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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

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Generics: Physicochemical identical to innovator drug Healthy subject pharmacokinetic equivalence to

innovatorBiosimilars: 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

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Biosimilar: Extensive Data Package

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DataOmnitrope®

(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

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

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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

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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.

Legislation

The Future?

Will It Happen This Year? Top Democrat pushes for action on biotech drugsBy 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.

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

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

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?

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

Call, e-mail, fax or write:

Michael A. Swit, Esq.Vice President

The Weinberg Group Inc.336 North Coast Hwy. 101

Suite CEncinitas, CA 92024

Phone 760.633.3343Fax 760.454.2979Cell 760.815.4762

michael.swit@weinberggroup.comwww.weinberggroup.com

Questions?

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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