Biosimilars in the Pharmaceutical Industry U.S. Update

							                 Biosimilars in the Pharmaceutical Industry:
                                  U.S. Update




Darryl Webster
Wyeth

January 2008
AIPLA
IP Practice in Japan Committee
                  URGENT NEW FLASH


    This presentation reflects my personal view.
    This presentation should not be construed to
    reflect, in any way, the view of Wyeth or its
    affiliates.




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    Biosimilars in the Pharmaceutical Industry:
    U.S. Update


       A biologic is a preparation, such as a drug or vaccine,
        that is made from living organisms. In contrast, a
        chemical drug is synthesized via a chemical process.
        A biosimilar or “follow-on biologic” is similar but not
        identical to the innovator (brand-name) product.

       The FDA and others consider the use of the word
        generic to be inaccurate because generic implies
        identical. FDA often uses the term follow-on protein
        product since many biologics are proteins.
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    Biosimilars in the Pharmaceutical Industry:
    U.S. Update


       When did it all start – Europe?

       U.S. - Omnitrope and beyond?

       U.S legislation
        –   Senator Waxman, H.R. 1038/S 6231
        –   Senators Waxman, Kennedy and Clinton, S 1695

       The Crux of the Biosimilar Issue

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    Biosimilars in the Pharmaceutical Industry:
    Where did it all start – Europe?

       In the EU, a legal tool for approving biosimilars in 2003
         –   Can only be approved centrally (EMEA), not nationally
         –   Manufacturer allowed to perform all necessary tests before patent
             expiry (2005)
         –   Analytical, preclinical and clinical comparability. Commitment to
             patient long-term follow-up)
       In 2005-2006: EMEA development guidelines
       In 2006: EU approvals of two hGH biosimilars (Omnitrope and
        Valtropin) and 3 other evaluations started
         –   Data from ~200 patients, 9-12 months study duration
         –   Same INN-name as brand name product, no EMEA guidance
             regarding interchangeability
         –   Comparatively simple biotech-generated products

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    Biosimilars in the Marketplace


       Europe- Sandoz – Omnitrope (hGH), Binocrit (epoetin
        alpha, often called “EPO” or erythropoetin);
        Biopartners - Valtropin (hGH); Hexal –EPO version;
        U.S. – Sandoz Omnitrope
       China – EPO versions, Interferons, IL-2, IL-11, GM-
        CSF, hGHs
       India – hGH. EPO, Interferon alpha 2b, insulin
       Australia – Omnitrope (Sandoz)
       Cuba, Egypt, Africa – EPO versions

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    Biosimilars in the Pharmaceutical Industry:
    U.S. Update

       In the U.S., most biologics are regulated under the Public Health
        Service Act (PHSA)
         – For biologics approved via the PHSA, currently there is no
            abbreviated approval pathway (legislation is being considered)
         – Some less complex biologics, e.g., insulin and human growth
            hormone, are regulated as pharmaceuticals under the Federal
            Food, Drug, and Cosmetic Act (FFDCA) and therefore may be
            used as reference products for a streamlined application under
            FFDCA section 505(b)(2)
         – Biosimilar legislation is currently under review in the U.S.
       Many countries have no established biosimilars approval pathway
         – WHO is considering promulgating guidance



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    Biosimilars in the Pharmaceutical Industry:
    U.S. Update


       U.S legislation
           February 14, 2007, Senator Waxman et al., H.R. 1038/S.6231
           Waxman, Schumer and Clinton introduced the Access to Life-
           Saving Medicine Act.

       Amend the PHSA to authorize the Secretary of Health
        & Human Services (HHS) to approve abbreviated
        applications for biological products that „comparable” to
        previously approved (reference) biological products.

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    Biosimilars in the Pharmaceutical Industry:
    U.S. Update - Senator Waxman et al., H.R. 1038/S.6231

       An application for a comparable biological product
        must demonstrate that there are no clinically
        meaningful differences between the two products with
        respect to safety or effectiveness.
       The application must show that the new product and
        the reference product contain highly similar „principal
        molecular structural features” and the same
        mechanism(s) of action, if known.
       The Secretary has discretion on a product-by-product
        basis to determine what studies are necessary to
        establish comparability.

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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary - Senator Waxman et al., H.R. 1038/S.6231

     Patent Provisions
      An applicant for a comparable biological
       product may elect to ask the holder of the
       reference product for a list of patents on the
       product (and process) and may elect to notify
       the reference product holder and owner of the
       patent(s) identified that the applicant filed for a
       comparable biological product application.
      In other words, notice by the applicant to the
       innovator/patent owner is optional.
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary - Senator Waxman et al., H.R. 1038/S.6231

     Patent Provisions
      If the applicant sends the notice, the notice must
       contain a detailed statement on why the patents
       identified is invalid, unenforceable, or not infringed.
      If the reference product holder fails to disclose a
       relevant patent, then the product holder may not
       enforce that patent against the applicant.
      If no patent infringement action is brought within 45
       days of the notice of challenge, the remedy in any later
       action to enforce that patent against the applicant is
       limited to a reasonable royalty.
      The Bill has additional listing, notifications procedures
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary - Senator Waxman et al., H.R. 1038/S.6231

     Additional Provisions
      The Secretary will publish the determination of
       interchangeability at the time of approval for
       the comparable biological product

        If approved as interchangeable, the label may
         state that it is interchangeable with the
         reference product for the specific conditions of
         use.
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary - Senator Waxman et al., H.R. 1023/S.6231

     Additional Provisions
      The 1st approved Applicant for the comparable product
       receives market exclusivity of the earlier of
         –   180 days from its 1st commercial marketing;.
         –   1 year after a final court decision or dismissal with prejudice of
             all patent infringement cases instituted, pursuant to this Bill;
         –   36 months after approval if such patent litigation is ongoing; or
         –   1 year after approval, if no such patent litigation was instituted.
        During the above exclusivity period, the bill prohibits
         the marketing of a rebranded interchangeable product
         that is distributed with the authorization of the
         reference product holder.
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary - Senator Waxman et al., H.R. 1038/S.6231

     Additional Provisions
      The Secretary must approve or disapprove an
       application by applicant 8 months after
       submission or 180 days after the application is
       accepted for filing by the Secretary, whichever
       is earlier, unless the final action date is
       extended by joint agreement of the applicant
       and secretary.
      The bill does not mention any data exclusivity
       period for the innovator/reference product.
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     Biosimilars in the Pharmaceutical Industry:
     U.S. Update - U.S legislation S1695


        June 27, 2007, Senate Health Education Labor &
         Pensions (HELP) Committee approved the bill
         introduced by Senators Kennedy, Hatch Clinton and
         Enzi
         - entitled the “Biological Price Competition and
         Innovation Act of 2007”.

        This bill amends the PHSA, the Federal Food, Drug,
         and Cosmetic Act (FFDCA) and the Patent Act to
         create a pathway for the licensure of “biosimilar
         biological products”.
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     Biosimilars in the Pharmaceutical Industry:
     U.S. Update - U.S legislation S1695


        A “biosimilar product applicant would be required to
         demonstrate that there is no clinically meaningful
         difference in safety, purity, potency between its product
         and the brand product (reference sponsor product).
        The bill allows the FDA to approve the “follow-on
         biologic as interchangeable; however the applicant
         must provide evidence that its product will produce the
         same clinical result as the reference product in any
         given patient and present no additional safety risks or
         diminished efficacy if a patient alternates or is switched
         between products. Let’s go right to the IP provisions!
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary – Senate Bill 1695

     IP Provisions
      No patent listing process like the H.R. 1038 bill?
      As alternative to the patent listing of the previous Bill,
        there is an exchange of information.
      Data Exclusivity for the 1st licensure – 12 years.
      No biosimilar product applications can be filed until 4
        years after the date on which the reference product
        was first licensed.
      The 1st biosimilar product may receive marketing
        exclusivity of one year (I.e.more than than the 180
        days in the previous Bill.
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary – Senate Bill 1695

     IP Provisions
      Proposed 351(l) of the PHSA provides for a
       default scheme by which the reference product
       sponsor and subsection (k) applicant exchange
       information about patents. The parties may
       also agree to use an alternative scheme for
       exchange of information.
      The exchange is interesting…
       Confidential Access to Application
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     Biosimilars in the Pharmaceutical Industry:
     Bill Summary – Senate Bill 1695

        Confidential Access
        When applicant submits the 351(k) application, the
         applicant must provide, to one in-house lawyer (an
         employee of the reference product sponsor) and one or
         more outside counsel designated by the reference
         product sponsor, none of whom participates in the
         prosecution of the related reference product,
         confidential access to the (k) application and
         information describing the manufacturing processes for
         the subsection (k) product.
        Others may receive access – patent owners who
         exclusively license to product sponsor.
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     Biosimilars in the Pharmaceutical Industry:
     Senate Bill 1695 - Confidential Access cont’d


        Recipients of the confidential information may not
         disclose it to any other person or entity, including other
         outside counsel, outside scientific consultants, or other
         reference product sponsor employees, without the prior
         written consent of the applicant, such consent cannot
         be unreasonably withheld.
        The confidential information may be used only for the
         purpose of determining, with respect to patents
         assigned to or exclusively licensed by the reference
         product sponsor, whether a claim of patent
         infringement could reasonably be asserted upon
         manufacture, use, offer for sale, sale, importation of the
20       biosimilar product.
     Biosimilars in the Pharmaceutical Industry:
     Senate Bill 1695 - Confidential Access cont’d


        If the reference product sponsor files a patent
         infringement suit, these confidentiality provisions
         continue to govern until the court enters a protective
         order concerning the information. Applicant may then
         re-designate confidential information in accordance
         with the terms of that order.
        No confidential information may be included in the
         publicly available complaint or pleading.
        Section 351(l) also provides that nothing in the
         information exchange provisions shall be regarded as
         (1) an admission regarding validity, (2) an
         agreement/admission concerning the competency,
21       relevance or materiality of any confidential information.
     Biosimilars in the Pharmaceutical Industry:
     Senate Bill 1695 - Confidential Access cont’d


        Section 351(l) also provides that nothing in the
         information exchange provisions shall be regarded as
         (1) an admission regarding validity, or (2) an
         agreement/admission concerning the competency,
         relevance or materiality of any confidential information.

        Disclosure of confidential information in violation of
         these rules will be deemed to cause applicant
         „irreparable harm” for which there is no adequate legal
         remedy. The court shall consider immediate injunctive
         relief to be an appropriate and necessary remedy for
         such violation.
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     Biosimilars in the Pharmaceutical Industry:
     Senate Bill 1695 - Confidential Access cont’d


     Ah yes, but, there is a listing!!

        –   Applicant must provide the reference product sponsor with a
            copy of the application and information, as noted above, within
            20 days of acceptance of the (k) application.
        –   Within 60 days of receipt of the application and information,
            the reference product sponsor must provide the applicant with
            a list of patents (owned or licensed) as to which it believes
            could reasonably assert a claim of patent infringement. The
            reference product sponsor must also identify those patents on
            the list that it would be willing to license to the applicant.
        –   Now, the parties start to exchange statements that identify in
            detail why patents are valid, enforceable and infringed or vice
            versa, depending on the side chosen.
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     Biosimilars in the Pharmaceutical Industry:
     Senate Bill 1695 - Confidential Access cont’d


        The alternative procedure -
         –   Then, negotiations in good faith must take place for 15 days to
             decide on a list of patent to litigate.
         –   If the parties cannot assemble the complete list within 15 days,
             then an alternative procedure will be used for this
             determination in order to expedite litigation. Applicant will
             notify Sponsor the number of patent it plans to list. Then, in an
             exchange process (within 5 days) both must simultaneously
             exchange patent lists, which specify the patents for litigation.
         –   The sponsor ordinarily may not list more patents than the
             applicant. However, if the applicant lists zero, the sponsor
             may list one patent. Rationale???
         –   Sponsor must bring an infringement suit within 30 days of the
             exchange date, with respect to every patent listed (on either
24           list). Be ready….
     Biosimilars in the Pharmaceutical Industry:
     Senate Bill 1695 –IP Provisions


        Other IP provisions
         –   Notice and Publication of the Complaint (Secretary
             publishes the complaint in the Federal Register.
         –   Newly Issued patents
         –   Notice of Commercial Marketing and Preliminary
             Injunction
         –   Limitations on Declaratory Judgments
         –   Artificial acts of Infringement
         –   Permanent Injunction

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     The Crux of the Biosimilar issue

        U.S. Health Care Spending – A Big Number

        The government„s participation as a provider in the Rx market
         continues to grow (approx 28% of Rx coverage in 2005).

        2007 Estimate = $2.26 TRILLION
         and 10% is prescription pharmaceuticals(National Health Statistics
         Group)

        The specialty/biologic market is a clear growth area.
          – In 2007, this market grew to 15% and 25% of the cancer and
            arthritis markets, respectively.

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     The Crux of the Biosimilar issue


                                                                       Rx Drugs
                                Other                                    10%
                                22%



                                                                                  Hospitals
                                                                                    31%
            Physicians
               21%

                                  Home Health &                             Admin Costs
                                  Nursing Home                                  7%
                                       9%
27   Source: CMS, Office of the Actuary, National Health Statistics Group
     The Crux of the Biosimilar issue

     Not Just $$$
        Safety & Labeling – small molecule generic vs. the
         unique character of biosimilars
        Interchangeability
        The Bio Position
         –   A “biosimilar” medicine is a distinct medicine claimed to be
             similar in terms of quality, safety and efficacy to a reference
             medicine that already has marketing authorization.
         –   Unlike traditional small molecule generic medicines,
             biosimilars are not identical to the reference innovative
             product.

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     The Crux of the Biosimilar issue

     BIO position
        A system of unique identification of biological
         medicines should be established including distinct
         international non-proprietary names (INNs).
         –   This would support pharmacovigilance, avoid inadvertent
             substitution, enhance means of traceability


        Should each biological medicine should have an
         original label?


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     The Crux of the Biosimilar issue

     BIO Position…
     Each biological medicine should have an original label
        –   Provide healthcare professionals with specific information
            regarding each biological medicine in order to make an
            informed decision regarding use of the product.
        –   Include information about product substitution and
            interchangeability on the label.
        –   A “biosimilar” would not meet the Orange Book definition of
            therapeutic equivalents



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     The Crux of the Biosimilar issue

     FDA on Therapeutic Equivalents…
       Drug products are considered to be therapeutic
       equivalents only if they are pharmaceutical equivalents
       and if they can be expected to have the same clinical
       effect and safety profile when administered to the
       patients under the conditions specified in the labeling

       How do the 3-dimensional structure and glycosylation
       patterns factor into evaluating the equivalence
       standard?


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     Biosimilars in the Pharmaceutical Industry:
     U.S. Update

     Valuable Resources:
       FDA Orange Book,
       see http.www.fda.gov/cder/orange/obannual.pdf

       Biotechnology Industry Organization for BIO positions,
       See http://bio.org/healthcare/followonbkg/
       U.S legislation by Clinton or Waxman
       see http://www.hillaryclinton.com/feature/healthcare/
       or www.waxman.house.gov/issues/health/generic_biologics.htm

       Also: search for news on the issue at
       http://www.patentbaristas.com/archives/cat_
       biogenerics.php
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     Biosimilars in the Pharmaceutical Industry:
     U.S. Update




                      Thank you!


                     Darryl Webster



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