Biosimilars in the Pharmaceutical Industry: U.S. Update Darryl Webster Wyeth January 2008 AIPLA IP...

Biosimilars in the Pharmaceutical Industry:U.S. Update

Darryl Webster

Wyeth

January 2008

AIPLA

IP Practice in Japan Committee

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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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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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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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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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U.S legislationFebruary 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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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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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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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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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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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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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 biosimilar product.

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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, relevance or materiality of any confidential information.

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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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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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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 list). Be ready….

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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.

27 Source: CMS, Office of the Actuary, National Health Statistics Group


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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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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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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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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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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 Waxmansee 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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Thank you!

Darryl Webster

Biosimilars in the Pharmaceutical Industry: U.S. Update Darryl Webster Wyeth January 2008 AIPLA IP...

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