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US Regulatory Pathway For Biosimilars

Practical Legal/Regulatory Considerations Arising In The Course Of The Pathway’s Implementation

John M. Engel, Esq.Managing Partner

ENGEL & NOVITT, LLPTHE LAW FIRM THAT KNOWS ITS SCIENCE

AIPLA - American Intellectual Property Law AssociationBiotechnology Committee Webinar

25 September 2012

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DISCLAIMERThe Material And Viewpoints Set Forth In This Slide Deck And Conveyed During The Presentation Are

Presented By The Author In His Capacity As Founding & Managing Partner Of Engel & Novitt, LLP. They Do Not Represent And Do Not Purport To Represent The Views Of The Law Firm Or Of Any Former, Current Or

Prospective Client Of The Firm, And Should Not Be Construed As Such.This Presentation Does Not Provide Legal Advice, And Nothing In This Presentation Constitutes Legal Advice, Which Should Be Sought From Independently Engaged Legal Counsel Based Upon Individual Circumstances .

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US Statutory Framework For Biosimilars US Regulatory Framework For Biosimilars Practical Considerations In Implementation

351(k) vs. 351(a) What’s In A Name? Do Constitutional (Takings) Issues Remain? How Safe Is The 271(e)(1) Safe Harbor? Surviving A Rube Goldberg-Like Patent Scheme

Further Reading That Might Be Of Interest

PRESENTATION OUTLINE – US BIOSIMILARS PATHWAY

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US Statutory Framework For Biosimilars (1)• Biosimilars pathway enacted as part of health-care

reform, Patient Protection & Affordable Care Act, Public Law No. 111-148, 124 STAT. 119-1024 (23 March 2010)– Available at

http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname =111_cong_public_laws&docid=f:publ148.111.pdf

• The “Biologics Price Competition and Innovation Act” (Title VII, Subtitle A) establishes “biosimilars pathway”– Derived from unamended, Senate-passed BPCIA (S. 1695) adopted in 110th

Congress by Senate HELP Committee (27 June 2007; reported 19 Nov 2008)

• Grants FDA express new authority to review applications for, license, and regulate biosimilar biological products– New PHS Act provisions for biosimilars are much more explicit and detailed

than 50-plus yr-old provisions for originator BLAs3

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US Statutory Framework For Biosimilars (2)

• A “biosimilar” is a biological product that is– Highly similar in quality attributes to the reference, with minor differences

in clinically inactive components OK– Has no clinically meaningful differences from the reference in terms of

safety, purity, and potency

• An “interchangeable biosimilar” is a biologic that is– Biosimilar to the reference biological product– Expected to produce same clinical result in any given patient– During repeat administration, presents no greater risk in terms of safety or

diminished efficacy from alternating or switching products than use of reference without switching• “Interchangeable”/”Interchangeability” mean the biosimilar may be

substituted for reference without the intervention of the health care provider who prescribed the reference

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• Biosimilar is limited to single reference biologic (RB)• Biosimilar must rely on FDA’s prior S&E finding for RB• Biosimilar sponsors effectively follow two-step process:

1) Biosimilarity based on specific statutory requirements• Analytics, preclinical, & clinical studies incl. immunogenicity

Any of these can be waived by FDA

2) Interchangeability presumably based on switching studies• Biosimilar sponsors can pursue a subset of indications• Clinical studies in all uses not mandated if MoA is shared

– Facilitates extrapolation consistent with sound science

• Biosimilar applications can proceed w/out FDA guidance• Biosimilars must follow standard biologics’ requirements

– User fees, risk-mitigation strategies, etc.5

US Statutory Framework For Biosimilars (3)

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• FDA issued three draft biosimilar guidances (Feb. 2012)1) Scientific Considerations in Demonstrating Biosimilarity to a Reference

Product2) Biosimilars: Q&A Regarding Implementation of the Biologics Price

Competition and Innovation Act of 20093) Quality Considerations in Demonstrating Biosimilarity to a Reference

Protein Product– NOTE: AIPLA submitted comments on all three guidances addressing

issues impacting IP rights (focusing on 12-year exclusivity for biologics)

• Three draft biosimilar guidances focus on technical regulatory aspects of biosimilar development and review

– Characterizing a proposed biosimilar product and the reference product [Scientific Considerations; Quality Considerations]

– Delineating necessary data, such as pharmacokinetic/ pharmacodynamic, preclinical, and clinical data [Scientific Considerations; Q&A]

– Answering common questions regarding FDA’s interpretation of certain statutory terms and requirements [Q&A]

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US Regulatory Framework For Biosimilars (1)

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• FDA’s stated goal in issuing guidances is an efficient, predictable, and transparent regulatory pathway

• FDA convened public hearing on guidances (May 2012)• At public hearing, FDA heard testimony on these issues

and also sought stakeholder input on future guidances– 351(k) applications seeking a determination of interchangeability

– Requests for reference product exclusivity

– Naming issues

– Clinical pharmacology evaluation of biosimilar products

– Q&As regarding implementation of BPCI Act (next set of Q&As)

• Guidances not yet finalized heading into FY‘13• As new Fiscal Year approaches (Oct 1st), FDA has said it is working

“diligently” to finalize the guidances, but timeline not provided7

US Regulatory Framework For Biosimilars (2)

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• Debate persists over the viability of the biosimilars pathway and the value of pursuing approval of a biological product under 351(k) rather than 351(a)– Significant questions remain as to whether the regulatory burden and

timelines for development and approval of a 351(k) biosimilar are that much less than those for development and approval of a traditional 351(a)

– Any approved biosimilar is not expected to be interchangeable with its reference, thus requiring a sales force like a traditional 351(a) biologic

– FDA itself recently has warned that the biosimilars program will be “under-resourced” for the next several years because user fees will accrue slowly over time given the absence of established facilities/products, and Congress did include biosimilar user fees in the recently-passed CR

– FDA already has demonstrated the capacity to a biosimilar-like 351(a) BLA• Teva’s BLA (125294) for Neutroval® (tbo-filgrastim) approved 8/29/12• Pre-BPCIA BLA based upon Teva’s biosimilar approved in the EU with

clinicals using a foreign (non-U.S.-approved) filgrastim comparator8

Practical Considerations In Implementation:351(k) vs. 351(a)

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• High-pitched debate about biosimilars sharing the same names as their reference products continues to escalate– The BPCIA includes no provision on USANs/INNs/established names for

biosimilars, and FDA’s draft guidances are silent on naming– Originators generally contend that, because biosimilars are merely similar

and not the same, biosimilars must have distinctive names to be distinguished from their counterparts to prevent marketplace confusion, enable track and trace, and facilitate pharmacovigilance

– Biosimilar companies generally contend that, as with other highly similar biological products, a biosimilar should carry the identical USAN/INN/ established name as its reference product in order to minimize confusion and mitigate counter-detailing, with pharmacovigilance managed as it always has been using NDCs and lot #s

– In approving Neutroval®, FDA went to great lengths to underscore that the “requirement for a unique nonproprietary name,” tbo-filgrastim, “is separate from any future decision FDA will make regarding the naming scheme for biosimilar and interchangeable products”

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Practical Considerations In Implementation:What’s In A Name?

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• Although Chief Justice Roberts’ Opinion in NFIB et al. v Sebelius has taken the PPACA constitutional limelight, a separate constitutional claim is percolating at FDA– On April 2, 2012, Abbott Laboratories filed a Citizen’s Petition presenting

various Fifth Amendment Takings claims challenging the BPCIA on its face and as applied to Abbott’s Humira® (adalimumab) or any other biological product approved pursuant to a BLA prior to the BPCIA’s enactment date

– In at least three pre-BPCIA administrative decisions, and, importantly, one post-BPCIA decision issued just two months prior to Abbott’s Petition, FDA previously has rejected all such Takings claims

– Applying the Supreme Court’s regulatory-taking decisions in Ruckelshaus v. Monsanto Co. (1984) and its progeny, it is unclear whether a colorable Takings claim can be established under the BPCIA, which does not require disclosure of trade secret data to third parties like biosimilar applicants

– Abbott’s Petition does not address its post-enactment concession (in an 2010 docket submission) as to the absence of any Takings claims as a result of the “just compensation” Congress bestowed in the BPCIA

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Practical Considerations In Implementation:Do Constitutional (Takings) Issues Remain?

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• Conflicting 2-1 decisions by two CAFC panels have opened debate on the 271(e)(1) safe harbor’s application– In Classen Immunotherapies , Inc. v. Biogen Idec (2006-1634, 8/31/11), the

panel ruled that 271(e)(1) safe harbor did not apply to patented methods used in studies to evaluate the correlation between child vaccination schedules and the incidence of immune-mediated disorders, because activities involved information routinely reported to FDA post-approval• Petition for a writ of certiorari is pending before the Supreme Court

– In Momenta Pharmaceuticals v. Amphastar Pharmaceuticals (2012-1062, 8/3/12), another panel distinguished Classen and held, over Chief Judge Rader’s dissent, that batch testing methods for enoxaparin (a biological drug regulated under the FD&C Act) were pivotal to the alleged infringer’s “very ability to continue its FDA approval” and manufacturing/marketing• Opinion by Judge Moore (dissenter in Classen); Chief Judge Rader

(who had been in majority in Classen) suggested an en banc hearing– These rulings, and any decision forthcoming from the Supreme Court,

could have potentially-significant implications for biosimilars given analytical-method patents claiming FDA-mandated testing methods

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Practical Considerations In Implementation:How Safe Is The 271(e)(1) Safe Harbor?

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Practical Considerations In Implementation:Surviving A Rube Goldberg-Like Patent Scheme

(Making “Apple v. Samsung” Litigation Look Simple By Comparison)

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FDA files the Subsection (k) biosimilar BLA (accepts it for review)

20 Days

Subsection (k) biosimilar BLA applicant notifies reference biologic BLA holder & provides copy of BLA & entire mf’g process

60 Days

Reference biologic BLA holder provides list of patents it “reasonably believes would be” infringed to Subsection (k) biosimilar BLA applicant, identifying those prepared to license

60 Days

Subsection (k) biosimilar BLA applicant provides detailed statement to reference biologic BLA holder: it “does not intend” to market pre-expiry; or asserting non-infringement, invalidity, unenforceability

60 Days

Reference biologic BLA holder responds to Subsection (k) biosimilar BLA applicant’s statements

Negotiations

If negotiations fail (presumed)

15 Days 5 Days

Subsection (k) biosimilar BLA applicant notifies reference biologic BLA holder of # of patents to be litigated

Parties exchange lists of patents to be litigated

30 Days

Reference biologic BLA holder must initiate “immediate” infringement action

Nebulous Negotiation Trigger

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Further Reading That Might Be Of Interest

Most recently-published manuscripts presenting additional background and analysis from this author’s perspective: John M. Engel, Biosimilars Approvals In The US: The Path

Forward, Biopharm International (Sep. 2010): 46-52 (addressing the law’s unprecedented patent provisions)

(Available at http://digital.findpharma.com/nxtbooks/advanstar/biopharm0910/#/48)

John M. Engel, Biosimilars In The US: Applying Europe’s Leadership on Biosimilars & FDA’s Century Of Experience Implementing The Broad Provisions Of The PHS Act, DIA Global Forum EGA Special Issue (Vol. 3, Feb. 2011):30-34 (addressing the global comparability (highly similar) standard applied to all biological products)

(Available at http://www.globalforum-digital.org/globalforum/20110203?pg=35#pg33) (Restricted Access – DIA Members)

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Thank You!Any Questions?

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John M. Engel, Esq.Managing Partner

ENGEL & NOVITT, LLPTHE LAW FIRM THAT KNOWS ITS SCIENCE

jengel@engelnovitt.com202.207.3303 (Direct)202.460.0170 (Mobile)

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