Generic Drugs and Biosimilars

Solving FDA Legal Challenges for the Life of a Life Sciences Company -1- www.fdacounsel.com
LAW OFFICES OF MICHAEL A. SWIT
Generic Drugs and Biosimilars
SDRAN RAC Review Course
June 14, 2018
Michael A. Swit, Esq.
Managing Principal

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.
• These slides are intended to provide general
educational information and are not intended to
convey legal advice.

The Basics
➢ In the beginning, there were no legal generics…
➢ The 1906 Act and Drug Law
– Misbranding
– Adulteration
– No new drug application provisions
➢ The 1938 Act
– Added new drug provisions

Basics …
➢ 1938 Act …
– Did not directly address generics
➢ Marketplace reality
– “Not new drug” rulings – early ’40’s
– “Me too’s” entered market
➢ 1962 Act
– Efficacy added
– D.E.S.I created

D.E.S.I.
➢ Laid foundation for first approved generics
➢ By 1970, the ANDA created
➢ Problem
– Only applied to pre-’62 drug found effective under DESI
➢ Solution??? -- the “Paper NDA” -- 1978

1984 …
➢ Not just a cool novel
➢ Birth of the modern generic industry
➢ Compromise – smoke-filled room legislation
➢ “Drug Price Competition and Patent Term
Restoration Act of 1984”
➢ Enacted – September 24, 1984

Waxman-Hatch Basics
➢ Any person could file an ANDA for a drug approved
under § 505(b) of the Federal Food, Drug, and Cosmetic
Act – “the listed drug”
➢ Requirements
– Same active ingredient
– Same conditions of use (labeling)
– Same dosage form
– Same strength
– Same route of admin.
– Bioequivalent
– Patent Certification

Basics …
➢ ANDA Suitability Petitions – for some changes
➢ Listing of patents and approved drugs – the “Orange
Book”
➢ Patent term restoration –
– On new chemical entities – maximum is five years
– Formula = 50% development time + 100% review time (less any
non-diligent time) up to 5 years with a maximum length after
extension of 14 years

Basics …
➢ Exclusivity
– 5-year – NCE
– 3-year – new uses for previously approved drugs
• New clinical investigations
• Conducted or sponsored
• By applicant
• Essential to approval
– 180-day for ANDAs (more later)
• patent challenge-related
• competitive generic therapies

Basics …
➢ Patent listings – by innovator
– 30 days of new approval
– 30 days of issuance if drug already approved
➢ Patent Certifications – by ANDA applicant
– I – no information filed
– II – filed patent has expired
– III – will await patent expire
– IV – won’t infringe or patent invalid – requires notice to patent
holder with detailed statement of law and fact for why patent
should not block ANDA

Safe Harbor for ANDA R&D on Patent-
Protected RLD
➢ History: Court held “patent infringement” includes
precommercial testing of product
(flurazepam/Dalmane®)
(Roche v. Bolar, Federal Circuit, 1984)
➢ Waxman Hatch Act -- Overturned Roche v. Bolar –
– may make, use or sell a patented drug during the patent life if
solely for uses reasonably related to the development and
submission of information under a federal law which regulates
the manufacture, use or sale of drugs

Safe Harbor for ANDA R&D on Patent-
Protected RLD
➢ Safe Harbor -- applies to innovator and generic firms
(Bristol-Myers Squibb v. Rhone-Poulenc Rorer, S.D.N.Y. 2001, aff’d, 3rd Circuit,
2003)
➢ “Reasonably Related” -- means having a decent prospect that the
“use” would generate the kind of information relevant to FDA approval
requirements
– Construed:
• Intermedics v. Ventritex, N.D.Ca. 1991, aff’d, Federal Circuit, 1993 – clinical
trials on intermediates, yes
• Medtronic v. Lohr, U.S. Supreme Court, 1996 – applies to medical devices
• Integra Life Sciences v. Merck, U.S. Supreme Court, 2005 – preclinical research
to identify future candidate, yes

The Concept of the Listed Drug
➢ Required for ANDA Approval
➢ Generic must be the same as the RLD
➢ Before 1984 – Federal Register Notices Declared
DESI Drugs to be “Effective”
➢ Now Appear in FDA’s Orange Book, updated
monthly

The Orange Book

Electronic Orange Book
Source: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm

Electronic Orange Book
➢ Search in 4 Categoris
– Proprietary Name, Active Ingredient, or Application #
– Applicant
– Dosage Form
– Route of Administration
➢ Discontinued
– Request FDA Determination that RLD Was Not Withdrawn
from the Market for Reasons of Safety or Efficacy
• FDA Answers: Approved Discontinued Drug Products Safety and
Effectiveness Determinations

➢ Orange Book Annual Edition (PDF - 8.6MB)
38th Edition - The publication identifies drug products approved on the basis of
safety and effectiveness by the Food and Drug Administration under the Federal
Food, Drug, and Cosmetic Act.
➢ Orange Book Current Cumulative Supplement 2018 (PDF - 850KB)
The monthly Cumulative Supplement publication provides information on newly
approved drugs, changes and revisions to current data including therapeutic
equivalence evaluations, and updated patent and exclusivity data.
➢ Appendix A: Product Name Index (PDF - 168KB)
Prescription and OTC drug product lists. An index of drug products by
established or trade name. Updated quarterly.
➢ Appendix B: Product Name Sorted by Applicant (PDF - 410KB)
Product Name Index listed by Applicant (prescription and OTC product lists).
Cross-references applicants to drug products. Updated quarterly.
➢ Appendix C: Uniform Terms (PDF - 25KB)
Uniform terms used to designate dosage forms and routes of administration;
abbreviations used to designate strengths.
Orange Book – Other Publications
17

➢ Additions/Deletions for Prescription and OTC Drug Product Lists
Additions and deletions to the Prescription and OTC Drug Product Lists for a specific
month
➢ Orange Book Data Files (compressed) (ZIP - 701KB)
Download the Orange Book Data files (updated monthly). For more information, including
the descriptions of data fields in the Orange Book Search, see Orange Book Data Files.
➢ Reference Listed Drugs by ANDA Reference Standard List (PDF - 91KB)
List of drug products approved under an Abbreviated New Drug Application (ANDA) that
FDA has selected as reference standards and the associated reference listed drugs
(RLDs). More
➢ Orange Book Patent Listing Dispute List
➢ Frequently Asked Questions on The Orange Book
➢ Frequently Asked Questions on Patents and Exclusivity Drug patents and exclusivity: FDA
answers the most frequently asked questions (FAQs).
➢ Orange Book Preface -- provides info on how the book came to be, relevant terms and
codes, user responsibilities and more.
➢ FDA introduces reference standard data updates to the Orange Book An outline of data
updates to "Approved Drug Products with Therapeutic Equivalence Evaluations," or the
Orange Book, completed January 25, 2017.
Orange Book – Additional Resources
18

Another Waxman-Hatch Creation –
The 505(b)(2) NDA
➢ Not a completely new product (usually)
➢ Not a generic
➢ A product with some differences from a previously
approved product
➢ Approval requires (usually) clinical data, but the
studies may have been conducted by others.

How is 505(b)(2) Different?
➢ The applicant and FDA may rely on prior FDA
safety and efficacy determinations, based on
studies conducted by someone else even though
the applicant does not have a right of reference to
the data. 21 U.S.C. § 355(b)(2)
➢ Safety and efficacy can also be supported by
published reports

Types of 505(b)(2) NDAs
➢ New Chemical Entity (rarely)
➢ Changes to a Previously Approved Drug
– New dosage form, dosing regimen, strength, or route of
administration
– New indication
– New active ingredient
– New inactive ingredient that requires studies beyond limited
confirmatory studies
– Rx → OTC switch (Claritin)
➢ Duplicates of approved drugs that cannot be
approved under an ANDA

Exclusivity
Under Waxman-Hatch

Statutory Exclusivities Under
Waxman-Hatch
➢ New Chemical Entity (NCE) Exclusivity
– Prohibits the filing of an ANDA (or 505(b)(2) NDA) for a
product that contains the NCE for 5 years after approval of
the first NDA.
• (4 years if ANDA includes a Paragraph IV challenge to listed patent)
– NCE: "a drug that contains no active moiety that has been
approved by FDA in any other [NDA]."

Statutory Exclusivities …
➢ 3-Year Exclusivity
– Available for NDAs which contain:
• Reports of "new" "clinical trials"
• That were "essential to approval" of the NDA
• Conducted or sponsored by the applicant
– FDA may not approve (but can submit) an ANDA or
505(b)(2) NDA for 3 years after approval
– Applies for new indications, Rx → OTC switch, new dosing
regimen, and some other labeling changes.

Statutory Exclusivities -- Other
➢ Orphan Drug Exclusivity
– 7 year exclusivity
– Drugs for rare conditions (<200,000 people in U.S.)
➢ Pediatric Exclusivity
– 6-month extension of existing patent or Waxman-Hatch
exclusivity
➢ 180-day generic (ANDA) exclusivity
– patent challenges
– competitive generic therapies

“180-Day” or “ANDA” Exclusivity
➢ Basics:
– First person to file an ANDA with a Paragraph IV certification
gets 180 days during which no other ANDA can be approved for
that drug
– Must either (a) not be sued by brand co. in 45-day period or (b)
prevail in litigation (or get favorable settlement)
– 180 days starts from earlier of:
• Date of first commercial marketing (changed in 2003; used to peg to a court
decision as well)

“180-Day” or “ANDA” Exclusivity
➢ Advantage – ideally, incentive to pick apart patents, thus
getting generics to market earlier
➢ Problems:
– Complicated by FDA interpretations later ruled wrong by courts
– e.g., must be sued to get it
– Subject to abuse -- if first to file (and, thus, eligible for ANDA
Exclusivity) stays off market, but there is no court decision (e.g.,
via settlement with brand name) –means no other generic can
get approved as 180-day period is never triggered – addressed by
2003 legislation

➢ Enacted under FDARA (2017) -- adds §506H of
FFDCA
➢ Designation – if there is no more than one RLD or one
generic under that RLD
– request before or upon submission of an ANDA
➢ 180-day exclusivity – for first “CGT” to get approval for
an RLD for which there are no unexpired exclusivities or
patents
“Competitive Generic Therapies”
28

29
Labeling Carve-Outs (“Little viii” Statement) –
An Exclusivity-generated Situation
➢ Authorized by FFDCA, Sec. 505(j)(2)(A)(v)
– Generic drug must have same labeling as RLD, except for changes
required because of different manufacturers
➢ Preferred by FDA, 21 CFR 314.94(a)(7), (8)
– Generic labeling may omit an indication or other labeled aspect that is
protected by patent or exclusivity
➢ Upheld by Courts
– “The statute expresses the legislature's concern that the new generic be safe and effective
for each indication that will appear on its label; whether the label for the new generic lists
every indication approved for the use of the pioneer is a matter of indifference.“ Bristol
Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1500 (D.C. Cir. 1996).
– Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F .3d 141 (4th Cir. 2002) (orphan drug
exclusivity).

30
Labeling Carve-Outs …
➢ Differences must not render the proposed product less safe or
effective than the RLD for all remaining, non-protected
conditions of use. 21 CFR 314.127(a)(7)
➢ Rapamune (sirolimus) – Carve-out Denied
– 3-yr Excl. for cyclosporine withdrawal regimen, extensive info from
clinical study throughout labeling, protected labeling info essential to
safe and effective use of the drug
– FDA: Labeling contains extensive, critical prescribing info that
doctors should receive to determine treatment for any indication.
Sept. 20, 2004, Docket FDA-2003-P-00002.
➢ Oxandrin (oxandrolone) – Carve-out Upheld
– 3-yr Excl. for geriatric use, clinical study info in labeling
– FDA: all S&E issues within general adult population are adequately
addressed in labeling without geriatric-specific info. Dec. 1, 2006,
Docket FDA-2005-P-0368.

Waxman-Hatch & Patents
31

32
Generic Firm’s Duties -- Triggered By Patents
➢ Be Aware Of Patent Status
– Infringement = triple damages
– Search Orange Book and PTO
➢ Patent Certification, 21 CFR 314.94(a)(12)
➢ Amend Patent Cert. Until ANDA Approval

33
ANDA Patent Certifications
No -- Orange Book Patent
• Paragraph 1 – Patent
information not submitted to
FDA
• Paragraph 2 – Patent has
expired
• No Relevant Patents
Statement – No Patents exist
Yes -- Orange Book Patent
• Paragraph 3 – Will not market
until patent expires
• Paragraph 4 – Challenging the
patent as invalid, unenforceable
or not infringed
• Little viii Statement – Patent
not infringed because not seeking
approval for that use; use will not
be on label (Method of Use
Carve-Out)

34
Para. IV Patent Certification
➢ Submit Completed ANDA
➢ Receive FDA Letter That ANDA Has Been
Received
➢ Send Notice To NDA Sponsor/Patent Holder
➢ Notice Must Contain:
- ANDA No. - Drug Info.
- Patent No. - Expiry Date
- Scientific Rationale why no infringement/invalid
- Offer to Provide Access to ANDA, if no infringement
- Legal Brief supporting position

35
Para. IV Patent Certification
➢ Amend ANDA to Inform FDA of Notice
➢ Get Receipt of Delivery Confirmation and Submit
to FDA, 21 CFR 314.95
➢ NDA Sponsor Has 45 Days to Sue, Starting Day
After Notice is Received
➢ Suit Triggers 30-month Stay Against ANDA
Approval
➢ Amend ANDA “Immediately” to Inform FDA of
Suit

36
30-Month Stay Rules
➢ FDA Is Prohibited From Approving The
ANDA For A Period Of:
– Either 30 Months Counted From Day of NDA
Holder’s Receipt of Notice
– Or Until the Day of a Favorable Court Decision
– Whichever Occurs First

37
30-Month Stay Rules
➢ Definition of “Favorable Court Decision” –
either of these:
– District Court Judgment or Settlement Order
– Appellate Court Judgment or Settlement Order

38
30-Month Stay Rules
➢ FDA Amendments Act of 2007
➢ 30-Month Stay Can Be Extended -- if FDA Decides
that a Pending Citizen Petition Must Cause a Necessary
Delay in the ANDA Approval
➢ Extension Equals -- Length of Time from FDA’s
Receipt of Petition to FDA’s Grant/Denial of Petition

39
Later-Listed Patents
➢ Definition: Patents Listed With FDA After An
ANDA Is Filed With FDA
– Submit Patent Cert. & Notice, But 45-Day Clock & 30-
Month Stay Are NOT Triggered

Other Issues on Patents & Exclusivity
➢ Key provisions:
– Declaratory judgment action by ANDA applicant – have
to wait until 45-day period over and not sued
– “Delisting” Counterclaim to Infringement Action --
[505(j)(5)(C)(ii)]
• Not an independent cause of action
– 180-day Exclusivity
• Can be forfeited
• Pegged solely to commercial marketing – thus, implicitly allow
“authorized generics” – by any “first applicant”

Anti-Generic Strategies
➢ Patent listing, litigation
– Development of follow-on/ancillary patents
• Strategy now impacted by Title XI – Access to Affordable Pharmaceuticals
Act – part of 2003 Medicare Reform
➢ Amendments seeking 3-year exclusivity
– New indication for original product (limited utility)
– Changed dosage form
– New dosing regimen
– New strength(s)

What’s in a Name?
➢ Drug Price Competition and Patent Term
Restoration Act of 1984
➢ “Waxman-Hatch Act” – universally called that until
1994
➢ 1994 – Republicans take control of Congress – “Hatch-
Waxman Act”
➢ 2006 – Democrats take control of Congress
➢ So what do you call it now? – well, the first part of the
statutory name – Drug Price Competition – relates to
Waxman’s role; and the second part – Patent Term
Restoration – refers to Hatch’s role in pushing the 1984
compromise.

Biosimilars
43

The Future is Here – “Biosimilars!”
➢ Previously – no legal mechanism can be used to
support approval of a “generic” biologic
➢ Why?
– Legally, biologics licensed under Public Health Service Act, not
Waxman-Hatch
– Difficulty in characterization

“Generic” “Biologics”
"One cannot completely characterize the biological product
and that in itself is an issue, and quite frankly with
biological products you really don’t have a homogeneous
product, you have a defined range of biological
components for which you find consistency in a particular
clinical outcome. The challenges of analytical technology
are still very great for characterizing biologics."
-- Katherine Zoon, CBER

Biosimilars Under 505(b)(2)
➢ For Biologics originally approved under an NDA,
FDA will accept a 505(b)(2) for a generic or
biosimilar version
– Examples include naturally-derived active ingredients (from
animal or botanical sources) or those derived from recombinant
technology (e.g., insulin, HGH)
– None have a TE rating
– Lovenox® – (LMWH) -- approved in July 2010 and arguably a
biologic – approved as an ANDA
➢ For BLA-approved products, no “generic” or
abbreviated approval pathway existed

The 2010 Law – the BPCIA
➢ Creates an “abbreviated” pathway for Biosimilars
➢ “Biosimilar” defined
– that the biological product is highly similar to the reference product
notwithstanding minor differences in clinically inactive
components; and
– there are no clinically meaningful differences between the
biological product and the reference product in terms of the
safety, purity, and potency of the product.
– Contrast to small molecule – ANDA – drug must be same
– Reason – so difficult to characterize and process

Basics
➢ To show biosimilarity, application must contain:
– analytical studies that demonstrate that the biological product is
highly similar to the reference product notwithstanding minor
differences in clinically inactive components;
– animal studies (including the assessment of toxicity); and
– a clinical study or studies (including the assessment of
immunogenicity and pharmacokinetics or pharmacodynamics) that
are sufficient to demonstrate safety, purity, and potency in 1 or
more appropriate conditions of use for which the reference product
is licensed and intended to be used and for which licensure is
sought for the biological product.
➢ FDA can waive any of those

Basics …
➢ The biological product and reference product must
utilize the same mechanism or mechanisms of action for the
condition or conditions of use prescribed,
recommended, or suggested in the proposed labeling,
but only to the extent the mechanism or mechanisms of
action are known for the reference product;
➢ The condition or conditions of use prescribed,
recommended, or suggested in the labeling proposed for
the biological product have been previously approved for
the reference product;

Basics …
➢ The route of administration, the dosage form, and
the strength of the biological product are the same
as those of the reference product
➢ The facility in which the biological product is
manufactured, processed, packed, or held meets
standards designed to assure that the biological
product continues to be safe, pure, and potent.

Interchangeability
➢ Not required, but allowed
– The term ‘interchangeable’ or ‘interchangeability,’ in reference to a
biological product -- means that the biological product may be
substituted for the reference product without the intervention of the
health care provider who prescribed the reference product.
➢ However, to prove interchangeability, FDA has said:
– To establish that two protein products would be therapeutically
equivalent (interchangeable), a sponsor of the follow-on protein
product would need to demonstrate, among other things that repeated
switches from the follow-on protein product to the referenced product,
and vice versa, would have no negative effect on the safety and
effectiveness of the products.

Exclusivity
➢ Innovator –12 years from date of first licensure
– Retroactive – captures BLAs approved before statute’s
enactment in March 2010
– Can also qualify for pediatric exclusivity extension
– First four years – abbreviated app. can NOT be submitted

Exclusivity …
➢ First Interchangeable Biosimilar
– Applicant gets period of time where no other interchangeable for
same Reference Product (i.e., innovator) can be approved
– Length varies depending on a variety of factors; earliest of:
• One year of first commercial marketing
• 18 months of favorable final court decision in patent litigation
• 42 months of approval if First Interchangeable tied up in patent litigation
• 18 months of First Interchangeable if no law suit

First Two 351(k) Approvals
➢ Sandoz – July 24, 2014 – announced FDA had
accepted for filing its Biosimilar application for a
version of Amgen’s Neupogen® (filgrastim)
– Approved March 2015 as “Zarxio”
➢ Celltrion – August 11, 2014 – announced it had
“completed the filing process” at FDA for its
Biosimilar application for a version of Janssen’s
Remicade®
– using its own trade name -- was Remsima®, but changed to
Inflectra
– first MAB biosimilar
– Approved on April 5, 2016

➢ State laws – patchwork of various requirements relating
to prescribing and/or substitution
➢ Pricing – difference from innovators are not great
➢ NOT a generic – is a “branded” play due to expense of
devleopment
➢ Reimbursement – runs gamut, but many plans require
patient to use brand first
➢ Naming – FDA will apply a unique suffix to the
biosimilar established (generic) name such as “filgrastim-
vkzt” for Teva/Cephalon’s Granix®
Many Issues Remain on Biosimilars
55

Questions?
➢ Call, e-mail or write:
Michael A. Swit, Esq.
San Diego, California 92130
m: 760-815-4762
e: mswit@fdacounsel.com
web: www.fdacounsel.com
➢ Follow me on:
– LinkedIn: http://www.linkedin.com/in/michaelswit
– Twitter: https://twitter.com/FDACounsel

About Your Speaker
Michael A. Swit, Esq., has been addressing critical FDA legal and regulatory issues for over 30
years. Before returning to his private law practice in late 2017, he served for 3 years as the chief
regulatory counsel at Illumina, Inc., the world’s leading developer of gene sequencing technologies.
Prior to that, Swit was a special counsel in the FDA Law Practice at the global law firm of
Duane Morris LLP, in its San Diego office. Before joining Duane Morris in March 2012, Swit served
for seven years as a vice president at The Weinberg Group Inc., a preeminent scientific and
regulatory consulting firm in the Life Sciences.
His expertise includes product development, compliance and enforcement, recalls and crisis
management, submissions and related traditional FDA regulatory activities, labeling and advertising,
and clinical research efforts for all types of life sciences companies, with a particular emphasis on
drugs, biologics, therapeutic biotech products, medical devices, and IVDs.
His FDA legal and regulatory work also has included tenures in private practice with McKenna &
Cuneo and Heller Ehrman, and as vice president, general counsel and secretary of Par
Pharmaceutical, a top public generic and specialty drug firm, where he helped spearhead the
company’s emergence from the Generic Drug Scandal. He also was, from 1994 to 1998, CEO of
FDANews.com, a premier publisher of regulatory newsletters and other specialty information
products for FDA-regulated firms.
He has taught and written on many topics relating to FDA regulation and associated commercial
activities and is a past member of the Food & Drug Law Journal Editorial Board. He earned his
A.B., magna cum laude, with high honors in history, at Bowdoin College, and his law degree at
Emory University.

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