ABBREVIATED NEW DRUG
APPLICATIONS
&
PATENT/EXCLUSIVITY ISSUES
FDLI Introduction to Biotech Law
San Francisco
June 15-16, 2005
Michael A. Swit, Esq.
Vice President, Life Sciences
Why Do We Care?
• Generic Biologics – one of key issues facing
biotech industry today -- to understand potential
future, need to know the small molecule model
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HISTORY OF FDA REGULATION
OF GENERIC DRUGS
• 1938 – 1962 – Little or no regulation
– “Me too” letters – revoked in 1968
– Many products entered the marketplace
• 1962 – Drug Amendments – implement the Drug
Efficacy Study Implementation (DESI) – reviews all
drugs approved from 1938 to 1962
– DESI Effective Drugs could be subject to ANDAs
• Problem – no mechanism to approve post-62 drugs
• The “Paper NDA” – a very partial solution
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Waxman-Hatch ACT
• The Drug Price Competition and Patent Term
Restoration Act of 1984– PL 98-417
• W-H Act -- major provisions:
– Created -- by statute -- the Abbreviated New Drug
Application (“ANDA”) - § 505(j) of Federal Food, Drug, and
Cosmetic Act (FFDCA)
– Patent Term Restoration – 35 USC § 156
– Non-Patent Market Exclusivity – enforced by FDA by
precluding ability to approve ANDAs or 505(b)(2) NDAs
– Created “505(b)(2) NDA” – where no right of reference
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W-H Act -- Major Provisions …
• “Roche v. Bolar Exception” –
– 35 U.S.C. § 271(e) – allows pre-patent expiration use
of patented inventions;
– Applies to devices –Lilly v. Medtronic – 1990
– Applies to clinical testing of intermediates –
Intermedics v. Ventritex -- 1991
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“Roche v. Bolar Exception” …
• Merck KGA v. Integra; USSC # 03-1237 (argued on
4/20/05)
– QUESTION PRESENTED – “… Did the Federal Circuit
err in concluding that this drug-research safe harbor does not
protect animal studies of the sort that are essential to the
development of new drugs, where the research will be
presented to the FDA, and where barring the research until
expiration of the patent could mean years of delay in the
availability of life-saving new drugs?”
– ANSWER – Yes – June 13, 2005 – Supreme Ct. unanimously
reversed the decision
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“Roche v. Bolar Exception” …
• Merck KGA v. Integra – Holding:
– “The use of patented compounds in preclinical studies is
protected under §271(e)(1) at least as long as there is a reasonable
basis to believe that the compound tested could be the subject of
an FDA submission and the experiments will produce the types of
information relevant to an IND or NDA.”
– “…§271(e)(1) provides a wide berth for the use of patented drugs
in activities related to the federal regulatory process, including uses
reasonably related to the development and submission of any
information under the FDCA.”
– Made clear that the protection of §271(e)(1):
• Applies “… even when the patented compounds do not themselves
become the subject of an FDA submission”
• Applies even if the experiments do NOT get included in an ultimate
submission
• Is not limited to the generic drug process
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The Basics of the ANDA
• To Be Eligible for an ANDA:
– generic drug must be identical to a “listed drug” (i.e., one
already approved) as far as:
•
•
•
•
•
Active pharmaceutical ingredient (“API”)
Dosage form
Dosage strength
Route of Administration
Conditions of Use (i.e., labeling)
– Generic drug must be bioequivalent to listed drug
– ANDA also must contain:
• CMC information
• Patent Certification
• Labeling
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Eligibility for ANDA Consideration
• Must be a “Listed Drug” – i.e.:
– FDA’s “Orange Book” -- Approved Drug Products with
Therapeutic Equivalence Evaluations
– DESI Effective Determinations – in Federal Register
– The ANDA “Suitability Petition”
• Minor changes for which clinical safety or effectiveness
studies are not required
• FDA must approve petition within 90 days of submission
unless it concludes that clinical safety or efficacy studies
are needed
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Eligibility for ANDA Consideration …
• The ANDA “Suitability Petition”
– Examples
• Dosage form -- tablet to capsule change
• Strength – usually lower or intermediate if consistent with labeled
dosing regimen; higher – rare
• Route of administration – possible, but rarer
– PPA Patch -- denied
• Ingredient – only a single ingredient in a combination drug
– Different salts – not allowed
– Advantage – product line extension
– Disadvantage – no exclusivity; anyone else can do same thing;
timing is important
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Bioequivalence -- Lynchpin to ANDA
process -- § 505(j)(8)
•
•
(A) ``bioavailability'' means the rate and extent to which the active ingredient or therapeutic
ingredient is absorbed from a drug and becomes available at the site of drug action.
(B) A drug shall be considered to be bioequivalent to a listed drug if–
– (i) the rate and extent of absorption of the drug do not show a significant difference from
the rate and extent of absorption of the listed drug when administered at the same molar
dose of the therapeutic ingredient under similar experimental conditions in either a single
dose or multiple doses; or
– (ii) the extent of absorption of the drug does not show a significant difference from the
extent of absorption of the listed drug when administered at the same molar dose of the
therapeutic ingredient under similar experimental conditions in either a single dose or
multiple doses and the difference from the listed drug in the rate of absorption of the
drug is intentional, is reflected in its proposed labeling, is not essential to the attainment
of effective body drug concentrations on chronic use, and is considered medically
insignificant for the drug.
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Bioequivalence – Definitions by
Regulation -- 21 CFR Part 320
• Bioavailability means the rate and extent to which
the active ingredient or active moiety is absorbed
from a drug product and becomes available at
the site of action. For drug products that are not
intended to be absorbed into the bloodstream,
bioavailability may be assessed by measurements
intended to reflect the rate and extent to which
the active ingredient or active moiety becomes
available at the site of action.
– 21 CFR 320.1(a)
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Bioequivalence – Definitions by
Regulation -- 21 CFR Part 320 …
• Pharmaceutical equivalents means drug products in identical dosage
forms that contain identical amounts of the identical active drug
ingredient, i.e., the same salt or ester of the same therapeutic
moiety, or, in the case of modified release dosage forms that
require a reservoir or overage or such forms as prefilled syringes
where residual volume may vary, that deliver identical amounts
of the active drug ingredient over the identical dosing period; do
not necessarily contain the same inactive ingredients; and meet
the identical compendial or other applicable standard of identity,
strength, quality, and purity, including potency and, where
applicable, content uniformity, disintegration times, and/or
dissolution rates. 21 CFR 320.1(c)
• To be rated “therapeutically equivalent” –products must be a
pharmaceutical equivalent and be proven bioequivalent
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Bioequivalence … Practical Aspects of
Proving
• Classic – in vivo blood level study – 24 healthy
volunteers; two-week cross-over
– Problem – not applicable to many types of dosage forms –
e.g., topicals
• In vitro – possible if correlated to in vivo bioavailability
• Clinical studies – may require a placebo arm
• Waiver – allowed in circumstances where bioavailability
can be presumed – e.g., oral and I.V. solutions
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ANDA – Content and Organization
• Regulations – 21 CFR 314.94
• Guidance – February 1999 – “Organization of an
ANDA”
• http://www.fda.gov/cder/guidance/2623fnl.pdf
• Key parts of an ANDA
– Comparison to “Reference Listed Drug”
•
•
•
•
•
Conditions of Use
Active ingredients
Inactive ingredients (if appropriate)
Route of administration, dosage form & strength
Labeling comparison
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ANDA – Content and Organization …
• Key parts of an ANDA …
– Patent Certifications – tell FDA when it can approve ANDA
•
•
•
•
I – no patent information listed – immediate approval
II – listed patent has expired – immediate approval
III – applicant does not seek to market until listed patent expires
IV – patent listed; applicant seeks to market before patent expiration
because:
– ANDA product does not infringe (i.e., engineer around)
– Patent is invalid
– Patent is unenforceable
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ANDA – Content and Organization …
• Key parts of an ANDA …
– Patent Certifications …the Paragraph IV -• Notice -- if you submit an ANDA containing a Paragraph
IV certification, upon learning FDA has accepted the
submission, you must send a notice to holder of listed
NDA and patent owner (if different) that contains a
detailed statement of law and fact as to why your
marketing of the product prior to patent expiration will
not infringe patent, or why patent is invalid or
unenforceable
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ANDA – Content and Organization …
• Key parts of an ANDA …
– Patent Certifications …the Paragraph IV -• 45 Day Period – upon receipt of notice, holder of listed
NDA (or patent holder if different) has 45 days in which
to sue you
• 30-Month Stay – if ANDA applicant is sued in the 45-day
period, FDA may not approve the ANDA until the earlier
of:
– Expiration of 30 months from NDA holder’s receipt of notice;
or
– Favorable court decision for the ANDA applicant
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ANDA – Content and Organization …
• Key parts of an ANDA …
–
–
–
–
Bioequivalence testing – or waiver
Chemistry, Manufacturing & Controls Sections
Samples
Stability data
• Post-approval commitment
– Generic Drug Enforcement Act of 1992
Certification
– Sterilization section – if applicable
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Exclusivity Under Waxman-Hatch
• Advantage – runs parallel – or in place of –
patent protection
• Prevents FDA from approving ANDAs or
505(b)(2) NDAs based on the listed drug that
enjoys exclusivity
• Does not prevent filing of an ANDA (except
for 5-year exclusivity)
• Does not preclude a full NDA for product or
use protected by exclusivity
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Waxman-Hatch – Exclusive Marketing
Provisions
• New Chemical Entities (NCEs) – get five years during
which no ANDA can be approved or even submitted,
except that, after 4 years, ANDA can be submitted if it
contains a Paragraph IV patent certification
– “NCE” – in statute -- relates to an NDA that contains an
API where no active ingredient (including any ester or salt of
the active ingredient) of which has been approved in any
other application under § 505(b) of FFDCA
– Under § 505(b) –
• Not applicable, originally, to antibiotics – changed by FDAMA
• Not applicable to biologics; but some biotech products – e.g., HGH –
were approved under § 505(b)
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Waxman-Hatch – Exclusive Marketing
Provisions …
• New Chemical Entities (NCEs) – 5-Year Exclusivity
– Regulations – FDA treats differently -- 21 CFR 314.108
• New chemical entity means a drug that contains no active moiety that
has been approved by FDA in any other application submitted under
section 505(b) of the act.
• Active moiety means the molecule or ion, excluding those appended
portions of the molecule that cause the drug to be an ester, salt
(including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of
the molecule, responsible for the physiological or pharmacological
action of the drug substance.
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Waxman-Hatch – Exclusive Marketing
Provisions …
• 3-Year Exclusivity – changes supported by
clinical investigations
– New NDA or supplement of approved NDA
covering a previously active drug ingredient that
contains:
•
•
•
•
•
New
Clinical Investigations
Conducted or sponsored
By Applicant
Where Clinicals Were Essential To Approval
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Waxman-Hatch – Exclusive Marketing
Provisions …
• 3-Year Exclusivity – changes supported by
clinical investigations …
– “New”
• Not temporal
• Means not previously relied upon by FDA to support OK
– “Clinical”
• Must be in “man” – no animal studies
• Does not include bioavailability studies (by statute)
• But, includes studies where drug not administered – e.g.,
label comprehension for OTC switch study
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Waxman-Hatch – Exclusive Marketing
Provisions …
• 3-Year Exclusivity – changes supported by clinical
investigations …
– “Conducted or sponsored”
• IND sponsorship – presumed to satisfy this element
• Substantial support – certified by a CPA
– “By Applicant”
• Implies you can’t buy the studies
• Does cover predecessors in interest
– “Essential to Approval” – sine qua non – i.e., the application
would not have been approved if the study had not been
done
• Rogaine® OTC Switch – not essential
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Pediatric Exclusivity
• Not creature of Waxman-Hatch, but the 1997
Food and Drug Administration Modernization
Act (FDAMA) – added § 505a of FFDCA
• ``Pediatric studies'' or ``studies'' means at least
one clinical investigation (that, at the Secretary's
discretion, may include pharmacokinetic studies)
in pediatric age groups (including neonates in
appropriate cases) in which a drug is anticipated
to be used
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Pediatric Exclusivity …
• Qualifying:
– “Secretary” (of HHS; delegated to FDA)
• Determines that information on the drug’s use in pediatric population
may “produce health benefits” in that population
• Makes written request to do studies
• Sponsor does and submits studies (regardless of whether study shows
drug is effective)
– Six months “tacked on” to any existing exclusivity or listed
patent life – FDA is precluded from approving an ANDA
– Can qualify twice
– Attaches to all of the applicant’s products that have the active
moiety that was the subject of the pediatric studies
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Orphan Drug Exclusivity
• Created by 1983 Orphan Drug Act
• Originally – only available if no patent
protection available – changed in 1985
• Basics
– 7 years during which no other applicant can secure
approval of the orphan drug for the orphan use
– Thus – unlike with W-H exclusivity -- can’t even
“remake the wheel”
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Orphan Drug Exclusivity …
• Controversies
– What is the “drug”?
• Human Growth Hormone – a single amino acid
difference between Lilly and Genentech products led to
FDA conclusion that they were not the same drug and
exclusivity was irrelevant to the other firm’s product
– Race to approval line
– Off label use/abuse
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180-Day – or Generic -- Exclusivity
• Basics
– First applicant to submit a complete ANDA
containing a Paragraph IV certification gets 180-days
during which FDA may not approve another ANDA
for same drug
– 180 days runs from date of first commercial
marketing of product
• Old rule – earlier of 1st marketing or a favorable court
decision
• Fraught with complications and controversy
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180-Day – or Generic – Exclusivity …
• Controversies and Problems …
– Race to FDA – camping outside to be first to file
(e.g., at end of 4 years of a 5-year NCE exclusivity
period)
– What was a court decision?
– Did you need to be sued?
– What was a complete application?
– What if first to file lost and later won patent
litigation?
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180-Day – or Generic – Exclusivity …
• Medicare Modernization Act of 2003 (“MMA”) –
Changes to 180-day Exclusivity:
– Shared Exclusivity sanctioned
– Trigger changed to just date of first commercial marketing
– First to file could forfeit 180-day exclusivity if it fails to
market the drug within 75 days of:
• Earlier of FDA approval or 30 months after ANDA submission; or
• Non-appealed favorable district court decision or favorable appellate
court decision; or
• Favorable settlement entered
• Later of patent expiration or withdrawal
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180-Day – or Generic – Exclusivity …
• 180-Day Exclusivity Changes Under MMA: …
– Only patents for which a Para. IV certification is
made on the first day that any applicant makes a
Para. IV certification can lead to 180-day Exclusivity
– Commercial marketing by a first applicant under an
Authorized Generic deal triggers the 180-day period
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Patent Term Extension – 35 USC § 156
• Major element of the W-H Act compromise of
1984
• Applies to:
– Any product, method of using a product, or method
of manufacturing a product
– Patent is not expired, has not been extended before,
and was the subject of a “regulatory review period”
before its commercial marketing or use
– The commercial marketing was the “first permitted
commercial marketing” of the product
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Patent Term Extension …
• Exceptions to the “first commercial marketing”
requirement:
– Methods of manufacturing patents that claim
recombinant DNA technology are the first
marketing of a product under the claimed process
– Veterinary drugs or biologics – focuses on first
commercial marketing in food-producing animals
• Amount of extension – basically ½ the time
drug was under an IND + all the time following
submission to FDA
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Patent Term Extension …
• Caps on Extension
– Maximum is five years – 35 USC § 156(g)(6)
– Maximum life of patent after extension can not
exceed 14 years – 35 USC § 156(c)(3)
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ANDAs – Other Changes Implemented
by MMA
• 30-month stay – just one per product – the patent has
to have been listed as of the date the first ANDA
comes in
• Notice of non-infringement under a Paragraph IV
certification can include an offer by ANDA or
505(b)(2) applicant to provide relevant portions of the
(A)NDA under a binding confidentiality agreement
– Generic applicant controls
– If not offered, generic applicant can not pursue declaratory
judgment action if it is not sued
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ANDAs – Other Changes Implemented
by MMA …
• Counterclaim created -- to delist a patent that
allegedly does not claim the listed drug that is
the subject of the ANDA or an approved use of
the listed drug
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Brand – Generic Wars
Strategies & Tactics
• Goals
– Brand – franchise life extension
– Generic – early market penetration
• Generic Tactics
– Patent challenges
• Engineering around
• Invalidity claims
– Use of ANDA Suitability Petitions
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Brand – Generic Wars
Strategies & Tactics …
• Brand Tactics
– FDA Citizen Petition Process – over 40 petitions filed
over past 15 years by brand companies seeking to
impact the regulatory process for ANDAs – such as:
• Clozaril® – require bioequivalence testing in patients
• Premarin® –
– we can’t characterize the molecule’s impurities, therefore the
generic can’t be the same as us
– Generic has to match our impurities profile
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Brand – Generic Wars
Strategies & Tactics …
• Brand Tactics …
– The “Ever Changing” Listed Drug
•
•
•
•
Going from capsule to tablet
Dose regimen changes
Immediate Release to Sustained Release
Improved molecules – Seldane to Allegra
– Patent “Evergreening” –
• Used to be keyed to triggering additional 30-month stays (abrogated
by MMA)
• Still a crucial problem
– The “Authorized Generic” – cuts into potential generic
market
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Generic Drug Enforcement Act
(GDEA) of 1992
• Direct result of Generic Drug Scandal of 1988 -1990
– Gratuities
– Fraud in applications
• Dyazide® bioequivalence switch
• Maxzide
• Site change falsification
• Debarment
– Mandatory
– Permissive
– Use of debarred individual barred – must certify in ANDA
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GDEA …
• Responsibilities of Supervisory Personnel
– Park Doctrine – strict liability – misdemeanor
– Prosecutors – work up the line
– Sarbanes-Oxley – arguably creates different burden
to ensure supervisors are properly tracking and
reporting problems
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Generic Biologics
• Challenges
– Legal – no mechanism because vast majority of
biotech/biologic products are cleared under the Public
Health Service Act; ANDA process only applies to drugs
cleared under § 505(b) of FDCA
• Small loophole – HGH and other biologics cleared under NDAs
– Challenge still – bioequivalence rating
– Characterization – large molecules that are not well defined
• Generic industry – look to FDA guidance on changes to wellcharacterized biologics as lynchpin of process
• Stay tuned – I think will require legislation.
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Questions?
Call, e-mail, fax or write:
Michael A. Swit, Esq.
Vice President, Life Sciences
THE WEINBERG GROUP INC.
336 North Coast Hwy. 101
Suite C
Encinitas, CA 92024
Phone 760.633.3343
Fax 760.633.3501
Cell 760.815.4762
D.C. Office 202.730.4123
michael.swit@weinberggroup.com
www.weinberggroup.com
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