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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?.

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fdli introduction to biotech law san francisco june 15 16 2005


FDLI Introduction to Biotech Law

San Francisco

June 15-16, 2005

Michael A. Swit, Esq.Vice President, Life Sciences

why do we care
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


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


waxman hatch act
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


w h act major provisions
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


roche v bolar exception
“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


roche v bolar exception7
“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


the basics of the anda
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


eligibility for anda consideration
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


eligibility for anda consideration10
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


bioequivalence lynchpin to anda process 505 j 8
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.


bioequivalence definitions by regulation 21 cfr part 320
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)


bioequivalence definitions by regulation 21 cfr part 32013
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


bioequivalence practical aspects of proving
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


anda content and organization
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


anda content and organization16
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


anda content and organization17
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


anda content and organization18
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


anda content and organization19
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


exclusivity under waxman hatch
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


waxman hatch exclusive marketing provisions
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)


waxman hatch exclusive marketing provisions22
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.


waxman hatch exclusive marketing provisions23
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


waxman hatch exclusive marketing provisions24
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


waxman hatch exclusive marketing provisions25
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


pediatric exclusivity
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


pediatric exclusivity27
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


orphan drug exclusivity
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”


orphan drug exclusivity29
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


180 day or generic exclusivity
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


180 day or generic exclusivity31
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?


180 day or generic exclusivity32
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


180 day or generic exclusivity33
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


patent term extension 35 usc 156
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


patent term extension
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


patent term extension36
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)


andas other changes implemented by mma
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


andas other changes implemented by mma38
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


brand generic wars strategies tactics
Brand – Generic WarsStrategies & Tactics
  • Goals
    • Brand – franchise life extension
    • Generic – early market penetration
  • Generic Tactics
    • Patent challenges
      • Engineering around
      • Invalidity claims
    • Use of ANDA Suitability Petitions


brand generic wars strategies tactics40
Brand – Generic WarsStrategies & 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


brand generic wars strategies tactics41
Brand – Generic WarsStrategies & 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


generic drug enforcement act gdea of 1992
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


  • 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


generic biologics
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 well-characterized biologics as lynchpin of process
  • Stay tuned – I think will require legislation.




Call, e-mail, fax or write:

Michael A. Swit, Esq.

Vice President, Life Sciences


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




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