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ANDA Hatch-Waxman Act: Global Impact, Issues and Challenges

ANDA Hatch-Waxman Act: Global Impact, Issues and Challenges

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  • 1. Picture 2ANDAHatch-Waxman Act: GlobalImpact, Issues andChallenges Rajashri Ojha Director, Raaj GPRAC
  • 2. IntroductionThe Hatch-Waxman Act also known as Drug Price Competition and Patent Term restoration Act, is an act dealing with the approval of generic drugs and associated conditions for getting their approval from the “Food and Drug Administration(FDA),market exclusivity, right of exclusivity, patent term extension and Orange Book Listing.”
  • 3. Henry Arnold WaxmanHenry Arnold Waxman (born September 12, 1939) is an American politician. He has represented California’s 30th congressional district in the U.S.
  • 4. Orrin Grant HatchOrrin Grant Hatch (born March 22,1934) is a Republican United States Senator from Utah, serving since 1977.
  • 5. HistoryYear Legislation Impact on Drug Regulation1906 The Pure Food and Drug Act Established regulation of food and drugs in the United States1938 Federal Food, Drug, and Required new drugs to be demonstrated as safe Cosmetic Act before marketing. Drug product marketed prior to this act were not affected and became known as "grandfather” or”pre-1938” drugs.1962 Kefauver-Harris Drug Introduced efficacy concept into regulation. Drug Amendments product marketed between 1938 and 1962 Amendments known as “DESI”drugs.1984 Drug Price Competition and Expedited availibility of less costly generic Patent Term restoration Act drugs & provided incentives for development of new innovative medicines.
  • 6. Necessity of Hatch-Waxman Act Absence of Generic drug manufacturer Cumbersome regulatory procedure Patients were denied the option of cheaper drugs
  • 7. The Hatch Waxman Act (1984) simplified theapproval process for generic drugs Started the generic drug industry Provided for ANDAs (cheaper, faster) Generic Drugs can be manufactured even while originals are still under patent FDA Orange Book  Purpose: To make generic pharmaceutical firms aware of patents protecting brand-name drugs  All patents that claim a new drug, or some method of using this drug are listed in the Orange Book All new patent-protected drugs since Hatch-Waxman are listed in the Orange Book
  • 8. Objectives of Hatch-Waxman Act Reducing the cost associated with the approval of a generic drug Allowing Early-Experimental Use Motivating the generic drug manufacturers
  • 9. General Provision of the Act Maintaining list of patents which would be infringed Only Bioavailability studies and not clinical trials needed for approval Para I,II,III and IV certifications Data exclusivity period for NMEs Data exclusivity period for supplements Extension of the original patent term
  • 10. Key Features -Hatch-Waxman Acto Streamlined generic approval processo “Safe Harbor” for pre-approval activitieso Patent term restoration to offset lengthy regulatory approval processo Non-patent exclusivity for innovators and genericso Framework for patent notification and litigation
  • 11. Hatch-Waxman BasicsTitle I – Abbreviated New Drug ApplicationTitle II - Patent ExtensionTitle III - Amendments to the Textile Fiber ProductIdentification Act and Wool products Labeling Act of1939
  • 12. Drug Approval Process a full, formal process –NDA (New Drug Application) a more streamlined process that allows an applicant to rely partially on existing safety and efficacy data (Paper NDA) a route designed to allow “copycat” drugs to be rapidly approved (ANDA)
  • 13. Generic Drugs Generic drug is a drug which is produced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredient
  • 14. Reference Listed Drug (RLD) A reference listed drug (21 CFR 314.94(a)(3)) means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA.
  • 15. Generics usually cheaper thaninnovator drugs No cost of identification and isolation of New Chemical Entity No cost of research and development Minimum marketing cost because branded drug is already approved as safe and effective
  • 16. Generics works the same asbrand name drug
  • 17. FDA Requirements for ApprovalTo gain FDA approval, a generic drug must: contain same active ingredients as the innovator drug be identical in strenght,dosage form, and route of administration have same use/indications have same batch requirements for Identity,Safety,Purity and Quality follow strict standards of FDA’s GMPs
  • 18. Generic product Development FDA Approval FDA Approval NDA Submitted FDA Review 2 ½ yrs ANDA 1 ½ – 2 ½ yrs Extensive Human Submitted FDA 3 yrs Clinical Studies Review Clinical Studies- 2 yrs Formulation Effectiveness ½ - 1 ½ yrs Bioavailability Study Clinical Studies- 1 yrs Safety & Efficacy Safety Established by Clinical trials ofLaboratory & Animal Studies 3 ½ yrs Innovators Branded Vs. Generic Product Development
  • 19. A generic drug can be produced for the drugs Where the patent has expired Which have never held patents In countries where a patent(s) is/are not in force Where the generic companies certify that the branded companies’ patent are either invalid, enforceable or will not be infringed
  • 20. Drug approval Requirements NDA ANDA- Chemistry • Chemistry" Manufacturing • Manufacturing" Controls • Controls" Labeling • Labeling • Testing" Testing • Bioequivalence" Animal Studies" Clinical Studies" Bioavailability
  • 21. Comparison of Innovator and Generic DrugS.N. PARAMETER INNOVATOR GENERIC DRUG DRUG 1. Active ingredient Same Same 2. Safety & Efficacy Same Same 3. Quality & Strength Same Same 4. Performance & Standards Same Same 5. Costs & Prescription Highly expensive Less expensive 6. FDA inspection of yes yes manufacturing facilities 7. FDA reviews reports of yes yes adverse reaction Cont….
  • 22. Cont…S.N. PARAMETER INNOVATOR GENERIC DRUG DRUG 8. FDA reviews drug labeling yes No 9. Extensive research and yes No development investments10. Expensive marketing & yes No advertising11. Patent protection yes No FDA review to show active12. --- yes ingredient is equivalent to original13. Product Development Time ~ 12 yrs 2~4 yrs
  • 23. Authorized generics The term Authorized generics refers to prescription drugs that are produced by brand companies under a new drug application (NDA) and marketed as generics under private label.
  • 24. Comparison - Authorized Genericand Generics
  • 25. Similarities between NDA AuthorizedGeneric and ANDA Generics - Provide consumer saving , and are approved by the FDA to be marketed to the consuming public.- Highly regulated and undergo a rigorous approval process resulting in a safe and effective treatment methodology.
  • 26. Market entry of Authorized generic Brand companies establish agreements with private label marketing and distribution Brand companies can establish subsidiaries to market Authorized generic of their own brands. Brand companies establish agreements with a generic drug manufacturer to permit them to offer the Authorized generic product until the generic company gets its ANDA approval.
  • 27. Advantage of Authorized Generics provide consumers the highest brand quality at lowergeneric prices reduce the cost of prescription drugs more than thereduction offered by the first generic entrant in themarket.The availability of raw materials and productioncapacity for Authorize generic reduces the possibilityof marketplace supply interruptions.
  • 28. Orange BookApproved Drug Product with Therapeutic Equivalence Evaluations
  • 29. Definition The publication, “Approved Drug Product with Therapeutic Equivalence Evaluation” (the list, commonly known as the Orange Book)identifies drug products approved on the basis of safety and effectiveness by the FDA under the Federal Food, Drug, and Cosmetic Act.
  • 30. Cont….. Hatch-Waxman Act requires that when a company submits a new drug application(NDA) to the FDA for approval, patent information associated with that pharmaceutical should be listed in this book.
  • 31. Paragraph IV filing Patent is invalid or will not be infringed by manufacture, use, or sale of the drug product for which the ANDA is submitted
  • 32. Contents of list Approved prescription drug product with therapeutics equivalence evaluation Approved over-the-counter(OTC) drug product for those drugs that may not be marketed without NDAs or ANDAs Drug product with approval under section 505 of the act A cumulative list of approved product that have never been marketed
  • 33. Therapeutic equivalence- related terms Pharmaceutical Equivalents Bioequivalent Drug Products Pharmaceutical Alternative Therapeutic Equivalents
  • 34. Pharmaceutical Equivalents When drug products contains same active ingredient(s), are of same dosage form, route of administration and are identical in strength or concentration.
  • 35. Pharmaceutical Alternative If drug products contain the same therapeutic moiety,but are different salts, esters, or complexes of thatmoiety, or are different dosage form or strengths.
  • 36. Bioequivalent Drug Products This term describes pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions.
  • 37. Therapeutic Equivalents If drug products are pharmaceutical equivalents and they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.
  • 38. Therapeutics equivalenceevaluation code A code- drug product that FDA considers to be therapeutically equivalent,i.e.drug product for which: no known bioequivalence problem,- AA,AN,AO,AP,AT Meeting Bioequivalence requirements- AB B code - drug product considers not to be therapeutic equivalent - B*,BC,BD,BE,BN,BP,BR,BS,BT,BX
  • 39. A codeAA product in conventional dosage forms not presenting bioequivalence problemAB,AB1,AB2,AB3…. Products meeting necessary bioequivalence requirements
  • 40. Three code character AB1, AB2, AB3……….These codes are assigned only in situations when more than one reference listed drug of the same strength has been designated.
  • 41. Cont……….. AN Solution and powders for aerosolization AO Injectable oil solution AP Injectable aqueous solution and, in certain instances, intravenous non-aqueous solution AT Topical products
  • 42. B codeB* Drug products requiring further FDA investigation and review to determine therapeutic equivalenceBC Extended- release dosage formBD Active ingredients and dosage form with documented bioequivalence problemsBE Delayed-release oral dosage formsBN Products in aerosol-nebulizer drug delivery systemsBP Active ingredients and dosage forms with potential bioequivalence problems
  • 43. Cont………BR Suppositories or enemas that deliver drugs for systemic absorptionBS Product having drug standard deficienciesBT topical products with bioequivalence issueBX Drug products for which data are insufficient to determine therapeutics equivalence
  • 44. ANDA “ ANDA” is the abbreviation for “abbreviated NewDrug Application” it contains data which whensubmitted to FDA’s center for Drug Evaluation andResearch, Office of generic drugs, provides reviewand approval of a generic drug product.
  • 45. Address to send ANDA ApplicationOffice of Generic Drugs (HFD -600)Center for Drug Evaluation and Research,Food and Drug AdministrationMetro Park North II,Room 150,7500 Standish place, Rockville, MD 20855
  • 46. ANDA CertificationsParagraph IParagraph IIParagraph IIIParagraph IV
  • 47. ANDA Review ProcessMajor components of an ANDA review include: Bioequivalence evaluation Chemistry / microbiologic evaluation Inspection of the manufacturing facility Review of the proposed label
  • 48. Bioequivalence requirementsAn applicant submitting ANDA under section 505 (j)(2) (c) of the act must demonstrate both pharmaceutical equivalence and bioequivalence between generic drug and innovator reference listed drug.
  • 49. ANDA Patent Certification OptionsParagraph I Paragraph II Paragraph III Paragraph IV(required patent (Patent has not expired (patent is invalid or notinformation (Patent has but will expire on a infringed by generic has not been filed) expired) particular date) applicant) FDA may FDA may FDA may approve ANDA Generic applicant approve approve effective on the that the provides notice to ANDA ANDA patent expires; one or patent holder & NDA immediately, immediately, more applicant may enter filer; entry of first filer one or more one or more generic applicant generic may or /may not occur may enter applicant may enter
  • 50. Paragraph IV Certification 45 days 45 days Patent holder does not sue; the FDA Patent holder sues generic applicant within 45 may approve ANDA assuming other days; trigger of automatic 30-month stay regulatory conditions are fulfilled Generic applicant may enter 30 – month stay not 30 – month stay expired; the FDA may expired be able to approve ANDA If court rules in If court rules in Patent brand-name generic applicant’s expires,FDA can For the first generic Subsequent company’s favor, favor, the FDA can approve applicant the 180-days generic applicants the FDA can not approve ANDA & ANDA;180-days exclusivity period may only approve ANDA 180-days exclusivity exclusivity does begins upon marketing be approved after until patent expires period begins not extend beyond or court decision, the first generic patent expiration whichever comes first applicant’s 180 days have expired First generic applicant may enter;No entry occurs until subsequent generic applicants may One or more generic applicants maypatent expiration only be approved after the first enter generic applicants 180 days have expired.
  • 51. Notice Letter Generic applicant who files a paragraph IVcertification must notify the patent and NDA holderwith a detailed statementPatent/NDA holder has 45 days to sueGeneric applicant can file a declaratory judgmentaction if not sued
  • 52. Generic Entry Legal stay(prohibition)Innovator company has 45 days from genericnotification to file suitFDA suspends generic approval until: final judicial ruling patent expires 30 months from generic notification dateInnovator may list additional patents prior to ANDAapproval and trigger new 30-month stay
  • 53. Contents of ANDA1. Application Form 356h2. Application copies3. Cover letter4. Table of contents5. Tabs6. Pagination7. Field copies – Additional information
  • 54. Application CopiesI. Archival copyII. Review copyIII. Field copy
  • 55. Cover Letter1) Purpose of application2) Type of submission (ANDA,amendments,supplements,annual report, or resubmission)3) Name , title, signature and address of the applicant4) Proprietary name and established name of the drug product5) Number of volume submitted6) Commitment to resolution of any issues identified in the methods validation process after approval7) Statement that the application or a portion of the submission is in electronic format8) Clearly identify submission that contain sterility assurance data
  • 56. Common Technical Document (CTD) Common Technical Document ( CTD)annexure I.docx Module 1: Administrative Information or Regional Module 2: summary Quality overall summary, drug substance and drug product information, clinical BE summary Module 3: Quality CMC information (3.2.S), (3.2.P) and (3.2.R) Module 4: Not applicable to ANDA submission Module 5: clinical study report
  • 57. Labeling Section 505(j)(2)(A)(v) of the Act states that an abbreviated application for a new drug must contain:“information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug except for changes required because of differences approved under a petition or because the new drug and the listed drug are produced or distributed by different manufacturers”
  • 58. The Pharmaceutical Patent A patent an exclusive rights granted by a state (national government) to an inventor or their assignee for a limited period of time in exchange for a public disclosure of an invention.
  • 59. Types of Infringement Direct Infringement – If a person makes, uses, or sells the patented invention. Indirect Infringement – If a person actively encourages another to make, use, or sell the patent invention. Contributory Infringement – If a person knowingly sells or supplies an items for which the only use is in connection with a patented invention.
  • 60. Duration of patentmost industrialized foreign countries - 20 years.
  • 61. ExclusivityExclusivity is a statutory provision and is granted to anNDA&ANDA applicant if statutory requirement aremet.
  • 62. Term of Exclusivity Orphan Drug - 7 years New Chemical Entity - 5 years Pediatric Exclusivity - 6 months Patent Challenge - 180 days Others Exclusivity - 3 yrs
  • 63. Patent and Exclusivity regulation inC.F.R. (Code of Federal Regulation) 21 C.F.R. 314.52 Notice of certification of invalidity or non infringement of a patent 21 C.F.R. 314.53 Submission of patent information 21 C.F.R. 314.107 Effective date of approval of a 505 (b)(2) application or abbreviated new drug application under section 505(j) of the act. 21 C.F.R. 314.108 New drug product exclusivity 21 C.F.R. 316.31 Scope of orphan- drug exclusive approval 21 C.F.R. 316.34 FDA recognition of exclusive approval
  • 64. Patent and Exclusivity Patent Exclusivity-by patent and trademark office -by FDA upon approval of a drug-continue along the development grants exclusivity and can runlifeline of a drug and can encompass a concurrently with a patent or not.wide range of claims.May expired before drug approval, granted upon approval of a drugissued after drug approval, and product if statutory provision are met.anywhere in between.
  • 65. Reward to the 1st ANDA FilerFirst ANDA filer with Paragraph IV 180 day exclusivity period No other ANDA approval for subsequent generics for 180 days Measured from the earlier date of marketing or court decision
  • 66. 180-days clock 180 –day clock begins the earlier of3. The day that the generic is commercially marketed or4. The day of a court decision finding that the brand –name patent is either invalid or not infringed by the generic.
  • 67. Multiple ExclusivityShared exclusivity-When more than applicant submit an ANDA for the same product on the same day
  • 68. Benefits of Exclusivity The 180-day generic drug exclusivity Strong financial incentive for an ANDA applicant
  • 69. Section 505 of the Act(1)section 505(b)(1)(2) section 505(b)(2)(3) section 505(j)
  • 70. Section 505(b) (2)A 505(b) (2) application is a new drug application(NDA)submitted under section 505(b)(1)approved under section 505(c) of the Act. Cont…
  • 71. Cont…..“A 505(b) (2) application is one for which one or more of the investigations relied upon by the applicant for approval "were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted" (21 U.S.C. 355(b) (2)”
  • 72. Type of information useful in 505 (b) (2)Application  Published literature  Agency’s finding of safety and effectiveness for an approved drug
  • 73. Benefits of 505(b) (2) Application First ,that distinguishes from the Abbreviated New Drug Application (ANDA) Second, an approved 505(b)(2) product, receive an "AB" substitutability rating in the Orange Book.
  • 74. ANDA Suitability PetitionsSuitability petition submitted to the Agency seeking permission to file an abbreviated new drug application for a change from a listed drug in dosage form, strength, route of administration, or active ingredient in a combination product.
  • 75. Type of changes which can be includedin ANDA Suitability Petition A different route of administration A different dosage form A different strength A different active ingredient in a combination product in which the other active ingredients match those of the RLD
  • 76. Loopholes in the Hatch-Waxman actThirty-Month Stay PeriodAuthorized GenericsCitizen PetitionsReverse Payment Agreements
  • 77. Thirty-Month Stay PeriodThe 30-month stay results from the filing of an infringement suit by the original patentee within 45 days of the prospective generic manufacturer filing a Paragraph IV Certification.
  • 78. Citizen Petitions A citizen petition submitted to the Agency seeking permission to file an abbreviated new drug application for a change from a listed drug in dosage form, strength, route of administration, or active ingredient in a combination product. This loophole utilized by the pioneer pharmaceutical companies to delay the arrival of generic on the market is the citizen petition mechanism.
  • 79. Authorized Generics a practice employed by pioneer pharmaceutical companies to bring their own “generics” to market, currently escapes coverage under the Hatch-Waxman Act . Competition from authorized generics substantially cuts into the share of profits
  • 80. Reverse Payment Agreements More recently, brand name drug manufacturers have begun entering into reverse payment agreements with generic drug makers, under which the brand company pays a substantial amount of money to the generic company to either not file an ANDA application or, if it has already filed the application, to stay out of the market for some period of time
  • 81. FDA Proposal for Legislative ChangesOn October 21, 2002, President Bush announced thatthe Food and Drug Administration would propose newrules associated with the 30-month stay and therequirements for listing patents in the Orange Book.several bills were introduced in the 107th Congressthat would make changes to the Hatch-Waxman Act ofwhich S. 812 passed the Senate. It has beenreintroduced in the 108th Congress.
  • 82. Bills Medicare Rx Drug Benefit and Discount Act of 2002 Greater Access to Affordable Pharmaceuticals Act (GAAP) (108th Congress) Consumer Access to Prescription Drugs Improvement Act Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (“the Medicare Act”) {Hatch-Waxman Reform Provision [section 1101], December 3,2003
  • 83. Greater Access to Pharmaceuticals Act This act would amend the Hatch-Waxman Act to excise the automatic 30-month stay associated with patents listed in the Orange Book. Instead, the NDA holder must obtain a preliminary injunction against the generic firm to prevent manufacture and marketing of the product during prosecution of the patent infringement suit.
  • 84. Medicare Rx Drug Benefit andDiscount Act of 2002 Medicare prescription issues permits the 180- day market exclusivity period to begin on the day of a court decision from which no appeal can or has been taken. The bill establishes conditions under which the first ANDA applicant must forfeit the 180-day exclusivity provided by the Food and Drug Administration.
  • 85. Greater Access to AffordablePharmaceuticals Act (GAAP) (108thCongress) It would limit the ability of brand name drug manufacturers to prevent generic competition by triggering multiple 30-month stays on the same drugs. The bill would generally allow only one stay per drug to be granted. Generic companies would have the right to assure that their drugs are not in violation of any patent before going to market.
  • 86. Consumer Access to PrescriptionDrugs Improvement Act It would allow for only one 30-month stay for those patents listed in the Orange Book as of the date of passage of the bill. The automatic stay is to be eliminated for all new drugs and associated patents listed in the Orange Book. Prospectively, NDA-holders must request a preliminary injunction from the court in order to prevent the FDA from approving the generic version filed under a paragraph IV certification.
  • 87. Medicare Prescription Drug, Improvement, andModernization Act of 2003 Non-extension of the 30-month period The 180-Day Exclusivity Provision Certain Conditions Result in Forfeiture of the 180-Day Exclusivity Period provision for Counterclaim for Delisting patents Provision regarding timing of notice of Paragraph IV certifications Provision for allowing declaratory judgment Benefit of exclusivity for several ANDAs filed on same day allowed FTC Review Provision
  • 88. The Outcome of the ActThe Rising Generic Industry
  • 89. Generic Pathway Under the ActAbbreviated New Drug Application (ANDA) No independent clinical trial for safety and efficacy Reliance on clinical data of innovator drug Bioequivalence to innovator drug No infringement for generic clinical testing prior to patent expiration Certifications to patents of innovator drug listed in Orange Book
  • 90. Controversial Strategies Multiple 30-month stays Listing patents in Orange Book after ANDA is filed No mechanism to de-list patent from the Orange Book Settlement agreement between generic and brand- name to postpone the triggering of 180-day exclusivity period
  • 91. Hatch-Waxman Summary Innovator gets: Patent term extension/restoration Guaranteed marketing exclusivity period Automatic 30 month stay of FDA approval if litigation Generic Gets: Streamlined approval process First-to-file 180-day marketing exclusivity Safe harbor and possibility of definitive decision prior to launch
  • 92. ConclusionThe enactment of act was the major upthrust in the history of American andGlobal generic pharmaceutical industry.Its main purpose was to encouragegeneric competition thereby providingcheap and economic medicines topublic. The main provision of this act is180 days exclusivity to first filer, 30month stay and patent listing.