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ABBRIVIATED NEW DRUG PPLICATION (ANDA)

SEMINAR ON:. ABBRIVIATED NEW DRUG PPLICATION (ANDA). Presented by: Nagori Stavan Arunkumar Department of Pharmaceutics L.M.College of Pharamcy. ANDA. Pool of topics:. Introduction History of ANDA Guidelines available for ANDA Filling of ANDA

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ABBRIVIATED NEW DRUG PPLICATION (ANDA)

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  1. SEMINAR ON: ABBRIVIATED NEW DRUG PPLICATION (ANDA) Presented by: Nagori Stavan Arunkumar Department of Pharmaceutics L.M.College of Pharamcy

  2. ANDA Pool of topics: • Introduction • History of ANDA • Guidelines available for ANDA • Filling of ANDA • Manufacturing and control requirements of the ANDA • 180 days exclusitivity under Hatch Waxman amendment • Concept of Paragraph I to IV • Substantially complete ANDA • House keeping regulation • Patent expiration regulation • Triggering period • Waivers of exclusitivity • 505(b)(2) application • Supplemental new drug applications • Case studies • List of ANDA approved • 2006 pending ANDA • ANDA filed by or with Indian Pharmaceutical company • List of references

  3. ANDA 1. Introduction ANDA contains data submitted to FDA's Center for Drug evaluation and Research, Office of Generic Drugs, for review and ultimate approval of a generic drug product. Once ANDA is approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public. A generic drug product is the one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use.

  4. ANDA • All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). • Generic drug applications are termed "abbreviated" • Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the WAXMAN-HATCH ACT.

  5. ANDA 2. HISTORY OF ANDA: • In 1938, proof of safety • In 1962, “THE KEFAUVER HARIS AMENDMENTS” • “THE KEFAUVER HARIS AMENDMENTS” led to “DRUG EFFICACY STUDY IMPLEMENTATION (DESI)”. • FDA’s realization • Mid 1966 notice in federal Register • DESI review ultimately led to evolution of ANDA concept.

  6. ANDA • On April 24th 1970, the ANDA policy was published with exception of DESI pending list drugs and exempt as per court order • In November 1984, The Drug Price Competition and Patent Term Restoration Act. • Title 1: ANDA regardless of time before or after 1962 • Title 2: Patent extension for life lost • Title 3: Textile and wood products • In April, 1992 FDA finalized the regulations outlining the requirements for ANDAs.

  7. ANDA • On November 21, 1997 Modernization Act was signed. • Section 506A-Changes for approved ANDA/NDA • Hatch-Waxman Amendments

  8. ANDA 3. GUIDELINES AVAILABLE FOR ANDA: • Guidelines describe format & content for the following sections. • Application summary • Chemistry, Manufacturing and controls section • Non clinical pharmacology and toxicology section • Human pharmacokinetics & bioavailability section • Clinical and statically section • Microbiology section

  9. ANDA • Guidelines available for ANDA includes: • Organization of ANDA • Electronic submission of data for ANDA • Submission of archival copy of application in Microfiche • Guideline for impurities in drug substances • Guideline for submitting supporting documentation for the Manufacture of Drug substance. • Guideline for submitting supporting documentation for the Manufacture of finished dosage forms.

  10. ANDA • Guideline for submitting supporting documentation for stability studies of Human drugs and Biologics. • Guideline for packaging • Guidelines for changes in approved ANDA and NDA • Variations in Drug Products that may be included in a single ANDA • 180 days exclusivity under Hatch Waxman amendment • Guidelines for alternate source of API in pending ANDAs • Post marketing reporting of Adverse Drug reactions • Guidelines for changes in approved ANDA and NDA

  11. ANDA 4. FILING OF ANDA:

  12. ANDA • Proper organization • Proper format, clear table of contents, correct folders (jackets), correct tabulation and pagination • Detail’s under 21 CFR 314.50, 21 CFR 314.94 and 21 CFR 314.440 • OGD’s recommendation of bioequivalence, chemistry and labeling portions of an application

  13. ANDA Paper based filing of ANDA: • Application copies and general format: • Submit Archival (reference, retained and official approved copy) and filed copy (duplicate, used by FDA investigators) in english • Translation copy with original reference copy

  14. ANDA • Review copy (duplicate, FDA viewer, destroyed) in 2 sets of binders (jackets) • In first binder CMC • In another BE data • Remaining data (table of contents, labeling) in both • Consistency in color coding binders, volume size and specifications, size and quality of paper

  15. ANDA

  16. ANDA

  17. ANDA II. Cover letter: • Purpose of submission • Type of submission (ANDA, amendment, supplement, annual report, or resubmission of a previously withdrawn application) • Name, title, address and signature of applicant • Proprietary name (if any) and name of drug product • Number of volumes submitted • Commitment to resolution of any issues identified in the methods validation process after approval • Statement that the application or a portion of the submission is in electronic process after approval • Clearly identify submissions that contain sterility assurance data

  18. ANDA III. Table of content{(21 CFR 314509B)}:

  19. ANDA

  20. ANDA IV. Tabs: • Contents Section Tabs • E.g. Section VI - Bioavailability/Bioequivalence) • Pagination: • Centre bottom of the page. VI. Field copy -additional information: • Foreign applicants should submit the field copy to the Office of Generic Drugs

  21. ANDA Electronic submission: • ADVANTAGES: • Consistent submission • Rapid review • Reduction in archiving and storage space • Establishment of structured database of technical information associated with generic drug applications. • OGD archiving capability no guidelines • OGD has process for some in hard and some in soft copy.

  22. ANDA • Electronic submissions separated into 2 parts: • To address bioequivalence information • To address information related to chemistry, manufacturing, and controls (CMC) • Applicant may choose to submit either or both parts • Each part consist three electronic files: • An electronic submission document(ESD) • A set of data files • A companion document.

  23. ANDA • Key element for entering information in electronic submission - Entry and Validation Application (EVA). • First step in submission –getting unique 3 digit number • Electronic submission along with hard copy to OGD • 30 days • Cover letter-CMC and/or bioequivalence ESD will be submitted as electronic version as new correspondence within 30 days.

  24. Difference between submission of NDA and ANDA:

  25. 5. MANUFACTURING AND CONTROL REQUIREMENTS OF THE ANDA:- • Very important • From 1977-1992, 105 Non approval letter issued by FDA

  26. FDA Manufacturing and Controls guidelines:- • Guideline for the format and content of an application summary. • Guideline for the format and content of the chemistry, manufacturing, and controls section of an application. • Guideline for stability studies for Human drugs and Biologics • Guideline for packaging of Human Drugs and Biologics. • Guideline for submitting supporting documentations in drug applications for the manufacture of drug substances. • Guideline for submitting supporting documentation for the manufacture of finished dosage forms. • Guidelines for drug master files.

  27. ANDA Requirements for Drug substances sources: • Copy of potential supplier’s most recent establishment inspection repot describing FDA’s findings • Supplier should have a DMF available at FDA for reference purposes Specifications for drug substances:- • Assay methodology is not specified into the monograph for older drugs or method described is not specific –FOIs requests to FDA-copy of pertinent assay • Check impurity peaks

  28. ANDA -Drug product requirements:- • Validation studies - to verify the accuracy, precision, specificity, recovery and sensitivity of the method (s) conducted by the sponsor’s product with those obtained with the original brand name product using the same methodology. -ANDA expiration dates:- • Tentative approval of two year expiration date for a product if satisfactory data reflecting at least three months storage under accelerated conditions • Final approval for the expiration date is obtained when acceptable shelf life data for two years on more than one production lot is made available

  29. ANDA 6. 180-Day Generic Drug Exclusivity under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act

  30. ANDA After Hatch-Waxman Amendment resulted into Increased availability of generics: 1984: 12% prescription were generics 2000: 44% 2003: 51% 10,357 FDA approved branded drugs vs. 7,602 generic counterparts Savings of $ 8 – 10 billions every year Average saving per prescription: approximately 53 $ 1% rise in Generic prescription = $ 1.3 billions saving

  31. ANDA 10,357 FDA approved branded drugs vs. 7,602 generic counterparts Savings of $ 8 – 10 billions every year Average saving per prescription: approximately 53 $ 1% rise in Generic prescription = $ 1.3 billions saving

  32. ANDA Generic Pharmaceuticals: Facts & Figures at a glance

  33. ANDA Generic Pharmaceuticals: Facts & Figures at a glance (contd.)

  34. ANDA Generic Pharmaceuticals: Facts & Figures at a glance (contd.)

  35. ANDA 7. Concept of paragraph I to IV: • For filing ANDA, generic company must include a patent certification as per section 505(j) (2) (A) (vii) of the Hatch Waxman Act. • The certificate has to make one of the following statements: • No patent information on the drug product that is the subject of the ANDA has been submitted to FDA • That such patent has expired • The date on which such patent expires • That such patent is invalid or will not be infringed by the manufacture, use, or sale of the drug product which the ANDA is submitted.

  36. ANDA • The first three paragraphs (I, II, III) results in no generic drug being sold during the term of the innovator’s patent protection. • In case paragraph IV certification generic drugs can be sold during the term of the innovator’s patent protection. with rule of 45days suit and 30 months ban. • Bann approved unless: • The court decides that such patent is invalid or not infringed. In this case ANDA approval is made effective on the date of the court decision • The court decides that such patent has been infringed and sets a date for approval of the ANDA as provided. • The court grants a preliminary injuction prohibiting the ANDA applicant from engaging in the commercial manufacture or sale of the drug until the court decides the issues of patent validity and infringement.

  37. ANDA 8. SUBSTANTIALLY COMPLETE ANDA: • “Substantially complete” means application with all required information like bioequivalence, etc. • If a new bioequivalence study required for ANDA approval- not substantially complete and the applicant would not be eligible for exclusivity. • Withdrawal of paragraph IV certification – voluntarily/ settlement/ defeat in patent litigation by first applicant-looses exclusitivity. • Again first applicant submit paragraph IV certificate for 180 days exclusivity and there are no subsequent applicants then first applicant would be eligible for exclusivity.

  38. ANDA 9. HOUSE KEEPING REGULATIONS • First generic loses patent litigation Para IV to III (loses exclusivity) • Same day submission first applicant • Happens if patent expires on that day or generic wants to challenge innovator’s ANDA for 5 years exclusivity and submits at end of 4 year • For 6 months pediatric exclusitivity happens if patent expires on that day or generic wants to challenge innovator’s ANDA for 5(1/2) years exclusivity and submits at end of 4(1/2) year

  39. ANDA 10. PATENT EXPIRATION REGULATION • Patent for which Para IV filed expires first generic loses exclusitivity Subsequent generics gets exclusitivity

  40. ANDA 11. TRIGGER PERIOD • Unnecessary delay or settlement Trigger period concept • Commencement of the 180-day exclusivity period for the first applicant is either the first commercial marketing of the first applicant’s product, or a decision of a court holding the patent invalid, not infringed, or unenforceable, whichever is earlier. • For exercising exclusitivity 180-day ‘triggering period’ court decision regarding the patent favorable to the first applicant or the first applicant must begin commercial marketing of its product if not first generic would lose its eligibility for exclusivity and subsequent generic filers for ANDA would be eligible for immediate approval.

  41. ANDA • There is new ‘triggering period’ which is separate and distinct from the 180-day ‘exclusivity period.’ The triggering period would begin upon the : • Tentative approval of a subsequent ANDA with a paragraph iv certification for the same drug product • Expiration of a 30 month stay of ANDA approval due to patent litigation • Expiration of a preliminary injunction prohibiting marketing of an ANDA product • Expiration of the statutorily described exclusivity periods for the listed drug

  42. ANDA • Delay of ANDA into market Mean while subsequent generics gets tentative approval FDA proposes 60 days trigger period for first generic to launch product into the market else lose exclusitivity

  43. ANDA • First generic sued Para IV certification and is facing patent litigation by innovator Triggering period would not begin at least until the 30 month period has lapsed At the end of the 30 month period, the triggering period would begin on the date a subsequent applicant receives tentative approval, or if a subsequent applicant had previously received tentative approval then on the date the 30 month period expired.

  44. ANDA 12. WAIVER OF EXCLUSIVITY • No regulations • Can waive to all subsequent and not single generic applicant

  45. ANDA 13. 505(b)(2) APPLICATION:- • Section 505 of the FD&C Act describes 3 types of new drug application : • An application that contains full reports of investigations of safety and effectiveness (Section 505 (b)(1)) • An application that contains full reports of investigations of safety and effectiveness but where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference (Section 505(b)(2)) • An application that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use, among other things, to a previously approved product (Section 505(j))

  46. ANDA What kind of information can be used for 505(b) (2) application? • Published literature • The FDA’s findings of safety and efficacy for a previously approved drug product without requiring the sponsor to obtain a right of reference from the original applicant.

  47. ANDA What kind of application can be submitted as a 505(b) (2) application? • New chemical entity (NCE)/new molecular entity (NME) • Changes to previously approved drugs

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