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  2. 2. TThhiiss iiss aa vvaasstt ttooppiicc aanndd aa sshhoorrtt oovveerrvviieeww iiss ggiivveenn aanndd iinn nnoo wwaayy ccoommpplleettee jjuussttiiccee ccaann bbee ddoonnee ffoorr tthhiiss
  3. 3. Dedicated ttoo mmyy ssoonn LLiioonneell CCrraassttoo,, He was only in first standard in school (dec2007) when I was Paralysed head to toe. His smiling face sees me through day in and day out. Vast readership from academia and industry motivates me, and keeps me going. I am helping millions with free websites and has 7 million hits on google Thanks for helping me to keep lionel smiling
  4. 4. READ MY ARTICLE AT anda/
  5. 5. TTOOPPIICCSS:: 1. Introduction 2. History of ANDA 3. Guidelines available for ANDA 4. Filling of ANDA 5. Manufacturing and control requirements of the ANDA 6. 180 days exclusitivity under Hatch Waxman amendment 7. Concept of Paragraph I to IV 8. Substantially complete ANDA 9. House keeping regulation 10. Patent expiration regulation 11. Triggering period 12. Waivers of exclusitivity 13. 505(b)(2) application 14. Supplemental new drug applications 15. Case studies 16. List of ANDA approved 17. 2006 pending ANDA 18. ANDA filed by or with Indian Pharmaceutical company 19. List of references
  6. 6. 11.. IInnttrroodduuccttiioonn 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.
  7. 7. 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.
  8. 8. 22.. HHIISSTTOORRYY OOFF AANNDDAA:: 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.
  9. 9. 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.
  10. 10. On November 21, 1997 Modernization Act was signed. Section 506A-Changes for approved ANDA/NDA Hatch-Waxman Amendments
  11. 11. 33.. GGUUIIDDEELLIINNEESS AAVVAAIILLAABBLLEE FFOORR AANNDDAA:: 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
  12. 12. 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.
  13. 13. 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
  15. 15. 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
  16. 16. PPaappeerr bbaasseedd ffiilliinngg ooff AANNDDAA:: I. 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
  17. 17. 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
  18. 18. 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
  19. 19. III. Table of content{(21 CFR 314509B)}:
  20. 20. IV. Tabs: Contents Section Tabs E.g. Section VI - Bioavailability/Bioequivalence) V. 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. 21. EElleeccttrroonniicc ssuubbmmiissssiioonn:: 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. 22. 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. 23. 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. 24. DDiiffffeerreennccee bbeettwweeeenn ssuubbmmiissssiioonn ooff NNDDAA aanndd AANNDDAA:: NDA requirements ANDA requirements Well-controlled clinical studies to demonstrate effectiveness Detailed descriptions of the components Preclinical and clinical data to show safety Manufacturing, controls, packaging, and labeling data sufficient to assure the bioavailability or bioequivalence of the drug to be marketed. Detailed descriptions of manufacturing and packaging procedures Proposed annotated labeling referencing all studies from which statement s contained in the package insert has been derived.
  26. 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. 27. 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. 28. -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. 29. 6. 180-Day Generic DDrruugg EExxcclluussiivviittyy uunnddeerr tthhee HHaattcchh--WWaaxxmmaann AAmmeennddmmeennttss ttoo tthhee FFeeddeerraall FFoooodd,, DDrruugg,, aanndd CCoossmmeettiicc AAcctt WAXMAN HATCH AMENMENTS BENIFITS TO INOVATOR’S COMPANIES TO GENERIC DRUG COMPANIES IF SUIT 180 DAY EXCLUSIVITY PERIOD TO CHALLEGE PATENT DRUG 45 DAY TO CLAIM NOT SUIT DELAYED FOR 30 MONTHS
  30. 30. After Hatch-WWaaxxmmaann AAmmeennddmmeenntt rreessuulltteedd iinnttoo 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. 31. 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. 32. GGeenneerriicc PPhhaarrmmaacceeuuttiiccaallss:: FFaaccttss && FFiigguurreess aatt aa ggllaannccee
  33. 33. GGeenneerriicc PPhhaarrmmaacceeuuttiiccaallss:: FFaaccttss && FFiigguurreess aatt aa ggllaannccee ((ccoonnttdd..))
  34. 34. 7. Concept ooff ppaarraaggrraapphh II ttoo IIVV:: 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: I. No patent information on the drug product that is the subject of the ANDA has been submitted to FDA II. That such patent has expired III. The date on which such patent expires IV. 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.
  35. 35. 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.
  36. 36. 88.. SSUUBBSSTTAANNTTIIAALLLLYY CCOOMMPPLLEETTEE AANNDDAA:: “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.
  37. 37. 99.. HHOOUUSSEE KKEEEEPPIINNGG RREEGGUULLAATTIIOONNSS 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
  38. 38. 1100.. PPAATTEENNTT EEXXPPIIRRAATTIIOONN RREEGGUULLAATTIIOONN Patent for which Para IV filed expires first generic loses exclusitivity Subsequent generics gets exclusitivity
  39. 39. 1111.. TTRRIIGGGGEERR PPEERRIIOODD 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.
  40. 40. 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
  41. 41. 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
  42. 42. 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.
  43. 43. 1122.. WWAAIIVVEERR OOFF EEXXCCLLUUSSIIVVIITTYY No regulations Can waive to all subsequent and not single generic applicant
  44. 44. 1133.. 550055((bb))((22)) AAPPPPLLIICCAATTIIOONN::-- 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))
  45. 45. What kkiinndd ooff iinnffoorrmmaattiioonn ccaann bbee uusseedd ffoorr 550055((bb)) ((22)) aapppplliiccaattiioonn?? 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.
  46. 46. What kind of aapppplliiccaattiioonn ccaann bbee ssuubbmmiitttteedd aass aa 550055((bb)) ((22)) aapppplliiccaattiioonn?? • New chemical entity (NCE)/new molecular entity (NME) • Changes to previously approved drugs
  47. 47. SSOOMMEE EEXXAAMMPPLLEESS OOFF 550055((BB)) ((22)) AAPPPPLLIICCAATTIIOONNSS Change in dosage form Change in route of administration Change in strength Change in dosage regimen Change in formulation (excipient) Change in active ingredient like use of different salt of same drug New molecular entity i.e. is prodrug of previously approved drug product Substitution of an active ingredient in a combination product Combination product: An application for a new combination product in which the active ingredients have been previously approved individually. Rx/OTC switch OTC monograph. Naturally derived or recombinant active ingredient. Bioinequivalence:
  48. 48. WWHHAATT CCAANN''TT BBEE SSUUBBMMIITTTTEEDD AASS 550055((BB)) ((22)) AAPPPPLLIICCAATTIIOONNSS?? • An application that is a duplicate of a listed drug and eligible for approval under section 505(j). • An application in which the only difference from the reference listed drug is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than the listed drug. • An application in which the only difference from the reference listed drug is that the rate at which its active ingredient(s) is absorbed or otherwise made available to the site of action is unintentionally less than that of the listed drug
  49. 49. typ What typee ooff ppaatteenntt aanndd//oorr eexxcclluussiivviittyy pprrootteeccttiioonn iiss aa 550055((bb)) ((22)) aapppplliiccaattiioonn eelliiggiibbllee ffoorr?? • Granted 3 years of Waxman-Hatch exclusivity if one or more of the clinical investigations other than BA/BE studies was essential to approval of the application and was conducted or sponsored by the applicant (21 CFR 314.50(j); 314.108(b)(4) and (5)). • Granted 5 years of exclusivity if it is for a new chemical entity (21 CFR 314.50(j); 314.108(b) (2)). • Eligible for orphan drug exclusivity (21 CFR 314.20-316.36) or pediatric exclusivity (section 505A of the Act).
  50. 50. BENEFIT OOFF 550055((bb)) ((22)) AAPPPPLLIICCAATTIIOONN:: • Filing of ANDA in form of NDA • 3 or 5 years of Hatch-Waxman marketing exclusivity . • An approved 505(b) (2) product, may receive an “AB” substitutability rating in the Orange Book.
  51. 51. CCUURRRREENNTT CCHHAALLLLEENNGGEE TTOO TTHHEE 550055((bb)) ((22)) MMEECCHHAANNIISSMM:: 505(b)(2) does to not allow FDA to unauthorizing rely on or use of an Innovator’s proprietary data to approve 505(b)(2) NDAs or to give rating “A” in orange book. A petition was filed with the FDA on behalf of two pharmaceutical industry giants (Pfizer/Pharmacia) to curtail the FDA’s approval of 505(b) (2) applications. The Pfizer/Pharmacia petition requested the FDA to Cease approval of all 505(b)(2) NDAs Refuse to grant “A” substitutability ratings to such products in orange book...
  52. 52. 1144.. SSUUPPPPLLEEMMEENNTTAALL NNEEWW DDRRUUGG AAPPPPLLIICCAATTIIOONNSS • Once an ANDA as an NDA has been approved, any significant changes in the conditions described in the application must first be approved via a supplemental NDA/ANDA. • Any substantive modifications proposed for the formulation may require the submission of additional data assuring the bioavailability of the drug. • Certain minor changes, however, as permitted by specific regulations, may be made without the filing of supplemental applications.
  53. 53. • Supplemental application I is filed for any the changes occurs in chemistry, manufacture of drug, use, labeling, safety, effectiveness, identity, strength, quality or purity of the drug or the adequacy of the manufacturing methods, facilitation, and controls to preserve these elements.
  54. 54. SSuupppplleemmeennttss ttoo nneeww ddrruugg aapppplliiccaattiioonnss rreeqquuiirriinngg FFDDAA aapppprroovvaall bbeeffoorree tthhee cchhaannggee iiss mmaaddee ffoorr tthhee ddrruugg ssuubbssttaannccee.. Relaxation of specification limits The establishment of new regulatory limits The deletion of a specification or analytical method. A revision in the method of synthesis, including the use of different solvents or alterations in the approved route. The use of different facility or establishment for the drug substances manufacture, where the process used to produce the drug substance differs materially from that approved in the NDA/ANDA and/or the facility has not received a current satisfactory, good manufacturing practice inspection within the last two years covering the manufacturing process.
  55. 55. Supplements ttoo nneeww ddrruugg aapppplliiccaattiioonnss rreeqquuiirriinngg FFDDAA aapppprroovvaall bbeeffoorree tthhee cchhaannggee iiss mmaaddee ffoorr tthhee ddrruugg pprroodduucctt.. • The addition or deletion of an ingredient or alteration of the composition (except for deletion of colorant.) • The relaxation of specification limits. • The establishment of a new regulations analytical method. • The deletion of a specification as regulatory analytical method. • A revision in the method of manufacture, including changing or relaxing and in process control. • The use of a different facility or establishment, including a different of contract, laboratory, on labels, to manufacture, process, test, or pack the drug. • The use of new container/closure system or a revision of a relevant specification (s) and regulatory analytical method(s). • A change in container size ( except for solid forms) • An extension of the expiration date based on data obtained using a new or an unapproved revised stability testing protocol. • The establishment of a new processing procedure for batches failing to meet quality assurance specifications. • All labeling changes except for those specifically exempted.
  56. 56. Supplements ffoorr cchhaannggeess tthhaatt mmaayy bbee mmaaddee bbeeffoorree FFDDAA aapppprroovvaall Full explanation of the basis for the such changes is required The cover letter and the supplement should be plainly marked, “ Special supplement changes being effected. Includes for: The addition of a new specification (s) or test method. Revisions in methods, facilities( Except for a new facility or controls to provide increase assurance of product, identity, quality, purity, and strength). Revisions in labeling to add or strengthen: – A contraindication, warning, precaution or adverse reaction. – An instruction about dosage and administration to further assure the safe use of the product. – A statement about drug abuse, dependence, or over dosage. – Revisions in labeling to delete false, misleading , or unsupported indications of use or claims for effectiveness. – Use of a different facilities or establishment to manufacture the drug substance, where the method of manufacture does not differ materially form that in the former facility and the new facility has received a satisfactory cGMP inspection within the last two year.
  57. 57. Changes ddeessccrriibbeedd iinn tthhee AAnnnnuuaall rreeppoorrtt • Revisions made to comply with an official compendium e.g. USP,NF. • Revisions in the package insert concerning the description section, or the how supplied section, that do not involve a change in dosage strength and / or form, or minor editorial changes in these and/or other sections. • Deletion of a colorant from the drug product. • Extension of expiration dating based on data obtained using a protocol approved in the application. • A switch to another container/closure system, where the material (s) used is the same general type as previously approved.(e.g. a change from one high-density polyethylene to another). • In the case of solid dosage forms a change in container size without a change in the container/closure system. • The deletion or addition of an alternate analytical method.
  58. 58. Supplemental nneeww ddrruugg aapppplliiccaattiioonn cchheecckklliisstt:: • Make all submissions in duplicate, including cover letters. • Include a brief description in the cover letter of what the supplement contains, including its objective and the headings , “supplemental expedited review requested” or “ special supplement changes being effected” when appropriate. • Whenever possible make a side by side comparison of current versus proposed conditions. • Use reference numbers for the NDA and the supplement if it is an additional submission. • Describe in detail all aspects of the change • Use dates when referring to previous submissions of FDA letters, particularly if the correspondence goes back more than several years. • When submitting photocopies make sure that all copies are clear and legible. • To assure legibility also type the name of the person signing the document. • When referring to drug master files (DMFs), confirm that they are up-to-date. Any changes submitted to a DMF must be relevant to the application (s) they affect. • Address all submissions concerning supplemental NDAs to the appropriate office and division of the FDA.
  59. 59. 1155.. CCAASSEE SSTTUUDDIIEESS:: A. Patent of PAXIL (Paroxetine HCL hemihydrate) • SmithKline Backhem (SKB) obtained patent of Paxil as NDA. • In 1998 Apotex filed Para IV certificate for getting ANDA • SKB filed legal suit for patent infringement • 30-months stay on Apotex approval • SKB filed patent extension 1: for use as liquid oral • 3 more patents in 1999 & 2000 for anhydrous form • 5th patent for Paroxetine methanosulfate in 2000 • Serial Patent submission tactics, with newer 30-month stay every time • Result: The patent of litigation expired, but Apotex could not enter due to the newer (later) patents
  60. 60. 1199.. LLiisstt ooff rreeffeerreenncceess:: 1. 2. 3. 4. 5. Richard A., Guarino M. D., “New drug approval process” second edition, Marcel dekker, 56, 325-356/427-446.
  61. 61. To take full advantage of Chemical Web content, it is essential to use several Software:Winzip,Chemscape Chime, Shockwave, Adobe Acrobat, Cosmo Player, Web Lab Viewer, Paint Shop Pro, Rasmol, ChemOffice, Quick Time,etc