Presentation on theme: "Presented by: SEMINAR ON: ABBRIVIATED NEW DRUG PPLICATION (ANDA)"— Presentation transcript:
1 Presented by: SEMINAR ON: ABBRIVIATED NEW DRUG PPLICATION (ANDA) Nagori Stavan ArunkumarDepartment of PharmaceuticsL.M.College of Pharamcy
2 Pool of topics: ANDA Introduction History of ANDA Guidelines available for ANDAFilling of ANDAManufacturing and control requirements of the ANDA180 days exclusitivity under Hatch Waxman amendmentConcept of Paragraph I to IVSubstantially complete ANDAHouse keeping regulationPatent expiration regulationTriggering periodWaivers of exclusitivity505(b)(2) applicationSupplemental new drug applicationsCase studiesList of ANDA approved2006 pending ANDAANDA filed by or with Indian Pharmaceutical companyList of references
3 ANDA1. IntroductionANDA 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 ANDAAll 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 2. HISTORY OF ANDA: 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 realizationMid 1966 notice in federal RegisterDESI review ultimately led to evolution of ANDA concept.
6 ANDAOn April 24th 1970, the ANDA policy was published with exception of DESI pending list drugs and exempt as per court orderIn November 1984, The Drug Price Competition and Patent Term Restoration Act.Title 1: ANDA regardless of time before or after 1962Title 2: Patent extension for life lostTitle 3: Textile and wood productsIn 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/NDAHatch-Waxman Amendments
8 3. GUIDELINES AVAILABLE FOR ANDA: Guidelines describe format & content for the following sections.Application summaryChemistry, Manufacturing and controls sectionNon clinical pharmacology and toxicology sectionHuman pharmacokinetics & bioavailability sectionClinical and statically sectionMicrobiology section
9 ANDA Guidelines available for ANDA includes: Organization of ANDA Electronic submission of data for ANDASubmission of archival copy of application in MicroficheGuideline for impurities in drug substancesGuideline for submitting supporting documentation for the Manufacture of Drug substance.Guideline for submitting supporting documentation for the Manufacture of finished dosage forms.
10 ANDAGuideline for submitting supporting documentation for stability studies of Human drugs and Biologics.Guideline for packagingGuidelines for changes in approved ANDA and NDAVariations in Drug Products that may be included in a single ANDA180 days exclusivity under Hatch Waxman amendmentGuidelines for alternate source of API in pending ANDAsPost marketing reporting of Adverse Drug reactions
12 ANDA Proper organization Proper format, clear table of contents, correct folders (jackets), correct tabulation and paginationDetail’s under 21 CFR , 21 CFR and 21 CFROGD’s recommendation of bioequivalence, chemistry and labeling portions of an application
13 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 englishTranslation copy with original reference copy
14 ANDAReview copy (duplicate, FDA viewer, destroyed) in 2 sets of binders (jackets)In first binder CMCIn another BE dataRemaining data (table of contents, labeling) in bothConsistency in color coding binders, volume size and specifications, size and quality of paper
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 applicantProprietary name (if any) and name of drug productNumber of volumes submittedCommitment to resolution of any issues identified in the methods validation process after approvalStatement that the application or a portion of the submission is in electronic process after approvalClearly identify submissions that contain sterility assurance data
23 ANDA IV. Tabs: Pagination: VI. Field copy -additional information: Contents Section TabsE.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
24 Electronic submission: ANDAADVANTAGES:Consistent submissionRapid reviewReduction in archiving and storage spaceEstablishment of structured database of technical information associated with generic drug applications.OGD archiving capability no guidelinesOGD has process for some in hard and some in soft copy.
25 ANDA Electronic submissions separated into 2 parts: To address bioequivalence informationTo address information related to chemistry, manufacturing, and controls (CMC)Applicant may choose to submit either or both partsEach part consist three electronic files:An electronic submission document (ESD)A set of data filesA companion document.
26 ANDAKey element for entering information in electronic submission - Entry and Validation Application (EVA).First step in submission –getting unique 3 digit numberElectronic submission along with hard copy to OGD30 daysCover letter-CMC and/or bioequivalence ESD will be submitted as electronic version as new correspondence within 30 days.
27 Difference between submission of NDA and ANDA: NDA requirementsANDA requirementsWell-controlled clinical studies to demonstrate effectivenessDetailed descriptions of the componentsPreclinical and clinical data to show safetyManufacturing, controls, packaging, andlabeling data sufficient to assure thebioavailability or bioequivalence of thedrug to be marketed.Detailed descriptions of manufacturing and packaging proceduresProposed annotated labeling referencing all studies from which statement s contained in the package insert has been derived.
28 5. MANUFACTURING AND CONTROL REQUIREMENTS OF THE ANDA:- Very importantFrom , 105 Non approval letter issued by FDA
29 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 BiologicsGuideline 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.
30 ANDA Requirements for Drug substances sources: Copy of potential supplier’s most recent establishment inspection repot describing FDA’s findingsSupplier should have a DMF available at FDA for reference purposesSpecifications 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 assayCheck impurity peaks
31 ANDA -Drug product requirements:- -ANDA expiration dates:- 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 conditionsFinal approval for the expiration date is obtained when acceptable shelf life data for two years on more than one production lot is made available
32 ANDADay Generic Drug Exclusivity under the Hatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act
33 After Hatch-Waxman Amendment resulted into ANDAAfter Hatch-Waxman Amendment resulted intoIncreased availability of generics:1984: 12% prescription were generics2000: 44%2003: 51%10,357 FDA approved branded drugs vs. 7,602 generic counterpartsSavings of $ 8 – 10 billions every yearAverage saving per prescription: approximately 53 $1% rise in Generic prescription = $ 1.3 billions saving
34 ANDA 10,357 FDA approved branded drugs vs. 7,602 generic counterparts Savings of $ 8 – 10 billions every yearAverage saving per prescription: approximately 53 $1% rise in Generic prescription = $ 1.3 billions saving
35 Generic Pharmaceuticals: Facts & Figures at a glance ANDAGeneric Pharmaceuticals: Facts & Figures at a glance
36 Generic Pharmaceuticals: Facts & Figures at a glance (contd.) ANDAGeneric Pharmaceuticals: Facts & Figures at a glance (contd.)
37 Generic Pharmaceuticals: Facts & Figures at a glance (contd.) ANDA
38 7. Concept of paragraph I to IV: ANDA7. 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 FDAThat such patent has expiredThe date on which such patent expiresThat such patent is invalid or will not be infringed by the manufacture, use, or sale of the drug product which the ANDA is submitted.
39 ANDAThe 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 decisionThe 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.
40 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.
41 9. HOUSE KEEPING REGULATIONS ANDA9. HOUSE KEEPING REGULATIONSFirst generic loses patent litigation Para IV to III(loses exclusivity)Same day submission first applicantHappens if patent expires on that day or generic wants to challenge innovator’s ANDA for 5 years exclusivity and submits at end of 4 yearFor 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
42 10. PATENT EXPIRATION REGULATION ANDA10. PATENT EXPIRATION REGULATIONPatent for which Para IV filed expires first generic loses exclusitivitySubsequent generics gets exclusitivity
43 11. TRIGGER PERIODANDAUnnecessary delay or settlement Trigger period conceptCommencement 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 day ‘triggering period’court decision regarding the patent favorable to the first applicant or the first applicant must begin commercial marketing of its productif not first generic would lose its eligibility for exclusivity and subsequent generic filers for ANDA would be eligible for immediate approval.
44 ANDAThere 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 productExpiration of a 30 month stay of ANDA approval due to patent litigationExpiration of a preliminary injunction prohibiting marketing of an ANDA productExpiration of the statutorily described exclusivity periods for the listed drug
45 ANDA Delay of ANDA into market Mean while subsequent generics gets tentative approvalFDA proposes 60 days trigger period for first generic to launch product into the market else lose exclusitivity
46 ANDAFirst generic sued Para IV certification and is facing patent litigation by innovatorTriggering period would not begin at least until the 30 month period has lapsedAt 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.
47 12. WAIVER OF EXCLUSIVITY ANDA No regulations Can waive to all subsequent and not single generic applicant
48 13. 505(b)(2) APPLICATION:- ANDA 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))
49 What kind of information can be used for 505(b) (2) application? ANDAWhat kind of information can be used for 505(b) (2) application?Published literatureThe 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.
50 What kind of application can be submitted as a 505(b) (2) application? ANDAWhat 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
51 SOME EXAMPLES OF 505(B) (2) APPLICATIONS ANDASOME EXAMPLES OF 505(B) (2) APPLICATIONSChange in dosage formChange in route of administrationChange in strengthChange in dosage regimenChange in formulation (excipient)Change in active ingredient like use of different salt of same drugNew molecular entity i.e. is prodrug of previously approved drug productSubstitution of an active ingredient in a combination productCombination product: An application for a new combination product in which the active ingredients have been previously approved individually.Rx/OTC switchOTC monograph.Naturally derived or recombinant active ingredient.Bioinequivalence:
52 WHAT CAN'T BE SUBMITTED AS 505(B) (2) APPLICATIONS? ANDAWHAT CAN'T BE SUBMITTED AS 505(B) (2) APPLICATIONS?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
53 ANDAWhat type of patent and/or exclusivity protection is a 505(b) (2) application eligible for?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 (j); (b)(4) and (5)).Granted 5 years of exclusivity if it is for a new chemical entity (21 CFR (j); (b) (2)).Eligible for orphan drug exclusivity (21 CFR ) or pediatric exclusivity (section 505A of the Act).
54 BENEFIT OF 505(b) (2) APPLICATION: ANDABENEFIT OF 505(b) (2) APPLICATION:Filing of ANDA in form of NDA3 or 5 years of Hatch-Waxman marketing exclusivity .An approved 505(b) (2) product, may receive an “AB” substitutability rating in the Orange Book.
55 CURRENT CHALLENGE TO THE 505(b) (2) MECHANISM: ANDACURRENT CHALLENGE TO THE 505(b) (2) MECHANISM: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 toCease approval of all 505(b)(2) NDAsRefuse to grant “A” substitutability ratings to such products in orange book...
56 14. SUPPLEMENTAL NEW DRUG APPLICATIONS ANDA14. SUPPLEMENTAL NEW DRUG APPLICATIONSOnce 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.
57 ANDASupplemental 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.
58 ANDASupplements to new drug applications requiring FDA approval before the change is made for the drug substance.Relaxation of specification limitsThe establishment of new regulatory limitsThe 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.
59 Supplements to new drug applications requiring FDA approval before the change is made for the drug product.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.
60 Supplements for changes that may be made before FDA approval ANDASupplements for changes that may be made before FDA approvalFull explanation of the basis for the such changes is requiredThe 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.
61 Changes described in the Annual report ANDAChanges described in the Annual reportRevisions 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.
62 Supplemental new drug application checklist: ANDASupplemental new drug application checklist: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 changeUse 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.
63 15. CASE STUDIES: ANDA Patent of PAXIL (Paroxetine HCL hemihydrate) SmithKline Backhem (SKB) obtained patent of Paxil as NDA.In 1998 Apotex filed Para IV certificate for getting ANDASKB filed legal suit for patent infringement30-months stay on Apotex approvalSKB filed patent extension 1: for use as liquid oral3 more patents in 1999 & 2000 for anhydrous form5th patent for Paroxetine methanosulfate in 2000Serial Patent submission tactics, with newer 30-month stay every timeResult: The patent of litigation expired, but Apotex could not enter due to the newer (later) patents
64 ANDA Patent of BUSPAR (BMS Pharmaceuticals) Mylan pharmaceuticals filed Para III ANDA in ‘98 (launch after the patent expiry). Got “Tentative” approval from US FDABMS Patent was to expire on 11:59 at midnight of 21st Nov. ’00Mylan pharmaceuticals loaded the trucks at midnight with generic versions of BUSPAR to launch in US on 22nd Nov.’0012 hours before patent expiry, BMS was granted a new patent by US Patent & Trademark officeBMS immediately submitted new patent to US FDAFDA updated the orange book and issued letter of incompleteness in ANDA to MylanMylan’s consignments remained on shipping dockIn end net result was BMS ruled for 15 years without competition from 1986 for Buspar
117 17. List of ANDA patents pending this year (from Jan 2006): Date FiledDocket #Name of Petitioner/Subject Matter02/09/20062006P-0070Pfizer Inc./Misbranding of generic azithromycin products marketed by Teva Pharmaceuticals USA and Sandoz Inc.02/10/20062006P-0072Olsson,Frank and Weeda, P.C./ANDA for prednisolone sodium phosophate, USP,oral solution, 10 mg prednisolone base/5mL
118 18. ANDA filed by or with Indian Pharmaceutical company