Pool of topics:1. Introduction2. History of ANDA3. Guidelines available for ANDA4. Filling of ANDA5. Manufacturing and control requirements of the ANDA6. 180 days exclusitivity under Hatch Waxman amendment7. Concept of Paragraph I to IV8. Substantially complete ANDA9. House keeping regulation10. Patent expiration regulation11. Triggering period12. Waivers of exclusitivity13. 505(b)(2) application14. Supplemental new drug applications15. Case studies16. List of ANDA approved17. 2006 pending ANDA18. ANDA filed by or with Indian Pharmaceutical company19. List of references
1. Introduction ANDA contains data submitted to FDAs Center for Drug evaluation andResearch, Office of Generic Drugs, for review and ultimate approval of ageneric drug product. Once ANDA is approved, an applicant may manufacture and market thegeneric drug product to provide a safe, effective, low cost alternative to theAmerican public. A generic drug product is the one that is comparable to an innovator drugproduct in dosage form, strength, route of administration, quality,performance characteristics and intended use.
All approved products, both innovator and generic, arelisted in FDAs Approved Drug Products with TherapeuticEquivalence Evaluations (Orange Book).Generic drug applications are termed "abbreviated"Use of bioequivalence as the base for approving genericdrug products was established by the "Drug PriceCompetition and Patent Term Restoration Act of 1984,"also known as the WAXMAN-HATCH ACT.
2. HISTORY OF ANDA:In 1938, proof of safetyIn 1962, “THE KEFAUVER HARIS AMENDMENTS”“THE KEFAUVER HARIS AMENDMENTS” led to “DRUGEFFICACY STUDY IMPLEMENTATION (DESI)”.FDA‟s realizationMid 1966 notice in federal RegisterDESI review ultimately led to evolution of ANDA concept.
On April 24th 1970, the ANDA policy was published withexception of DESI pending list drugs and exempt as percourt orderIn November 1984, The Drug Price Competition andPatent 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 therequirements for ANDAs.
On November 21, 1997 Modernization Act wassigned.Section 506A-Changes for approved ANDA/NDAHatch-Waxman Amendments
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
Guidelines available for ANDA includes:Organization of ANDAElectronic submission of data for ANDASubmission of archival copy of application in MicroficheGuideline for impurities in drug substancesGuideline for submitting supporting documentation for the Manufacture ofDrug substance.Guideline for submitting supporting documentation for the Manufacture offinished dosage forms.
Guideline for submitting supporting documentation for stabilitystudies 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 reactionsGuidelines for changes in approved ANDA and NDA
Proper organizationProper format, clear table of contents, correctfolders (jackets), correct tabulation and paginationDetail‟s under 21 CFR 314.50, 21 CFR 314.94and 21 CFR 314.440OGD‟s recommendation of bioequivalence,chemistry and labeling portions of an application
Paper based filing of ANDA: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
Review copy (duplicate, FDA viewer, destroyed)in 2 sets of binders (jackets)In first binder CMCIn another BE dataRemaining data (table of contents, labeling) inbothConsistency in color coding binders, volume sizeand specifications, size and quality of paper
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
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
Electronic submission:ADVANTAGES:Consistent submissionRapid reviewReduction in archiving and storage spaceEstablishment of structured database of technical informationassociated with generic drug applications.OGD archiving capability no guidelinesOGD has process for some in hard and some in soft copy.
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 bothpartsEach part consist three electronic files: – An electronic submission document (ESD) – A set of data files – A companion document.
Key element for entering information in electronicsubmission - Entry and Validation Application(EVA).First step in submission –getting unique 3 digitnumberElectronic submission along with hard copy toOGD30 daysCover letter-CMC and/or bioequivalence ESD will besubmitted as electronic version as new correspondence within30 days.
Difference between submission of NDA and ANDA:NDA requirements ANDA requirementsWell-controlled clinical studies to Detailed descriptions of the componentsdemonstrate effectivenessPreclinical and clinical data to show Manufacturing, controls, packaging, andsafety labeling data sufficient to assure the bioavailability or bioequivalence of the drug to be marketed.Detailed descriptions of manufacturingand packaging proceduresProposed annotated labelingreferencing all studies from whichstatement s contained in the packageinsert has been derived.
5. MANUFACTURING AND CONTROL REQUIREMENTS OF THE ANDA:- Very important From 1977-1992, 105 Non approval letter issued by FDA
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.
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 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 assay Check impurity peaks
-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
6. 180-Day Generic Drug Exclusivity under theHatch-Waxman Amendments to the Federal Food, Drug, and Cosmetic Act WAXMAN HATCH AMENMENTS BENIFITS TO INOVATOR’S COMPANIES TO GENERIC DRUG COMPANIES 180 DAY EXCLUSIVITY PERIOD 45 DAY TO CLAIM TO CHALLEGE PATENT DRUG IF SUIT NOT SUIT DELAYED FOR 30 MONTHS
After Hatch-Waxman Amendment resulted intoIncreased availability of generics:1984: 12% prescription were generics2000: 44%2003: 51%10,357 FDA approved branded drugs vs. 7,602generic counterpartsSavings of $ 8 – 10 billions every yearAverage saving per prescription: approximately 53 $1% rise in Generic prescription = $ 1.3 billions saving
10,357 FDA approved branded drugsvs. 7,602 generic counterpartsSavings of $ 8 – 10 billions every yearAverage saving per prescription:approximately 53 $1% rise in Generic prescription = $ 1.3billions saving
Generic Pharmaceuticals:Facts & Figures at a glance
Generic Pharmaceuticals:Facts & Figures at a glance (contd.)
Generic Pharmaceuticals:Facts & Figures at a glance (contd.)
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: 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.
The first three paragraphs (I, II, III) results in no generic drugbeing sold during the term of the innovator‟s patentprotection.In case paragraph IV certification generic drugs can be soldduring the term of the innovator‟s patent protection. with ruleof 45days suit and 30 months ban.Bann approved unless:The court decides that such patent is invalid or not infringed. In this case ANDAapproval is made effective on the date of the court decisionThe court decides that such patent has been infringed and sets a date for approval ofthe ANDA as provided.The court grants a preliminary injuction prohibiting the ANDA applicant fromengaging in the commercial manufacture or sale of the drug until the court decidesthe issues of patent validity and infringement.
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.
9. 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 tochallenge innovator‟s ANDA for 5 years exclusivity and submitsat end of 4 yearFor 6 months pediatric exclusitivity happens if patent expires onthat day or generic wants to challenge innovator‟s ANDA for5(1/2) years exclusivity and submits at end of 4(1/2) year
10. PATENT EXPIRATION REGULATIONPatent for which Para IV filed expires first generic loses exclusitivity Subsequent generics gets exclusitivity
11. TRIGGER PERIODUnnecessary delay or settlement Trigger period conceptCommencement of the 180-day exclusivity period for the first applicant iseither the first commercial marketing of the first applicant‟s product, or adecision 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 firstapplicant must begin commercial marketing of its productif not first generic would lose its eligibility for exclusivity and subsequentgeneric filers for ANDA would be eligible for immediate approval.
There is new „triggering period‟ which is separateand distinct from the 180-day „exclusivity period.‟The triggering period would begin upon the :Tentative approval of a subsequent ANDA with a paragraph ivcertification for the same drug productExpiration of a 30 month stay of ANDA approval due to patentlitigationExpiration of a preliminary injunction prohibiting marketing of anANDA productExpiration of the statutorily described exclusivity periods for the listeddrug
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
First generic sued Para IV certification and is facing patent litigation by innovatorTriggering 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.
12. WAIVER OF EXCLUSIVITYNo regulationsCan waive to all subsequent and not singlegeneric applicant
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))
What kind of information can beused 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.
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
SOME 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 inwhich the active ingredients have been previously approved individually.Rx/OTC switchOTC monograph.Naturally derived or recombinant active ingredient.Bioinequivalence:
WHAT CANT 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
What 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 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).
BENEFIT OF 505(b) (2) APPLICATION:• 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.
CURRENT 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 to Cease approval of all 505(b)(2) NDAs Refuse to grant “A” substitutability ratings to such products in orange book...
14. SUPPLEMENTAL NEW DRUG APPLICATIONS• 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.
• 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.
Supplements to new drug applications requiringFDA approval before the change is made for the drug substance. 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.
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.
Supplements for changes that may be made before FDA approval 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.
Changes described in the Annual report• 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.
Supplemental 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 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.
15. CASE STUDIES: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
B. 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 tolaunch in US on 22nd Nov.‟0012 hours before patent expiry, BMS was granted a new patent by US Patent & TrademarkofficeBMS 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
16. List of NDA/ANDA approved by FDA from 2004
17. List of ANDA patents pending this year (from Jan 2006):Date Docket Name of Petitioner/SubjectFiled # Matter02/09/2006 2006P-0070 Pfizer Inc./Misbranding of generic azithromycin products marketed by Teva Pharmaceuticals USA and Sandoz Inc.02/10/2006 2006P-0072 Olsson,Frank and Weeda, P.C./ANDA for prednisolone sodium phosophate, USP,oral solution, 10 mg prednisolone base/5mL
18. ANDA filed by or withIndian Pharmaceutical company
Ranbaxy‟s ANDA which are in pipeline for filing patent
Generics with DR. Reddies LimitedType NameANDA Ranitidine tab 75 mg (OTC)ANDA Ranitidine Cap (150, 300 mg)ANDA Famotidine tablet (10, 20,40 mg)ANDA Oxaprozin tablet (600mg)ANDA Fluxetine Capsule (40mg)ANDA Enalpril maleate with hydrochlorthiazide tablet (5- 12.5,10-25 mg)ANDA Ibuprofen tablet (400, 600 and 800 mg)ANDA Ibuprofen tablet (200 mg-OTC)
Type NameTentative ANDA Ciprofloxacin tablet (100, 250, 500, 750 mg)Tentative ANDA Omeprazole capsule (40mg)Tentative ANDA Fluxetine tablet (10 mg)Tentative ANDA Fluxetine Capsule (10, 20 mg)
19. List of references:1. www.fda.gov2. www.phorum.com3. www.morganfinnegan.com4. www.drugdeliverytech.com5. Richard A., Guarino M. D., “New drug approval process” second edition, Marcel dekker, 56, 325-356/427-446.
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