ANDA

PowerPoint Presentation: 

1 ABBREVIATED NEW DRUG APPLICATION (ANDA) Mr. Nitin Kadam R&D Formulation.

Introduction: 

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. Dosage form, strength, route of administration, quality, performance characteristics and intended use . Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). Why ???? "abbreviated“ The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug. Use of bioequivalence by the " Drug Price Competition and Patent Term Restoration Act of 1984 ," also known as the WAXMAN-HATCH ACT . 2

PowerPoint Presentation: 

In 1938,demonstration for proof of safety is required. In 1962, “THE KEFAUVER HARIS AMENDMENTS” “THE KEFAUVER HARIS AMENDMENTS” led to “DRUG EFFICACY STUDY IMPLEMENTATION (DESI)”. FDA’s realization  national research council ( drug efficacy evaluation) Only 12% were noted as effective for indication described on label. DESI review ultimately led to evolution of ANDA concept. ANDA policy was published on April 24, 1970 . 3

ANDA Guidelines :: 

ANDA Guidelines : 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 4

ANDA Guidelines :: 

ANDA Guidelines : 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. Guideline for submitting supporting documentation for stability studies of Human drugs and Biologics. Guideline for packaging. Guidelines for changes in approved ANDA and NDA . 180 days exclusivity under Hatch Waxman amendment. Guidelines for alternate source of API in pending ANDAs. Post marketing reporting of Adverse Drug reactions. 5

Filling of ANDA. : 

Filling of ANDA. 6

Difference: NDA and ANDA:: 

Difference: NDA and ANDA: 7 A New Drug Application (NDA) requires the submission of : Well-controlled clinical studies to demonstrate effectiveness Preclinical and clinical data to show safety Detailed descriptions of manufacturing and packaging procedures Proposed annotated labeling referencing all studies from which statements contained in the package insert has been derived. In contrast to NDA, ANDA requires the submission of : 1. Detailed descriptions of the components Manufacturing, controls, packaging, and labeling (which can be in final, printed form), data sufficient to assure the bioavailability or bioequivalence of the drug to be marketed . The manufacturing and controls information to be provided are the same as required for a New Drug Application

Manufacturing and control requirement of ANDA: 

Manufacturing and control requirement of ANDA From 1977-1992, 105 Non approval letter issued by FDA Requirements for Drug substances sources : copy of potential supplier’s most recent establishment inspection report describing FDA’s findings. This document should be reviewed by the applicant to check acceptability of that manufacturer by FDA. In addition, the supplier should have a DMF available at FDA for reference purposes .This will describes the facilities, personnel, equipment, and manufacturing & controls procedure used at the site (s) where the bulk drug substance is made . 8

Manufacturing and control requirement of ANDA: 

Manufacturing and control requirement of ANDA Specifications for drug substances:- Sometimes assay methodology is not specified into the monograph for older drugs or method described is not specific . In such cases FOI request to FDA for a copy of pertinent regulatory assay method . Carefully evaluate impurity peaks observed in a supplier’s bulk substance and compare them with those observed in the marketed product. The extent that the peaks differ may determine the need to obtain further information, including toxicity. If samples of impurities, degradation products are available from the supplier or are identified in published literature then the assay methods should be appropriately validated by the ANDA sponsor for their sensitivities and specifications with respect to them. It is also recommended that the sponsor of an ANDA set up and maintain a stability program for the bulk drug substance . 9

Manufacturing and control requirement of ANDA: 

Manufacturing and control requirement of ANDA ANDA Expiration dates:- The FDA will tentatively approve a two year expiration date for a product if satisfactory data reflecting at least three months storage under accelerated conditions is submitted. The sponsor is also expected to provide a commitment to continue to monitor the stability of the product periodically report the results to FDA, and to remove from market any batches failing to meet specifications prior to product’s labeled expiration period. 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 to FDA. 10

180-Day Generic Drug Exclusivity Hatch-Waxman Amendments: 

180-Day Generic Drug Exclusivity Hatch-Waxman Amendments 11

Resulted into: 

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 1% rise in Generic prescription = $ 1.3 billions saving 12

Generic Pharmaceuticals: Facts & Figures at a glance: 

Generic Pharmaceuticals: Facts & Figures at a glance 13

Concept of paragraph I to IV: 

Concept of paragraph I to IV 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. 14 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 .

Concept of paragraph I to IV: 

Concept of paragraph I to IV Bann approved unless: The court decides that such patent is invalid or not infringed. 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 injunction 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. 15

Substantially completed ANDA: 

Substantially completed ANDA Only first applicant submitting the first will be eligible for exclusivity. If a new bioequivalence study required for ANDA approval- not substantially complete and the applicant would not be eligible for exclusivity. [ If first ineligible that no other eligible. 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. 16

House keeping regulations: 

House keeping regulations First generic  loses patent litigation  Para IV to III  (loses any claim to exclusivity eligibility). Same day submission  first applicant. 17

Patent expiration regulation : 

Patent expiration regulation Patent for which Para IV filed expires first generic loses exclusitivity Subsequent applicant gets exclusitivity 18

Trigger period: 

Trigger period Unnecessary delay or settlement  Trigger period concept. Commencement of the 180-day exclusivity period first commercial marketing of the first applicant’s product, a decision of a court holding the patent invalid, not infringed, or unenforceable. 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 neither of this event occur would lose its eligibility for exclusivity and subsequent ANDA applicant would be eligible for immediate approval. FDA proposed shortening the length to 60 days 19

Trigger period: 

Trigger period 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. 20

Trigger period: 

Trigger period First generic is sued for its 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. 21

Waiver of exclusivity: 

Waiver of exclusivity No regulations. Can waive to all subsequent applicant and not to single particular generic applicant. 22

505(b)(2) Application:: 

505(b)(2) Application: Allow sponsor to obtain approval of new drug application NDA based on “full report of investigation” establishing a drug 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)). What kind of information can be used for 505(b) (2) application? Published literature from third party. The FDA’s prior 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. 23

What type of patent and/or exclusivity protection is a 505(b) (2) application eligible for?: 

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). 24

Benefits:: 

Benefits: 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. 25

Supplemental new drug application.: 

Supplemental new drug application. 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 changes occurring 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. 26

Supplements to new drug applications requiring FDA approval before the change is made for the drug substance.: 

Supplements to new drug applications requiring FDA 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. 27

Supplements to new drug applications requiring FDA approval before the change is made for the drug product.: 

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. 28

Supplements for changes that may be made before FDA approval: 

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. 29

Case studies:: 

Case studies: 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 30

Case studies:: 

Case studies: Patent of BUSPAR (BMS Pharmaceuticals) Mylan pharmaceuticals filled Para III ANDA in ‘98 (launch after the patent expiry). Got “Tentative” approval from US FDA BMS Patent was to expire on 11:59 at midnight of 21st Nov. ’00. Mylan pharmaceuticals loaded the trucks at midnight with generic versions of BUSPAR to launch in US on 22nd Nov.’00. 12 hours before patent expiry, BMS was granted a new patent by US Patent & Trademark office. BMS immediately submitted new patent to US FDA. FDA updated the orange book and issued letter of incompleteness in ANDA to Mylan. Mylan’s consignments remained on shipping dock. In end net result was BMS ruled for 15 years without competition from 1986 for Buspar . 31

List of NDA/ANDA approved by FDA from 2004: 

List of NDA/ANDA approved by FDA from 2004 32

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ANDA approved in October 2005: 

ANDA approved in October 2005 77

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Tentative ANDA approval (July2005): 

Tentative ANDA approval (July2005) 80

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ANDA filed by or with Indian Pharmaceutical company: 

ANDA filed by or with Indian Pharmaceutical company 82

Ranbaxy’s ANDA which are in pipeline for filing patent: 

Ranbaxy’s ANDA which are in pipeline for filing patent 83

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Generics with DR. Reddies Limited: 

Generics with DR. Reddies Limited Type Name ANDA 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) 86

PowerPoint Presentation: 

Type Name Tentative 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) 87

ANDAs with Zydus Cadila: 

ANDAs with Zydus Cadila Atenolol tablet Metformin HCl Promethazine tablet 88

Tentative ANDAs with Zydus cadila: 

Tentative ANDAs with Zydus cadila Divalproex Na DR tablet Gatifloxain tablet Ribavirin capsule and tablet 89

Generic products available with Cipla Pharmaceuticals : 

Generic products available with Cipla Pharmaceuticals 90

List of references:: 

List of references: www.fda.gov www.phorum.com www.morganfinnegan.com www.drugdeliverytech.com Richard A., Guarino M. D., “New drug approval process” second edition, Marcel dekker, 56, 325-356/427-446. 91