2. Pool of topics:
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
3. 1. Introduction
ANDA contains data submitted to FDA's Center for Drug evaluation and
Research, Office of Generic Drugs, for review and ultimate approval of a
generic drug product.
Once ANDA is approved, an applicant may manufacture and market the
generic drug product to provide a safe, effective, low cost alternative to the
American public.
A generic drug product is the one that is comparable to an innovator drug
product in dosage form, strength, route of administration, quality,
performance characteristics and intended use.
4. All approved products, both innovator and generic, are
listed in FDA's Approved Drug Products with Therapeutic
Equivalence Evaluations (Orange Book).
Generic drug applications are termed "abbreviated"
Use of bioequivalence as the base for approving generic
drug products was established by the "Drug Price
Competition and Patent Term Restoration Act of 1984,"
also known as the WAXMAN-HATCH ACT.
5. 2. HISTORY OF ANDA:
In 1938, proof of safety
In 1962, “THE KEFAUVER HARIS AMENDMENTS”
“THE KEFAUVER HARIS AMENDMENTS” led to “DRUG
EFFICACY STUDY IMPLEMENTATION (DESI)”.
FDA‟s realization
Mid 1966 notice in federal Register
DESI review ultimately led to evolution of ANDA concept.
6. On April 24th 1970, the ANDA policy was published with
exception of DESI pending list drugs and exempt as per
court order
In November 1984, The Drug Price Competition and
Patent Term Restoration Act.
Title 1: ANDA regardless of time before or after 1962
Title 2: Patent extension for life lost
Title 3: Textile and wood products
In April, 1992 FDA finalized the regulations outlining the
requirements for ANDAs.
7. On November 21, 1997 Modernization Act was
signed.
Section 506A-Changes for approved ANDA/NDA
Hatch-Waxman Amendments
8. 3. GUIDELINES AVAILABLE FOR
ANDA:
Guidelines describe format & content for
the following sections.
– Application summary
– Chemistry, Manufacturing and controls section
– Non clinical pharmacology and toxicology section
– Human pharmacokinetics & bioavailability section
– Clinical and statically section
– Microbiology section
9. Guidelines available for ANDA includes:
Organization of ANDA
Electronic submission of data for ANDA
Submission of archival copy of application in Microfiche
Guideline for impurities in drug substances
Guideline for submitting supporting documentation for the Manufacture of
Drug substance.
Guideline for submitting supporting documentation for the Manufacture of
finished dosage forms.
10. 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
12. Proper organization
Proper format, clear table of contents, correct
folders (jackets), correct tabulation and pagination
Detail‟s under 21 CFR 314.50, 21 CFR 314.94
and 21 CFR 314.440
OGD‟s recommendation of bioequivalence,
chemistry and labeling portions of an application
13. 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
14. Review copy (duplicate, FDA viewer, destroyed)
in 2 sets of binders (jackets)
In first binder CMC
In another BE data
Remaining data (table of contents, labeling) in
both
Consistency in color coding binders, volume size
and specifications, size and quality of paper
15.
16.
17. 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
23. 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
24. Electronic submission:
ADVANTAGES:
Consistent submission
Rapid review
Reduction in archiving and storage space
Establishment of structured database of technical information
associated with generic drug applications.
OGD archiving capability no guidelines
OGD has process for some in hard and some in soft copy.
25. 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.
26. 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.
27. Difference between submission of
NDA and ANDA:
NDA requirements ANDA requirements
Well-controlled clinical studies to Detailed descriptions of the components
demonstrate effectiveness
Preclinical and clinical data to show Manufacturing, controls, packaging, and
safety 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.
28. 5. MANUFACTURING AND CONTROL
REQUIREMENTS OF THE ANDA:-
Very important
From 1977-1992, 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 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.
30. 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
31. -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
32. 6. 180-Day Generic Drug Exclusivity under the
Hatch-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
33. After Hatch-Waxman Amendment
resulted into
Increased availability of generics:
1984: 12% prescription were generics
2000: 44%
2003: 51%
10,357 FDA approved branded drugs vs. 7,602
generic counterparts
Savings of $ 8 – 10 billions every year
Average saving per prescription: approximately 53 $
1% rise in Generic prescription = $ 1.3 billions saving
34. 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
38. 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.
39. 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.
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
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
42. 10. PATENT EXPIRATION
REGULATION
Patent for which Para IV filed expires first generic loses exclusitivity
Subsequent generics gets exclusitivity
43. 11. TRIGGER PERIOD
Unnecessary delay or settlement Trigger period concept
Commencement of the 180-day exclusivity period for the first applicant is
either the first commercial marketing of the first applicant‟s product, or a
decision of a court holding the patent invalid, not infringed, or unenforceable,
whichever is earlier.
For exercising exclusitivity 180-day „triggering period‟
court decision regarding the patent favorable to the first applicant or the first
applicant must begin commercial marketing of its product
if not first generic would lose its eligibility for exclusivity and subsequent
generic filers for ANDA would be eligible for immediate approval.
44. 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
45. 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
46. 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.
47. 12. WAIVER OF EXCLUSIVITY
No regulations
Can waive to all subsequent and not single
generic applicant
48. 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))
49. What kind of information can be
used for 505(b) (2) application?
Published literature
The FDA‟s findings of safety and efficacy for
a previously approved drug product without
requiring the sponsor to obtain a right of
reference from the original applicant.
50. 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
51. SOME EXAMPLES OF 505(B) (2)
APPLICATIONS
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:
52. WHAT 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. 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).
54. 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.
55. 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...
56. 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.
57. • 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.
58. 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.
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
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.
61. 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.
62. 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.
63. 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
64. B. Patent of BUSPAR (BMS Pharmaceuticals)
Mylan pharmaceuticals filed 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
65. 16. List of NDA/ANDA approved by
FDA from 2004
117. 17. List of ANDA patents pending
this year (from Jan 2006):
Date Docket Name of Petitioner/Subject
Filed # Matter
02/09/2006 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
118. 18. ANDA filed by or with
Indian Pharmaceutical company
123. 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)
124. 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)
128. 19. List of references:
1. www.fda.gov
2. www.phorum.com
3. www.morganfinnegan.com
4. www.drugdeliverytech.com
5. Richard A., Guarino M. D., “New drug
approval process” second edition, Marcel
dekker, 56, 325-356/427-446.
