2. INTRODUCTION
• The generic drug is a safe, effective and economical
substitute of a brand name drug product
• The act which surrounds the generic drug approval
process of the USFDA is the “Hatch Waxman Act of
1984” which we also identify by the “Drug price control
and Patent Term Restoration Act of 1984” which led to a
plethora of generic drugs entering into the market
• Early before the passage of the act the pharmaceutical
market was ruled by the brand name drug manufacturers
which we also call as the Innovators
• The generic drug manufacturers seldom used to compete
with them and invest their funds for the already existing
brands in the market
3. • There was a lack of competition and the innovator enjoyed
his elite monopoly period within which no other brand of
the drug can enter into the market
• This exclusivity period also allowed the innovator to quote
highest prices of the drugs
• To stop these practices and to make a user friendly drug
market, the US congress passed the Hatch Waxman Act in
1984 which was regarded as one of the most successful
segments of the US legislation at that time
• The act was passed taking into consideration the interests
of both the innovator and the brand name drug
manufacturer
4. • An Abbreviated New Drug Application (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 public.
• Generic drug applications are termed "abbreviated" because
they are generally not required to include preclinical (animal)
and clinical (human) data to establish safety and effectiveness.
5. • Instead, generic applicants must scientifically
demonstrate that their product is bioequivalent (i.e.,
performs in the same manner as the innovator drug).
• This will gives them the rate of absorption or
bioavailability of the generic drug, which they can then
compare to that of the innovator drug.
• The generic version must deliver the same amount of
active ingredients into a patient's bloodstream in the same
time as the innovator drug.
6. • 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
HATCH-WAXMAN ACT.
• It is because of this Act that there is the availability of less
costly generic drugs into the market without conducting
costly and duplicative clinical trials.
• At the same time, the brand-name companies (innovators) can
apply for up to five additional years longer patent protection
for the new medicines that they developed to make up the time
lost while their products were going through FDA's approval
process.
7. BIRTH OF GENERICS: THE HATCH
WAXMAN ACT OF 1984
• The act which gave rise to the generic drug industry
was passed as amendments of the Federal Food,
Drug, and Cosmetic Act (FFD & C).
• The main objectives of the act were to:
1. Offset the drug approval delay:
• Early before the passage of this act, the innovators
used to encounter a delay in approval of their New
Drug Applications (NDA) for brand name product
which eventually affected their brand entry in the
market and financial losses.
8. 2.Bring healthy competition and to avoid price rise:
• Early before its passage there was no scope of the generics to enter
the market until the patent term of the innovator has expired as no
provisions of challenging the validity of the innovator patent was
there.
• Also there were not many benefits expected by the generic in
investing capital to relaunch another version of already existing
brand of the drug after its patent expiry.
• This product monopoly kept competition away and the drug prices
high as per the innovators will.
3. Make life easier for the generic:
• Generic manufacturers used to face a lot of difficulties in doing all
the pre-clinical and clinical studies as done by the brand name
manufacturers to get their generic approved
9. • The act was passed keeping one eye on the interests of both
the brand name and the generic drug manufacturers providing
almost equal benefits to both.
• The benefits received by the brand name manufacturers are:
1. Regulatory delays in brand approval were deciphered.
2. The market exclusivity and the „effective patent life‟ (the time
left when the drug comes into the market after drug
development and FDA approval) was extended from 8.5 years
(1980) to 13 years (late 1980s) and now it‟s nearly 16-17
years.
10. • The benefits received by the generic manufacturers are:
1. The generic could challenge the validity of the patent issued to
the innovator
2. The act provided with the stipulation to file an Abbreviated
New Drug Application (ANDA) and to leave out the expensive
pre-clinical and clinical trials as done by the innovator and
provided with the provision of relying on the safety and
efficacy data of the innovator drug and to perform a much
cheaper substitutable study called „bioequivalence‟ to establish
equivalence with the innovator.
3. As per the act, once approved the generic gets an exclusivity
period of six months to rule the market along with the
innovator during which no other generic can be given
approval.
11. • The FDA publishes the information on every approved drug product in the
“Approved Drug Products with Therapeutic Equivalence Evaluations”
which we also know by the name of “Orange Book”.
• It lists the NDA‟s and ANDA‟s along with the expiry dates of patents and
generic exclusivities. It is a ready reference of brand name drug products
for the generic companies who usually use this information to identify the
reference for developing their generic versions.
• The Orange book also contains certain therapeutic equivalence codes.
• An A- prefixing product is considered to be substitutable and B- prefixing
is a safe and effective product for use but is regarded inequivalent and non-
substitutable with the brand name drug product.
12. Content and format of an abbreviated
application
1. Application form
2. Table of contents
3. Basis for abbreviated new drug application submission
4. Conditions of use
5. Active ingredients
6. Route of administration, dosage form and strength
7. Bioequivalence
8. Labeling
9. Chemistry, manufacturing and controls
10. Samples
11. Patent certification
13. 1. Application form.
• The applicant shall submit a completed and signed
application form.
2. Table of contents.
• The archival copy of the abbreviated new drug application is
required to contain a table of contents that shows the volume
number and page number of the contents of the submission.
3. Basis for abbreviated new drug application submission.
• The name of the reference listed drug, including its dosage
form and strength.
• For an abbreviated new drug application, a reference to FDA-
assigned docket number for the petition and a copy of FDA's
correspondence approving the petition.
14. 4. Conditions of use.
• A statement that the conditions of use prescribed,
recommended, or suggested in the labeling proposed
for the drug product have been previously approved
for the reference listed drug.
• A reference to the applicant's annotated proposed
labeling and to the currently approved labeling for
the reference listed drug provided.
15. 5. Active ingredients.
• Statement that the active ingredients of the proposed drug
product are the same as those of the reference listed drug,
or if one of the active ingredients differs from one of the
active ingredients of the reference listed drug,
• Information to show that the other active ingredients of the
drug product are the same as the other active ingredients of
the reference listed drug,
• Information to show that the different active ingredient is an
active ingredient of another listed drug and such other
information about the different active ingredient that FDA
may require.
16. 6. Route of administration, dosage form, and
strength.
• A statement that the route of administration, dosage
form, and strength of the proposed drug product are
the same as those of the reference listed drug.
• If the route of administration, dosage form, or
strength of the drug product differs from the
reference listed drug and the abbreviated application
is submitted such information about the different
route of administration, dosage form, or strength that
FDA may require.
17. 7. Bioequivalence .
a) Information that shows that the drug product is bioequivalent to the
reference listed drug upon which the applicant relies.
• A complete study report must be submitted for the bioequivalence study
upon which the applicant relies for approval.
• The applicant must submit either a complete or summary report. If a
summary report of a bioequivalence study is submitted and FDA
determines that there may be bioequivalence issues or concerns with the
product, FDA may require that the applicant submit a complete report of
the bioequivalence study to FDA.
b) If the abbreviated new drug application is submitted the results of any
bioavailability of bioequivalence testing required by the agency.
• any other information required by the agency to show that the active
ingredients of the proposed drug product are of the same pharmacological
or therapeutic class as those in the reference listed drug and that the
proposed drug product can be expected to have the same therapeutic effect
as the reference listed drug.
• If the proposed drug product contains a different active ingredient than the
reference listed drug, FDA will consider the proposed drug product to have
the same therapeutic effect as the reference listed drug if the applicant
provides information demonstrating that.
18. 8. Labeling
a) Listed drug labeling. A copy of the currently approved labeling
for the listed drug referred to in the abbreviated new drug
application, if the abbreviated new drug application relies on a
reference listed drug.
b) Copies of proposed labeling. Copies of the label and all labeling
for the drug product.
c) Statement on proposed labeling. A statement that the applicant's
proposed labeling including, if applicable, any Medication Guide
required is the same as the labeling of the reference listed drug.
d) Comparison of approved and proposed labeling. The applicant's
proposed labeling and labeling approved for the reference listed
drug may include differences in expiration date, formulation,
bioavailability, or pharmacokinetics, labeling revisions made to
comply with current FDA labeling guidelines or other guidance, or
omission of an indication or other aspect of labeling protected by
patent or accorded exclusivity.
19. 9. Chemistry, manufacturing, and controls.
a) The information required shall contain the proposed or actual
master production record, including a description of the
equipment, to be used for the manufacture of a commercial lot of
the drug product.
b) Inactive ingredients. an applicant shall identify and characterize
the inactive ingredients in the proposed drug product and provide
information demonstrating that such inactive ingredients do not
affect the safety or efficacy of the proposed drug product.
c) Inactive ingredient changes permitted in drug products intended
for parenteral use. Generally, a drug product intended for
parenteral use shall contain the same inactive ingredients and in
the same concentration as the reference listed drug identified by
the applicant
d) Inactive ingredient changes permitted in drug products intended
for ophthalmic or otic use. . Generally, a drug product intended for
ophthalmic or otic use shall contain the same inactive ingredients
and in the same concentration as the reference listed drug
identified by the applicant .
20. e)Inactive ingredient changes permitted in drug
products intended for topical use. Generally, a drug
product intended for topical use, solutions for
aerosolization or nebulization, and nasal solutions
shall contain the same inactive ingredients as the
reference listed drug identified by the applicant.
10. Samples. Samples need not be submitted until
requested by FDA.
21. 11. Patent certification
• While filing an ANDA, the generic manufacturer is
required to file one of the following four possible
certifications on the subject of the reference brand
name patent listed in the Orange Book.
1. Para I certification:
There is no patent for the drug listed in the orange
book
2. Para II certification:
Patent is listed but has expired
3. Para III certification:
Patent is listed, is valid but the generic wants
approval to market the drug once the pertinent patent
expires
22. Para IV certification:
The generic manufacturer either challenges the
validity of the brand name listed patent asserting it to
be invalid or fake, or it affirms not to cross the fringe
of the brand name patent claims.
• Para IV certification is the most critical of all and
gives rise to almost all the anti-competitive practices
associated with the Hatch Waxman amendments of
the FFD and C act.
23. Manufacturing and control
requirement of ANDA
Requirements for Drug substances sources:
1.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.
2.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.
24. ANDA Expiration dates
1.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.
2.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.
3.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.
