Abbreviated

New Drug Applications

(ANDAs)

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 History and Current Approval Process

 1938 US Congress enacted FDCA. Pre-market notification required

for new drugs. Drugs to be tested in humans for safety with IND
regulations and also that a NDA be submitted.

 Post 1938 FDA also began to permit generic versions of drugs

generally recognized as safe.

 In 1962 Thalidomide tragedy. Pre-market notification changed to

pre-market approval. Also not just evidence of safety but that of
effectiveness also required.

Retrospectively all NDAs approved between 1938 to 1962 were

reviewed for effectiveness. FDA withdrew approvals of some
NDAs, of which many were generic drug copies. FDA concluded
that generic products would be considered ‘new drugs’ and would
have their own approved NDAs.

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 ………….contd
 In 1970 FDA instituted ANDA process for generic versions of
pre-1962 pioneer drugs, using evaluations of the Drug Efficacy
Study Implementation program. However, no process
suggested for post – 1962 drugs. Also till that time information
contained in IND and NDA was considered as confidential.
Hence a generic manufacturer could not use that data to justify
his application.

 In 1982 FDA allowed approval of post-1962 drugs under its

‘paper NDA’ policy. Data could be sourced from well controlled
studies published in literature. However data was not available
for many drugs.

 During this period it was not cost – effective to develop

generic versions of post-1962 drugs. From 1962 to 1984, only
about one in ten off-patent drugs were subject to competition
from generic drugs.
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 ………….contd

 1984 Drug Price Competition and Patent Term Restoration Act

(Hatch Waxman Act) proposed the ANDA procedure. Concept
of therapeutic equivalence introduced.

 US Congress also directed the patent office to restore patent

life for a pioneer drug up to 5 years in order to compensate for
time lost during FDA process.

 Bolar exemptions (Roche versus Bolar Pharmaceuticals Co.

Inc,) also introduced thus facilitating entry of generic drugs.
- Permitting use of patented invention for developmental work
& submission of information to FDA

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Abbreviated New Drug Application (ANDA)

ANDA contains data for the review and ultimate approval of a

generic drug product. Once approved, an applicant may
manufacture and market the generic drug product to provide a
safe, effective, low cost alternative.

A generic drug product is one that is comparable

to an innovator drug product in dosage form,
strength, route of administration, quality,
performance characteristics and intended use.

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Problems before Hatch-Waxman Act Enactment
How/Why?

Problem for both branded & Generic companies

• Innovator companies: long approval process, resulting in very

little patent life after approval

• Generic companies : approval were arduous & expensive

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 Hatch-Waxman Act
(Drug Price Competition & Patent Term Restoration Act of 1984)

• To balance

Innovation

Protection to Competition
research, restore
some of the patent Affordable prescription drugs
term lost during drug
development & Foster generic drugs
approval process
ANDA process & ability to
use patented technology
in seeking FDA approval

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 Hatch Waxman Act

For Innovator companies –

 Patent term extension
 Provides New drug product exclusivity
 30 months stay for ANDA approval

For Generic manufacturers

 Created “Abbreviated New drug Application” approval
process for generic versions of innovator drugs
 File ANDAs with bioequivalence data using innovator
product
 180 day exclusivity for first-to-file
 Certification regarding each patent listed in the Orange
Book for the product: four certification options

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Hatch Waxman Act - “Patent Term Restoration”

 Patent Term Extension

• To make up for the loss of time during drug approval process

• Application for patent extension must be filed within 60 days of FDA
approval of the drug product
• Regulatory review period determination

Testing Phase Approval Phase

NDA Approval
IND Submission NDA Submission

Length of the patent extension calculated:

½ (IND submission to IND approval) + (NDA submission to NDA approval)

• Maximum extension of 5 yrs

• Total marketing exclusivity of not more than 14 yrs
• Each patent can be extended only once
• Only one patent may be extended per pharmaceutical product
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 Hatch Waxman Exclusivity

 New Drug Product Exclusivity

 Exclusivity provides approved new drug product holder limited

protection from new competition in the marketplace for the
innovation

 This precludes approval of 505(b)(2) applications or abbreviated

new drug applications (ANDAs) for prescribed periods of time

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 Hatch Waxman Exclusivity

Time periods of New drug product Exclusivity

 5 years – for New Chemical Entity

• NCE exclusivity runs from time of NDA approval and bars FDA
from accepting or reviewing any ANDA or 505(b)(2) application
for a drug containing the same active moiety
• 5 yrs if ANDA or 505(b)(2) does not contain a paragraph IV
certification to a listed patent
• 4 yrs if ANDA is submitted containing a paragraph IV certification
to a listed patent

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 Hatch Waxman Exclusivity

 3 years – for new clinical investigation for previously approved

drugs

• New clinical study exclusivity runs from time of NDA approval

• The exclusivity bars FDA from approving, for a three year
period, any ANDA or 505(b)(2) application

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 Hatch Waxman Exclusivity

 7 years – for Orphan drugs

Orphan exclusivity granted to drugs designated and approved to

treat diseases or conditions affecting fewer than 200,000 in the
U.S.
• Runs from time of approval of NDA
• Orphan exclusivity bars FDA from approving any other
application (ANDA, 505(b)(2) or “full”NDA) for the same drug
for the same orphan disease
• FDA may approve applications for the “same” drug for
indications not protected by orphan exclusivity

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 Hatch Waxman Exclusivity

 6 months – for Pediatric exclusivity

• Pediatric exclusivity is the only exclusivity that runs from the end of
other exclusivity protection (New Drug Product and Orphan Drug) or
patent protection
• Grants an additional 6 months of market protection at the end of
listed patents and/or exclusivity for sponsor’s drug products,
when the sponsor has conducted and submitted pediatric studies on
the active moiety in response to a Written Request from FDA
• A six-month pediatric exclusivity that attaches after a patent term is
not a patent extension; it is a FDA-enforced exclusivity period that
begins at the termination of the patent.
• Patent exclusivity dose not stand alone it attaches only to existing
exclusivity or patent

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 ANDA Submission

 NDA vs ANDA Review Process

NDA requirements ANDA requirements
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal studies
7. Clinical studies 6. Bioequivalence
8. Bioavailability

 ANDA : Does not require safety & effectiveness testing

requires less time and expense for approval, a shorter regulatory review
– Generic product development time: 12-18months
– US FDA approval process: 18-30months
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– Investment: $US1-2million
 Contents of ANDA
ANDA includes:

1. Information to show conditions of use prescribed in the labeling

have previously been approved for a drug listed in OB
2. Active ingredient is same as the active in of listed drug
3. Route of administration and strength of the drug are same as the
listed drug
4. Show bioequivalence to the listed drug
5. Labeling is same as the listed drug
6. Complete list of components of the generic drug
7. Statement of composition of the generic drug
8. Description of the methods & controls used in facilities for
manufacturing, processing & packaging
9. Samples of the generic drug
10. Labeling specimen
11. A patent certification
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 Contents of ANDA

Chemistry
• Components and composition
• Manufacturing and controls
• Batch formulation and records
• Description of facilities
• Specs and tests
• Packaging
• Stability

Labeling
• “Same” as brand name labeling
• May delete portions of labeling protected by patent or exclusivity
• May differ in excipients and how supplied

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 Contents of ANDA
ANDA Stability and Batch Requirements
• 3 months of accelerated stability data must be submitted with the
application
• Available room temperature stability data should also be included
• An update on subsequent RT data will be requested during the review
process
• One demonstration batch must be manufactured
- Source of BE study product
- Source of stability data
- Complete batch record for this batch

• Bioequivalence Studies
To prove therapeutic equivalence
Pharmaceutical equivalence + Bioequivalence = Therapeutic equivalence

Statistical Analysis (Two One-sided Tests)

AUC and Cmax – 90% Confidence Intervals (CI) must fit between 80% -125%
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 ANDA REVIEW PROCESS

Acceptable & N Refuse to file –

Applicant ANDA letter issued to Applicant
complete

Bioequivalence review Request for plant

OGD/CDER inspection
Chemistry/microbiology
Review labeling
review

Chemistry/
BE review Y Y microbiology
acceptable? review
acceptable?
N N

Preapproval
BE Deficiency Letter inspection Not Approval Letter
acceptable? N
Approval deferred
Y pending satisfactory
results 19
ANDA Approval
 ANDA Patent certification options

Patent information
has not been filed
Paragraph I
FDA may approve ANDA immediately;
one or more Generics may enter
Patent has Expired
Paragraph II
Patent has NOT expired
but will expire on a
FDA may approve ANDA on the date
particular date
Paragraph III that the patent expires; one or more
generics may enter
Patent is invalid or
non-infringed by
Generic applicant
Generic applicant provides notice to patent
Paragraph IV holder & NDA filer; entry of the first filer
may or may not occur

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 Paragraph IV Certification

 Innovator holds an active patent listed in Orange book

 Generic company claims either the patent is invalid or remains

non infringed by his application

 First-to-file generic rewarded with 180-days market

exclusivity for a successful ANDA approval

 ANDA filer certifying under Paragraph IV must provide notice

to patent owners and NDA holder

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 Paragraph IV Certification

 Innovator drug company has 45 days to initiate a patent suit

 If a patent infringement suit is filed within 45 days, FDA approval

of the ANDA is automatically stayed until the earliest of:

(i) the date the patents expire,

(ii) the date a final determination of non-infringement is entered in the patent

infringement litigation, or

(iii) the expiration of 30-months from the patentee's receipt of notice of the
Paragraph IV certification

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 Medicare Modernization Act

 On December 8, 2003 President Bush signed into law, the

Medicare Modernization Act (Public Law No. 180-176)

 Implications of MMA
 30-month stay period The Act allows only one 30-month stay
period per product (applicable to patents submitted to FDA on or
after August 18, 2003)
 No effect of subsequent (or later) listings on the stay period

 180-day exclusivity
 Triggering
 Sharing
 Forfeiture
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 180-DAY Exclusivity: old provisions

For products for which the first Paragraph IV certification was filed
prior to December 8, 2003 and for which exclusivity had not been
triggered by this date:

 Exclusivity is awarded against a particular patent (patent-by-

patent exclusivity)

180-DAY Exclusivity: MMA provisions

For products for which the first Paragraph IV certification was

filed on or after December 8, 2003:

 Exclusivity is awarded with respect to a drug product

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 180-DAY Exclusivity: MMA provisions

 Exclusivity is product-dependent
Given to the first applicant to submit an ANDA with a Paragraph
IV certification to any listed patent
A later applicant who is the first to file a Paragraph IV certification
to a different or later-listed patent will not be eligible for exclusivity

 Two ways to qualify as the first-to-file applicant

(i) Be the first applicant to submit a substantially complete ANDA for a
drug product containing a Paragraph IV certification against any Orange
Book patent; or
(ii) Be the first applicant to amend its ANDA to contain a Paragraph IV
certification

 Exclusivity is triggered by the

- first commercial marketing of the drug, or
- the date of decision of court in holding the subject patent invalid or
not infringed, whichever is earlier 25
 180-DAY Exclusivity: Shared Exclusivity

The “First Applicant” to submit a substantially complete

ANDA with a Paragraph IV certification will be eligible to
receive 180 days of marketing exclusivity

The Act specifies that the submission is measured as of the

day (not the time of day) the ANDA is filed

This change may result in “Shared Exclusivity” in case of

multiple first applicant

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 180-DAY Exclusivity: MMA provisions

Exclusivity Forfeiture
 Failure to market
 Withdrawal of ANDA (either voluntarily or by FDA)
 Failure to obtain tentative approval within 30 months
 Agreement with another ANDA applicant, NDA holder or patent owner
 Expiration of all the patents

Failure to market by later of two possible dates:1st possible date - earlier of

two dates:
- 75 days after ANDA approval
- 30 months after ANDA submission

Failure to market by later of two possible dates: 2nd Possible date - 75 days
after:
- Final court decision
- Settlement/consent order
- Patent is withdrawn
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 ANDA – Suitability Petition

• Permission to submit an ANDA for a product that

differs from RLD in:
– Dosage form
– Route of administration
– Strength
– Active ingredients in Combination Drug

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Authorized generics:
• Branded & generic companies come to an agreement that gives
the generic rights to sell a generic version of the drug
• Avoid patent challenge in court
• Overall financial benefit to branded company as royalty
• Generics gain market share
• Authorized generics are allowed marketing during the 180-days
exclusivity period

Pseudo-Generics:
• Branded companies launch their own generic product and
challenge patents & beat other generics to market

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 Biogenerics

Biogenerics are reproductions of biotechnologically manufactured

biopharmaceuticals that partially mimic proteins naturally present
in the body

Biogenerics are not identical to original preparations or naturally

occurring substances in the body

The biogenerics industry uses terms such as "follow-on biologics"

and "similar biological medicinal products"

Compared to new chemical generic drugs that are often granted a

fast-track approval that waives the conducting of clinical tests,
biogenerics have to submit to extensive studies

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