INTRODUCTION TO GENERIC

DRUG DEVELOPMENT

BY NALINI MOHAN KOUTHA

GENERIC DRUG PRODUCT

Is essentially similar or bioequivalent to an

innovator (brand name) product.

Bioequivalence implies that a generic drug

product is essentially similar to the brand

name drug product in terms of active
ingredient (s), strength, dosage form, route of
administration, quality, safety, efficacy, etc.
Generic and Brand Drug?
A Brand drug is marketed under a specific trade name by a
pharmaceutical manufacturer.

In most cases, Brand drugs are still under patent protection,
meaning the manufacturer is the sole source for the product
but in many countries around the world this is not the case
and a generic alternative is readily available .

Generic drug is made with the same active ingredients in the

same dosage form as a brand name drug.
The generic drug is therapeutically equivalent to the brand
name drug but is sold under its chemical or "generic" name.
SELECTION OF A GENERIC DRUG PRODUCT

Sales and potential market Share

Patent expiration and exclusivity issues

Availability of Active Pharmaceutical Ingredient

Timing

Technology

Formulation

Experience
APPROACH TO GENERIC DRUG
Generic drugs product manufactures must
Formulate a drug product that will have same
therapeutic efficacy, safety and performance as its
brand name counterpart
To get marketing Approval, a Generic drug

 Cannot be superior or better than the Brand name

drug product
 The Key factor is it should be therapeutically
equivalent and bioequivalent to the brand name
drug product. (reference)
 PRIOR TO 1980
Generics were required to conduct same clinical tests of
safety and efficacy as the innovator.

Secondly, FDA would not approve a generic drug until the

patents covering the innovative drug expired

Hence, Generics had to wait until the patent term expired to

begin the generic drug development process

Resulted in the lag between end of patent life and

introduction of generic drug
LEGISLATIVE AND REGULATORY ISSUES
 US Food and Drug Administration was formed in 1906 by way of

Federal Food, Drug, and Cosmetic Act.

 In 1984, the Drug Price Competition and Patent Term Restoration Act

(Hatch-Waxman Act) was Promulgated.

 Main purpose was to speed up the entry of generic drugs onto the

market once all the originating company’s patents on that drug have
expired (or been successfully challenged in court)
 To make this happen Hatch-Waxman Act proposed to eliminate the

requirement of clinical and non-clinical studies to demonstrate safety

and efficacy.
GENERIC DRUG APPROVAL

 FDA’S office of Generic Drugs is responsible for

reviewing the ANDA and approve the drug for
Marketing
Generic Drug Application reviewers focus on
 Bio-Equivalence data
 Chemistry

 Manufacturing Quality
 Plant Inspections

 Drug labeling information

 BIO-EQUIVALENCE
One test of bioequivalence is to measure the time
it takes the active ingredient in the drug to reach
the bloodstream and its concentration in the
bloodstream in 24 to 36 healthy volunteers.
This shows the rate and extent of the generic
drug’s absorption.
These characteristics are then compared with
those of the original drug.
FDA APPROVAL FOR GENERIC DRUG
To obtain FDA approval, a generic Drug must contain
Same active ingredient(s).
Same route of administration.
Same dosage form.
Same strength.
Same conditions of use.
Comparable to reference listed drug (RLD) (Branded
Product).
Approved Drug Products with Therapeutic
Equivalence
The Orange Book, “is an FDA-published document
available in paper and electronic form that lists all
FDA-approved drugs with any patents pertaining
thereto.
The Orange Book contains approved drug products
with therapeutic equivalence as well as the expiration
dates of patents on therapeutic small molecules and on
approved indications and compositions.
ORANGE BOOK PATENTS …

The Applicant shall file with the application the patent number
and expiration date of any patent which claims the drug for
which the applicant submitted the application
Or
which claims a method of using such drug and with respect
to which a claim of patent infringement could reasonably be
asserted if a person not licensed by the owner engaged in the
manufacture use, or sale of the drug
ORANGE BOOK PATENTS …
Permitted OB Patents

Drug substance (Active Ingredient) of the NDA

Drug Product (Formulation and Composition)

Different Polymorphs

Method of use of the NDA

ORANGE BOOK PATENTS
Not Permitted

Process patents

Patents claiming packaging, metabolites or

intermediates
PATENTS

It is negative right conferred to exclude others from :

- making
- using or
- selling the invention for a limited period.
Patent is a territorial right
PATENT TYPES

Product patents

Process patents

Use/Second Indication Patents

DURATION OF PATENTS
For a stipulated period

Period differs in different countries

Renew/Maintain

Lapsed patent cannot be renewed

ENFORCEMENT OF PATENT RIGHTS
Rights determined by claims

Claims different in different countries

Can be enforced only in the country of Grant

What are the reasons that a patent
expires?
Non-Payment of annual fees
The Patent is revoked through opposition proceedings
It is declared invalid by a judge
A written renouncement by the Patent owner
LENGTH OF TERMS
Patents on articles of manufacturer
and processes: 20 years
PATENT Design patents: 14 years
(Also differs in different countries)
Individual registrant: life of the
author plus 70 years
COPYRIGHT Business registrant: for the shorter
of either 120 years from the date of
creation or 95 years from the date of
publication
Original registration 10 years
TRADEMARK Renewal registration: unlimited
number of renewals for 10-year
terms
TYPICAL DRUG PATENTS
Genus and species of molecules
Methods of Use
Racemates and Enantiomers
Impurities
Intermediates in making the API
Process patents for making API/Formulation
Pharmacokinetics
Combination of two active ingredients-formulation,
method of use, pharmacokinetics
WHY ARE GENERIC DRUGS CHEAPER
Investment costs are not involved

Generics Manufactures do not incur the cost of Drug discovery

Exclusive right to sell the drug while patent is in effect.

Reverse engineer known drug compounds to allow them to

manufacture bioequivalent versions

No need to prove safety and efficacy of the drugs through

clinical trials
US AND EU GENERIC MARKETS

Large in Volume, but not in price when compared with

originator products
Demand in generics are bound to grow substantially in the next

few years with rise in ageing population and many blockbuster

drugs loosing patent and market exclusivity protection.
Present estimates show that drugs going off patent over the

next three years is valued at US 80 billion ( 320,000 crores)

ROAD BLOCKS-FOR GENERIC ENTRY
Product patents
Process patents
Formulation patents
Use/Indication patents
Exclusivities
Chemical Purity patents
Polymorphic Form Patents
Particle size of API
PRODUCT PATENTS
Active Ingredient/Formulation

Salts

Polymorphs

Metabolites sometimes ????

GENERIC PLAYERS REQUIREMENT
Product/MOT Patent expiry/Invalidation

Non-infringing Processes

Non-Infringing Formulations

DMF filings

ANDA filings

FDA Approved facilities

DRUG MASTER FILE (DMF)
Confidential document covering a specific manufacturing

facility, process or article used in manufacturing processing,

packaging, or storing of bulk drug
DMF by FDA is reviewed only if ANDA or NDA

referencing that particular DMF is filed

An ANDA or NDA will not be approved until any issues

with the DMF are resolved

 DATA EXCLUSIVITY
Generic companies can launch their drug only five years after

original drug
Generics cannot use the original clinical data generated by the

patent holding company to gain market approvals for a period of 5

yrs
Clinical trials are extremely expensive and it is unlikely that any

generic manufacture could conduct his own clinical trials and still
sell the drug at an affordable price.
AUTHORIZED GENERICS
 Authorized Generics are prescription drugs produced by brand

pharmaceutical companies and marketed under a private label, at

generic prices.
 Authorized Generics compete with generic products in that they are

identical to their brand counterpart in both active and inactive

ingredients
 Authorized Generics compete with generics on price, quality and

availability in the generic marketplace, and are marketed to consumers

during and after what is commonly known as “the 180-day exclusivity
period”.
BARRIERS TO ENTER REGULATED
MARKETS
Cost of doing business in the US and EU are higher because

modes of pharmaceutical distribution In these developed

countries are different from others
Local partner is needed to ease market entry

Good local firm that understands the rules of culture are

critical to successful launch.

GENERIC OPPORTUNITIES-USA

Governed by Patent Term Restoration act or Hatch-

Waxman Act
Enacted in 1984

Creation of ANDA (Eliminated clinical trials)

Bolar Provisions

Marketing Exclusivities
HATCH WAXMAN ACT
Established for the first time an Abbreviated New

Drug Application (ANDA) approval process

specifically for generic manufacturers.
Provided for Pre-patent expiration testing (Bolar

Provision) and Generic drug exclusivity

Facilitated faster introduction of Generics drugs
ABBREVIATED NEW DRUG APPLICATION
(ANDA)
 An Abbreviated New Drug Application (ANDA) contains data that, when
submitted to FDA's Center for Drug Evaluation and Research, Office of Generic
Drugs, provides for the review and ultimate approval of a generic drug product.

 Generic drug applications are called "abbreviated" because they are generally not
required to include preclinical (animal) and clinical (human) data to establish
safety and effectiveness.  Instead, a generic applicant must scientifically
demonstrate that its product is bioequivalent (i.e., performs in the same manner
as the innovator drug).

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

A company desiring to market a generic copy of an Orange

Book listed drugs has to file

An Abbreviated New Drug Application

Must indicate in its ANDA the following
certifications against each Orange Book patents
 Generics – US Market

ANDA – Regulatory Options

Para I Para II Para III Para IV

No Patent Info. Patent invalid or

non-infringement claim
Patent Expired

Patent not Expired but 45 days

product launch after expiry

No Infringement Suit Patentee sues

Generic gets approved 30 month stay

TYPES OF PATENT CERTIFICATIONS
Paragraph-I Such Patent information has not been filed

Paragraph II-Patents have expired

Paragraph III-Marketing after all the patents have expired

Paragraph IV Certification-Patents non-infringed or invalid

or unenforceable
EXCLUSIVITY
Why have Exclusivities

As an incentive to spur development and invention in

the pharmaceutical industry

Cause generics to challenge patents to expedite entry

of generics to consumers
TYPES OF EXCLUSIVITY
NCE exclusivity-5 years
Orphan Drug Exclusivity- 7 years

Study new uses for currently marketed drugs (3 years)

Pediatric Exclusivity- 6 months
Develop new dosage forms and combinations (3 years)
180 day generic Drug Exclusivity
CONSEQUENCES OF PARAGRAPH-IV
CERTIFICATION
Notification to the patent owner and the NDA holder
Litigation within 45 days of the receipt of notice
FDA may not give final approval to the ANDA for at least
30 months from the date of notice (Tentative approval)
The purpose of the stay is to allow the parties to litigate the
patent infringement claims while the ANDA filer pursues
FDA approval of its generic drug
TRIGGERING EVENTS FOR PARA IV
180 Exclusivity begins from the date of commercial

marketing of the generic drug product

or
From the date of court decision finding that the patent is

invalid, unenforceable or not infringed, whichever is first

ROLE OF IP DEPARTMENT
 New Product identification in Co-ordination with Business
Development group
 Patent Evaluation Reports

 Infringement Study/Clearance of process/Formulation

 Opinions from Attorney

 Patent Certifications

 Patent Drafting and Filings

WHAT DO WE NEED

Focused territories
For infringement study
For Filing Patent applications
DATABASES-IP DEPARTMENT

Sci finder Scholar

Micropat/Derwent (Online Patent searching directory)

IMS life cycles (Product Expiry details)

Dialog (Offers Scientific, technical, and IP information)

STN

CA on CD.