1. 1

2. Date:-12-11-2013
Presented by:
Swapnil N. Dharmshale
M.Pharm-1st (Q.A).
D.S.T.S Mandal’s College of Pharmacy, Solapur.
2

3. Content
Introduction
New drug
Overview of global Pharma. Industry
Global generic market
Indian relevance to global generic industry
FDA requirements for generic drugs
Hatch-Waxman Act
Orange book
USFDA approval process
Conclusion
3

4. Introduction
New drug : Generic name /Brand name
A generic drug is exactly the same molecule as branded drug.
Generic drug cost effective Alternative to branded drug.
Drug Approval:
Investigational New Drug (IND)
New Drug Application (NDA): New chemical entities
Abbreviated New Drug Application (ANDA): Generic Drug
4

5. Overview of the world
Pharmaceutical Industry
The data as per the year 2007 - the generic industry is growing at a rate
faster than the overall pharmaceutical industry
Reasons –
Economic changes
Changing consumer demands for low prices high quality drugs
Changing societal values
Significant health-care demands
Changing composition of workforces
The major contribution being the increase in competition amongst
the generic and the brand name industry which has come due to the
change in the USFDA approval process from a slow time
consuming to a comparatively faster process
5

6. GLOBAL GENERIC MARKETS
The global pharmaceuticals industry generated total revenues of $615.1 billion
in 2008.
The global market for generic drugs was worth $84 billion in 2009.
In 2014, the market is expected to amount to $129.3 billion, for a compound
annual growth rate (CAGR) of 9% in the 5-year period.
Sales of U.S. generic drugs currently dominate the market, at $34 billion in
2009 and projected to increase at a CAGR of 9.7% to $54 billion in 2014.
Japan‟s generic drugs market is expected to have the highest rate of growth
among major markets at 12.2%, increasing from $5.4 billion in 2009 to $9.6
billion in 2014.
Major Pharma company share will decrease due number of patent expiries and
intensifying competition from generics.
6

7. GLOBAL GENERIC MARKETS
Parameters
Size ($bn)
Global pharmaceutical
Generic share
industry
643
55
Growth rate
7%
11%
Key players
Expected growth
US ($245 bn)
Japan ($60 bn)
Germany ($27 bn)
France ($24 bn)
UK ($15 bn)
5-7%
US ($28 bn)
Japan ($5 bn)
Germany ($6 bn)
UK ($3.4 bn)
France ($2 bn)
13-15%
Projected size
(by 2010)
$812 bn at 6% growth
rate
$93 bn at 14%
growth rate
7

8. WHY GENERICS: A $90B GLOBAL
OPPORTUNITY
Western Europe
$17bn
US, Canada: $50bn
Eastern Europe &
Russia: $10bn
China: $3bn
Japan: $4bn
Rest of World: $4bn
Latin America: $2bn
Total World Pharmaceutical Sales: $600bn
8

9. BRAND V/S GENERIC PRICES
Drugs
Brand Price
$/30
Generic
price $/30
Lisinopril (Zestril® ) 20 mg
46.69
20.69
Citalopram (Celexa® ) 20 mg
100.99
52.99
Ciprofloxacin (Cipro®) 500 mg
215.99
88.59
Merformin (Glucophage®)
1000mg
71.59
30.69
Fluconazloe (Diflucan®) 200mg
609.99
372.99
Fluoxetine(Prozac®) 20mg
139.99
32.29
9

10. TOP 14 DRUG GOING OFF PATENT IN 4 YEARS
Drug
Therapeutic
Area
Company
Expiry
Year
Global Sales
(2008 billion $)
Lipitor (Atrovastin Calcium)
CVS
Pfizer
2011
13.5
Plavix ( clopidogrel bisulfate)
CVS
Sanofi Aventis BMS
2011
9.4
Advair ( Fluticasone Propionate
& Salmetraol)
Respiratory
GSK
2010
7.8
Diovan (Valsartan)
CVS
Novarties
2012
5.8
Zyprexa (Olanzapine)
CNS
Ell lily
2011
4.7
Singular (Montelukast)
Respiratory
Merck
2012
4.6
Seroquel(Quetiapine fumarate)
CNS
Astrazeneca
2011
4.6
Lovenox (Enoxaporin sodium)
CVS
Sanofi Aventis
2012
4.0
Actos (Pioglitazone)
Antidiabetic
Takeda
2011
3.9
Prevacid ( Lansoprazole)
GIT
Takeda
2010
3.7
Cozaar ( Losartan Potassium)
CVS
Merck
2010
3.6
Aricept (Donepezil)
CNS
Pfizer
2010
3.6
Lexapro (Escitalopram)
CNS
Forest Lab
2011
3.4
Eloxatin (Oxalipaltin)
Oncology
Sanofi Aventis
2013
3.0
10

11. Indian Relevance to global generics industry
Major Indian Players:
Ranbaxy : Amongst Top 10 global players
Dr Reddys
Cipla
Wochardt
Sun Pharmaceuticals
Glenmark
Lupin
Nicholas Piramal
Torrent
Matrix Laboratories
11

12. INDIAN GENERICS APPROVED BY FDA
120
100
80
Tentative
Final
60
40
20
0
1997
1998 1999
2000 2001
2002 2003
2004 2005
2006
12

13. GENERIC DRUG
Brand Name Drug - The brand name drug is the name under which a new
innovator medication is developed and marketed. When a pharmaceutical
company develops a new medication, they obtain patent for it.
Generic Drug – Generic drugs are considered identical, or bioequivalent to
the brand-name originals.
They contain the same active substances and have the same quality, efficacy
and safety.
Definition:
•GENERIC DRUG
IS A PHARMACEUTICAL PREPARATION THAT IS
ESSENTIALLY SIMILAR TO AN ORIGINAL PRODUCT, INVOLVING AN
ACTIVE INGREDIENT THAT IS NO LONGER PROTECTED BY A PATENT*
AND IS SOLD UNDER A COMMON NAME WITH LITTLE OR NO
PROMOTION.
* THOUGH THE FORMULATION MAY OR MAY NOT BE PATENTED
13

14. FDA REQUIREMENTS FOR GENERIC DRUG
Contain the same active ingredients (Pharmaceutical equivalent)
Be identical in strength, dosage form, and route of administration
Have the same indications
Phases
Of
validation
Meet the same batch requirements for identity, strength, purity, and
quality
Be bioequivalent
Be manufactured under the same strict standards of FDA's good
manufacturing practice regulations required for reference Listed drug
(RLD)-brand name Product listed in “Orange book”
(www.fda.gov/cder/ob).
14

15. DEFINITIONS
Pharmaceutical Equivalence
Same active drug ingredient ,same strength, same dosage form and
route of administration, comparable labeling, meets compendial or
applicable standard of strength.
Bioavailability
The rate and extent to which the active moiety is absorbed from a drug
Product and become available at site of action.
Bioequivalence
Two pharmaceutical equivalent drug product are bioequivalent if after drug
administration, the bioavailabilities (rate and extent of drug availability)
provide similar effect with respect to efficacy and safety.
Therapeutic Equivalence
Therapeutic equivalence means that a chemical equivalent of a
drug product (i.e., containing the same amount of the same drug in the same
dosage form) when administered to the same individuals in the same dosage
regimen will provide essentially the same
efficacy and toxicity.
15

16. ACT GOVERNING DRUG APPROVAL
The act governing generic drug approval process of the
USFDA
“Hatch-Waxman Act of 1984”
or
“Drug Price Control and Patent Term Restoration Act of
1984”.
16

17. Earlier Scenario (before “Hatch-Waxman Act of 1984” )
Market was ruled by brand name drug manufacturers – innovators
Lack of competition
Innovator enjoyed his elite monopoly period within which no other brand
of the same drug can enter into the market
Highest prices of the drugs
To stop these practices and to make user friendly drug market, the US
congress passed the Hatch Waxman Act in 1984
17

18. Birth of Generics: The Hatch-Waxman Act
The Drug Price Competition and Patent Term Restoration Act of 1984,
signed into Law on September 24, 1984
Hatch-Waxman was designed to speed entry of generic drugs to compete
with patented pharmaceuticals
The results of the act seek to balance the interests of the branded
manufacturers with those of generics
18

19. Objectives of the act
Offset the drug approval delay:
Earlier innovators used to encounter delay in approval of their NDA which
affected their brand entry in the market and hence financial loses!!!!!
Types to
Bring healthy competition andof avoid price rise:
Process
Earlier no scope for generics to enter the market until innovator patent
validation
term expired as no provisions to challenge the validity of innovator patent.
This product monopoly kept competion away and drug prices high as per
innovator will!!!!!!
Make life easier for the generic:
Generic manufacturers used to face a lot of difficulties in doing all the preclinical and clinical studies as done by brand manufacturer to get generic
approved!!!!!
19

20. Benefits received by the brand name manufacturers
Regulatory delays in brand approval were deciphered
The market exclusivity and the „effective patent life‟ was
extended from 8.5years (1980) to 13 years (late 1980s) and
now it‟s nearly 16-17years
20

21. Benefits received by the generic manufacturers
The generic could challenge the validity of the patent issued to the
innovator
The act provided with the stipulation to file an ANDA to leave out the
expensive pre-clinical and clinical trials as done by the innovator
Provided with the provision of relying on the safety and efficacy data of the
innovator drug and to perform a much cheaper „bioequivalence‟ to
establish equivalence with the innovator
Once approved the generic gets an exclusivity period of six months to
market the product along with the innovator during which no other generic
can be given approval
21

22. The Orange Book
The FDA publishes a list of all drugs approved for marketing in the US
under the title “Approved Drug Products with Therapeutic Equivalence
Evaluations” - “Orange Book”
Lists the NDA‟s and ANDA‟s along with the expiry dates of patents and
generic exclusivities
Ready reference of brand drug products for the generic companies who
usually use this information to identify the reference for developing their
generic version
Also contains therapeutic equivalence codes (two letter coding system e.g.
AB)
A- prefixing product is considered to be substitutable
B- prefixing is a safe and effective product for use but is regarded in22
equivalent and non-substitutable with the brand name drug product

23. ANDA certifications
Para I – there is no patent for the drug listed in the Orange
Book
Para II – patent is listed but has expired
Para III – patent is listed, is valid but the generic wants
approval to market the drug once the pertinent patent expires
Para IV – the generic manufacturer either challenges the
validity of the patent asserting it to be invalid or fake, or it
affirms the non-infringement of the brand name patent claims.
Most critical and gives rise to anti- competitive practices
23

24. USFDA approval requirements:
Brand name (NDA) vs Generic (ANDA)
The generic must have –
Same active ingredient,
Same route of administration,
Same dosage form,
Same strength,
Same condition of use
24

25. NDA vs ANDA Review Process
25

26. USFDA Approval Process (Para IV certification)
The ANDA applicant must provide appropriate notice of a paragraph IV
certification to each owner of the patent that is the subject of the
certification and to the holder of the approved NDA to which the ANDA
refers
The ANDA applicant may certify with a legal ground that a listed patent is
invalid or will not be infringed by the manufacture, use, or sale of the
generic product.
This gives an immediate right to innovator to file a patent infringement
lawsuit against the generic manufacturer
The innovator can file this lawsuit within 45 days of the ANDA filing
notice from the generic
This sets in a process which detains the FDA from giving approval to the
generic for a period of 30 months
FDA is free to grant approval after 30 months which depends upon the
result of the pending litigation
26

27. The six month generic exclusivity
An incentive to the „first approved generic‟ after filing a Para
IV certification
This incentive gives the first generic an exclusivity period of
180 days to market and earn profits
During this period, the brand name drug is the only
competition and FDA can not approve any other generic until
this exclusivity period perishes
The 180 day cycle begins on the day the generic comes into
the market for the first time or the day of courts decision in
favor of the generic
27

28. Loopholes in Hatch-Waxman Act
 Warehousing patents and frivolous lawsuits
Also referred to as “Evergreening” of patents
Innovator may patent multiple attributes of a product like manufacturing
process or metabolite and keeps on adding patents in the Orange
Book, forcing the generic to wait for the patent to expire or file para IV
which brings along risk of litigation and associated cost and delays!!!
28

29. CASE STUDY
Case Study – Buspar Case : BMS v Mylan Pharmaceuticals
BMS had US Patent 4,182,763 (Expiry – July 21, 2000)
Claims cover buspirone as an anxiolytic agent
Mylan filed para III against this patent and obtained tentative approval to
market the drug not before July 22, 2000
BMS obtained another patent just 12 hours before the expiry of first patent
covering the active metabolite of the buspirone having anxiolytic activity
and listed it in the OB
Mylan filed para IV against this newly listed patent
BMS responded by filing infringement lawsuit immediately halting the
final market approval
This gives the brand name manufacturer at least an additional two and a
half years of product monopoly
29

30. Maneuvering the six month Generic Exclusivity
Commonly referred to as “Sweetheart deals”
Allows the first generic manufacturer and the innovator to enter into an
agreement and to have control when to introduce the generic
This would not trigger the 180days generic exclusivity period offered to the
first generic
The FDA is bound not to approve another generic until the 180 day generic
exclusivity period perishes
This allows the innovator and first generic to share financial awards
keeping other generic competitors in an indeterminate state
30

31. CASE STUDY
1) Diltiazem hydrochloride (Cardizem CD by Hoechst-Marion Roussel,
Inc. (“HMRI”))
Used to treat angina and hypertension
Andrx Pharmaceuticals Inc. was first ANDA filer with para IV for Cardizem CD;
HMRI filed suit against Andrx
In September 1997, FDA tentatively approved Andrx‟s generic product
Andrx would have been expected to be able to enter the market upon the expiration
of 30 month stay in July 1998
However, Andrx and HMRI settled the litigation
In settling the litigation, both the parties agreed that, beginning upon the final FDA
approval of Andrx‟s generic product, HMRI would pay Andrx $10 million per
quarter not to enter the market with its generic product until the conclusion of the
31
patent litigation

32. CASE STUDY
2) Terazosin hydrochloride (Hytrin by Abbott)
Used for the treatment of high blood pressure and enlarged prostate
Litigation involves agreement between Abbott and Geneva Pharmaceuticals
Inc. and also between Abbott and Zenith Goldline Pharmaceuticals Inc.
Agreement between Abbott and Geneva was an “interim” settlement that
did not finally resolve the patent issues
Geneva agreed to accept $4.5 million per month from Abbott to refrain
from marketing generic product of Hytrin until another generic maker sold
a generic version in the USA or Geneva received a final, unappealable
judgement that its proposed generic tablet did not infringe Abbott‟s patents
Also, as part of the agreement, Geneva and Abbott allegedly agreed to
32
continue the patent infringement litigation on Geneva‟s generic tablet

33. FDA Generic Approval Criteria: Establishing In Vitro Equivalence
and Bioequivalence with the Reference Listed Product (RLP)
 Generic manufacturer must establish equivalence with the RLP
developed by the innovator
 FDA has established two basic criteria for the generic to be
equivalent with the innovator –
• In vitro equivalence criteria
• In vivo bioequivalence
33

34. In vitro equivalence criteria


Comparison of the dissolution profile of generic drug and brand name drug
by similarity factor of f2
f2 = 50 * log ( 1 + (1/n) summation (Rt –Tt) 2 ) 0.5 * 100
Comparison is done especially to assure similarity in product performance

Regulatory interest is knowing how similar the two curves are and to have
a measure which is more sensitive to large differences at any particular
time point

When the two profiles are identical, f2 = 100

FDA has set a public standard of f2 value between 50-100 to indicate
similarity between dissolution profiles
34

35.  Single dose; two-way crossover fasted or fed state studies - This means all the
test subjects receive both the generic and the brand name product, done in a crossover manner and products are given once to each subject on different occasions and
the pharmacokinetic data are compared between the two treatments between each
subject
 This study gives an idea of the inter-subject variability
 Replicate design – This design gives the same product to each subject more than
once.
 The overall number of subjects is reduced but the number of times each subject has
to come increases
 Two most common parameters which are studied and compared are Cmax and the
AUC related to rate and extent of drug absorption in the blood respectively
 These parameters are accessed using the 90% confidence intervals that must fit
between 80-125%
35

36. 
The dissolution measurements of the two products (test and reference)
should be made under the same test conditions

Dissolution time points should be same for both the products

f2 value of 50 or greater (50-100) ensures sameness or equivalence of the
two curves, and, thus, the performance of the two products

f2 value less than 50 does not necessarily mean lack of similarity
36

37. In vivo equivalence
 Generic manufacturer has to conduct bioequivalence study in place of preclinical and clinical studies to establish equality with the innovator
 Purpose of bioequivalence is to have a generic drug product which is
substitutable for a reference product „without any additional prescriber
intervention‟
 There should not be any change in the efficacy and no additional incidents
of side effects
 The usual study designs are single dose; two-way crossover fasted or fed
state studies and replicate designs
37

38. Biowaivers
FDA allows the generic manufacturers to not have to study every
single strength of a product and requires some in vitro tests for the
same
e.g. the testing on the low strength version of an already
bioequivalence established product. As lower strengths are
proportional to their matching higher strengths; FDA only requires
some in vitro testing
Other types of products which may be granted biowaiver include –
Parenteral solutions
Inhalational anaesthetics
topical solution
Oral solutions
38

39. CONCLUSIONS
US congress passed the Hatch Waxman
Act in 1984 for the benefit
of consumers in an attempt to stop
dominance and monopoly of the
innovator and to encourage the use of
cheaper and equally effective
drugs.ie. GENERICS
39

40. 40

41. 41