3.0 Analysis of India’s Bulk Drug Registrations...

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CHAPTER 3

3.0 Analysis of India’s Bulk Drug Registrations &Formulation Approvals with U.S.FDA

3.1 ANALYSIS OF INDIA’S STATUS IN BULK DRUG

REGISTRATIONS

The DMF Database provided by Center for Drug Evaluation and

Research (CDER) of U.S.FDA was retrieved and Type II DMFs which are

active as on 24 October 2011 have been analyzed to study India’s status in

bulk drug registrations. The analysis has been carried out for type II active

DMFs for its number, molecules and therapeutic categories.

3.1.1 Number of Type II Active DMF Registrations

From the analysis of the data available in CDER as on 24 October

2011, it is observed that a total of 7,652 Drug Master Files (DMFs) filed

starting since 1956 are still active (or being renewed periodically) with it.

These DMFs have been filed for approximately 2,276 drug substances

(APIs), Intermediates, materials used in them or for drug products of

innovator formulations and were filed by 1,857 companies from 53

countries. The complete details of the number of holder companies

belonging to different countries along with the number of type II active DMF

filings with U.S.FDA as on 24 October 2011 is provided in Table 3.1.

Table 3.1: Total Number of Type II Active DMFs filed with U.S.FDA ason 24 Oct 2011

133

Data Source: U.S.FDA DMF Database

Confidential

India is the leader in terms of number of filings and number of

companies filing on Indian facilities. The number of type II active DMFs

filed along with number of holder companies for top 10 countries are

depicted in Figure 3.1. The top 10 countries accounted for 84.54% of all

DMFs filed with U.S.FDA. India is the holder of largest number of DMFs

with 2667 followed by United States (1183) and China (720). It is second to

USA in number of molecules. As on 24 October 2011, the country has 2667

DMFs (34.85%) for 632 (27.77%) molecules filed by 340 companies

(18.39%).

Figure 3.1: Total Number of Type II Active DMFs filed with U.S.FDAalong with number of holder companies for top 10 countries (as on 24

Oct 2011).

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Data Source: U.S.FDA DMF Database

3.1.2 Yearly growth rate in Type II Active DMF Filings

Analysis of year wise type II DMF filings with U.S.FDA has been

carried out on the data provided in U.S.FDA DMF Database. It is observed

that the first DMF was filed from India in the year 1972 and is currently

owned by Dr. Reddy’s Laboratories. Another DMF is filed by the same

company after six years in 1978. A year later third DMF is filed by Franco

Indian Pharmaceutical Company. However, filings began in earnest only

since 1986 and the country has not looked back since then.

India experienced a rapid growth in number of DMFs during the last

10 years, especially so between the past six years from 2004 to 2010.

There are only 104 active DMFs that were filed from India during a span of

28 years prior to the year 2000. Since that year, the number increased

exponentially from 33 active DMFs in 2000 to 351 in 2010. Nearly, 84.36%

of all the current active DMFs have been filed during the last 10 years with

more than two third of them during the last 6 years alone (Table 3.2).

Table 3.2: Year wise Cumulative Number of DMFs filings of India withU.S.FDA from 1972 to 2010

(Data Source: U.S.FDA DMF Database)

Year

No. of DMF filings

from India

Cumulative

No. of DMFs

of India

1972 1 1

135

1973 - 1

1974 - 1

1975 - 1

1976 - 1

1977 - 1

1978 1 2

1979 1 3

1980 - 3

1981 - 3

1982 - 3

1983 - 3

1984 - 3

1985 - 3

1986 3 6

1987 3 9

1988 4 13

1989 5 18

1990 1 19

1991 5 24

1992 2 26

1993 7 33

1994 1 34

136

1995 4 38

1996 6 44

1997 17 61

1998 20 81

1999 23 104

2000 33 137

2001 43 180

2002 59 239

2003 103 342

2004 164 506

2005 247 753

2006 277 1030

2007 309 1339

2008 350 1689

2009 347 2036

2010 351 2387

Year wise comparison of type II active DMF filings of India with 5

other top filers (USA, Italy, China, Japan and ROW) was made from the

data retrieved from DMF Database and tabulated in Table 3.3. The same

comparison has been presented in Figure 3.2. India is the top filer during

2004 to 24 October 2011.

Table 3.3: Yearly number of Type II active DMFs filed by top Countrieswith U.S.FDA as on 24 Oct 2011

137

Data Source: U.S.FDA DMF Database

Confidential

Figure 3.2: Yearly number of Type II active DMFs filed by topCountries with U.S.FDA as on 24 Oct 2011

Data Source: U.S.FDA DMF Database

3.1.3 Company and Country Competition

Country wise analysis of Type II active DMFs filed with U.S.FDA for

the data available on 24 October 2011 has been carried out to study

company and country-wise competition. It is observed that over 18% of the

companies having DMFs with U.S.FDA are on Indian facilities. Eight of the

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top 10 companies that filed DMFs, are from India. Among Indian

companies, Aurobindo ranks first followed by Matrix and Dr.Reddy’s. The

list of top 10 companies having type II active DMFs with U.S.FDA as on 24

October 2011 is tabulated in Table 3.4.

Table 3.4: Top companies having Type II Active DMFs with U.S.FDAData Source: U.S.FDA DMF Database;

Rank Company CountryNo. of Type - II

Active DMFs

%

Share

1 Teva Group Israel 200 2.61

2 Aurobindo Pharma Ltd India 147 1.92

3 Matrix Laboratories Limited India 157 2.05

4 Dr Reddys Laboratories Ltd India 136 1.78

5 Cadila Pharmaceuticals Ltd India 131 1.71

6 Cipla Ltd India 123 1.61

7 Lupin Ltd India 108 1.41

8 Ranbaxy Lab Ltd India 100 1.31

9Sun Pharmaceutical

Industries LtdIndia 98 1.28

10 Mallinckrodt Chemical Inc USA 75 0.98

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3.1.4 Molecules wise DMFs filings

Further analysis of molecules for which DMFs were filed as on 24

October 2011 using the DMF Database provided by U.S.FDA is carried out.

The analysis reveals that out of total 632 molecules filed by India, there are

four or more DMFs in 193 molecules (30.54%). For example for

Atorvastatin, out of the total 37 DMFs filed with U.S.FDA by all countries,

India alone accounts for 26 DMFs. The list of molecules having 15 or more

than 15 type II active DMFs as on 24 October 2011 is provided in Table

3.5.

Table 3.5: List of molecules having 15 or more than 15 type II activeDMFs active from India

Data Source: U.S.FDA DMF Database

Sl.No. Subject No.of DMFs

1 Citalopram hydrobromide 15

2 Esomeprazole magnesium 15

3 Lansoprazole 15

4 Montelukast sodium 15

5 Olanzapine 15

6 Ondansetron 15

7 Rabeprazole sodium 15

8 Rivastigmine 15

9 Rizatriptan Benzoate 15

10 Zolpidem tartrate 15

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11 Carvedilol 16

12 Efavirenz 16

13 Lamivudine 16

14 Lamotrigine 16

15 Levetiricetam 16

16 Sertraline hydrochloride 16

17 Sumatriptan 16

18 Valsartan 16

19 Duloxetine hydrochlororide 17

20 Escitalopram oxalate 17

21 Amlodipine bisulfate 18

22 Aripiprazole 18

23 Donepezil hCl 18

24 Omeprazole 18

25 Irbesartan 19

26 Metoprolol succinate 19

27 Pioglitazone hydrochloride 19

28 Telmisartan 19

29 Losartan potassium 21

30 Pantoprazole sodium 21

31 Cefuroxime axetil 23

32 Venlafaxine hydrochloride 24

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33 Quetiapine fumarate 25

34 Clopidogrel bisulfate 26

35 Risedronate sodium 26

36 Atorvastatin 26

Similarly, over 80% of the DMFs in several top molecules such as

Clopidogrel, Lamivudine, Sertraline, Ramipril, Sildenafil, Zidovudine,

Fluvastatin, Tadalafil, Citalopram, etc., are filed from Indian facilities. This

implies that the country is vying for top molecules. For 137 molecules like

Esomeprazole, Escitalopram, Celecoxib, Lopinavir, Naratriptan, Salmeterol,

Tenofovir, etc., only India has filed DMFs.

3.1.5 Therapeutic Category wise DMF filings

An examination of therapeutic categories of molecules for their number

of DMFs reveals that India is strong in Anti-hypertensive, Anti-HIV, Anti-

diabetic, GI Tract, Anti-virals, Anti-infectives, etc. However, the country is

absent mostly in fermentation products, controlled substances and

steroids. For example, India does not have any DMFs for several important

fermentation products such as Penicillin G, Clavulanate, Fludarabine,

Heparin, Acarbose, etc., controlled substances like Morphine, Fentanyl,

Amphetamine, Propoxyphene, Codeine, Dronabinol, Hydromorphone, etc.

and corticosteroids like Cortisone, Hydrocortisone, Fludrocortisone,

Predinisone, Methyl prednisolone.

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3.3 Analysis of India’s Status in Formulations Approvals with

U.S.FDA

The list of all pharmaceutical products approved till 28 December

2010 by U.S.FDA were identified from Drug@fda, Electronic Orange Book

and National Drug Code Directory (NDC Database) by studying approval

history, letters, reviews and other related documents. A comprehensive

analysis is then carried out on this data to study India’s strengths in

product approvals. Product Approvals were studied for New drugs (NDA –

New Drug Application), Biological (BLA – Biological Licensing Application),

Generics (ANDA – Abbreviated New Drug Application) and New molecules

(NME – New Molecular Entity). Using the data, analysis has been carried

out for all types of above said product registrations in various categories

such as prescription, OTC, discontinued and tentative approvals.

3.2.1 NUMBER OF PRODUCT APPROVALS OF U.S.FDA

From the analysis of product approvals granted by CDER as on 28

December 2010, it is observed that, of the total 26,232 product approvals

granted, 43% (11,327) were discontinued and only 57% (14,905) are still

active (Table 3.6 & Figure 3.3). Out of these total, active pharmaceutical

product approvals (14,905), 91% (13,555) are prescription products while

4% (531) are OTC products and the remaining are tentative approvals

(Figure 3.4, Table 3.6).

143

Figure 3.3% Share of Product Approvals

with U.S.FDA

Figure. 3.4% Share of Active ANDAs

with U.S.FDA (As on 28 Dec 2010)Data Source: Orange Book

Table 3.6………(3 pages)

Confidential

There are 1,255 prescription products and 11 OTC products which areolder than 29 years (approved prior to 1982) still being marketed in USA(Table 3.7).

Table 3.7: Number of Product Approvals granted by U.S.FDA prior to1982

Data Source: Electronic Orange Book, NDC Directory, Drugs@FDA

S.No.Country

Product

Approval Prescription Discontinued OTC Tentative

Grand

Total

144

1 USA

BLA 1 ₋ ₋ ₋ 1Generic 316 1946 ₋ ₋ 2262

NDA 393 888 10 ₋ 1291NME 203 374 ₋ ₋ 577

2 IndiaGeneric 1 3 ₋ ₋ 4

NDA 2 1 ₋ ₋ 33 Israel

Generic 34 195 ₋ ₋ 225NDA 5 12 ₋ ₋ 93NME 2 11 ₋ ₋ 13

4 Switzerland

Generic 55 151 ₋ ₋ 206NDA 33 96 ₋ ₋ 129NME 14 83 ₋ ₋ 97

5 Canada

Generic 2 9 ₋ ₋ 11NDA ₋ 3 ₋ ₋ 3NME 5 ₋ ₋ ₋ 5

6 UK

Generic 2 86 ₋ ₋ 88NDA 9 113 ₋ ₋ 122NME 16 62 ₋ ₋ 78

7 Germany

Generic 1 29 ₋ ₋ 30NDA 41 77 1 ₋ 119NME 2 11 ₋ ₋ 13

8 Japan Generic 2 12 ₋ ₋ 14

145

NDA 9 5 ₋ ₋ 14NME 3 7 ₋ ₋ 10

9 Iceland

Generic 9 3 ₋ ₋ 12NDA 1 ₋ ₋ ₋ 1NME ₋ ₋ ₋ ₋ ₋

10 Ireland

Generic 1 4 ₋ ₋ 5NDA 17 31 ₋ ₋ 48NME 2 5 ₋ ₋ 7

11 France

Generic 4 22 ₋ ₋ 26NDA 12 34 ₋ ₋ 46NME 12 42 ₋ ₋ 54

12 Belgium

Generic 5 59 ₋ ₋ 64NDA ₋ 13 ₋ ₋ 13NME 5 3 ₋ ₋ 8

13 Italy

Generic 3 2 ₋ ₋ 5NDA 8 32 ₋ ₋ 40NME 2 5 ₋ ₋ 7

14 Denmark

Generic 1 8 ₋ ₋ 9NDA 3 20 ₋ ₋ 23NME 7 8 ₋ ₋ 15

15 Sweden Generic 3 ₋ ₋ ₋ 3

146

NDA 3 2 ₋ ₋ 5NME 2 1 ₋ ₋ 3

16 Puerto Rico Generic 4 7 ₋ ₋ 1117 Australia Generic - 2 ₋ ₋ 218 Greece Generic - 6 ₋ ₋ 619 Singapore Generic - 2 ₋ ₋ 2

20

Website

not

Available

Generic ₋ 250 ₋ ₋ 250NDA ₋ 97 ₋ ₋ 97NME ₋ 12 ₋ ₋ 12

21 Poland Generic ₋ 1 ₋ ₋ 122 Armenia Generic ₋ 1 ₋ ₋ 1

Grand Total 1255 4846 11 0 6184

Since 1982, the number of yearly approvals granted which averaged

212 per year increased to nearly 884 per year (five year average for the year

between 2006-2010). This shows the rapidity of increasing competition

from generic prescription products in U.S. markets.

3.2.1.1 NUMBER OF GENERIC DRUG APPROVALS OF INDIA

India has been experiencing a spurt in generic registrations across

the world (Table 3.8). Analysis of India’s generic approvals with U.S.FDA

reveals that the country has emerged among the top countries in its

regulatory approvals granted. Analysis of India’s approvals in various top

stringent regulated countries and semi regulated countries using the online

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databases provided by respective countries also has been carried out. The

analysis reveals that India stands first in number of approvals granted by

EDQM, by number of valid CEPs. Nearly one out every four valid CEPs

granted are to India, or by the number of molecules (31.88%) or companies

(18.84%). The country stands first in Ethiopia accounting for over 17% of

approvals and also in Tanzania with 39.32% of all market authorizations

granted by that country. Similarly, India has strong presence in CIS

countries, South Africa, etc. The country has majority of qualifications

granted by global procuring agency World Health Organisation (WHO).

Table 3.8: Regulatory Compliance status of India with variousRegulatory Authorities of the World

Data source: U.S.FDA DMF Database, Orange Book & NDC Database

EDQM Online Database

UK MHRA Online Database

DACA Ethiopia Online Database

TFDA Online Database

Azerbaijan Regulatory website

CDSCO website

148

Confidential

3.2.1.2 Yearly Growth Rate of India’s Prescription Generic drug

Approvals

India is currently experiencing a boom in generic drug approvals.

India’s number of approvals for generic prescription products (ANDA

approvals excluding OTC, discontinued and tentative approvals) with

U.S.FDA have grown tremendously during the last six years from 2005 to

2010 with 1363 approvals compared with meager 171 approvals it has

prior to it. Year wise number and % share of India and four other top

countries in prescription generic product approvals granted by U.S.FDA is

presented in Table 3.9.

Table 3.9: Year wise % share of India, USA, Israel and Switzerland inPrescription Generics Approvals granted by U.S.FDA

Data Source: Electronic Orange Book, NDC Directory

Year

PrescriptionGener

icWorld

PrescriptionGener

icIndia

%Share

ofIndia

inPrescriptionGener

icprodu

ct

PrescriptionGener

icUSA

%Share

ofUSAin

PrescriptionGener

icprodu

ct

PrescriptionGener

icIsrael

%Share

ofIsrael

inPrescriptionGener

icprodu

ct

PrescriptionGeneric of

Switzerland

%Share

ofSwitzer

landin

Prescription

Generic

product

P-1982*

443 1 0.23% 31671.33

% 347.67

% 5512.42%

149

1982 60 4

6.67% 42

70.00% 7

11.67% 0

0.00%

1983 65 3

4.62% 48

73.85% 3

4.62% 2

3.08%

1984 78 5

6.41% 48

61.54% 14

17.95% 5

6.41%

1985 103 4

3.88% 75

72.82% 13

12.62% 2

1.94%

1986 155 2

1.29% 124

80.00% 11

7.10% 9

5.81%

1987 205 6

2.93% 131

63.90% 16

7.80% 14

6.83%

1988 187 1

0.53% 134

71.66% 13

6.95% 27

14.44%

1989 60 0

0.00% 47

78.33% 9

15.00% 2

3.33%

1990 2 0

0.00% 1

50.00% 0

0.00% 0

0.00%

1991 86 5

5.81% 69

80.23% 6

6.98% 5

5.81%

1992 93 1

1.08% 58

62.37% 24

25.81% 6

6.45%

1993 134 0

0.00% 84

62.69% 22

16.42% 13

9.70%

1994 111 2

1.80% 81

72.97% 18

16.22% 8

7.21%

1995 167 0

0.00% 91

54.49% 42

25.15% 23

13.77%

1996 200 3

1.50% 111

55.50% 45

22.50% 31

15.50%

1997 269 12

4.46% 160

59.48% 52

19.33% 22

8.18%

1998 232 7

3.02% 133

57.33% 35

15.09% 20

8.62%

150

1999 185 3

1.62% 110

59.46% 35

18.92% 3

1.62%

2000 317 6

1.89% 163

51.42% 50

15.77% 33

10.41%

2001 327 42

12.84% 156

47.71% 55

16.82% 19

5.81%

2002 524 12

2.29% 242

46.18% 105

20.04% 51

9.73%

2003 384 19

4.95% 192

50.00% 59

15.36% 24

6.25%

2004 582 33

5.67% 301

51.72% 105

18.04% 21

3.61%

2005 562 90

16.01% 256

45.55% 86

15.30% 49

8.72%

2006 653 142

21.75% 312

47.78% 69

10.57% 35

5.36%

2007 930 256

27.53% 419

45.05% 90

9.68% 35

3.76%

2008 954 299

31.34% 430

45.07% 77

8.07% 34

3.56%

2009 926 290

31.32% 383

41.36% 73

7.88% 71

7.67%

2010 958 286

29.85% 385

40.19% 69

7.20% 64

6.68%

*P-1982: Prior to 1982

Comparison of % share of yearly prescription generic product

approvals granted to India and 3 other top countries (USA, Israel and

Switzerland) from 1991 to 2010 provided in Table 3.9 is presented in Figure

3.5.

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Figure 3.5: Changing scenario of Prescription Generic productapprovals (1991 to 2010)Data Source: Electronic Orange Book, NDC Directory

3.2.1.8 Country wise Pharmaceutical Product Approvals

Country wise analysis of pharmaceutical product approvals granted

by U.S.FDA for biological, new drugs, generic drugs, and new molecular

entities has been carried out for the data available in Orange Book as on 28

December 2010. India accounts for 12.24% of all approvals (prescription,

OTC and tentative) and is second to USA which has a share of 53.61% of all

approvals in that country. Also only 27 Indian companies hold these

ANDAs compared with 211 companies from USA. It has products for 35.4%

of all molecules. India is closely followed by Israel, Switzerland and Canada

in that order. Of the total 37 countries having active product approvals in

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USA, top 10 countries account for 93.68%. (Figure 3.6, 3.7, 3.8, 3.9 and

Table 3.10).

India accounts for 11.32% and 9.23% in prescription generics and

OTC approvals respectively and country stands second next to USA. Israel

(9.30%), Switzerland (7.32%) and Canada (3.04%) occupy 3rd, 4th and 5th

positions in active prescription product approvals. It has very low share in

number of discontinued products given that files majorly generic products.

The growing presence of India in U.S.FDA is attested by the fact that it

competes with in number of Tentative Approvals being granted to the

country. Currently, it accounts for 15.47% of the prescription and OTC

generic products approvals.

Figure 3.6:% Share of Top 10Countries in Prescription Product

Approvals

Figure 3.7:% Share of Top 10 Countriesin OTC Product Approvals

153

Figure 3.8:% Share of Top 10Countries I

Tentative Product Approvals

3.9:% Share of Top 10 Countriesin Discontinued Product Approvals

Table 3.10: % Share of All Countries in all Pharmaceutical ProductApprovals [Biological Licensing

Applications (BLA), Generic drug, New Drug Application (NDA), NewMolecular Entity (NME)] in

Prescription, OTC, Tentative and Discontinued Products

Data Source: Electronic Orange Book, NDC Directory, Drugs@FDA

Confidential

3.2.1.4 Country wise Company Approvals of ANDAs

Out of total companies that have been granted approvals in generics

(prescription and OTC) belonging to 27 countries, India has second largest

number of companies (27) though second to USA (211) (Table 3.11). The

top 5 companies among them are very aggressive. A few other top Indian

generic companies in domestic market and in exports have not yet entered

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into U.S. markets. Besides, several foreign companies hold ANDA approvals

on Indian facilities both for innovator as well as generics which are taken

into consideration. From the above, it must be noted that the present

research does not include 265 prescription & OTC generic products

belonging to erstwhile Indian companies of Ranbaxy, Matrix, Dabur

Oncology and Minrad (subsidiary of Piramal Healthcare) which now belong

to foreign acquirer companies but include 90 approvals held by Indian

subsidiaries abroad.

Currently there is only one Indian company out of the top 10 generic

companies of the world, though most of them have their manufacturing

units in India. This clearly demonstrates India’s strengths in generic

formulations and there are good chances of more companies from India

would be among top 10 generic companies of the world.

Table 3.11: Number of Active Companies from different countries &their product basket with U.S.FDA

Data Source: Orange Book & NDC Directory

Confidential

Analysis of company-wise approvals reveals that in prescription

generics, Teva is the leader with 623 products followed by Mylan and

Watson. The top 16 companies account for more than 50% of the total

prescription generic product approvals among which two companies viz.,

Aurobindo (9th position) and Dr. Reddy’s (16th position) are from India.

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Among the total 60 companies that have product approvals in OTC sector,

Perrigo with a share of 21·75% is the leader followed by Watson Labs and

Dr. Reddy’s.

In spite of India’s regulatory strengths in various markets, currently

there is only one Indian company which appears in the list of top 10

generic companies of the world by total pharmaceutical sales in 2010. The

list of top 25 generic companies along with their product approvals were

tabulated in Table 3.12.

Table 3.12: Top 25 Companies with Generic Drug Product Approvalswith U.S.FDA

Data Source: Electronic Orange Book & NDC Directory

Confidential

As on the date of analysis, Aurobindo Pharma which is previously

known as bulk drug manufacturing also stands first in number of product

approvals granted extending the company’s position from bulk drugs to

formulations. It is followed by Dr. Reddy’s, Zydus Group, Sun Pharma,

Wockhardt and Lupin Pharma (Table 3.13)

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Table 3.13: Number of Indian Companies & their Product approvalBasket with U.S.FDA

Data Source: Electronic Orange Book & NDC Directory

Confidential

3.2.1.5 Therapeutic category wise Product Approvals granted by

U.S.FDA

Therapeutic category wise analysis of total pharmaceutical product

approvals granted by U.S.FDA has been carried out to study India’s status

in various therapeutic categories. Highest number of product approvals

was granted in the Anti infective category which has a share of 14.52%. It

is followed by CNS (14.04%), Cardiovascular (9.65%), Corticosteroids

(7.14%) and Diagnostics (6.34%) (Figure 3.10).

157

Figure 3.10: Therapeutic category Wise Share of All PharmaceuticalProduct Approvals Granted by U.S.FDA

Data Source: Orange Book, NDC Directory

Therapeutic Category Wise Analysis of Prescription, OTC, Tentative

and Discontinued Approvals Granted by U.S.FDA

Most number of prescription approvals is for CNS (24%) and

Respiratory (17%). Anti infective stands third with a share of 13% followed

by corticosteroids (6%) (Figure 3.11).

Among OTC product approvals granted by U.S.FDA, GI Tract (21%),

Analgesic and Anti inflammatory (19%) occupy 1st and 2nd positions,

whereas Anti infective (16%) and CNS (10%) occupy 3rd and 4th positions

respectively (Figure 3.11).

Analysis of Tentative approvals granted by U.S.FDA revealed that

more than one third of tentative approvals were granted in CNS (36%)

category. This is followed by Cardiovascular (17%), Anti HIV (14%), Anti

cancer (8%) and Anti infective (7%) and Anti diabetic (6%) categories. A

relatively less number of tentative approvals were granted in GIT,

Metabolic, Anti Viral and Respiratory categories (Figure 3.11).

Majority of the discontinued approvals were in CNS (21%), CVS (13%)

and anti-infective categories (Figure 3.11, Table 3.14).

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Figure 3.11: Therapeutic category wise share of all generic approvals(Prescription, OTC, Tentative and Discontinued) granted by U.S.FDA

Data Source: Orange Book, NDC Directory

% Share in Prescription productApprovals

% Share in OTC product Approvals

% Share in Tentative Approvals % Share in Discontinued productApprovals

159

Table 3.14: % Share in Prescription, OTC, Tentative, Discontinuedproduct approvals

Data Source: Orange Book, NDC Directory

Confidential

3.2.1.5.1 Therapeutic category wise analysis of product approvals of

USA

Therapeutic category wise analysis of all pharmaceutical product

approvals granted by U.S.FDA were analyzed and presented in Figure 3.13.

160

Figure 3.13: % Share of Therapeutic category wise Generic DrugApprovals of

Data Source: Orange Book, NDC Directory

Table 3.15: % Share in Prescription, OTC, Tentative and Discontinuedproduct Approvals of

Data Source: Orange Book, NDC Directory

Confidential

3.2.1.5.2 Therapeutic Category wise analysis of product approvals of

India

India’s approvals are broadly in synchrony with the approval

therapy-wise approval trends in U.S.FDA. The country also has highest

number of approvals in CNS category (35%), cardiovascular (20%), anti

infectives (16%) and GI tract (6%). It is comparatively stronger in number

of approvals in anti retrovirals, anti microbials, CVS, anti-diabetics and

dermatological. However, it is poor in Corticosteroids, Anti-cancer and

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diagnostics (Figure 3.14,Table 3.16). Further examination reveals the

country is weak in Biotechnology products including fermentation

products, complex chemistry, advanced dosage formulations and specialty

formulations.

Figure 3.14: Therapeutic category wise Approvals of IndiaData Source: Orange Book, NDC Directory

Table 3.16: % Share in Prescription, OTC, Tentative and Discontinuedproduct Approvals of India

Data Source: Orange Book, NDC Directory

Confidential

It may be noted that the top therapy categories are not necessarily

have top market shares. The market value is determined by sales value of

number of innovator molecules in the category. As per the IMS Health

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report of 2010, it is reported that in U.S., Oncologics is top therapy by

value occupying US$22.3bn. of the market respectively.91 Respiratory

agents, Lipid Regulators are the other top therapies in 2010. However,

Attention Deficit Hyperactivity Disorder (ADHD), HIV antivirals and

Angiotensin II blockers tops the list in growing therapies. The IMS Report

on top therapeutic categories in U.S. in 2010 is presented in Figure 3.15.

Figure 3.15: Top Therapy Category's of USA by Value and their CAGR(2006-2010) (US$ bn.& %)

Source: IMS Health, 201087

3.2.1.6 Molecule wise India’s Presence in Prescription GenericsAnalysis of the molecule-wise prescription approvals granted by

U.S.FDA using the data provided by orange book as on 28 December 2010,

it is observed that out of total molecules having prescription ANDAs, India

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is present only in 14% of the molecules. Further, analysis indicates that in

twelve molecules such as Cefipime hydrochloride, Cefixime, Desloratadine,

Dexchlorpheniramine Maleate, Brompheniramine Maleate,

Dextromethorphan hydrobromide, Pseudoephedrine, Enflurane,

Promethazine hydrochloride, Codeine phosphate, Amifostine, and Lithium

Carbonate only India has prescription ANDAs. At the same time it has more

than 50% share in product approvals of several anti retrovirals (ARVs) and

antibiotics such as Zidovudine, Rivastigmine, Stavudine, Didanosine,

Cefotaxime, Ciprofloxacin, and Cefepime. A comparision of the India’s

status in approvals of prescription generic molecules for the top 25

molecules are tabulated in Table 3.17.

Table 3.17: India’s status in approval wise Prescription genericmolecules

Data Source: Orange Book, NDC Directory

Confidential

It is observed that, in several other molecules having more than 20

prescription approvals such as Diltiazem HCL, Gentamicin Sulfate,

Amitriptyline HCL, Lorazepam, Clonazepam, Diazepam, Acyclovir, Fentanyl,

Morphine, Theophyline, Meperidine HCL, India does not have any

approvals. Several of these molecules pertain to corticosteroids, controlled

substances and fermentation based products (Table 3.18).

164

Table 3.18: Approval wise Top Generic Prescription products in whichIndia is absent

Data Source: Orange Book, NDC Directory

Rank in

all

molecul

es

Active

Ingredient

Broad

TherapeuticUSA

Indi

aIsrael

Grand

Total (All

countries)

12Diltiazem

HydrochlorideCardiovascular 44 0 6 71

22Gentamicin

Sulfate

Anti Infective

(Fermentation

based product)

37 0 2 54

28

Acetaminophe

n; Oxycodone

Hydrochloride

CNS (controlled

substance)39 0 1 49

33 LorazepamCNS (controlled

substance)34 0 3 46

40Sotalol

HydrochlorideCardiovascular 26 0 7 44

50Doxazosin

MesylateCardiovascular 20 0 8 40

56Hydrocortison

eCorticosteroid 26 0 6 38

165

59 ClonazepamCNS (controlled

substance)20 0 8 37

61Amitriptyline

HydrochlorideCardiovascular 29 0 - 35

71Meperidine

Hydrochloride

CNS (controlled

substance)26 0 2 33

75 Doxycycline

Anti Infective

(fermentation

based product)

20 0 1 32

79 Cimetidine Anti Infective 15 0 8 31

91Morphine

Sulfate

CNS (controlled

substance)23 0 - 28

93 Acyclovir Anti Viral 11 0 6 27

96Epirubicin

HydrochlorideAnti Cancer 17 0 2 26

97

Amphetamine

Aspartate;

Amphetamine

Sulfate;

Dextroamphet

amine

Saccharate;

CNS (controlled

substance)4 0 11 26

166

Dextroamphet

amine Sulfate

99Phentermine

HydrochlorideCNS 11 0 5 26

102 Fentanyl

Analgesic &

Anti-

Inflammatory

(controlled

substance)

9 0 4 25

104 DiazepamCNS (controlled

substance)16 0 6 25

107 TheophyllineRespiratory

(NTI)20 0 24

3.2.1.7 Dosage form wise India’s Presence in Product Approvals

India’s strength in various dosage forms has been analyzed for the

data available as on 28 December 2010. For the purpose of analysis, all the

dosage types have been classified into three broad categories, namely

advanced, non conventional and conventional formulations. Advanced

formulation consists of controlled release products, implants, patches,

depot preparation and inhalations and so on. Non conventional dosage

forms include products meant for rectal, vaginal and urethral routes.

167

Conventional dosage forms include oral, topical and injectables which are

self explanatory.

Study of products approved from India reveals that 83 per cent are

oral, mostly conventional tablets (690) and capsules (137). India has very

little presence in advanced formulations accounting for just 14 per cent of

its total products. India is also completely absent from nonconventional

dosage form (Table 3.19).

Table 3.19: Dosage form wise approvals in Prescription, OTC,Tentative & Discontinued products

Data Source: Drugs@FDA, Orange Book, NDC Directory

Confidential

168

3.3 Emerging Opportunities for India in Global Pharmaceutical Market

It has been observed that patents of several innovator molecules

whose sales are between US$723mn. to US$12.73bn. are expiring in the

coming five years. Atorvastatin, Montelukast Sodium, Esomeprazole

Magnesium, etc. are among the top molecules whose patents are expiring.

The opportunity from these top 50 molecules alone is valued at

US$63.85bn. even if their sales are assumed to remain same as in 2009.

Of this 80% market value will erode after patent expiry which implies that

the market or generics is valued at US$12.77bn. Generic companies can

potentially capture 20-30% of this market estimated at US$2.55-3.83bn.

(Table 3.20).

Table 3.20: Selected Block Buster Drugs going Off Patent in differentTherapeutic Category

Data Source: Orange Book & Drugs@FDA

Confidential

3.3.1Emerging Opportunities for India in U.S. PharmaceuticalMarketA complete list of Molecule wise USA Patent & Exclusivity Expiry

Analysis is attached in Appendix I.

3.3.2Therapeutic Category wise Molecule opportunities

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Therapeutic category wise penetration of generics in total number of

molecules is analyzed using the data provided in Orange Book, Drugs@FDA

as on 28 December 2010. The % share of molecules whose drug patent as

well as product patent expired and no generics are filed but are still active

as on 28 December 2010 are given in Table 3.18. Analysis indicates that

generic companies only target molecules having large number of molecules

in that therapeutic category. Penetration is strong in CVS, Analgesics,

Antiviral and CNS products. Generic penetration is week in Electrolyte

Replenishers, Nutritional Supplements, Diagnostics, etc. An analysis

based on the % share of generics and % share of molecules where generics

are not available and whose patent will be expiring, further penetration is

possible in CNS, Renal and Oncology categories (Table 3.21).

Table 3.21: Therapeutic category wise Molecule Opportunity withU.S.FDA

Data Source: Orange Book, Drugs@FDA, NDC Directory

Confidential

170

3.4 WARNING LETTERS ISSUED

Analysis of number of warning letters issued by U.S.FDA to

companies belonging to various countries during 1996 to October 2011 has

been carried out using the data available in U.S.FDA website. Examination

of number of warning letters issued by U.S.FDA indicates that Indian

companies have been issued very few warning letters compared to the

number of approvals as compared to USA (326) and China (19) and others

(Figure 3.15). In spite of the fact that India’s only recent emergence as top

filer in USA (1996 to October 2011), only 18 warning letters have been

issued so far indicating strong compliance capability of the country (Figure

3.16,Table 3.22).

Figure 3.16: Issue of U.S.FDA Warning Letters to different Countries(1996 to Oct 2011)

Data Source: U.S.FDA website

Year wise analysis of total number of warning letters issued by

U.S.FDA is carried out and presented in Figure 3.17. Also a comparison of

171

total number of warning letters received by India, USA and China is done

and the same is tabulated in Table 3.22.

Figure 3.17: Year wise total number of Warning Letters issued byU.S.FDA

Data Source: U.S.FDA websiteTable 3.22: Year wise number of Warning letters issued to three

countriesData Source: U.S.FDA website

Year wiseNo. of Warning letters

USA India China

1996 1 0 0

1997 12 0 0

1998 8 0 1

1999 15 1 0

2000 6 1 4

2001 0 1 0

172

2002 79 2 0

2003 4 0 0

2004 1 0 2

2005 22 0 0

2006 15 2 0

2007 40 0 0

2008 33 2 1

2009 34 1 2

2010 30 6 6

Oct-11 26 2 3

Total 326 18 19

Reasons for all warning letter issued to Indian companies are

presented in Table 3.23. Analysis indicates that out of 18 warning letters,

four were issued to API companies while the rest were for formulations.

Out of the 18 warning letters 12 were for cGMP deviations while two were

due to accord of new drug substance status.

Table 3.23: Total number of Warning Letters Issued to IndianCompanies with the Reasons

Data Source: U.S.FDA website data

S.

NoCompanies Year Reason for Warning letter

1 Claris 2010 Finished Pharmaceutical/Unapproved New

173

Lifesciences

Limited

Drugs/Adulterated

2 Synbiotics Ltd 2010 CGMP for Deviations/Adulterated

3

CP

Pharmaceutica

ls, Ltd. 2010

CGMP for Finished

Pharmaceuticals/Adulterated

4Choksi

Laboratory 2010

CGMP for Finished

Pharmaceuticals/Adulterated

5

Stericon

Pharma Pvt.

Ltd. 2010

CGMP for Finished

Pharmaceuticals/Adulterated

6Shreeji Homeo

Clinic 2010

Unapproved/Uncleared/Unauthorized

Products Related to the H1N1 Flu Virus

7Yag Mag Labs

Private Limited 2011

CGMP for Finished

Pharmaceuticals/Adulterated

8

Cadila

Healthcare

Limited 2011

CGMP/Finished

Pharmaceuticals/Adulterated

9 Lupin Limited 2009CGMP for Finished

Pharmaceuticals/Deviations/Adulterated

10Ranbaxy

Laboratories,2008 CGMP/Drug/Deviations/Adulterated

174

Ltd., Dewas,

India

11

Ranbaxy

Laboratories,

Ltd., Ponta

Sahib, India

2008 CGMP/Drug/Deviations/Adulterated

12

Ranbaxy

Laboratories

Limited

2006Current Good Manufacturing Practices for

Finished Pharmaceuticals/Adulterated

13 Wockhardt Ltd 2006

Current Good Manufacturing

Practices/Active Pharmaceuticals

Ingredient/Adulterated

14

Ranbaxy

Pharmaceutica

ls Inc.

2002

Certain Drugs Accord New Drug Status

through Rulemaking

Procedures/Guaifenesin

15

M G

Acquisition

LLC

2002

Certain Drugs Accorded New Drug Status

through Rulemaking

Procedures/Guaifenesin

16Granules India

Limited2001

Active Pharmaceutical Ingredient

Manufacturing Facility/Adulterated

17

SOLPharmaceuticals Limited (Dr.Reddy)

2000 Good Manufacturing Practices for ActivePharmaceutical Ingredient

175

18 FDC Ltd. 1999 Active Pharmaceutical Ingredient

3.5 OPPORTUNITIES IN PARAGRAPH IV CHALLENGES

Relying solely on commodity generics may no longer be seen as a

viable option, leaving companies no choice but to target niche products,

among them biologics, or by picking up for development those drugs

dropped by innovators for clinical or commercial reasons.

Bioequivalent generic versions of drugs that are not protected by

patents can be produced and marketed in the U.S. by any company,

subject to FDA approval. However, a generic company may obtain FDA

approval before patent expiry if it certifies its product does not infringe the

listed patents or the patents are invalid (paragraph IV certification). Patent

holders may then sue the ANDA filer for patent infringement. If the patent

holder sues the ANDA filer within 45 days of notification, the FDA may not

approve the ANDA for 30 months from the date of notification. If no suit is

filed within 45 days, the FDA may approve the ANDA at any time.

180-DAY EXCLUSIVITY

In order to encourage generic companies to develop non-infringing

products and challenge invalid patents, the Hatch- Waxman act provides

the incentive of 180 days of market exclusivity for the first company to file

an ANDA with paragraph IV certification for a product. The FDA may not

approve additional ANDAs for a period of 180 days commencing from the

first commercial marketing of the first-to-file product. In cases where more

176

than one ANDA with Paragraph IV certification is filed on the same day, the

period of exclusivity may be shared.

Analysis of Para IV challenges filed by various companies in USA

during the last 5 year period indicates that Teva continued to be by far the

most prolific filer of ANDAs with patent challenges of 161 products. Mylan

has stayed in second place with links to patent challenges on 108 different

products; Novartis occupying third place challenged 97 products. Four

Indian companies viz., Ranbaxy (Daiichi), Sun, Dr. Reddy’s and Lupin find

place among the top 10 challengers. (Figure 3.18). It indicates the growing

skills in patents domain and confidence in Indian companies.

Figure 3.18: Companies with the Patent Challenges on record as onJune 201188

177

3.6 ANALYSIS OF INDIA’S PHARMACEUTICAL BILATERAL

TRADE

Analysis of Bilateral trade of India, both pharmaceutical exports and

imports has been carried out using HS codes classification to identify the

commodity type. Initially the data provided by DGCI&S is extracted from a

package known as “India Trades” provided by a private agency, CMIE.

Using this data, HS codes classification, each commodity is identified and

analysis has been performed to derive the category wise, country wise and

region wise exports and imports.

Research on India’s HS Codes revealed that the country’s trade in

pharmaceuticals sector is actually higher than the current understanding.

India’s total exports of drugs, pharmaceutical and fine chemicals in the

year 2010-11 stood at approximately US$13,233·12mn. and including

medical equipment and surgical, the figure stands at US$13,831·28mn.

much higher than the officially estimated figure of US$10,393.54mn. The

sector grew to a compounded annual growth rate (CAGR) of 15.1% during

the five year period from 2006-07 to 2010-11. The imports are approx. at

US$10,778·33mn. during the same period including imports of medical

devices and surgicals which are valued at US$13831.28mn. The country

thus had a positive trade balance of US$3,052·95mn. in this sector. India

exports to 201 countries and territories of the world during 2010-11.

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3.6.1 Category wise Exports of India’s Pharmaceuticals

Composition of exports of India’s pharmaceuticals has been analysed

using the HS Codes. The analysis revealed that formulation exports

including biologicals occupy approximately 34% of the country’s exports

followed by fine chemicals (28%), bulk drugs (23%), herbals (6%), medical &

diagnostic equipment and surgical with a share of 3% and 2% respectively.

Both excipients and medical devices are estimated to have a share of 1%

(Figure 3.19).

Figure 3.19: % Share of India’s Pharmaceutical sector ExportsData Source: DGCI&S Data

3.6.2 Category wise Imports of India’s Pharmaceuticals

Majority of the imports of India are fine chemicals with a share of

69% followed by bulk drugs (19%), medical & diagnostic equipment

intermediates and excipients at 19%, Medical & diagnostic equipment at

179

8%. Formulations along with biologicals at 9% and surgical at 4%

respectively. The percentage share of each category of India’s

Pharmaceuticals imports are presented in Figure 3.20.

Figure 3.20: % Share of India’s Pharmaceutical Sector ImportsData Source: DGCI&S Data

3.6.3 Region wise share of India’s Pharmaceutical Imports andExports.

3.6.3.1 Region wise share of India’s Pharmaceutical Imports

Analysis of the India’s pharmaceutical imports from the data

provided by DGCI&S, Ministry of Commerce and Industry revealed that

Asia is the largest sourcing region for imports followed by European Union

(18%). Asean and Middle East regions occupy an equal share of 14% in

India’s imports of drugs, pharmaceuticals & fine chemicals. North America

180

has a share of 10%, other European countries and Africa collectively

occupy a share of 5% respectively (Figure 3.21,Table 3.24).

Table 3.24 : Region wise share of India’s Import of Pharmaceuticals(2006-07 to 2010-11) (figs. in US $ mn., %)

Data Source: DGCI&S Data

Confidential

Figure 3.21: Region wise share of India’s Imports of Drugs,Pharmaceuticals & Fine chemicals, 2010-11(figs. in %)

Data Source: DGCI&S Data3.6.3.2 Region wise share of India’s Pharmaceutical Exports

Analysis of India’s exports of pharmaceuticals revealed that North

America is the largest export destination of India’s pharmaceuticals

181

(excluding Medical devices and fine chemicals) followed by Europe and

Africa. Middle East, Asean, Latin American Countries (LAC), CIS Countries,

Asia and South Asia region occupy the 4th, 5th, 6th and 7th position in

India’s pharmaceutical exports. (Figure 3.22,Table 3.25). The details of

calculation involved in the derivation of region wise share of India’s

Pharmaceutical exports are presented in Appendix II.

Figure 3.22: Region wise share of India’s Exports of Drugs,Pharmaceuticals & Fine Chemicals 2010-11 (figs. in US $ mn., %)

Data Source: DGCI&S DataTable 3.25: Region wise share of India’s Exports of India’s Drugs,

Pharmaceuticals & Fine Chemicals (2006-07 to 2010-11) (figs. in US $mn., %)

Data Source: DGCI&S Data

182

Confidential

For bulk drugs & intermediates, North America is the most important

destination with exports over US$2.5bn. and the region is also among the

important destinations for India’s formulations. An estimated 52·36% on

the exports to the region are bulk drugs & intermediates followed by

formulations with a share of 44·38%. North America is followed by EU

which is an important destination for formulations, biologicals as well as

bulk drugs & intermediates. Africa is another most important destination

for India’s formulation exports valued at nearly US$1.7bn. growing at a five

year CAGR of 22%. Exports of bulk drugs & intermediates, biologicals and

excipients are also growing at very high CAGRs to this region. The country

majorly exports formulations to CIS region. In Asia, the major importers of

bulk drugs & intermediates from India are China, Israel, Turkey, S. Korea,

and Thailand and nearly two thirds to LAC region.India’s exports potential

to Oceania region is largely untapped as evident from the country’s share

compared with market size of the region.

India’s Exports to USA

India’s exports to USA based on statistics provided by U.S.

Government in US Trade Stat Express have been analyzed from 1989 to

2010. India’s rank in total imports (bulk drugs and formulation) of USA,

183

year wise number of exports of bulk drugs and formulation, its share in

U.S. imports and yearly cumulative number of DMFs and ANDA approvals

were presented in Table 3.26.

The analysis indicates that the country’s bulk drug exports have

started growing during the last 15 years. However, the exports crossed

US$100mn. only since 2001. During the five years from 2006 to 2010 the

country’s exports have increased nearly three to four times with growth

respect to number of DMFs. During 2010, it exported over 1% of bulk drug

to USA making it 18th largest country behind Spain, Sweden and

Singapore.

Table 3.26: India’s Rank in Bulk drugs and Formulations Exports 1989to 2010) (figs. in US $ mn., %)

Data Source: DGCI&S Data

Confidential

184

Figure 3.23: % Share of India’s Exports of Bulk drugs andPharmaceutical products to USA (figs. in US$ mn).

Source: US Trade Stat Express (SITC 541 & SITC 542)

However, India is 10th largest formulation exporting country with a

share of 4.66% and 18th largest bulk drug exporting country. Considering

the number of filings, molecules going off patents and country’s growing

185

strength in drug registrations, increasing filings of foreign company DMFs

on Indian facilities leading to growth in contract manufacturing

opportunities, during last 5 years, it can be concluded that India’s exports

would continue to grow. Given the cost advantage offered by Indian

facilities and growth dependency on sourcing from India, foreign MNCs

would increase their M & A (Mergers and Acquisitions) activities.

Figure 3.24: India’s Bulk Drug and Formulation Exports to USA (figs.in US $ mn.,)

Source: US Trade Stat Express (SITC 541 & SITC 542)