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N.K. Ganguly

Former Director General


Indian Council of Medical Research

President



Jawaharlal Institute of Postgraduate Medical Education and Research

Distinguished Biotechnology Research Professor

National Institute of Immunology, New Delhi, India


32
nd

Session of WHO SEA
-
ACHR, Thailand 11
-
13 October, 2011

Drug Development Efforts
in India

Organizations

IND Molecules

CDRI,
Lucknow

Anti
-
hyperglycaemic

agent

DRDO, New Delhi

Adjuvant in the radiotherapy of cerebral
glioma

patients

Ranbaxy, New Delhi

For treatment of overactive bladder and urinary incontinence

Ranbaxy, New Delhi

Anti
-
microbial agent

Ranbaxy, New Delhi

For treatment of benign prostatic hyperplasia

Wockhardt Ltd., Mumbai

Antibacterial agent

Dr.Reddy’s

Lab., Hyderabad

Anticancer agent

Lupin Ltd, Mumbai

Nasal formulation for migraine

Lupin Ltd., Mumbai

Herbal preparation for psoriasis

Lupin Ltd., Mumbai

Anti
-
tuberculosis agent

Sun Pharma, Baroda

Anti
-
histaminic agent

Malladi, Chennai

Thrombolytic agent

Dr.Reddy’s Lab., Hyderabad

Dyslipidemic

agent

Zydus Cadila, Ahmedabad

Dyslipidemic

agent



87% of drugs manufactured in the SEAR that attain
WHO prequalification are manufactured in India.




HIV / AIDS Drugs (single & combo) :
93


Tuberculosis Drugs (single & combo) :
17


Anti
-
Malarial Drugs (single & combo) :
5

Molecules

Therapeutic applications

Hepatitis B vaccine (r
-

HBsAg

based)

Immunization against Hepatitis B virus

Erythropoietin

Treatment of anemia

Interferon alpha 2B

Treatment of leukemia, Hepatitis B and Hepatitis C

Epidermal Growth factor (EGF)

Organ morphogenesis and mitogenesis

Streptokinase

Dissolution of clot in acute myocardial infarction

Human insulin

Treatment of diabetes

GM
-
CSF; G
-
CSF

Treatment of chemotherapy induced
neutropenia
; treatment of
neutropenia


Interferon alpha 2A

Chronic myeloid leukemia

Human growth hormone

Treatment of dwarfism in children

Nimotuzumab

Treatment of breast cancer

Rituximab

Treating non
-
Hodgkin’s lymphoma & arthritis.

Tissue Plasminogen Activator

Dissolution of clot in acute myocardial infarction

Blood factor VIII

Treatment of hemophilia type A

Follicle stimulating hormone

Treatment of reproductive disorders

Teriparatide (Forteo)

Parathyroid hormone for treating osteoporosis

Drerecogin alpha (Xigris)

Burns and severe sepsis

Platelet Derived Growth Factor (PDGF)

Receptor antagonist in certain types of cancer

Interleukin 2; interleukin 11

Treatment of renal cell carcinoma; treatment of thrombocytopenia

Blood factor VII (Eptacogalpha)

To control bleeding in hemophilia patients

Interferon gamma

To treat chronic
granulomatous

disease & osteoporosis

Therapeutic category

No. of drugs

AIDS / HIV / infection / Related Conditions

22

Autoimmune disorders

44

Blood Disorders

10

Cancer / Related conditions

210

Cardiovascular Diseases

22

Diabetes / Related Conditions

15

Digestive Disorders

14

Eye conditions

6

Genetic Disorders

9

Growth Disorders

4

Infectious Diseases

50

Neurological Disorders

17

Respiratory Disorders

13

Skin Disorders

7

Transplantation

4

Other

18

Total

465



AZ and PA124
are two effective anti
-
tubercular lead molecules developed.




CSIR has carried out Technology Transfer.




Currently awaiting further development.

Vaccine Development Efforts
in India

Rotavirus

Vaccines

Source: WHO

Rotavirus Type A: The
most
common cause of
infections
in
humans


First
dose is given within the recommended age range
of 6

12 weeks in infants.


The maximum age for the last dose was 32 wee
ks.


6
weeks and 14 weeks in Latin America or 6 weeks and
15 weeks in Europe.


The maximum age for the last dose was 24 weeks 6
days.
Source: CDC and
WHO

Rotavirus Vaccine Efficacy Studies

Source: WHO


Strain 116E human rotavirus Serotype G9, P with single
gene coding VP4.


1
×
10
5

Focus forming unit found safe and immunogenic
in clinical trials in USA and India. Robust immune
response after 3 administrations.


4 fold increase rotavirus
IgA

titer in 89.7% of infants
recipient of ORV


Technical Collaborators: DBT (
india
) CDC (USA), NIH
(USA). Stanford University and PATH


Development by Bharat Biotech International Limited
(Hyderabad, India)

Bhandari

et
al.
J Infect
Dis

2009; 200: 421
-
429


Bharat Biotech Limited:

Has plans to develop a
Rotavirus vaccine “
Rotavac
”, priced at only USD1
in collaboration with GAVI and DBT.




Sanofi

Pasteur (
Shantha

Biotech):


In
collaboration with PATH, coming up with
Rotavirus vaccines.

Involves
14 countries

in
collaboration with WHO,
PATH and CDC (Atlanta).

Source: Vaccine 2009; 27S: F1
-
F5

Hib

Vaccines


Polysaccharide Vaccine

`
The first
Hib

vaccine licensed was a pure polysaccharide vaccine,
first marketed in the US in 1985


Conjugate Vaccine:
The shortcomings of the polysaccharide vaccine
led to the production of the
Hib

polysaccharide
-
protein conjugate
vaccine. Attaching
Hib

polysaccharide to a protein carrier greatly
increased the ability of the immune system of young children to
recognize the polysaccharide and develop immunity.


Hib

conjugate vaccines have been effective against all manifestations
of
Hib

disease, with a clinical efficacy between 95
-
100%.




Multiple combinations of
Hib

and other vaccines have
been licensed in the United States, reducing the number
of shots necessary to vaccinate a child.
Hib

vaccine
combined with diphtheria
-
tetanus
-
pertussis
-
polio
vaccines and Hepatitis B vaccines are available in the US.
The World Health Organization (WHO) has certified
several
Hib

vaccine combinations, including a
pentavalent

DTP+HBsAg+Hib

combos for use in
developing countries.


Vaccine under development at
Bharat Biotech Limited.



Serum Institute of India


Pentavalent

Combo of
DTP+HBsAg+Hib

?C
Date of WHO prequalification: September 22, 2010.



Sanofi

Pasteur (
Shantha

Biotech)


Shan5



A
pentavalent

Combo of
DTP+HBsAg+Hib


?C
Issues with Shan5:
Facing Vaccine Quality issues regarding
physical appearance reported to WHO by Colombia, Comoros,
and Nepal ⇨ No AEFI reported so far ⇨ However, Shan5 likely
to be removed from the list of WHO prequalified vaccines if
corrective measures are not instituted within 2 months.


Panacea
Biotec


Easy five
-

Pentavalent

Combo of
DTP+HBsAg+Hib


Issues with
Easyfive
:

During site audit (27 June
-
1 July
2011) at
Lalru
, Panacea failed to meet the quality
requirements for WHO prequalification ⇨ As per the
recommendations of the
ad hoc
Committee,
Easyfive

has
be delisted from the WHO prequalified list of vaccines.

H1N1 Vaccines


Serum Institute of India


NASOVAC

-

Human, Live Attenuated Pandemic (H1N1) (Freeze
-
Dried).


Sanofi

Pasteur


VAXIGRIP
-

Split
virion

inactivated H1N1 vaccine (
Susp
. for
Injection).


Influenza virus, split, inactivated, containing antigens equivalent
to:
A/New Caledonia/20/99 (H1N1) like strain; A/Fujian/411/2002
(H3N2) like strain; B/Shanghai/361/2002 like strain


Zydus

Cadila


Vaxiflu
-
S


Single
-
shot H1N1 vaccine created from a strain
obtained from WHO.


Costs only INR 350.


Cadila

Biopharmaceuticals



H1N1 vaccine developed using Virus
-
like particle (VLP) platform.





Chiron Panacea Vaccines


Agrippal



Injectable

vaccine that offers dual
protection against H1N1 and seasonal flu virus.


Agrippal

is a single
-
shot vial (0.5 ml), and costs
INR 390.


A dose of 0.25 ml is advised for children < 3 years.


A dose of 0.5ml is advised for adults.



Vaccines for Pneumonia


Prevnar



Heptavalent vaccine, manufactured by Wyeth. In the
USA, vaccination with
Prevnar

is recommended for all
children <2 years, and for unvaccinated children (24
-
59 months) at high risk for pneumococcal infections.


Synflorix



Decavalent

vaccine, produced by GSK. Contains 10
serotypes of
pneumococcus

(1, 4, 5, 6B, 7F, 9V, 14,
18C, 19F, and 23F), conjugated to a carrier protein.


Synflorix

received a positive opinion from the
European Medicines Agency for use in the EU in
January 2009.


GSK received European Commission authorization to
market
Synflorix

in March 2009.



Prevnar

13



A 13
-
valent vaccine produced by Pfizer.


Contains 13 serotypes of
pneumococcus

(1, 3,
4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F),
conjugated to a carrier protein.


Prevnar

13 was approved by the US
-
FDA on
February 24, 2010.


It is to be given on the same schedule as was
Prevnar
.



M
-
VAC


Live attenuated measles virus (
Edmonston

Zagreb Strain)
propagated on Human Diploid Cells.


SII Measles Vaccine (M
-
VAC™) fulfils the relevant requirements
of WHO.


Meningitis A, Y, C, W
-
13 Quadrivalent

Vaccine


Pneumococcal Polysaccharide and Conjugate Vaccine



Institutional Capacity and Framework


Mapping of research capacity and networking.


Creation of Bio
-
repositories.


Need to strengthen Public
-
Private
-
Partnerships.


Need for initiatives for product development for public
health emergencies.


Vaccine Quality Regulatory System


Laboratory testing of vaccine for QC and QA.


Fast
-
track clearance of vaccines needed for emergencies.


Clinical trials of vaccines as per GCP.


Strengthening and streamlining IPR and Tech Transfer.



Vaccine Production and Supply


Need for financial sustainability plan (FSP) for
immunization.


Creation of expanded vaccine fund through innovative
financing mechanism.


Vaccine Introduction in UIP


Indentifying vaccines of local relevance.


Setting criteria for selection of vaccines e.g. Grades of
Recommendation Assessment, Development and
Evaluation (GRADE) System.


Role of the National Technical Advisory Group on
Immunization (NTAGI) in the decision
-
making process.



Operational Efficiency of UIP


Improving vaccine coverage


Robust AEFI and VPD Surveillance System


Vaccine forecasting, procurement and management


Accountability for vaccine wastage


Management of the cold
-
chain


Stockpiling vaccines for disasters/outbreaks


Management of Human Resources


Advocacy and Communication


Ethics and Equity


Need for ethical use and equitable
access to vaccines

Innovation

Open Source Drug Discovery (OSDD
) Model

“Team India Consortium with International Participation”

Council of Scientific and

Industrial Research (CSIR), India

Current Partners

Mycobacterium tuberculosis




Wiki Portal

Exchange of Ideas/Results

Community Participation

Lead

Molecules

Drug

Contract
Research
Organisations

Academia

& Hospitals

Open Synthesis and
Exchange

of Knowledge

PRECLINICAL & CLINICAL
TRIAL

Candidate

Targets

in silico
SCREENING

in vivo

VALIDATION

Lead Organization

Some partner organizations

OSDD: Many Eyeballs make the Bug Shallow

Clinical
trials

Public Funding
of Clinical
Trials

Drug Target
Identification

Virtual
Screening

Chemical
Synthesis/library

Screening/ Hit
identification

Hit to Lead

18

19

9

6

2

Status: OSDD Projects

Other projects aim to
develop tools,
databases and
repositories for the
OSDD community

OSDD : A Global
Community
-

4511
members from more than 130 countries

Affordable Healthcare for All

Collaborations, Partnerships and
Networks

Mapping Exercises are a pre
-
requisite
for establishing networks…

WHO/TDR Project:

Mapping of Products R&D
Landscape in Drugs, Diagnostics
and Vaccines in India

Brief Outline of the Project


Mapping of
the product R&D landscape for infectious diseases of
public health importance in India through literature surveys
, and
internet/database
searches.


The
Mapping
included
the
following:


a.
Cover
R&D activities in the area of drugs, diagnostics and
vaccines for infectious tropical
diseases.



b. Identify
gaps and opportunities for product innovation in
India.



c. Create
a database of institutions (public and private) with relevant
R&D capacity for discovery and development and
manufacturing.


d.

Create
a database of available resources including technologies,
pathogen strains, screening assays as well as potential regional
funding sources that could support such regional
efforts.






The link of the database in the form of web
portal: http
://www.indiandi.org

Questionnaire Administration to Organizations
Associated with R&D / Manufacture of DRUGS,
DIAGNOSTICS and VACCINES

PUBLIC SECTOR

PRIVATE SECTOR

9 Diseases Targeted as per TDR
Mandate:

Malaria, TB, HIV
-
AIDS, Dengue,
Filariasis
, Leprosy,
Leishmaniasis
,
Helminthiasis
, STDs

PCR (900
gm) Machine

Lateral Flow
Machine

Product
Name

Stage of
Development

Status

Future

Funding
Status

Public/Private
Funding

Comment

HRP II/
pLDH

based rapid
diagnostic test
for differential
diagnosis of
malaria.

Recombinant
antigens have
been
produced.

Native antigen
underway.


Indigenous
production of
double
window based
immuno
-
chromatograp
hic lateral flow
rapid
diagnostic
tests.


RDT Will be
produced
indigenously.

current
funding is
OK.


Needs more
freedom in
spending the
fund



work is funded
by DBT under
SBIRI
programme
.

M/S Bhat
Biotech (I)
Pvt. Ltd,
Bangalore is
the industrial
partner .

This is a good
move by DBT
to have Public
Private
Partnership
initiative.


Micro PCR
based
differential
diagnosis of
malaria.


RT PCR for
Plasmodium
falciparum

and
P. vivax

has been
developed.

Indigenous
production of
chips for micro
PCR is
underway.

Production
can be made.

Currently this
work is being
carried out
within the
available
fund.



This work is
funded by
Bigtec Lab Pvt.
Ltd., Bangalore

This work is
partially
funded by
Bigtec

Lab
Pvt. Ltd.,
Bangalore.


India is an endemic country for several
Infectious

diseases.

`
Diagnostics is still unavailable for some of the diseases.

`
Evaluation is a problem.

`
Lack of networking among investigators.


Lack of platform technology development, a change visible
in recent times.

`
Kits and chips also were not in sight earlier, which are
coming up now.

`
Insufficient Industry
-
Academia partnership.


Hurdles in IP procedure.


As identified from the inputs collected from the Principal Investigators:


Finance.

`
Infrastructure.

`
Reagents.

`
More basic research for neglected tropical diseases.

`
Inability to differentiate between active and latent
disease or active disease
vs.

contacts.

`
Not enough clinical samples.

`
Lack of containment facilities.

`
Lack of human resources.


Quality assurance.


Limited option for test validation.

`
Inaccessibility to good quality validated panels of sera.

`
Imported kits, chips, reagents make diagnostics costly.

MAPPING OF DRUGS


Gaps and roadblocks, as perceived by
respondents from Academia :



Lack of manpower.

?C
Lack of funding.

?C
Lack of infrastructure.

?C
Neglect of some diseases over others.


Vaccine manufacturers from India started the journey by
manufacturing
EPI vaccine,

a niche created by exit of few
multinationals from the area.






But they have gone a long way after that …


WHO prequalification regulations getting more stringent.

Older public sector units have been converted to testing centers.

New manufacturers have entered the scene.


Few have done very well .

New Products


Aerosol measles vaccine


In phase III clinical trials


Acellular Pertussis vaccine




Ready for preclinical studies


Rotavirus vaccine


Ready for preclinical studies


Pandemic influenza vaccine


In development



New Concepts


Liposomal vaccines


For simplifying the vaccine

delivery




Liposomal anticancer products


`

Conjugated therapeutic proteins


To increase the half life of the
products



Created in 2001 as a partnership between WHO and
PATH


Affordable price

through

innovative international
partnerships

PROJECT STATUS



Phase I clinical trials completed




Phase II clinical trials completed: Vaccine is highly immunogenic




Phase III clinical trials started in Mali, Senegal and India in 1Q 2010




Applied for WHO prequalification


What India needs
is many more such
partnerships…..

Institute/

Company

Team leaders

Strategy

Stage of
development/

activity



Partners

Cadila
Pharmaceuticals
Ltd.Ahmedabad

Dr. Bakulesh
Khamar

-

Target discovery

-

ICGEB, New Delhi

Dr. V.S.
Chauhan

NAb

from gp41 protein

Target discovery

IISc, Bangalore and
IAVI

LRS, New Delhi

Dr. D. Behera

-

Putative site for
clinical trials



NARI, Pune

Dr.R. Paranjape

HIV
-
I
Neutralising

epitopes

-

Duke university,
Durham, SA

NIRRH, Mumbai



Dr. A.H.
Bandivedekar

Development

of Recombinant

Vaccine against

HIV
-
1 subtype C

-

USA Primate center,
USA

TRC, Chennai

Dr.V.D
Ramanathan

Engineering gp41 of
HIV
-
1 on
nano

particles
as vaccine candidates.

Target discovery,
development and
clinical trials

DBT funded project
Collaborators are
IAVI, New York;
NARI, Pune; YRG
Care Centre,
Chennai; MKU
Madurai

Summary of the HIV/AIDS vaccine related activity
in India:

Institute/

Company

Target
Discovery

Development

Clinical
Trials


Manufacturing


Partners

NII

MIP (
M.
indicus

pranii
) formerly
Mw

Cadila
Pharma
Ltd.







NII

CDRI

M. habana
-

based



ICRC

High MW
pr潴ein fr潭
ICRC bacilli


Licensed in 1998.

`
Technology from NII, Manufactured by
Cadila

Pharmaceuticals.

`
Therapeutic Vaccine for multi
-
bacillary leprosy.


Used as an adjunct to the Multidrug therapy.


These patients require long duration of treatment.

`
The vaccine reduces duration of therapy by 50% as it
hastens bacterial killing & bacterial clearance in leprosy.

`
Now being developed for management of TB.

WHO/SEARO Project: Mapping of
National
Centres

/ Institutes in
Tropical Diseases in India

Another

WHO
-
SEARO

Sponsored

Project

was

done

on



Mapping

of

National

Centres

/

Institutions

on

Tropical

Diseases

in

India

A

thorough

mapping

of
:

All

relevant

National

medical,

technological,

research

organizations,

universities

centres/institutions

The

selection

criteria

were

their

strengths

by

way

of

contribution

in

the

area

of

Tropical

Diseases

research,

teaching,

as

well

as

training
.


The

major

aims

and

objectives
:


To

assess

the

profile,

strengths

and

comparative

advantages

of

the

institutes

and

establish

how

each

of

them

could

contribute

towards

control

and

elimination

of

Tropical

Diseases

from

the

region
.


The major areas where information was collected were:


(
i
) profile of institution / university,

(ii) strengths,

(iii) Funding obtained from National , International agencies, and
NGOs

(iv) outputs.




The profile provided :


Name of Institution / University



Agency



Established



Location



Vision and Mission



Contribution to Tropical Diseases



The strengths of a particular institution were evaluated on the
basis of:


Expertise


Scientists




Infrastructure


Facilities, Services, Platform Technologies




Programs


Training, Courses, Workshops




Basic Research




Product Development


Drugs, Diagnostics, Vaccines




Clinical Trials




Grants


National, International, NGOs



Outputs



Publications



Patents




Comparative Analysis of Institutions for Tropical Diseases


Agency

Five Year Plan (in Crore
**
)

9
th


10
th


11
th

DBT

621

1450

6500

ICMR

NA

1023

5000

Proposed outlay

CSIR

Basic Research

3939



6413



8400



DST

1497

3400

11000

UGC

2000

3500

56,364

Proposed outlay


Example on Funding: Science Budget (Excluding Defense,
Space and Atomic Energy)


*Source
-
DBT


** 1
Crore

= 10 million

Cumulative H Index of Publications on different Diseases in
2000
-
2010

The

detailed

analytical

data

is

available

in

the

following

website

:

http
:
//apw
-
nii
.
webs
.
com


Thank You