32nd Session of WHO SEA-ACHR, Thailand 11-13 October, 2011
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
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.


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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
Rotavirus Type A: The most common cause of
infections in humans
Source: WHO
• 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
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Strain 116E human rotavirus Serotype G9, P with single
gene coding VP4.
1×105 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
◦ Date of WHO prequalification: September 22, 2010.

Sanofi Pasteur (Shantha Biotech)
◦ Shan5 – A pentavalent Combo of DTP+HBsAg+Hib
◦ 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) (FreezeDried).

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 (2459 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
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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
◦
◦
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◦
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.
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Operational Efficiency of UIP
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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”
Open Synthesis and
Exchange
of Knowledge
Candidate
Targets
Lead
Molecules
PRECLINICAL & CLINICAL
in silico SCREENING
TRIAL
in vivo VALIDATION
Mycobacterium tuberculosis
Wiki Portal
Academia
& Hospitals
Contract
Research
Organisations
Exchange of Ideas/Results
Community Participation
Some partner organizations
Lead Organization
Council of Scientific and
Industrial Research (CSIR), India
Current Partners
Drug
OSDD: Many Eyeballs make the Bug Shallow
Clinical
trials
Public Funding
of Clinical
Trials
Status: OSDD Projects
18
Other projects aim to
develop tools,
databases and
repositories for the
OSDD community
19
9
6
2
Affordable Healthcare for All
OSDD : A Global Community - 4511 members from more than 130 countries
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
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
immunochromatograp
hic lateral flow
rapid
diagnostic
tests.
RDT Will be
produced
indigenously.
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.
Funding
Status
Public/Private
Funding
current
funding is
OK.
Needs more
freedom in
spending the
fund
work is funded
by DBT under
SBIRI
Currently this
work is being
carried out
within the
available
This work is
funded by
Bigtec Lab Pvt.
Ltd., Bangalore
fund.
.
programme
Comment
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.
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.
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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.
◦ Lack of funding.
◦ Lack of infrastructure.
◦ 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 Concepts
New Products

Aerosol measles vaccine
 In phase III clinical trials

Ready for preclinical studies
Rotavirus vaccine
 Ready for preclinical studies

Pandemic influenza vaccine
 In development
Liposomal vaccines
 For simplifying the vaccine delivery
Acellular Pertussis vaccine

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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
Fermentation, Cell Bank
SynCo
Cobra
SIIL
GATES
What India needs
is many more such
partnerships…..
PATH
MVP
Conjugation
WHO
Lyophi
-lization
CDC
NIBSC
Aerial
CBER/
US FDA
Analytical
Clinical
Summary of the HIV/AIDS vaccine related activity
in India:
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
LRS, New Delhi
Dr. D. Behera
-
Putative site for
clinical trials
IISc, Bangalore and
IAVI
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
Institute/ Target
Company Discovery
NII
Development
Clinical
Trials
Manufacturing
Partners



NII
MIP (M. indicus
pranii) formerly
Mw
Cadila
Pharma
Ltd.
CDRI
M. habana based
ICRC
High MW
protein from
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.

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
•
•
•
•
•
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
Example on Funding: Science Budget (Excluding Defense,
Space and Atomic Energy)
**
Agency
Five Year Plan (in Crore )
DBT
ICMR
9th
621
NA
CSIR
3939
Basic Research
DST
1497
UGC
2000
*Source-DBT
10th
1450
1023
11th
6500
5000
Proposed outlay
6413
8400
3400
3500
11000
56,364
Proposed outlay
** 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