Pharmaceutical Innovations in India's Drug Development Landscape
India has been a key player in drug development efforts, with organizations like CDRI, DRDO, and Ranbaxy leading the way in producing a diverse range of therapeutic molecules. With 87% of WHO-prequalified drugs in the SEAR region manufactured in India, the country has made significant contributions in areas such as HIV/AIDS, tuberculosis, and anti-malarial drugs. Various molecules developed in India cater to different therapeutic applications, from vaccines to treatments for cancer, diabetes, and other chronic diseases.
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32 32nd nd Session of WHO SEA Session of WHO SEA- -ACHR, Thailand 11 ACHR, Thailand 11- -13 October, 2011 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 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. 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 5 93 17
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 tubercular lead molecules developed. AZ and PA124 are two effective anti- CSIR has carried out Technology Transfer. Currently awaiting further development.
Vaccine Development Efforts in India Vaccine Development Efforts in India
Rotavirus Rotavirus Vaccines Vaccines
Rotavirus Type A: The most common cause of infections in humans Source: WHO
RotaTeq First of 6 The maximum age for the last dose was 32 wee Rotarix 6 15 weeks in Europe. The maximum age for the last dose was 24 weeks 6 days. RotaTeq First dose is given within the recommended age range of 6 12 weeks in infants. The maximum age for the last dose was 32 weeks. Rotarix 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. dose is given within the recommended age range 12 weeks in infants. ks. weeks and 14 weeks in Latin America or 6 weeks and Source: CDC and WHO
Rotavirus Vaccine Efficacy Studies Source: WHO
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: Rotavirus vaccine Rotavac , priced at only USD1 in collaboration with GAVI and DBT. Sanofi collaboration with PATH, coming up with Rotavirus vaccines. Bharat Biotech Limited: Has plans to develop a Sanofi Pasteur ( Pasteur (Shantha Shantha Biotech): Biotech): In
Involves 14 countries in collaboration with WHO, PATH and CDC (Atlanta). Source: Vaccine 2009; 27S: F1-F5
Hib Hib Vaccines Vaccines
Polysaccharide Vaccine Polysaccharide Vaccine The first Hib vaccine licensed was a pure polysaccharide vaccine, first marketed in the US in 1985 Conjugate 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. Conjugate Vaccine: The shortcomings of the polysaccharide vaccine Hib of Hib conjugate vaccines have been effective against all manifestations of Hib conjugate vaccines have been effective against all manifestations Hib disease, with a clinical efficacy between 95 disease, with a clinical efficacy between 95- -100%. 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. Bharat Biotech Limited.
Serum Institute of India Pentavalent Date of WHO prequalification: September 22, 2010. Serum Institute of India Pentavalent Combo of Combo of DTP+HBsAg+Hib DTP+HBsAg+Hib Sanofi Shan5 Issues with Shan5: 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. Sanofi Pasteur ( Shan5 A Issues with Shan5: Facing Vaccine Quality issues regarding Pasteur (Shantha A pentavalent Shantha Biotech) pentavalent Combo of Biotech) DTP+HBsAg+Hib Combo of DTP+HBsAg+Hib
Panacea Panacea Biotec Biotec Easy five Easy five - - Pentavalent Combo of DTP+HBsAg+Hib Issues with 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. Issues with Easyfive Easyfive: : During site audit (27 June-1 July
H1N1 Vaccines H1N1 Vaccines
Serum Institute of India NASOVAC Dried). Sanofi VAXIGRIP 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 Vaxiflu obtained from WHO. Costs only INR 350. Cadila H1N1 vaccine developed using Virus-like particle (VLP) platform. Serum Institute of India NASOVAC - - Human, Live Attenuated Pandemic (H1N1) (Freeze- Sanofi Pasteur VAXIGRIP - - Split virion inactivated H1N1 vaccine (Susp. for Pasteur Zydus Cadila Vaxiflu- -S S Single-shot H1N1 vaccine created from a strain Cadila Cadila Biopharmaceuticals Biopharmaceuticals
Chiron Panacea Vaccines Agrippal protection against H1N1 and seasonal flu virus. Agrippal INR 390. A dose of 0.25 ml is advised for children < 3 years. A dose of 0.5ml is advised for adults. Chiron Panacea Vaccines Agrippal Injectable vaccine that offers dual Agrippal is a single-shot vial (0.5 ml), and costs
Vaccines for Pneumonia 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 Synflorix
Prevnar 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. Prevnar 13 13
M M- -VAC 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 Meningitis A, Y, C, W- -13 Quadrivalent 13 Quadrivalent Vaccine Vaccine Pneumococcal Polysaccharide and Conjugate 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. Institutional Capacity and Framework Vaccine Quality Regulatory System
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. Vaccine Production and Supply Vaccine Introduction in UIP
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 Operational Efficiency of UIP
Innovation Innovation
Open Source Drug Discovery (OSDD) Model Team India Consortium with International Participation Open Synthesis and Exchange of Knowledge Open Synthesis and Exchange of Knowledge Candidate Targets Candidate Targets Lead Molecules Lead Molecules Drug Drug PRECLINICAL & CLINICAL TRIAL PRECLINICAL & CLINICAL TRIAL in silico SCREENING in silico SCREENING in vivo in vivo VALIDATION VALIDATION Mycobacterium tuberculosis Mycobacterium tuberculosis Wiki Portal Wiki Portal Contract Research Organisations Contract Research Organisations Academia & Hospitals Academia & Hospitals Exchange of Ideas/Results Community Participation Exchange of Ideas/Results Community Participation Some partner organizations Some partner organizations Lead Organization Lead Organization Current Partners Current Partners Council of Scientific and Industrial Research (CSIR), India Council of Scientific and Industrial Research (CSIR), India
OSDD: Many Eyeballs make the Bug Shallow OSDD: Many Eyeballs make the Bug Shallow Clinical trials Clinical trials Public Funding of Clinical Trials Public Funding of Clinical Trials
Status: OSDD Projects Status: OSDD Projects Virtual Screening Virtual Screening Screening/ Hit identification Screening/ Hit identification Chemical Synthesis/library Chemical Synthesis/library Drug Target Identification Drug Target Identification Hit to Lead Hit to Lead 18 18 Other projects aim to develop tools, databases and repositories for the OSDD community Other projects aim to develop tools, databases and repositories for the OSDD community 19 19 9 9 6 6 2 2
Logo Affordable Healthcare for All Affordable Healthcare for All OSDD : A Global OSDD : A Global Community Community - - 4511 4511 members from more than 130 countries members from more than 130 countries
Collaborations, Partnerships and Networks Collaborations, Partnerships and Networks
Mapping Exercises are a pre for establishing networks Mapping Exercises are a pre- -requisite for establishing networks requisite
WHO/TDR Project: Mapping of Products R&D Landscape in Drugs, Diagnostics and Vaccines in India WHO/TDR Project: Mapping of Products R&D Landscape in Drugs, Diagnostics and Vaccines in India
Brief Outline of the Project 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 The link of the database in the form of web portal: http portal: http://www.indiandi.org ://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 Malaria, TB, HIV Leishmaniasis 9 Diseases Targeted as per TDR Mandate: Malaria, TB, HIV- -AIDS, Dengue, Leishmaniasis, , Helminthiasis Mandate: , Leprosy, , STDs AIDS, Dengue, Filariasis Helminthiasis, STDs Filariasis, Leprosy,
PCR (900 PCR (900 gm) Machine gm) Machine Lateral Flow Lateral Flow Machine 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 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 Hurdles in IP procedure. India is an endemic country for several Infectious 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. Infectious diseases. diseases. Academia partnership.
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 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. 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. 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. vs. contacts. contacts.
MAPPING OF DRUGS MAPPING OF DRUGS
Gaps and roadblocks, as perceived by respondents from Academia : Gaps and roadblocks, as perceived by respondents from Academia : Lack of manpower. Lack of funding. Lack of infrastructure. Neglect of some diseases over others. Lack of manpower. Lack of funding. Lack of infrastructure. Neglect of some diseases over others.
Vaccine manufacturers from India started the journey by manufacturing multinationals from the area. Vaccine manufacturers from India started the journey by manufacturing EPI vaccine, multinationals from the area. But they have gone a long way after that EPI vaccine, a niche created by exit of few a niche created by exit of few 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. 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 . Few have done very well .
New Concepts New Concepts New Products 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 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 Liposomal vaccines For simplifying the vaccine Liposomal vaccines For simplifying the vaccine delivery delivery Liposomal anticancer products Liposomal anticancer products Conjugated therapeutic proteins To increase the half life of the products Conjugated therapeutic proteins To increase the half life of the products
Created in 2001 as a partnership between WHO and PATH Affordable price partnerships PROJECT STATUS Created in 2001 as a partnership between WHO and PATH Affordable price through partnerships PROJECT STATUS through innovative international innovative international Phase I clinical trials completed Phase I clinical trials completed Phase II clinical trials completed: Vaccine is highly immunogenic Phase II clinical trials completed: Vaccine is highly immunogenic Phase III clinical trials started in Mali, Senegal and India in 1Q 2010 Phase III clinical trials started in Mali, Senegal and India in 1Q 2010 Applied for WHO prequalification Applied for WHO prequalification
