Report on SEA-ACHR Subcommittee on Drug and Vaccine Development 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
32nd Session of WHO SEA-ACHR, Thailand 11-13 October, 2011
Drug Development Efforts in India
IND Molecules in Clinical Trials 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
WHO Prequalified Drugs from the SEAR 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
Recombinant Therapeutic Drugs Approved for Marketing in India 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
Biotechnology based Drugs in Development in India 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
Indian Anti-tubercular Drug Development Initiative 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
Rotavirus Vaccines 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.
Source: CDC and WHO
Rotavirus Vaccine Efficacy Studies Source: WHO
Development of Oral Rotavirus Vaccine (ORV) Using Indian Neonatal Strain116E 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
Indian Rotavirus Vaccines in Pipeline 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.
Asian Rotavirus Surveillance Network Involves 14 countries in collaboration with WHO, PATH and CDC (Atlanta). Source: Vaccine 2009; 27S: F1-F5
Hib Vaccines
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%.
Hib Combo Vaccines 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.
Indian Hib Vaccine Manufacturers 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. Indian Hib Vaccine Manufacturers
H1N1 Vaccines
H1N1 Vaccine Manufacturers India 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.
H1N1+Seasonal Flu Combo Vaccine 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
Pneumonia Vaccines 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.
Pneumonia Vaccines 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.
Vaccines from Serum Institute of India
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.
Major Recommendations
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.
Major Recommendations
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 Major Recommendations
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
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OSDD: Many Eyeballs make the Bug Shallow
Public Funding of Clinical Trials
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Clinical trials
18 19 9 6 2 Status: OSDD Projects Other projects aim to develop tools, databases and repositories for the OSDD community
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Drug Target Identification
Virtual Screening
Chemical Synthesis/library
Screening/ Hit identification
Hit to Lead
OSDD : A Global Community - 4511 members from more than 130 countries Affordable Healthcare for All
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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:
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.
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
Mapping Outline 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
Diagnostics: Examples of Information Gathered
Genomix Molecular Diagnostics (P) Ltd, Hyderabad, (A.P) is developing and testing POC instrumentation for Lateral Flow and Isothermal PCR (LAMP) assays for Malaria, Dengue, Chikungunya etc.
Also, developing antibody Lateral Flow assays for Taeniasis and cysticercosis in collaboration with Dr. Patricia Wilkins, CDC, USA
PCR (900 gm) Machine Lateral Flow Machine
Example of Malaria Diagnostic Development by National Institute of Malaria Research, Banagalore 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-chromatographic 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.
Diagnostics: Challenges 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.
Diagnostics: Gaps and Roadblocks 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
Drugs: Gaps and Roadblocks 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 Manufacturing in India 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 .
An Example: Serum Institute of India Limited, Pune 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
Meningitis Vaccine Project 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
MVP Partnerships
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 protein from ICRC bacilli
Mapping Results: Leprosy as an Example
Immuvac : Unique Poly-antigenic Vaccine 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.
Brief Outline of the Project 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
Brief Outline 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 **) 9th 10th 11th 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
Website Designed on the Project The detailed analytical data is available in the following website : http://apw-nii.webs.com
Thank You
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