Agenda 3.1.3 Follow up Actions of 30th SEA-ACHR: Promotion of Research and Development on Drugs and Vaccines N.K. Ganguly Distinguished Biotechnology Fellow & Advisor Translational Health Science and Technology Institute National Institute of Immunology New Delhi Thirty-first Session of WHO South-East Asia Advisory Committee on Health Research, 21-23 July 2009, Kathmandu, Nepal Outline of Talk zExisting facilities & strengths zChallenges zThe way forward R&D Facilities for Drugs & Vaccines in SEAR Thailand Indonesia Korea IndiaBangladesh Drugs & Vaccines : R&D Facilities z Thailand z US Military HIV Research Program z Vaccine Trial Center z Mahidol University z Indonesia z Bio Farma z South Korea z The International Vaccine Institute z LG Life Sciences Ltd. z Crucell / Berna Biotech Korea Corp. z India z Various organizations Major R&D Facilities : India z Public Sector z Indian Immunologicals Ltd. z Bharat Immunologicals & Biologicals Corp. Ltd. z Central Drug Research Institute z Haffkine Bio- Pharmaceutical Corp. Ltd. z Private Sector z Serum Institute of India Ltd. z Panacea Biotech Ltd. z Bharat Biotech International Ltd. z Biological E. Ltd. z Shantha Biotechnics Ltd. z Zydus Cadila z Cipla z Ranbaxy Anti-tuberculosis drugs Anti-malarial drugs Anti-cancer drugs Cholesterol- lowering drugs Anti-diabetic agents Anti- Dyslipidemic agents Oseltamivir Anti-HIV drugs 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 Educational & Research Institutes Medical Colleges & Hospitals Human Resource Indian Pharma Industry Bio-Safety Level 2, 3, 4 Facilities Transgenic Animal Facility National Animal Resource Facility Drugs Testing Laboratories Toxicology Research Centres CROs Clinical Trial Centres National Ethical / Regulatory Guidelines Top ten pharmaceutical companies in India : revenue growth rate in 2007 Company Revenue growth Ranbaxy INR 42 billion Dr. Reddy’s Laboratories INR 42 billion Cipla INR 38 billion Sun Pharma Industries INR 25 billion Lupin Labs INR 22 billion Aurobindo Pharma INR 21 billion Glaxo Smith Kline Pharma INR 18 billion Cadila Health Care INR 17 billion Aventis Pharma INR 10 billion Ipca Laboratories INR 10 billion WHO prequalified drugs from the SEAR z 87% of drugs manufactured in the SEAR that attain WHO prequalification are manufactured in India. z HIV / AIDS Drugs (single & combo) : 93 z Tuberculosis Drugs (single & combo) : 17 z Anti-Malarial Drugs (single & combo) : 5 Challenges z Slowdown in pharmaceutical innovation after 2000. z Escalating costs and prolonged time taken to develop new drugs. z Stringent regulatory focus on drug safety. z A single drug development process takes over USD 1.2 billion investment. z A single vaccine development process takes over USD 0.5 billion investment. Preclinical development Phase I Phase II Phase III Phase IV : Post marketing surveillance Animal experiments for ADME-TOX studies, carcinogenicity, mutagenicity / teratogenicity Phase II 150-350 subjects with disease – to determine safety and dosage recommendations Phase IV Post-approval studies to determine specific safety issues Phase III 250-4000 more varied patient groups – to determine short-term safety and efficacy Phase I 20-50 healthy volunteers to gather preliminary data Development Registration Post Registration Drug development pathway Single drug : USD 1.2 billion investment !!! Vaccine development pathway Preclinical toxicity Laboratory development Technology transfer GMP grade material No GoPhase I trial No Go Phase II trial No Go Phase III trial Production No Go USD 0.5 billion !!! Post-marketing surveillance further adds to the cost ! CHALLENGES Access Public funding Drug financingTreatment costs Global trade Antimicrobial resistance The Way Forward Neglected Diseases : A High Priority for the SEAR z Drugs for Neglected Diseases Initiative (DNDi) set up in 2003 to tackle specifically the issue of neglected diseases. z Scientific Advisory Group on Tropical Diseases was established by WHO. z Focus on drug development efforts for : z Soil transmitted Helminthiasis z Leishmaniasis – Drawbacks of Miltefosine. Need for cheaper AmBisome z Need for more antimalarials Promoting R&D in Drugs : Role of Collaborative Networks z DNDi : Anti-leishmania combos (DNDi & ICMR collaboration) z Ambisome + Paramomycin z Ambisome + Miltefosin z Paramomycin + Miltefosin z Stop TB partnership : Established in 2000 to realize the goal of eliminating TB – vision for a TB free world. z TB Alliance : Development of new affordable TB drugs for short treatment time, activity against MDR-TB, compatibility with HIV anti-retrovirals. Mainly funded by B&M Gates Foundation, Govts of USA, UK and the Netherlands. Amphotericin B deoxycholate (the standard) Vs Complete report will be available in 2010 Tackling Antibiotic Resistance : RISHI Chembiotek Clininvent Drug Discovery Initiative z Application of genomics technologies to develop new antimicrobial compounds against essential proteins in bacteria. z Targeting 6 essential enzymes involved in bacterial cell wall synthesis. z Novel way of tackling multi-drug resistant bacterial infections since it will be extremely difficult for bacteria to develop resistance to critical house-keeping proteins. Promoting more clinical trials in the SEAR z Low cost for clinical trial implementation. z Genetically diverse population. z Faster regulatory approvals. z Presence of pharmaceutical know-how and well trained technical personnel. z High quality clinical trial set-up. z More clinical trials translates into more opportunities for manufacture of generic drugs. The SEAR countries are conducive for clinical trials… Promoting Manufacture and Uptake of Generic Drugs An important way of reducing cost and increasing access to life-saving drugs. z Generic versions of drugs are 30-80% cheaper than the branded product. z Generic versions can be manufactured legally when the drug is off-patent. z Generic versions can be produced as “approved generics” with license from the manufacturer of the parent drug. z Generic versions can be legally manufactured in countries that take part in clinical trials of the original drug. Promoting Biosimilars z Over 60% of the top players in the global biosimilars market are based in the SEAR. z Top companies working on Biosimilars – Biocon, Bioton, Emcure (Gennova), Hospira, Intas, Bio Farma, LG Life Sciences, Novartis (Sandoz), Ranbaxy, Teva, and Wockhardt. z Elaxim (Tenecteplase) and erythropoietin, manufactured by Gennova, have been approved by the USFDA. Source : Business Insights, May 2009 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 Promoting R&D in Vaccines z Gaining strength by acquisitions and joint ventures in SEAR : Cadila Pharmaceuticals (India) and Novavax (USA) to conduct R&D of VLP-based vaccines for seasonal flu and HPV. z WHO prequalified pentavalent vaccine suppliers from SEAR : Serum Institute of India (India), Panacea Biotech (India), Shant, Panacea Biotech (India), Shantha Biotechnics (India), and Berna Biotech/Crucell/Novartis (Korea). z Developing Country Vaccine Manufacturers Network (DCVMN) members from SEAR : Bharat Immunologicals & Biologicals Corp. (India), Bharat Biotech Intl. Ltd. (India), Bio Farma* (Indonesia), Haffkine Bio-Pharmaceutical Corp. Ltd. (India), Indian Immunologicals Ltd. (India), Queen Saovabha Memorial Institute (Thailand), LG Life Sciences* (Korea), Panacea Biotech* (India), Biological E (India), Serum Institute of India* (India), and Zydus Cadila (India). * WHO prequalified vaccine manufacturers Surveillance Networks Hib Initiative India Indonesia Bangladesh Sri Lanka Nepal Pneumococcal Vaccines Accelerated Development and Introduction Plan (PneumoADIP) ICDDR,B Invasive Bacterial Infection Surveillance/ South Asian Pneumococcal Alliance (IBIS/SAPNA) International Emerging Infections Program (IEIP) IVI Major Vaccine Initiatives Diseases for the Most Impoverished (DOMI) Cholera Vaccine Initiative (CHOVI) Pediatric Dengue Vaccine Initiative (PDVI) Vi based Vaccines for Asia (VIVA) Rotavirus Vaccine Programme (RVP) Malaria Vaccine Initiative (MVI) DOMI Cholera Program Field Studies in the SEAR Type of study Bangladesh Indonesia India Prospective disease surveillance √ √ Cost-of-illness studies √√√ Socio- behavioural surveys √√ Vaccine trials √ (Phase I and II Peru-15 trials) √ (Phase II and III killed WC trials) Vaccine private demand surveys √√√ Vaccine delivery cost analyses √ DOMI Typhoid Program : Vi Vaccine Demonstration Projects in the SEAR Criteria N. Jakarta, Indonesia Kolkata, India Setting Urban slum Urban slum Design Mass immunization Randomized control trial Vaccine delivery School-based Community-based Target population Grades 1 – 5 2 years and above Number of vaccinees 4,828 37,686 Vaccination coverage 91% 69% TB Vaccine Trials in India z The AERAS Global TB Vaccine Foundation is working with the Oxford-Emergent Tuberculosis Consortium to develop the vaccine, called MVA85A/AERAS-485, with additional funding from the Wellcome Trust. z AERAS Global TB Vaccine Foundation is conducting epidemiological studies to find out the burden of TB in India. z Funding is being provided by CDC to develop TB vaccine trial sites in India. z AERAS is also planning to conduct a Phase I clinical trial at St Johns' Research Institute, India, during the course of 2009. PATH MVI : Malaria Vaccine Candidates GSK RTS,S ASO1/ASO2 ICGEB PvRII Sanaria PfSPZ Platform S. cerevisiae E. coli Live attenuated sporozoites Antigen RTS,S (consists of sequences of the circumsporozoite (CS) protein and the hepatitis B surface antigen (HBsAg). Region II of blood- stage Duffy Binding Protein of P. vivax Sporozoite and liver- stage complex. Adjuvant AS02: proprietary oil-in-water emulsion formulated with MPL® and Stimulon® QS21 immunostimulants. AS01: liposome formulation with MPL® and QS21 immunostimulants. Formulation with AS02 selected for clinical development. NA Development stage Phase II trials; preparation for Phase III. Scale up (50L) and cGMP production – Bharat Biotech, Hyderabad. Biodistribution study and preparation for Investigational New Drug (IND) ongoing. Project timeline 2005-2011 2001-2008 2006-2009 HIV Vaccine Clinical Trials in India : Previous Phase I Trials z tgAAC09 HIV-1 Vaccine trial started in Feb 05 at NARI, Pune z Adeno-associated virus based vaccine. z Vaccine is well tolerated and safe in the 3 dosages used. z Weakly immunogenic in the doses used in the trial. z Evidence of high baseline titer of AAV2 neutralizing antibody in Indian population as compared to European participants. z MVA Vaccine trial started in Jan 06 at TRC, Chennai z TBC-M4 – Modified Vaccinia Ankara HIV-1, clade C, multigenic; developed in collaboration with NICED (Kolkata). z Dose-dependant response seen. z TBC-M4 immmunogenic at both low and high dose with 75% and 100% of low and high dose vaccinees responding after 3 injections. z Most of responses are balanced, directed to both env and gag, then against pol, nef or tat-rev. z Lack of impact of previous small pox vaccination on response rate. Indian Council of Medical Research Current HIV Vaccine Phase I Clinical Trial in India : Prime - Boost Strategy � TBC-M4 was found to be safe, well tolerated. � Modest immune response in 100% volunteers. � To enhance the breadth and magnitude of immune response a prime-boost approach has been initiated in Feb 09. � ADVAX, a DNA vaccine with synthetic copies of HIV-1 clade C genes env, gag, pol, nef and tat will be used to prime and TBC-M4 will be used to boost. � ADVAX was designed by the Aaron Diamond AIDS Research Centre in New York, in collaboration with the Rockefeller University in New York and IAVI. � NARI and TRC to conduct Phase I trial with YRG Care, an NGO to support TRC for advocacy and community mobilization for the trial. H5N1 / H1N1 Vaccine : Urgent need for production in the SEAR z Organizations from SEAR having capacity to produce seasonal influenza vaccines (LAIV and IIV) : z Serum Institute of India Ltd. (India) z Cadila (India) z Bio Farma (Indonesia) z Government Pharmaceutical Organization (Thailand) z Need for increasing production capacity for manufacturing H5N1 / H1N1 vaccines to cope with increasing demands. z Need to attain self-sufficiency in pandemic influenza vaccine stocks in the SEAR. Cadila’s Vaccine Initiative •Platform Technology Identification for affordable scalable technology • Virus Like Particles (VLP) •Became major stake holder and Board Member in a key company ( NOVAVAX) •Formed a special JV – CPL BIOLOGICALS Single Protein Crystalline VLP e.g. Gardasil ® (HPV vaccine) multi-component influenza VLP vaccine Lipid Envelope Exclusive composition of matter on Target Surface Proteins Patent protection for VLP matrix platforms Preparedness for Pandemic H1N1 Influenza Ferret studies successfully completed April-2009 May-2009 TASK NAME H1N1 vaccine starts Genes from CDC Genes cloned Recombinant clone VLP - Pre-clinical HA- Reagent H1N1 bulk 2 3 4 5 6 7 GLP batch shipped on June 2, 2009 Contract signed with NIAID for clinical testing of H1N1 VLPs 1 The road ahead… z Prioritization of regional needs by thorough mapping of prevalent diseases. z Develop a better infrastructure for identifying disease pathways. z Need for better tools for choosing and validating successful targets. z Improvement of industry-academic interface. z Improve accessibility and affordability of essential medicines. z Need to improve infrastructure of healthcare system. The road ahead… z Promote health insurance schemes. z Promote knowledge sharing between basic scientists and clinicians at national and international level. z Exposure of teaching faculties and students to translational research. z Harness the IT strength in the region. z Capacity building of all stakeholders. z More dedicated HRD for drugs and vaccine research. z Strengthening of the regulatory and testing facilities. The road ahead… z Develop safe and efficacious biosimilars. z Promote manufacture of off-patent drugs. z Promote contract research / manufacturing. z More focused clinical research. z More rigorous clinical trials. z Increase investment in biomedical field. z Promote research in chemoprophylaxis. z Promote traditional medicine and herbal / herbal-mineral drug development.
Thirty-first session of WHO South-East Asia Advisory Committee on Health Research Kathmandu, Nepal, 21-23 July 2009 SEA/ACHR/31/7 18 July 2009 Agenda Item 3.1.3 FOLLOW-UP ACTIONS ON THE RECOMMENDATIONS OF THE THIRTIETH SESSION OF WHO SEA-ACHR: RESEARCH MANAGEMENT IN COUNTRIES FOLLOW-UP ACTIONS ON THE RECOMMENDATIONS OF THE THIRTIETH SESSION OF WHO SEA-ACHR: RESEARCH MANAGEMENT IN COUNTRIES 1. Ethics in research It is very important that, in the conduct of research, the highest standards of ethics shall be followed. Every research proposal would need to be approved by the Ethics Committee of the institution where the research is to be carried out. If it is a multi-central study, then all the participating institutes should clear the proposal. If the project is being funded by SEARO or other agency, that agency should also clear the proposal on ethical grounds. There are many areas where good guidance of the ethics committee is needed. Unethical and unjustified clinical trials have, in the recent past and in earlier years, been carried out in the countries of the region and in the most advanced countries. Every effort needs to be made to ensure this does not happen. One of the problems with the functioning of Institute Ethics Committees is that there is a vast amount of material to be read and the members of the Ethics Committees do not have time to read the background material. Members of the Ethics Committee need to be reimbursed for the time and effort they put into review of a proposal. If such an honorarium is paid, then members of the committee will perhaps put in more effort to read the proposals. The lay members of the Institute Ethics Committee do not understand the technical jargon in the proposal. They need to be provided with a short write-up of the essential features of the proposal pointing out to the members what the ethical implications are. Informal consent is always a contentious issue in countries, particularly when the clinical trial is being carried out on a poor or marginalized or largely illiterate population. Every effort shall be made to explain the Information Sheet to the participant. Unfortunately, very often, particularly in a multi-centred clinical trial by a pharmaceutical company the Information Sheet runs into series of pages with a 1 lot of complex medical terms. Again, it would be useful to rephrase a long Information Sheet to a shorter simpler sheet. Finally, it is not the different elements such as informed consent, the use of the placebo, confidentiality and ownership of the data which are the most important factors. The most important factor is that the clinical investigator must sincerely believe that he/she does not want to harm the patient. In this, he/she should not look upon the Ethics Committee as a block to the research. Institute Ethics Committees should never be regarded as impediments to research. The clinical investigator should prepare his project proposal not with on eye as to how he would get ethical approval, but in a way that will safeguard the interests of the subject. He and also the Institute where he works, should regard Institute Ethics Committees as a help to conducting good research. 2. Twinning of research centres Countries in the region vary in their capacity for conducting good research as well as in possessing the facilities needed for quality and relevant research. What is evident is that investigators and more so, respective governments want research to be carried out. Less developed research centres need help while sophisticated centres of research in the countries can provide help. It is proposed that a Twinning Programme be considered in which a centre with poor infrastructure is linked with a sophisticated centre. Together, the partners will evolve a relationship and develop research programmes and then implement these as partners. Training in research methodology and in preparing proposals could be imparted by one centre to another through the Training Programme. Too much examples of “Twinning” in earlier years were the collaboration between the Postgraduate Institute of Medical Education and Research, Chandigarh (India) and the Royal Postgraduate Medical School, London and the Swiss Tropical Institute, Basel (Switzerland) and the Research Institute at Biafra (Tanzania). It can be unequivocally stated that the high standard of research being carried out at Chandigarh is largely the result of this collaboration. As one middle level researcher from Chandigarh stated after a stay in London – “By going to London 2 and working at the Postgraduate Medical School, our eyes were opened as to what is really possible”. Any programme of “Twinning” should be carried out in a spirit of equality and partnership and the more advanced institute should not enter into the collaboration with a superior attitude. If that happens, then the training programme is not likely to succeed. Very often, it is seen that the early enthusiasm wanes as the collaboration proceeds and second rate mediocre persons visit the less developed institute. This is dangerous. It is very important that the best and most respected scientists from the developed institute visit the partner institute. 3. Preparation of paper based on results Very often this is the weakest link in the chain which begins with the preparation of the proposal and should end with policy changes being introduced as a result of the results obtained in the research. The paper is sometimes not written for years. In the research management framework being proposed, the WHO Country office and/or the WHO Regional Office again need to play a proactive role till the investigators become competent to write a paper in a style which would be accepted by the Lancet or the New England Journal of Medicine. The Regional Office should identify scientists, perhaps retired scientists who have vast experience in writing papers and link these persons with the investigators who have collected the data but who have probably neither the time nor the skills to write a first-class paper. This process will also, in itself, be a training exercise. If the aim is quality research published in a quality journal, this help needs to be provided. The WHO Country office could keep an up-to-date database of such potential helpers preferably according to the areas of this expertise. The help provided by these scientists should be acknowledged in the paper. 4. Dissemination of research results to policy makers and bureaucrats In any good system of Health Research Management, the end point would be when the results of the research reach the health planner, the bureaucrat and the political leadership of the country. The scientific paper or the report of the study is 3 not in a form which would interest or excite them as the scientific paper has been written for another audience – the paper for scientists and the report for the programme managers. This information needs to be rephrased into simple reader- friendly language contained in one or two pages. The implication of the results on health care, the interventions that could be introduced into the health system, the savings which could be made as a result of the intervention are points which need to be highlighted. These are the points in which the politicians and the civil servants are interested in. Information needs to be provided to the media on the results of research. However, such information should be carefully prepared and provided to the press in a written form. Very often interviews on the results of research given by scientists ends up in the lay press with a touch of the sensational or by giving emphasis to a minor finding while ignoring the major findings. This can be avoided if a written description of the salient features of the research results are provided. The media are always looking for good stories. It is up to the scientist to judge what story should be given to them. Any research team has several members. If the press requests for information, only one member, perhaps the Chief Investigator, should be the spokesman for the team. Finally, premature results before validation should not be given to the press as this raises hopes of the lay public which are later not realized. This results not only in disappointment but in reducing the credibility of the researcher, the research team and the institute. Handled well, the media could prove to be a valuable tool for promotion of research. Handled badly could result in disaster. O:\EIP\RPC\ACHR\31 ACHR\ Final documents\SEA-ACHR-31-7_research management in countries_18 July 09 at 1800 hrs 4