1. Presented by- Piyush A. Bafna 2013H146077H M. Pharm.(Pharmaceutics)-1st year 28th October 2013

2. A Vaccine is biological preparation that improves immunity to particular disease. A Vaccine may be prophylactic or therapeutic. A Vaccines can be made of Live, Killed or attenuated micro organisms. The term vaccine was firstly used by Edward Jenner in 1796. Edward Jenner is thus well known as Father of Immunology. Vaccine Clinical trial 3. Year Discovery 1796 Edward Jenner introduced Small pox vaccine 1880 Louis Pasteur developed attenuated cholera vaccine 1882 Robert Koch isolated tubercle bacilli 1882 Louis pasteur successfully prevented rabies by post exposure vaccination 1908 Karl Landsteiner and Erwin Popper discovered poliovirus 1924 BCG is introduced as live tuberculosis vaccine Vaccine Clinical trial 4. Year Discovery 1961 Albert Sabin developed oral attenuated polio vaccine 1960- 1969 Live attenuated vaccines for Measles , Mumps and Rubella were developed 2006 First HPV (Human papilloma virus) vaccine is licensed 2012 Polio was eliminated from India Vaccine Clinical trial 5. 1. Phase I trial- are usually small scale. 2. Phase II trial- are to assess the safety, early efficacy of selected dose of vaccine. 3. Phase III trial- are usually large in scale and are to confirm the Efficacy of vaccine in target population. Vaccine Clinical trial 6. 4.Phase IV- are usually conducted for collecting information regarding long term safety or efficacy of vaccine to full fill with regulatory requirement. Vaccine Clinical trial 7. 1.Safety studies Acc.to FDA guidelines, the studies should be randomized and controlled. Follow up safety should be actively monitored and planned. Follow up should be continued at least 30 days for live or killed vaccines. 2.Immunogenicity- The main objective of comparative immunogenicity study is to rule out the difference between response to study vaccine and a control. The differences between Geometric Mean Titers and/or Sero conversion rates are studied. Vaccine Clinical trial 8. 3.Efficacy-Endpoint used to evaluate efficacy could range from disease incidence to well established marker with activity. 4.Statistical Considerations- Stratified Randomization may be recommended . For sample size, the FDA requires that sample size calculation for each study endpoint should be performed and Vaccine Clinical trial 9. And accordingly the sample size should be selected. Vaccine Clinical trial 10. What is TBE-: It is the disease condition which is caused by the TBE viruses which are positive-stranded RNA viruses. Infectious TBE Viruses enters cells by receptor mediated endocytosis. TBE Virus is the Flavi virus infection, that has been known from more than 50 yrs. Vaccine Clinical trial 11. TBE has recently joined the diseases under surveillance in the European Union; on 5 September 2012, it was included in the list of notifiable diseases in the European Union. Vaccine Clinical trial 12. TBEV is transmitted by 11 tick species, but only 2 species are important vectors: Ixodes ricinus for TBEV-Eu and Ixodes persulcatus for TBEV-Sib. Ticks act as both the vector and reservoir for TBEV. Vaccine Clinical trial 13. Sponsor of trial- Novartis vaccines Estimated Enrollment 300 Location countries- Germany Status of study- Completed Vaccine Clinical trial 14. - Prepare protocol(s) for human studies. -Apply for investigational New drug (IND) approval. -Submit Product Licensure Application MCC approval . -Advisory Committees review and make recommendations. Vaccine Clinical trial 15. - Post Marketing Surveillance for safety and effectiveness (Phase IV). - Long term process and Usually takes 10- 15 years. Vaccine Clinical trial 16. Official title of study- A Phase IV, Randomized, Controlled, Single-Blind, Multi-Center Study in Children to Evaluate the Safety, Tolerability and Immunogenicity of Two TBE Vaccines Administered According to Two Different Schedules. Purpose/Objective of study- The purpose of this study is to evaluate the safety, immunogenicity and tolerability of TBE vaccines administered to children. Vaccine Clinical trial 17. Primary Outcome Measures: Immunogenicity of two pediatric TBE vaccines as measured by neutralization test and ELISA on days 28, 42, 300, and 321. Secondary Outcome Measures: Tolerability of two paediatric TBE vaccines with respect to local and systemic reactions including fever. Vaccine Clinical trial 18. Study type- Interventional Study phase- Phase IV Study Design- Vaccine Clinical trial Sr.no. Design 1. Allocation- Randomized 2. End point classification- Safety/Efficacy 3. Intervention Model: Parallel Assignment 19. Sr. no. Design 4. Type- Single blinded 5. 1 purpose- Prevention Vaccine Clinical trial 20. The administration scheme for both vaccines is three doses given intra muscularly, the first two given with a gap of three week to 3 month apart and the third one given nine to twelve months after the second. Thereafter, a booster dose every fifth year is recommended. Vaccine Clinical trial 21. Sr. No. Vaccination stage Age 1. Primary immunization 1 year 2. 1st booster 1 year 3. 2nd booster 49 years * Vaccine Clinical trial 22. All subjects who already had pre immunization TBE titers showed at least a fourfold increase post immunization. The latter subjects had naturally acquired immunity against TBE and therefore can be regarded as protected against TBE disease. Substantial level of neutralizing TBE antibodies were already be detected. Vaccine Clinical trial 23. Vaccine Clinical trial 24. 1.Healthy male and female children, age group in between 1 to 10 years. 2. Willingness to sign written informed consent form. 3. Subject agrees to enroll into protocol- driven long- term follow up for 2 years after randomization. Vaccine Clinical trial 25. 1. Age more than 18 years. 2. Pregnancy or lactation. 3. History of autoimmune disease. 4. Administration of other vaccine 4 weeks before or after day zero. 5. Administration of immuno globulins 6 Weeks prior to any vaccination. 6. Any contraindication specified by manufacturer. Vaccine Clinical trial 26. % reduction in attack rate of disease-: VE (%) = (ARU-ARV) X 100 (ARU) Where; ARU-unvaccinated individual ARV- vaccinated individual Vaccine Clinical trial 27. Vaccine efficacy- Is given as Reduction in the incidence of a disease. VE =1- where; =Relative risk of infection Vaccine Clinical trial 28. Marketed formulations-: 1. TBE Moscow Vaccine (Russia) 2. FSME-Immun (Baxter,Austria) 3. Encepur (Novartis Vaccine, Germany) Vaccine Clinical trial 29. Vaccine Clinical trial Vaccines Adjuvant Shelf life Age limit FSME-IMMUN 0.5ML Adults Al(OH)3 24 months MT 16 years FSME-IMMUN 0.25ML Junior. Al(OH)3 24 months 1-16 years Encepur adults Al(OH)3 24 months MT 14 years Encepur children Al(OH)3 24 months 1-12 years 30. -Subjects are analyzed for immunogenicity achieved after post immunization levels of TBE antibodies. -Common range of the side effects already noted for licensed TBE vaccines was reported. After the distribution of more than five million vaccine doses,no potential safety risk was noted. Vaccine Clinical trial 31. Vaccination is the most effective protective measure against TBE. Immunization against TBE has also proved cost effective. It is advisable to increase vaccination coverage not only among people living in regions considered at risk of TBE, but also among travelers who plan to spend some time in countries where TBE is endemic. Vaccine Clinical trial 32. Post-marketing experience supports results from clinical trials showing that these new TBE vaccines may safely be used for the vaccination of children, adolescents, and adults. The evaluation of safety and tolerability in adolescents and adults in the present clinical program was focused on the monitoring of local and systemic reactions and the detection of uncommon or unexpected side effects. Vaccine Clinical trial 33. No serious or unexpected adverse events related to vaccination were reported in these comprehensive clinical studies involving more than 7,500 voluntary subjects. Post-marketing experience has confirmed the generally high degree of safety and acceptance of the new TBE vaccines. Vaccine Clinical trial 34. 1. Low to High grade fever 2. Fatigue and appetite loss 3. Hypersensitivity and local reactions. Vaccine Clinical trial 35. 1. Liposomal delivery systems 2. Polymeric nanoparticle delivery systems 3. Virosomes 4. Micellar delivery systems 5. Dendrimer based delivery system Vaccine Clinical trial 36. Webpages-: 1. Clinicaltrials.gov 2. www.ncbi.nlm.nih.gov/pubmed 3. Par Anderson , Immunological Effects of TBE Vaccination, 2008. 4. CH Saroja , PK Lakshmi, Shyamala Bhaskaran, Recent trends in vaccine delivery systems, vol. I,April 2001. 5. Daniela Amicizia, A. Domnich; Epidemiology of TBE, Italy, May 2013.Vaccine Clinical trial 37. Books-: 1. Design and Analysis of clinical trials, 2nd edition, S. Chung Chow and J. P. Liu. 2. Fundamentals of Clinical trials, 3rd edition, L. M. Friedman, C. D. Furberg , D. L. DeMets. Vaccine Clinical trial 38. Vaccine Clinical trial Thank u For listening Any Question ?