National Regulatory Authority Republic of Cuba

1. National Regulatory Authority Republic of Cuba Dr. Lazara Martinez Muñoz Live Vaccine Meeting April 6-7 2009 WHO, Geneva

2. CECMED. NATIONAL REGULATORY AUTHORITY. REPUBLIC OF CUBA NRA evaluate by WHO, as part of process of prequalification of vaccines AENOR Quality Certificate

3. NRA of Republic of Cuba . All Functions on Vaccines • Marketing Authorization and Licensing Activities • Regulatory Inspection • NRA Lot Release • Laboratory Access • Authorization/Approval Clinical Trials • Post- Marketing including surveillance of adverse events following immunization (AEFI)

4. Non-clinical

5. Characteristic of Personnel from Biological Department: • 14 specialist: 1 Microbiologist, 6 Pharmacist, 2 Biochemistry and 4 Physician. • Master Science: 9 • Experience at work: 6-20 years • Strengthening expertise and effectiveness of the NRA is achieved through training in capacity building activities, national and international courses and interchange with other NRA • All personal are training as internal Auditor • 2 specialist are member of “ Developing Countries Vaccine Regulators Network (DCVRN) 1 specialist is coordinating of PANDRH Vaccine Group and 1 specialist is member of GLP/WHO/TDR Network • 9 have been temporary advisers in WHO/PAHO activities

6. Evaluation of Vaccines Dossier National Guidelines, Rules and SOP WHO Guidelines on Vaccines, Others international Applicable Guidelines, Bibliographical revision Normative Context Peer review in Department Meeting AS EVIDENCE Register of evaluation for each specialist Document of integrated results Meetings records COMPREHENSIVE EVALUATION OF DOSSIER Decision Approval Refused Additional Information Revising decision at Institutional Technical Board Committee

7. Interaction between NRA and Industry during R+D process Compulsory: During Clinical Trials Authorization Inspection Clinical Trials Site Non-clinical GLP laboratories inspection Pilot Manufacturing Plant Inspection Marketing Authorization and Licensing Optional Consulting strategies of R+D Meeting for presentations results previous to formal dossier Consulting on CTD (Common Technical Dossier)

8. Vaccines from Local Manufacturer

9. Imported vaccines

10. TB Disease in Cuba

11. TB:Prevention and therapeutic activities • 100% of childbirths assisted by institutionalized qualified personnel • 100 % of BCG vaccination to newborn • National Program to detect new cases at local level (Family´s Physician):The patients' reception are performed by Physicians of the family health system and municipal policlinic • Control of Focus and study for diagnosis of the sick person contacts • Treatment controlled during at least a year by health personnel • 100% Salary compensation during 1 year

12. Non-clinical Development of Living Attenuated TB vaccines: Regulatory considerationsNon-clinical Point of View of NRA

13. A relevant non-clinical question “How can preclinical test be better used to decide which new candidate TB vaccine will moved forward into clinical testing?” PloSMed 4(8):e252 doi:10.1371/ journal.pmed.0040252 This question has deep regulatory implications: Requirement of data for appropriate risk-benefit balance/methodological guidelines to aid in an efficient R+D process

14. CLINICAL PHASES MUST BE AN OVERLAPPING PROCESS WITH SPECIFICPRECLINICAL PACKAGE

15. First battery non-clinical studies Phase I and II in Healthy adults Proof of concept Reactogenicity Safety Immunogenicity Correlates of protection? Focus: select candidate Goal: Non inferiority to BCG Vaccine, Identification of correlates to protection? Immunologic, pharmacodynamic and safety studies in healthy animals comparative with BCG vaccine Challenge: Virulent and multidrug resistant mycobacterium Data from animals of challenge satellite groups: Recovery alive mycobacterium Period free of disease Delayed Toxicity Mice, guinea pigs and rabbits

16. Phase III clinical trial in healthy subjects Confirm correlate of protection? +Results of previous clinical trials Second battery non-clinical studies Risk/Benefit Balance Focus: Studies in outbred animals efficiency in immunocompromised animals. Need different dose levels? Efficacy studies in non-human primate Goal: Protection of TB in dormant TB models and immunocompromised animals Challenge: Virulent and multidrug resistant mycobacterium Data from animals of challenge satellite groups: Recovery alive mycobacterium Period free of disease Delayed Toxicity Immunologic, pharmacodynamic and safety studies in immunocompromised animals and dormant latent TB animals models comparative with BCG vaccine Behavioral after anti inflammatory therapy in vaccinated dormant TB models

17. Phase I/II clinical trial in immunodepressed subjects Results of previous clinical and non-clinical studies Third battery non-clinical studies Risk/Benefit Balance Focus: efficiency in HIV animal models Risk of IRIS Need different dose levels or different schedule? Goal: Protection of TB and impact of retroviral therapy Phase I/II in HIV patients Challenge: Virulent and multidrug resistant mycobacterium Data from animals of challenge satellite groups: Recovery alive mycobacterium Period free of disease Delayed Toxicity “in vitro” and “in vivo” studies in HIV animals models. (SCID mice, NKO, others) Effects of vaccination Behavioral after anti retroviral therapy in vaccinated animals

18. Results of previous clinical and non-clinical studies Phase I/II clinical trial in adolescent subjects Third battery non-clinical studies Risk/Benefit Balance Focus: Risk in adolescent population Goal: risk for fetuses Challenge: Virulent and multidrug resistant mycobacterium Data from animals of challenge satellite groups: Recovery alive mycobacterium Period free of disease Delayed Toxicity Studies in new born and juvenile animals and malnourished animals Evaluated risk on pregnant animals

19. Evaluation of all non clinical and clinical results to determine necessity to different schedule by immunological category of target population Introducing animal vaccinated with BCG vaccine, could contribute to understand some findings Exploratory studies in animal models for different doses and schedule Clinical Trials Phase II to exploring dose and schedule in different target population

20. Quality Practices Usually Good Laboratory Practices are no mandatory for Pharmacological studies. Characteristic of immunological response, TB disease and animals models require exquisite animal care, control of experiments and facilities environment Validated animal model and methods to evaluate duration of efficient immunological and response to challenge would be required

21. Quality Practices Quality Practices in Biomedical Research and non-clinical GLP would be mandatory to Immunological and Pharmacodynamic Studies of Candidate TB Vaccine

22. As NRA, we express our disposition to participate in the cooperated revision of protocols and dossiers of the TB vaccines as soon as you request it to us Thanks for your attention