National Regulatory Authority Republic of Cuba

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National Regulatory Authority Republic of Cuba

• Dr. Lazara Martinez Muñoz
• Live Vaccine Meeting April 6-7 2009
• WHO, Geneva

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

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Non-clinical
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• 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

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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
COMPREHENSIVE EVALUATION OF DOSSIER
AS EVIDENCE Register of evaluation for each
specialist Document of integrated
results Meetings records
Revising decision at Institutional Technical
Board Committee
Decision Approval Refused Additional Information
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Interaction between NRA and Industry during RD
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 RD
• Meeting for presentations results previous to
  formal dossier
• Consulting on CTD (Common Technical Dossier)

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Vaccines from Local Manufacturer
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Imported vaccines
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TB Disease in Cuba
1980 1990 2000 2004 2005 2006 2007
Confirmed Disease/ 100,000 hab 11.6 5.1 10.1 6.6 6.5 6.4 6.7
Mortality by TB disease/ 100,000 hab. 7.3 1.4 0.4 - - 0.3 0.2
Number of deceased 622 135 44 33 25
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TBPrevention 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 (Familys 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

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Non-clinical Development of Living Attenuated TB
vaccines Regulatory considerationsNon-clinical
Point of View of NRA
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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
• doi10.1371/
• journal.pmed.0040252
• This question has deep regulatory implications
• Requirement of data for appropriate risk-benefit
  balance/methodological guidelines to aid in an
  efficient RD process

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CLINICAL PHASES MUST BE AN OVERLAPPING PROCESS
WITH SPECIFICPRECLINICAL PACKAGE
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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
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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
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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
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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
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• 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
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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

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Quality Practices

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

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• 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