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Vaccine Trials

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Vaccine trials

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Vaccine Trials

  2. 2. OUTLINE Introduction Vaccine development: overview Pre-clinical evaluation Phases of a vaccine trial Phase I, Phase II, Phase III & Phase IV Emergency approval Post-licensure vaccine safety activities Notable vaccine safety issues Improving global monitoring Conclusion
  3. 3. INTRODUCTION • >2.7 million children under 5 years die from vaccine preventable diseases. • One of the highest priorities - to evaluate new vaccines. • Absence of effective therapies for many infectious diseases. • Types – Live, Killed, Combination, Toxoid, New Generation.
  4. 4. •Immunogenicity & efficacy → safety of vaccines. •The public has become increasingly sensitive to potential safety issues of vaccines → need to demonstrate vaccine safety. •Economic considerations also play an increasing role in vaccine implementation.
  5. 5. VACCINES vs. DRUGS Prevention in healthy population, large. Infants & children. Acceptability of risk low. Complex biological product: lot to lot variation high. Cold chain critical. Benefit not immediate. Treatment of sick population, small. Adults. Risk acceptance is higher. Chemical product: batch to batch variation low. Storage at room temp. Immediate benefit.
  7. 7. PRE-CLINICAL EVALUATION •In compliance with Good Laboratory Practice guidelines. • Production, characterization and quality assurance of candidate vaccines. • Toxicity and safety testing. •Potency. • Immunogenicity. • Adjuvants and Additives.
  8. 8. Phase I Safety & immunogenicity study Phase II Safety/ Dose ranging study Phase III Large scale safety/efficacy study PHASES OF A VACCINE TRIAL
  9. 9. ETHICAL CONSIDERATIONS (WHO) •Good Clinical Practices (GCP) to be followed. •Ethics Committee. •Informed Consent in writing. •No exposure to unreasonable or serious risks. •Economically and socially deprived communities - not exploited. •No harm to benefits of existing national vaccine programmes.
  10. 10. PHASE I STUDY DESIGN: • Open label (not randomized with placebo). •Adequate laboratory support; very carefully monitored. TRIAL SUBJECTS: 20-100 Low Risk healthy human volunteers. GOAL: Define safety, reactogenicity, immunogenicity.
  11. 11. •Other vaccines/ therapeutic agents avoided. •Laboratory testing - establish a baseline database. •A short period of evaluation/ observation is recommended. •Live attenuated vaccines (viral/ bacterial) are potential causes of clinically significant infections.
  12. 12. PHASE II STUDY DESIGN: •Often randomized and well controlled. •Evaluate age, ethnicity, gender, pre- existing antibodies, genotype. TRIAL SUBJECTS: Several hundreds of High Risk subjects. GOAL: Define optimal dose & schedule, safety profile.
  13. 13. •Other factors: Dose, Interval, Number, Route. •Live attenuated vaccine - continued active monitoring till 2nd & 3rd week. •Responders - described based on predefined criteria for assessing immune response.
  14. 14. •Level, class, subclass and function of the specific antibodies produced. •Other relevant information to be recorded: Neutralizing antibodies. Cross-reactive antibodies. Immune complex formation. Cell mediated immunity. •Immunological data should be presented by dividing the pre- and post-vaccination titres.
  15. 15. • Vaccine Efficacy: IV = incidence rate for the vaccine group IC = incidence rate for the control group PHASE III TRIAL SUBJECTS: Multicentric; Several thousands of subjects. GOAL: To provide data on efficacy & safety. C V I I VE  1
  16. 16. STUDY CONSIDERATIONS: •Prospective randomized double-blind controlled trials. •Other approaches: • Secondary attack rate study; • Observational cohort studies; • Case–control studies. •Size of trial. •Choice of control. •Immune responses. •Duration of protection & need for booster. •Safety evaluations.
  17. 17. Bridging studies •Efficacy, safety and immunogenicity. • Situations: Change in manufacturing process. New dosing schedules. New population. Insufficient confidence. Bridging studies for safety.
  18. 18. Special Considerations for Combination Vaccines •Efficacy of each component vaccine + safety of combination. •Immunogenicity of new combination vs. administration of the individual vaccine. •Non-inferiority trials. •Multiple strains/ serotypes : prevention/ modify the course. •Simultaneous administration with other vaccines - any interference.
  19. 19. •Safety evaluation: Active Passive Mixed PHASE IV TRIAL SUBJECTS: Entire population/ its subset. GOAL: To detect the rarer or unexpected events.
  20. 20. • Evaluation of “Effectiveness” (≠ Efficacy). • Study design Observational cohort studies. Case–control studies. •‘Lot-to-lot Consistency’ Studies.
  21. 21. EMERGENCY APPROVAL Regulatory Decision Regulatory Decision Paniflow
  22. 22. POST-LICENSURE VACCINE SAFETY ACTIVITIES Phase IV Trials Passive Surveillance •VAERS (US) •CDSCO, IDsurv (India) Active Surveillance •Linked Databases.
  23. 23. ADR Vaccine Pharmacovigilance is different. Adverse Event Following Immunization (AEFI) A medical incident that takes place after an immunization, causes concern and is believed to be caused by immunization. (WHO) Vaccine reaction. Programme error. Injection Reaction. Co-incidental. Unknown.
  24. 24. NOTABLE VACCINE SAFETY EVENTS • 1880s: PASTEUR RABIES VACCINE Seizure, paralysis, coma. • 1942: YELLOW FEVER VACCINE Contaminated with infectious hepatitis B virus; 62 deaths. • 1955: CUTTER LABORATORIES INCIDENT Failed to inactivate vaccine preparation; 10 deaths.
  25. 25. • ROTASHIELD® Intussusception. • ROTATEQ® AND ROTARIX® Clinical trials involved 72,000 & 63,000 infants; No association found. • THIOMERSAL - AUTISM CONTROVERSY. • THE “WAKEFIELD PAPER”. MMR & Autism.
  26. 26. Wakefield, AJ. et al. Lancet 351:637-641. 1998 13 12 MMR and Autism
  27. 27. IMPROVING GLOBAL MONITORING (WHO) •Vaccine Safety Net Project. •Expert committee at global level. (GACVS) •Brighton Collaboration.
  29. 29. CONCLUSION
  30. 30. THANK YOU