Vaccine trials

1. VACCINE TRIALS
DR SAHIL KUMAR

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. 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. •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. 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.

6. VACCINE DEVELOPMENT

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. Phase I
Safety &
immunogenicity
study
Phase II
Safety/ Dose
ranging study
Phase III
Large scale
safety/efficacy
study
PHASES OF A VACCINE TRIAL

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. 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. •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. 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. •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. •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. • 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.
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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. Bridging studies
•Efficacy, safety and immunogenicity.
• Situations:
Change in manufacturing process.
New dosing schedules.
New population.
Insufficient confidence.
Bridging studies for safety.

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. •Safety evaluation:
Active
Passive
Mixed
PHASE IV
TRIAL SUBJECTS:
Entire population/ its subset.
GOAL:
To detect the rarer or unexpected events.

20. • Evaluation of “Effectiveness” (≠ Efficacy).
• Study design
Observational cohort studies.
Case–control studies.
•‘Lot-to-lot Consistency’ Studies.

21. EMERGENCY APPROVAL
Regulatory
Decision
Regulatory
Decision
Paniflow

22. POST-LICENSURE
VACCINE SAFETY ACTIVITIES
Phase IV Trials
Passive Surveillance
•VAERS (US)
•CDSCO, IDsurv (India)
Active Surveillance
•Linked Databases.

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. 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. • 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. Wakefield, AJ. et al. Lancet 351:637-641. 1998
13
12
MMR and Autism

27. IMPROVING GLOBAL MONITORING
(WHO)
•Vaccine Safety Net Project.
•Expert committee at global level. (GACVS)
•Brighton Collaboration.

28. GLOBAL ADVISORY COMMITTEE ON VACCINE
SAFETY (GACVS)

30. CONCLUSION

31. THANK YOU