1. General considerations for clinical trials of vaccines
Ming-Hsiao Chan, MD,MPH
Researcher/Team Leader,
Division of Clinical Sciences,
Center for Drug Evaluation, Taiwan

2. Disclaimer
The views expressed in this presentation are those of the speaker, and are not necessarily those of CDE and/or Department of Health (DOH) in Taiwan.

3. Introduction References: 1.國內法規 2. Guidelines or guidance of WHO, FDA,
臨床試驗報告之格式及內容基準(92年2月08日)
藥品臨床試驗計畫書主要審查事項(93年2月18日)
藥品優良臨床試驗準則(94年1月6日)
2. Guidelines or guidance of WHO, FDA,
and EMA
3. Medical journals
4. Review experiences from cases at CDE

4. Introduction
Note:
Vaccines are a heterogeneous class of agents, and the evaluation will need to be adapted for each individual product.
Therapeutic vaccines (e.g. viral-vector-based gene therapy, tumor vaccines) are not considered here.

5. Introduction 1. Phase I : safety
Phases of clinical development (I,II,III)
1. Phase I : safety
2. Phase II : preliminary information about
vaccine’s effect and its general safety
3. Phase III: fully assess the efficacy and
safety

6. Safety is always primary
CDE’s primary objectives in reviewing an IND are to assure the safety and rights of subjects.

7. Outlines Background, rationale and expected value
Assure rights of subjects
Study population
Inclusion and exclusion criteria
Dose, route of administration, and vaccination schedule
Safety evaluations
Concomitant medication
Efficacy endpoints and design of clinical trial
Other studies (Lot-to-lot consistency study)

8. Background, rationale and expected value
Mechanism
Epidemiology of target disease
Licensed vaccine available?
Unmet medical need
Prognosis and clinical presentation of target disease

9. Background, rationale and expected value
Preclinical studies
a. Toxicity and safety testing
b. Potency and immunogenicity
Early phase clinical studies

10. Background, rationale and expected value
Preclinical studies
a. Potency:
- Ideally, the potency assay should mimic the
clinically expected function of the vaccine in
humans
- Examples: challenge models (intracerebral
mouse test for rabies vaccine)

11. Background, rationale and expected value
Preclinical studies
b. Immunogenicity
- Help in the selection the doses, schedules and routes of
administration to be evaluated in clinical trials
- Assess relevant immune response, e.g. seroconversion
rates, geometric mean Ab titers, cell-mediated immunity
- What’s the primary concern in interpreting the data

12. Background, rationale and expected value
Before phase I studies:
a. Appropriate animal challenging model
b. Other approaches providing proof of
concept

13. Background, rationale and expected value
Plans for development of the candidate vaccine and clarify requirements for carrying out clinical trials
Expected clinical benefits of the candidate vaccine

14. Assure rights of subjects
Is there a need for controlled trials?
Depending on the developmental stage
Do we need a controlled trial in phase I study ?
Choice of control:
Placebo control
a. What’s the potential harm to the controlled
group without the vaccination? Is it reversible
or curable?
b. Inert placebo or vaccine without protection on
target disease
c. May not be necessary for already-licensed
vaccine

15. Assure rights of subjects
Choice of control
Active control
a. A comparator vaccine indicated for the same disease
b. A different formulation (e.g. liquid vs lyophilized;
adjuvant change; changed excipient or preservative;
changed Ag dose)
c. A new method of administration
d. A placebo control arm for internal validation
should sometimes be considered

16. Study population Study population Phase I study:
- Healthy, immunocompetent adults
- Low risk of infection or complication
Phase II, III study:
- Trial population could represent the target
population

17. Study population Study population
Care should be taken to identify the correct
target population (demographic, epidemiological, socioeconomic factors of the population)
Consideration for vaccines intended for children or
vulnerable population
- tested in a small number of subjects first

18. Inclusion and exclusion criteria
Again, safety is the primary concern
Subjects should be excluded if they do not meet the medical or other eligibility criteria, for example:
a. Chronic illness (e.g. cardiac or renal failure)
b. Progressive neurological disease
c. Uncontrolled epilepsy
d. Receiving long-term antibiotics treatment

19. Inclusion and exclusion criteria
Subjects should be excluded if they do not meet the medical or other eligibility criteria, for example:
e. Immune status (e.g. immunodeficiency,
immunosuppression and/or prematurity)
f. Allergic history
g. Recent vaccinations

20. Dose, route of administration, and vaccination schedule
Determination should be based on scientific justification:
Preclinical studies
Clinical studies
a. Dose-response data from dose-finding studies
(especially important for novel antigens)
b. Dose-finding studies may also incorporate
exploration of schedules
Dose-response data should be explored as early as possible

21. Dose, route of administration, and vaccination schedule
To identify appropriate schedules:
a. Nature of antigens
b. Target population
c. Kinetic profile of the vaccine-induced antibody
response
Specific patients group with impaired immune
function (e.g. premature infants, the immunosuppressed and haemodialysis patients)

22. Dose, route of administration, and vaccination schedule
Phase I:
Clinical tolerance, safety, and preliminary
information on immunogenicity
The dose and method of administration should also be assessed with respect to these parameters.
Phase II:
Define the optimal dose, initial schedule and safety profile before the phase III study

23. Safety evaluations Safety evaluations
Include all subjects who receive at least one dose of vaccine
Safety surveillance should begin from the start of enrollment
Safety issues identified during preclinical studies and early phase clinical studies should be provided

24. Safety evaluations Monitoring and reporting adverse events
An AE in a vaccine trial is any untoward medical occurrence in a clinical trial
A specific monitoring plan with timetable and methods
Methods for collection of safety data (e.g. diary cards, questionnaire, telephone contact)
Intervals for collection of the data (e.g. daily or weekly)

25. Safety evaluations Monitoring and reporting adverse events
The safety report should include evaluation of injection-site reactions and systemic events at baseline, at pre-specified vaccination times and following vaccination.
Total duration of follow-up:
In principle, all vaccines under development need a
long-term evaluation plan.
In most confirmatory clinical trials, a follow-up period of at least 6 months subsequent to the last
vaccination is needed.

26. Safety evaluations Monitoring and reporting adverse events
Total duration of follow-up
Different follow-up periods should be considered
on a case-by-case basis.
Consider following factors:
- Disease incidence
- The characteristic of immune response of the
candidate vaccines
- The expected safety profile

27. Safety evaluations Safety evaluations
Randomized studies in Phase III trials:
a. To provide reliable rates of common
adverse events (>1/100 and <1/10)
b. To detect less common adverse events
(<1/10,000)

28. Safety evaluations Reporting adverse events (including SAEs)
All AEs should be well documented
a. Type of adverse events
b. How long after the vaccination
c. Actions taken
d. Patient characteristics
e. Course of the adverse event

29. Safety evaluations Causality assessment of the AEs: (NDA)
Attributing causality is sometimes difficult (e.g. SIDS in infant population)
Additional clinical safety studies may be needed

30. Safety evaluations Post-marketing surveillance
Uncommon AEs (long-term or acute)
Active or passive processes
Passive surveillance
Voluntary reporting
Effective in detecting severe or lethal events
and unusual clinical response

31. Concomitant medication
Less restriction, in general no concern regarding drug interaction
Usually restrict the use of immune modifying drugs (e.g. systemic steroids, cytotoxic drugs)
Exclude the subjects administered with blood products or immunoglobulins recently
Should have instructions for concomitant use of other vaccines
All concomitant medication use during the study should be recorded

32. Efficacy endpoints and design of clinical trial
In phases II and III, clinical protection outcome may be measured
Performed in areas where an appropriate impact of active immunization can be expected, and where a controlled trial is feasible
Vaccine efficacy and/or vaccine effectiveness
Immunogenicity studies may be sufficient to demonstrate clinical efficacy for vaccines containing a known antigen for which the level of protective antibody is well established. (e.g. diphtheria, tetanus)

33. Efficacy endpoints and design of clinical trial
Outcome measurement:
Vaccine efficacy:
The reduction of chance of developing disease after vaccination relative to the chance when unvaccinated.
Vaccine efficacy measures direct protection.
VE = {(Iu-Iv)/Iu} × 100 %
- Iu: incidence in unvaccinated population
- Iv: incidence in vaccinated population

34. Efficacy endpoints and design of clinical trial
Outcome measurement:
Vaccine effectiveness
The protection rate conferred by vaccination in a specified population.
It measures both direct (vaccine induced) and indirect protection (population related )during routine use.

35. Efficacy endpoints and design of clinical trial
Vaccine efficacy
Randomized, double-blind, controlled trials (the most effective)
Other approaches: secondary attack rate study,
observational cohort study, case-control study
Vaccine efficacy could be measured as outcome of clinical protection and/or as an immunological surrogate end-point based on immunological response.

36. Efficacy endpoints and design of clinical trial
Clinical endpoints
If an organism is able to cause a range of infections (e.g. from life-threatening invasive infection to otitis media), the primary endpoint should be selected in accordance with the proposed indication.
Alternative primary endpoints:
Clinical manifestations of latent infection (e.g. vaccine intended to prevent herpes zoster )
Laboratory evidence that a candidate vaccine reduces primary infection rates (e.g. candidate vaccine against hepatitis C)
Other markers that predict progression to clinically apparent disease (e.g. HPV vaccine)

37. Efficacy endpoints and design of clinical trial
Clinical endpoints
Case definition
Well-validated methods
- Clinically apparent disease
- Clinically non-apparent infections
Case detection
The same methodology applied
For clinically non-apparent disease
- Monitored at regular intervals

38. Efficacy endpoints and design of clinical trial
Surrogate endpoints
Feasibility
Validity
Justify the use of surrogate endpoint

39. Other studies (Lot-to-lot consistency study)
Considered on a case by case basis
Inherent and unavoidable variability in the final formulation of the vaccine
Show consistency of manufacturing and performance of the final product
Ideally, adequately tested during the confirmatory studies of immunogenicity and, if feasible, in protective efficacy studies
Determining the number of lots to be compared

40. Other studies (Lot-to-lot consistency study)
Pre-defined criteria for concluding comparability between lots (usually based on immunological parameters)
Comparison of safety data is also important
Important consideration:
Which immunological parameters are the most valid and clinically relevant
How large a difference between lots might be clinically significant

41. Other studies (Lot-to-lot consistency study)
Example: Seasonal influenza inactivated vaccines
3 consecutively manufactured final formulated bulk lots of vaccine
HI antibody assay
Ratio of GMTs for each viral strain contained in the three vaccine lots as the primary endpoint
A pair-wise comparison
The two-sided 95% CI on the GMT ratio:

42. Thanks for your attention!